Longitudinal impact of intracerebral low-grade glioma disease on health-related quality of life.

BACKGROUND: The aim of this study was to assess health-related quality of life (HRQOL) before and after treatment for intracerebral low-grade glioma. METHODS: Patients with low-grade glioma who underwent surgical tumor removal between 2012 and 2018 were eligible for this study. All individuals and their closest relatives received thorough preoperative (

Risk factors for poor outcome after aneurysmal subarachnoid hemorrhage in patients with initial favorable neurological status.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating diagnosis. A poor outcome is known to be highly dependent on the initial neurological status. Our goal was to identify other parameters that favor the risk of complications and poor outcome in patients with aSAH and initially favorable neurologic status. METHODS: Consecutive aSAH cases treated at our hospital between 01/2003 and 06/2016 with the initial World Federation of Neurosurgical Societies grades I-III were included. Data on demographic characteristics, previous medical history, initial aSAH severity, and functional outcome after aSAH were collected. The study endpoints were the occurrence of cerebral infarcts, in-hospital mortality, and unfavorable outcome at 6 months after aSAH (modified Rankin scale > 3). RESULTS: In the final cohort (n= 582), the rate of cerebral infarction, in-hospital mortality, and unfavorable outcome was 35.1%, 8.1%, and 17.6% respectively. The risk of cerebral infarction was independently related to the presence of acute hydrocephalus (adjusted odds ratio [aOR]=2.33, p<0.0001), aneurysm clipping (aOR=1.78, p=0.003), and use of calcium channel blockers concomitant to nimodipine (aOR=2.63, p=0.002). Patients' age (>55 years, aOR=4.24, p<0.0001), acute hydrocephalus (aOR=2.43, p=0.036), and clipping (aOR=2.86, p=0.001) predicted in-hospital mortality. Baseline characteristics associated with unfavorable outcome at 6 months were age (aOR=2.77, p=<0.0001), Fisher grades III-IV (aOR=2.81, p=0.016), acute hydrocephalus (aOR=2.22, p=0.012), clipping (aOR=3.98, p<0.0001), admission C-reactive protein>1mg/dL (aOR=1.76, p=0.035), and treatment intervals (aOR=0.64 per-5-year-intervals, p=0.006). CONCLUSIONS: Although cerebral infarction is a common complication in aSAH individuals with favorable initial clinical condition, >80% of these patients show favorable long-term outcome. The knowledge of outcome-relevant baseline characteristics might help to reduce the burden of further complications and poor outcome in aSAH patients who tolerated the initial bleeding event well.

KDM5B predicts temozolomide-resistant subclones in glioblastoma.

Adaptive plasticity to the standard chemotherapeutic temozolomide (TMZ) leads to glioblastoma progression. Here, we examine early stages of this process in patient-derived cellular models, exposing the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion. By integration of a reporter, we show its preferential activity in rare, stem-like ALDH1A1+ cells, immediately increasing expression upon TMZ exposure. Naive, genetically unmodified KDM5Bhigh cells phosphorylate AKT (pAKT) and act as slow-cycling persisters under TMZ. Knockdown of KDM5B reverses pAKT levels, simultaneously increasing PTEN expression and TMZ sensitivity. Pharmacological inhibition of PTEN rescues the effect. Interference with KDM5B subsequent to TMZ decreases cellular vitality, and clonal tracing with DNA barcoding demonstrates high individual levels of KDM5B to predict subclonal expansion already before TMZ exposure. Thus, KDM5Bhigh treatment-naive cells preferentially contribute to the dynamics of drug resistance under TMZ. These findings may serve as a cornerstone for future biomarker-assisted clinical trials.

Natural course of cerebral and spinal cavernous malformations: a complete ten-year follow-up study.

Knowledge of the bleeding risk and the long-term outcome of conservatively treated patients with cavernous malformations (CM) is poor. In this work, we studied the occurrence of CM-associated hemorrhage over a 10-year period and investigated risk factors for bleeding. Our institutional database was screened for patients with cerebral (CCM) or intramedullary spinal cord (ISCM) CM admitted between 2003 and 2021. Patients who underwent surgery and patients without completed follow-up were excluded. Analyses were performed to identify risk factors and to determine the cumulative risk for hemorrhage. A total of 91 CM patients were included. Adjusted multivariate logistic regression analysis identified bleeding at diagnosis (p = 0.039) and CM localization to the spine (p = 0.010) as predictors for (re)hemorrhage. Both risk factors remained independent predictors through Cox regression analysis (p = 0.049; p = 0.016). The cumulative 10-year risk of bleeding was 30% for the whole cohort, 39% for patients with bleeding at diagnosis and 67% for ISCM. During an untreated 10-year follow-up, the probability of hemorrhage increased over time, especially in cases with bleeding at presentation and spinal cord localization. The intensity of such increase may decline throughout time but remains considerably high. These findings may indicate a rather aggressive course in patients with ISCM and may endorse early surgical treatment.

Outcome after conservative or surgical treatment for new-onset epilepsy in children with cerebral cavernous malformation.

OBJECTIVE: This study aimed to investigate and compare the outcome of conservatively or surgically treated children with cerebral cavernous malformation (CCM) and new-onset CCM-related epilepsy (CRE) during a 5-year period. METHODS: In this observational monocentric cohort study, data were collected ambispectivley. Our database was screened for CCM patients treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging dataset, clinical baseline characteristics, and diagnosis of new-onset CRE were included. Definite seizure control was classified as International League Against Epilepsy class <2. Functional outcome was assessed using the modified Rankin Scale score. CRE patients were separated into two groups according to their treatment modality. Seizure control, intake of antiseizure medication, and functional outcomes were assessed. Systematic literature research was performed to identify other cases of new-onset CRE in children and to compare the collected data with published data. RESULTS: Thirty-nine pediatric CRE patients were analyzed. A total of 18 (46.1%) patients were conservatively treated, while 21 (53.8%) underwent surgical CCM removal. While the functional outcome was similar in both groups at the last follow-up, definite seizure control was better in the surgical group (77.8%) than in the conservative group (25.0%) both after 5-years of follow-up (p = 0.038), and at last follow-up with 85.7% versus 50% respectively (p = 0.035). We found substantially higher rates of discontinuation of antiseizure medication at the last available follow-up in patients undergoing surgical resection (p = 0.009). The systematic literature review identified 4 studies with a total of 30 additional children with early onset CRE. CONCLUSION: Surgical treatment of pediatric patients with new-onset CRE had higher rates of complete seizure control and early discontinuation of antiseizure medication than conservative treatment. Neurological outcomes of patients managed surgically or conservatively were comparable. These results encourage early surgical management of children with CRE even in the absence of pharmacoresistant epilepsy, but randomized control trials are urgently needed for further decision-making.

Towards clinical applicability and computational efficiency in automatic cranial implant design: An overview of the AutoImplant 2021 cranial implant design challenge.

Cranial implants are commonly used for surgical repair of craniectomy-induced skull defects. These implants are usually generated offline and may require days to weeks to be available. An automated implant design process combined with onsite manufacturing facilities can guarantee immediate implant availability and avoid secondary intervention. To address this need, the AutoImplant II challenge was organized in conjunction with MICCAI 2021, catering for the unmet clinical and computational requirements of automatic cranial implant design. The first edition of AutoImplant (AutoImplant I, 2020) demonstrated the general capabilities and effectiveness of data-driven approaches, including deep learning, for a skull shape completion task on synthetic defects. The second AutoImplant challenge (i.e., AutoImplant II, 2021) built upon the first by adding real clinical craniectomy cases as well as additional synthetic imaging data. The AutoImplant II challenge consisted of three tracks. Tracks 1 and 3 used skull images with synthetic defects to evaluate the ability of submitted approaches to generate implants that recreate the original skull shape. Track 3 consisted of the data from the first challenge (i.e., 100 cases for training, and 110 for evaluation), and Track 1 provided 570 training and 100 validation cases aimed at evaluating skull shape completion algorithms at diverse defect patterns. Track 2 also made progress over the first challenge by providing 11 clinically defective skulls and evaluating the submitted implant designs on these clinical cases. The submitted designs were evaluated quantitatively against imaging data from post-craniectomy as well as by an experienced neurosurgeon. Submissions to these challenge tasks made substantial progress in addressing issues such as generalizability, computational efficiency, data augmentation, and implant refinement. This paper serves as a comprehensive summary and comparison of the submissions to the AutoImplant II challenge. Codes and models are available at https://github.com/Jianningli/Autoimplant_II.

Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy.

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs in vitro in human medulloblastoma cells.

Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.

BACKGROUND: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations. METHODS: Tumor cell invasion and proliferation were longitudinally determined in real-time using 3D in vivo 2-photon laser scanning microscopy over weeks. Glioblastoma cells expressed fluorescent markers that permitted the identification of their mitotic history or their cycling versus non-cycling cell state. RESULTS: Live reporter systems were established that allowed us to dynamically determine the invasive behavior, and previous or actual proliferation of distinct glioblastoma cells, in different tumor regions and disease stages over time. Particularly invasive tumor cells that migrated far away from the main tumor mass, when followed over weeks, had a history of marked proliferation and maintained their proliferative capacity during brain colonization. Infiltrating cells showed fewer connections to the multicellular tumor cell network, a typical feature of gliomas. Once tumor cells colonized a new brain region, their phenotype progressively transitioned into tumor microtube-rich, interconnected, slower-cycling glioblastoma cells. Analysis of resected human glioblastomas confirmed a higher proliferative potential of tumor cells from the invasion zone. CONCLUSIONS: The detection of glioblastoma cells that harbor both particularly high proliferative and invasive capabilities during brain tumor progression provides valuable insights into the interrelatedness of proliferation and migration-2 central traits of malignancy in glioma. This contributes to our understanding of how the brain is efficiently colonized in this disease.

The value of ventricular measurements in the prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Chronic hydrocephalus requiring shunt placement is a common complication of aneurysmal subarachnoid hemorrhage (SAH). Different risk factors and prediction scores for post-SAH shunt dependency have been evaluated so far. We analyzed the value of ventricle measurements for prediction of the need for shunt placement in SAH patients. METHODS: Eligible SAH cases treated between 01/2003 and 06/2016 were included. Initial computed tomography scans were reviewed to measure ventricle indices (bifrontal, bicaudate, Evans', ventricular, Huckman's, and third ventricle ratio). Previously introduced CHESS and SDASH scores for shunt dependency were calculated. Receiver operating characteristic analyses were performed for diagnostic accuracy of the ventricle indices and to identify the clinically relevant cut-offs. RESULTS: Shunt placement followed in 221 (36.5%) of 606 patients. In univariate analyses, all ventricular indices were associated with shunting (all: p<0.0001). The area under the curve (AUC) ranged between 0.622 and 0.662. In multivariate analyses, only Huckman's index was associated with shunt dependency (cut-off at ≥6.0cm, p<0.0001) independent of the CHESS score as baseline prediction model. A combined score (0-10 points) containing the CHESS score components (0-8 points) and Huckman's index (+2 points) showed better diagnostic accuracy (AUC=0.751) than the CHESS (AUC=0.713) and SDASH (AUC=0.693) scores and the highest overall model quality (0.71 vs. 0.65 and 0.67), respectively. CONCLUSIONS: Ventricle measurements are feasible for early prediction of shunt placement after SAH. The combined prediction model containing the CHESS score and Huckman's index showed remarkable diagnostic accuracy regarding identification of SAH individuals requiring shunt placement. External validation of the presented combined CHESS-Huckman score is mandatory.

Parkinson's disease may disrupt overlapping subthalamic nucleus and pallidal motor networks.

There is an ongoing debate about differential clinical outcome and associated adverse effects of deep brain stimulation (DBS) in Parkinson's disease (PD) targeting the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi). Given that functional connectivity profiles suggest beneficial DBS effects within a common network, the empirical evidence about the underlying anatomical circuitry is still scarce. Therefore, we investigate the STN and GPi-associated structural covariance brain patterns in PD patients and healthy controls. We estimate GPi's and STN's whole-brain structural covariance from magnetic resonance imaging (MRI) in a normative mid- to old-age community-dwelling cohort (n = 1184) across maps of grey matter volume, magnetization transfer (MT) saturation, longitudinal relaxation rate (R1), effective transversal relaxation rate (R2*) and effective proton density (PD*). We compare these with the structural covariance estimates in patients with idiopathic PD (n = 32) followed by validation using a reduced size controls' cohort (n = 32). In the normative data set, we observed overlapping spatially distributed cortical and subcortical covariance patterns across maps confined to basal ganglia, thalamus, motor, and premotor cortical areas. Only the subcortical and midline motor cortical areas were confirmed in the reduced size cohort. These findings contrasted with the absence of structural covariance with cortical areas in the PD cohort. We interpret with caution the differential covariance maps of overlapping STN and GPi networks in patients with PD and healthy controls as correlates of motor network disruption. Our study provides face validity to the proposed extension of the currently existing structural covariance methods based on morphometry features to multiparameter MRI sensitive to brain tissue microstructure.

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Acute hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (SAH). Several ventricular indices have been introduced to enable measurements of ventricular morphology. Previously, researchers have showed their diagnostic value for various neurological disorders. In this study, we evaluated the association between ventricular indices and the clinical course, occurrence of complications and outcome of SAH. METHODS: A total of 745 SAH patients with available early admission computed tomography scans were included in the analyses. Six ventricular indices (bifrontal, bicaudate, ventricular and third ventricle ratios and Evans' and Huckman's indices) were measured. Primary endpoints included the occurrence of cerebral infarctions, in-hospital mortality and a poor outcome at 6 months. Secondary endpoints included different adverse events in the course of SAH. Clinically relevant cut-offs for the indices were determined using receiver operating curves. Univariate analyses were performed. Multivariate analyses were conducted on significant findings in a stepwise backward regression model. RESULTS: The higher the values of the ventricular indices were and the older the patient was, the higher the WFNS and Fisher's scores were, and the lower the SEBES score was at admission. Patients with larger ventricles showed a shorter duration of intracranial pressure increase > 20 mmHg and required decompressive craniectomy less frequently. Ventricular indices were independently associated with the parameters of inflammatory response after SAH (C-reactive protein in serum and interleukin-6 in cerebrospinal fluid and fever). Finally, there were independent correlations between larger ventricles and all the primary endpoints. CONCLUSIONS: The lower risk of intracranial pressure increase and absence of an association with vasospasm or systemic infections during SAH, and the poorer outcome in individuals with larger ventricles might be related to a more pronounced neuroinflammatory response after aneurysmal bleeding. These observations might be helpful in the development of specific medical and surgical treatment strategies for SAH patients depending on the initial ventricle measurements.

Giant Cavernous Malformation Mimicking an Infiltrative Intracranial Neoplasm in Children-Case Report and Systematic Review of the Literature.

BACKGROUND: Giant cavernous malformations (GCMs) are rare and poorly characterized neurovascular lesions in adults or children and often misclassified. In this study, we provide a review of pediatric GCM cases to highlight this rare entity as an important differential diagnosis in preoperative assessment. METHODS: We report a pediatric case of GCM that presented as an intracerebral, periventricular, and infiltrative mass lesion. We performed a systematic review of published literature describing cases of GCM in children using the PubMed, Embase, and Cochrane Library databases. Studies describing cerebral or spinal cavernous malformation >4 cm were included. Demographic, clinical, radiographic, and outcome data were extracted. RESULTS: Thirty-eight studies accounting for 61 patients were reviewed. most patients were 1-10 years old and 55.73% were male. Average lesion sizes ranged between 4 and 6 cm (40.98% >6 cm; 8.19% >10 cm). Supratentorial localization was most common (75.40%), with frontal and parieto-occipital regions being frequent localizations. Infratentorial lesions (24.60%) were located within the cerebellum (16.39%) and brainstem (8.19%). One case of spinal cavernoma was found. The main clinical manifestations were seizures (44.26%), focal neurologic deficit (36.06%), and headache (22.95%). Imaging showed contrast enhancement (36.06%), cystic features (27.86%), and infiltrative growth pattern (4.91%). CONCLUSIONS: GCMs show variable clinical and radiologic features, representing a diagnostic challenge for treating surgeons. Imaging may show various tumorlike features such as cystic or infiltrative patterns with contrast enhancement. The existence of GCM should be considered preoperatively. Gross total resection should be attempted whenever possible, because it correlates with a good recovery and long-term outcomes. Also, a clear definition criteria of when a cerebral cavernous malformation is termed giant should be established.

Functional neurological outcome of spinal cavernous malformation surgery.

PURPOSE: Spinal cavernous malformations (SCM) present a risk for intramedullary hemorrhage (IMH), which can cause severe neurologic deficits. Patient selection and time of surgery have not been clearly defined. METHODS: This observational study included SCM patients who underwent surgery in our department between 2003 and 2021. Inclusion required baseline clinical factors, magnetic resonance imaging studies, and follow-up examination. Functional outcome was assessed using the Modified McCormick scale score. RESULTS: Thirty-five patients met the inclusion criteria. The mean age was 44.7 ± 14.5 years, and 60% of the patients were male. In univariate analysis, the unfavorable outcome was significantly associated with multiple bleeding events (p = .031), ventral location of the SCM (p = .046), and incomplete resection (p = .028). The time between IMH and surgery correlated with postoperative outcomes (p = .004), and early surgery within 3 months from IMH was associated with favorable outcomes (p = .033). This association remained significant in multivariate logistic regression analysis (p = .041). CONCLUSIONS: Removal of symptomatic SCM should be performed within 3 months after IMH when gross total resection is feasible. Patients with ventrally located lesions might be at increased risk for postoperative deficits.

Modifiable vascular risk factors in patients with cerebral and spinal cavernous malformations: a complete 10-year follow-up study.

BACKGROUND AND PURPOSE: The aim was to investigate the effect of modifiable vascular risk factors on the risk of first and recurrent bleeding for patients with a cavernous malformation (CM) of the central nervous system (CNS) over a 10-year period. METHODS: A retrospective review of our CM institutional database was performed spanning from 2003 to 2021. The inclusion criteria were non-missing serial magnetic resonance imaging studies and clinical baseline metrics such as vascular risk factors. The exclusion criteria were patients who underwent surgical CM removal and patients with less than a decade of follow-up. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative risk (10 years) of hemorrhage. RESULTS: Eighty-nine patients with a CM of the CNS were included. Our results showed a non-significant increased risk of hemorrhage during 10 years of follow-up in patients using nicotine (hazard ratio 2.11, 95% confidence interval 0.86-5.21) and in patients with diabetes (hazard ratio 3.25, 95% confidence interval 0.71-14.81). For the presence of modifiable vascular risk factors at study baseline different cumulative 10-year risks of bleeding were observed: arterial hypertension 42.9% (18.8%-70.4%); diabetes 66.7% (12.5%-98.2%); hyperlipidemia 30% (8.1%-64.6%); active nicotine abuse 50% (24.1%-76%); and obesity 22.2% (4%-59.8%). Overall cumulative (10-year) hemorrhage risk was 30.3% (21.3%-41.1%). CONCLUSIONS: The probability of hemorrhage in untreated CNS CM patients increases progressively within a decade of follow-up. None of the modifiable vascular risk factors showed strong indication for an influence on hemorrhage risk, but our findings may suggest a more aggressive course in patients with active nicotine abuse or suffering from diabetes.

Functional outcome after pediatric cerebral cavernous malformation surgery.

The purpose of this study was to investigate the functional outcome following surgical resection of cerebral cavernous malformations (CCM) in pediatric patients. We screened our institutional database of CCM patients treated between 2003 and 2021. Inclusion regarded individuals younger or equal than 18 years of age with complete clinical baseline characteristics, magnetic resonance imaging dataset, and postoperative follow-up time of at least three months. Functional outcome was quantified using the modified Rankin Scale (mRS) score and assessed at admission, discharge, and last follow-up examination. The primary endpoint was the postoperative functional outcome. As a secondary endpoint, predictors of postoperative functional deterioration were assessed. A total of 49 pediatric patients with a mean age of 11.3 ± 5.7 years were included for subsequent analyses. Twenty individuals (40.8%) were female. Complete resection of the lesion was achieved in 44 patients (89.8%), and two patients with incomplete resection were referred for successive remnant removal. The mean follow-up time after surgery was 44 months (IQR: 13 - 131). The mean mRS score was 1.6 on admission, 1.7 at discharge, and 0.9 at the latest follow-up. Logistic regression analysis adjusted to age and sex identified brainstem localization (aOR = 53.45 [95%CI = 2.26 - 1261.81], p = .014) as a predictor of postoperative deterioration. This study indicates that CCM removal in children can be regarded as safe and favorable for the majority of patients, depending on lesion localization. Brainstem localization implies a high risk of postoperative morbidity and indication for surgery should be balanced carefully. Minor evidence indicates that second-look surgery for CCM remnants might be safe and favorable.

Functional outcome after initial and multiple intracerebral hemorrhages in children with cerebral cavernous malformations.

BACKGROUND AND PURPOSE: We aimed to assess the course and predictors of functional outcome after single and multiple intracerebral hemorrhage (ICH) in pediatric patients with cerebral cavernous malformations (CCMs) and to conduct a risk assessment of a third bleed during the first follow-up year after second ICH. METHODS: We included patients aged ≤18 years with complete baseline characteristics, a magnetic resonance imaging dataset, ≥1 CCM-related ICH and ≥1 follow-up examination, who were treated between 2003 and 2021. Neurological functional status was obtained using modified Rankin Scale scores at diagnosis, before and after each ICH, and at last follow-up. Kaplan-Meier analysis was performed to determine the cumulative 1-year risk of third ICH. RESULTS: A total of 55 pediatric patients (median [interquartile range] age 12 [11] years) were analyzed. Univariate analysis identified brainstem cavernous malformation (BSCM; p = 0.019) as a statistically significant predictor for unfavorable outcome after second ICH. Outcome after second ICH was significantly worse in 12 patients (42.9%; p = 0.030) than after first ICH and in five patients (55.6%; p = 0.038) after a third ICH compared to a second ICH. Cumulative 12-month risk of rebleeding during the first year after a second ICH was 10.7% (95% confidence interval 2.8%-29.37%). CONCLUSIONS: Pediatric patients with a BSCM have a higher risk of worse outcome after second ICH. Functional outcome improves over time after an ICH but worsens following each ICH compared to baseline or previous ICH. Second bleed was associated with neurological deterioration compared to initial ICH, and this deteriorated further after a third ICH.

Pre-Surgery Patient Health Contributes to Aggravated Sino-Nasal Outcome and Quality of Life after Pituitary Adenomectomy.

Objectives: The transphenoidal bi-nostril endoscopic resection of pituitary adenomas is regarded as a minimally invasive treatment nowadays. However, sino-nasal outcome and health-related quality of life (HRQoL) might still be impaired after the adenomectomy, depending on patients' prior medical history and health status. A systematic postoperative comparison is required to assess differences in perceived sino-nasal outcome and HRQoL. Methods: In this single-center observational study, we collected data from 81 patients, operated between August 2016 and August 2021, at a 3-6-month follow-up after adenomectomy. We employed the sino-nasal outcome test for neurosurgery (SNOT-NC) and the HRQoL inventory Short Form (SF)-36 to compare sino-nasal and HRQoL outcome in patients with or without allergies, previous nose surgeries, presence of pain, snoring, sleep apnea, usage of continuous positive airway pressure (cpap), and nose drop usage. Results: At the 3-6-month follow-up, patients with previous nasal surgery showed overall reduced subjective sino-nasal health, increased nasal and ear/head discomfort, increased visual impairment, and decreased psychological HRQoL (all p ≤ 0.026) after pituitary adenomectomy. Patients with pain before surgery showed a trend-level aggravated physical HRQoL (p = 0.084). Conclusion: Our data show that patients with previous nasal surgery have an increased risk of an aggravated sino-nasal and HRQoL outcome after pituitary adenomectomy. These patients should be thoroughly informed about potential consequences to induce realistic patient expectations. Moreover, the study shows that patients with moderately severe allergies, snoring, and sleep apnea (± cpap) usually do not have to expect a worsened sino-nasal health and HRQoL outcome.

A Sequential Targeting Strategy Interrupts AKT-Driven Subclone-Mediated Progression in Glioblastoma.

PURPOSE: Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy. EXPERIMENTAL DESIGN: To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts. RESULTS: We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy. CONCLUSIONS: Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

Reevaluation of risk factors for aneurysmal subarachnoid hemorrhage associated epilepsy.

BACKGROUND: Symptomatic epilepsy is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) associated with poor outcome. We sought to analyze the risk factors leading to post-SAH epilepsy. METHODS: All consecutive aSAH cases treated between 01/2003 and 06/2016 were retrospectively included. Post-aSAH period was followed up to 03/2020 for the occurrence of epilepsy. Demographic characteristics and previous medical history of the patients, parameters of initial severity, performed treatments, certain early and late complications of aSAH, as well as routine laboratory and vital parameter measurements were collected. Functional outcome was assessed at discharge and 6 months after aSAH using the modified Rankin scale (mRS). RESULTS: During the post-aSAH follow-up (median: 8.93 months/patient), 85 of 948 individuals (9%) in the final analysis developed symptomatic epilepsy (median: 3.43 months). In the majority of cases, epilepsy was diagnosed >3 weeks after aSAH (n = 67, 78.8%) and in survivors with poor outcome at discharge (mRS = 4-5, 15.8% vs. 5.3%, p < 0.0001). Of over 150 analyzed potential risk factors, the following parameters were independently associated with the risk of symptomatic epilepsy after aSAH: thyroid dysfunction (aHR = 1.81, p = 0.029), need for decompressive craniectomy (aHR = 2.32, p = 0.011) and shunt placement (aHR = 1.94, p = 0.022), prolonged tachycardia (≥4 days, aHR = 2.06, p = 0.025), as well as anemia signs (mean red blood cell count <3.6 × 1012 /L [aHR = 2.4, p = 0.015] and mean hematocrit <31% [aHR = 2.13, p = 0.044]) during first 2 weeks after aSAH. CONCLUSION: Symptomatic epilepsy occurs predominantly in individuals with poor outcome at discharge and after the acute phase of aSAH. Knowledge of risk factors associated with aSAH-related epilepsy might help in early identification and treatment of compromised individuals, and therefore, help to improve their outcome.

Comparing radiographic scores for prediction of complications and outcome of aneurysmal subarachnoid hemorrhage: Which performs best?

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high morbidity and mortality proceeding from the initial severity and following complications of aSAH. Various scores have been developed to predict these risks. We aimed to analyze the clinical value of different radiographic scores for prognostication of aSAH outcome. METHODS: Initial computed tomography scans (≤48 h after ictus) of 745 aSAH cases treated between January 2003 and June 2016 were reviewed with regard to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and Claassen, Barrow Neurological Institute (BNI), Hijdra, original Graeb and Fisher scale scores. The primary endpoints were development of delayed cerebral ischemia (DCI), in-hospital mortality and unfavorable outcome (modified Rankin Scale score >3) at 6 months after subarachnoid hemorrhage. Secondary endpoints included the different complications that can occur during aSAH. Clinically relevant cutoffs were defined using receiver-operating characteristic curves. The radiographic scores with the highest values for area under the curve (AUC) were included in the final multivariate analysis. RESULTS: The Hijdra sum score had the most accurate predictive value and independent associations with all primary endpoints: DCI (AUC 0.678, adjusted odds ratio [aOR] 2.83; p < 0.0001); in-hospital mortality (AUC 0.704, aOR 2.83; p < 0.0001) and unfavorable outcome (AUC 0.726, aOR 2.91; p < 0.0001). Multivariate analyses confirmed the independent predictive value of the radiographic scales for risk of decompressive craniectomy (SEBES and Fisher score), cerebral vasospasm (SEBES, BNI score and Fisher score) and shunt dependency (Hijdra ventricle score and Fisher score) after aSAH. CONCLUSIONS: Initial radiographic severity of aSAH was independently associated with occurrence of different complications during aSAH and the final outcome. The Hijdra sum score showed the highest diagnostic accuracy and robust predictive value for early detection of risk of DCI, in-hospital mortality and unfavorable outcome after aSAH.