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The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactivated in malignant glioma and plays a key role in promoting cell survival, thereby increasing the acquired apoptosis resistance of these tumors. Here we investigated the STAT3/myeloid cell leukemia 1 (MCL1) signaling pathway as a target to overcome the resistance of glioma cells to the Bcl-2-inhibiting synthetic BH3 mimetic ABT-737. Stable lentiviral knockdown of MCL1 sensitized LN229 and U87 glioma cells to apoptotic cell death induced by single-agent treatment with ABT-737 which was associated with an early activation of DEVDase activity, cytochrome c release, and nuclear apoptosis. Similar sensitizing effects were observed when ABT-737 treatment was combined with the multikinase inhibitor sorafenib which effectively suppressed levels of phosphorylated STAT3 and MCL1 in MCL1-proficient LN229 and U87 glioma cells. In analogous fashion, these synergistic effects were observed when we combined ABT-737 with the STAT3 inhibitor WP-1066. Lentiviral knockdown of the activating transcription factor 5 combined with subsequent quantitative polymerase chain reaction analysis revealed that sorafenib-dependent suppression of MCL1 occurred at the transcriptional level but did not depend on activating transcription factor 5 which previously had been proposed to be essential for MCL1-dependent glioma cell survival. In contrast, the constitutively active STAT3 mutant STAT3-C was able to significantly enhance MCL1 levels under sorafenib treatment to retain cell survival. Collectively, these data demonstrate that sorafenib targets MCL1 in a STAT3-dependent manner, thereby sensitizing glioma cells to treatment with ABT-737. They also suggest that targeting STAT3 in combination with inducers of the intrinsic pathway of apoptosis may be a promising novel strategy for the treatment of malignant glioma.
Purpose: Surgery of KOOS IV vestibular schwannoma remains challenging regarding the balance of extent of tumor resection (EoR) and functional outcome. Our aim was to evaluate the outcome of surgical resection and define a cut-off value for safe resection with low risk for tumor regrowth of KOOS IV vestibular schwannoma.
Methods: All patients presenting at the authors’ institution between 2000 and 2019 with surgically treated KOOS IV vestibular schwannoma were included. Outcome measures included EoR, facial/hearing nerve function, surgical complications and progression of residual tumor during the median follow-up period of 28 months.
Results: In 58 patients, mean tumor volume was 17.1 ± 9.2 cm3, and mean EoR of 81.6 ± 16.8% could be achieved. Fifty-one patients were available for the follow-up analysis. Growth of residual tumor was observed in 11 patients (21.6%) followed by adjuvant treatment with stereotactic radiosurgery or repeat surgery in 15 patients (29.4%). Overall serviceable hearing preservation was achieved in 38 patients (74.5%) and good facial outcome at discharge was observed in 66.7% of patients, significantly increasing to 82.4% at follow-up. Independent predictors for residual tumor growth was EoR ≤ 87% (OR11.1) with a higher EoR being associated with a very low number of residual tumor progression amounting to 7.1% at follow-up (p=0.008).
Conclusions: Subtotal tumor resection is a good therapeutic concept in patients with KOOS IV vestibular schwannoma resulting in a high rate of good hearing and facial nerve function and a very low rate of subsequent tumor progression. The goal of surgery should be to achieve more than 87% of tumor resection to keep residual tumor progression low.
Highlights
• Consider tissue expanders for challenging DBS cases in PD patients with hardware erosion.
• Placement of tissue expander is essential in planning the reconstruction.
• MRI-compatibility of the tissue expander is paramount for shortening the total duration of anesthesia.
• Role of routine skin biopsies to identify PD patients at additional risk for developing scalp defects should be investigated.
Patient care in a neurointensive care unit (neuro-ICU) is challenging. Multidrug-resistant organisms (MDROs) are increasingly common in the routine clinical practice. We evaluated the impact of infection with MDROs on outcomes in patients with subarachnoid hemorrhage (SAH). A single-center retrospective analysis of SAH cases involving patients treated in the neuro-ICU was performed. The outcome was assessed 6 months after SAH using the modified Rankin Scale [mRS, favorable (0–2) and unfavorable (3–6)]. Data were compared by matched-pair analysis. Patient characteristics were well matched in the MDRO (n = 61) and control (n = 61) groups. In this center, one nurse was assigned to a two-bed room. If a MDRO was detected, the patient was isolated, and the nurse was assigned to the patient infected with the MDRO. In the MDRO group, 29 patients (48%) had a favorable outcome, while 25 patients (41%) in the control group had a favorable outcome; the difference was not significant (p > 0.05). Independent prognostic factors for unfavorable outcomes were worse status at admission (OR = 3.1), concomitant intracerebral hematoma (ICH) (OR = 3.7), and delayed cerebral ischemia (DCI) (OR = 6.8). Infection with MRDOs did not have a negative impact on the outcome in SAH patients. Slightly better outcomes were observed in SAH patients infected with MDROs, suggesting the benefit of individual care.
Background: Atypical intracerebral hemorrhage is a common form of primary manifestation of vascular malformations.
Objective: The aim of the present study is to determine clues to the cause of bleeding according to hemorrhage pattern (lobar, basal ganglia, infratentorial).
Methods: We retrospectively evaluated 343 consecutive neurosurgical patients with intracerebral hemorrhage (ICH), who were admitted to our neurosurgical department between 2006 and 2016. The study cohort includes only neurosurgical patients. Patients who underwent treatment by neurologists are not represented in this study. We assessed location of hemorrhage, hematoma volumes to rule out differences and predicitve variables for final outcome.
Results: In 171 cases (49.9%) vascular malformations, such as arteriovenous malformations (AVMs), cavernomas, dural fistulas and aneurysms were the cause of bleeding. 172 (50.1%) patients suffered from an intracerebral hemorrhage due to amyloid angiopathy or long standing hypertension. In patients with infratentorial hemorrhage a malformation was more frequently detected as in patients with supratentorial hemorrhage (36% vs. 16%, OR 2.9 [1.8;4.9], p<0.001). Among the malformations AVMs were most common (81%). Hematoma expansion was smaller in vascular malformation than non-malformation caused bleeding (24.1 cm3 vs. 64.8 cm3, OR 0.5 [0.4;0.7], p < 0.001,). In 6 (2.1%) cases diagnosis remained unclear. Final outcome was more favorable in patients with vascular malformations (63% vs. 12%, OR 12.8 [4.5;36.2], p<0.001).
Conclusion: Localization and bleeding patterns are predictive factors for origin of the hemorrhage. These predictive factors should quickly lead to appropriate vascular diagnostic measures. However, due to the inclusion criteria the validity of the study is limited and multicentre studies with further testing in general ICH patients are required.
Background: The prognostic factors and outcome of aneurysms appear to be dependent on its locations. Therefore, we compared left- and right- sided aneurysms in patients with aneurysmal subarachnoid hemorrhage (SAH) in terms of differences in outcome and prognostic factors.
Methods: Patients with SAH were entered into a prospectively collected database. A total of 509 patients with aneurysmal subarachnoid hemorrhage were retrospectively selected and stratified in two groups depending on side of ruptured aneurysm (right n = 284 vs. left n = 225). Midline aneurysms of the basilar and anterior communicating arteries were excluded from the analysis. Outcomes were assessed using the modified Rankin Scale (mRS; favorable (mRS 0–2) vs. unfavorable (mRS 3–6)) six months after SAH.
Results: We did not identify any differences in outcome depending on left- and right-sided ruptured aneurysms. In both groups, the significant negative predictive factors included clinical admission status (WFNS IV+V), Fisher 3- bleeding pattern in CT, the occurrence of delayed cerebral ischemia (DCI), early hydrocephalus and later shunt-dependence. The side of the ruptured aneurysm does not seem to influence patients´ outcome. Interestingly, the aneurysm side predicts the side of infarction, with a significant influence on patients´ outcome in case of left-sided infarctions. In addition, the in multivariate analysis side of aneurysm was an independent predictor for the side of cerebral infarctions.
Conclusion: The side of the ruptured aneurysms (right or left) did not influence patients’ outcome. However, the aneurysm-side predicts the side of delayed infarctions and outcome appear to be worse in patients with left-sided infarctions.
Objective: Cerebral vasospasm (CVS) after a ruptured arteriovenous malformation (AVM) is rarely reported. This study is aimed at evaluating the predictive variables in AVM hemorrhage for CVS. Methods: A total of 160 patients with ruptured AVMs were admitted to our neurosurgical department from 2002 to 2018. The frequency of cerebral vasospasm after AVM hemorrhage and the impact of AVM-associated aneurysms were evaluated. We compared different bleeding patterns, such as intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) or a combination of both (ICH + SAH) and evaluated predictive variables for outcome in last follow-up. Results: A total of 62 (39%) patients had AAA, mostly located prenidal (75.8%). AVMs with ruptured aneurysms often resulted in ICH with SAH component (p < 0.001). Eighty-two patients (51%) presented a SAH component, and CVS occurred in 6 patients (7.3%), mostly due to a ruptured infratentorial AVM (p < 0.03). Infratentorial location and the amount of SAH component (p < 0.001) predicted the incidence of CVS significantly. Cerebral infarction was significantly associated with CVS (p < 0.02). Conclusion: SAH component and infratentorial location of ruptured AVMs may harbor a higher risk for CVS. Follow-up with angiographic imaging should be considered in patients with infratentorial AVM hemorrhage and delayed neurologic deterioration to rule out CVS.
Short- and long-term effects of rehabilitation after perimesencephalic subarachnoid hemorrhage
(2021)
n about 25% of patients with spontaneous subarachnoid hemorrhage (SAH), a bleeding source cannot be identified during radiological diagnostics. Generally, the outcome of perimesencephalic or prepontine (PM) SAH is known to be significantly better than after non-PM SAH. Data about long-term follow-up concerning physical and mental health are scarce, so this study is reports on long-term results. We measured the influence of PM SAH on a quality-of-life modified Rankin (mRs) scale after six months. For long-term follow-up, a SF-36 questionnaire was used. Questionnaires were sent out between 18 and 168 months after ictus. In 37 patients, a long-term follow-up was available (up to 14 years after SAH). Data detected with the SF-36 questionnaire are compared to reference applicability to the standard population. In total, 37 patients were included for further analysis and divided in 2 subgroups; 13 patients (35%) received subsequent rehabilitation after clinical stay and 24 (65%) did not. In the short-term outcome, a significant improvement from discharge until follow-up was identified in patients with subsequent rehabilitation, but not in the matched pair group without rehabilitation. When PM SAH was compared to the standard population, a reduction in quality of life was identified in physical items (role limitations because of physical health problems, physical functioning) as well as in psychological items (role limitations because of emotional problems). Subsequent rehabilitation on PM SAH patients probably leads to an increase in independence and better mRs. While better mRs was shown at discharge in patients without subsequent rehabilitation, the mRs of rehabilitants was nearly identical after rehabilitation. Patients with good mRs also reached high levels of health-related quality of life (HRQoL) without rehabilitation. Thus, subsequent rehabilitation needs to be encouraged on an individual basis. Indication criteria for subsequent rehabilitation should be defined in further studies to improve patient treatment and efficiency in health care.
Background: The surgical treatment of giant olfactory groove meningiomas (OGMs) with marked perilesional brain oedema is still a surgical challenge. After tumour resection, increase of brain oedema may occur causing dramatic neurological deterioration and even death of the patient. The objective of this paper is to describe surgical features of a two-step staged resection of these tumours performed to counter increase of postoperative brain oedema.
Methods: This two-step staged resection procedure was carried out in a consecutive series of 19 patients harbouring giant OGMs. As first step, a bifrontal craniectomy was performed followed by a right-sided interhemispherical approach. About 80% of the tumour mass was resected leaving behind a shell-shaped tumour remnant. In the second step, carried out after the patients’ recovery from the first surgery and decline of oedema, the remaining part of the tumour was removed completely followed by duro- and cranioplasty.
Results: Ten patients recovered quickly from first surgery and the second operation was performed after a mean of 12.4 days. In eight patients, the second operation was carried out later between day 25 and 68 due to surgery-related complications, development of a trigeminal zoster, or to a persisting frontal brain oedema. Mean follow-up was 49.3 months and all but one patient had a good outcome regardless of surgery-related complications.
Conclusions: Our results suggest that a two-step staged resection of giant OGMs minimizes the increase of postoperative brain oedema as far as possible and translates into lower morbidity and mortality.
Background: Previous studies reported decreased volumes of acute stroke admissions during the COVID-19 pandemic. We aimed to examine whether aneurysmal subarachnoid hemorrhage (aSAH) volumes demonstrated similar declines in our department. Furthermore, the impact of the pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in the neurosurgical department of the university hospital Frankfurt including patients with the diagnosis of aSAH during the first year of the COVID pandemic. One year cumulative volume for aSAH hospitalization procedures was compared to the year before (03/2020 – 02/2021 vs. 03/2019 – 02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications, and outcome were analyzed.
Results: Compared to the 84 hospital admissions during the pre-pandemic years, the number of aSAH hospitalizations (n = 56) declined during the pandemic without reaching significance. No significant difference in the analyzed patient characteristics including clinical condition at onset, treatment, complications, and outcome, between 56 patients with aSAH admitted during the COVID pandemic and the treated patients in the last 5 years in the pre-COVID period were found. In our multivariable analysis, we detected young age (p < 0.05; OR 4.2) and no existence of early hydrocephalus (p < 0.05; OR 0.13) as important factors for a favorable outcome (mRS ≤ 0–2) after aSAH during the COVID pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age < 50years, p < 0.05; OR 10.5) with an increased rate of cerebral vasospasm after aSAH onset (p < 0.05; OR 26). Nevertheless, past COVID-infection did not reach significance as a high-risk factor for unfavorable outcomes.
Conclusion: There was a relative decrease in the number of patients with aSAH during the COVID-19 pandemic. Despite the extremely different conditions of hospitalization, there was no impairing significant effect on the treatment and outcome of admitted patients with aSAH. A past COVID infection seemed to be an irrelevant limiting factor concerning favorable outcomes.