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1.
Global Spine J ; : 21925682241250328, 2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38679888

ABSTRACT

STUDY DESIGN: Prospective case series. OBJECTIVES: Drawing from prospective data, this study delves into the frequency and nature of adverse events (AEs) following spinal surgery specifically in octogenarians, shedding light on the challenges and implications of treating this specific cohort as well as on risk factors for their occurrence. METHODS: Octogenarians who received spinal surgery and were discharged between January 2019 and December 2022 were proactively included in our study. An AE was characterized as any incident transpiring within the initial 30 days after surgery that led to an unfavorable outcome. RESULTS: From January 2020 to December 2022, 184 octogenarian patients (average age: 83.1 ± 2.8 years) underwent spinal surgeries. Of these, 81.5% were elective and 18.5% were emergencies, with 69.0% addressing degenerative pathologies. Using the Charlson Comorbidity Index, the mean score was 8.1 ± 2.2, highlighting cardiac diseases as predominant. Surgical details show 71.2% had decompression, with 28.8% receiving instrumentation. AEs included wound infections 3.1% for degenerative, 13.3% for tumor and dural leaks. The overall incidence of dural leaks was found to be 2.7% (5/184 cases), and each case underwent surgical revision. Pulmonary embolism resulted in two fatalities post-trauma. Wound infections (26.7%) were prevalent in infected spine cases. Significant AE risk factors were comorbidities, extended surgery durations, and instrumentation procedures. CONCLUSIONS: In octogenarian spinal surgeries, AEs occurred in 15.8% of cases, influenced by comorbidities and surgical complexities. The 2.2% mortality rate wasn't linked to surgeries. Accurate documentation remains crucial for assessing outcomes in this age group.

2.
Brain Spine ; 4: 102768, 2024.
Article in English | MEDLINE | ID: mdl-38510610

ABSTRACT

Introduction: In light of an aging global population, understanding adverse events (AEs) in surgeries for older adults is crucial for optimal outcomes and patient safety. Research question: Our study compares surgical outcomes and AEs in patients aged 65-79 with those aged ≥80, focusing on clinical outcomes, morbidity and mortality rates, and age-related risk factors for AEs. Material and methods: Our study, from January 2019 to December 2022, involved patients aged 65-79 and ≥ 80 undergoing spinal surgery. Each patient was evaluated for AEs post-discharge, defined as negative clinical outcomes within 30 days post-surgery. Patients were categorized based on primary spinal diagnoses: degenerative, oncological, traumatic, and infectious. Results: We enrolled 546 patients aged 65-79 and 184 octogenarians. Degenerative diseases were most common in both groups, with higher infection and tumor rates in the younger cohort. Octogenarians had a higher Charlson Comorbidity Index and longer ICU/hospital stays. Surgery-related AE rates were 8.1% for 65-79-year-olds and 15.8% for octogenarians, with mortality around 2% in both groups. Discussion and conclusion: Our prospective analysis shows octogenarians are more susceptible to surgical AEs, linked to greater health complexities. Despite higher AEs in older patients, low mortality rates across both age groups highlight the safety of spinal surgery. Tracking AEs is crucial for patient communication and impacts healthcare accreditation and funding.

3.
Acta Neurochir (Wien) ; 166(1): 126, 2024 Mar 08.
Article in English | MEDLINE | ID: mdl-38457057

ABSTRACT

INTRODUCTION: Brain tumor surgery represents a critical and high-risk area within the field of neurosurgery. Our study aims to offer a comprehensive analysis of adverse events (AEs) from a prospectively maintained database at a leading neurosurgical tertiary center, with a specific focus on different types of tumor entities. METHODS: From January 2022 to September 2023, our study focused on adult patients, who underwent surgery for intracranial tumors. Each patient in this demographic was thoroughly assessed for adverse events (AEs) by their attending physicians at discharge. An AE was defined as any event occurring within the first 30 days post-surgery. RESULTS: A total of 1173 patients with an average age of 57.4 ± 15.3 years underwent surgical procedures. The majority of these surgeries were elective, accounting for 93.4% (1095 out of 1173), while emergency surgeries constituted 13.9% (163 out of 1173). The incidence of surgery-related AEs was relatively low at 12.7%. The most common surgical indications were meningioma and glioma pathologies, representing 31.1% and 28.2% of cases, respectively. Dural leaks occurred in 1.5% of the cases. Postoperative hemorrhage was a significant complication, especially among glioma patients, with ten experiencing postoperative hemorrhage and eight requiring revision surgery. The overall mortality rate stood at 0.8%, corresponding to five patient deaths. Causes of death included massive postoperative bleeding in one patient, pulmonary embolism in two patients, and tumor progression in two others. CONCLUSIONS: Surgical interventions for intracranial neoplasms are inherently associated with a significant risk of adverse events. However, our study's findings reveal a notably low mortality rate within our patient cohort. This suggests that thorough documentation of AEs, coupled with proactive intervention strategies in neurosurgical practices, can substantially enhance patient outcomes.


Subject(s)
Brain Neoplasms , Glioma , Neurosurgery , Adult , Humans , Middle Aged , Aged , Prospective Studies , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Brain Neoplasms/surgery , Brain Neoplasms/complications , Postoperative Hemorrhage , Glioma/complications
4.
J Neurooncol ; 167(2): 245-255, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38334907

ABSTRACT

PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.


Subject(s)
Brain Neoplasms , Glioma , Humans , Reoperation , Brain Neoplasms/genetics , Brain Neoplasms/surgery , Brain Neoplasms/pathology , Retrospective Studies , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/surgery , Precision Medicine , Glioma/genetics , Glioma/surgery , Glioma/pathology
5.
J Neurosurg ; : 1-8, 2023 Dec 15.
Article in English | MEDLINE | ID: mdl-38100765

ABSTRACT

OBJECTIVE: Tuberculum sellae meningiomas (TSMs) are typically in the proximity of the optic nerves and the optic chiasm, thus making the primary aim of surgery the enhancement or stabilization of the patients' visual acuity. The authors therefore undertook a retrospective review of their 17-year experience with the pterional approach to ascertain the resection rate, neurological outcome, and visual outcome. METHODS: Patients who underwent TSM surgery between September 2003 and December 2020 at the authors' institution were retrospectively evaluated. Patient demographics, tumor characteristics, surgical parameters, postoperative visual outcomes, and complications were analyzed. Gross-total resection (GTR) and subtotal resection (STR) rates were assessed, along with the impact of surgical approach on visual outcomes. RESULTS: A total of 71 patients with a mean age of 56.9 ± 14.3 years were enrolled in the study. The mean tumor volume was 10.2 ± 12.8 cm3. Postoperatively, 38.7% of patients experienced visual improvement, 45.2% had stable visual acuity, and 16.1% showed visual deterioration. Ipsilateral or contralateral surgical approaches were performed based on the side of the most affected visual acuity. No significant difference in postoperative visual outcomes was observed between the two approaches. GTR was achieved in 84.0% and STR in 16.0%. Minor complications occurred in 3 patients (4.2%), while major complications were found in 4 patients (5.6%). Seven patients (9.8%) showed recurrent tumor growth after 53 months. Progression-free survival after GTR was 123.9 ± 12.9 months, and it was 59.3 ± 13.2 months after STR. CONCLUSIONS: This study highlighted the finding that TSMs can be successfully resected using a transcranial pterional approach with a low risk of complications and sufficient visual outcomes. Further studies with larger sample sizes are warranted to confirm these findings and optimize surgical strategies for TSM resection.

6.
Neurosurg Rev ; 46(1): 309, 2023 Nov 21.
Article in English | MEDLINE | ID: mdl-37987881

ABSTRACT

This study aimed to compare and assess clinical outcomes of spinal metastasis with epidural spinal cord compression (MESCC) in patients aged 65-79 years and ≥ 80 years with an acute onset of neurological illness who underwent laminectomy. A second goal was to determine morbidity rates and potential risk factors for mortality. This retrospective review of electronic medical records at a single institution was conducted between September 2005 and December 2020. Data on patient demographics, surgical characteristics, complications, hospital clinical course, and 90-day mortality were also collected. Comorbidities were assessed using the age-adjusted Charlson comorbidity index (CCI). A total of 99 patients with an overall mean age of 76.2 ± 3.4 years diagnosed with MESCC within a 16-year period, of which 65 patients aged 65-79 years and 34 patients aged 80 years and older were enrolled in the study. Patients aged 80 and over had higher age-adjusted CCI (9.2 ± 2.1) compared to those aged 65-79 (5.1 ± 1.6; p < 0.001). Prostate cancer was the primary cause of spinal metastasis. Significant neurological and functional decline was more pronounced in the older group, evidenced by Karnofsky Performance Index (KPI) scores (80+ years: 47.8% ± 19.5; 65-79 years: 69.0% ± 23.9; p < 0.001). Despite requiring shorter decompression duration (148.8 ± 62.5 min vs. 199.4 ± 78.9 min; p = 0.004), the older group had more spinal levels needing decompression. Median survival time was 14.1 ± 4.3 months. Mortality risk factors included deteriorating functional status and comorbidities, but not motor weakness, surgical duration, extension of surgery, hospital or ICU stay, or complications. Overcoming age barriers in elderly surgical treatment in MSCC patients can reduce procedural delays and has the potential to significantly improve patient functionality. It emphasizes that age should not be a deterrent for spine surgery when medically necessary, although older MESCC patients may have reduced survival.


Subject(s)
Spinal Cord Compression , Spinal Neoplasms , Aged , Male , Humans , Aged, 80 and over , Follow-Up Studies , Spinal Neoplasms/surgery , Neurosurgical Procedures , Laminectomy , Karnofsky Performance Status
7.
J Clin Med ; 12(19)2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37834851

ABSTRACT

Free flap reconstruction is the standard of care for extensive defects of the head and neck area. In this study, two types of free flaps, the antero-lateral thigh flap (ALT) and the vastus lateralis muscle flap, were compared. The primary endpoint was flap success, secondary endpoints were complication rates, hospitalization and surgery time. Cases with defect situations of the scalp and consecutive microvascular free flap reconstructions using either ALT flaps or vastus lateralis muscle flaps between 2014 and 2022 were retrospectively analyzed. Indications, perioperative handling and outcomes were compared. Twenty patients were included in the analysis. Ten patients (50%) received a free flap reconstruction using an ALT flap and ten patients (50%) received a vastus lateralis flap. A simultaneous two-team approach was possible in each case and the flap success rate was 100% with the need for one successful anastomosis revision. The mean defect size in our cohort was 147 ± 46 cm2. There were no significant differences in surgery time, duration of hospitalization or complication rate between both cohorts. Both free flaps, the ALT and the vastus lateralis flap, are suitable for the closure of large scalp defects. They provide high success rates, short surgery times without the need for patient repositioning and low donor-site morbidity. The vastus lateralis muscle flap bares the advantage of being perforator-independent and allows for the preparation of long vessels for anastomosis if needed while baring the disadvantage of a prolonged period of healing via granulation or the need for secondary surgery in terms of covering by split-thickness skin grafts which may interfere with necessary adjuvant treatment in oncological patients.

8.
Clin Cancer Res ; 29(22): 4685-4697, 2023 11 14.
Article in English | MEDLINE | ID: mdl-37682326

ABSTRACT

PURPOSE: Targeting immunosuppressive and pro-tumorigenic glioblastoma (GBM)-associated macrophages and microglial cells (GAM) has great potential to improve patient outcomes. Colony-stimulating factor-1 receptor (CSF1R) has emerged as a promising target for reprograming anti-inflammatory M2-like GAMs. However, treatment data on patient-derived, tumor-educated GAMs and their influence on the adaptive immunity are lacking. EXPERIMENTAL DESIGN: CD11b+-GAMs freshly isolated from patient tumors were treated with CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. Phenotypical changes upon treatment were assessed using RNA sequencing, flow cytometry, and cytokine quantification. Functional analyses included inducible nitric oxide synthase activity, phagocytosis, transmigration, and autologous tumor cell killing assays. Antitumor effects and changes in GAM activation were confirmed in a complex patient-derived 3D tumor organoid model serving as a tumor avatar. RESULTS: The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to the downregulation of M2-related markers, IL6, IL10, ERK1/2, and MAPK signaling pathways, while M1-like markers, gene set enrichment indicating activated MHC-II presentation, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived GBM organoids with GW2580 confirmed successful reprogramming, resulting in impaired tumor cell proliferation. In line with its failure in clinical trials, PLX3397 was ineffective in our analysis. CONCLUSIONS: This comparative analysis of CSF1R-targeting drugs on patient-derived GAMs and human GBM avatars identified GW2580 as the most powerful inhibitor with the ability to polarize immunosuppressive GAMs to a proinflammatory phenotype, supporting antitumor T-cell responses while also exerting a direct antitumor effect. These data indicate that GW2580 could be an important pillar in future therapies for GBM.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Microglia/pathology , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Macrophages/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism
9.
Cells ; 12(8)2023 04 20.
Article in English | MEDLINE | ID: mdl-37190109

ABSTRACT

Patients diagnosed with isocitrate dehydrogenase mutant (IDHmut) gliomas suffer frequently from seizures. Although the clinical course is less aggressive than that of its IDH wildtype counterpart, recent discoveries have shown that epileptic activity can promote tumor proliferation. However, it is not known if antiepileptic drugs confer additional value by inhibiting tumor growth. In this study, the antineoplastic properties of 20 FDA-approved antiepileptic drugs (AEDs) were tested in six patient-derived IDHmut glioma stem-like cells (GSCs). Cell proliferation was assessed using the CellTiterGlo-3D assay. Two of the screened drugs (oxcarbazepine and perampanel) demonstrated an antiproliferative effect. A subsequent eight-point dose-response curve proved the dose-dependent growth inhibition for both drugs, but only oxcarbazepine reached an IC50 value below 100 µM in 5/6 GSCs (mean 44.7 µM; range 17.4-98.0 µM), approximating the possible cmax for oxcarbazepine in patient serums. Furthermore, the treated GSC spheroids were 82% smaller (mean volume 1.6 nL vs. 8.7 nL; p = 0.01 (live/deadTM fluorescence staining)), and the apoptotic events increased by more than 50% (caspase-3/7 activity; p = 0.006). Taken together, this drug screen of a large series of antiepileptic drugs identified oxcarbazepine as a potent proapoptotic drug in IDHmut GSCs, which combines antiepileptic and antineoplastic properties to treat this seizure-prone patient population.


Subject(s)
Brain Neoplasms , Glioma , Humans , Anticonvulsants/pharmacology , Oxcarbazepine/pharmacology , Isocitrate Dehydrogenase/genetics , Brain Neoplasms/pathology , Glioma/drug therapy , Glioma/genetics , Glioma/pathology
10.
Cancers (Basel) ; 15(9)2023 Apr 27.
Article in English | MEDLINE | ID: mdl-37173969

ABSTRACT

The preoperative grading of non-enhancing glioma (NEG) remains challenging. Herein, we analyzed clinical and magnetic resonance imaging (MRI) features to predict malignancy in NEG according to the 2021 WHO classification and developed a clinical score, facilitating risk estimation. A discovery cohort (2012-2017, n = 72) was analyzed for MRI and clinical features (T2/FLAIR mismatch sign, subventricular zone (SVZ) involvement, tumor volume, growth rate, age, Pignatti score, and symptoms). Despite a "low-grade" appearance on MRI, 81% of patients were classified as WHO grade 3 or 4. Malignancy was then stratified by: (1) WHO grade (WHO grade 2 vs. WHO grade 3 + 4) and (2) molecular criteria (IDHmut WHO grade 2 + 3 vs. IDHwt glioblastoma + IDHmut astrocytoma WHO grade 4). Age, Pignatti score, SVZ involvement, and T2/FLAIR mismatch sign predicted malignancy only when considering molecular criteria, including IDH mutation and CDKN2A/B deletion status. A multivariate regression confirmed age and T2/FLAIR mismatch sign as independent predictors (p = 0.0009; p = 0.011). A "risk estimation in non-enhancing glioma" (RENEG) score was derived and tested in a validation cohort (2018-2019, n = 40), yielding a higher predictive value than the Pignatti score or the T2/FLAIR mismatch sign (AUC of receiver operating characteristics = 0.89). The prevalence of malignant glioma was high in this series of NEGs, supporting an upfront diagnosis and treatment approach. A clinical score with robust test performance was developed that identifies patients at risk for malignancy.

11.
Acta Neurochir (Wien) ; 165(3): 585-593, 2023 03.
Article in English | MEDLINE | ID: mdl-36624233

ABSTRACT

PURPOSE: To prospectively identify and quantify neurosurgical adverse events (AEs) in a tertiary care hospital. METHODS: From January 2021 to December 2021, all patients treated in our department received a peer-reviewed AE-evaluation form at discharge. An AE was defined as any event after surgery that resulted in an undesirable clinical outcome, which is not caused by the underlying disease, that prolonged patient stay, resulted in readmission, caused a new neurological deficit, required revision surgery or life-saving intervention, or contributed to death. We considered AEs occurring within 30 days after discharge. AEs were categorized in wound event, cerebrospinal fluid (CSF) event, CSF shunt malfunction, post-operative infection, malpositioning of implanted material, new neurological deficit, rebleeding, and surgical goal not achieved and non-neurosurgical AEs. RESULTS: 2874 patients were included. Most procedures were cranial (45.1%), followed by spinal (33.9%), subdural (7.7%), CSF (7.0%), neuromodulation (4.0%), and other (2.3%). In total, there were 621 AEs shared by 532 patients (18.5%). 80 (2.8%) patients had multiple AEs. Most AEs were non-neurosurgical (222; 8.1%). There were 172 (6%) revision surgeries. Patients receiving cranial interventions had the most AEs (19.1%) although revision surgery was only necessary in 3.1% of patients. Subdural interventions had the highest revision rate (12.6%). The majority of fatalities was admitted as an emergency (81/91 patients, 89%). Ten elective patients had lethal complications, six of them related to surgery (0.2%). CONCLUSION: This study presents the one-year results of a prospectively compiled AE database. Neurosurgical AEs arose in one in five patients. Although the need for revision surgery was low, the rate of AEs highlights the importance of a systematic AE database to deliver continued high-quality in a high-volume center.


Subject(s)
Neurosurgery , Humans , Neurosurgical Procedures/adverse effects , Spine/surgery , Hospitalization , Postoperative Complications/etiology
12.
J Clin Neurosci ; 109: 39-43, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36709624

ABSTRACT

BACKGROUND: Anatomical differences of the mastoid pneumatization in Asian and Caucasian patients must be considered when performing the retrosigmoid craniotomy since it may have implications to avoid specific complications such as cerebrospinal fluid infections or fistula. METHODS: We selected cranial CT scans of 120 Asian and 120 Caucasian patients, who were treated at the Mitsui Memorial Hospital (Japan) and at the Heidelberg University Hospital (Germany). Mastoid pneumatization was classified according to the relationship of the mastoid air cells (MAC) to the sigmoid sinus (Type I - III). The risk of mastoid air cell opening through craniotomy increases from Type I to III. Comparative analyses between gender and ethnicities were performed using the Chi2 Test and the independent T-Test and considered significant if p < 0.05. RESULT: In Caucasians, Type III pneumatization was significantly overrepresented compared to Type II or I, compared to the Asian cohort (Type III:II:I in Caucasians = 60 %:26 %:14 %; in Asians = 28 %:43 %:29 %). Importantly, we found significant differences in pneumatization types between Caucasians and Asians in both gender subgroups (m: Type III 60 % vs 35 %; Type II 30 % vs 36.7 %; Type I 10 % vs 28.3 %, p = 0.008; f: Type III 60 % vs 23.3 %, Type II 21.7 % vs 48.3 %, Type III 18.3 % vs 28.3 %, p < 0.001; Chi2 Test). CONCLUSION: Caucasian patients are more prone to the opening of the mastoid air cells than Asian patients when performing a retrosigmoid craniotomy due to differences in the degree of mastoid pneumatization. This may help to avoid complications such as postoperative infections or cerebrospinal-fluid fistula.


Subject(s)
Asian People , Mastoid , White People , Humans , Cranial Sinuses , Germany , Mastoid/diagnostic imaging , Mastoid/surgery , Tomography, X-Ray Computed
13.
Br J Neurosurg ; 37(5): 1006-1009, 2023 Oct.
Article in English | MEDLINE | ID: mdl-33956553

ABSTRACT

OBJECTIVE: Injury to vascular structures such as the internal carotid artery (ICA) is a rare but catastrophic complication of minimally invasive transsphenoidal surgery. Thorough preoperative planning, and knowledge of anatomical landmarks, such as the intercarotid distance (ICD) reduce this risk. Numerous anatomical studies have been conducted regarding the transsphenoidal approach, but none have taken racial disparities into account. METHODS: Since differences of the cranium, especially of the skull base exist, we sought to analyze anatomical differences of the sellar region in thin sliced T2-weighted MRI scans of 187 (87 male and 100 female) Asian, African American and Caucasian patients provided by the 'Human Connectome Project' (HCP). RESULTS: We found significant differences in the ICD between males and females across all races. Furthermore, we found that the ICD was up to 2.4 mm smaller in the Caucasian cohort compared to the African American/Asian cohort. CONCLUSION: These findings indicate that racial disparities regarding the sellar anatomy should be considered in patients undergoing pituitary surgery.


Subject(s)
Pituitary Diseases , Pituitary Neoplasms , Humans , Male , Female , Pituitary Neoplasms/surgery , Pituitary Gland/diagnostic imaging , Pituitary Gland/surgery , Skull Base/surgery , Head
14.
Cells ; 9(6)2020 06 03.
Article in English | MEDLINE | ID: mdl-32503220

ABSTRACT

The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDHmut GSCs) resulted in a paucity of preclinical models in IDHmut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDHmut GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDHmut GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC50) below 1 µM and maximum inhibitory effects (Emax) below 25%. These findings were validated in an additional four IDHmut GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC50 values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDHmut gliomas.


Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Drug Approval , Drug Screening Assays, Antitumor , Glioma/drug therapy , Isocitrate Dehydrogenase/genetics , Mutation/genetics , Neoplastic Stem Cells/pathology , Annexin A5/metabolism , Antineoplastic Agents/pharmacology , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Glioma/enzymology , Glioma/genetics , Glioma/pathology , Humans , Inhibitory Concentration 50 , Propidium/metabolism , Reproducibility of Results , United States , United States Food and Drug Administration
15.
Int J Mol Sci ; 19(10)2018 Sep 25.
Article in English | MEDLINE | ID: mdl-30257451

ABSTRACT

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1wt than in IDH1mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1mut and IDH1wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders.


Subject(s)
Brain Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Glioma/genetics , Isocitrate Dehydrogenase/genetics , Neoplastic Stem Cells/metabolism , Tumor Hypoxia , Adult , Aged , Aged, 80 and over , Brain Neoplasms/diagnosis , Brain Neoplasms/pathology , Female , Gene Expression Profiling , Glioma/diagnosis , Glioma/pathology , Humans , Male , Middle Aged , Mutation , Neoplastic Stem Cells/pathology , Prognosis
16.
World Neurosurg ; 117: e571-e574, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29935317

ABSTRACT

OBJECTIVE: Racial differences in anatomy of the cranium exist but have not been specifically considered in neurosurgical access planning. We sought to find differences in the anatomy of the posterior fossa in a cohort study consisting of Asian, African American, and Caucasian patients. METHODS: Magnetic resonance imaging data of 60 Asian, 57 African American, and 70 Caucasian individuals were obtained from the Human Connectome Project. Measurements were done in axial, coronal, and sagittal planes in T2-weighted thin-sliced images. P values were calculated using 2-tailed Student t test. P < 0.05 was considered significant. RESULTS: We measured distance in millimeters from the z values (craniocaudal axis) from the internal acoustic meatus to the transition of the transverse sinus into the sigmoid sinus. We discovered significant differences across all races. Our results show that the junction of the transverse to sigmoid sinus is lowest in Caucasians followed by Asians and African Americans. CONCLUSIONS: Significant differences in anatomy have practical implications in the retrosigmoid approach to the cerebellopontine angle. Based on our findings, the junction of the transverse sinus with the sigmoid sinus can differ up to 0.5 cm in the craniocaudal axis depending on race. As neuronavigation is not standard to the approach to the cerebellopontine angle, the study aimed to provide the neurosurgeon operating in the retrosigmoid area additional knowledge to avoid sinus injury with subsequent complications, such as blood loss, sinus occlusion, or air embolism.


Subject(s)
Asian People , Black or African American , Cranial Fossa, Posterior/anatomy & histology , Cranial Fossa, Posterior/diagnostic imaging , White People , Adult , Biological Variation, Individual , Cohort Studies , Cranial Fossa, Posterior/surgery , Female , Humans , Magnetic Resonance Imaging , Male , Neurosurgical Procedures , Organ Size , Young Adult
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