Suppression of NANOG Expression Reduces Drug Resistance of Cancer Stem Cells in Glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that harbors therapy-resistant cancer stem cells (CSCs). Due to the limited effectiveness of conventional chemotherapies and radiation treatments against CSCs, there is a critical need for the development of innovative therapeutic approaches. Our previous research revealed the significant expression of embryonic stemness genes, NANOG and OCT4, in CSCs, suggesting their role in enhancing cancer-specific stemness and drug resistance. In our current study, we employed RNA interference (RNAi) to suppress the expression of these genes and observed an increased susceptibility of CSCs to the anticancer drug, temozolomide (TMZ). Suppression of NANOG expression induced cell cycle arrest in CSCs, specifically in the G0 phase, and it concomitantly decreased the expression of PDK1. Since PDK1 activates the PI3K/AKT pathway to promote cell proliferation and survival, our findings suggest that NANOG contributes to chemotherapy resistance in CSCs through PI3K/AKT pathway activation. Therefore, the combination of TMZ treatment with RNAi targeting NANOG holds promise as a therapeutic strategy for GBM.

Correlation of Preoperative High-Resolution Neurovascular Imaging and Surgical Success in Neurovascular Compression Syndromes.

BACKGROUND: Neurovascular compression syndromes (NVCSs) are a group of neurological disorders characterized by compression of a cranial nerve and include trigeminal neuralgia (TN), hemifacial spasm, geniculate neuralgia, glossopharyngeal neuralgia, vestibular paroxysmia, and trochlear palsy. The European Academy of Neurology recommends constructive interference in steady-state/fast imaging employing steady-state (CISS/FIESTA) magnetic resonance imaging (MRI) in the evaluation of medically intractable TN, but similar recommendations do not exist for the remaining NVCSs. METHODS: We conducted a retrospective chart review of 300 patients with an NVCS who underwent microvascular decompression (MVD) by a single neurosurgeon from 2004 to 2021. Data were collected on preoperative diagnosis, pre- and postoperative symptoms, presence/absence of preoperative high-spatial-resolution CISS/FIESTA MRI, and intraoperative findings. Rates of symptomatic improvement were used as a correlate of surgical success. RESULTS: The rate of symptomatic improvement in the patients with a preoperative CISS/FIESTA MRI was 5.8% greater than those without preoperative high-spatial-resolution neuroimaging (98.8% vs. 93%, respectively; P = 0.008). Stratified by diagnosis, patients with TN had the greatest difference in surgical success between the 2 groups (99.3% vs. 92.9%, n = 268; P = 0.006). No statistically significant differences were observed in the other NVCSs, although positive trends were noted. CONCLUSIONS: Preoperative CISS/FIESTA MRI correlated with greater rates of surgical success in cases of medically intractable TN; however, definitive conclusions could not be made regarding the remaining NVCSs. We support the recommendation that this imaging modality be included as part of the standard of practice for the evaluation and management of TN and encourage future studies to further elucidate this relationship for the less common NVCSs using a larger cohort.

Coculture with Neural Stem Cells May Shift the Transcription Profile of Glioblastoma Multiforme towards Cancer-Specific Stemness.

Glioblastoma multiforme (GBM) possesses a small but significant population of cancer stem cells (CSCs) thought to play a role in its invasiveness, recurrence, and metastasis. The CSCs display transcriptional profiles for multipotency, self-renewal, tumorigenesis, and therapy resistance. There are two possible theories regarding the origin of CSCs in the context of neural stem cells (NSCs); i.e., NSCs modify cancer cells by conferring them with cancer-specific stemness, or NSCs themselves are transformed into CSCs due to the tumor environment created by cancer cells. To test the theories and to investigate the transcriptional regulation of the genes involved in CSC formation, we cocultured NSC and GBM cell lines together. Where genes related to cancer stemness, drug efflux, and DNA modification were upregulated in GBM, they were downregulated in NSCs upon coculture. These results indicate that cancer cells shift the transcriptional profile towards stemness and drug resistance in the presence of NSCs. Concurrently, GBM triggers NSCs differentiation. Because the cell lines were separated by a membrane (0.4 µm pore size) to prevent direct contact between GBM and NSCs, cell-secreted signaling molecules and extracellular vesicles (EVs) are likely involved in reciprocal communication between NSCs and GBM, causing transcription modification. Understanding the mechanism of CSC creation will aid in the identification of precise molecular targets within the CSCs to exterminate them, which, in turn, will increase the efficacy of chemo-radiation treatment.

Analysis of regulatory sequences in exosomal DNA of NANOGP8.

Exosomes participate in intercellular communication by transporting functionally active molecules. Such cargo from the original cells comprising proteins, micro-RNA, mRNA, single-stranded (ssDNA) and double-stranded DNA (dsDNA) molecules pleiotropically transforms the target cells. Although cancer cells secrete exosomes carrying a significant level of DNA capable of modulating oncogene expression in a recipient cell, the regulatory mechanism is unknown. We have previously reported that cancer cells produce exosomes containing NANOGP8 DNA. NANOGP8 is an oncogenic paralog of embryonic stem cell transcription factor NANOG and does not express in cells since it is a pseudogene. However, in this study, we evaluated NANOGP8 expression in glioblastoma multiforme (GBM) tissue from a surgically removed brain tumor of a patient. Significantly higher NANOGP8 transcription was observed in GBM cancer stem cells (CSCs) than in GBM cancer cells or neural stem cells (NSCs), despite identical sequences of NANOGP8-upstream genomic region in all the cell lines. This finding suggests that upstream genomic sequences of NANOGP8 may have environment-dependent promoter activity. We also found that the regulatory sequences upstream of exosomal NANOGP8 GBM DNA contain multiple core promoter elements, transcription factor binding sites, and segments of human viruses known for their oncogenic role. The exosomal sequence of NANOGP8-upstream GBM DNA is different from corresponding genomic sequences in CSCs, cancer cells, and NSCs as well as from the sequences reported by NCBI. These sequence dissimilarities suggest that exosomal NANOGP8 GBM DNA may not be a part of the genomic DNA. Exosomes possibly acquire this DNA from other sources where it is synthesized by an unknown mechanism. The significance of exosome-bestowed regulatory elements in the transcription of promoter-less retrogene such as NANOGP8 remains to be determined.

Retrospective Review of Surgical Site Infections after Endoscopic Endonasal Sellar and Parasellar Surgery: Multicenter Quality Data from the North American Skull Base Society.

Introduction Transnasal access to the anterior skull base provides a minimally invasive approach for sellar and parasellar masses compared with its open counterparts. The unique microbiome of the sinonasal mucosa provides distinct challenges not encountered with other cranial approaches. The use of antibiotics in these cases has not been standardized, and data remain scarce regarding infectious outcomes. Methods We conducted a multicenter retrospective analysis of shared quality data points for the endoscopic endonasal approach (EEA) for pituitary adenomas, along with other sellar and parasellar region masses that were included by participating institutions. Patient and operative characteristics, perioperative and postoperative antibiotic regimens and their durations, intraoperative and postoperative cerebrospinal fluid leak, and onset of postoperative meningitis and sinusitis were compared. Results Fifteen institutions participated and provided 6 consecutive months' worth of case data. Five hundred ninety-three cases were included in the study, of which 564 were pituitary adenomectomies. The incidences of postoperative meningitis and sinusitis were low (0.67 and 2.87% for all pathologies, respectively; 0.35% meningitis for pituitary adenomas) and did not correlate with any specific antibiotic regimen. Immunocompromised status posed an increased odds of meningitis in pituitary adenomectomies (28.6, 95% confidence interval [1.72-474.4]). Conclusions The results show no clear benefit to postoperative antimicrobial use in EEA, with further larger studies needed.

Laser Ablation of Abnormal Neurological Tissue Using Robotic Neuroblate System (LAANTERN): Procedural Safety and Hospitalization.

BACKGROUND: Stereotactic laser ablation (SLA) has demonstrated potential utility for a spectrum of difficult to treat neurosurgical pathologies in multiple small and/or retrospective single-institutional series. Here, we present the safety profile of SLA of intracranial lesions from the Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN; Monteris Medical) multi-institutional, international prospective observational registry. OBJECTIVE: To determine the procedural safety of SLA for intracranial lesions. METHODS: Prospective procedural safety and hospitalization data from the first 100 treated LAANTERN patients was collected and analyzed. RESULTS: Mean age and baseline Karnofsky Performance Status (KPS) were 51(± 17) yr and 83(± 15), respectively. In total, 81.2% of patients had undergone prior surgical or radiation treatment. Most patients had a single lesion (79%) ablated through 1 burr hole (1.2 ± 0.7 per patient), immediately following a lesion biopsy. In total, >90% of the lesion was ablated in 72% of treated lesions. Average total procedural time was 188.2 ± 69.6 min, and average blood loss was 17.7 ± 55.6 ccs. The average length of intensive care unit (ICU) and hospital stays before discharge were 38.1 ± 62.7 h and 61.1 ± 87.2 h, respectively. There were 5 adverse events (AEs) attributable to SLA (5/100; 5%). After the procedure, 84.8% of patients were discharged home. There was 1 mortality within 30 d of the procedure (1/100; 1%), which was not attributable to SLA. CONCLUSION: SLA is a safe, minimally invasive procedure with favorable postprocedural ICU and hospital utilization profiles.

Patterns of Clinical Use of Stereotactic Laser Ablation: Analysis of a Multicenter Prospective Registry.

BACKGROUND: Stereotactic laser ablation (SLA), also termed laser interstitial thermal therapy, is a minimally invasive procedure that is increasingly used in neurosurgery. We wished to examine how and whether SLA is changing the landscape of treatment options for neurosurgical patients. METHODS: Patients undergoing stereotactic laser ablation were prospectively enrolled in the Laser Ablation of Abnormal Neurological Tissue (LAANTERN) registry. Data from the first 100 enrolled patients are presented here. RESULTS: Clinical indications for SLA include treatment of primary intracranial tumors (48%; 81% being high-grade gliomas [HGGs]), brain metastases (BMs, 34%), epilepsy (16%), and other (2%). For HGGs, SLA was equally likely used for newly diagnosed (45%) or previously treated/recurrent lesions (55%, P = 0.54). By contrast, SLA was predominantly used as treatment for BMs in which radiation therapy/radiosurgery had failed (91%), with only 9% of SLAs performed as initial treatment for newly diagnosed lesions (P < 0.001). Of all SLAs performed, 45% of the procedures were in lieu of surgical resection, with 43% performed because the lesion was not accessible by conventional neurosurgical techniques. CONCLUSION: HGGs and BMs are the leading indications for SLA in the LAANTERN study. For HGGs, SLA is equally used in the presenting or previously treated/recurrent setting. For BMs, SLA is typically used in the recurrent setting. SLAs are equally likely to be performed for difficult-to-access lesions or in lieu of conventional open surgery.

Attention-Deficit Hyperactivity Disorder Status and Baseline Neurocognitive Performance in High School Athletes.

Approximately 136,000 concussions occur annually in American high school sports. Neuropsychological data indicate that children with preexisting cognitive difficulties, such as attention-deficit hyperactivity disorder (ADHD), may have protracted recovery from concussion. ADHD, with an estimated prevalence of 11% in youth, may increase an athlete's vulnerability to sustaining sports-related traumatic brain injury (TBI). The preponderance of evidence focusing on TBI and ADHD has derived from motor vehicle accidents rather than sports-related incidents. Thus, it is paramount to explore how ADHD may relate to injury in the sports concussion context, as well as to assess how ADHD may affect baseline neurocognitive testing. Adolescent athletes with ADHD (n = 256) demonstrated significantly reduced Verbal Memory, Visual Motor, and Impulse Control index scores compared with their peers without ADHD (n = 256). Athletes with ADHD were nearly twice as likely to have sustained a prior concussion (ADHD, 14.1%; non-ADHD, 7.8%). Knowledge regarding the unique neurocognitive profile of athletes with ADHD may enhance clinical management decisions.

Role of Gamma Knife® Radiosurgery for the Treatment of Brain Metastases from Gynecological Cancers.

OBJECTIVE: Gamma Knife® (GK) (Elekta Instruments, Stockholm, Sweden) radiosurgery is well established for treatment of brain metastases. There are limited data on patients treated with GK from gynecological cancers. The authors sought to determine the effectiveness of the GK in patients with brain metastases from gynecological cancers. METHODS: An IRB-approved database was queried for patients with gynecologic cancers treated with GK between June 1996 and May 2016. Imaging studies were reviewed post-SRS (stereotactic radiosurgery) to evaluate local control (LC) and distant brain control (DC). Overall survival (OS), local control, and distant brain control were calculated using the Kaplan-Meier (KM) method and log-rank test.  Results: Thirty-three patients underwent SRS for 73 separate cranial lesions. The median age was -58.5 years, and 17 (52%) also had extracranial metastases. Ten (30%) patients had previously received whole brain radiotherapy (WBRT), and 11 (33%) underwent concurrent WBRT. The median tumor volume was 0.96 cm3. Median radiographic follow-up was 11 months. At the time of treatment, 39% of patients were categorized as recursive partitioning analysis (RPA) Class I, 55% as RPA Class II, and 6% as RPA Class III. The local failure rate was 8%. Five patients (15%) developed new brain lesions outside the radiation field with a median progression-free survival (PFS) of seven (range: 3-9) months. Median OS was 15 months from GK treatment. One-year OS was 72.9% from GK treatment. Primary cancer histology was a significant predictor of OS, favoring ovarian and endometrial cancer (p = 0.03). CONCLUSIONS: Gamma Knife stereotactic radiosurgery for gynecologic brain metastases leads to excellent control rates of treated lesions. Primary histology may have a significant impact on OS following GK, with improved survival seen with ovarian and cervical cancer following Gamma Knife radiosurgery (p = 0.03).

The effects of histone deacetylase inhibitors on glioblastoma-derived stem cells.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited effective treatment options. Cancer stem cells (CSCs), a subpopulation of cancer cells with stem cell properties found in GBMs, have been shown to be extremely resistant to radiation and chemotherapeutic agents and have the ability to readily reform tumors. Therefore, the development of therapeutic agents targeting CSCs is extremely important. In this study, we isolated glioblastoma-derived stem cells (GDSCs) from GBM tissue removed from patients during surgery and analyzed their gene expression using quantitative real-time PCR and immunocytochemistry. We examined the effects of histone deacetylase inhibitors trichostatin A (TSA) and valproic acid (VPA) on the proliferation and gene expression profiles of GDSCs. The GDSCs expressed significantly higher levels of both neural and embryonic stem cell markers compared to GBM cells expanded in conventional monolayer cultures. Treatment of GDSCs with histone deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates of the cells and expression of the stem cell markers, indicating differentiation of the cells. Since differentiation into GBM makes them susceptible to the conventional cancer treatments, we posit that use of histone deacetylase inhibitors may increase efficacy of the conventional cancer treatments for eliminating GDSCs.

Return to golf after spine surgery.

OBJECT: no published evidence indicates when patients can resume golfing after spine surgery. The objective of this study is to provide data from surveys sent to spine surgeons. METHODS: a survey of North American Spine Society members was undertaken querying the suggested timing of return to golf. Of 1000 spine surgeons surveyed, 523 responded (52.3%). The timing of recommended return to golf and the reasons were questioned for college/professional athletes and avid and recreational golfers of both sexes. Responses were tallied for lumbar laminectomy, lumbar microdiscectomy, lumbar fusion, and anterior cervical discectomy with fusion. RESULTS: the most common recommended time for return to golf was 4-8 weeks after lumbar laminectomy and lumbar microdiscectomy, 2-3 months after anterior cervical fusion, and 6 months after lumbar fusion. The results showed a statistically significant increase in the recommended time to resume golf after lumbar fusion than after cervical fusion in all patients (p < 0.01). The same holds true for the return to play after cervical fusion compared with either lumbar laminectomy or lumbar microdiscectomy for all golfer types (p < 0.01). There was a statistically significant shorter recommended time for professional and college golfers compared with noncompetitive golfers after lumbar fusion (p < 0.01), anterior cervical discectomy and fusion (p < 0.01), and lumbar microdiscectomy (p < 0.01). CONCLUSIONS: the return to golf after spine surgery depends on many variables, including the general well-being of patients in terms of pain control and comfort when golfing. This survey serves as a guide that can assist medical practitioners in telling patients the average times recommended by surgeons across North America regarding return to golf after spine surgery.

Posttraumatic migraine characteristics in athletes following sports-related concussion.

OBJECT: The object of this study was to compare symptom status and neurocognitive functioning in athletes with no headache (non-HA group), athletes complaining of headache (HA group), and athletes with characteristics of posttraumatic migraine (PTM group). METHODS: Neurocognitive tests were undertaken by 261 high-school and collegiate athletes with a mean age of 16.36 +/- 2.6 years. Athletes were separated into three groups: the PTM group (74 athletes with a mean age of 16.39 +/- 3.06 years), the HA group (124 athletes with a mean age of 16.44 +/- 2.51 years), and the non-HA group (63 patients with a mean age of 16.14 +/- 2.18 years). Neurocognitive summary scores (outcome measures) for verbal and visual memory, visual motor speed, reaction time, and total symptom scores were collected using ImPACT, a computer software program designed to assess sports-related concussion. Significant differences existed among the three groups for all outcome measures. The PTM group demonstrated significantly greater neurocognitive deficits when compared with the HA and non-HA groups. The PTM group also exhibited the greatest amount of departure from baseline scores. CONCLUSIONS: The differences among these groups can be used as a basis to argue that PTM characteristics triggered by sports-related concussion are related to increased neurocognitive dysfunction following mild traumatic brain injury. Thus, athletes suffering a concussion accompanied by PTM should be examined in a setting that includes symptom status and neurocognitive testing to address their recovery more fully. Given the increased impairments observed in the PTM group, in this population clinicians should exercise increased caution in decisions about treatment and when the athlete should be allowed to return to play.

Evidence of systematic expressed sequence tag IMAGE clone cross-hybridization on cDNA microarrays.

We present evidence of a potentially serious source of error intrinsic to all spotted cDNA microarrays that use IMAGE clones of expressed sequence tags (ESTs). We found that a high proportion of these EST sequences contain 5'-end poly(dT) sequences that are remnants from the oligo(dT)-primed reverse transcription of polyadenylated mRNA templates used to generate EST cDNA for sequence clone libraries. Analysis of expression data from two single-dye cDNA microarray experiments showed that ESTs whose sequences contain repeats of consecutive 5'-end dT residues appeared to be strongly coexpressed, while expression data of all other sequences exhibited no such pattern. Our analysis suggests that expression data from sequences containing 5' poly(dT) tracts are more likely to be due to systematic cross-hybridization of these poly(dT) tracts than to true mRNA coexpression. This indicates that existing data generated by cDNA microarrays containing IMAGE clone ESTs should be filtered to remove expression data containing significant 5' poly(dT) tracts.

Symptomatic cavernous sinus aneurysms: management and outcome after carotid occlusion and selective cerebral revascularization.

BACKGROUND AND PURPOSE: Therapeutic internal carotid artery (ICA) occlusion for symptomatic intracavernous artery aneurysms can result in ischemic infarction despite normal clinical balloon test occlusion (BTO). We evaluated outcomes in patients with symptomatic cavernous sinus aneurysms in whom clinical BTO was normal, who underwent carotid occlusion with selective bypass surgery guided by physiologic BTO using quantitative cerebral blood flow (CBF) analysis by means of stable xenon-enhanced CT. METHODS: After a normal clinical BTO, 26 consecutive patients with symptomatic cavernous sinus aneurysms underwent a baseline xenon-enhanced CT CBF analysis followed by a second CBF analysis, during which repeat BTO was performed. Patients with a decrease in cortical CBF to below 30 mL/100 g/min were considered moderate risk and those with greater than 30 mL/100 g/min were low risk for developing postocclusion ischemic infarction. Moderate-risk patients underwent cerebral revascularization followed by proximal carotid occlusion. Low-risk patients underwent carotid occlusion alone. Patients were clinically followed up for at least 3 months after carotid occlusion. All patients underwent head CT at least 1 month after carotid occlusion. RESULTS: Eight patients were moderate risk and 18 low risk. Mean follow-up was 15.3 months. Mean CT follow-up was 10.2 months. No low-risk patient developed a postocclusion ischemic deficit by examination or infarct by CT. One patient in the moderate-risk group developed right hemiparesis and a left posterior middle cerebral artery infarction by CT 2 months after carotid occlusion. CONCLUSION: In this series, BTO combined with quantitative CBF analysis was a safe and reliable technique for identification of patients at risk for ischemic infarction after carotid occlusion, despite a normal clinical BTO.

Does age play a role in recovery from sports-related concussion? A comparison of high school and collegiate athletes.

OBJECTIVE: To evaluate symptoms and neurocognitive recovery patterns after sports-related concussion in high school and college athletes. STUDY DESIGN: College athletes (n = 371) and high school athletes (n = 183) underwent baseline neuropsychological evaluation between 1997 and 2000. Individuals who received a concussion during athletic competition (n = 54) underwent serial neuropsychologic evaluation after injury and were compared with a noninjured within-sample control group (n = 38). Main outcome measures included structured interview, four memory measures, and Concussion Symptom Scale ratings. Baseline to postinjury change scores and multiple analyses of variance were used to compare recovery curves within and between groups. RESULTS: High school athletes with concussion had prolonged memory dysfunction compared with college athletes with concussion. High school athletes performed significantly worse than age-matched control subjects at 7 days after injury (F = 2.90; P <.005). College athletes, despite having more severe in-season concussions, displayed commensurate performance with matched control subjects by day 3 after concussion. Self-report of postconcussion symptoms by student athletes was not predictive of poor performance on neuropsychologic testing. CONCLUSIONS: Caution and systematic evaluation should be undertaken before returning athletes with concussion to competition. Sole reliance on the self-report of the athlete may be inadequate. Preliminary data may suggest a more protracted recovery from concussion in high school athletes.

Relationship between postconcussion headache and neuropsychological test performance in high school athletes.

BACKGROUND: The relevance of headache to outcome after sports-related concussion is poorly understood. HYPOTHESES: High school athletes reporting headache approximately 1 week after injury will have significantly more other concussion symptoms and will perform more poorly on neuropsychological tests than athletes not experiencing headache. STUDY DESIGN: Prospective cohort study. METHODS: Study participants included 109 high school athletes who had sustained concussion and who were divided into two groups: those reporting headache 7 days after injury and those reporting no headaches. The two groups were compared regarding on-field markers of concussion severity at the time of injury and symptoms and neurocognitive test results collected via ImPACT, a computerized neuropsychological test battery and postconcussion symptom scale, at a mean of 6.8 days after injury. RESULTS: Athletes reporting posttraumatic headache demonstrated significantly worse performance on reaction time and memory ImPACT neurocognitive composite scores. These athletes also reported significantly more symptoms other than headache and were more likely to have demonstrated on-field anterograde amnesia. CONCLUSIONS: Findings suggest that any degree of postconcussion headache in high school athletes 7 days after injury is likely associated with an incomplete recovery after concussion.

Recovery from mild concussion in high school athletes.

OBJECT: A computerized neuropsychological test battery was conducted to evaluate memory dysfunction and self-reporting of symptoms in a group of high school athletes who had suffered concussion. METHODS: Neuropsychological performance prior to and following concussion was compared with the test performance of an age-matched control group. Potentially important diagnostic markers of concussion severity are discussed and linked to recovery within the 1st week of injury. CONCLUSIONS: High school athletes who had suffered mild concussion demonstrated significant declines in memory processes relative to a noninjured control group. Statistically significant differences between preseason and postinjury memory test results were still evident in the concussion group at 4 and 7 days postinjury. Self-reported neurological symptoms such as headache, dizziness, and nausea resolved by Day 4. Duration of on-field mental status changes such as retrograde amnesia and posttraumatic confusion was related to the presence of memory impairment at 36 hours and 4 and 7 days postinjury and was also related to slower resolution of self-reported symptoms. The results of this study suggest that caution should be exercised in returning high school athletes to the playing field following concussion. On-field mental status changes appear to have prognostic utility and should be taken into account when making return-to-play decisions following concussion. Athletes who exhibit on-field mental status changes for more than 5 minutes have longer-lasting postconcussion symptoms and memory decline.