miRNA-mediated loss of m6A increases nascent translation in glioblastoma.

Within the glioblastoma cellular niche, glioma stem cells (GSCs) can give rise to differentiated glioma cells (DGCs) and, when necessary, DGCs can reciprocally give rise to GSCs to maintain the cellular equilibrium necessary for optimal tumor growth. Here, using ribosome profiling, transcriptome and m6A RNA sequencing, we show that GSCs from patients with different subtypes of glioblastoma share a set of transcripts, which exhibit a pattern of m6A loss and increased protein translation during differentiation. The target sequences of a group of miRNAs overlap the canonical RRACH m6A motifs of these transcripts, many of which confer a survival advantage in glioblastoma. Ectopic expression of the RRACH-binding miR-145 induces loss of m6A, formation of FTO/AGO1/ILF3/miR-145 complexes on a clinically relevant tumor suppressor gene (CLIP3) and significant increase in its nascent translation. Inhibition of miR-145 maintains RRACH m6A levels of CLIP3 and inhibits its nascent translation. This study highlights a critical role of miRNAs in assembling complexes for m6A demethylation and induction of protein translation during GSC state transition.

The epidemiology of crib-related head injuries: A ten-year nationwide analysis.

INTRODUCTION: Falls from cribs resulting in head injury are understudied and poorly characterized. The purpose of this study was to advance current understanding of the prevalence, descriptive characteristics of injury victims, and the types of crib fall-related head injuries (CFHI) using queried patient cases from the National Electronic Injury Surveillance System (NEISS) database. METHODS: Using the US Consumer Product Safety Commission's System NEISS database, we queried all CFHIs among children from over 100 emergency departments (EDs). Patient information regarding age, race, sex, location of the incident, diagnoses, ED disposition, and sequelae were analyzed. The number of CFHI from all US EDs during each year was also collected from the database. RESULTS: There were an estimated 54,799 (95% CI: 30,228-79,369) total visits to EDs for CFHIs between 2012 and 2021, with a decrease in incidence of approximately 20% during the onset of the COVID-19 pandemic (2019: 5616 cases, 2020: 4459 cases). The annual incidence of injuries showed no significant trend over the 10-year study period. An available subset of 1782 cases of head injuries from approximately 100 EDs was analyzed, and 1442 cases were included in final analysis. Injuries were sorted into three primary categories: unspecified closed head injury (e.g., closed head injury, blunt head trauma, or traumatic brain injury), concussion, or open head injury and skull fracture. Unspecified closed head injuries were the most common of all head injuries (95.4%, 1376/1442). Open head injuries (14/1442, 0.97%) and concussions 3.6% (52/1442, 3.6%) were rare. Most injuries involved children under the age of 1 (42.6%) compared to children who were 1, 2, 3, or 4-years old. About a fourth of patients had other diagnoses in addition to their primary injury including scalp/forehead hematomas, emesis, and contusions. Female patients were more likely to present with other diagnoses in addition to their primary head injury (Difference: 12.3%, 95% CI: 9.87%-15.4%, p < .0001). CONCLUSION: Despite minimum rail height requirements set by the Consumer Safety Product Commission (CPSC), head injuries associated with crib falls are prevalent in the United States. However, most injuries were minor with a vast majority of patients being released following examination and treatment.

Pediatric all-terrain vehicle (ATV) related head injury rates and patterns: A 10-year nationwide analysis.

INTRODUCTION: The use of all-terrain vehicles (ATVs) carries significant risk of permanent injury and death, disproportionately affecting children. These injuries commonly affect the head and are especially severe among children as they are often unhelmeted and more likely than adults to experience rollover injuries. Many studies examining patients with ATV-related injuries are single-center cohort studies, with few focusing specifically on head injuries. In the present study, we aimed to characterize the annual incidence of ATV-related head injuries between 2012 and 2021, classify and compare head injury types, and identify descriptive characteristics of ATV-related head injury victims. METHODS: Using the US Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) database, we queried all head injuries associated with operating or riding an ATV in children under 18 years-old from over 100 emergency departments (EDs). Patient information regarding age, race, sex, location of incident, diagnoses, and sequelae were analyzed. We also collected the estimated number of ATV-related head injuries from all US EDs using the NEISS algorithm provided by the database. RESULTS: Using the NEISS algorithm we identified 67,957 (95% CI: 43,608 - 92,305) total pediatric ATV-related head injuries between 2012 and 2021. The annual incidence of ATV-related head injury was similar throughout this study period except for a 20% increase during the COVID-19 pandemic period of 2019-2021 (2019: 6382 injuries, 2020: 6757 injuries, 2021: 7600 injuries). A subset of 1890 cases from approximately 100 EDs were then analyzed. Unspecified closed head injuries were the prevailing type of injury (38%, 900/1890), followed by concussions (27%, 510/1890). More severe injuries included intracranial hemorrhages in 91 children (3.8%, 91/1890). Injuries of all types were predominantly seen in 14-17 year-old's (780/1890, 41%) and in males (64.1%, 1211/1890). In addition, ATV-associated injuries were significantly more common in those coded as white (58.0%, 1096/1890) than any other racial group. ATV-associated accidents among children younger than 9 more commonly occurred at the home compared to accidents involving children older than 9 (57% vs. 32%, p < 0.0001). CONCLUSION: ATV-related head injuries cause a significant annual burden among children, with growing incidence in recent years. Further research may wish to explore potential benefits of helmet use and supervision of younger children in possible prevention of these accidents and their associated economic and non-economic costs.

Brain tumor craniotomy outcomes for dual-eligible medicare and medicaid patients: a 10-year nationwide analysis.

INTRODUCTION: Dual-eligible (DE) patients, simultaneous Medicare and Medicaid beneficiaries, have been shown to have poorer clinical outcomes while incurring higher resource utilization. However, neurosurgical oncology outcomes for DE patients are poorly characterized. Accordingly, we examined the impact of DE status on perioperative outcomes following glioma, meningioma, or metastasis resection. METHODS: We identified all admissions undergoing a craniotomy for glioma, meningioma, or metastasis resection in the National Inpatient Sample from 2002 to 2011. Assessed outcomes included inpatient mortality, complications, discharge disposition, length of stay (LOS), and hospital costs. Multivariable regression adjusting for 13 patient, severity, and hospital characteristics assessed the association between DE status and outcomes, relative to four reference insurance groups (Medicare-only, Medicaid-only, private insurance, self-pay). RESULTS: Of 195,725 total admissions analyzed, 3.0% were dual-eligible beneficiaries (n = 5933). DEs were younger than Medicare admissions (P < 0.001) but older than Medicaid, private, and self-pay admissions (P < 0.001). Relative to other insurance groups, DEs also exhibited higher severity of illness, risk of mortality, and Charlson Comorbidity Index scores as well as treatment at low-volume hospitals (all P < 0.001). DEs had lower mortality than self-pay admissions (odds ratio [OR] 0.47, P = 0.017). Compared to Medicare, Medicaid, private, and self-pay admissions, DEs had lower rates of discharge disposition (OR 0.53, 0.50, 0.34, and 0.27, respectively, all P < 0.001). DEs also had higher complications (OR 1.23 and 1.20, respectively, both P < 0.05) and LOS (ß = 1.06 and 1.13, respectively, both P < 0.01) than Medicare and private insurance beneficiaries. Differences in discharge disposition remained significant for all three tumor subtypes, but only glioma DE admissions continued to exhibit higher complications and LOS. CONCLUSIONS: DEs undergoing definitive craniotomy for brain tumor had higher rates of unfavorable discharge disposition compared to all other insurance groups and, especially for glioma surgery, had higher inpatient complication rates and LOS. Practice and policy reforms to improve outcomes for this vulnerable clinical population are warranted.

The effect of levetiracetam treatment on survival in patients with glioblastoma: a systematic review and meta-analysis.

BACKGROUND: Levetiracetam (LEV) is an anti-epileptic drug (AED) that sensitizes glioblastoma (GBM) to temozolomide (TMZ) chemotherapy by inhibiting O6-methylguanine-DNA methyltransferase (MGMT) expression. Adding LEV to the standard of care (SOC) for GBM may improve TMZ efficacy. This study aimed to pool the existing evidence in the literature to quantify LEV's effect on GBM survival and characterize its safety profile to determine whether incorporating LEV into the SOC is warranted. METHOD: A search of CINAHL, Embase, PubMed, and Web of Science from inception to May 2021 was performed to identify relevant articles. Hazard ratios (HR), median overall survival, and adverse events were pooled using random-effect models. Meta-regression, funnel plots, and the Newcastle-Ottawa Scale were utilized to identify sources of heterogeneity, bias, and statistical influence. RESULTS: From 20 included studies, 5804 GBM patients underwent meta-analysis, of which 1923 (33%) were treated with LEV. Administration of LEV did not significantly improve survival in the entire patient population (HR 0.89, p = 0.094). Significant heterogeneity was observed during pooling of HRs (I2 = 75%, p < 0.01). Meta-regression determined that LEV treatment effect decreased with greater rates of MGMT methylation (RC = 0.03, p = 0.02) and increased with greater proportions of female patients (RC = - 0.05, p = 0.002). Concurrent LEV with the SOC for GBM did not increase odds of adverse events relative to other AEDs. CONCLUSIONS: Levetiracetam treatment may not be effective for all GBM patients. Instead, LEV may be better suited for treating specific molecular profiles of GBM. Further studies are necessary to identify optimal GBM candidates for LEV.

Predicting access to postoperative treatment after glioblastoma resection: an analysis of neighborhood-level disadvantage using the Area Deprivation Index (ADI).

PURPOSE: Social determinants of health (SDoH)-socioeconomic and environmental factors-impact outcomes. The Area Deprivation Index (ADI), a composite of seventeen SDoH factors, has been correlated with poorer outcomes. We aimed to compare outcomes and treatment access for glioblastoma, a universally fatal malignant brain tumor, in patients more (ADI 34-100%) versus less disadvantaged (ADI 0-33%). METHODS: A 5-year retrospective study of Rhode Island Hospital and Mayo Clinic databases was conducted from 2012 to 2017 for patients ≥ 18 years with glioblastoma. Patient addresses were matched to ADI percentiles and grouped into more (top 66% ADI) and less disadvantaged. Adjusted multivariable regressions were used to compare outcomes between groups. RESULTS: A total of 434 patients met inclusion; 92.9% were insured, 56.2% were more disadvantaged (n = 244), and the more disadvantaged cohort was younger on average (62 years). After adjustment, the more disadvantaged group had decreased odds of receiving gross total resection (adjusted odds ratio (aOR) 0.43, 95% CI [0.27-0.68]; p < 0.001). This cohort also had decreased odds of undergoing chemotherapy (aOR 0.51[0.26-0.98]), radiation (aOR 0.39[0.20-0.77]), chemoradiation (aOR 0.42[0.23-0.77]), tumor-treating fields (aOR 0.39[0.16-0.93]), and clinical trial participation (aOR 0.47[0.25-0.91]). No differences in length of survival or postoperative Karnofsky Performance Status Scale were observed. CONCLUSION: More disadvantaged glioblastoma patients had decreased odds of receiving gross total resection. They also exhibited decreased odds of receiving standard of care like chemoradiation as well as participating in a clinical trial, compared to the less disadvantaged group. More research is needed to identify modifiable SDoH barriers to post-operative treatment in disadvantaged patients with glioblastoma.

Cranial Irradiation for Childhood Cancers and Adult Risk of Meningioma.

INTRODUCTION: Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening. METHODS: At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM: a total of 684 cases were identified in 36 publications. RESULTS: Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense. CONCLUSIONS: We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Tumor-treating fields as a fourth treating modality for glioblastoma: a meta-analysis.

BACKGROUND: We aim to review the available literature on patients suffering from glioblastoma treated with tumor-treating fields (TTFields) plus radio chemotherapy or conventional radio chemotherapy alone, to compare the efficacy and safety of the two methods. METHODS: A systematic literature search was performed in PubMed, Cochrane library, and Scopus databases, in accordance with the PRISMA guidelines. Six studies met the inclusion criteria incorporating 1806 patients for the qualitative analysis and 1769 for the quantitative analysis. RESULTS: This study reveals increased median overall survival (weighted mean difference (WMD) 3.29 [95% confidence interval (CI) 2.37, 4.21]; p < 0.00001), survival at 1 year (odds ratio (OR) 1.81 [95% CI 1.41, 2.32]; p < 0.00001) and 2 years (OR 2.33 [95% CI 1.73, 3.14]; p < 0.00001), and median progression-free survival (WMD 2.35 [95% CI 1.76, 2.93]; p < 0.00001) along with progression-free survival at 6 months (WMD 6.86 [95% CI 5.91, 7.81]; p < 0.00001) for the patients treated with TTFields. Survival at 3 years was comparable between the two groups. TTFields were associated with fewer adverse events compared to chemotherapy along with similar incidence of skin irritation. CONCLUSIONS: TTFields are a safe and efficient novel treatment modality. More randomized controlled studies, with longer follow-up, are necessary to further assess the clinical outcomes of TTFields.

Notch receptor expression in human brain arteriovenous malformations.

The roles of the Notch pathway proteins in normal adult vascular physiology and the pathogenesis of brain arteriovenous malformations are not well-understood. Notch 1 and 4 have been detected in human and mutant mice vascular malformations respectively. Although mutations in the human Notch 3 gene caused a genetic form of vascular stroke and dementia, its role in arteriovenous malformations development has been unknown. In this study, we performed immunohistochemistry screening on tissue microarrays containing eight surgically resected human brain arteriovenous malformations and 10 control surgical epilepsy samples. The tissue microarrays were evaluated for Notch 1-4 expression. We have found that compared to normal brain vascular tissue Notch-3 was dramatically increased in brain arteriovenous malformations. Similarly, Notch 4 labelling was also increased in vascular malformations and was confirmed by western blot analysis. Notch 2 was not detectable in any of the human vessels analysed. Using both immunohistochemistry on microarrays and western blot analysis, we have found that Notch-1 expression was detectable in control vessels, and discovered a significant decrease of Notch 1 expression in vascular malformations. We have demonstrated that Notch 3 and 4, and not Notch 1, were highly increased in human arteriovenous malformations. Our findings suggested that Notch 4, and more importantly, Notch 3, may play a role in the development and pathobiology of human arteriovenous malformations.

Technological Advances in the Treatment of Cancer: Combining Modalities to Optimize Outcomes.

The anticancer treatment modality tumor treating fields (TTFields; Optune, Novocure) use the lower frequency range of the electromagnetic spectrum to destroy tumor cells during mitosis. This treatment has been evaluated in several trials of patients with glioblastoma. In these patients, TTFields are delivered through 4 transducer arrays applied to the scalp. In a phase 3 clinical trial of patients with recurrent glioblastoma, TTFields were as effective as chemotherapy, and were associated with fewer and milder systemic toxicities. Data from a phase 3 trial in newly diagnosed glioblastoma suggested that the addition of TTFields to postoperative radiation therapy and chemotherapy represents an important advance in the management of newly diagnosed glioblastoma. Ongoing clinical trials are investigating the efficacy and safety of TTFields in other tumor types, including pancreatic cancer, mesothelioma, ovarian cancer, and non­small cell lung cancer. Other recent advances in the management of cancer have been seen with immunomodulatory therapy, including immune checkpoint inhibitors. Further study will be necessary to evaluate whether TTFields will enhance or impair other established and newly emerging therapies.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

The effect of field strength on glioblastoma multiforme response in patients treated with the NovoTTF™-100A system.

The NovoTTF™-100A system is a portable device that delivers intermediate frequency alternating electric fields (TTFields, tumor treating fields) through transducer arrays arranged on the scalp. An ongoing trial is assessing its efficacy for newly diagnosed glioblastoma multiforme (GBM) and it has been FDA-approved for recurrent GBM.The fields are believed to interfere with formation of the mitotic spindle as well as to affect polar molecules at telophase, thus preventing cell division. The position of the four arrays is unique to each patient and optimized based on the patient's imaging. We present three patients with GBM in whom the fields were adjusted at recurrence and the effects of each adjustment. We believe there may be a higher risk of treatment failure on the edges of the field where the field strength may be lower. The first patient underwent subtotal resection, radiotherapy with temozolomide (TMZ), and then began NovoTTF Therapy with metronomic TMZ. She had good control for nine months; however, new bifrontal lesions developed, and her fields were adjusted with a subsequent radiographic response. Over the next five months, her tumor burden increased and death was preceded by a right insular recurrence. A second patient underwent two resections followed by radiotherapy/TMZ and NovoTTF Therapy/TMZ. Six months later, two new distal lesions were noted, and he underwent further resection with adjustment of his fields. He remained stable over the subsequent year on NovoTTF Therapy and bevacizumab. A third patient on NovoTTF Therapy/TMZ remained stable for two years but developed a small, slow growing enhancing lesion, which was resected, and his fields were adjusted accordingly. Interestingly, the pathology showed giant cell GBM with multiple syncitial-type cells. Based on these observations, we believe that field strength may play a role in 'out of field' recurrences and that either the presence of a certain field strength may select for cells that are of a different size or that tumor cells may change size to avoid the effects of the TTFields.

Molecular biology of brain metastasis.

Metastasis to the central nervous system (CNS) remains a major cause of morbidity and mortality in patients with systemic cancer. As the length of survival in patients with systemic cancer improves, thanks to multimodality therapies, focusing on metastases to the CNS becomes of paramount importance. Unique interactions between the brain's micro-environment, blood-brain barrier, and tumor cells are hypothesized to promote distinct molecular features in CNS metastases that may require tailored therapeutic approaches. This review will focus on the pathophysiology, epigenetics, and immunobiology of brain metastases in order to understand the metastatic cascade. Cancer cells escape the primary tumor, intravasate into blood vessels, survive the hematogenous dissemination to the CNS, arrest in brain capillaries, extravasate, proliferate, and develop angiogenic abilities to establish metastases. Molecular biology, genetics, and epigenetics are rapidly expanding, enabling us to advance our knowledge of the underlying mechanisms involved. Research approaches using cell lines that preferentially metastasize in vivo to the brain and in vitro tissue-based studies unfold new molecular leads into the disease. It is important to identify and understand the molecular pathways of the metastatic cascade in order to target the investigation and development of more effective therapies and research directions.

Social determinants of health and outcome disparities in spine tumor surgery. Part 2: Neighborhood disadvantage and long-term outcomes.

OBJECTIVE: Neighborhood-level resource disadvantage has been previously shown to predict extent of resection, oncological follow-up, adjuvant treatment, and clinical trial participation for malignancies, including glioblastoma. The authors aimed to characterize the association between neighborhood disadvantage and long-term outcomes after spine tumor surgery. METHODS: The authors analyzed all patients who underwent surgery for primary or secondary (all metastatic pathologies) spine tumors at a single spinal oncology specialty center in the United States from 2015 to 2022. The Area Deprivation Index (ADI), a validated metric compositing 17 social determinants of health variables that ranges continuously from 0% (higher advantage) to 100% (higher disadvantage), was used to quantify neighborhood disadvantage. Patient addresses were matched to ADI on the basis of the census block of residence. Subsequently, the study population was dichotomized into advantaged (ADI 0%-33%) and disadvantaged (ADI 34%-100%) cohorts. The primary endpoint was functional status, as defined by Eastern Cooperative Oncology Group (ECOG) Performance Status Scale grade, with secondary endpoints including inpatient outcomes, mortality, readmissions, reoperations, and clinical research participation. Multivariable logistic, gamma log-link, and Cox regression adjusted for 14 confounders, including patient and oncological characteristics, general and tumor-related presenting severity, and treatment. RESULTS: In total, 237 patients underwent spine tumor surgery from 2015 to 2022, with an average age of 53.9 years, and 57.0% had primary tumors whereas 43.0% had secondary tumors; 55.3% (n = 131) were classified by ADI into the disadvantaged cohort. This cohort had higher rates of ambulation deficits on presentation (39.1% vs 23.5%, p = 0.015) and nonelective surgery (35.1% vs 23.6%, p = 0.030). Postoperatively, disadvantaged patients exhibited higher odds of residual tumor (OR 2.55, p = 0.026), especially for secondary tumors (OR 4.92, p = 0.045). Patients from disadvantaged neighborhoods additionally exhibited significantly higher odds of poor functional status at follow-up (OR 3.94, p = 0.002). Postoperative survival was 74.7% (mean follow-up 17.6 months), with the disadvantaged cohort experiencing significantly shorter survival (HR 1.92, p = 0.049). Moreover, this population had higher odds of readmission (OR 1.92, p = 0.046) and, for primary tumors, reoperation (OR 9.26, p = 0.005). Elective participation in prospective clinical research was lower among the disadvantaged cohort (OR 0.45, p = 0.016). CONCLUSIONS: Neighborhood disadvantage predicts higher rates of residual tumor, readmission, and reoperation, as well as poorer functional status, shorter postoperative survival, and decreased elective research participation. The ADI may be used to risk stratify spine oncology patients and guide targeted interventions to ameliorate neurosurgical disparities and to reduce barriers to research participation.

Social determinants of health and outcome disparities in spine tumor surgery. Part 1: An analysis of 6.6 million nationwide admissions.

OBJECTIVE: Earlier research has demonstrated that social determinants of health (SDoH) impact neurosurgical access and outcomes, but these trends are less characterized for spine tumors relative to intracranial tumors. The authors aimed to elucidate the association between SDoH and outcomes for a nationwide cohort of spine tumor surgery admissions. METHODS: The authors identified all admissions with a spine tumor diagnosis in the National Inpatient Sample (NIS) from 2002 to 2019. Four SDoH were analyzed: race and ethnicity, insurance, household income, and safety-net hospital (SNH) treatment. Hospitals in the top quartile of safety-net burden (in terms of percentage of patients receiving Medicaid or uninsured) were categorized as SNHs. Multivariable regression queried the association between 22 variables and 5 perioperative outcomes: mortality, discharge disposition, complications, length of stay (LOS), and hospitalization costs. Interaction term analysis with hospitalization year was used to assess longitudinal changes in outcome disparities. Finally, the authors constructed random forest machine learning models to assess the impact of SDoH variables on prognostic accuracy and to quantify the relative importance of predictors for disposition. RESULTS: Of 6,593,392 total admissions with spine tumors, 219,380 (3.3%) underwent surgery. Non-White race (OR 0.80-0.91, p < 0.001) and nonprivate insurance (OR 0.76-0.83, p < 0.001) were associated with lower odds of receiving surgery. Among surgical admissions, presenting severity, including of myelopathy and plegia, was elevated among non-White, nonprivate insurance, and low-income admissions (all p < 0.001). Black race (OR 0.70, p < 0.001), Medicare (OR 0.70, p < 0.001), Medicaid (OR 0.90, p < 0.001), and lower income (OR 0.88-0.93, all p < 0.001) were associated with decreased odds of favorable discharge disposition. Increased LOS and costs were observed among non-White (+6%-10% in LOS and +5%-9% in costs, both p < 0.001) and Medicaid (+16% in LOS and +6% in costs, both p < 0.001) admissions. SNH treatment was also associated with higher mortality (OR 1.49, p < 0.001) and complication (OR 1.20, p < 0.001) rates. From 2002 to 2019, disposition improved annually for Medicaid patients (OR 1.03 per year, p = 0.022) but worsened for Black patients (OR 0.98 per year, p = 0.046). Random forest models identified household income as the most important predictor of discharge disposition. CONCLUSIONS: For spine tumor admissions, SDoH predicted surgical intervention, presenting severity, and perioperative outcomes. Over 2 decades, disparities improved for Medicaid patients but worsened for Black patients. Finally, SDoH significantly improve prognostic accuracy for outcomes after spine tumor surgery. Further study toward ameliorating patient disparities for this population is warranted.

Barriers to overcoming immunotherapy resistance in glioblastoma.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor, known for its poor prognosis and high recurrence rate. Current standard of care includes surgical resection followed by combined radiotherapy and chemotherapy. Although immunotherapies have yielded promising results in hematological malignancies, their successful application in GBM remains limited due to a host of immunosuppressive factors unique to GBM. As a result of these roadblocks, research efforts have focused on utilizing combinatorial immunotherapies that target networks of immune processes in GBM with promising results in both preclinical and clinical trials, although limitations in overcoming the immunosuppressive factors within GBM remain. In this review, we aim to discuss the intrinsic and adaptive immune resistance unique to GBM and to summarize the current evidence and outcomes of engineered and non-engineered treatments targeted at overcoming GBM resistance to immunotherapy. Additionally, we aim to highlight the most promising strategies of targeted GBM immunotherapy combinatorial treatments and the insights that may directly improve the current patient prognosis and clinical care.

The burden of unhelmeted motorcycle injury: A nationwide scoring-based analysis of helmet safety legislation.

INTRODUCTION: Motorcycle collisions comprise a large portion of motor vehicle injuries and fatalities with over 80,000 injuries and 5,500 fatalities per year in the United States. Unhelmeted riders have poor medical outcomes and generate billions in costs. Despite helmet use having been shown to lower the risk of neurological injury and death, helmet compliance is not universal, and legislation concerning helmet use also varies widely across the United States. METHODS: In this study, we systematically reviewed helmet-related statutes from all US jurisdictions. We evaluated the stringency of these statutes using a legislative scoring system termed the Helmet Safety Score (HSS) ranging from 0-7 points, with higher scores denoting more stringent statutes. Regression modeling was used to predict unhelmeted mortality using our safety scores. RESULTS: The mean score across all jurisdictions was 4.73. We found jurisdictions with higher HSS's generally had lower percentages of unhelmeted fatalities in terms of total fatalities as well as per 100,000 people and 100,000 registered motorcycles. In contrast, some lower-scoring jurisdictions had over 100 times more unhelmeted fatalities than higher-scoring jurisdictions. Our HSS significantly predicted unhelmeted motorcycle fatalities per 100,000 people (ß = -0.228 per 1-point increase, 95% CI: -0.288 to -0.169, p < .0001) and per 100,000 registered motorcycles (ß = -6.17 per 1-point increase, 95% CI: -8.37 to -3.98, p < .0001) in each state. Aspects of our score concerning helmet exemptions for riders and motorcycle-type vehicles independently predicted higher fatalities (p < .0001). Higher safety scores predicted lower unhelmeted fatalities. CONCLUSION: Stringent helmet laws may be an effective mechanism for decreasing unhelmeted mortality. Therefore, universal helmet laws may be one such mechanism to decrease motorcycle-related neurological injury and fatality burden. In states with existing helmet laws, elimination of exemptions for certain riders and motorcycle-type vehicles may also decrease fatalities.

Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma.

Chitinase 3-like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of ß-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/ß-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. SIGNIFICANCE: Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.