The Legacy of Harrington's Rod and the Evolution of Long-Segment Constructs in Spine Surgery.

This paper delves into the historical evolution of spinal surgery, focusing on the pivotal role of the Harrington rod in treating spinal deformities. Introduced in 1955, the Harrington rod marked a significant breakthrough in neurosurgery, especially for scoliosis treatment, by offering a novel approach to spinal stabilization. Through a retrospective analysis, this study examines the development and impact of the Harrington rod, highlighting Dr. Paul Harrington's contributions to spinal surgery. His innovative technique revolutionized the management of spinal deformities, laying the groundwork for future advancements in spinal instrumentation. Despite initial skepticism, Harrington's methods gained acceptance, significantly influencing neurosurgical practices and patient outcomes. This study also explores subsequent advancements that built on Harrington's work, including the transition to long-segment spine constructs and the introduction of segmental pedicle screws, which allowed for more precise deformity correction. Reflecting on Harrington's legacy, this paper acknowledges the continuous evolution of spinal surgery, driven by the interplay between clinical challenges and technological innovations. Harrington's pioneering spirit exemplifies the ongoing pursuit of better surgical outcomes, underscoring the importance of innovation in the field of neurosurgery.

Association of geographical disparities and segregation in regional treatment facilities for Black patients with aneurysmal subarachnoid hemorrhage in the United States.

Background and objectives: This study investigates geographic disparities in aneurysmal subarachnoid hemorrhage (aSAH) care for Black patients and aims to explore the association with segregation in treatment facilities. Understanding these dynamics can guide efforts to improve healthcare outcomes for marginalized populations. Methods: This cohort study evaluated regional differences in segregation for Black patients with aSAH and the association with geographic variations in disparities from 2016 to 2020. The National Inpatient Sample (NIS) database was queried for admission data on aSAH. Black patients were compared to White patients. Segregation in treatment facilities was calculated using the dissimilarity (D) index. Using multivariable logistic regression models, the regional disparities in aSAH treatment, functional outcomes, mortality, and end-of-life care between Black and White patients and the association of geographical segregation in treatment facilities was assessed. Results: 142,285 Black and White patients were diagnosed with aSAH from 2016 to 2020. The Pacific division (D index = 0.55) had the greatest degree of segregation in treatment facilities, while the South Atlantic (D index = 0.39) had the lowest. Compared to lower segregation, regions with higher levels of segregation (global F test p < 0.001) were associated a lower likelihood of mortality (OR 0.91, 95% CI 0.82-1.00, p = 0.044 vs. OR 0.75, 95% CI 0.68-0.83, p < 0. 001) (p = 0.049), greater likelihood of tracheostomy tube placement (OR 1.45, 95% CI 1.22-1.73, p < 0.001 vs. OR 1.87, 95% CI 1.59-2.21, p < 0.001) (p < 0. 001), and lower likelihood of receiving palliative care (OR 0.88, 95% CI 0.76-0.93, p < 0.001 vs. OR 0.67, 95% CI 0.59-0.77, p < 0.001) (p = 0.029). Conclusion: This study demonstrates regional differences in disparities for Black patients with aSAH, particularly in end-of-life care, with varying levels of segregation in regional treatment facilities playing an associated role. The findings underscore the need for targeted interventions and policy changes to address systemic healthcare inequities, reduce segregation, and ensure equitable access to high-quality care for all patients.

Curative transvenous embolization for congenital multi-hole pial arteriovenous fistula.

OBJECTIVE: Congenital intracranial pial arteriovenous fistula (PAVF) is a rare cerebral vascular pathology characterized by a direct shunt between one or more pial feeding arteries and a cortical draining vein. Transarterial endovascular embolization (TAE) is widely considered first line therapy. Curative TAE may not be achievable in the multihole variant due to the potential to harbor innumerable small feeding arteries. Transvenous embolization (TVE) may be considered to target the final common outlet of the lesion. Here, we present a series of four patients with complex multi-hole congenital PAVF treated with staged TAE followed by TVE. METHODS: A retrospective review was conducted on patients who underwent treatment for congenital, multi-hole PAVFs treated by a combined TAE/TVE approach at our institution since 2013. RESULTS: We identified four patients with multi-hole PAVF treated by a combined TAE/TVE. Median age was 5.2 (0-14.7) years. Median follow-up of 8 (1-15) months by catheter angiography and 38 (23-53) months by MRI/MRA was obtained. TVE achieved complete occlusion in three patients that proved durable on radiographic follow-up and demonstrated excellent clinical outcomes with a modified Rankin Score (mRS) of 0 or 1. Complete occlusion of the draining vein was not achieved by TVE in one case. This patient is graded as pediatric mRS=5 three years post-procedure. CONCLUSIONS: With thorough technical considerations, our series indicates that TVE of multi-hole PAVF that are refractory to TAE is feasible and effective in arresting the consequences of chronic, high-flow AV shunting produced by this pathology.

Race and socioeconomic disparities in mortality and end-of-life care following aneurysmal subarachnoid hemorrhage.

BACKGROUND: This study explores racial and socioeconomic disparities in aneurysmal subarachnoid hemorrhage (aSAH) care, highlighting the impact on treatment and outcomes. The study aims to shed light on inequities and inform strategies for reducing disparities in healthcare delivery. METHODS: In this cohort study the National Inpatient Sample database was queried for patient admissions with ruptured aSAH from 2016 to 2020. Multivariable analyses were performed estimating the impact of socioeconomic status and race on rates of acute treatment, functional outcomes, mortality, receipt of life-sustaining interventions (mechanical ventilation, tracheostomy, gastrostomy, and blood transfusions), and end-of-life care (palliative care and do not resuscitate). RESULTS: A total of 181 530 patients were included. Minority patients were more likely to undergo treatment (OR 1.15, 95% CI 1.09 to 1.22, P<0.001) and were less likely to die (OR 0.89, 95% CI 0.84 to 0.95, P<0.001) than White patients. However, they were also more likely to have a tracheostomy (OR 1.47, 95% CI 1.33 to 1.62, P<0.001) and gastrostomy tube placement (OR 1.43, 95%CI 1.32 to 1.54, P<0.001), while receiving less palliative care (OR 0.75, 95% CI 0.70 to 0.80, P<0.001). This trend persisted when comparing minority patients from wealthier backgrounds with White patients from poorer backgrounds for treatment (OR 1.10, 95% CI 1.00 to 1.21, P=0.046), mortality (OR 0.82, 95% CI 0.74 to 0.89, P<0.001), tracheostomy tube (OR 1.27, 95% CI 1.07 to 1.48, P<0.001), gastrostomy tube (OR 1.34, 95% CI 1.18 to 1.52, P<0.001), and palliative care (OR 0.76, 95% CI 0.69 to 0.84, P<0.001). CONCLUSIONS: Compared with White patients, minority patients with aSAH are more likely to undergo acute treatment and have lower mortality, yet receive more life-sustaining interventions and less palliation, even in higher socioeconomic classes. Addressing these disparities is imperative to ensure equitable access to optimal care and improve outcomes for all patients regardless of race or class.

Behavior of glioblastoma brain tumor stem cells following a suborbital rocket flight: reaching the "edge" of outer space.

The emerging arena of space exploration has created opportunities to study cancer cell biology in the environments of microgravity and hypergravity. Studying cellular behavior in altered gravity conditions has allowed researchers to make observations of cell function that would otherwise remain unnoticed. The patient-derived QNS108 brain tumor initiating cell line (BTIC), isolated from glioblastoma (GBM) tissue, was launched on a suborbital, parabolic rocket flight conducted by EXOS Aerospace Systems & Technologies. All biologicals and appropriate ground controls were secured post-launch and transported back to our research facility. Cells from the rocket-flight and ground-based controls were isolated from the culture containers and expanded on adherent flasks for two weeks. In vitro migration, proliferation, and stemness assays were performed. Following cell expansion, male nude mice were intracranially injected with either ground-control (GC) or rocket-flight (RF) exposed cells to assess tumorigenic capacity (n = 5 per group). Patient-derived QNS108 BTICs exposed to RF displayed more aggressive tumor growth than the GC cells in vitro and in vivo. RF cells showed significantly higher migration (p < 0.0000) and stemness profiles (p < 0.01) when compared to GC cells. Further, RF cells, when implanted in vivo in the brain of rodents had larger tumor-associated cystic growth areas (p = 0.00029) and decreased survival (p = 0.0172) as compared to those animals that had GC cells implanted.

Advances in computational and translational approaches for malignant glioma.

Gliomas are the most common primary brain tumors in adults and carry a dismal prognosis for patients. Current standard-of-care for gliomas is comprised of maximal safe surgical resection following by a combination of chemotherapy and radiation therapy depending on the grade and type of tumor. Despite decades of research efforts directed towards identifying effective therapies, curative treatments have been largely elusive in the majority of cases. The development and refinement of novel methodologies over recent years that integrate computational techniques with translational paradigms have begun to shed light on features of glioma, previously difficult to study. These methodologies have enabled a number of point-of-care approaches that can provide real-time, patient-specific and tumor-specific diagnostics that may guide the selection and development of therapies including decision-making surrounding surgical resection. Novel methodologies have also demonstrated utility in characterizing glioma-brain network dynamics and in turn early investigations into glioma plasticity and influence on surgical planning at a systems level. Similarly, application of such techniques in the laboratory setting have enhanced the ability to accurately model glioma disease processes and interrogate mechanisms of resistance to therapy. In this review, we highlight representative trends in the integration of computational methodologies including artificial intelligence and modeling with translational approaches in the study and treatment of malignant gliomas both at the point-of-care and outside the operative theater in silico as well as in the laboratory setting.

Evaluating Match and Attrition Rates for Women and African Americans in Neurosurgery.

BACKGROUND: Previous efforts to increase diversity in neurosurgery have been aimed primarily at female inclusion while little analysis of other under-represented groups has been performed. OBJECTIVE: To evaluate match and retention rates of under-represented groups in neurosurgery, specifically Black and female applicants compared with non-Black and male applicants. METHODS: Match lists, Electronic Residency Application Service data, and National Resident Matching Program data were retrospectively reviewed along with publicly available residency program information for successful matriculants from 2017 to 2020. Residents were classified into demographic groups, and analysis of match and retention rates was performed. RESULTS: For 1780 applicants from 2017 to 2020, 439 identified as female while 1341 identified as male. Of these 1780 applicants, 128 identified as Black and 1652 identified as non-Black. Male and female applicants matched at similar rates ( P = .76). Black applicants matched at a lower rate than non-Black applicants ( P < .001). From 2017 to 2020, neither race nor sex was associated with retention as 94.1% of male applicants and 93.2% of female applicants were retained ( P = .63). In total, 95.2% of Black residents and 93.9% of non-Black residents were retained ( P = .71). No intraregional or inter-regional differences in retention were found for any group. CONCLUSION: Although sex parity has improved, Black applicants match at lower rates than non-Black applicants but are retained after matriculation at similar rates. Neurosurgery continues to recruit fewer female applicants than male applicants. More work is needed to extend diversity to recruit under-represented applicants. Future studies should target yearly follow-up of retention and match rates to provide trends as a measure of diversification progress within the field.

Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications.

Glioblastoma (GBM) is the most common primary brain tumor in adults an carries and carries a terrible prognosis. The current regiment of surgical resection, radiation, and chemotherapy has remained largely unchanged in recent years as new therapeutic approaches have struggled to demonstrate benefit. One of the most challenging hurdles to overcome in developing novel treatments is the profound immune suppression found in many GBM patients. This limits the utility of all manner of immunotherapeutic agents, which have revolutionized the treatment of a number of cancers in recent years, but have failed to show similar benefit in GBM therapy. Understanding the mechanisms of tumor-mediated immune suppression in GBM is critical to the development of effective novel therapies, and reversal of this effect may prove key to effective immunotherapy for GBM. In this review, we discuss the current understanding of tumor-mediated immune suppression in GBM in both the local tumor microenvironment and systemically. We also discuss the effects of current GBM therapy on the immune system. We specifically explore some of the downstream effectors of tumor-driven immune suppression, particularly myeloid-derived suppressor cells (MDSCs) and other immunosuppressive monocytes, and the manner by which GBM induces their formation, with particular attention to the role of GBM-derived extracellular vesicles (EVs). Lastly, we briefly review the current state of immunotherapy for GBM and discuss additional hurdles to overcome identification and implementation of effective therapeutic strategies.

Functional Characterization of Brain Tumor-Initiating Cells and Establishment of GBM Preclinical Models that Incorporate Heterogeneity, Therapy, and Sex Differences.

Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4 All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Cancer Mortality Rates Increasing vs Cardiovascular Disease Mortality Decreasing in the World: Future Implications.

OBJECTIVE: To highlight the current global trends in mortality for cardiovascular disease and cancer. METHODS: The World Health Organization and the World Bank DataBank databases were used to analyze mortality rates for cancer and cardiovascular disease by calculating age-standardized mortality rates (ASRs) from 2000 to 2015 for high-income, upper-middle-income, and lower-middle-income countries. Data for cancer mortality and population for 43 countries representing 5 of the 7 continents (except Australia and Antarctica) were analyzed. RESULTS: From 2000 to 2015, there was an increase in the ASR for cancer for both men and women irrespective of a country's income status, representing an overall 7% increase in cancer ASR (Pearson r, +0.99; P<.00001). We report a higher ASR for cancer in high-income countries than in upper-middle-income and lower-middle-income countries specifically; high-income countries saw a 3% increase in cancer ASR vs +31% for upper-middle-income and +19% for lower-middle-income countries (P<.01). There has been a decrease in the ASR for cardiovascular disease for the 15 years analyzed (P<.00001). In addition, high-income countries had a higher ASR for cardiovascular disease than upper-middle-income countries during the 15-year period (P<.05). CONCLUSION: We suspect that because of early detection and targeted interventions, cardiovascular disease mortality rates have decreased during the past decade. On the basis of our results, cancer mortality rates continue to rise, with the projection of surpassing cardiovascular disease mortality rates in the near future.

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities.

Gliomas represent the most common malignant primary brain tumors, and a high-grade subset of these tumors including glioblastoma are particularly refractory to current standard-of-care therapies including maximal surgical resection and chemoradiation. The prognosis of patients with these tumors continues to be poor with existing treatments and understanding treatment failure is required. The dynamic interplay between the tumor and its microenvironment has been increasingly recognized as a key mechanism by which cellular adaptation, tumor heterogeneity, and treatment resistance develops. Beyond ongoing lines of investigation into the peritumoral cellular milieu and microenvironmental architecture, recent studies have identified the growing role of mechanical properties of the microenvironment. Elucidating the impact of these biophysical factors on disease heterogeneity is crucial for designing durable therapies and may offer novel approaches for intervention and disease monitoring. Specifically, pharmacologic targeting of mechanical signal transduction substrates such as specific ion channels that have been implicated in glioma progression or the development of agents that alter the mechanical properties of the microenvironment to halt disease progression have the potential to be promising treatment strategies based on early studies. Similarly, the development of technology to measure mechanical properties of the microenvironment in vitro and in vivo and simulate these properties in bioengineered models may facilitate the use of mechanical properties as diagnostic or prognostic biomarkers that can guide treatment. Here, we review current perspectives on the influence of mechanical properties in glioma with a focus on biophysical features of tumor-adjacent tissue, the role of fluid mechanics, and mechanisms of mechanical signal transduction. We highlight the implications of recent discoveries for novel diagnostics, therapeutic targets, and accurate preclinical modeling of glioma.

Outcomes in single-level posterior cervical spine surgeries performed in the sitting and prone positions.

OBJECTIVE: The sitting or semisitting position in neurosurgery allows for several technical advantages, including improved visualization of the surgical field. However, it has also been associated with an increased risk of venous air embolisms and positioning-related complications that limit its commonplace adoption. The authors report a large, single-center series of cervical spine procedures performed with patients in the sitting or prone position in order to assess the perceived risk of intraoperative and postoperative complications associated with the sitting position. METHODS: Noninstrumented, single-level posterior cervical spine procedures performed with patients in the sitting/semisitting or prone position from 2000 to 2016 at a single institution were reviewed. Institutional abstraction tools (DataMart and Chart Plus) were used to collect data from the medical records. The two positions were compared with regard to preoperative factors, intraoperative variables, and postoperative outcomes. Multivariable logistic regression models were fitted for 30-day readmission, 30-day return to the operating room, and complication rates. RESULTS: A total of 750 patients (sitting, n = 480; prone, n = 270) were analyzed. The median age was 53 years for those who underwent surgery in the prone position and 50 years for those who underwent surgery in the sitting position (IQRs 45-62 years and 43-60 years, respectively), and 35% of the patients were female. Sitting cases were associated with significantly longer anesthetic times (221 minutes [range 199-252 minutes] vs 205 minutes [range 179-254 minutes]) and operative times (126 minutes [range 101-163 minutes] vs 149 minutes [120-181 minutes]). Cardiorespiratory events in the postanesthesia care unit (PACU) were comparable between the two groups, with the exception of episodes of apnea (2.6% vs 0.6%, p = 0.041) and hypoventilation (4.4% vs 0.8%, p < 0.003), which were more frequent in the prone-position cohort. On multivariable analysis, the effect of the sitting versus the prone position was not significant for 30-day readmission (OR 0.77, 95% CI 0.34-1.71, p = 0.52) or reoperation (OR 0.71, 95% CI 0.31-1.60, p = 0.40). The sitting position was associated with lower odds of developing any complication (OR 0.31, 95% CI 0.16-0.62, p < 0.001). CONCLUSIONS: Based on the intraoperative and postoperative complications chosen in this study, the sitting position confers a similar safety profile to the prone position. This can be explained by a more anatomic positioning accounting for reduced temporary neurological deficits and reduced PACU-associated hypoventilation noted in this series. Nevertheless, the findings may also reflect institutional familiarity, experience, and mastery of this position type, and outcomes may not reflect practices in general.

Potential differences between monolingual and bilingual patients in approach and outcome after awake brain surgery.

INTRODUCTION: 20.8% of the United States population and 67% of the European population speak two or more languages. Intraoperative different languages, mapping, and localization are crucial. This investigation aims to address three questions between BL and ML patients: (1) Are there differences in complications (i.e. seizures) and DECS techniques during intra-operative brain mapping? (2) Is EOR different? and (3) Are there differences in the recovery pattern post-surgery? METHODS: Data from 56 patients that underwent left-sided awake craniotomy for tumors infiltrating possible dominant hemisphere language areas from September 2016 to June 2019 were identified and analyzed in this study; 14 BL and 42 ML control patients. Patient demographics, education level, and the age of language acquisition were documented and evaluated. fMRI was performed on all participants. RESULTS: 0 (0%) BL and 3 (7%) ML experienced intraoperative seizures (P = 0.73). BL patients received a higher direct DECS current in comparison to the ML patients (average = 4.7, 3.8, respectively, P = 0.03). The extent of resection was higher in ML patients in comparison to the BL patients (80.9 vs. 64.8, respectively, P = 0.04). The post-operative KPS scores were higher in BL patients in comparison to ML patients (84.3, 77.4, respectively, P = 0.03). BL showed lower drop in post-operative KPS in comparison to ML patients (- 4.3, - 8.7, respectively, P = 0.03). CONCLUSION: We show that BL patients have a lower incidence of intra-operative seizures, lower EOR, higher post-operative KPS and tolerate higher DECS current, in comparison to ML patients.

Does pituitary compression/empty sella syndrome contribute to MRI-negative Cushing's disease? A single-institution experience.

OBJECTIVE: Cushing's disease arises from functioning adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing's disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing's disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing's disease. METHODS: A single-institution database of Cushing's disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing's disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI. RESULTS: Of the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61-6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002). CONCLUSIONS: Empty sella syndrome is associated with an increased rate of MRI-negative Cushing's disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.

Long-Term Mortality After Carotid Stenting.

BACKGROUND: Carotid artery stenting (CAS) is an established procedure for the treatment of atherosclerotic disease affecting the extracranial internal carotid artery. Recent population-based studies have suggested that long-term survival after CAS may be limited, thereby questioning its efficacy in a real-world scenario. METHODS: We retrospectively reviewed outcomes of patients undergoing CAS for asymptomatic or symptomatic carotid stenosis by a neurosurgeon or interventional neuroradiologist at our institution between 2008 and 2018. Patient and disease characteristics were recorded, as was the incidence of periprocedural and overall ischemia and mortality after CAS. Risk factors for recurrent ischemia and mortality were identified using a Cox proportional hazards model. RESULTS: There were 238 patients who met inclusion criteria. Mean age was 69.7 years and most patients were male (69.7%); 62.2% underwent CAS for symptomatic carotid stenosis. The use of CAS for treatment of asymptomatic stenosis declined over the study period (P = 0.006). Fourteen patients (5.9%) experienced new or recurrent ipsilateral ischemia during follow-up, with 8 (3.4%) experiencing a stroke with permanent neurologic deficit. Fifty-nine patients (24.8%) died during follow-up, with a median time to death of 111.3 months (95% confidence interval [CI], 95.1-133.6) on Kaplan-Meier analysis. Increasing age at time of CAS (unit risk ratio, 1.05; 95% CI, 1.01-1.10; P = 0.011) and comorbid congestive heart failure (risk ratio, 2.40; 95% CI, 1.39-4.13; P = 0.002) were independent risk factors for mortality during follow-up. CONCLUSIONS: Unlike population-based studies, our results indicate acceptable long-term survival after CAS in adequately selected patients.

Glioblastoma Recurrence Versus Treatment Effect in a Pathology-Documented Series.

OBJECTIVE: Patients diagnosed with glioblastoma (GBM) are treated with surgery followed by fractionated radiotherapy with concurrent and adjuvant temozolomide. Patients are monitored with serial magnetic resonance imaging (MRI). However, treatment-related changes frequently mimic disease progression. We reviewed a series of patients undergoing surgery for presumed first-recurrence GBM, where pathology reports were available for tissue diagnosis, in order to better understand factors associated with a diagnosis of treatment-related changes on final pathology. METHODS: Patient records at a single institution between 2005 and 2015 were retrospectively reviewed. Pathology reports were reviewed to determine diagnosis of recurrent GBM or treatment effect. Survival analysis was performed interrogating overall survival (OS) and progression-free survival (PFS). Correlation with radiation treatment plans was also examined. RESULTS: One-hundred-twenty-three patients were identified. One-hundred-sixteen patients (94%) underwent resection and seven underwent biopsy. Treatment-related changes were reported in 20 cases (16%). These patients had longer median OS and PFS from the time of recurrence than patients with true disease progression. However, there was no significant difference in OS from the time of initial diagnosis. Treatment effect was associated with surgery within 90 days of completing radiation. In patients receiving radiation at our institution (n = 53), larger radiation target volume and a higher maximum dose were associated with treatment effect. CONCLUSION: Treatment effect was associated with surgery nearer to completion of radiation, a larger radiation target volume, and a higher maximum point dose. Treatment effect was associated with longer PFS and OS from the time of recurrence, but not from the time of initial diagnosis.

Poly(ethylene glycol)-Poly(beta-amino ester)-Based Nanoparticles for Suicide Gene Therapy Enhance Brain Penetration and Extend Survival in a Preclinical Human Glioblastoma Orthotopic Xenograft Model.

Glioblastoma (GBM) is the most devastating brain cancer, and cures remain elusive with currently available neurosurgical, pharmacological, and radiation approaches. While retrovirus- and adenovirus-mediated suicide gene therapy using DNA encoding herpes simplex virus-thymidine kinase (HSV-tk) and prodrug ganciclovir has been suggested as a promising strategy, a nonviral approach for treatment in an orthotopic human primary brain tumor model has not previously been demonstrated. Delivery challenges include nanoparticle penetration through brain tumors, efficient cancer cell uptake, endosomal escape to the cytosol, and biodegradability. To meet these challenges, we synthesized poly(ethylene glycol)-modified poly(beta-amino ester) (PEG-PBAE) polymers to improve extracellular delivery and coencapsulated plasmid DNA with end-modified poly(beta-amino ester) (ePBAE) polymers to improve intracellular delivery as well. We created and evaluated a library of PEG-PBAE/ePBAE nanoparticles (NPs) for effective gene therapy against two independent primary human stem-like brain tumor initiating cells, a putative target to prevent GBM recurrence. The optimally engineered PEG-PBAE/ePBAE NP formulation demonstrated 54 and 82% transfection efficacies in GBM1A and BTIC375 cells respectively, in comparison to 37 and 66% for optimized PBAE NPs without PEG. The leading PEG-PBAE NP formulation also maintained sub-250 nm particle size up to 5 h, while PBAE NPs without PEG showed aggregation over time to micrometer-sized complexes. The comparative advantage demonstrated in vitro successfully translated into improved in vivo diffusion, with a higher amount of PEG-PBAE NPs penetrating to a distance of 2 mm from the injection site. A significant increase in median survival from 53.5 to 67 days by PEG-PBAE/pHSV-tk NP and systemic ganciclovir treatment compared to a control group in orthotopic murine model of human glioblastoma demonstrates the potential of PEG-PBAE-based NPs as an effective gene therapy platform for the treatment of human brain tumors.

Effect of fixed-setting versus programmable valve on incidence of shunt revision after ventricular shunting for idiopathic normal pressure hydrocephalus.

OBJECTIVE: Although ventricular shunting is an effective therapy for idiopathic normal pressure hydrocephalus (iNPH), the effect of shunt valve type on the incidence of revision surgery is not well defined. To address this issue, shunt revision rates between patients with iNPH receiving a fixed-setting valve (FSV) versus a programmable valve (PV) were compared. METHODS: Patients with iNPH treated with ventricular shunting between 2001 and 2017 were included for analysis. The incidence of shunt revision was noted and risk factors for revision were identified using a Cox proportional hazards model. Costs associated with admission for ventricular shunt procedures were obtained from the Vizient national database. RESULTS: There were 348 patients included for analysis, with 98 patients (28.1%) receiving a PV. Shunt revision occurred in 73 patients (21.0%), with 12 patients (3.4%) undergoing multiple revisions. Overall revision rates were lower in patients receiving a PV (13.3% vs 24.0%; p = 0.027), as was the incidence of multiple revisions (0.0% vs 4.8%; p = 0.023). Patients with initial placement of an FSV were also more likely to undergo valve exchange during follow-up (12.4% vs 2.0%; p = 0.003). Patients with a PV were less likely to undergo revision due to persistent symptoms without obstruction (2.0% vs 8.8%; p = 0.031) and distal obstruction (1.0% vs 6.8%; p = 0.030). In a multivariate Cox proportional hazards model, initial placement of a PV was associated with reduced risk of revision due to persistent symptoms without obstruction (OR 0.27, 95% CI 0.04-0.93; p = 0.036). PVs were associated with more frequent shunt series (1.3 vs 0.6; p < 0.001) and head CT scans (3.6 vs 2.7; p = 0.038) during follow-up. There was no significant difference in mean total costs between patients receiving an FSV and a PV ($24,282.50 vs $24,396.90; p = 0.937). CONCLUSIONS: The authors' results suggest that PVs lead to reduced rates of shunt revision in patients with iNPH, and decreased risk of revision due to persistent symptoms of iNPH, thereby justifying the higher upfront cost of PVs despite similar overall treatment costs between these devices.

Bevacizumab Use in Refractory Adult Pilocytic Astrocytoma: A Single-Center Case Series.

Pilocytic astrocytomas (PA) are highly vascular tumors with vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor-2 (VEGFR-2) signaling present in the tumor vasculature. PA may, therefore, be responsive to VEGF blockade with bevacizumab (BEV). Data regarding the use of BEV in refractory PA in adults are limited primarily to case reports and case series of patients with recurrent PA. We conducted a single-center, retrospective cohort study from 2009 to 2018. We screened 426 patients with pathologically confirmed PA. We identified 5 adult patients with PA who received BEV at our institution with sufficient clinical follow-up to derive evidence of the efficacy and toxicity. All 5 patients experienced tumor progression after initial therapies which included surgery, radiation, and chemotherapy. Four patients received BEV as monotherapy, whereas 1 received BEV with the continuation of previously initiated alkylating chemotherapy (temozolomide). The average duration of BEV therapy was 10.2 months (range, 1 to 20 mo) with an average follow-up of 47 months (range, 6 to 112 mo). One patient had a severe necrotizing rash in areas of skin contact and discontinued after 1 cycle of BEV. All patients had stabilization per RANO criteria, with 1 patient experiencing progression after 10 months on treatment. One patient had disease progression 5 years after completion of BEV, but the tumor responded to repeat treatment with BEV. Our institution's experience with the use of BEV in recurrent PA is in line with previous reports of therapeutic benefit in recurrent adult PA.

Comparison of Complication and Revision Rates After Frontal Versus Parietal Approach for Ventricular Shunt Placement in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Ventricular shunts are most commonly placed via a frontal or parietal approach. However, there is a paucity of data comparing complication and revision rates associated with these approaches in the idiopathic normal pressure hydrocephalus (iNPH) population. METHODS: Patients with iNPH treated with ventricular shunting between 2001 and 2017 at our institution were included for analysis. Patient characteristics, catheter accuracy, and incidence of revision were determined from the medical record. Catheter accuracy was determined using axial computed tomography imaging and classified as grade 1, 2, or 3 based on location of the catheter tip. RESULTS: There were 348 patients included for analysis with 266 (76.4%) and 82 (23.6%) receiving a frontal versus parietal shunt, respectively. Patients undergoing the parietal approach were more likely to receive a programmable valve (37.8% vs. 25.2%; P = 0.026). Neuronavigation was used more frequently for patients undergoing the parietal approach (26.8% vs. 4.1%; P < 0.001); however, a minority of cases used neuronavigation in general (9.5%). There was no difference in catheter accuracy between the 2 approaches and no difference in catheter accuracy with the use of neuronavigation. The overall revision rate was 21.0%, and there were no differences in the incidence of revisions between the frontal and parietal approaches (21.8% vs. 18.3%, respectively; P = 0.495). There were no differences in revision subtypes between the approaches. CONCLUSIONS: These results suggest that the type of approach for shunting may not have a significant impact on complication and revision rates in patients with iNPH, and either approach is a reasonable first-line option.