Titan skin v3.6.71 download lin

Introduction

Surgical services that work in open admission units often encompass various difficulties with managing their patients related to daily work flow in comparison with traditional medical services. A Neurosurgery Nursing Communication Tool (NNCT) was adapted to the pediatric neurosurgery (NSGY) population to improve team communication and understanding of patient care. There is limited research on rounding tools amongst the multi-disciplinary care team especially NSGY with nurses (RNs).

Methods

This is a prospective cohort study utilizing a pre/post-implementation surveys with RNs on the pediatric unit was distributed to assess perceptions of baseline team communication. Each NNCT was assessed for various data components.

Results

The pre-implementation survey showed that 63% felt their concerns were addressed and 42% feel confident speaking in team rounds. In the first month, there was a NNCT completion rate of 65% with less than 50% of NCCT data completed. Admission diagnoses were only correct on 55.6% of NCCTs. Post implementation surveys showed 85.7% felt it was user friendly. All RNs felt it took less than 5 minutes to complete. 71.4% of RNs felt it has helped to know more about their patient, 81.2% felt their concerns are addressed and 85.7% reported that it has improved communication. There was also an increase of RN confidence. Of RNs surveyed, 71.4% expressed that the NCCT could be helpful for other patients and surgical teams. It found that 72.7% of RNs learn their patient diagnosis from RN report.

Conclusions

By implementing a brief NNCT, there was improved RN confidence and RN understanding of their patient, as well as, improved quality of RN-NCCT perceived communication after a month. This pilot study empathizes that all team members are accountable in patient care and communication. It also demonstrates the need for larger studies with better nursing involvement.

Introduction

Readmissions within 30 days of hospitalization are utilized as a quality of care benchmark. We reviewed 30 day hospital readmissions for Neuroscience patients over 4 years at Mayo Clinic.

Methods

We conducted a Mayo Clinic Kern Center for Science of Health Care Delivery retrospective analysis reviewing neurosurgery patients who were readmitted to the hospital within 30 days. The following data points were utilized in the review: age, sex, length of stay, Charlson comorbidity index, ICU stay, elective or urgent surgery, and discharge disposition.

Results

All patients were reviewed from January 2013 to December 2017, totaling 3966 patients that were not readmitted and 295 (6.9%) patients that were unplanned readmissions within 30 days. Factors associated with readmission included: increased length of stay (p <0.0001, mean 5.4 days (SD 6.8) versus 3.8 (SD 4.5), Charlson comorbidity myocardial infarct, congestive heart failure, peripheral vascular disease, cerebrovascular disease (p<0.0001), dementia (p<0.0001), chronic pulmonary disease (p<0.0001), ulcer, diabetes (p<0.0001), hemiplegia (p<0.0001), moderate or severe renal disease, metastatic solid tumor (p<0.0001), other cancer (p<0.0001), brain/nervous system tumor (p<0.0001), total disease flag count (p<0.0001), ICU stay (p<0.0001), discharge to skilled nursing facility or rehabilitation facility (p<0.0001). Factors without statistical significance included: age, sex, mild liver disease, AIDS, rheumatic disease.

Conclusion

This study has the largest total sample size examining neuroscience patient risk factors for readmission. This data suggests that patients with more comorbidities or decreased functional ability are associated with readmissions. This analysis is the basis for a future a prospective multivariate regression model to quantify readmission risk in neuroscience patients to guide future interventions.

Introduction

Optimal post-operative pain control is critical after lumbar fusion surgery. However, there is significant variability in the use of intravenous opioid patient-controlled analgesia (PCA) and little data evaluating its utility compared to multimodal nurse-controlled analgesia (NCA) in this patient population.

Methods

A single institution retrospective review was conducted in patients receiving posterior lumbar fusion for degenerative pathology. Baseline demographics, treatment data, and clinical outcomes were collected. Patients were divided into two cohorts: those treated postoperatively with PCA and NCA. Post-operative numerical rating scale (NRS) pain scores, length of stay, and total opioid consumption were collected. Patients were stratified according to pre-operative opioid consumption as naïve, low (<60 morphine milligram equivalents (MME) daily), high (61-90 MME) or very high (>90 MME).

Results

240 patients were identified: 62 and 178 in PCA and NCA groups, respectively. PCA patients had higher mean pre-operative opioid consumption compared to the NCA patients (49.2 vs 24.3 MME, p=0.009). After stratifying by preoperative opioid consumption, PCA patients had higher 72-hour opioid consumption in all groups. With opioid naïve patients, PCA was associated with higher post-operative NRS scores at 24 and 24-72 hours (p=0.046 and 0.023, respectively) despite greater opioid intake. In the Very High opioid consumption group (>90MME), PCA had increased maximal reported pain scores between 24-72 hours (p=0.014) and a greater rate of opioid-related adverse events per patient (0.86 vs 0.43, p=0.046). Pain control and adverse event rates were comparable between PCA and NCA in the middle groups (1-90 MME).

Conclusion

Postoperative PCA utilization is associated with significantly more opioid consumption and equal or worse post-operative pain scores compared to NCA after lumbar spinal fusion surgery, particularly in opioid naïve patients. The increased opioid consumption with PCA may also lead to higher rates of opioid-related adverse events in subsets of patients.

Introduction

Thoracolumbar fusion is indicated in a variety of spinal pathologies, including trauma, tumor, degenerative disk disease, and scoliosis. However, significant variability exists in the implementation of postoperative orthoses following these procedures. The potential stability conferred by immobilization must be balanced by the potential morbidity and associated discomfort. Limited clinical evidence is available to codify the risks and benefits of bracing following thoracolumbar fusion. Via a systematic review of the literature, this study aims to assess the utility of external fixation of the thoracolumbar spine following fusion procedures.

Methods

A systematic review was performed using Medline. Our search included studies that evaluated the impact of post-operative bracing on complications or quality-of-life following spinal fusion, and was limited to literature published between 1990 and 2018.

Results

Our search identified a total of 1706 publications. Of these, 29 publications evaluated bracing in the post-operative setting. These were subsequently narrowed to only five studies that specifically analyzed postoperative bracing in thoracolumbar patients following spinal fusion. Data extracted from each of the five papers included demographic information, surgical details, complication rates, and a variety of quality of life measures. Mean complication rates, instrumentation failure rates, pseudarthrosis rates, Oswestry Disability indices, visual analog scale Spine Scores, SF-12v2 scores, American Spinal Injury Association impairment scores, and Roland Morris Disability scores, were calculated across bracing and control cohorts and compared using independent samples t-test. Ultimately, thoracolumbar bracing was not found to significantly affect complication rates, or impact postoperative quality of life.

Conclusion

This study does not find any significant effect of postoperative bracing on complication rates or quality-of-life for patients recovering from thoracolumbar fusion. This systematic review was limited by a dearth of available literature, and indicates a need for further exploration of this topic to determine optimal postoperative management of such patients.

Introduction

Multiple intracranial aneurysms represents 30% of all unruptured intracranial aneurysms, and have been associated with cerebrovascular disorder, familiar history, and previous subarachnoid hemorrhage. Here, we investigated the incidence and risk factors associated with multiple intracranial aneurysms.

Methods

1404 patients, admitted in Hospital das Clínicas de São Paulo, Brazil, between September 2009 and August 2018, enrolled this study. There were 314 male (22.4%) and 1090 female (77.6%). Diagnosis was performed with digital subtraction angiography. Multiplicity was defined as 2 or more intracranial aneurysms. Individuals characteristics such as sex, age, smoking and hypertension were evaluated.

Results

512 patients (36.4%) were diagnosed with multiple intracranial aneurysms, accounting for 1362 aneurysms. There was an increased frequency of females with multiple aneurysms (p < 0.001, OR= 1.883, 95% CI= 1.386-2.560). Smoking was associated with multiple aneurysms development, as well as advanced age (p= 0.001, OR= 1.458, 95% CI= 1.160-1.833, and p < 0.001, OR= 1.938, 95% CI= 1.438-2.611, respectively). We observed no significant associations concerning hypertension (p= 0.702). Sorting by size, 60.6% had a diameter between 3-10 mm. We observed higher incidence of baby aneurysms (less than 3 mm) in the group of patients with multiple aneurysms, while giant aneurysms (more than 25 mm) were most found in the group of patients with only one aneurysm (p < 0.001).

Conclusion

Risk factors to the development of intracranial aneurysms, such as sex, advanced age and smoking, were most found in patients with multiple aneurysms when compared with individuals with only one aneurysm.

Introduction

Prior studies have shown potential bias in the surgical treatment of traumatic brain injury patients without insurance. The Patient Protection and Affordable Care Act was passed in 2010. After the enactment of the PPACA, it is unknown if this potential bias persists. This study was undertaken to address this question.

Methods

The Nationwide Inpatient Sample was queried for years 2012-2016. Patients with traumatic intracranial hemorrhage as the primary admitting diagnosis were isolated and compared for surgical treatment and survival relative to patient insurance status. A multivariate analysis including variables of patient gender, age by decade, admission severity score, and teaching hospital status was performed to compare outcome measures between years.

Results

The percentage of uninsured patients declined from 11% to 4% during the queried timeframe. Overall, mortality was 11% for uninsured patients compared with 8% for insured patients. In multivariate analysis, uninsured status was associated with mortality in all years, p < 0.001. Multivariate regression analysis suggests an Odds Ratio of 0.82 for surgery in uninsured patients in 2012-2015 (p<0.001) and OR of 0.86 in 2016 (p<0.03).

Conclusion

This analysis supports prior studies that uninsured patients were previously less likely to undergo surgery after admission for traumatic brain hemorrhage compared to insured patients; however, after the enactment of the PPACA, this gap seems to be diminishing. Despite this, mortality rates are higher in uninsured patients.

Introduction

The natural history of unilateral moyamoya disease remains an enigma in modern vascular neurosurgery. Few, small series with limited follow up have reported relatively high rates of contralateral stenosis progression. We sought to review a large series of unilateral moyamoya patients at our medical center.

Methods

We included all unilateral moyamoya cases treated from 1991 through 2017 and followed at least 1 year. We examined time to contralateral radiographic progression as well as contralateral progression requiring surgery. Using a time to event analysis, we sought to create a prediction model for contralateral progression, including variables such as baseline stenosis, sex, age, syndrome (NF1, Down syndrome, hemaglobinopathy), race, family history, hypertension, hyperlipidemia and smoking history. This study was approved by our IRB.

Results

There were 184 patients treated for unilateral moyamoya. One hundred twenty-nine (70%) were female, and the average age at first surgery was 33 (range 2-68). Average follow up was 5.4 yrs (range 1-22 yrs). Fifteen (8.2%) patients developed contralateral progression. Seven (3.8%) of these developed progression requiring bypass surgery. A time to event analysis revealed potential predictors of contralateral progression.

Conclusion

Previous series showed relatively high rates of progression in unilateral moyamoya, but these studies were small and long term follow up was not available. Our large series with long term follow up indicates that the rate of progression is lower than previously reported but still warrants yearly non-invasive screening.

Introduction

Evaluating for tumor recurrence in post-treatment glioma is a challenge as radiographically appearing contrast-enhancing (CE) regions are a mixture of tumor cells and treatment effect. This study characterizes intratumoral heterogeneity using quantitative digital pathology to correlate intraoperative MRI-localized biopsies with histopathology in the post-treatment setting. These findings are being used to inform a multiparametric radiographic model of intratumoral heterogeneity.

Methods

A retrospective review was performed on adult patients with MRI-localized biopsies obtained during resection for post-treatment recurrent high grade glioma. 46 patients and 133 MRI-localized samples were analyzed (median 2 samples/patient). A histopathological classification was developed to assess each sample for relative abundances of treatment effect and recurrent tumor. Immunohistochemistry (IHC) with SOX2, CD68, and Ki67 was used to validate the classification and further characterize the samples. Slides were digitized and quantified using an automated cell-counting algorithm. IHC quantification was compared across histological groups using ANOVA and paired t-tests.

Results

Of 34 patients with multiple biopsies, 25 (74%) demonstrated heterogeneity (as assessed by histopathological classification). 71/133 (53%) biopsies showed predominantly treatment effect and of those, 40/71 (56%) specimens were CE. 19% (12/62) of non-enhancing specimens contained predominantly recurrent tumor. Cell density was correlated with histopathological classification (p=2.2e-16). SOX2 and Ki67 staining were higher in specimens containing predominantly tumor (p=2.2e-16, p=1.269e-14). CD68 staining was higher in specimens containing substantial treatment effect (p=1.733e-07).

Conclusion

This study shows that contrast enhancement is not a reliable predictor of tumor presence in post-treatment recurrent malignant gliomas. A majority of patients demonstrated marked intratumoral heterogeneity, highlighting the difficulty of adequate tumor sampling and diagnostic accuracy in the post-treatment setting. In addition to validating the histological classification, IHC revealed that SOX2 is a useful marker for quantifying tumor burden. These results are being used in the development of radiographic models to map intratumoral heterogeneity.

Introduction

On May 5th, 1961 Alan B. Shepard, Jr. piloted the Freedom 7 craft into a suborbital flight to become the first American man in space. His promising astronautical career was soon scuttled by spells of dizziness and tinnitus later diagnosed as Ménière’s disease.

Methods

Primary and secondary sources were used in preparation of this historical vignette.

Results

Once diagnosed with Ménière’s, Alan Shepard was grounded and relegated to a desk job at NASA; a small chance remained, though, that he might be made flight ready once more if his Ménière’s could only be treated. In 1968 William F. House—considered the father of neurotology and a pioneer in surgery for vestibular schwannomas—implanted an endolymphatic-subarachnoid shunt, which at the time was a virtually experimental procedure. Shepard’s debilitating Ménière’s disease was cured, but not quite in time for him to pilot the doomed Apollo 13 mission; he was reassigned to Apollo 14 and as a result would step foot on the moon on February 5th, 1971.

Conclusion

This historical vignette depicts the tale of how the career trajectories of Alan B. Shepard, Jr. and William F. House—two notable figures in their respective fields—fatefully intersected.

Introduction

Health facilities in low and middle income countries (LMICs) could benefit from decision support technologies to reduce time to diagnosis and treatment for patients with traumatic brain injury (TBI). CRASH and IMPACT are robust examples of TBI prognostic models. Despite the strengths of these two models, advanced statistical techniques and improved data quality in LMICs provide an opportunity to develop more accurate, and context specific, prognostic models. We developed a machine learning-based prognostic model using a TBI registry from a hospital in Tanzania. In this study, we compare the performance of our model against CRASH and IMPACT.

Methods

We used the CRASH and IMPACT online risk calculators to generate risk scores for each patient in a TBI registry from a regional referral hospital in Moshi, Tanzania. We compared the discrimination (area under the curve [AUC]) and calibration (agreement between predicted and observed outcomes) for CRASH, IMPACT, and our model. We calculated the AUC using Youden’s index and provided the 95% confidence interval (CI). The outcome of interest was unfavorable in-hospital outcome defined as a Glasgow outcome scale score of one, two or three.

Results

We used a 3138 patient TBI registry for the three model comparison. There was an 11% observed unfavorable outcome

rate. The AUC for our model, CRASH and IMPACT was 90.3 (CI: 88.6, 92.1), 85.8 (CI: 83.3, 88.3) and 82.0 (CI: 79.3, 84.7), respectively. The interquartile range for predicted risk scores were 10-36% (median = 16%) for our model, 5-14% (median = 5%) for CRASH, and 15-32% (median = 21%) for IMPACT.

Conclusion

Our model had better discrimination and similar calibration compared to CRASH and IMPACT models. This finding supports the hypothesis that locally derived prognostic models will outperform imported prognostic models. Further work is needed to externally validate our model.

Introduction

Opioid abuse is a crisis in the United States. Opportunities exist in the perioperative period for alternative modes of analgesia to minimize opioid utilization. The aim of this study is to explore the use of lidocaine infusions in the setting of cranial surgery, with a focus on feasibility and safety.

Methods

Patients who received a lidocaine infusion associated with cranial surgery between 2015 and 2017 were identified through an electronic health record search. Postoperative opioid pain medication consumption in the first and second days were converted into oral morphine milligram equivalents (MME). Non-parametric distributions were compared with the Mann-Whitney U or Wilcoxon signed-rank tests as appropriate.

Results

A total of 55 eligible patients were identified (69.1% female, median age 47, median BMI 30.4). The average length of stay was 4.7 days, with an average ICU length of stay of 1.5 days. The median lidocaine infusion time was 17 hours (IQR: 13-22) in the intraoperative +/- immediate postoperative period, with a median cumulative dosage of 1084 mg (IQR: 785-1703). In the first postoperative day, a median of 60 morphine milligram equivalent (IQR: 34.5-85) was consumed. This declined to 36.5 MME (IQR: 16-70) by the second day (p=0.016).There was no difference in the lidocaine infusion duration, total dose, MME at 24 or 48 hours between the sexes or smoking status. No correlation was found between BMI and MME at 24 or 48 hours. Preoperative opioid use was associated with a higher MME in the second (70.0 v 30.5, p = 0.009) but not the first (64.0 v 54.8, p = 0.124) postoperative day. No adverse events or complications related to the lidocaine infusion were identified.

Conclusion

Lidocaine infusions appear to be a promising and safe adjunct in perioperative analgesia for cranial surgery. Future steps include prospective randomized controlled trials.

Introduction

Success in epilepsy surgery is most commonly judged by post-operative seizure frequency. We wished to identify whether absolute post-operative seizure frequency, absolute reduction in seizure frequency, or relative seizure frequency reduction best predicted patient-reported quality of life after epilepsy surgery.

Methods

We prospectively surveyed patients at outpatient visits to the Cleveland Clinic Epilepsy Center before and after receiving epilepsy surgery (n=550), between 2007 and 2017. The QOL measure of interest was the previously validated Quality of Life in Epilepsy (QOLIE-10) score at the patient’s most recent office visit. We used a multivariate linear regression model to predict post-operative QOLIE-10. Variables included in the model included pre-operative QOLIE-10 as well as pre-operative and post-operative depression score (PHQ9), anxiety score (GAD7), absolute seizure frequency, absolute reduction in seizure frequency, relative reduction in seizure frequency, follow-up time, and relevant interaction terms.

Results

For the 550 patients included in the analysis, median follow-up time was 24.7 months (IQR 8.5-54.5). Our model provided good prediction of post-operative QOLIE-10 (R2=0.72, P<0.001). Effect tests demonstrated that the most important predictive variables were post-operative PHQ9 (F=75, p<0.001), pre-operative QOLIE-10 (F=14, p<0.001), and relative seizure reduction (F=11, p=0.0012). Absolute seizure reduction, absolute post-operative seizure frequency. and follow-up time did not show statistically significant effects.

Conclusion

Our results demonstrate that patients are likely to report a high quality of life after epilepsy surgery as long as there is a significant relative reduction in their seizure frequency after surgery, even if the absolute seizure frequency reduction is non-zero. Most literature evaluating surgical outcomes in epilepsy uses Engel classification to classify surgical success, which focuses on absolute seizure frequency and ignores patient-reported quality of life outcomes. QOL measures should play a bigger role in the evaluation of surgical outcomes.

Introduction

Prognostication for outcomes following pediatric traumatic brain injury (TBI) has traditionally been based upon initial Glasgow Coma Scale (GCS) and other clinical and radiologic indicators. Although the inflammatory cascade following TBI can be both neuroprotective and destructive, inflammatory markers have not been utilized to help predict outcomes in pediatric TBI. This study is the first to utilize the neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker widely utilized in other specialties, to help predict outcomes in pediatric TBI.

Methods

A retrospective review of pediatric patients presenting to our institution with TBI from 2007 to 2017 was performed (n=188, age=0-18 years). Absolute neutrophil count and absolute lymphocyte count on admission and approximately twenty-four and forty-eight hours post-injury were used to calculate NLRs. Data points included GCS on admission, extended Glasgow Outcome Scale (GOS-E) score, and presence of post-traumatic amnesia and/or loss of consciousness. Patients were stratified based on GOS-E score: none to mild disability (GOS-E=1-2), moderate to severe disability (GOS-E=3-6), or vegetative state/death (GOS-E=7-8).

Results

A one-way ANOVA demonstrated statistically significant differences in NLR among patients stratified by GOS-E at 24 hours [F(2,55)=6.26, p=0.004] and 48 hours [F(2,24)=7.59, p=0.003]. No significant differences in NLR or neutrophils were observed at any time point based on GCS category or post-traumatic amnesia. Patients who experienced loss of consciousness had a significantly higher NLR on admission (p=0.013) and at 24 hours (p=<0.001) compared to those who did not lose consciousness.

Conclusion

In this study, a higher NLR twenty-four hours post-TBI predicted worse outcomes in pediatric patients. There was no difference based upon admit NLR. This suggests that NLR may be a useful outcome predictor in pediatric TBI as well as a possible future target for therapeutic intervention. Further study is warranted with larger prospective trials, different time points, and alternative inflammation markers.

Introduction

There remains limited data on the safety and efficacy of posterior vertebral column subtraction osteotomy (PVCSO) for the treatment of tethered cord syndrome (TCS). The purpose of this prospective study was to evaluate surgical outcomes following PVCSO in adult patients with a history of failed detethering surgery caused by lipomyelomeningocele.

Methods

From January 2011 to October 2018, select patients were enrolled and treated with PVCSO at Barrow Neurological Institute and The Johns Hopkins Hospital. Inclusion criteria for surgery were age 18 years and greater, TCS caused by lipomyelomeningocele, history of failed detethering surgery, recurrent symptom progression less than 2 years, and treatment willingness. Herein, all patients undergoing surgery with a one-month minimum follow-up were evaluated.

Results

Twenty patients (mean age: 36 years; sex: 5M/15F) met the inclusion criteria and were evaluated. The average number of previous detethering procedures was 3.7 (range: 1-17). The most common presenting symptom was back pain (95%), followed by urinary incontinence (80%), leg pain (75%), fecal incontinence (55%), sensory abnormalities (50%), and motor deficits (50%). At an average follow-up of 11.2 months (range: 1.8-26 months), symptomatic improvement/resolution was most notable for leg pain (93%), followed by back pain (84%), sensory abnormalities (80%), motor deficits (80%), fecal incontinence (55%), and urinary incontinence (50%). Oswestry Disability Index improved significantly from a mean of 56.1 pre-operatively to 38.4 at end follow-up (p=0.006). The mean spinal column height reduction was 23.7 mm (range: 18-28 mm). Three complications were noted, one each for durotomy, wound infection requiring debridement, and new sensory abnormality.

Conclusion

We report the first prospective study on the safety and efficacy of PVCSO in 20 adult patients with a history of failed detethering surgery caused by lipomyelomeningocele. Our results suggest that PVCSO is an attractive alternative, extradural approach that may afford definitive treatment in this subpopulation.

Introduction

In response to rising national health expenditures the patient protection and affordable care act (ACA) was passed in 2010, with major provisions implemented in 2014. The American Academy of Neurological Surgeons and Congress of Neurological Surgeons stated that the ACA vastly expands the federal governments role and fails to address the shortcomings of the healthcare system. In this study we evaluate trends in neurosurgical reimbursement, productivity and compensation before and after the implementation of the major provisions of the ACA.

Methods

Results from Neurosurgery Executives Resource Value and Education Society (NERVES) surveys were collected, representing data from 2011-2016.Based on the responses from different practice settings across the six years categorized into Before/After 2014, we performed inverse variance-weighted averaging within the frameworks of (a) a one-way ANOVA model with practice setting (Private/Hospital/Academic) as the sub-group factor and (b) a two-way ANOVA model with practice setting and Year (Before/After 2014) as the two sub-group factors. Within these frameworks, we used F-tests to detect any significant difference.

Results

The NERVES survey was distributed to neurosurgery practices in the United States. Response rate ranged from 19.6% to 36%. While medians values during a period of average annual GDP-growth of 2.05% for compensation, productivity and reimbursement were lower after the majority of the regulatory changes associated with the ACA were implemented (January 1,2014) no statistically significant differences were noted within practice type for neurosurgeons in academic, private-practice or hospital-employed groups for annual compensation, annual collections, gross charges, number of annual surgeries performed, total and work RVUs

Conclusion

Though the ACA has led to significant changes in healthcare, survey data suggests that no statistically significant differences in reimbursement, compensation and productivity have occurred for academic, private-practice, or hospital-employed neurosurgeons since implementation of the major provisions of the ACA.

Introduction

CTA is the primary non-invasive diagnostic imaging modality for detecting cerebral aneurysms. However, aneurysm diagnosis by CTA can be challenging for clinicians due to lack of experience or subspecialty neuroradiology training, complex neurovascular anatomy, or the labor-intensive nature of identifying aneurysms. We aimed to develop and validate a novel 3D convolutional neural network architecture to automatically detect intracranial aneurysms on CTA and produce location-specific segmentations.

Methods

We retrospectively collected a dataset of 818 CTA head exams from 662 patients with 328 (40.1%) exams containing at least one clinically significant intracranial aneurysm (>3mm) and 490 (59.9%) exams (controls) without intracranial aneurysms between 2003 and 2017 at Stanford University Medical Center. We excluded exams with hemorrhage, ruptured aneurysm, post-traumatic or infectious pseudoaneurysm, arteriovenous malformation, and any surgical or endovascular hardware. The exams were split into a training set (611 exams, 494 patients) used to train our model, a development set (92 exams, 86 patients) used for model selection, and a test set (115 exams, 82 patients) to evaluate the final model’s performance. The ability of the model to augment clinician readers’ performance was investigated with a crossover study design involving 8 clinical experts.

Results

Clinical experts augmented with model segmentations had a statistically significant increase in both their micro-average sensitivity and accuracy. The clinical experts’; mean sensitivity increased from 0.831 to 0.890 and mean accuracy increased from 0.893 to 0.932. There was also an increase in inter-rater reliability among clinical experts, with an exact Fleiss’ kappa of 0.799 without augmentation and 0.858 with augmentation. The time to diagnosis for each clinical expert decreased on average by 5.96 seconds per case with augmentation.

Conclusion

Our results suggest that segmentation models offer a promising approach for integrating deep learning into the clinical workflow and significantly improving human clinician diagnosis of intracranial aneurysms.

Introduction

The Geisinger MyCode initiative is one of the world’s largest biorepositories with integrated longitudinal electronic health record (EHR) linked to genetic data. Currently, approximately 92,000 MyCode participants have high density single nucleotide polymorphism (SNP) array and whole exome sequence data. Leveraging this multimodal dataset, we can identify powerful associations and advance genomics-guided therapies. Spinal conditions account for the third largest United States healthcare expenditure, yet the genetics underlying degenerative spine conditions have not been significantly explored.

Methods

We identified all patients (n = 3,985) with an EHR diagnosis of spinal osteoarthritis or spondylosis who had genotype data available as part of our DiscovEHR collaboration with the Regeneron Genetics Center. We also identified 12,257 controls who did not have any diagnosis of osteoarthritis or degeneration. We sought to identify SNPs associated with spinal osteoarthritis or spondylosis using logistic regression in a genome-wide association analysis.

Results

Across the 3,985 cases and 12,257 controls, 39 SNPs demonstrated suggestive association with p-values < 5 * 10-5. One SNP (rs9379137) was below the threshold for genome-wide significance (p = 1.203 * 10-8). This SNP is located in the coding region of the bone morphogenetic protein-6 (BMP-6) gene. BMP-6 belongs to the transforming growth factor-beta family and has been shown to be involved in bone and cartilage growth.

Conclusion

We describe the use of a massive database of genotypes combined with phenotypic EHR data to identify an association between the BMP-6 gene and the development of spinal osteoarthritis. We are expanding this analysis to the larger 150,000 participant MyCode database. Long-term, we will define precision medicine relationships between the genome and the development of degenerative spinal conditions, as well as identify those patients most likely to respond to surgery and other therapies.

Introduction

Anaerobic respiration, marked by lactate dehydrogenase alpha (LDHA), has recently been found to play an important role in epileptogenesis. However, the metabolic state of excited neurons is unknown. In this study, we demonstrate a switch from aerobic to anaerobic respiration in chronically activated neurons in human and murine models of epilepsy. Using an in vitro epilepsy model, we establish the AMP-activated protein kinase/hypoxia-inducible factor-1a (AMPK/HIF1a) hypoxia pathway as a key regulator leading to increased LDHA expression and anaerobic respiration.

Methods

First, we analyzed human tissue for LDHA expression based on electrographic characteristics of overlying subdural electrodes, as determined during intracranial monitoring (epileptic vs normal cortex). Second, two epilepsy mouse models (pentylenetetrazole (PTZ) and electrical stimulation) were probed for LDHA after seizure development. Finally, a low Mg2+ in vitro epilepsy model was developed to elucidate AMPK/HIF1a’s role in regulating the metabolic switch from aerobic to anaerobic metabolism.

Results

In human and mouse studies, LDHA expression was significantly upregulated in epileptic neurons. PTZ and electrical stimulation confirmed a positive correlation between seizure frequency and LDHA expression. Treatment of cultured neurons with low Mg2+ caused an increase in bursting activity, or in vitro seizures. Neuronal bursting caused depletion of intracellular ATP and subsequent activation of the AMPK/HIF1a pathway through phosphorylation of AMPK. Furthermore, chronic activation of AMPK led to HIF1a and LDHA upregulation and a subsequent switch from an aerobic to a glycolytic cellular phenotype in neurons.

Conclusion

These data suggest that seizures cause a metabolic switch from aerobic to anaerobic respiration in neurons, which occurs through activation of the canonical AMPK/HIF1a hypoxia pathway. To our knowledge this is the first study to demonstrate the metabolic consequences of neuronal over-activation and the key regulatory pathway responsible. We believe our data opens up significant potential for future investigation into mechanisms of epilepsy and new therapeutic targets.

Introduction

Several studies have documented improved outcomes at high-volume hospitals for neurosurgical procedures. However, the relationship between neurosurgical volume and costs remains poorly understood.

Methods

Using neurosurgery-specific DRG codes, we identified adult neurosurgical admissions in the National Inpatient Sample from 2002 to 2014. We stratified hospitals by annual neurosurgical volume as high-volume (top 20%) or low-volume centers (bottom 80%). We performed survey-weighted analyses to examine the impact of case volume on inpatient costs. Multivariate regression adjusted for patient age, sex, race, insurance, income, severity of illness, length of stay, emergency admission, wage index, hospital ownership, location/teaching status, hospital region, and DRG weights. We created a model for centralization of neurosurgical care, where non-emergency admissions with minor risk of mortality were considered as transfer candidates.

Results

12,129,029 total admissions underwent neurosurgery from 2002 to 2014, with 59.6% treated at high-volume hospitals. Patients at high-volume centers were more likely to privately insured, present with higher risk of mortality, and undergo higher DRG-weight procedures than those at low-volume centers (P<0.001). High-volume hospital admissions were on average 9% or $1,791 more expensive than their low-volume counterparts. However, following adjustment for patient, hospital, and case-mix differences, high-volume hospitals were 4.3% less expensive than low-volume centers ($21,825 vs. $22,924, P<0.01). If 10% of transfer candidates were rather treated at high-volume centers, we estimate an annual saving of $192 million, culminating in a total saving of $2.5 billion.

Conclusion

High-volume institutions appear to have higher costs due to their case-mix of higher patient and procedural severity. After adjusting for this, we found that treating a similar patient at a low-volume hospital would be 4.3% more expensive, suggesting that high-volume hospitals may provide more cost-effective neurosurgical care. Amidst sharply rising medical costs, treatment at high-volume neurosurgical institutions may be a promising strategy to delivering higher value care.

Introduction

Intracranial gunshot wounds (GSW) are often fatal, with most patients dying before intervention can occur. Surgical management, when indicated, results in decreased mortality. However, our knowledge of the outcomes and economic costs of intracranial GSW remains limited.

Methods

We conducted a retrospective analysis using the longitudinal claims Truven MarketScan®; database from 2000 to 2016. Mortality was the primary outcome of interest and complications, length of stay and payment were secondary outcomes. Multivariable logistic and linear regression was performed to assess the relationship between age, gender, insurance type and the number of comorbidities to the outcomes measured.

Results

We identified 418 patients (Median age = 26.0y, IQR= 18, 44; 23.4% female) who received craniotomy or craniectomy for intracranial GSW. Mortality occurred in 50 patients (11.96%) and 286 patients (68.42%) experienced complications. The median length of stay was 10 days (IQR=4; 22days) and cost was $62,574.00 (IQR=$28,111.00; $143,980.00). Increasing age by 1-year increments demonstrated increases in complications (OR=1.023; 95% CI=1.007 - 1.038), mortality (OR=1.023; 95% CI=1.002 - 1.044), length of stay (RR=1.01; 95% CI=1.003 - 1.017) and payment (RR=1.01; 95% CI= 1.002 - 1.017). When comparing Medicaid to commercial insurance, patients with Medicaid had a longer length of stay (RR=1.299; 95% CI=1.049 - 1.608) and less payment (RR=0.571; 95% CI=0.454 - 0.718). Finally, increases in the Elixhauser index by 1-comorbitiy increments was associated with increased complications (OR=1.233; 95% CI=1.024 - 1.485), length of stay (RR=1.292; 95% CI=1.188 - 1.405) and payment (RR=1.208; 95% CI=1.104 - 1.322).

Conclusion

Although these findings must be interpreted in the context of the limitations inherent to studies using national administrative data, the current study provides additional insight into the relationship between patient characteristics and outcomes after surgery for intracranial GSW.

Introduction

The pre-operative diagnosis of shunt failure typically depends on detecting a difference in ventricular caliber between the current cranial imaging and the most recent well-scan. Patients with hydrocephalus often present with concerns for shunt failure to their local emergency department, which may not have access to previous cranial imaging for comparison. Radiology reports typically describe ventricular caliber in qualitative terms. Thus, a comparison of ventricular caliber by telephone is usually unreliable. We sought to develop and validate a computer program to rigorously measure the 3D ventricular volume on MRI and CT scans to make objective comparisons possible.

Methods

A computer program was developed in Matlab to semi-automatically calculate the 3D volume of cerebrospinal fluid within the entire ventricular system on brain MRI and head CTs, within seconds. A combination of k-means clustering and nearest-neighbor techniques were used for the 3D segmentation. The algorithm was tested on 52 scans from 16 pediatric patients with shunted hydrocephalus. Shunt failure scans confirmed with subsequent shunt exploration were compared to the most recent well-scan. Well-scans were compared to the preceding well-scan for control.

Results

Mean ventricular volume change was +600% +/- 212% for failure-scans and -2.5% +/- 9% for well-scans (p < 0.01). A ventricular volume increase cut-off of 20% was 100% sensitive and 89% specific for shunt failure in this cohort.

Conclusion

A computer program was developed to rapidly calculate the volume of the ventricular system on both brain MRIs and head CTs. This method could be used to objectively detect shunt failure between institutions that are not able to share images. This benefit would apply only to patients whose ventricles enlarge during shunt failure. Prospective analysis of a large multi-center cohort will be necessary prior to implementation.

Introduction

As various studies show, damage to white matter pathways leads to permanent functional deficits in a high percentage of patients. Particularly the subcortical language network is complex, and its visualization has a tremendous relevance for neurosurgeons. This pilot study aims to correlate language-eloquent white matter pathways with the course of language function after the resection of left-sided perisylvian gliomas.

Methods

We included patients who underwent resection of highly language-eloquent high- and low-grade gliomas. We performed navigated repetitive transcranial magnetic stimulation (nrTMS)-based tractography via diffusion tensor imaging fiber trackings (DTI FT) preoperatively (PRE-1), postoperatively (POST-1), and at long-term follow-up or tumor recurrence (PRE-2). We separately tracked the inferior fronto-occipital fascicle (IFOF), the frontal aslant tract (FAT), and the superior longitudinal and arcuate fascicle (SLF/AF), and correlated the amount of visualized fibers to the patients’ language function at each date.

Results

The changes of nrTMS-based DTI FTs of single white matter pathways correlated with the according status of language function for any of the pathways in 80% of patients and in 19 of 30 single pathway comparisons between PRE-1 and POST-1. Between POST-1 and PRE-2 the nrTMS-based DTI FTs correlated with the status of language function for any of the pathways in all patients and in 24 of 30 single pathway comparisons. Single FT results correlated with the according status of language function at POST-1 in 60%, 70%, and 60% of cases, and with the according status of language function at PRE-2 in 60%, 90%, and 90% of cases for the tracking of the IFOF, FAT, and SLF/AF, respectively.

Conclusion

By the present results we were able to show that nrTMS-based DTI FT of the IFOF, FAT, and SLF/AF correlates with the according status of language function preoperatively, postoperatively, and at long-term follow-up after the resection of left-sided perisylvian gliomas.

Introduction

The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is utilized nationally to query patient perception of their healthcare across a broad array of domains, such as quality of care, communication, and overall hospital experience. Previous studies have established a correlation between demographic factors - such as race, ethnicity, gender, and socioeconomic status - and patient perception of the adequacy of their pain control. In this study, we examined the link between HCAHPS pain-domain responses and patient demographic variables in order to further characterize this relationship.

Methods

This study included 107,287 records for adult patients discharged from a tertiary university-affiliated hospital between October 2015 and June 2017. Patient responses to HCAHPS pain management questions were collected. Of all records reviewed, 13,026 included responses to at least one HCAHPS pain management question. Systematic statistical analysis was then performed in order to evaluate potential interactions between demographic variables and HCAHPS response rates and types.

Results

Hispanic and Black or African American respondents were more likely to report successful pain control when compared to Not Hispanic and Caucasian/White patients, respectively (ORs 1.60, 1.22). Additionally, among female patients, Black or African American respondents were more likely to have reported positive Staff Helpfulness than Caucasian/White respondents (OR 1.38). Notably, Hispanic and Black/African American patients were each less likely to respond to the HCAHPS pain-domain questions (OR 2.03, 2.74) than other respondents.

Conclusion

Several demographic variables, including race/ethnicity and gender, appear to affect both the rate and type of response to HCAHPS questions centered around adequacy of pain control. Based on the above results, Hispanic and Black/African American patients may underreport negative experiences. Further investigation into this complex relationship is warranted, as demographic biases in HCAHPS responses could potentially undermine the utility of this data to inform healthcare decision-making and practice.

Introduction

The Hydrogel Embolic System (HES) coil (Microvention, Aliso Viejo, CA), which is a hydrogel coated platinum coil, was designed to improve packing density and long-term obliteration rates of intracranial aneurysms. The first-generation HES demonstrated lower recurrence rates than bare platinum coils (BPC); however, its use was limited by technical difficulties. A second-generation HES was designed to withstand longer working times and reproduce the ease of use of BPC. The New Generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT) compares the second-generation HES with BPC in 600 subjects, over a period of 2 years.

Methods

HEAT is a multicenter randomized controlled clinical trial that enrolled subjects 18-75 years of age with 3-14 mm ruptured or unruptured brain aneurysms eligible for endovascular treatment. Randomization occurred in a 1:1 fashion across 46 sites in the US and Canada. Subjects assigned to the Hydrogel arm received 90% second-generation HES, at least. The primary outcome of the study was aneurysm recanalization. Secondary outcomes were initial occlusion, packing density, hemorrhage, retreatment, mortality, and aneurysm recanalization assessed by other scales.

Results

Enrollment began in 2012 and ended in 2016. 86.2% of the 600 enrolled subjects had at least one follow-up angiogram or MRA evaluation. Recanalization rates were 4.4% for HES and 15.4% for BPC (p<0.001). In terms of secondary outcomes, there were no differences in adverse events (p=0.498) mortality (p=0.641), retreatment (p=0.162), and rehemorrhage rates (p=0.297) between both arms.

Conclusion

In the HEAT trial, the second-generation Hydrogel Coil was found to be superior to the bare platinum coil in reducing aneurysm recurrence rates. Adverse events and Clinical outcomes were similar between both arms of the study. The findings of this trial suggest that second-generation hydrogel coils are associated with greater durability of treatment when compared to bare platinum coils without any increase in morbidity.

William H. Sweet Young Investigator Award

Alexander B. Dru, MD (Gainesville, FL); Lauren Dewberry, BS; Kevin Otto, PhD; Kyle Allen, PhD; Daniel Hoh, MD

Introduction

Literature evaluating procedural reimbursements and national financial trends in modern neurosurgery is lacking. A comprehensive understanding of neurosurgical economic trends and financial health is important to ensure the sustained success of the specialty moving forward. This study evaluated monetary trends in Medicare reimbursement rates from 2000 to 2018 for the 10 most common spinal and cranial neurosurgical procedures.

Methods

The Physician Fee Schedule Look-Up Tool from the Centers for Medicare & Medicaid Services was queried for the top 10 most utilized CPT codes in spinal and cranial neurosurgery. Comprehensive reimbursement data was extracted. The raw percent change in Medicare reimbursement rate from 2000 to 2018 was calculated for each procedure and averaged. This was compared to the percent change in the consumer price index over the same time. Data was adjusted for inflation and trend analysis performed. The average annual and the total percentage change in reimbursement were calculated based on these adjusted trends, and the compound annual growth rate was calculated for each procedure.

Results

From 2000 to 2018, the average reimbursement for all procedures decreased by an average of 25.80%. The adjusted reimbursement rate for all procedures decreased by an average of 1.59% each year and experienced an average compound annual growth rate of -1.66%, indicating a steady annual decline in reimbursement when adjusted for inflation.

Conclusion

This is the first study to evaluate comprehensive trends in Medicare reimbursement in neurosurgery. When adjusted for inflation, Medicare reimbursement for all included procedures has steadily decreased from 2000 to 2018, with similar rates of decline observed between cranial and spinal neurosurgery procedures. Increased awareness and consideration of these trends will be important moving forward as continued progress is made to advance agreeable reimbursement models that allow for the sustained future growth of neurosurgery in the United States.

Introduction

Cervical spondylotic myelopathy (CSM) is the leading cause of spinal cord dysfunction. Surgical decompression is effective. Nonetheless, many patients suffer from significant residual disability. Based on preclinical evidence, we hypothesized that the sodium/glutamate blocking drug, riluzole, may enhance clinical outcomes following surgical decompression for CSM.

Methods

In this multi-center, double-blinded, placebo-controlled randomized trial (ClinicalTrials.gov NCT01257828), adults (18-80 years) with moderately-severe CSM (mJOA 8-14) were assigned to surgical decompression plus riluzole (50 mg PO BID for 14 days before surgery and 28 days after surgery) or surgical decompression plus placebo. The primary outcome was change in mJOA score from baseline to 6 months post-operatively. Secondary outcomes included measures of function (Nurick grade), disability (NDI), QOL (SF-36, EQ-5D), neurological function (ASIA scores), grip strength, and pain (VAS). Outcomes were evaluated at enrollment, pre-operative hospital admission, 35 days, 6 months, and 1 year.

Results

Two-hundred and ninety patients were enrolled (n=141 riluzole; n=149 placebo). Mean age was 58.0 ± 10.1 years. Subjects in both trial arms improved in all endpoints for functional status, disability, QOL, neurological function, grip strength, and pain. There was no difference between riluzole and placebo groups in change in mJOA at 6 months (2.45 vs. 2.82, respectively; P=0.16) or 1 year. Patients treated with riluzole showed a significantly greater reduction in pain (VAS) at 35 days than those who received placebo; this effect was maintained at 6 months and 1 year (P<0.05). There was a strong trend toward superior recovery in ASIA motor score with riluzole versus placebo at 1 year (P=0.053).

Conclusion

Adjuvant treatment for 6 weeks peri-operatively with riluzole in the setting of CSM does not enhance functional recovery beyond surgical decompression, which dominates the clinical picture. However, the effects of riluzole in reducing pain in CSM patients are of clinical interest and merit further study.

Truong Do, MD (Minneapolis, MN); Michael Olin, PhD; Elisabet Ampudia-Mesias, MSc; Christopher Pennell, PhD; Zhengming Xiong; Susan Rathe, PhD; David Largaespada, PhD; Aaron Sarver, PhD; Christopher Moertel, MD; G. Elizabeth Pluhar, DVM, PhD; Clark Chen, MD, PhD

American Brain Tumor Association Young Investigator Award

Rupa Juthani, MD (New York, NY); Brian Madajewski, PhD; Li Zhang, MD; Yoo Barney, PhD; Pei-Ming Chen, PhD; Feng Chen, PhD; Kai Ma, PhD; Michael Overholtzer, PhD; Jason Huse, MD, PhD; Ulrich Weisner, PhD; Michelle Bradbury, MD, PhD; Cameron Brennan, MD

Ronald L. Bittner Award on Brain Tumor Research

Chibawanye Ene, MD, PhD (Seattle, WA); Shannon Kreuser; Miyeon Jung; Ian Parney; Courtney Crane; Eric Holland

Rosenblum-Mahaley Clinical Research Award

Peter Nakaji, MD, FAANS (Phoenix, AZ); Emad Youssef, MD; Christopher Dardis, MD; Kris Smith, MD; Dilini Pinnaduwage, PhD; David Brachman, MD

Maryam Rahman, MD, FAANS (Gainesville, FL); Aida Karachi, DVM; Changlin Yang, MD, PhD; Farhad Dastmalchi, DVM; Elias Sayour, MD, PhD; Jianping Huang, MD, PhD; Duane Mitchell, MD, PhD

Introduction

Microglia the resident immune cells of the brain, rapidly change state in response to their environment. Through development they conform to a number of phenotypes that support homeostasis however, in animal models these are lost with ageing and these cells ultimately support immune function in adults. The study of live human tissue is limited. Here in we present the most comprehensive analysis of human microglia at the single cell level.

Methods

We analysed the RNA expression profiles of over 10,000 individual microglia from 124 patients between 18-87 years of age. Samples were obtained from normal cortex, removed from the surgical tract during a surgical procedure where clinically indicated. Expression quantitative trait locus (QTL) mapping was performed to identify common genetic variants that alter gene expression in primary human microglia and compared available genome wide association studies (GWAS) of neurodegenerative disorders to identify if common variants in microglia were driving neurological disease.

Results

We uncovered seven transcriptionally distinct microglia substates, and characterised how these expression profiles changed with age and with patient type. We found 33 eQTLs that strongly colocalised known neurological disease risk loci.

Conclusion

Our novel and extensive analysis of human microglia has demonstrated for the first time, unique microglia signatures that can be used to better understand microglia function and provides the opportunity to manipulate specific subpopulations in health and disease.

Introduction

Methyl-Guanine Methyl Transferase (MGMT) promoter unmethylated glioblastomas are intrinsically refractory to concurrent radiation-temozolomide(TMZ) treatment and remain a therapeutic challenge in neuro-oncology. Here we show that miR-603 regulate radiation and TMZ resistance by simultaneously down regulating MGMT expression and suppressing the stem cell state through inhibition of IGF signaling.

Methods

Analysis of clinical glioblastoma specimens, in vitro and in vivo glioblastoma models, immuno-florescent and Western-blot analysis

Results

Orthogonal profiling of miR-603 targets revealed genes which are key components of the Insulin-like Growth Factor (IGF) signaling (IGF1, IGF1R, and IGFBP5), a pathway critical for maintaining the stem-cell state and radiation resistance in glioblastoma as well as MGMT. miR-603 mimic transfection into glioblastoma cells suppressed the expression of the IGF genes as well as MGMT, while miR-603 inhibitor transfection displayed opposite effects. miRNA affinity pull-down and luciferase reporter assay confirmed miR-603 binding to 3’ UTR of IGF1, IGF1R, IGFBP5 and MGMT mRNA.Phenotypically, miR-603 suppressed glioblastoma expression of stem-cell markers (SOX2, Musashi, and Nestin), tumorigenicity, as well as radiation resistance. These effects were abolished by exogenous expression or addition of IGF1, suggesting the existence of a miR-603-IGF1 axis that regulate glioblastoma radiation resistance through modulating the transition between stem-cell and non-stem-cell state. In clinical glioblastoma specimens, low expression of miR-603 was associated with poor 6-months progression free survival in patients with MGMT promoter unmethylated glioblastomas. miR-603 injection suppressed MGMT expression and the stem-cell state in mice bearing MGMT promoter unmethylated glioblastomas. Impressively, combination of miR-603 and temozolomide led to cures in <90% of mice bearing MGMT promoter unmethylated glioblastomas.

Conclusion

Our results suggest miR-603 suppresses DNA repair and stem-cell state and plays key roles in glioblastoma therapeutic resistance. As such, miR-603 in combination with temozolomide is a promising therapy for MGMT promoter unmethylated glioblastomas.

Introduction

Therapeutic resistance stemming from the presence of multiple cellular genotypes, phenotypes and epigenetic states within the same tumor is a significant impediment towards development of effective therapeutics for Glioblastoma (GBM). MicroRNAs simultaneously modulate the expression of multiple proteins, potentially counteracting resistance emanating from such intra-tumoral heterogeneity. Our in-silico analysis identified microRNA-34a as a unique microRNA which modulates multiple oncoproteins in GBM.

Methods

Therapeutic effects of microRNA-34a were studied in three primary patient-derived lines (GBM 6, GBM118 and GBM 126, respectively belonging to classical, mesenchymal and proneural subtypes), four established cell lines (T98G, U251, A172, LN229) and two cell lines with acquired resistance to temozolomide (A172-TR, LN229-TR) in vitro. An orthotopic nude mouse model was used for in vivo studies. Nanocells (400 nm diameter) were derived from genetically modified bacteria, provided with a bispecific antibody targeting EGFR and loaded with microRNA-34a. Nanocells were injected intravenously while temozolomide was administered by oral gavage. Treatment response was quantified by measuring tumor growth (qBLI) and animal survival.

Results

GBM cell lines showed variable responses to temozolomide but microRNA 34a inhibited proliferation in all cell lines. Furthermore, microRNA 34a also sensitized multiple tested cell lines to temozolomide (combination index < 0.6, p=.03) and radiation treatment (dose enhancement factor 1.7-2.2, p=0.02). PCR arrays confirmed downregulation of multiple therapeutic resistance proteins (shared and unique to different cell lines), and we further validated the direct downregulation of cMET and Bcl-2 protein as a major contributor to therapeutic sensitization. Importantly, we successfully delivered microRNA-34a to orthotopic implanted tumors after systemic intravenous administration and observed significant reduction in tumor growth (p=0.021), increased survival (p<0.001) with microRNA-34a monotherapy and synergy in combination with temozolomide.

Conclusion

microRNA-34a nanocell therapy has shown promising preclinical data and we are developing this technology for phase I clinical trials for GBM patients.

Introduction

Brain metastasis represents a growing clinical problem. The number of cases of brain metastasis reaching medical attention has nearly doubled over a span of roughly twenty years, with a current estimated cumulative incidence of 10-15% of cancer patients. Recent development of techniques to isolate and study circulating tumor cells (CTCs) provides an unprecedented opportunity to study cancer cells in the act of metastasis.

Methods

Using the CTC iChip, a technology that combines microfluidics, magnetophoresis, and inertial focusing, we isolated circulating tumor cells from the blood of seven patients with widely metastatic breast cancer. These circulating tumor cells were cultured and then engineered to overexpress firefly luciferase and green fluorescent protein. Subsequently, the cells were stereotactically injected into the right frontal lobe of immunocompromised mice.

Results

CTC lines from all seven patients formed brain tumors after stereotactic injection. Samples from 2/7 patients formed rapidly growing brain tumors that killed 100% of injected mice within 6 weeks. Samples from 2/7 patients form tumors that grew at an intermediate rate, and the remainder formed slowly growing tumors. In all cases, CTC lines formed parenchymal tumors histologically similar to human brain metastases. Samples derived from patients who themselves suffered from brain metastases grew more rapidly after injection into mouse brain. RNA seq was performed and strong growing CTC lines were compared to weak growing CTC lines. LDHB emerged as a gene whose transcription was highly upregulated in strong growing CTC lines. In another experiment, CTCs were isolated directly from widely metastatic breast cancer patients with and without brain metastases. RNA seq was performed directly after CTC isolation. NXPHI and IMMP2L emerged as genes whose upregulation is associated with brain metastasis.

Conclusion

Analysis of circulating tumor cells reveal LDHB, NXPHI, and IMMP2L as genes associated with brain metastasis.

Introduction

There remains a large discrepancy in vestibular schwannoma (VS) growth expectations among surgeons. These expectations impact clinical decisions, especially concerning intervening or observing. Previous studies of VS natural growth remain limited, mostly confined to linear measurements, often without high resolution, thin-sequence imaging. This study comprehensively assessed tumor growth rates using volumetric measurements.

Methods

212 treatment-naïve patients diagnosed with unilateral VS between 2012 and 2018 were evaluated. A total of 699 MRIs were assessed, with a range of 2 to 11 MRIs per patient. All MRIs preceded any intervention, with patients subsequently being observed through completion of data analysis (36%) or treated with stereotactic radiosurgery (32%) or microsurgical resection (32%). Tumor volume was measured by summing the products of tumor area outlined by hand in each slice and slice thickness (99% of scans were 1-mm slice thickness or less). A multilevel model was used to assess mean volume change over time. Each tumor was categorized as growing (growth rate >20% per year), fast growing (>100% per year), stable (between -20% and 20% per year), and shrinking (< -20% per year).

Results

The mean VS volumetric growth rate was 33.5% per year (95% CI 26.9% - 40.5%, p<0.001). When assessing the frequencies of individual tumor annual growth rates, 66% demonstrated growth (with 30% fast growing), 33% were stable, and 1% exhibited shrinking. Larger tumors were associated with increased absolute growth, but there was no relationship between tumor size and proportional growth rate.

Conclusion

This study comprehensively assessed VS volumetric growth rates using high-resolution imaging. About one third of the VSs studied remained stable while two thirds exhibited growth (with one third demonstrating a growth rate of more than 100% per year). These findings may inform clinical decisions and contribute to a consensus understanding of tumor behavior.

Introduction

Bevacizumab treatment of glioblastoma is limited by transient responses and acquired invasive resistance. We identified biomarkers of therapeutic window closure and upstream regulators whose targeting could prolong the treatment window.

Methods

Using microarrays, we transcriptionally profiled paired patient specimens before and after bevacizumab-resistance and two xenograft models of bevacizumab-resistance. Invasion was assessed using bioengineered 3D models of perivascular and parenchymal tumor invasion. Stem cell enrichment was analyzed by functional stem cell assays. Seahorse extracellular flux analyzer assays were performed for metabolic studies. CRISPR/Cas9 and honokiol, a natural phenolic compound, were used to target ZEB1 in bevacizumab-resistant cells.