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Gene therapy has the potential to provide therapeutic benefit to millions of people with neurodegenerative diseases through several means, including direct correction of pathogenic mechanisms, neuroprotection, neurorestoration, and symptom control. Therapeutic efficacy is therefore dependent on knowledge of the disease pathogenesis and the required temporal and spatial specificity of gene expression. An additional critical challenge is achieving the most complete transduction of the target structure while avoiding leakage into neighboring regions or perivascular spaces. The gene therapy field has recently entered a new technological era, in which interventional MRI-guided convection-enhanced delivery (iMRI-CED) is the gold standard for verifying accurate vector delivery in real time. The availability of this advanced neurosurgical technique may accelerate the translation of the promising preclinical therapeutics under development for neurodegenerative disorders, including Parkinson's, Huntington's, and Alzheimer's diseases.

Purpose Surgery is the treatment of choice for large vestibular schwannomas (VS). Stereotactic radiosurgery (SRS) has been suggested as an alternative to resection in selected patients. However, the safety and efficacy of SRS in Koos grade IV patients ≤ 45 years old has not been evaluated. The aim of this study is to describe the clinical and radiological outcomes of Koos grade IV in young patient managed with a single-session SRS. Methods This retrospective, multicenter analysis included SRS-treated patients, ≤ 45 years old presenting with non-life threatening or incapacitating symptoms due to a Koos Grade IV VS and with follow-up ≥ 12 months. Tumor control and neurological outcomes were evaluated. Results 176 patients [median age of 36.0 (IQR 9) and median tumor volume of 9.3 cm 3 (IQR 4.7)] were included. The median prescription dose was 12 Gy (IQR 0.5). Median follow-up period was 37.5 (IQR 53.5) months. The 5- and 10-year progression-free survival was 90.9% and 86.7%. Early tumor enlargement occurred in 10.9% of cases and was associated with tumor progression at the last follow-up. The probability of serviceable hearing preservation at 5- and 10-years was 56.8% and 45.2%, respectively. The probability of improvement or preservation of facial nerve function was 95.7% at 5 and 10-years. Adverse radiation effects were noted in 19.9%. New-onset hydrocephalus occurred in 4.0%. Conclusion Single-session SRS is a safe and effective alternative to surgical resection in selected patients ≤ 45 years old particularly those with medical co-morbidities and those who decline resection. Longer term follow up is warranted.

BackgroundThere is a concern that glioma patients undergoing repeat craniotomies are more prone to complications. The study’s goal was to assess if the complication profiles for initial and repeat craniotomies were similar, to determine predictors of complications, and to compare results with those in the literature.MethodsA retrospective study was conducted of glioma patients (WHO grade II–IV) who underwent either an initial or repeat craniotomy performed by the senior author from 2012 until 2019. Complications were recorded by discharge, 30 days, and 90 days postoperatively. New neurologic deficits were recorded by 90 days postoperatively. Multivariate regression was performed to identify factors associated with complications. A meta-analysis was performed to identify rates of complications based on number of prior craniotomies.ResultsWithin the cohort of 714 patients, 400 (56%) had no prior craniotomies, 218 (30.5%) had undergone 1 prior craniotomy, and 96 (13.5%) had undergone ≥ 2 prior craniotomies. There were 27 surgical and 10 medical complications in 30 patients (4.2%) and 19 reoperations for complications in 19 patients (2.7%) with no deaths by 90 days. Complications, reoperation rates, and new neurologic deficits did not differ based on number of prior craniotomies. On multivariate analysis, older age (OR1.5, 95%CI 1.0–2.2) and significant leukocytosis due to steroid use (OR12.6, 95%CI 2.5–62.9) were predictors of complications. Complication rates in the cohort were lower than rates reported in the literature.ConclusionContrary to prior reports in the literature, repeat craniotomies can be as safe as initial operations if surgeons implement best practices.

Here we evaluated the utility of MRI to monitor intrathecal infusions in nonhuman primates. Adeno-associated virus (AAV) spiked with gadoteridol, a gadolinium-based MRI contrast agent, enabled real-time visualization of infusions delivered either via cerebromedullary cistern, lumbar, cerebromedullary and lumbar, or intracerebroventricular infusion. The kinetics of vector clearance from the cerebrospinal fluid (CSF) were analyzed. Our results highlight the value of MRI in optimizing the delivery of infusate into CSF. In particular, MRI revealed differential patterns of infusate distribution depending on the route of delivery. Gadoteridol coverage analysis showed that cerebellomedullary cistern delivery was a reliable and effective route of injection, achieving broad infusate distribution in the brain and spinal cord, and was even greater when combined with lumbar injection. In contrast, intracerebroventricular injection resulted in strong cortical coverage but little spinal distribution. Lumbar injection alone led to the distribution of MRI contrast agent mainly in the spinal cord with little cortical coverage, but this delivery route was unreliable. Similarly, vector clearance analysis showed differences between different routes of delivery. Overall, our data support the value of monitoring CSF injections to dissect different patterns of gadoteridol distribution based on the route of intrathecal administration.

Treatment of a large, symptomatic skull metastasis requires surgical excision and in many cases postoperative radiation therapy. Immediate reconstruction of the skull for cerebral protection usually involves cranioplasty with titanium mesh and/or methyl methacrylate. Preoperative synthetic cranioplasty technology is yet to evolve sufficiently to allow computer-generated prostheses to precisely fit a defined craniectomy defect created at the time of tumor removal. We document the techniques used for simultaneous craniectomy and composite cranioplasty in the setting of a large occipital renal cell skull metastasis. Preoperative computed tomography (CT) and magnetic resonance (MR) imaging identified the pathological anatomy of an occipital skull metastasis presenting as an exophytic scalp mass. Preoperative angiography and embolization was performed followed by craniectomy in the semi-sitting position and composite cranioplasty using titanium mesh and methyl methacrylate. A series of steps in the surgical procedure are outlined to assist with safely and accurately performing the craniectomy and cranioplasty to guarantee the best surgical and cosmetic outcome. Postoperative CT imaging confirmed excellent contours of the cranioplasty. The method described herein allows for a single-step surgical procedure to excise a large skull metastasis and create a structurally sound and cosmetically acceptable composite cranioplasty. This method can also be used for the excision and repair of other skull tumors or anomalies requiring excision.

Huntington's disease (HD) is caused by a toxic gain-of-function associated with the expression of the mutant huntingtin (htt) protein. Therefore, the use of RNA interference to inhibit Htt expression could represent a disease-modifying therapy. The potential of two recombinant adeno-associated viral vectors (AAV), AAV1 and AAV2, to transduce the cortico-striatal tissues that are predominantly affected in HD was explored. Green fluorescent protein was used as a reporter in each vector to show that both serotypes were broadly distributed in medium spiny neurons in the striatum and cortico-striatal neurons after infusion into the putamen and caudate nucleus of nonhuman primates (NHP), with AAV1-directed expression being slightly more robust than AAV2-driven expression. This study suggests that both serotypes are capable of targeting neurons that degenerate in HD, and it sets the stage for the advanced preclinical evaluation of an RNAi-based therapy for this disease.

INTRODUCTION Metastasis of melanoma to the brain is associated with poor outcomes. Recent trials demonstrate improved survival after treatment with immune checkpoint inhibitors. METHODS This retrospective, single-center study included patients undergoing first-time surgery for melanoma brain metastases. A multivariate Cox proportional model was used to estimate the association of patient and treatment factors with OS and CNS progression. Kaplan-Meier curves were used to plot survival and progression time observations. RESULTS 85 patients (mean age 60) underwent first-time resection of 97 melanoma brain metastases with a median follow-up of 9.5 months. Checkpoint inhibitors (Pembrolizumab, Ipilimumab, and/or Nivolumab) were used in 55.1% of cases (19 pre-op; 47 post-op; median 9 cycles). Patients treated with checkpoint inhibitors had similar peri-op systemic disease status and KPS but had been treated with more systemic agents and had more instances of CNS progression prior to surgery. Median OS and time to CNS progression for the cohort were 1 year and 237 days, respectively. In a multivariate Cox regression model, age (HR 1.03 by decade; P = .02), treatment with a checkpoint inhibitor (HR 0.27; P < .0001), prior radiotherapy (HR 2.44; P = .007), and number of brain metastases at the time of surgery (HR 1.05 per metastasis; P = .04) were significant predictors of OS. Checkpoint inhibitor treatment was associated with longer OS from surgery (median 3 vs 0.5 yrs, log-rank P = .004). However, patients who underwent craniotomy after prior checkpoint inhibitor treatment had poor OS (median 0.56 yrs). Prior radiotherapy was associated with poor OS (median 0.53 yrs). A threshold of 10 brain metastases differentiated OS in the subgroup of checkpoint inhibitor treated patients (P = .03). Although extent of resection predicted OS in the entire cohort (P = .02), it did not impact OS in the subgroup of checkpoint inhibitor treated patients (p = 0.57). CONCLUSION While checkpoint inhibitor treatment was associated with improved survival in this surgical cohort of melanoma brain metastases, patients who require resection after checkpoint inhibitor treatment or radiotherapy are poor surgical candidates.

Background Surgery is the preferred treatment for large vestibular schwannomas (VS). Good tumor control and cranial nerve outcomes were described in selected Koos IV VS after single-session stereotactic radiosurgery (SRS), but outcomes in elderly patients have never been specifically studied. The aim of this study is to report clinical and radiological outcomes after single-session SRS for Koos IV VS in patients ≥ 65 years old. Method This multicenter, retrospective study included patients ≥ 65 years old, treated with primary, single-session SRS for a Koos IV VS, and at least 12 months of follow-up. Patients with life-threatening or incapacitating symptoms were excluded. Tumor control rate, hearing, trigeminal, and facial nerve function were studied at last follow-up. Results One-hundred and fifty patients (median age of 71.0 (IQR 9.0) years old with a median tumor volume of 8.3 cc (IQR 4.4)) were included. The median prescription dose was 12.0 Gy (IQR 1.4). The local tumor control rate was 96.0% and 86.2% at 5 and 10 years, respectively. Early tumor expansion occurred in 6.7% and was symptomatic in 40% of cases. A serviceable hearing was present in 16.1% prior to SRS and in 7.4% at a last follow-up of 46.5 months (IQR 55.8). The actuarial serviceable hearing preservation rate was 69.3% and 50.9% at 5 and 10 years, respectively. Facial nerve function preservation or improvement rates at 5 and 10 years were 98.7% and 91.0%, respectively. At last follow-up, the trigeminal nerve function was improved in 14.0%, stable in 80.7%, and worsened in 5.3% of the patients. ARE were noted in 12.7%. New hydrocephalus was seen in 8.0% of patients. Conclusion SRS can be a safe alternative to surgery for selected Koos IV VS in patients ≥ 65 years old. Further follow-up is warranted.

The protection of crops from pests eventually contributes to increase crop yields. In this study, we build a mathematical model for prey–predator and describe an ecosystem that includes crops, susceptible pests, infected pests, and natural enemies of the pest. Further, the dynamic behavior of the framework, the description of steady-state equilibrium behavior, and pest control are discussed. The basic reproduction number and sensitivity analysis are addressed to determine the most influential parameters. Furthermore, a comprehensive analysis of the optimal control strategy is performed. The study discusses the strategic planning of pests, which provides optimal control of pests in contexts of operating costs and ecological harm. Pontryagin’s maximum principle is used to develop an optimal strategy for pest control. Finally, numerical simulations are carried out to support the analytical results and explain the various dynamic systems that are used in the model.

This paper addresses the use of a customer character model as a determinant of used auto loan churn among a unique population of subprime borrowers. The customer character model (i.e restricted model) is compared to a full model consisting of the 4 Cs of capacity, collateral, credit, and character of churn prediction. The results reveal that there is a difference between the full model and the customer character model. Additionally, different supervised classification methods, such as logistic regression (LR), linear discriminant analysis (LDA), decision trees (DTs), and random forests (RFs), are applied and compared in terms of multiple predictive performance measures. The RF classification measures report the strongest performance. Additionally, different classification methods suggest the importance of different customer character variables. Therefore, from a practical perspective, effective borrower character screening is recommended to determine customer profiles more accurately for the purposes of target marketing and customer retention. This study also deepens understanding of subprime credit markets and reveals additional insights to credit screening using machine learning techniques.