A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results: We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion: This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

Neuroimaging in Disorders of Consciousness and Recovery.

There is a clinical need for more accurate diagnosis and prognostication in patients with disorders of consciousness (DoC). There are several neuroimaging modalities that enable detailed, quantitative assessment of structural and functional brain injury, with demonstrated diagnostic and prognostic value. Additionally, longitudinal neuroimaging studies have hinted at quantifiable structural and functional neuroimaging biomarkers of recovery, with potential implications for the management of DoC.

Redirecting the specificity of tripartite motif containing-21 scaffolds using a novel discovery and design approach.

Hijacking the ubiquitin proteasome system to elicit targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to target and destroy intracellular proteins at the post-translational level. Small molecule-based TPD approaches, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, have shown potential, with several agents currently in clinical trials. Biological PROTACs (bioPROTACs), which are engineered fusion proteins comprised of a target-binding domain and an E3 ubiquitin ligase, have emerged as a complementary approach for TPD. Here, we describe a new method for the evolution and design of bioPROTACs. Specifically, engineered binding scaffolds based on the third fibronectin type III domain of human tenascin-C (Tn3) were installed into the E3 ligase tripartite motif containing-21 (TRIM21) to redirect its degradation specificity. This was achieved via selection of naïve yeast-displayed Tn3 libraries against two different oncogenic proteins associated with B-cell lymphomas, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and embryonic ectoderm development protein (EED), and replacing the native substrate-binding domain of TRIM21 with our evolved Tn3 domains. The resulting TRIM21-Tn3 fusion proteins retained the binding properties of the Tn3 as well as the E3 ligase activity of TRIM21. Moreover, we demonstrated that TRIM21-Tn3 fusion proteins efficiently degraded their respective target proteins through the ubiquitin proteasome system in cellular models. We explored the effects of binding domain avidity and E3 ligase utilization to gain insight into the requirements for effective bioPROTAC design. Overall, this study presents a versatile engineering approach that could be used to design and engineer TRIM21-based bioPROTACs against therapeutic targets.

Frailty in older people: Rehabilitation Treatment Research Examining Separate Settings (FORTRESS): protocol for a hybrid type II stepped wedge, cluster, randomised trial.

BACKGROUND: Frailty in older people is associated with increased risk of falls, longer length of stay in hospital, increased risk of institutionalisation and death. Frailty can be measured using validated tools. Multi-component frailty interventions are recommended in clinical practice guidelines but are not routinely implemented in clinical practice. METHODS: The Frailty in Older people: Rehabilitation, Treatment, Research Examining Separate Settings (FORTRESS) trial is a multisite, hybrid type II, stepped wedge, cluster, randomised trial with blinded assessment and intention-to-treat analysis being conducted in Australia. The study aims to determine the effectiveness and cost-effectiveness of an embedded individualised multicomponent frailty intervention (commencing in hospital and continuing in the community) on readmissions, frailty and quality of life when compared with usual care. Frail older people admitted to study wards with no significant cognitive impairment, who are expected to return home after discharge, will be eligible to participate. Participants will receive extra sessions of physiotherapy, pharmacy, and dietetics during their admission. A Community Implementation Facilitator will coordinate implementation of the frailty management strategies and primary network liaison. The primary outcome is number of days of non-elective hospital readmissions during 12 month follow-up period. Secondary outcomes include frailty status measured using the FRAIL scale; quality of life measured using the EQ-5D-5L; and time-to-event for readmission and readmission rates. The total cost of delivering the intervention will be assessed, and cost-effectiveness analyses will be conducted. Economic evaluation will include analyses for health outcomes measured in terms of the main clinical outcomes. Implementation outcomes will be collected as part of a process evaluation. Recruitment commenced in 2020 and we are aiming to recruit 732 participants over the three-year duration of the study. DISCUSSION: This study will reveal whether intervening with frail older people to address factors contributing to frailty can reduce hospital readmissions and improve frailty status and quality of life. If the FORTRESS intervention provides a clinically significant and cost-effective result, it will demonstrate an improved approach to treating frail patients, both in hospital and when they return home. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000760976p . ANZCTR registered 24 July 2020.

Methamphetamine augments HIV-1 gp120 inhibition of synaptic transmission and plasticity in rat hippocampal slices: Implications for methamphetamine exacerbation of HIV-associated neurocognitive disorders.

Methamphetamine (Meth) abuse and human immunodeficiency virus type 1 (HIV-1) infection are two major public health problems worldwide. Being frequently comorbid with HIV-1 infection, Meth abuse exacerbates neurocognitive impairment in HIV-1-infected individuals even in the era of combined antiretroviral therapy. While a large body of research have studied the individual effects of Meth and HIV-1 envelope glycoprotein 120 (gp120) in the brain, far less has focused on their synergistic influence. Moreover, it is well-documented that the hippocampus is the primary site of spatial learning and long-term memory formation. Dysregulation of activity-dependent synaptic transmission and plasticity in the hippocampus is believed to impair neurocognitive function. To uncover the underlying mechanisms for increased incidence and severity of HIV-1-associated neurocognitive disorders (HAND) in HIV-1-infected patients with Meth abuse, we investigated acute individual and combined effects of Meth (20 µM) and gp120 (200 pM) on synaptic transmission and plasticity in the CA1 region of young adult male rat hippocampus, a brain region known to be vulnerable to HIV-1 infection. Our results showed that acute localized application of Meth and gp120 each alone onto the CA1 region reduced short-term dynamics of input-output responses and frequency facilitation, and attenuated long-term potentiation (LTP) induced by either high frequency stimulation or theta burst stimulation. A synergistic augmentation on activity-dependent synaptic plasticity was observed when Meth and gp120 were applied in combination. Paired-pulse facilitation results exhibited an altered facilitation ratio, suggesting a presynaptic site of action. Further studies revealed an involvement of microglia NLRP3 inflammasome activation in Meth augmentation of gp120-mediated attenuation of LTP. Taken together, our results demonstrated Meth augmented gp120 attenuation of LTP in the hippocampus. Since LTP is the accepted experimental analog of learning at the synaptic level, such augmentation may underlie Meth exacerbation of HAND observed clinically.

Laser interstitial thermal therapy (LITT) for intracranial lesions: a single-institutional series, outcomes, and review of the literature.

INTRODUCTION: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment method in managing primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address. Although the use of lasers is not a new concept in neurosurgery, advances in technology have enabled surgeons to perform laser treatment with the aid of real-time MRI thermography as a guide. In this report, we present our institutional series and outcomes of patients treated with LITT. METHODS: We retrospectively evaluated 19 patients (age range, 28-77 years) who underwent LITT at one or more targets from 2015 to 2019. Primary endpoint observed was mean progression free survival (PFS) and overall survival (OS). RESULTS: Seven patients with glial neoplasms and 12 patients with metastatic disease were reviewed. Average hospitalization was 2.4 days. Median PFS was 7 and 4 months in the metastatic group and primary glial neoplasm group, respectively (p = 0.01). Median OS from time of diagnosis was 41 and 32 months (p = 0.02) and median OS after LITT therapy was 25 and 24 months (p = 0.02) for the metastatic and primary glial neoplasm groups, respectively. One patient experienced immediate post-procedural morbidity secondary to increased intracerebral edema peri-lesionally while one patient experienced post-operative mortality and expired secondary to hemorrhage 1-month post-procedure. Median follow-up was 10 months. CONCLUSION: Laser interstitial thermal therapy (LITT) is a safe, minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions. Both PFS and OS appear to be more favorable after LITT in patients with metastatic disease. In properly selected patients, this modality offers improved survival outcomes in conjunction with other salvage therapies.

Arterial Spin Labeling Reveals Elevated Cerebral Blood Flow with Distinct Clusters of Hypo- and Hyperperfusion after Traumatic Brain Injury.

Imaging detection of brain perfusion alterations after traumatic brain injury (TBI) may provide prognostic insights. In this study, we used arterial spin labeling (ASL) to quantify cross-sectional and longitudinal changes in cerebral blood flow (CBF) after TBI and correlated changes with clinical outcome. We analyzed magnetic resonance imaging scans from adult participants with TBI requiring hospitalization in the acute (2 weeks post-injury, n = 33) and chronic (6 months post-injury, n = 16) phases, with 13 participants scanned longitudinally at both time points. We also analyzed 18 age- and sex-matched healthy controls. Whole-brain CBF maps were derived using a three-dimensional pseudo-continuous arterial spin label technique. Mean CBF across tissue-based regions (whole brain, gray matter, and white matter) was compared cross-sectionally and longitudinally. In addition, individual-level clusters of abnormal perfusion were identified using voxel-based z-score analysis of relative CBF maps, and number and volume of abnormally hypo- and hyperperfused clusters were assessed cross-sectionally and longitudinally. Finally, all CBF measures were correlated with clinical outcome measures. Mean global and gray matter CBF were significantly elevated in acute and chronic TBI participants compared to controls. Participants with better outcome at 6 months post-injury tended to have higher CBF in the acute phase compared to those with poorer outcome. Acute TBI participants had a significantly greater volume of hypo- and hyperperfused brain tissue compared to controls, with these regions partially normalizing by the chronic phase. Our findings demonstrate global elevation of CBF with focal hypo- and hyperperfusion in the early post-injury period and suggest a reparative role for acute elevation in CBF post-TBI.

Output Consistency Scale to Standardize Ostomate Output Description in Clinical Practice and Studies.

Stool descriptors have become popular due to the large diffusion of the Bristol Stool Form Scale (BSFS) via clinical studies, clinical trials, and social media. The applications have been numerous and centered around standardization of terminology that can be used by health care professionals and patients alike, as well as individuals interested in their wellness and the associated partners in the wellness industry. For a portion of the population, the digestive content is rerouted to an external manufactured pouch or bag, making the use of the BSFS visual descriptors of stool difficult. From day one post-resection surgery, ostomates are challenged with output management. The lack of standardized descriptors may hinder proper communication between the individual and the support team, as well as providing proper characterization in clinical studies and clinical trials. We propose the Lincoln Ostomy Output Consistency Scale for jejunostomy, ileostomy and colostomy (LOOCS) to overcome the limitations of the BSFS for qualifying ostomy outputs. The design was based on the need to describe perceived consistency from the ostomate point of view. We anticipate that the LOOCS scale can be effective in pediatric and adult clinical research settings, as well as self-monitoring to manage the quality of life.

High-Sensitivity C-Reactive Protein is a Prognostic Biomarker of Six-Month Disability after Traumatic Brain Injury: Results from the TRACK-TBI Study.

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p < 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies.

Predictors of Treatment Interruption During Frameless Gamma Knife Icon Stereotactic Radiosurgery.

PURPOSE: The Gamma Knife (GK) Icon allows for the delivery of stereotactic radiosurgery using a thermoplastic mask in combination with intrafraction motion monitoring using high definition motion management. The system pauses treatment if the magnitude of motion in all directions exceeds 1 to 1.5 mm, causing a break in treatment and prolongation of the session. We reviewed the records of patients treated in a frameless manner on our GK Icon system to determine predictors for treatment interruption. METHODS AND MATERIALS: We reviewed the records of patients treated between May 2019 and May 2020 on the GK Icon using a frameless technique for brain metastases, gliomas, schwannomas, and meningiomas. We recorded treatment time as noted in the plan document, actual treatment delivery time, and any pauses in treatment. We tabulated baseline characteristics including age, gender, diagnosis, performance status, and shifts at time of treatment. We used a receiver operating curve analysis to determine a timepoint corresponding with treatment interruption. We then conducted a logistic regression analysis to generate odds ratios for likelihood of treatment. RESULTS: We identified 150 patients meeting inclusion criteria. The majority (82%) were patients with brain metastases. The median age was 63 and the median dose was 27 Gy (16-30 Gy) in 3 fractions (1-5 fractions). The median treatment time was 23 minutes (4-108 minutes). Sixty-nine patients (46%) had at least 1 pause in treatment (range, 1-7). Receiver operating curve analysis revealed treatment time >19 minutes and rotation >0.47 degrees to be associated with interruption. Multivariable logistic regression revealed rotation >0.47 degrees and treatment time >19 minutes as predictive of interruption. CONCLUSIONS: For patients with rotations exceeding 0.47 degrees or an extended treatment time, physicians should expect treatment interruptions, consider fractionation to lessen table time, or use a frame-based approach.

Adaptation of a Gamma Knife Icon stereotactic radiosurgery program in the face of the COVID-19 pandemic.

Objective: The COVID-19 pandemic necessitated drastic and rapid changes throughout the field of radiation oncology, some of which were unique to the discipline of radiosurgery. Guidelines called for reduced frame use and reducing the number of fractions. Our institution implemented these guidelines, and herein we show the resultant effect on patient treatments on our Gamma Knife Icon program. Methods: In early March 2020 we rapidly implemented suggested changes according to ASTRO and other consensus guidelines as they relate to stereotactic radiosurgery in the COVID-19 era. We reviewed the GK Icon schedule at our institution between January 01 and April 30, 2020. We documented age, condition treated, technique (frame vs. mask), and number of fractions. We then tabulated and graphed the number of patients, framed cases, and fractions delivered. Results: Seventy-seven patients were treated on the GK Icon over that period, for a total of 231 fractions. The number of unique patients varied from 18 (April) to 22 (January). Of the 77 patients only 5 were treated using a frame. The number of fractions per month decreased significantly over time, from 70 in January to 36 in April. Likewise, the percentage of single fraction cases increased from 4.5% per month in January to 67% in April. Conclusions: The results presented here show that it is possible to quickly and efficiently change work flows to allow for reduced fractionation and frame use in the time of a global pandemic. Multidisciplinary cooperation and ongoing communication are integral to the success of such programs.

Radiotherapeutic treatment of brain metastases in patients with gynecologic malignancies: A nationwide analysis.

Objectives: Brain metastases are a rare finding in patients with primary gynecologic malignancies having a poor outcome despite treatment. We sought to use the National Cancer Database (NCDB) to characterize the incidence of brain metastases and types of treatment administered. Methods: We queried the NCDB from 2010-16 for patients with endometrial, cervical, and ovarian primaries with brain metastases at diagnosis treated with radiation-whole brain radiation (WBRT) or stereotactic radiosurgery (SRS). We tabulated baseline characteristics and performed a multivariable logistic regression to identify predictors of SRS. Multivariable Cox regression was used to identify predictors of death. Propensity matching was done to account for indication bias. Results: We identified 765 patients meeting above criteria, representing <1% of patients. Of patients with brain metastases, 287 received radiation to the brain. The median age was 60 (40-90). The majority of patients (80%) received WBRT. On multivariable logistic regression the only predictor of SRS was receipt of chemotherapy. Median follow up was 4.9 months. The overall survival for the entire cohort was 5.2 months. On Cox regression predictors of improved survival were receipt of chemotherapy, no extracranial disease, and SRS. After propensity matching, median survival was 8.3 months compared to 6.3 months in favor of SRS. Conclusions: This study represents the largest series to date of patients with brain metastases from gynecologic malignancies, confirming an incidence of <1% and overall poor prognosis. Radiation remains a viable treatment option.

Long-term follow-up of neurosurgical outcomes for adult patients in Uganda with traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of mortality and morbidity in Uganda and other low- and middle-income countries (LMICs). Due to the difficulty of long-term in-person follow-up, there is a paucity of literature on longitudinal outcomes of TBI in LMICs. Using a scalable phone-centered survey, this study attempted to investigate factors associated with both mortality and quality of life in Ugandan patients with TBI. METHODS: A prospective registry of adult patients with TBI admitted to the neurosurgical ward at Mulago National Referral Hospital was assembled. Long-term follow-up was conducted between 10.4 and 30.5 months after discharge (median 18.6 months). Statistical analyses included univariable and multivariable logistic regression and Cox proportional hazards regression to elucidate factors associated with mortality and long-term recovery. RESULTS: A total of 1274 adult patients with TBI were included, of whom 302 (23.7%) died as inpatients. Patients who died as inpatients received surgery less frequently (p < 0.001), had more severe TBI at presentation (p < 0.001), were older (p < 0.001), and were more likely to be female (p < 0.0001). Patients presenting with TBI resulting from assault were at reduced risk of inpatient death compared with those presenting with TBI caused by road traffic accidents (OR 0.362, 95% CI 0.128-0.933). Inpatient mortality and postdischarge mortality prior to follow-up were 23.7% and 9%, respectively. Of those discharged, 60.8% were reached through phone interviews. Higher Glasgow Coma Scale score at discharge (continuous HR 0.71, 95% CI 0.53-0.94) was associated with improved long-term survival. Tracheostomy (HR 4.38, 95% CI 1.05-16.7) and older age (continuous HR 1.03, 95% CI 1.009-1.05) were associated with poor long-term outcomes. More than 15% of patients continued to suffer from TBI sequelae years after the initial injury, including seizures (6.1%) and depression (10.0%). Despite more than 60% of patients seeking follow-up healthcare visits, mortality was still 9% among discharged patients, suggesting a need for improved longitudinal care to monitor recovery progress. CONCLUSIONS: Inpatient and postdischarge mortality remain high following admission to Uganda's main tertiary hospital with the diagnosis of TBI. Furthermore, posttraumatic sequelae, including seizures and depression, continue to burden patients years after discharge. Effective scalable solutions, including phone interviews, are needed to elucidate and address factors limiting in-hospital capacity and access to follow-up healthcare.

Localized Disruption of Blood Albumin-Phenytoin Binding Using Transcranial Focused Ultrasound.

Plasma protein binding (PPB) plays an important role in drug pharmacokinetics, particularly for central nervous system drugs, as PPB affects the blood concentration of unbound drug available to cross the blood-brain barrier (BBB). We report the non-invasive, spatially specific disruption of PPB to phenytoin, an anti-epileptic drug with high affinity to albumin, using 250-kHz focused ultrasound (FUS) delivered in a pulsed manner (55-ms tone burst duration, 4-Hz pulse repetitions). Equilibrium dialysis performed on sonicated phosphate-buffered saline solution containing phenytoin and bovine serum albumin revealed a 27.7% elevation in the unbound phenytoin concentration compared with an unsonicated control. Sonication of a unilateral brain hemisphere in rats (n = 10) after intraperitoneal phenytoin injection revealed increased parenchymal phenytoin uptake compared with the unsonicated hemisphere, without evidence of temperature change or BBB disruption. These findings illustrate the use of FUS as a novel technique for spatially selective disruption of PPB, which may be applied to a wide range of drug-plasma protein interactions.

Cancer Stem Cell Chemotherapeutics Assay for Prospective Treatment of Recurrent Glioblastoma and Progressive Anaplastic Glioma: A Single-Institution Case Series.

BACKGROUND: Chemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine. METHODS: We present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria. RESULTS: Of the 14 cases reviewed, the median age of our patient cohort was 49 years (21-63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0-10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies. CONCLUSIONS: The results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival. IMPORTANCE OF THE STUDY: Glioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp's protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient's derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1-10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies.

Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model.

Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.

Central Nervous System Tumors in Uganda: Outcomes of Surgical Treatment and Complications Assessed Through Telephone Survey.

BACKGROUND: Uganda has one of the largest unmet neurosurgical needs in the world, but has seen major improvements in neurosurgery-largely centered at Mulago National Referral Hospital (MNRH). This study implements the first long-term follow-up and outcomes analysis of central nervous system tumor patients in Uganda. METHODS: Inpatient data were collected using a prospective database of patients presenting to the MNRH neurosurgical ward between 2014 and 2015. Follow-up health care status was assessed in the patient's language using phone surveys. Analysis was performed to identify which factors were associated with patient outcomes. RESULTS: The MNRH neurosurgical ward saw 112 patients with central nervous system tumors (adult N = 87, female: 70%, median age: 37 years). Meningiomas (21%) comprised the most common tumor diagnosis. In-hospital mortality (18%), 30-day mortality (22%), and 1-year mortality (35%) were high. Thirty percent of patients underwent tumor resection in-patient and had greater median overall survival (66.5 months vs. 5.1 months for nonsurgical patients, P = 0.025). For those with known pathologic diagnoses, patients with glioblastomas had decreased median overall survival (0.83 months vs. 59 months for meningiomas, P = 0.02). Phone interviews yielded an 85% response rate. Of the survivors at the time of follow-up, 55% reported a subjective return to normalcy, and 75% received follow-up care for their tumor with most returning to MNRH. CONCLUSIONS: We show evidence for improved overall survival with surgical care at MNRH. In addition, phone interviews as a method of measuring health outcomes provided an effective means of follow-up, showing that most patients do seek follow-up care.

Frameless Robot-Assisted Deep Brain Stimulation Surgery: An Initial Experience.

BACKGROUND: Modern robotic-assist surgical systems have revolutionized stereotaxy for a variety of procedures by increasing operative efficiency while preserving and even improving accuracy and safety. However, experience with robotic systems in deep brain stimulation (DBS) surgery is scarce. OBJECTIVE: To present an initial series of DBS surgery performed utilizing a frameless robotic solution for image-guided stereotaxy, and report on operative efficiency, stereotactic accuracy, and complications. METHODS: This study included the initial 20 consecutive patients undergoing bilateral robot-assisted DBS. The prior 20 nonrobotic, frameless cohort of DBS cases was sampled as a baseline historic control. For both cohorts, patient demographic and clinical data were collected including postoperative complications. Intraoperative duration and number of Microelectrode recording (MER) and final lead passes were recorded. For the robot-assisted cohort, 2D radial errors were calculated. RESULTS: Mean case times (total operating room, anesthesia, and operative times) were all significantly decreased in the robot-assisted cohort (all P-values < .02) compared to frameless DBS. When looking at trends in case times, operative efficiency improved over time in the robot-assisted cohort across all time assessment points. Mean radial error in the robot-assisted cohort was 1.40 ± 0.11 mm, and mean depth error was 1.05 ± 0.18 mm. There was a significant decrease in the average number of MER passes in the robot-assisted cohort (1.05) compared to the nonrobotic cohort (1.45, P < .001). CONCLUSION: This is the first report of application of frameless robotic-assistance with the Mazor Renaissance platform (Mazor Robotics Ltd, Caesarea, Israel) for DBS surgery, and our findings reveal that an initial experience is safe and can have a positive impact on operative efficiency, accuracy, and safety.

Temporal Delays Along the Neurosurgical Care Continuum for Traumatic Brain Injury Patients at a Tertiary Care Hospital in Kampala, Uganda.

BACKGROUND: Significant care continuum delays between acute traumatic brain injury (TBI) and definitive surgery are associated with poor outcomes. Use of the "3 delays" model to evaluate TBI outcomes in low- and middle-income countries has not been performed. OBJECTIVE: To describe the care continuum, using the 3 delays framework, and its association with TBI patient outcomes in Kampala, Uganda. METHODS: Prospective data were collected for 563 TBI patients presenting to a tertiary hospital in Kampala from 1 June to 30 November 2016. Four time intervals were constructed along 5 time points: injury, hospital arrival, neurosurgical evaluation, computed tomography (CT) results, and definitive surgery. Time interval differences among mild, moderate, and severe TBI and their association with mortality were analyzed. RESULTS: Significant care continuum differences were observed for interval 3 (neurosurgical evaluation to CT result) and 4 (CT result to surgery) between severe TBI patients (7 h for interval 3 and 24 h for interval 4) and mild TBI patients (19 h for interval 3 and 96 h for interval 4). These postarrival delays were associated with mortality for mild (P = .05) and moderate TBI (P = .03) patients. Significant hospital arrival delays for moderate TBI patients were associated with mortality (P = .04). CONCLUSION: Delays for mild and moderate TBI patients were associated with mortality, suggesting that quality improvement interventions could target current triage practices. Future research should aim to understand the contributors to delays along the care continuum, opportunities for more effective resource allocation, and the need to improve prehospital logistical referral systems.