Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

Hi5 Protocol for the Use of Microfocused Ultrasound with Visualization.

Background: Microfocused ultrasound with visualization (MFU-V) is used for lifting and tightening of facial tissues. Standard protocols are completed in a single session. Despite excellent outcomes, we identified several barriers of entry for a significant number of patients. Therefore, we devised an individualized pan-facial protocol that is delivered as a series of short, intense treatments to address these issues. Methods: We enrolled 12 participants with mild-to-moderate skin and fibromuscular laxity to receive one superficial and one deep pass per visit (average 280 lines). Qualitative improvements were rated by both patients and physicians at 6 or 10 months due to COVID-19 delays. Changes in the submentum and eyebrow heights were quantified. Results: Ten patients (age range: 31-61 years) underwent an average of four MFU-V treatments. Two patients were excluded after massive weight gain. Skin and fibromuscular ptosis and overall soft tissue laxity improved in all patients. Mean brow height increased by 1.7 mm, whereas the mean submental lift was 78.7 mm2. All patients and treating physicians rated an improvement in appearance, whereas independent physicians rated improvements in 87% of cases. Four patients self-rated as "markedly improved." Pain was rated at up to 6.2 (out of 10). Although mask-wearing was mandatory, loss of elasticity, wrinkles, and skin roughness all improved. Superficial welts (n = 5), erythema (n = 3), tenderness (n = 3), and mild bruising (n = 2) occurred, but all resolved within a few days and no severe or permanent adverse events occurred. Conclusion: The Hi5 protocol was noninferior to standard single-session protocols and improved brow heights and submental lifting.

New Therapeutics in Alzheimer's Disease Longitudinal Cohort study (NTAD): study protocol.

INTRODUCTION: With the pressing need to develop treatments that slow or stop the progression of Alzheimer's disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease. METHODS AND ANALYSIS: The New Therapeutics in Alzheimer's Disease study (NTAD) aims to identify a biomarker set from magneto/electroencephalography that is sensitive to disease and progression over 1 year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimer's disease and 30 healthy controls aged between 50 and 85 years. Measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and MRI) of all participants will be taken at baseline. These measurements will be repeated after approximately 1 year on participants with Alzheimer's disease or mild cognitive impairment, and clinical and cognitive assessment of these participants will be repeated again after approximately 2 years. To assess reliability of magneto/electroencephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimer's disease will also undergo repeat magneto/electroencephalography 2 weeks after baseline. Baseline and longitudinal changes in neurophysiology are the primary analyses of interest. Additional outputs will include atrophy and cognitive change and estimated numbers needed to treat each arm of simulated clinical trials of a future disease-modifying therapy. ETHICS AND DATA STATEMENT: The study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

Insights on Skin Quality and Clinical Practice Trends in Asia Pacific and a Practical Guide to Good Skin Quality from the Inside Out.

Objective: We sought to examine the current skin quality trends and gaps in clinical practice in the Asia Pacific region and develop a practical guide to improve skin quality. Methods: Medical practitioners from 11 countries in the Asia Pacific region completed an online survey on current trends in skin quality treatment. A panel of 12 leading experts convened for a virtual meeting to develop a practical guide for skin quality improvement. Results: A total of 153 practitioners completed the survey. The four most common skin quality issues were uneven skin tone, skin surface unevenness, skin laxity, and sebaceous gland hyperactivity and enlarged pores. Most practitioners reported using a combination of treatment modalities for each skin quality issue. It was also observed that each treatment modality could be used to treat several skin quality issues. A multimodal approach targeting different interrelated issues across the tissue planes was recommended for balanced results. The panel developed a practical guide for the appropriate combinations and sequence of treatments, and created treatment protocols for specific skin quality outcome goals. The guide employed an "inside-out" approach, treating the deeper tissue planes prior to the superficial layers to achieve harmonious results. Limitations: Future studies are needed to support the recommended treatment protocols for skin quality improvement. Conclusion: These findings provide valuable insights on current skin quality trends and gaps in clinical practice. The practical guide provides a framework for practitioners to customize their treatment plan according to each patient's needs.

Leveraging the neurosurgical operating room for therapeutic development in NeuroOncology.

Glioblastoma (GBM) remains a disease with a dismal prognosis. For all the hope and promise immunotherapies and molecular targeted therapies have shown for systemic malignancies, these treatments have failed to show any promise in GBM. In this context, the paradigm of investigation of therapeutics for this disease itself must be examined and modifications considered. The unique challenge of the presence of blood-brain and blood-tumor barriers (BBB/BTB) raises questions about both the true levels of systemic drug delivery to the affected tissues. Window-of-opportunity (WoO) trials in neuro-oncology allow for proof-of-concept at the start of a classic phase I-II-III clinical trial progression. For therapeutics that do not have the ability to cross the BBB/BTB, direct delivery into tumor and/or tumor-infiltrated brain in the setting of a surgical procedure can provide a novel route of therapeutic access. These approaches permit neurosurgeons to play a greater role in therapeutic development for brain tumors.

Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.

BACKGROUND: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. OBJECTIVE: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. METHODS: The effect of LY3202626 versus vehicle on amyloid-ß (Aß) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aß levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics. RESULTS: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aß1-40 and 0.228±0.244 nM for Aß1-42 in PDAPP neuronal cultures. In dogs, CSF Aß1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aß1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. CONCLUSION: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

Surgical and anatomic factors predict development of leptomeningeal disease in patients with melanoma brain metastases.

BACKGROUND: Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, of which there is an unclear etiology. The aim of this study is to determine if surgical or anatomic factors can predict LMD in patients with metastatic melanoma. METHODS: A retrospective chart review was performed of 1162 patients treated at single institution for melanoma brain metastases (MBM). Patients with fewer than 3 months follow-up or lacking appropriate imaging were excluded. Demographic information, surgical, and anatomic data were collected. RESULTS: Eight hundred and twenty-seven patients were included in the final review. On multivariate analysis for the entire cohort, female gender, dural-based and intraventricular metastasis, and tumor bordering CSF spaces were associated with increased risk of LMD. Surgical resection was not significant for risk of LMD. On multivariate analysis of patients who have undergone surgical resection of a metastatic tumor, dural-based and intraventricular metastasis, ventricular entry during surgery, and metastasis in the infratentorial space were associated with increased risk of LMD. On multivariate analysis of patients who did not undergo surgery, chemotherapy after initial diagnosis and metastasis bordering CSF spaces were associated with increased risk of LMD. CONCLUSION: In a single-institution cohort of MBM, we found that surgical resection alone did not result in an increased risk of LMD. Anatomical factors such as dural-based and intraventricular metastasis were significant for developing LMD, as well as entry into a CSF space during surgical resection. These data suggest a strong correlation between anatomic location and tumor cell seeding in relation to the development of LMD.

Molecular Classification and Therapeutic Targets in Ependymoma.

Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the spinal, infratentorial, and supratentorial compartments, each with its own distinct clinical and molecular characteristics. In this review, the history, histopathology, standard of care, prognosis, oncogenic drivers, and hypothesized molecular targets for all subgroups of ependymoma are explored. This review emphasizes that despite the varied behavior of the ependymoma subgroups, it remains clear that research must be performed to further elucidate molecular targets for these tumors. Although not all ependymoma subgroups are oncologically aggressive, development of targeted therapies is essential, particularly for cases where surgical resection is not an option without causing significant morbidity. The development of molecular therapies must rely on building upon our current understanding of ependymoma oncogenesis, as well as cultivating transfer of knowledge based on malignancies with similar genomic alterations.

Single Treatment, Single Depth Superficial Microfocused Ultrasound with Visualization for Rhytid Improvement.

BACKGROUND: Standard lifting and tightening protocols with microfocused ultrasound with visualization (MFU-V, Ultherapy) comprise the use of multiple transducer depths. We developed a shortened, single depth treatment protocol for patients seeking skin rejuvenation. METHODS: Single-center, prospective case series. Subjects with static periorbital wrinkles, perioral wrinkles, or accordion lines had a single MFU-V treatment comprising up to 340 lines (periorbital 120, perioral 100, and accordion 120) with the superficial depth transducer (10.0 MHz/1.5 mm). Efficacy was assessed using established rating scales as well as clinician- and subject-reported Global Aesthetic Improvement Scales at baseline, 90, and 180 days, and each subject served as their own control. Adverse events were documented. RESULTS: Nine subjects, women aged 38-64, received treatment. At 180 days, post treatment clinicians reported visible improvements in periorbital lines (6/6 cases), accordion lines (5/6 cases), and perioral lines (3/6 cases). Subjects' self-assessments mirrored those of the clinicians, reporting improvements in accordion lines (5/6 cases improved, 1/6 cases much improved), periorbital lines (3/6 cases improved, 3/6 cases much improved) and perioral lines (2/6 cases improved, 2/6 cases much improved). Subject-rated satisfaction was high (accordion lines 6/6 cases, periorbital lines 4/6 cases and perioral lines 4/6 cases). All subjects experienced mild, transient erythema; in one subject, wheals persisted for 24 hours, resolving on application of mild topical corticosteroid. CONCLUSIONS: Shortened protocol, single depth MFU-V treatment was well-tolerated. It provided aesthetic improvements in periorbital and accordion lines, and to a lesser extent in perioral lines. Its utility as a noninvasive therapy for superficial skin rejuvenation warrants further investigation.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.

Evaluation of open and minimally invasive spinal surgery for the treatment of thoracolumbar metastatic epidural spinal cord compression: a systematic review.

BACKGROUND: Metastatic epidural spinal cord compression (MESCC) is a debilitating sequela of cancer that results in pain, disability, and neurologic deficits. Surgical techniques have included open surgical (OS) techniques with anterior and/or posterior decompression and fusion procedures. Further technical evolution has led to minimally invasive spinal (MIS) decompression and fusion. The objective of this study is to compare MIS to OS techniques in the treatment of thoracolumbar MESCC. METHODS: A review of the literature was performed using PubMed database. Inclusion criteria included patients 18 years or older, thoracolumbar MESCC, and surgeries with instrumented fusion. A total of 451 articles met the inclusion criteria and further analysis narrowed them down to 81 articles. Variables collected included blood loss, length of stay, operative time, pre- and postoperative Frankel grade, and complications. RESULTS: A total of 5726 papers were collected, with a total of 81 papers meeting final inclusion criteria: 26 papers with MIS technique and 55 with OS. A total of 2267 patients were evaluated. They were split into three surgical subtypes of MIS and OS: posterior decompression and fusion, partial corpectomy, and complete corpectomy. Overall, MIS had lower operative time, blood loss, and complications compared to OS. A timeline analysis showed reduction of complication rates in MIS surgery between papers published over a 28-year period. CONCLUSION: MESCC carries significant morbidity and mortality. Surgical approaches for palliative treatment should account for this fact. We conclude that MIS techniques offer a viable alternative to traditional OS approaches with lower overall morbidity and complications.

Donanemab (LY3002813) dose-escalation study in Alzheimer's disease.

INTRODUCTION: This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia. METHODS: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week follow-up period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12-week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase. RESULTS: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose. DISCUSSION: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.

Utility of intraoperative ultrasonography for resection of pituitary adenomas: a comparative retrospective study.

BACKGROUND: The evolution of pituitary surgery has made it a safe and effective form of treatment; however, risks of inadequate tumor resection, cerebrospinal fluid (CSF) leak, pituitary dysfunction, and vascular injury still exist. The use of intraoperative ultrasonography (IOUS) in pituitary surgery has been well described. Recent advancements in ultrasound technology have allowed for expanded utility as described here. METHODS: A retrospective review was performed between January 2016 and December 2019. One hundred thirty-eight patients (mean age 53.7 years, 47% females) were identified undergoing transsphenoidal surgery for pituitary tumors. Thirty-four patients had IOUS performed using a side-firing ultrasound probe, while 104 did not. Data was analyzed for preoperative (demographics, clinical, and radiographic features), perioperative (blood loss, operative time), and postoperative (complications, length of stay, hormone remission, and extent of resection) outcomes. RESULTS: There were no significant differences in patient age, gender, tumor volume, Knosp grade, and hormone-secreting status between the two groups. Patients treated using IOUS had significantly higher rates of gross total resection (79% vs. 44%, p = 0.0008), shorter operative times (74 vs. 146 min, p < 0.0001), lower blood loss (119 vs. 284 cc, p < 0.0001), and hospital stays (2.9 vs. 4.2 days, p = 0.001). Overall complication rates were lower in the IOUS group compared to standard pituitary surgery but did not reach significance. CONCLUSIONS: Recent improvements in ultrasound technology have allowed for miniaturization of probes capable of delivering high-resolution images. The use of IOUS in transsphenoidal pituitary surgery may significantly increase rates of gross total resection, while decreasing blood loss, hospital LOS, and operative time.

The cortical organization of language: distilling human connectome insights for supratentorial neurosurgery.

Connectomics is the production and study of detailed "connection" maps within the nervous system. With unprecedented advances in imaging and high-performance computing, the construction of individualized connectomes for routine neurosurgical use is on the horizon. Multiple projects, including the Human Connectome Project (HCP), have unraveled new and exciting data describing the functional and structural connectivity of the brain. However, the abstraction from much of these data to clinical relevance remains elusive. In the context of preserving neurological function after supratentorial surgery, abstracting surgically salient points from the vast computational data in connectomics is of paramount importance. Herein, the authors discuss four interesting observations from the HCP data that have surgical relevance, with an emphasis on the cortical organization of language: 1) the existence of a motor speech area outside of Broca's area, 2) the eloquence of the frontal aslant tract, 3) the explanation of the medial frontal cognitive control networks, and 4) the establishment of the second ventral stream of language processing. From these connectome observations, the authors discuss the anatomical basis of their insights as well as relevant clinical applications. Together, these observations provide a firm platform for neurosurgeons to advance their knowledge of the cortical networks involved in language and to ultimately improve surgical outcomes. It is hoped that this report encourages neurosurgeons to explore new vistas in connectome-based neurosurgery.

Risk of ventriculoperitoneal shunt infection with coexisting percutaneous endoscopic gastrostomy tube and associated factors.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) tubes and ventriculoperitoneal shunts (VPS) are commonly placed in neurologically impaired patients. There is concern about safety of VPS coexisting with PEG tubes due to the potential for an increased risk of infection. In this study, we assess the risk of VPS infection and the amount of time between both procedures. PATIENTS AND METHODS: Retrospective chart review of patients from our institution who had VPS and PEG tubes placed during the same hospitalization between 2014 and 2018. Our primary focus was assessing risk of VPS infection and timing of procedures in this patient population. Additionally, we assessed other factors which may contribute to VPS infection including SIRS criteria at time of VPS placement, comorbidities and other procedures performed. None of the SIRS factors were associated with VPS infection. RESULTS: 45 patients met inclusion criteria. Our VPS infection rate was found to be 7% (n = 3). These patients had 4, 16, and 36 days between procedures. 89% of our patients had PEG tube placed prior to VPS with 2 of these patients developing a VPS infection. At the time of VPS placement 42% of patients had SIRS. None of the SIRS factors were associated with VPS infection. CONCLUSION: Our VPS infection rate remained low even when they were performed during the same hospitalization as a PEG tube placement. SIRS is not associated with the development of VPS infections and is not an absolute contraindication to placing a VPS.

Strategies for posterior-only minimally invasive surgery in thoracolumbar metastatic epidural spinal cord compression.

BACKGROUND: Metastatic epidural spinal cord compression (MESCC) is a debilitating sequela of cancer. Here, we evaluated various subtypes of posterior-only minimally invasive spinal (MIS) procedures utilized to address different cancers. METHODS: Within this retrospective review, we analyzed the treatment of thoracolumbar MESCC treated with three MIS techniques: decompression and fusion (Subgroup A), partial corpectomy (Subgroup B), and full corpectomy (Subgroup C). RESULTS: There were 51 patients included in the study; they averaged 58.7 years of age, and 51% were females. Most tumors were in the thoracic spine (51%). The average preoperative Frankel grade was D (62.7%); 69% (35) improved postoperatively. The patients were divided as follows: subgroup A (15 patients = 29.4%), B (19 patients = 37.3%), and C (17 patients = 33.3%). The length of hospitalization was similar (~5.4 days) for all groups. The overall complication rate was 31%, while blood loss was lower in Subgroups A and B versus C. CONCLUSION: Different MIS surgical techniques were utilized in patients with thoracic and/or lumbar MESCC. Interestingly, clinical outcomes were similar between MIS subgroups, in this study, with a trend toward higher complications and greater blood loss associated with those undergoing more aggressive MIS procedures (e.g., full corpectomy and fusion).

Laryngeal manifestations of cranial nerve IX/X compression at the brainstem.

OBJECTIVE: We report an association between lower cranial nerve (CN IX/X) vascular compression at the brainstem with laryngeal symptoms utilizing a stepwise algorithm that systematically evaluates and eliminates all other common etiologies. Our experiences with retromastoid craniectomy with lower cranial nerve (LCN) decompression versus non-neurosurgical treatments are detailed. STUDY DESIGN: Retrospective chart review at a tertiary care academic medical center with follow-up telephone survey. METHODS: Baseline demographics, clinical characteristics, quality-of-life surveys, and treatment outcomes were recorded for patients with laryngeal symptoms associated with LCN compression at the brainstem. RESULTS: Forty-nine patients demonstrated LCN compression at the brainstem on imaging and presented with chief complaints of dysphonia (25 of 49, 51%), chronic cough (19 of 49, 39%), dysphoric breathing (3 of 49, 6%), and dysphagia (2 of 49, 4%). Poor initial scores were noted for Voice-Related Quality of Life (V-RQOL), Reflux Symptom Index, and Glottal Closure Index. Twenty-four patients underwent LCN decompression, of which 21 of 24 (88%) reported partial, near-complete, or complete improvement. Major perioperative complications occurred in four of 24 patients (17%). Patients who had undergone decompression were more likely to obtain complete/near-complete symptom resolution (10 of 24 patients, 42%) compared to those undergoing conservative treatments (2 of 25 patients, 8%) (P = 0.02). V-RQOL scores improved more in surgical patients [mean change score, 33.0 (standard deviation [SD], 31.2) than nonsurgical patients (mean change score 9.6, SD 20.9) (P = 0.03) (mean follow-up 3.0 years, SD 2.0). CONCLUSION: Lower cranial nerve compression at the brainstem should be considered when all other etiologies are excluded. Retromastoid craniectomy with LCN decompression demonstrates an acceptable safety profile. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:2105-2111, 2019.

A Novel Surgical Technique for Management of Giant Central Calcified Thoracic Disk Herniations: A Dual Corridor Method Involving Tubular Transthoracic/Retropleural Approach Followed by a Posterior Transdural Diskectomy.

BACKGROUND: Thoracic disk herniations (TDHs) represent only 0.15% to 1.8% of surgically managed disk herniations but have posed a particular challenge to spine surgeons. Numerous surgical approaches have been cited in the literature with varying degrees of success, technical complexity, and complication profiles. OBJECTIVE: To report a case of a combined lateral retropleural and dorsal transdural approach for complex thoracic discectomy. METHODS: In this report, we describe a combined lateral/retropleural and posterior transdural approach for a patient with a giant calcified TDH that was not amenable to safe removal using a single approach. RESULTS: In complex situations such as this, a dual corridor approach allows for improved visualization and maximal resection opportunity and opens up yet another option to address recalcitrant TDH. CONCLUSION: The staged dual corridor approach is safe and represents a further surgical option for extremely difficult TDH.

Current clinical management of patients with glioblastoma.

BACKGROUND: Glioblastoma (GB) is the most aggressive primary brain tumor, historically resistant to treatment, and with overall fatal outcome. RECENT FINDINGS: Recently, several molecular subgroups and rare genetic alterations have been described in GB. In this review article, we will describe the current clinical management of patients with GB in the United States, discuss selected next-generation molecular-targeted therapies in GB, and present ongoing clinical trials for patients with GB. This review is intended for clinical and preclinical researchers who conduct work on GB and would like to understand more about the current standard of treatment of GB patients, historical perspectives, current challenges, and ongoing and upcoming clinical trials. CONCLUSIONS: GB is an extremely complex disease, and despite recent progress and advanced therapeutic strategies, the overall patient's prognosis remains dismal. Innovative strategies and integrative ways of approach to disease are urgently needed.

Single agent efficacy of the HDAC inhibitor DATS in preclinical models of glioblastoma.

PURPOSE/INTRODUCTION: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models. METHODS: Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS. RESULTS: Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. CONCLUSIONS: DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.