Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Cochlear Fibrosis after Vestibular Schwannoma Resection via the Middle Cranial Fossa Approach.

OBJECTIVE: The aim of this study was to determine the incidence of cochlear fibrosis after vestibular schwannoma (VS) resection via middle cranial fossa (MCF) approach. DESIGN: A retrospective case review was conducted. SETTING: The review was conducted in a tertiary care academic medical center. PARTICIPANTS: Patients who (1) underwent resection of VS via MCF approach between 2013 and 2018, (2) had complete pre- and post-audiometric testing, and (3) had clinical follow-up with magnetic resonance imaging (MRI) for at least 1 year after surgery were included. MAIN OUTCOME MEASURE(S): The main outcome of this study was cochlear fibrosis as assessed by MRI 1 year after surgery. RESULTS: Fifty-one patients underwent VS resection via MCF technique during the study period. Of 31 patients with AAO-HNS class A or B preoperative hearing ability, 18 (58.0%) maintained class A, B, or C hearing postoperatively. Of 16 patients who lost hearing and had MRI 1 year after surgery, 11 (61.1%) had MRI evidence of fibrosis in at least some portion of the labyrinth and 4 (22.2%) showed evidence of cochlear fibrosis. Of 16 patients with preserved hearing and MRI 1 year after surgery, 4 (25%) had fibrosis in some portion of the labyrinth, with no fibrosis in the cochlea. CONCLUSIONS: In patients who lose hearing during VS resection with the MCF approach, there is usually MRI evidence of fibrosis in the labyrinth 1 year after surgery. However, there is also, but less commonly, fibrosis involving the cochlea. It is unclear if this will affect the ability to insert a cochlear implant electrode array.

Surgical Interventions for Supratentorial Intracranial Hemorrhage: The Past, Present, and Future.

Spontaneous supratentorial intracranial hemorrhage is extremely disabling and is associated with high mortality. Primary treatment for patients with this disease process is maximal medical management with blood pressure control and correction of clotting disorders due to comorbid conditions or medications. Over the past decade, significant strides have been made in understanding the benefits of surgical intervention in the treatment of intracranial hemorrhage through multiple clinical trials. In this article, we review the evolution of surgical treatments beginning with the STICH trials, discuss new developments with minimally invasive surgical strategies, and provide a brief update regarding ongoing trials and future directions in the treatment of spontaneous supratentorial intracranial hemorrhage.

Insights into potential targeted nonsurgical therapies for the treatment of moyamoya disease.

Since its initial description in 1957 as an idiopathic disease, moyamoya disease has proved challenging to treat. Although the basic pathophysiology of this disease involves narrowing of the terminal carotid artery with compensatory angiogenesis, the molecular and cellular mechanisms underlying these changes are far more complex. In this article, the authors review the literature on the molecular and cellular pathophysiology of moyamoya disease with an emphasis on potential therapeutic targets.

Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis.

Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the NF2 gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.

Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III.

BACKGROUND/OBJECTIVE: Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials. METHODS: In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint. RESULTS: Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors. CONCLUSIONS: Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

Understanding the complex pathophysiology of idiopathic intracranial hypertension and the evolving role of venous sinus stenting: a comprehensive review of the literature.

Idiopathic intracranial hypertension (IIH) is a disease defined by elevated intracranial pressure without established etiology. Although there is now consensus on the definition of the disorder, its complex pathophysiology remains elusive. The most common clinical symptoms of IIH include headache and visual complaints. Many current theories regarding the etiology of IIH focus on increased secretion or decreased absorption of cerebrospinal fluid (CSF) and on cerebral venous outflow obstruction due to venous sinus stenosis. In addition, it has been postulated that obesity plays a role, given its prevalence in this population of patients. Several treatments, including optic nerve sheath fenestration, CSF diversion with ventriculoperitoneal or lumboperitoneal shunts, and more recently venous sinus stenting, have been described for medically refractory IIH. Despite the availability of these treatments, no guidelines or standard management algorithms exist for the treatment of this disorder. In this paper, the authors provide a review of the literature on IIH, its clinical presentation, pathophysiology, and evidence supporting treatment strategies, with a specific focus on the role of venous sinus stenting.

Predicting symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage with an artificial neural network in a pediatric population.

PURPOSE: Artificial neural networks (ANN) are increasingly applied to complex medical problem solving algorithms because their outcome prediction performance is superior to existing multiple regression models. ANN can successfully identify symptomatic cerebral vasospasm (SCV) in adults presenting after aneurysmal subarachnoid hemorrhage (aSAH). Although SCV is unusual in children with aSAH, the clinical consequences are severe. Consequently, reliable tools to predict patients at greatest risk for SCV may have significant value. We applied ANN modeling to a consecutive cohort of pediatric aSAH cases to assess its ability to predict SCV. METHODS: A retrospective chart review was conducted to identify patients < 21 years of age who presented with spontaneously ruptured, non-traumatic, non-mycotic, non-flow-related intracranial arterial aneurysms to our institution between January 2002 and January 2015. Demographics, clinical, radiographic, and outcome data were analyzed using an adapted ANN model using learned value nodes from the adult aneurysmal SAH dataset previously reported. The strength of the ANN prediction was measured between - 1 and 1 with - 1 representing no likelihood of SCV and 1 representing high likelihood of SCV. RESULTS: Sixteen patients met study inclusion criteria. The median age for aSAH patients was 15 years. Ten underwent surgical clipping and 6 underwent endovascular coiling for definitive treatment. One patient experienced SCV and 15 did not. The ANN applied here was able to accurately predict all 16 outcomes. The mean strength of prediction for those who did not exhibit SCV was - 0.86. The strength for the one patient who did exhibit SCV was 0.93. CONCLUSIONS: Adult-derived aneurysmal SAH value nodes can be applied to a simple AAN model to accurately predict SCV in children presenting with aSAH. Further work is needed to determine if ANN models can prospectively predict SCV in the pediatric aSAH population in toto; adapted to include mycotic, traumatic, and flow-related origins as well.

Cocaine Constrictor Mechanisms of the Cerebral Vasculature.

Cocaine constriction of the cerebral vasculature is thought to contribute to the ischemia associated with cocaine use. However, the mechanisms whereby cocaine elicits relevant vasoconstriction remain elusive. Indeed, proposed intra- and intercellular mechanisms based on over 3 decades of ex vivo vascular studies are, for the most part, of questionable relevancy due to the generally low contractile efficacy of cocaine combined with the use of nonresistance-type vessels. Furthermore, the significance attached to mechanisms derived from in vivo animal studies may be limited by the inability to demonstrate cocaine-induced decreased cerebral blood flow, as observed in (awake) humans. Despite these apparent limitations, we surmise that the vasoconstriction relevant to cocaine-induced ischemia is elicited by inhibition of dilator and activation of constrictor pathways because of cocaine action on the neurovascular unit (neuron, astrocyte, and vessel) and on vessels outside the unit. Furthermore, previous cocaine exposure, that is, conditions present in human subjects, downregulates and sensitizes these dilator and constrictor pathways, respectively, thereby enhancing constriction to acute cocaine. Identification of specific intra- and intercellular mechanisms requires investigations in the isolated microvasculature and the neurovascular unit from species chronically exposed to cocaine and in which cocaine decreases cerebral blood flow.

Functional ET(A)-ET(B) Receptor Cross-talk in Basilar Artery In Situ From ET(B) Receptor Deficient Rats.

The role of endothelin (ET)(A)-ET(B) receptor cross-talk in limiting the ET(A) receptor antagonist inhibition of ET-1 constriction is revealed by the partial or complete dependency of the ET(A) receptor antagonist inhibition on functional removal of the ET(B) receptor. Although functional removal of the ET(B) receptor is generally accomplished with ET(B) receptor antagonist, a novel approach using rats containing a naturally occurring deletion mutation in the ET(B) receptor [rescued "spotting lethal" (sl) rats; ET(B)(sl/sl)] demonstrated increased ET(A) receptor antagonist inhibition of ET-1 constriction in vena cava. We investigated whether this deletion mutation was also sufficient to remove the ET(B) receptor dependency of the ET(A) receptor antagonist inhibition of ET-1 constriction in the basilar artery. Consistent with previous reports, ET-1 plasma levels were elevated in ET(B)(sl/sl) as compared with ET(B)(+/+) rats. ET(B) receptor antagonist failed to relax the ET-1 constricted basilar artery from ET(B)(+/+) and ET(B)(sl/sl) rats. Relaxation to combined ET(A) and ET(B) receptor antagonist was greater than relaxation to ET(A) receptor antagonist in the basilar artery from ET(B)(+/+) and, unexpectedly, ET(B)(sl/sl) rats. These findings confirm the presence of ET(A)-ET(B) receptor cross-talk in the basilar artery. We speculate that mutant ET(B) receptor expression produced by alternative splicing may be sufficient to allow cross-talk.

Beyond textbook neuroanatomy: The syndrome of malignant PCA infarction.

Given its limited vascular territory, occlusion of the posterior cerebral artery (PCA) usually does not result in malignant infarction. Challenging this concept, we present 3 cases of unilateral PCA infarction with secondary malignant progression, resulting from extension into what would classically be considered the posterior middle cerebral artery (MCA) territory. Interestingly, these were true PCA infarctions, not "MCA plus" strokes, since the underlying occlusive lesion was in the PCA. We hypothesize that congenital and/or acquired variability in the distribution and extent of territory supplied by the PCA may underlie this rare clinical entity. Patients with a PCA infarction should thus be followed closely and offered early surgical decompression in the event of malignant progression.

Cocaine constriction of rat basilar artery in situ: roles of nitric oxide and endothelin-1.

This study investigated whether cocaine constriction of rat basilar artery in situ is mediated by nitric oxide (NO) inhibition and/or endothelin (ET)-1 release. Cocaine (3-100 µmol/l) concentration-dependently constricted the basilar artery to a maximum of 18%. Nω-nitro-L-arginine (100 µmol/l) was without effect on constriction to 3 and 10 µmol/l cocaine. PD145065 (1 and 10 µmol/l), an ETA/B receptor antagonist, variably and at most partially inhibited the 100 µmol/l cocaine constriction. Capsaicin denervation of sensory nerves innervating the basilar, which contain ET-1 and NO synthase, also failed to influence cocaine constriction. These findings suggest that cocaine constriction of cerebral vessels (1) varies with respect to the involvement of ET-1 release and (2) unlike findings in the peripheral vasculature, the constriction is not mediated by inhibition of NO.

Anatomical Study of the Supratentorial Extension for the Retrolabyrinthine Presigmoid Approaches.

BACKGROUND: Supratentorial craniotomy represents the upper part of the combined trans-tentorial or the supra-infratentorial presigmoid approach. In this study, we provide qualitative and quantitative analyses for the supratentorial extension of the presigmoid retrolabyrinthine suprameatal approach (PRSA). METHODS: The infratentorial PRSA followed by the supratentorial extension craniotomy with dividing and removal of the tentorial strip were performed on both sides of 5 injected human cadaver heads (n = 10 sides). Quantitative analysis was performed for the surface area gained (surgical accessibility) by adding the supratentorial craniotomy. Qualitative analysis was performed for the parts of the brainstem, cranial nerves, and vascular structures that became accessible by adding the supratentorial craniotomy. The anatomical obstacles encountered in the added operative corridor were analyzed. RESULTS: The supratentorial extension of PRSA provides an increase in surgical accessibility of 102.65% as compared to the PRSA standalone. The mean surface area of the exposed brainstem is 197.98 (standard deviation: 76.222) and 401.209 (standard deviation: 123.96) for the infratentorial and the combined supra-infratentorial presigmoid approach, respectively. Exposure for parts of III, IV, and V cranial nerves is added after the extension, and the surface area of the outer craniotomy defect has increased by 60.32%. Parts of the basilar, anterior inferior cerebellar, and superior cerebellar arteries are accessible after the supratentorial extension. CONCLUSIONS: The supratentorial extension of PRSA allows access to the supra-trigeminal area of the pons and the lower part of the midbrain. Considering this surgical accessibility and exposure significantly assists in planning such complex approaches while targeting central skull base lesions.

Cortical incisions and transcortical approaches for intra-axial and intraventricular lesions: A scoping review.

Background: Transcortical approaches, encompassing various surgical corridors, have been employed to treat an array of intraparenchymal or intraventricular brain pathologies, including tumors, vascular malformations, infections, intracerebral hematomas, and epileptic surgery. Designing cortical incisions relies on the lesion location and characteristics, knowledge of eloquent functional anatomy, and advanced imaging such as tractography. Despite their widespread use in neurosurgery, there is a noticeable lack of systematic studies examining their common lobe access points, associated complications, and prevalent pathologies. This scoping review assesses current evidence to guide the selection of transcortical approaches for treating a variety of intracranial pathologies. Methods: A scoping review was conducted using the PRISMA-ScR guidelines, searching PubMed, EMBASE, Scopus, and Web of Science. Studies were included if ≥5 patients operated on using transcortical approaches, with reported data on clinical features, treatments, and outcomes. Data analysis and synthesis were performed. Results: A total of 50 articles encompassing 2604 patients were included in the study. The most common primary pathology was brain tumors (60.6%), particularly gliomas (87.4%). The transcortical-transtemporal approach was the most frequently identified cortical approach (70.48%), and the temporal lobe was the most accessed brain lobe (55.68%). The postoperative course outcomes were reported as good (55.52%), poor (28.38%), and death (14.62%). Conclusion: Transcortical approaches are crucial techniques for managing a wide range of intracranial lesions, with the transcortical-transtemporal approach being the most common. According to the current literature, the selective choice of cortical incision and surgical corridor based on the lesion's pathology and anatomic-functional location correlates with acceptable functional outcomes.

A Comprehensive Analysis of Tobacco Smoking History as a Risk for Outcomes after Endoscopic Transsphenoidal Resection of Pituitary Adenoma.

Objectives This study seeks to comprehensively analyze the impact of smoking history on outcomes after endoscopic transsphenoidal hypophysectomy (TSH) for pituitary adenoma. Design This was a retrospective study. Setting This study was done at the tertiary care center. Participants Three hundred and ninety-eight adult patients undergoing TSH for a pituitary adenoma. Main Outcome Measures Clinical and tumor characteristics and operative factors were collected. Patients were categorized as never, former, or active smokers, and the pack-years of smoking history was collected. Years since cessation of smoking was obtained for former smokers. Specific outcomes included postoperative cerebrospinal fluid (CSF) leak, length of hospitalization, 30-day return to the operating room, and 30-day readmission. Smoking history details were comprehensively analyzed for association with outcomes. Results Any history of smoking tobacco was associated with return to the operating room (odds ratio [OR] = 2.67, 95% confidence interval [CI]: 1.05-6.76, p = 0.039), which was for persistent CSF leak in 58.3%. Among patients with postoperative CSF leak, any history of smoking was associated with need for return to the operating room to repair the CSF leak (OR = 5.25, 95% CI: 1.07-25.79, p = 0.041). Pack-years of smoking was positively associated with a return to the operating room (OR = 1.03, 95% CI: 1.01-1.06, p = 0.048). In all multivariable models, all negative outcomes were significantly associated with the covariate: occurrence of intraoperative CSF leak. Conclusion This is the first study to show smoking may have a negative impact on healing of CSF leak repairs after TSH, requiring a return to the operating room. This effect appears to be dose dependent on the smoking history. Secondarily, intraoperative CSF leak as covariate in multivariable models was significantly associated with all negative outcomes.

A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

PURPOSE: High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. PATIENTS AND METHODS: We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 µmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. RESULTS: Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 µmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. CONCLUSIONS: On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema.

BACKGROUND AND PURPOSE: Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. METHODS: Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. RESULTS: Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm(3) for the surgical cohort and 40.7±13.9 cm(3) for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm(3) than medical cohort: 41.7±14.6 cm(3) (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm(3); and surgical aspiration only, 24.5±14.0 cm(3) (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm(3) and 24.4±8.6 cm(3) in surgical aspiration only (P=0.41). CONCLUSIONS: Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.

Endovascular management of posthemorrhagic cerebral vasospasm: indications, technical nuances, and results.

Posthemorrhagic cerebral vasospasm (PHCV) is a common problem and a significant cause of mortality and permanent disability following aneurysmal subarachnoid hemorrhage. While medical therapy remains the mainstay of prevention against PHCV and the first-line treatment for symptomatic patients, endovascular options should not be delayed in medically refractory cases. Although both transluminal balloon angioplasty (TBA) and intra-arterial vasodilator therapy (IAVT) can be effective in relieving proximal symptomatic PHCV, only IAVT is a viable treatment option for distal vasospasm. The main advantage of TBA is its long-lasting therapeutic effect and the very low rate of retreatment. However, its use has been associated with a significant risk of serious complications, particularly vessel rupture and reperfusion hemorrhage. Conversely, IAVT is generally considered an effective and low-risk procedure, despite the transient nature of its therapeutic effects and the risk of intracranial hypertension associated with its use. Moreover, newer vasodilator agents appear to have a longer duration of action and a much better safety profile than papaverine, which is rarely used in current clinical practice. Although endovascular treatment of PHCV has been reported to be effective in clinical series, whether it ultimately improves patient outcomes has yet to be demonstrated in a randomized controlled trial.