Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

Distress, Depression, and the Effect of ZIP Code in Pancreaticobiliary Cancer Patients and Their Significant Others.

BACKGROUND: Distress screening of cancer patients is mandated by the American College of Surgeons Commission on Cancer. Clinical implementation remains limited, particularly in surgical oncology settings in individuals with pancreaticobiliary cancers. STUDY DESIGN: This study evaluated differences in mean distress scores based on the National Comprehensive Cancer Network Distress Thermometer & Problem List for patients with pancreaticobiliary cancers, benign pancreatic conditions, and for their significant others (SOs). The distress screening was conducted at the first office visit and postoperatively in a subset of those who had surgery. Distress Thermometer (DT) scores were dichotomized at ≤5 vs >5 and at ≥7 and correlated with Problem List items. The US ZIP Code database was used to correlate income range, percent poverty, and unemployment in the patient's self-identified ZIP code. Regression models were fitted to identify independent predictors of distress. RESULTS: A total of 547 patients and 184 SOs were evaluated. Thirty percent of patients had DT scores >5, with pancreatic adenocarcinoma patients reporting the highest levels of distress. SOs of pancreatic adenocarcinoma patients reported even greater distress than the patients themselves. As the number of pre-existing medical problems increased; so did DT scores. Distress correlated with physical and emotional problems and worry about insurance coverage and transportation. Higher income level predicted higher DT scores, although poverty predicted lower DT scores. Depression was present in 12% of the patients. Distress improved in those undergoing surgery. CONCLUSIONS: Distress and depression in pancreaticobiliary cancer patients and SOs are prevalent. The findings of this study have multiple actionable implications and require diagnosis, treatment, and referral to supportive care resources.

One-Year Outcome Trajectories and Factors Associated with Functional Recovery Among Survivors of Intracerebral and Intraventricular Hemorrhage With Initial Severe Disability.

Importance: Patients who survive severe intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) typically have poor functional outcome in the short term and understanding of future recovery is limited. Objective: To describe 1-year recovery trajectories among ICH and IVH survivors with initial severe disability and assess the association of hospital events with long-term recovery. Design, Setting, and Participants: This post hoc analysis pooled all individual patient data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial in multiple centers across the US, Canada, Europe, and Asia. Patients were enrolled from August 1, 2010, to September 30, 2018, with a follow-up duration of 1 year. Of 999 enrolled patients, 724 survived with a day 30 modified Rankin Scale score (mRS) of 4 to 5 after excluding 13 participants with missing day 30 mRS. An additional 9 patients were excluded because of missing 1-year mRS. The final pooled cohort included 715 patients (71.6%) with day 30 mRS 4 to 5. Data were analyzed from July 2019 to January 2022. Exposures: CLEAR-III participants randomized to intraventricular alteplase vs placebo. MISTIE-III participants randomized to stereotactic thrombolysis of hematoma vs standard medical care. Main Outcomes and Measures: Primary outcome was 1-year mRS. Patients were dichotomized into good outcome at 1 year (mRS 0 to 3) vs poor outcome at 1 year (mRS 4 to 6). Multivariable logistic regression models assessed associations between prospectively adjudicated hospital events and 1-year good outcome after adjusting for demographic characteristics, ICH and IVH severity, and trial cohort. Results: Of 715 survivors, 417 (58%) were male, and the overall mean (SD) age was 60.3 (11.7) years. Overall, 174 participants (24.3%) were Black, 491 (68.6%) were White, and 49 (6.9%) were of other races (including Asian, Native American, and Pacific Islander, consolidated owing to small numbers); 98 (13.7%) were of Hispanic ethnicity. By 1 year, 129 participants (18%) had died and 308 (43%) had achieved mRS 0 to 3. In adjusted models for the combined cohort, diabetes (adjusted odds ratio [aOR], 0.50; 95% CI, 0.26-0.96), National Institutes of Health Stroke Scale (aOR, 0.93; 95% CI, 0.90-0.96), severe leukoaraiosis (aOR, 0.30; 95% CI, 0.16-0.54), pineal gland shift (aOR, 0.87; 95% CI, 0.76-0.99]), acute ischemic stroke (aOR, 0.44; 95% CI, 0.21-0.94), gastrostomy (aOR, 0.30; 95% CI, 0.17-0.50), and persistent hydrocephalus by day 30 (aOR, 0.37; 95% CI, 0.14-0.98) were associated with lack of recovery. Resolution of ICH (aOR, 1.82; 95% CI, 1.08-3.04) and IVH (aOR, 2.19; 95% CI, 1.02-4.68) by day 30 were associated with recovery to good outcome. In the CLEAR-III model, cerebral perfusion pressure less than 60 mm Hg (aOR, 0.30; 95% CI, 0.13-0.71), sepsis (aOR, 0.05; 95% CI, 0.00-0.80), and prolonged mechanical ventilation (aOR, 0.96; 95% CI, 0.92-1.00 per day), and in MISTIE-III, need for intracranial pressure monitoring (aOR, 0.35; 95% CI, 0.12-0.98), were additional factors associated with poor outcome. Thirty-day event-based models strongly predicted 1-year outcome (area under the receiver operating characteristic curve [AUC], 0.87; 95% CI, 0.83-0.90), with significantly improved discrimination over models using baseline severity factors alone (AUC, 0.76; 95% CI, 0.71-0.80; P < .001). Conclusions and Relevance: Among survivors of severe ICH and IVH with initial poor functional outcome, more than 40% recovered to good outcome by 1 year. Hospital events were strongly associated with long-term functional recovery and may be potential targets for intervention. Avoiding early pessimistic prognostication and delaying prognostication until after treatment may improve ability to predict future recovery.

Intracranial Pressure and Cerebral Perfusion Pressure in Large Spontaneous Intracranial Hemorrhage and Impact of Minimally Invasive Surgery.

Introduction: We investigated the effect of hematoma volume reduction with minimally invasive surgery (MIS) on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in patients with large spontaneous intracerebral hemorrhage (ICH). Methods: Post-hoc analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) study, a clinical trial with blinded outcome assessments. The primary outcome was the proportion of ICP readings ≥20 and 30 mmHg, and CPP readings <70 and 60 mm Hg. Secondary outcomes included major disability (modified Rankin scale >3) and mortality at 30 and 365 days. We assessed the relationship between proportion of high ICP and low CPP events and MIS using binomial generalized linear models, and outcomes using multiple logistic regression. Results: Of 499 patients enrolled in MISTIE III, 72 patients had guideline based ICP monitors placed, 34 in the MIS group and 38 in control (no surgery) group. Threshold ICP and CPP events ≥20/ <70 mmHg occurred in 31 (43.1%) and 52 (72.2%) patients respectively. On adjusted analyses, proportion of ICP readings ≥20 and 30 mmHg were significantly lower in the MIS group vs. control group [Odds Ratio (OR) 0.27, 95% Confidence Interval [CI] 0.11-0.63 (p = 0.002); OR = 0.18, 0.04-0.75, p = 0.02], respectively. Proportion of CPP readings <70 and 60 mm Hg were also significantly lower in MIS patients [OR 0.31, 95% CI 0.15-0.63 (p = 0.001); OR 0.30, 95% CI 0.11-0.83 (p = 0.02)], respectively. Higher proportions of CPP readings <70 and 60 mm were significantly associated with short term mortality (p = 0.04), and (p = 0.006), respectively. Long term mortality was significantly associated with higher proportion of time with ICP ≥ 20 (p = 0.04), ICP ≥ 30 (p = 0.04), and CPP <70 mmHg (p = 0.01). Conclusion: Our results are consistent with the hypothesis that surgical reduction of ICH volume decreases proportion of high ICP and low CPP events and that these variables are associated with short- and long-term mortality.

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Post-Stroke Depression in Patients with Large Spontaneous Intracerebral Hemorrhage.

OBJECTIVES: To determine factors associated with post-stroke depression (PSD) and relationship between PSD and functional outcomes in spontaneous intracerebral hemorrhage (ICH) using prospective data from a large clinical trial. MATERIALS AND METHODS: MISTIE III, a randomized, multicenter, placebo-controlled trial, was conducted to determine if minimally invasive surgery with thrombolysis improves outcome compared to standard medical care. Our primary outcome was post-stroke depression at 180 days. Secondary outcomes were change in blinded assessment of modified Rankin Scale (mRS) from 30 to 180 days, and from 180 to 365 days. Logistic regression models were used to assess the relationship between PSD and outcomes. RESULTS: Among 379 survivors at day 180, 308 completed Center for Epidemiologic Studies Depression Scale, of which 111 (36%) were depressed. In the multivariable analysis, female sex (Adjusted Odds Ratio [AOR], 95% Confidence Interval [CI]: 1.93 [1.07-3.48]), Hispanic ethnicity (3.05 [1.19-7.85]), intraventricular hemorrhage (1.88 [1.02-3.45]), right-sided lesions (3.00 [1.43-6.29]), impaired mini mental state examination at day 30 (2.50 [1.13-5.54]), and not being at home at day 30 (3.17 [1.05-9.57]) were significantly associated with higher odds of PSD. Patients with PSD were significantly more likely to have unchanged or worsening mRS from day 30 to 180 (42.3% vs. 25.9%; p=0.004), but not from day 180 to 365. CONCLUSIONS: We report high burden of PSD in patients with large volume ICH. Impaired cognition and not living at home may be more important than physical limitations in predicting PSD. Increased screening of high-risk post-stroke patients for depression, especially females and Hispanics may be warranted.

Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage.

Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.

Intracerebral Hemorrhage Volume Reduction and Timing of Intervention Versus Functional Benefit and Survival in the MISTIE III and STICH Trials.

BACKGROUND: The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. OBJECTIVE: To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. METHODS: Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n = 84) were compared to STICH II all lobar cases (n = 259) for volumetric analyses. All MISTIE III surgical patients (n = 240) were compared to both STICH I and II (n = 722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. RESULTS: End-of-treatment ICH volume ≤28.8 mL in MISTIE III and ≤30.0 mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180 d (P = .01 and P = .003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180 d with STICH I and II (P = .0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. CONCLUSION: Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

Randomised pilot trial of cash incentives for reducing paediatric asthmatic tobacco smoke exposures from maternal caregivers and members of their social network.

BACKGROUND: The primary aim was to evaluate the efficacy of financial incentives for reducing paediatric tobacco smoke exposures (TSEs) through motivating cigarette usage reduction among low-income maternal caregivers and members of their social network. DESIGN: Randomised control pilot trial over a 6-month study follow-up time period. The study was undertaken from May 2017 to -May 2018. Once monthly follow-up visits occurred over the 6-month study period. SETTING: Baltimore City, Maryland, USA. PARTICIPANTS: We grouped 135 participants into 45 triads (asthmatic child (2-12 years of age), maternal caregiver and social network member). Triads were assigned in a 1:1 allocation ratio. The maternal caregiver and social network members were active smokers and contributed to paediatric TSE. INTERVENTIONS: Triads were randomised to receive either usual care (TSE education and quitline referrals) or usual care plus financial incentives. Cash incentives up to $1000 were earned by caregivers and designated social network participants. Incentives for either caregivers or social network participants were provided contingent on their individual reduction of tobacco usage measured by biomarkers of tobacco usage. Study visits occurred once a month during the 6-month trial. MAIN OUTCOME MEASURES: The main outcome measure was mean change in monthly paediatric cotinine levels over 6 months of follow-up interval and was analysed on an intention-to-treat basis. RESULTS: The mean change in monthly child cotinine values was not significantly different in the intervention cohort over the 6-month follow-up period, compared with the control group (p=0.098, CI -0.16 to 1.89). Trends in child cotinine could not be ascribed to caregivers or social network members. Despite decreasing mean monthly cotinine values, neither the intervention cohort's caregivers (difference in slope (control-intervention)=3.30 ng/mL/month, CI -7.72 to 1.13, p=0.144) or paired social network members (difference in slope (control-intervention)=-1.59 ng/mL/month, CI -3.57 to 6.74, p=0.546) had significantly different cotinine levels than counterparts in the control group. CONCLUSIONS: Financial incentives directed at adult contributors to paediatric TSE did not decrease child cotinine levels. TRIAL REGISTRATION NUMBER: NCT03099811.

Refractory Hypocalcemia Following Stomach Intestinal Pylorus-Sparing Bariatric Surgery and Thyroidectomy: Successful Management With Creation of a Proximal Roux-en-Y Gastric Bypass.

Some forms of bariatric surgery make patients susceptible to calcium malabsorption, and the parathyroid hormone (PTH) axis is important for maintaining normocalcemia in these patients. Injury to the parathyroid glands due to anterior neck surgery commonly causes PTH axis disruption and can result in severe hypocalcemia in bariatric surgery patients. Herein, we present a case of a patient with a history of stomach intestinal pylorus-sparing bariatric surgery who developed refractory hypocalcemia requiring daily intravenous (IV) calcium 2 years after thyroidectomy. PTH levels were inappropriately normal during episodes of hypocalcemia, and urinary calcium level was <3.0 mg/dL following large oral doses of calcium, suggesting that both inadequate PTH response and malabsorption contributed to her severe hypocalcemia. In order to enhance calcium absorptive capacity while minimizing the risk of weight regain, she was surgically treated with a Roux-en-Y gastric bypass proximal to the prior operation. The surgery successfully improved blood calcium levels; the patient was successfully weaned from IV calcium and was able to maintain normocalcemia with oral supplements. We discuss the case in the context of available literature and provide our recommendations.

Linkage of Maternal Caregiver Smoking Behaviors on Environmental and Clinical Outcomes of Children with Asthma: A Post-Hoc Analysis of a Financial Incentive Trial Targeting Reduction in Pediatric Tobacco Smoke Exposures.

(1) Background: Monthly variability in smoking behaviors in caregivers of pediatric asthmatics yields questions of how much and when does smoking reduction result in improved environmental and clinical outcomes. (2) Methods: Post hoc analysis of data from a 6 month pilot randomized-control trial occurring from May 2017 to May 2018 in Baltimore City (MD, USA). The initial trial's primary intervention explored the utility of financial incentives in modifying caregiver smoking behaviors. Post hoc analyses examined all dyads independent of the initial trial's randomization status. All caregivers received pediatric tobacco smoke harm reduction education, in addition to monthly encouragement to access the state tobacco quitline for individual phone-based counseling and nicotine replacement therapy. Maternal caregivers who were active cigarette smokers and their linked asthmatic child (aged 2-12 years) were grouped into two classifications ("high" versus "low") based on the child and caregiver's cotinine levels. A "low" cotinine level was designated by at least a 25% reduction in cotinine levels during 3 months of the trial period; achieving ≤2 months of low cotinine levels defaulted to the "high" category. Twenty-seven dyads (caregivers and children) (total n = 54) were assigned to the "high" category, and eighteen dyads (caregivers and children) (total n = 36) were allocated to the "low" category. The primary outcome measure was the correlation of caregiver cotinine levels with pediatric cotinine values. Secondary outcomes included asthma control, in addition to caregiver anxiety and depression. (3) Results: Caregivers with 3 months of ≥25% decrease in cotinine levels had a significantly greater mean change in child cotinine levels (p = 0.018). "Low" caregiver cotinine levels did not significantly improve pediatric asthma control (OR 2.12 (95% CI: 0.62-7.25)). Caregiver anxiety and depression outcomes, measured by Patient Health Questionnaire (PHQ)-4 scores, was not significantly different based on cotinine categorization (p = 0.079); (4) Conclusion: Reduced pediatric cotinine levels were seen in caregivers who reduced their smoking for at least 3 months, but clinical outcome measures remained unchanged.

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.

The number of microspheres in Y90 radioembolization directly affects normal tissue radiation exposure.

PURPOSE: In Y90 radioembolization, the number of microspheres infused varies by more than a factor of 20 over the shelf-life of the glass radioembolization device. We investigated the effect of the number of Y90 microspheres on normal liver tissue. METHOD: Healthy pigs received lobar radioembolization with glass Y90 microspheres at 4, 8, 12, and 16 days post-calibration, representing a > 20× range in the number of microspheres deposited per milliliter in tissue. Animals were survived for 1-month post-treatment and the livers were explanted and scanned on a micro CT system to fully characterize the microscopic distribution of individual microspheres. A complete 3D microdosimetric evaluation of each liver was performed with a spatially correlated analysis of histopathologic effect. RESULTS: Through whole-lobe microscopic identification of each microsphere, a consistent number of microspheres per sphere cluster was found at 4, 8, and 12 days postcalibration, despite an 8-fold increase in total microspheres infused from days 4 to 12. The additional microspheres instead resulted in more clusters formed and, therefore, a more homogeneous microscopic absorbed dose. The increased absorbed-dose homogeneity resulted in a greater volume fraction of the liver receiving a potentially toxic absorbed dose based on radiobiologic models. Histopathologic findings in the animals support a possible increase in normal liver toxicity in later treatments with more spheres (i.e., ≥ day 12) compared to early treatments with less spheres (i.e., ≤ day 8). CONCLUSION: The microdosimetric evidence presented supports a recommendation of caution when treating large volumes (e.g., right lobe) using glass 90Y microspheres at more than 8 days post-calibration, i.e., after "2nd week" Monday. The favorable normal tissue microscopic distribution and associated low toxicity of first week therapies may encourage opportunities for dose escalation with glass microspheres and could also be considered for patients with decreased hepatic reserve.

A randomized 500-subject open-label phase 3 clinical trial of minimally invasive surgery plus alteplase in intracerebral hemorrhage evacuation (MISTIE III).

RATIONALE AND HYPOTHESIS: Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials. METHODS AND DESIGN: MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study. STUDY OUTCOMES: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.

Bariatric Embolization of Arteries for the Treatment of Obesity (BEAT Obesity) Trial: Results at 1 Year.

Background Bariatric embolization is a new endovascular procedure to treat patients with obesity. However, the safety and efficacy of bariatric embolization are unknown. Purpose To evaluate the safety and efficacy of bariatric embolization in severely obese adults at up to 12 months after the procedure. Materials and Methods For this prospective study (NCT0216512 on ClinicalTrials.gov ), 20 participants (16 women) aged 27-68 years (mean ± standard deviation, 44 years ± 11) with mean body mass index of 45 ± 4.1 were enrolled at two institutions from June 2014 to February 2018. Transarterial embolization of the gastric fundus was performed using 300- to 500-µm embolic microspheres. Primary end points were 30-day adverse events and weight loss at up to 12 months. Secondary end points at up to 12 months included technical feasibility, health-related quality of life (Short Form-36 Health Survey ([SF-36]), impact of weight on quality of life (IWQOL-Lite), and hunger or appetite using a visual assessment scale. Analysis of outcomes was performed by using one-sample t tests and other exploratory statistics. Results Bariatric embolization was performed successfully for all participants with no major adverse events. Eight participants had a total of 11 minor adverse events. Mean excess weight loss was 8.2% (95% confidence interval [CI]: 6.3%, 10%; P < .001) at 1 month, 11.5% (95% CI: 8.7%, 14%; P < .001) at 3 months, 12.8% (95% CI: 8.3%, 17%; P < .001) at 6 months, and 11.5% (95% CI: 6.8%, 16%; P < .001) at 12 months. From baseline to 12 months, mean SF-36 scores increased (mental component summary, from 46 ± 11 to 50 ± 10, P = .44; physical component summary, from 46 ± 8.0 to 50 ± 9.3, P = .15) and mean IWQOL-Lite scores increased from 57 ± 18 to 77 ± 18 (P < .001). Hunger or appetite decreased for 4 weeks after embolization and increased thereafter, without reaching pre-embolization levels. Conclusion Bariatric embolization is well tolerated in severely obese adults, inducing appetite suppression and weight loss for up to 12 months. Published under a CC BY-NC-ND 4.0 license. Online supplemental material is available for this article.

Surgical Performance Determines Functional Outcome Benefit in the Minimally Invasive Surgery Plus Recombinant Tissue Plasminogen Activator for Intracerebral Hemorrhage Evacuation (MISTIE) Procedure.

BACKGROUND: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial.

BACKGROUND: Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. METHODS: MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. FINDINGS: Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). INTERPRETATION: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. FUNDING: National Institute of Neurological Disorders and Stroke and Genentech.

Trial Readiness in Cavernous Angiomas With Symptomatic Hemorrhage (CASH).

BACKGROUND: Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE: To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS: This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES: We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION: The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.

Association between second hand smoke (SHS) exposure and caregiver stress in children with poorly controlled asthma.

Objective: Urban children with asthma experience high rates of second hand smoke (SHS) exposure. The objective was to examine whether SHS exposure is associated with symptom frequency in children with poorly controlled asthma. Methods: Children were enrolled in a RCT to test the efficacy of an environmental control behavioral intervention versus an attention control group and followed over 12 months. SHS exposure assessed using salivary cotinine measurement. Frequency of child asthma symptoms, healthcare utilization, household smoking and caregiver daily life stress were obtained via caregiver report. Time of enrollment was recorded to assess seasonal factors. Symptom days and nights were the primary outcomes. Multivariable models and odds ratios examined factors that best predicted increased frequency of daytime/nighttime symptoms. Results: Children (n = 222) with a mean age of 6.3 (SD 2.7) years, were primarily male (65%), African American (94%), Medicaid insured (94%), and had poorly controlled asthma (54%). The final multivariable model indicated symptoms in the fall (OR 2.78; 95% CI 1.16, 6.52) and increased caregiver daily life stress (OR 1.13, 95% CI 1.02, 1.25) were significantly associated with increased symptom days when controlling for cotinine level, intervention status, child age and home and car smoking restrictions. Conclusions: There was no impact of SHS exposure on increased symptom frequency. High caregiver daily life stress and symptoms in fall season may place children with asthma at risk for increased day/nighttime symptoms. Close monitoring of symptoms and medication use during the fall season and intervening on caregiver life stress may decrease asthma morbidity in children with poorly controlled asthma.