PBAF loss leads to DNA damage-induced inflammatory signaling through defective G2/M checkpoint maintenance.

The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer.

Early Outpatient Treatment for Covid-19 with Convalescent Plasma.

BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.gov; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% (P=0.03) and 100% (P=0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years (P=0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

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.

Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage.

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a "worst-case" safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury.

Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial.

BACKGROUND: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. RESULTS: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups. CONCLUSIONS: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04323800.

Transfusion reactions associated with COVID-19 convalescent plasma in outpatient clinical trials.

BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.

How do I implement an outpatient program for the administration of convalescent plasma for COVID-19?

Convalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID-19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID-19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID-19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody-based therapies.

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.

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.

Predicting synthetic lethal interactions using conserved patterns in protein interaction networks.

In response to a need for improved treatments, a number of promising novel targeted cancer therapies are being developed that exploit human synthetic lethal interactions. This is facilitating personalised medicine strategies in cancers where specific tumour suppressors have become inactivated. Mainly due to the constraints of the experimental procedures, relatively few human synthetic lethal interactions have been identified. Here we describe SLant (Synthetic Lethal analysis via Network topology), a computational systems approach to predicting human synthetic lethal interactions that works by identifying and exploiting conserved patterns in protein interaction network topology both within and across species. SLant out-performs previous attempts to classify human SSL interactions and experimental validation of the models predictions suggests it may provide useful guidance for future SSL screenings and ultimately aid targeted cancer therapy development.

Enhancing the Informed Consent Process Using Shared Decision Making and Consent Refusal Data from the CLEAR III Trial.

BACKGROUND: The process of informed consent in National Institutes of Health randomized, placebo-controlled trials is poorly studied. There are several issues regarding informed consent in emergency neurologic trials, including a shared decision-making process with the patient or a legally authorized representative about overall risks, benefits, and alternative treatments. METHODS: To evaluate the informed consent process, we collected best and worst informed consent practice information from a National Institutes of Health trial and used this in medical simulation videos to educate investigators at multiple sites to improve the consent process. Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) (clinicaltrials.gov, NCT00784134) studied the effect of intraventricular alteplase (n = 251) versus saline (placebo) injections (n = 249) for intraventricular hemorrhage reduction. Reasons for ineligibility (including refusing to consent) for all screen failures were analyzed. The broadcasted presentation outlined best practices for doctor-patient interactions during the consenting process, as well as anecdotal, study-specific reasons for consent refusal. Best and worst consent elements were then incorporated into a simulation video to enhance the informed consent process. This video was disseminated to trial sites as a webinar around the midpoint of the trial to improve the consent process. Pre- and post-intervention consent refusals were compared. RESULTS: During the trial, 10,538 patients were screened for eligibility, of which only three were excluded due to trial timing. Pre-intervention, 77 of 5686 (1.40%) screen eligible patients or their proxies refused consent. Post-intervention, 55 of 4849 (1.10%) refused consent, which was not significantly different from pre-intervention (P = 0.312). The incidence of screen failures was significantly lower post-intervention (P = 0.006), possibly due to several factors for patient exclusion. CONCLUSION: The informed consent process for prospective randomized trials may be enhanced by studying and refining best practices based on trial-specific plans and patient concerns particular to a study.

Intracranial Hypertension and Cerebral Perfusion Pressure Insults in Adult Hypertensive Intraventricular Hemorrhage: Occurrence and Associations With Outcome.

OBJECTIVES: Elevated intracranial pressure and inadequate cerebral perfusion pressure may contribute to poor outcomes in hypertensive intraventricular hemorrhage. We characterized the occurrence of elevated intracranial pressure and low cerebral perfusion pressure in obstructive intraventricular hemorrhage requiring extraventricular drainage. DESIGN: Prospective observational cohort. SETTING: ICUs of 73 academic hospitals. PATIENTS: Four hundred ninety-nine patients enrolled in the CLEAR III trial, a multicenter, randomized study to determine if extraventricular drainage plus intraventricular alteplase improved outcome versus extraventricular drainage plus saline. INTERVENTIONS: Intracranial pressure and cerebral perfusion pressure were recorded every 4 hours, analyzed over a range of thresholds, as single readings or spans (≥ 2) of readings after adjustment for intracerebral hemorrhage severity. Impact on 30- and 180-days modified Rankin Scale scores was assessed, and receiver operating curves were analyzed to identify optimal thresholds. MEASUREMENTS AND MAIN RESULTS: Of 21,954 intracranial pressure readings, median interquartile range 12 mm Hg (8-16), 9.7% were greater than 20 mm Hg and 1.8% were greater than 30 mm Hg. Proportion of intracranial pressure readings from greater than 18 to greater than 30 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 70 mm Hg were associated with day-30 mortality and partially mitigated by intraventricular alteplase. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and intracranial pressure greater than 20 mm Hg in spans were associated with both 30-day mortality and 180-day mortality. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 60 mm Hg were associated with poor day-30 modified Rankin Scale, whereas cerebral perfusion pressure less than 65 and less than 75 mm Hg were associated with poor day-180 modified Rankin Scale. CONCLUSIONS: Elevated intracranial pressure and inadequate cerebral perfusion pressure are not infrequent during extraventricular drainage for severe intraventricular hemorrhage, and level and duration predict higher short-term mortality and long-term mortality. Burden of low cerebral perfusion pressure was also associated with poor short- and long-term outcomes and may be more significant than intracranial pressure. Adverse consequences of intracranial pressure-time burden and cerebral perfusion pressure-time burden should be tested prospectively as potential thresholds for therapeutic intervention.

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.

The Incidence of Catheter Tract Hemorrhage and Catheter Placement Accuracy in the CLEAR III Trial.

BACKGROUND: Incidence of catheter tract hemorrhage (CTH) after initial ventriculostomy placement ranges from 10 to 34%. We investigated CTH incidence in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III trial. METHODS: Prospective observational analysis of 1000 computer tomography (CT) scans from all 500 patients enrolled in the trial. All catheters were evaluated on first CT post-placement and on last CT prior to randomization for placement location and CTH size, location, and severity. Clinical variables were assessed for association with CTH with multivariable logistic regression. RESULTS: Of 563 catheters, CTH was detected in 14 and 21% of patients on first and last CT (median 3.7 and 43.4 h after catheter placement, respectively). All, but one were asymptomatic. Majority of CTH (86%) occurred within 24 h after placement, were located within 1 cm of the skull, and had at least one diameter > 5 mm. Most catheters (71%) terminated in the third or lateral ventricle ipsilateral to insertion site. Factors significantly associated with CTH were pre-admission use of antiplatelet drugs, accuracy of catheter placement, non-operating room catheter placement, Asian race, and intraventricular hemorrhage expansion. CONCLUSIONS: CTH incidence on initial catheter placement and during stabilization was relatively low, despite emergent placement in a high-risk population. Catheter placement accuracy was similar or better than convenience samples from the published literature. Decreasing risk of CTH may be achieved with attention to catheter placement accuracy and placement in the operating room. Antiplatelet agent use was an independent risk factor for CTH.

ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. METHODS: We tested the hypothesis that intraoperative computerized tomographic image-guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. RESULTS: The intraoperative computerized tomographic image-guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59-84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5-2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0-3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). CONCLUSIONS: Early computerized tomographic image-guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

Early Therapy Intensity Level (TIL) Predicts Mortality in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Outcome from spontaneous intracerebral hemorrhage (sICH) may depend on patient-care variability. We developed as ICH-specific therapy intensity level (TIL) metric using evidence-based elements in a high severity sICH cohort. METHODS: This is a cohort study of 170 patients with sICH and any intraventricular hemorrhage treated in 2 academic neuroICUs. Pre-defined quality indicators were identified based on current guidelines, scientific evidence, and likelihood of care documentation in first 72 h of hospital admission. We assessed performance on each indicator and association with discharge mortality. Significant indicators were aggregated to develop a TIL score. The predictive validity of the best fit TIL score was tested with threefold cross-validation of multivariate logistic regression models of in-hospital survival and good outcome (modified Rankin score 0-3). RESULTS: Median ICH score was 3; discharge mortality was 51.2%. Five/19 tested variables were significantly associated with lower discharge mortality: no DNR/withdrawal of treatment within 24 h of admission, target glucose within 4 h of high glucose, no recurrent hyperpyrexia, clinical reversal of herniation/intracranial pressure >20 mmHg within 60 min of detection, and reversal of INR (<1.4) within 2 h of first elevation. One point was given for each or if not applicable. Median TIL score was significantly higher in survivors versus non-survivors (5[1] vs. 3[1]; P < 0.001). A 4-point aggregated TIL score was most predictive of discharge survival (area under receiving operating characteristic curve 0.85, 95% CI 0.80-0.90) and good outcome (AUC 0.84) and was an independent predictor of both (survival: OR 7.10; 95% CI 3.57-14.11; P < 0.001; good outcome: OR 3.10; 95% CI 1.06-8.79; P < 0.001). CONCLUSION: A simplified TIL score using evidenced-based patient-care parameters within first 3 days of admission after sICH was significantly associated with early mortality and good outcome. The next step is prospective validation of the simplified TIL score in a large clinical trial.

Anger in Adolescent Communities: How Angry Are They?

Anger is a common factor in two causes of death in adolescence: homicide and suicide. This study looked at the level of anger in non-clinical convenience sample of adolescents (N = 139) between the ages of 12 and 19 years (early: 12 to 14 years, mid: 15 to 16 years, late: 17 to 19 years) from a large Southeastern Baptist church. Participants completed the State-Trait Anger Expression Inventory, Beck and Children's Depression Inventories, and Children of Alcoholics Screening Test (CAST). The level of self-reported anger was low. The difference in anger between the three age groups was not statistically significant. Differences in gender were generally not significant statistically. A strong correlation exists between stress and anger. A minor relationship between parental drinking behaviors, as measured by the CAST, and anger was found. A significant relationship between anger and depression, and frequency of participation in religious activity and decreased anger was established. By increasing the current knowledge of anger in adolescents, it may be possible to gain insight into risk factors or triggers that cause anger. Interventions must be implemented early to prevent juvenile detention and to help adolescents remain in the community. Public policies addressing anger in adolescents are essential. Health care providers must work together to identify adolescents with disorders or feelings of isolation or disconnect and provide treatment based in communities so adolescents can still function and not be isolated. It is relevant that a mentor or someone that can be trusted is provided to build a safe and secure environment. This greater knowledge may aid in assessment and treatment of adolescents with dysfunctional anger.

A randomized prospective study of lumpectomy margin assessment with use of MarginProbe in patients with nonpalpable breast malignancies.

BACKGROUND: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins. METHODS: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted. RESULTS: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant. CONCLUSIONS: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

Impact of factors affecting the residual tumor size diagnosed by MRI following neoadjuvant chemotherapy in comparison to pathology.

BACKGROUND AND OBJECTIVES: To investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC). METHODS: Ninety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure. RESULTS: The mean (±SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 ± 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P < 0.05). Multivariate regression analyses demonstrated that only tumor type, tumor morphology, and biomarker status considering both HR and HER-2 were independent predictors (P = 0.0014, 0.0032, and 0.0286, respectively). CONCLUSION: The accuracy of MRI in evaluating residual tumor size depends on tumor type, morphology, and biomarker status. The information may be considered in surgical planning for NAC patients.