Cu(II) Specifically Disassembles Insulin Amyloid Nanostructures via Direct Interaction with Cross-ß Fibrils.

In this work, we demonstrate direct evidence of the antiamyloid potential of Cu(II) ions against amyloid formation of insulin. The Cu(II) ions were found to efficiently disassemble the preformed amyloid nanostructures into soluble species and suppress monomer fibrillation under aggregation-prone conditions. The direct interaction of Cu(II) ions with the cross-ß structure of amyloid fibrils causes substantial disruption of both the interchain and intrachain interactions, predominantly the H-bonds and hydrophobic contacts. Further, the Cu(II) ions show a strong affinity for the aggregation-prone conformers of the protein and inhibit their spontaneous self-assembly. These results reveal the possible molecular mechanism for the antiamyloidogenic potential of Cu(II) which could be important for the development of metal-ion specific therapeutic strategies against amyloid linked complications.

Tailoring the Molecular Structure of 6-Gingerol for Targeting the Phase Separation in Human Lysozyme.

Human lysozyme undergoes a phase-separation process to form insoluble amyloid-architects that cause several pathologies including systemic amyloidosis. Here we have tailored 6-gingerol by extending its molecular framework with active functional groups to specifically target lysozyme phase-transition events. Aggregation assay revealed that tailored 6-gingerol with 4-aromatic moieties (MTV4) substantially suppressed the conversion of the lysozyme low-density liquid phase (LDLP) to solid-phase structured amyloids. The data obtained from biophysical, computational, and microscopic imaging tools suggest direct intervention of MTV4 with the liquid-liquid phase separation. The CD data suggest that MTV4 was able to retain the native conformation of lysozyme. Both biomolecular and computational data reveal the interference of MTV4 with the aggregation-prone hydrophobic stretches within the lysozyme, thereby retaining the native structure and reversing the misfolded intermediates to active monomers. Also, MTV4 was able to induce rapid dissolution of preformed-toxic amyloid fibrils. These results reinforce the importance of the aromatic-aromatic interaction in preventing human lysozyme phase separation.

Prognostic biomarkers of intracerebral hemorrhage identified using targeted proteomics and machine learning algorithms.

Early prognostication of patient outcomes in intracerebral hemorrhage (ICH) is critical for patient care. We aim to investigate protein biomarkers' role in prognosticating outcomes in ICH patients. We assessed 22 protein biomarkers using targeted proteomics in serum samples obtained from the ICH patient dataset (N = 150). We defined poor outcomes as modified Rankin scale score of 3-6. We incorporated clinical variables and protein biomarkers in regression models and random forest-based machine learning algorithms to predict poor outcomes and mortality. We report Odds Ratio (OR) or Hazard Ratio (HR) with 95% Confidence Interval (CI). We used five-fold cross-validation and bootstrapping for internal validation of prediction models. We included 149 patients for 90-day and 144 patients with ICH for 180-day outcome analyses. In multivariable logistic regression, UCH-L1 (adjusted OR 9.23; 95%CI 2.41-35.33), alpha-2-macroglobulin (aOR 5.57; 95%CI 1.26-24.59), and Serpin-A11 (aOR 9.33; 95%CI 1.09-79.94) were independent predictors of 90-day poor outcome; MMP-2 (aOR 6.32; 95%CI 1.82-21.90) was independent predictor of 180-day poor outcome. In multivariable Cox regression models, IGFBP-3 (aHR 2.08; 95%CI 1.24-3.48) predicted 90-day and MMP-9 (aOR 1.98; 95%CI 1.19-3.32) predicted 180-day mortality. Machine learning identified additional predictors, including haptoglobin for poor outcomes and UCH-L1, APO-C1, and MMP-2 for mortality prediction. Overall, random forest models outperformed regression models for predicting 180-day poor outcomes (AUC 0.89), and 90-day (AUC 0.81) and 180-day mortality (AUC 0.81). Serum biomarkers independently predicted short-term poor outcomes and mortality after ICH. Further research utilizing a multi-omics platform and temporal profiling is needed to explore additional biomarkers and refine predictive models for ICH prognosis.

Molecular insights into the phase transition of lysozyme into amyloid nanostructures: Implications of therapeutic strategies in diverse pathological conditions.

Lysozyme, a well-known bacteriolytic enzyme, exhibits a fascinating yet complex behavior when it comes to protein aggregation. Under certain conditions, this enzyme undergoes flexible transformation, transitioning from partially unfolded intermediate units of native conformers into complex cross-ß-rich nano fibrillar amyloid architectures. Formation of such lysozyme amyloids has been implicated in a multitude of pathological and medical severities, like hepatic dysfunction, hepatomegaly, splenic rupture as well as spleen dysfunction, nephropathy, sicca syndrome, renal dysfunction, renal amyloidosis, and systemic amyloidosis. In this comprehensive review, we have attempted to provide in-depth insights into the aggregating behavior of lysozyme across a spectrum of variables, including concentrations, temperatures, pH levels, and mutations. Our objective is to elucidate the underlying mechanisms that govern lysozyme's aggregation process and to unravel the complex interplay between its structural attributes. Moreover, this work has critically examined the latest advancements in the field, focusing specifically on novel strategies and systems, that have been implemented to delay or inhibit the lysozyme amyloidogenesis. Apart from this, we have tried to explore and advance our fundamental understanding of the complex processes involved in lysozyme aggregation. This will help the research community to lay a robust foundation for screening, designing, and formulating targeted anti-amyloid therapeutics offering improved treatment modalities and interventions not only for lysozyme-linked amyloidopathy but for a wide range of amyloid-related disorders.

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Clinical characteristics and outcomes of patients with post-stroke epilepsy: protocol for an individual patient data meta-analysis from the International Post-stroke Epilepsy Research Repository (IPSERR).

INTRODUCTION: Despite significant advances in managing acute stroke and reducing stroke mortality, preventing complications like post-stroke epilepsy (PSE) has seen limited progress. PSE research has been scattered worldwide with varying methodologies and data reporting. To address this, we established the International Post-stroke Epilepsy Research Consortium (IPSERC) to integrate global PSE research efforts. This protocol outlines an individual patient data meta-analysis (IPD-MA) to determine outcomes in patients with post-stroke seizures (PSS) and develop/validate PSE prediction models, comparing them with existing models. This protocol informs about creating the International Post-stroke Epilepsy Research Repository (IPSERR) to support future collaborative research. METHODS AND ANALYSIS: We utilised a comprehensive search strategy and searched MEDLINE, Embase, PsycInfo, Cochrane, and Web of Science databases until 30 January 2023. We extracted observational studies of stroke patients aged ≥18 years, presenting early or late PSS with data on patient outcome measures, and conducted the risk of bias assessment. We did not apply any restriction based on the date or language of publication. We will invite these study authors and the IPSERC collaborators to contribute IPD to IPSERR. We will review the IPD lodged within IPSERR to identify patients who developed epileptic seizures and those who did not. We will merge the IPD files of individual data and standardise the variables where possible for consistency. We will conduct an IPD-MA to estimate the prognostic value of clinical characteristics in predicting PSE. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. The results will be published in peer-reviewed journals. This study will contribute to IPSERR, which will be available to researchers for future PSE research projects. It will also serve as a platform to anchor future clinical trials. TRIAL REGISTRATION NUMBER: NCT06108102.

Polygenic Risk of Epilepsy and Post-Stroke Epilepsy.

Background and Aims: Epilepsy is highly heritable, with numerous known genetic risk loci. However, the genetic predisposition's role in post-acute brain injury epilepsy remains understudied. This study assesses whether a higher genetic predisposition to epilepsy raises post-stroke or Transient Ischemic Attack (TIA) survivor's risk of Post-Stroke Epilepsy (PSE). Methods: We conducted a three-stage genetic analysis. First, we identified independent epilepsy-associated ( p <5x10 -8 ) genetic variants from public data. Second, we estimated PSE-specific variant weights in stroke/TIA survivors from the UK Biobank. Third, we tested for an association between a polygenic risk score (PRS) and PSE risk in stroke/TIA survivors from the All of Us Research Program. Primary analysis included all ancestries, while a secondary analysis was restricted to European ancestry only. A sensitivity analysis excluded TIA survivors. Association testing was conducted via multivariable logistic regression, adjusting for age, sex, and genetic ancestry. Results: Among 19,708 UK Biobank participants with stroke/TIA, 805 (4.1%) developed PSE. Likewise, among 12,251 All of Us participants with stroke/TIA, 394 (3.2%) developed PSE. After establishing PSE-specific weights for 39 epilepsy-linked genetic variants in the UK Biobank, the resultant PRS was associated with elevated odds of PSE development in All of Us (OR:1.16[1.02-1.32]). A similar result was obtained when restricting to participants of European ancestry (OR:1.23[1.02-1.49]) and when excluding participants with a TIA history (OR:1.18[1.02-1.38]). Conclusions: Our findings suggest that akin to other forms of epilepsy, genetic predisposition plays an essential role in PSE. Because the PSE data were sparse, our results should be interpreted cautiously.

Outcomes in Patients With Poststroke Seizures: A Systematic Review and Meta-Analysis.

Importance: Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors' knowledge. Objective: To investigate outcomes in people with PSS compared with people without PSS. Data Sources: MEDLINE, Embase, PsycInfo, Cochrane, LILACS, LIPECS, and Web of Science, with years searched from 1951 to January 30, 2023. Study Selection: Observational studies that reported PSS outcomes. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used for abstracting data, and the Joanna Briggs Institute tool was used for risk-of-bias assessment. Data were reported as odds ratio (OR) and standardized mean difference (SMD) with a 95% CI using a random-effects meta-analysis. Publication bias was assessed using funnel plots and the Egger test. Outlier and meta-regression analyses were performed to explore the source of heterogeneity. Data were analyzed from November 2022 to January 2023. Main Outcomes and Measures: Measured outcomes were mortality, poor functional outcome (modified Rankin scale [mRS] score 3-6), disability (mean mRS score), recurrent stroke, and dementia at patient follow-up. Results: The search yielded 71 eligible articles, including 20 110 patients with PSS and 1 166 085 patients without PSS. Of the participants with PSS, 1967 (9.8%) had early seizures, and 10 605 (52.7%) had late seizures. The risk of bias was high in 5 studies (7.0%), moderate in 35 (49.3%), and low in 31 (43.7%). PSSs were associated with mortality risk (OR, 2.1; 95% CI, 1.8-2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8-2.8), greater disability (SMD, 0.6; 95% CI, 0.4-0.7), and increased dementia risk (OR, 3.1; 95% CI, 1.3-7.7) compared with patients without PSS. In subgroup analyses, early seizures but not late seizures were associated with mortality (OR, 2.4; 95% CI, 1.9-2.9 vs OR, 1.2; 95% CI, 0.8-2.0) and both ischemic and hemorrhagic stroke subtypes were associated with mortality (OR, 2.2; 95% CI, 1.8-2.7 vs OR, 1.4; 95% CI, 1.0-1.8). In addition, early and late seizures (OR, 2.4; 95% CI, 1.6-3.4 vs OR, 2.7; 95% CI, 1.8-4.1) and stroke subtypes were associated with poor outcomes (OR, 2.6; 95% CI, 1.9-3.7 vs OR, 1.9; 95% CI, 1.0-3.6). Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that PSSs were associated with significantly increased mortality and severe disability in patients with history of stroke. Unraveling these associations is a high clinical and research priority. Trials of interventions to prevent seizures may be warranted.

Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy. METHODS: We searched articles until January 25, 2022, in MEDLINE, Embase, PsycInfo, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker's pooled standardized mean difference (SMD) and 95% CI. Molecular interaction network and enrichment analyses were conducted in Cytoscape (PROSPERO CRD42021297110). RESULTS: We included 22 studies with 1,499 cases with post-brain injury epilepsy and 7,929 controls without post-brain injury epilepsy. Forty-five biomarkers in the blood or CSF were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most of the biomarkers (28/45) were investigated in single studies; only 9 provided validation data, and studies used variable definitions for early-onset and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in 4 studies were significantly higher in patients with poststroke epilepsy (PSE) than those without PSE (SMD 0.44; CI 0.19-0.69). From individual studies, 15 biomarkers in the blood and 7 in the CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (interleukin [IL]-6, IL-1ß]) were predominantly inflammation related. DISCUSSION: We cannot yet recommend using the reported biomarkers for designing antiepileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Although our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual's genetic susceptibilities might contribute to his/her risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted.

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Comparison of Sex-Based In-Hospital Procedural Outcomes and Hospital Readmission Frequency After Patent Foramen Ovale Occluder Device Placement: A Propensity Matched National Cohort.

Patent foramen ovale (PFO) occluder device has been shown to reduce the chance of recurrent stroke. Per guidelines, stroke is higher in females but procedural efficacy and complications based on sex difference is understudied. The nationwide readmission database (NRD) was used to create sex cohorts using ICD-10 Procedural code for elective PFO occluder device placement performed during the years 2016-2019. The 2 groups were compared using propensity score matching (PSM) and multivariate regression models that matched for confounders to report multivariate odds ratio (mOR) for primary and secondary cardiovascular outcomes. Outcomes included in-hospital mortality, acute kidney injury (AKI), acute ischemic stroke, postprocedure bleeding, and cardiac tamponade. Statistical analysis was performed using STATA v. 17. A total of 5818 patients who underwent PFO occluder device placement were identified, of which 3144 (54.0%) were females, and 2673 (46.0%) were males. There was no difference in periprocedural in-hospital mortality, new onset acute ischemic stroke, postprocedural bleeding, or cardiac tamponade between both sexes undergoing occluder device placement. AKI incidence was higher in males compared to females after matching for CKD (mOR = 0.66; 95% CI [0.48-0.92]; P = 0.016) this can be procedural or can be secondary to volume status or nephrotoxins. Males also had a higher length of stay (LOS) at their index hospitalization (2 days vs 1 day) which led to slightly higher total hospitalization cost ($26,585 vs $24,265). Our data did not show a statistically significant difference in the readmission LOS trends between the 2 groups at 30, 90, and 180 days. This national retrospective cohort study of PFO occluder outcomes shows similar efficacy and complication rates between sexes, with the exception of AKI incidence which was higher in males. AKI occurrence was high in males that can be limited due to unavailability of data about hydration status and nephrotoxic medications.

Vancomycin functionalized WO3 thin film-based impedance sensor for efficient capture and highly selective detection of Gram-positive bacteria.

In this study, we report a facile, reusable, and highly sensitive label-free impedance sensor for discriminating Gram-positive and Gram-negative bacteria. The impedance sensor was fabricated using gold interdigitated electrodes onto a tungsten oxide thin film. X-Ray diffraction confirmed the formation of polycrystalline tungsten oxide. Field emission scanning electron microscopy and atomic force microscopy revealed that tungsten oxide has a porous structure. Tungsten oxide was functionalized with vancomycin, a glycopeptide antibiotic known to have a specific interaction with the peptidoglycan layer of Gram-positive bacteria. Fourier transform infrared microscopy and scanning electron microscopy were employed to test the morphological coating of vancomycin on interdigitated electrodes/tungsten oxide sensor. The functionalized tungsten oxide sensor was highly efficient in the capture of Gram-positive bacteria. The impedance measurement was also sensitive to differentiate between viable and non-viable Gram-positive bacteria. Limit of detection 102 colony forming unit/ml, linear dynamic range 102-107 colony forming unit/ml under physiological conditions and reusable nature of this vancomycin coated impedance sensor provide a label-free strategy for quick, sensitive and highly selective detection of Gram-positive bacteria.

Sex-Specific Outcomes After Transcatheter Aortic Valve Replacement: FDA Patient-Level Meta-Analysis of Premarket Clinical Trials.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a less invasive alternative approach to surgery. Individual randomized clinical trials evaluating the safety and efficacy of TAVR were mostly underpowered for conducting separate analyses for women and men. We pooled data from premarket TAVR clinical trials comparing short (30 days)- and long-term (∼2 years) outcomes by sex. METHODS: Patient-level data from the TAVR arms of six clinical trials were pooled (2515 patients). Random-effects models for time-to-event outcomes (odds ratios [ORs] for 30-day outcomes and hazard ratios [HRs] for complete follow-up for mortality, ischemic stroke, kidney injury, major bleeding, myocardial infarction, and device migration) and dichotomous outcomes (ORs for reintervention, rehospitalization, and pacemaker implantation) were then fit to directly compare outcomes between women and men. RESULTS: Overall, the pattern of individual comorbidities was more severe in men. There was no difference in mortality risk at 30 days (female-to-male OR = 1.00 [0.69-1.46]); however, at follow-up completion (∼2 years post-TAVR), women had a 24% lower mortality risk than men (HR = 0.76 [95% CI: 0.65-0.89]). Women also had a 30% lower risk of kidney injury at 30 days (OR = 0.70 [0.49-0.98]), which increased to 33% over the complete follow-up period (HR = 0.67 [0.51-0.87]). Major bleeding was more common in women compared to men at both 30 days (OR = 1.44 [1.19-1.76]) and long-term follow-up (HR = 1.22 [1.04-1.43]). For dichotomous outcomes, women had a 68% lower risk for reinterventions (OR = 0.32 [0.18-0.58]). We did not observe any difference in the risk of ischemic stroke, myocardial infarction, device migration, rehospitalizations, or pacemaker implantations between sexes. CONCLUSIONS: This patient-level data meta-analysis of six premarket clinical trials found that women who received TAVR had fewer comorbidities at baseline. Acute outcomes (30 day) with respect to mortality were similar. Women were observed to have a lower risk of kidney injury, but higher risk of major bleeding compared to men receiving TAVR at 30 days. At complete follow-up, statistically significant advantages for women emerged in improved survival and lower reintervention risk. No differences in ischemic stroke, pacemaker implantation, or rehospitalization were observed. That women are healthier at baseline and develop fewer postprocedural complications than men may explain their higher survival.

Time From Imaging to Endovascular Reperfusion Predicts Outcome in Acute Stroke.

BACKGROUND AND PURPOSE: This study aims to describe the relationship between computed tomographic (CT) perfusion (CTP)-to-reperfusion time and clinical and radiological outcomes, in a cohort of patients who achieve successful reperfusion for acute ischemic stroke. METHODS: We included data from the CRISP (Computed Tomographic Perfusion to Predict Response in Ischemic Stroke Project) in which all patients underwent a baseline CTP scan before endovascular therapy. Patients were included if they had a mismatch on their baseline CTP scan and achieved successful endovascular reperfusion. Patients with mismatch were categorized into target mismatch and malignant mismatch profiles, according to the volume of their Tmax >10s lesion volume (target mismatch, <100 mL; malignant mismatch, >100 mL). We investigated the impact of CTP-to-reperfusion times on probability of achieving functional independence (modified Rankin Scale, 0-2) at day 90 and radiographic outcomes at day 5. RESULTS: Of 156 included patients, 108 (59%) had the target mismatch profile, and 48 (26%) had the malignant mismatch profile. In patients with the target mismatch profile, CTP-to-reperfusion time showed no association with functional independence (P=0.84), whereas in patients with malignant mismatch profile, CTP-to-reperfusion time was strongly associated with lower probability of functional independence (odds ratio, 0.08; P=0.003). Compared with patients with target mismatch, those with the malignant mismatch profile had significantly more infarct growth (90 [49-166] versus 43 [18-81] mL; P=0.006) and larger final infarct volumes (110 [61-155] versus 48 [21-99] mL; P=0.001). CONCLUSIONS: Compared with target mismatch patients, those with the malignant profile experience faster infarct growth and a steeper decline in the odds of functional independence, with longer delays between baseline imaging and reperfusion. However, this does not exclude the possibility of treatment benefit in patients with a malignant profile.

Computed tomographic perfusion to Predict Response to Recanalization in ischemic stroke.

OBJECTIVE: To assess the utility of computed tomographic (CT) perfusion for selection of patients for endovascular therapy up to 18 hours after symptom onset. METHODS: We conducted a multicenter cohort study of consecutive acute stroke patients scheduled to undergo endovascular therapy within 90 minutes after a baseline CT perfusion. Patients were classified as "target mismatch" if they had a small ischemic core and a large penumbra on their baseline CT perfusion. Reperfusion was defined as >50% reduction in critical hypoperfusion between the baseline CT perfusion and the 36-hour follow-up magnetic resonance imaging. RESULTS: Of the 201 patients enrolled, 190 patients with an adequate baseline CT perfusion study who underwent angiography were included (mean age = 66 years, median NIH Stroke Scale [NIHSS] = 16, median time from symptom onset to endovascular therapy = 5.2 hours). Rate of reperfusion was 89%. In patients with target mismatch (n = 131), reperfusion was associated with higher odds of favorable clinical response, defined as an improvement of ≥8 points on the NIHSS (83% vs 44%; p = 0.002, adjusted odds ratio [OR] = 6.6, 95% confidence interval [CI] = 2.1-20.9). This association did not differ between patients treated within 6 hours (OR = 6.4, 95% CI = 1.5-27.8) and those treated > 6 hours after symptom onset (OR = 13.7, 95% CI = 1.4-140). INTERPRETATION: The robust association between endovascular reperfusion and good outcome among patients with the CT perfusion target mismatch profile treated up to 18 hours after symptom onset supports a randomized trial of endovascular therapy in this patient population. Ann Neurol 2017;81:849-856.

The PARP Inhibitor Veliparib Can Be Safely Added to Bendamustine and Rituximab and Has Preliminary Evidence of Activity in B-Cell Lymphoma.

Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20-400 mg twice a day, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2 Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702 Clin Cancer Res; 23(15); 4119-26. ©2017 AACR.