Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy.

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

Global Transient Amnesia as the Predominant Symptom of Cardiac Myxoma: A Case Report.

BACKGROUND The most common neurological symptoms from cardiac myxoma-induced stroke include territories of middle cerebral arteries, rendering posterior stroke less common. Although transient global amnesia usually has a benign prognosis, amnesia in the setting of concerning cerebellar symptoms should raise the suspicion for posterior circulation involvement. These benign-appearing symptoms can be manifestations of an acute cerebrovascular accident (CVA). This unusual presentation can delay workup for underlying pathology. CASE REPORT A 67-year-old woman presented to the local emergency department after an episode of global amnesia that lasted about 15 minutes and was associated with some dizziness. The patient also reported a history of chronic disequilibrium. The head CT scan was negative for any acute findings. A follow-up MRI of the brain demonstrated acute small lacunar infarcts within the left cerebellum and right parietal lobe. An echocardiogram was performed due to concern for the cardioembolic source, which revealed left atrial myxoma. She was transferred to a tertiary center for immediate surgical intervention due to the high risk of embolization associated with the condition. The patient subsequently underwent successful surgical excision of the lesion. CONCLUSIONS Cardiac myxoma, although a rare cause of posterior stroke, needs prompt intervention as it is associated with a high risk of systemic embolization, including recurrent CVA. Transient global amnesia is an atypical presentation of cardiac myxoma that can easily be overlooked, delaying timely diagnosis and prompt intervention. Early recognition and surgical resection are crucial to prevent potentially life-threatening consequences.

Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160.

Rural Residence and Antihypertensive Medication Use in US Stroke Survivors.

Background Relatively greater increases in hypertension prevalence among US rural residents may contribute to geographic disparities in recurrent stroke. There is limited US information on poststroke antihypertensive medication use by rural/urban residence. We assessed antihypertensive use and lifestyle characteristics for US rural compared with urban stroke survivors and residence-based trends in use between 2005 and 2019. Methods and Results US stroke survivors with hypertension were identified in the 2005 to 2019 national Behavioral Risk Factor Surveillance System surveys. We ascertained the survey-weighted prevalence of reported antihypertensive use and lifestyle characteristics (ie, physical activity, diabetes, cholesterol, body mass index, and smoking) among respondents with hypertension in odd years over this period by rural/urban residence. Separate trend analyses were used to detect changes in use over time. Survey-weighted logistic regression was used to calculate unadjusted and adjusted (sociodemographic and lifestyle factors) odds ratios for antihypertensive use by year. Our study included 82 175 individuals (36.4% rural residents). Lifestyle characteristics were similar between rural and urban residents except for higher smoking prevalence among rural residents. Antihypertensive use was similar between rural and urban stroke survivors in unadjusted and adjusted analyses (>90% in both populations). Trend analyses showed a small but significant increase in antihypertensive use over time among urban (P=0.033) but not rural stroke survivors (P=0.587). Conclusions Our findings indicate that poststroke antihypertensive use is comparable in rural and urban residents with a reported history of hypertension, but additional work is merited to identify reasons for a trend for increased use of these drugs among urban residents.

Cardiovascular Risk Factor Profiles, Emergency Department Visits, and Hospitalizations for Women and Men with a History of Stroke or Transient Ischemic Attack: A Cross-Sectional Study.

Background: The relationship between cardiovascular disease risk factors (CVD-RFs) and health care utilization may differ by sex. We determined whether having more CVD-RFs was associated with all-cause emergency department (ED) visits and all-cause hospitalizations for women and men with prior stroke/transient ischemic attack (TIA). Materials and Methods: In this cross-sectional study, we used nationally representative Medical Expenditure Panel Survey (2012-2015) data for persons aged ≥18 years with a prior stroke/TIA. CVD-RF summary scores include six self-reported factors (hypertension, diabetes, high cholesterol, physical inactivity, smoking, and obesity). Sex-specific covariate-adjusted logistic regression models assessed associations between CVD-RF scores and having one or more all-cause ED visits and one or more all-cause hospitalizations. Results: The weighted sample represents 9.1 million individuals (mean age 66.6 years; 54.3% women). Prevalence of low (0-1 risk factors), intermediate (2-3), and high (4-6) CVD-RF scores was 19.4%, 60.5%, and 20.1% for women and 14.6%, 60.2%, and 25.2% for men, respectively. Women having intermediate and high scores had a 1.58-fold (95% confidence interval [CI], 1.14-2.18) and 2.21-fold (95% CI, 1.50-3.25) increased odds of ED visits compared with women with low scores. Women with high CVD-RF scores had a 2.18-fold (95% CI, 1.42-3.34) increased odds of hospitalizations, but there was no association for women with intermediate CVD-RF profiles. There was no association between CVD-RF scores and either outcome for men. Conclusions: Women, but not men, with high and intermediate CVD-RF profiles had increased odds of all-cause ED visits; women with high CVD-RF profiles had increased odds of all-cause hospitalizations. The burden of CVD-RFs may be a sex-specific predictor of higher health care utilization in women with a history of stroke/TIA.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

NEK5 activity regulates the mesenchymal and migratory phenotype in breast cancer cells.

PURPOSE: Breast cancer remains a prominent global disease affecting women worldwide despite the emergence of novel therapeutic regimens. Metastasis is responsible for most cancer-related deaths, and acquisition of a mesenchymal and migratory cancer cell phenotypes contributes to this devastating disease. The utilization of kinase targets in drug discovery have revolutionized the field of cancer research but despite impressive advancements in kinase-targeting drugs, a large portion of the human kinome remains understudied in cancer. NEK5, a member of the Never-in-mitosis kinase family, is an example of such an understudied kinase. Here, we characterized the function of NEK5 in breast cancer. METHODS: Stably overexpressing NEK5 cell lines (MCF7) and shRNA knockdown cell lines (MDA-MB-231, TU-BcX-4IC) were utilized. Cell morphology changes were evaluated using immunofluorescence and quantification of cytoskeletal components. Cell proliferation was assessed by Ki-67 staining and transwell migration assays tested cell migration capabilities. In vivo experiments with murine models were necessary to demonstrate NEK5 function in breast cancer tumor growth and metastasis. RESULTS: NEK5 activation altered breast cancer cell morphology and promoted cell migration independent of effects on cell proliferation. NEK5 overexpression or knockdown does not alter tumor growth kinetics but promotes or suppresses metastatic potential in a cell type-specific manner, respectively. CONCLUSION: While NEK5 activity modulated cytoskeletal changes and cell motility, NEK5 activity affected cell seeding capabilities but not metastatic colonization or proliferation in vivo. Here we characterized NEK5 function in breast cancer systems and we implicate NEK5 in regulating specific steps of metastatic progression.

Role of calcium in hormone-independent and -resistant breast cancer.

Approximately one-third of estrogen receptor (ER) positive breast tumors fail to respond to or become resistant to hormonal therapy. Although the mechanisms responsible for hormone resistance are not completely understood, resistance is associated with alterations in ERα; overexpression of proteins that interact with the receptor; and hormone-independent activation of the receptor by growth factor signal transduction pathways. Our previous studies show that in estrogen dependent breast cancer cells, activation of the epidermal growth factor signaling pathway increases intracellular calcium which binds to and activates ERα through sites in the ligand-binding domain of the receptor and that treatment with extracellular calcium increases the concentration of intracellular calcium which activates ERα and induces hormone-independent cell growth. The present study asked whether overexpression of calcium channels contributes to the hormone-independent and -resistant phenotype of breast cancer cells and whether clinically used calcium channel blockers reverse hormone independence and resistance. The results show that hormone-independent and -resistant cells overexpress calcium channels, have high concentrations of intracellular calcium, overexpress estrogen responsive genes and, as expected, grow in the absence of estradiol and that treatment with calcium channel blockers decreased the concentration of intracellular calcium, the expression of estrogen responsive genes and cell growth. More importantly, in hormone-resistant cells, treatment that combined a calcium channel blocker with an antiestrogen reversed resistance to the antiestrogen.

Correction: Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor.

[This corrects the article DOI: 10.1371/journal.pone.0226464.].

Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database.

BACKGROUND: Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non-HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk-benefit profiles, timely identification of emerging safety signals, and comparisons between treatments. OBJECTIVES: Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies. PATIENTS/METHODS: We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept. RESULTS: PwcHA share mortality causes with the non-HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%). CONCLUSIONS: A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach.

Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B-cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression-free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.

Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor.

Metaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due to rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers. We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, and in vivo implanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass. DACi significantly suppressed the total number of lung metastasis in vivo using our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genes in vitro, tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC. This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated.

A novel screening approach comparing kinase activity of small molecule inhibitors with similar molecular structures and distinct biologic effects in triple-negative breast cancer to identify targetable signaling pathways.

Breast cancer affects women globally; the majority of breast cancer-related mortalities are due to metastasis. Acquisition of a mesenchymal phenotype has been implicated in the progression of breast cancer cells to an invasive, metastatic state. Triple-negative breast cancer (TNBC) subtypes have high rates of metastases, recurrence, and have poorer prognoses compared to other breast cancer types, partially due to lack of commonly targeted receptors. Kinases have diverse and pivotal functions in metastasis in TNBC, and discovery of new kinase targets for TNBC is warranted. We previously used a screening approach to identify intermediate-synthesis nonpotent, nonselective small-molecule inhibitors from the Published Kinase Inhibitor Set that reversed the mesenchymal phenotype in TNBC cells. Two of these inhibitors (GSK346294A and GSK448459A) are structurally similar, but have unique kinase activity profiles and exhibited differential biologic effects on TNBC cells, specifically on epithelial-to-mesenchymal transition (EMT). Here, we further interrogate these effects and compare activity of these inhibitors on transwell migration, gene (qRT-PCR) and protein (western blot) expressions, and cancer stem cell-like behavior. We incorporated translational patient-derived xenograft models in these studies, and we focused on the lead inhibitor hit, GSK346294A, to demonstrate the utility of our comparative analysis as a screening modality to identify novel kinase targets and signaling pathways to pursue in TNBC. This study introduces a new method for discovering novel kinase targets that reverse the EMT phenotype; this screening approach can be applied to all cancer types and is not limited to breast cancer.

Tracking Cardiac Rehabilitation Participation and Completion Among Medicare Beneficiaries to Inform the Efforts of a National Initiative.

BACKGROUND: Despite cardiac rehabilitation (CR) being shown to improve health outcomes among patients with heart disease, its use has been suboptimal. In response, the Million Hearts Cardiac Rehabilitation Collaborative developed a road map to improve CR use, including increasing participation rates to ≥70% by 2022. This observational study provides current estimates to measure progress and identifies the populations and regions most at risk for CR service underutilization. METHODS AND RESULTS: We identified Medicare fee-for-service beneficiaries who were CR eligible in 2016, and assessed CR participation (≥1 CR session attended), timely initiation (participation within 21 days of event), and completion (≥36 sessions attended) through 2017. Measures were assessed overall, by beneficiary characteristics and geography, and by primary CR-qualifying event type (acute myocardial infarction hospitalization; coronary artery bypass surgery; heart valve repair/replacement; percutaneous coronary intervention; or heart/heart-lung transplant). Among 366 103 CR-eligible beneficiaries, 89 327 (24.4%) participated in CR, of whom 24.3% initiated within 21 days and 26.9% completed CR. Eligibility was highest in the East South Central Census Division (14.8 per 1000). Participation decreased with increasing age, was lower among women (18.9%) compared with men (28.6%; adjusted prevalence ratio: 0.91 [95% CI, 0.90-0.93]) was lower among Hispanics (13.2%) and non-Hispanic blacks (13.6%) compared with non-Hispanic whites (25.8%; adjusted prevalence ratio: 0.63 [0.61-0.66] and 0.70 [0.67-0.72], respectively), and varied by hospital referral region and Census Division (range: 18.6% [East South Central] to 39.1% [West North Central]) and by qualifying event type (range: 7.1% [acute myocardial infarction without procedure] to 55.3% [coronary artery bypass surgery only]). Timely initiation varied by geography and qualifying event type; completion varied by geography. CONCLUSIONS: Only 1 in 4 CR-eligible Medicare beneficiaries participated in CR and marked disparities were observed. Reinforcement of current effective strategies and development of new strategies will be critical to address the noted disparities and achieve the 70% participation goal.

Systematic model of peripheral inflammation after subarachnoid hemorrhage.

OBJECTIVE: To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models. METHODS: This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: <24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously. RESULTS: Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity. CONCLUSIONS: Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Treatment Strategies to Attenuate Perihematomal Edema in Patients With Intracerebral Hemorrhage.

Spontaneous intracerebral hemorrhage (SICH) continues to be a significant cause of neurologic morbidity and mortality throughout the world. Although recent advances in the treatment of SICH have significantly decreased mortality rates, functional recovery has not been dramatically improved by any intervention to date. There are 2 predominant mechanisms of brain injury from intracerebral hemorrhage: mechanical injury from the primary hematoma (including growth of that hematoma), and secondary injury from perihematomal inflammation. For instance, in the hours to weeks after SICH as the hematoma is being degraded, thrombin and iron are released and can result in neurotoxicity, free radical damage, dysregulated coagulation, and harmful inflammatory cascades; this can clinically and radiologically manifest as perihematomal edema (PHE). PHE can contribute to mass effect, cause acute neurologic deterioration in patients, and has even been associated with poor long-term functional outcomes. PHE therefore lends itself to being a potential therapeutic target. In this article, we will review 1) the pathogenesis and time course of the development of PHE, and 2) the clinical series and trials exploring various methods, with a focus on minimally invasive surgical techniques, to reduce PHE and minimize secondary brain injury. Promising areas of continued research also will be discussed.

Failure mode analysis of the Endologix endograft.

OBJECTIVE: Type III (T-III) endoleaks following endovascular aneurysm repair (EVAR) remain a major concern. Our center experienced a recent concentration of T-III endoleaks requiring elective and emergency treatment and prompted our review of all EVAR implants over a 40-month period from April 2011 until August 2014. This report represents a single center experience with T-III endoleak management with analysis of factors leading to the T-III-related failure of EVAR. METHODS: A retrospective review of all the operative reports, medical records, and computed tomography scans were reviewed from practice surveillance. Using Society for Vascular Surgery aneurysm reporting standards, we analyzed the morphology of the aneurysms before and after EVAR implant using computed tomography. Index procedure and frequency of reinterventions required to maintain aneurysm freedom from rupture were compared across all devices using SAS v 9.4 (SAS Institute, Inc, Cary, NC). Major adverse events (MAEs) requiring secondary interventions for aneurysm treatment beyond primary implant were analyzed for methods of failure. Aneurysm morphology of patients requiring EVAR was compared across all endograft devices used for repair. For purposes of MAE analysis, patients receiving Endologix (ELX) endograft were combined into group 1; Gore, Cook, and Medtronic endograft patients were placed into group 2. RESULTS: Overall, technical success and discharge survival were achieved in 97.3% and 98% of patients regardless of device usage. There was no significant device related difference identified between patient survival or freedom from intervention. MAEs involving aneurysm treatment were over seven-fold more frequent with ELX (group 1) vs non-ELX (group 2) endografts (P < .01). Group 1 patients with aneurysm diameters larger than 65 mm were associated with a highly significant value for development of a T-III endoleak (odds ratio, 11.16; 95% confidence interval, 2.17, 57.27; P = .0038). CONCLUSIONS: While EVAR technical success and survival were similar across all devices, ELX devices exhibited an unusually high incidence of T-III endoleaks when implanted in abdominal aortic aneurysms with a diameter of more than 65 mm. Frequent reinterventions were required for Endologix devices for prevention of aneurysm rupture due to T-III endoleaks.