Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19⁺ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity. Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR. See related commentary by Mackall and Miklos, p. 1371. This article is highlighted in the In This Issue feature, p. 1355

We developed a high-throughput mass spectrometry–based method to simultaneously quantify numerous small-molecule thiols and disulfides in blood plasma. Application of this assay to analyze plasma from patients with known oxidative stress (sickle cell disease and sepsis) and from a patient with sickle cell disease treated with the antioxidant N-acetylcysteine suggests that cysteine disulfides, in particular protein-bound cysteine, serve as sensitive plasma biomarkers for the extent of oxidative stress and effectiveness of antioxidant treatment.

Objectives: Spontaneous bacterial peritonitis (SBP) is a common and high-mortality infectious complication of patients with cirrhosis. New inflammatory markers are associated with morbidity/mortality in various diseases. The aim of our study was to find the 30-day mortality rate of SBP and their predictors. Patients and methods: Seventy patients with cirrhosis complicated with SBP and 55 non-SBP controls were enrolled into the study, and patients were evaluated for mortality rate and its predictors. Results: The 30-day and 3-month mortality rates in the SBP group were 26.1 and 50.7%, respectively. Mortality rates were higher in the SBP group than in the controls. Symptoms at hospital admission and cell counts in ascitic fluid made no difference in predicting 30-day mortality. Patients with SBP with high serum neutrophil counts, high neutrophil–lymphocyte ratio, high C reactive protein (CRP)/albumin ratio, and high model for end-stage liver disease (MELD) score had higher 30-day mortality rates. We determined optimal cutoff values of MELD scores and serum neutrophil counts for predicting 30-day mortality as 20.5 and 6850/mm³, respectively. The sensitivity and specificity for the MELD cutoff value were 83.3 and 80.4%, respectively. We also followed up patients for 60 months after SBP; the patients with high inflammatory markers and MELD scores at the time of SBP diagnosis had worse survival compared with the group with lower levels. Conclusion: Our results suggest that SBP has high 30-day mortality. MELD scores and inflammatory markers (CRP, CRP albumin ratio, neutrophil–lymphocyte ratio) may be used to predict mortality in patients with SBP.

Platelets are stored at room temperature for 5 to 7 days (room temperature–stored platelets [RSPs]). Because of frequent and severe shortages, the US Food and Drug Administration recently approved up to 14-day cold-stored platelets (CSPs) in plasma. However, the posttransfusion function of CSPs is unknown and it is unclear which donors are best suited to provide either RSPs or CSPs. In this study, we sought to evaluate the posttransfusion platelet function and its predictors for platelets stored for the maximum approved storage times (7-day RSPs and 14-day CSPs) in healthy volunteers on acetylsalicylic acid (ASA). We conducted a randomized crossover study in 10 healthy humans. Individuals donated 1 platelet unit, stored at either 22°C or 4°C based on randomization. Before transfusion, participants ingested ASA to inhibit endogenous platelets. Transfusion recipients were tested for platelet function and lipid mediators. Platelet units were tested for lipid mediators only. A second round of transfusion with the alternative product was followed by an identical testing sequence. RSPs reversed platelet inhibition significantly better in αIIbβ3 integrin activation–dependent assays. In contrast, CSPs in recipients led to significantly more thrombin generation, which was independent of platelet microparticles. Lysophosphatidylcholine-O species levels predicted the procoagulant capacity of CSPs. In contrast, polyunsaturated fatty acid concentrations predicted the aggregation response of RSPs. In summary, we provide, to our knowledge, the first efficacy data of extended-stored CSPs in plasma. Our results suggest that identifying ideal RSP and CSP donors is possible, and pave the way for larger studies in the future. This trial is registered at www.ClinicalTrials.gov as #NCT0511102.