Background Intracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes. Methods Serum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline. Results A total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0–3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days. Conclusions Aseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes.

Natural killer (NK) cells are critical effectors of the immune system. NK cells recognize unhealthy cells by specific ligands [e.g., MHC- class I chain related protein A or B (MIC-A/B)] for further elimination by cytotoxicity. Paradoxically, cancer cells down-regulate MIC-A/B and evade NK cell’s anticancer activity. Recent data indicate that cellular-stress induces MIC-A/B, leading to enhanced sensitivity of cancer cells to NK cell-mediated cytotoxicity. In this Perspective article, we hypothesize that current chemotherapeutics at sub-lethal, non-toxic dose may promote cellular-stress and up-regulate the expression of MIC-A/B ligands to augment cancer’s sensitivity to NK cell-mediated cytotoxicity. Preliminary data from two human breast cancer cell lines, MDA-MB-231 and T47D treated with clinically relevant therapeutics such as doxorubicin, paclitaxel and methotrexate support the hypothesis. The goal of this Perspective is to underscore the prospects of current chemotherapeutics in NK cell immunotherapy, and discuss potential challenges and opportunities to improve cancer therapy.

Background: Intracerebral hemorrhage (ICH) results in significant mortality and morbidity and initiates a cascade of inflammatory cell activation. Leukocyte subtypes have different effects, with monocytes contributing to increased hematoma expansion and mortality and neutrophils decreasing hematoma expansion. However, the response of cerebrospinal fluid (CSF) leukocytes to ICH with IVH has not been investigated. Methods: We retrospectively analyzed CSF and serum leukocyte counts from patients enrolled in CLEAR-III. After correction for CSF red blood cell (RBC) counts, data were plotted chronologically. Linear mixed-effects models were used to assess the differences in leukocyte subtypes after intraventricular saline or alteplase. Generalized linear models are being created to assess the relationship between CSF leukocyte subtypes and IVH volumes and 30, 60, 90, and 180-day outcomes. Results: Data were available for 237 and 228 patients in the saline and alteplase groups, respectively. Serum total white blood cell (WBC) and neutrophil counts increased after ICH, peaking at two days. Significant increases occurred in serum monocyte and lymphocyte counts, peaking at 6 and 10 days, respectively. Intraventricular alteplase had no effect on serum leukocyte counts. Peak CSF leukocyte counts occurred on day 1 after IVH (pretreatment) in the saline group. However, intraventricular alteplase resulted in a significant increase in WBC ( P =0.0001), neutrophil ( P =0.0003), monocyte ( P =0.0064), and lymphocyte counts ( P= 0.0339), peaking two days after starting treatment. No significant associations between peak serum or CSF cell counts and 30, 180, and 365 day modified Rankin Scale were found. Conclusions: ICH drives an increase in serum leukocyte counts. Intraventricular alteplase results in an increase in all CSF leukocyte subtypes. Further work will be presented on the complex interactions between leukocyte counts, ICH severity, and outcomes.