Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

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During mouse cytomegalovirus (CMV) infection, a population of Ly49H ؉ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C ؉ NK cells expanded and were potent producers of IFN␥. NKG2C ؉ NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulinlike receptors were required for robust IFN␥ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56 dim NK cells. Strikingly, increased frequencies of NKG2C ؉ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C ؉ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFN␥ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFN␥, T-bet, and IL-15R␣ mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation. (Blood. 2012; 119(11):2665-2674) IntroductionNatural killer (NK) cells are important effectors during the host innate immune response to viral infections. They can recognize and eliminate virally infected cells, interact with dendritic cells, and produce a range of cytokines and chemokines (eg, IFN␥, TNF-␣, MIP-1␣, MIP-1␤, and RANTES) that recruit and modulate the adaptive immune response.Under normal homeostatic conditions, a balance of activating and inhibitory signals tightly controls NK-cell function. 1,2 The best-characterized inhibitory receptors are the inhibitory killer cell immunoglobulin-like receptors (KIRs) that recognize allelic epitopes present on certain class I human leukocyte antigens (HLAs) and the C-type lectin-like receptor NKG2A, which recognizes the nonclassic class I HLA, HLA-E. 3,4 Activating signals are mediated by receptor families, including activating KIR, NKG2C, NKG2D, the natural cytotoxicity receptors (NKp30, NKp44, and NKp46), CD16, and CD244. 1 When self HLA is down-regulated, cells are susceptible to NK-cell lysis because of the lack of ligands for the inhibitory receptors, a phenomenon known as the "missing self" hypothesis. 5,6 Human cytomegalovirus (CMV), a member of the Herpesviridae family, causes asymptomatic or mild illness in healthy people. 7 CMV remains latent in infected hosts and, by adulthood, approximately 60% of people in the United States are seropositive for CMV. 8 However, for patients immunosuppressed due to HIV infection or solid organ or hematopoietic call transplantatio...

• Activated NK cells loose CD16 (FcRgIII) and CD62L through a metalloprotease called ADAM17. • Inhibition of ADAM17enhances CD16 mediated NK cell function by preserving CD16 on the NK cell surface to enhance ADCC.The Fc receptor CD16 is present on essentially all CD56 dim peripheral blood natural killer (NK) cells. Upon recognition of antibody-coated cells it delivers a potent signal to NK cells, which eliminate targets through direct killing and cytokine production. Here we investigated the regulation of CD16 surface expression after NK cell activation. Cytokine activation and target cell stimulation led to marked decreases in CD16 expression. Activation of CD56 dim NK cells by cross-linking CD16 with antibodies resulted in a loss of CD16 and CD62L, which correlated with increased interferon-g production. A disintegrin and metalloprotease-17 (ADAM17) is shown to be expressed by NK cells, and its selective inhibition abrogated CD16 and CD62L shedding, and led to enhanced interferon-g production, especially when triggering was delivered through CD16. Fc-induced production of cytokines by NK cells exposed to rituximab-coated B cell targets was also enhanced by ADAM17 inhibition. This supports an important role for targeting ADAM17 to prevent CD16 shedding and improve the efficacy of therapeutic antibodies. Our findings demonstrate that over-activation of ADAM17 in NK cells may be detrimental to their effector functions by down-regulating surface expression of CD16 and CD62L. (Blood. 2013;121(18):3599-3608)

We have previously shown that NKG2C+ NK cells from CMV naïve umbilical cord blood (UCB) grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation (HCT). In this study, recipients of adult donor HCT were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C+ NK cells in order to determine responses to secondary CMV events. Expansion of NKG2C+ NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV positive recipients receiving grafts from CMV seropositive or seronegative donors. These in vivo expanded NKG2C+ NK cells had an increased capacity for target cell induced cytokine production, expressed an inhibitory KIR for self HLA and preferentially acquired CD57. Most importantly, NKG2C+ NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared to NKG2C+ NK cells from seronegative donors. We conclude that NKG2C+ memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV antigen in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.