Xianghua Luo

Summary Report on the Graded Prognostic Assessment: An Accurate and Facile Diagnosis-Specific Tool to Estimate Survival for Patients With Brain Metastases

PURPOSE Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians. METHODS A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis. RESULTS Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined. CONCLUSION 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.

Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients.

PURPOSE Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). METHODS AND MATERIALS A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. RESULTS The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. CONCLUSION The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.

Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

We have previously shown that NKG2C+ NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C+ NK cells 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 killer Ig-like receptor 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 with 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 Ag in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.

Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

PURPOSE The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. METHODS AND MATERIALS A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. RESULTS Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. CONCLUSIONS The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)

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-γ 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-γ 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.

Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition.

Purpose: The graft versus leukemia effect by natural killer (NK) cells prevents relapse following hematopoietic stem cell transplantation. We determined whether a novel bispecific killer cell engager (BiKE) signaling through CD16 and targeting CD33 could activate NK cells at high potency against acute myelogenous leukemia (AML) targets. Experimental Design: We investigated the ability of our fully humanized CD16 × CD33 (CD16 × 33) BiKE to trigger in vitro NK cell activation against HL60 (CD33+), RAJI (CD33−), and primary AML targets (de novo and refractory) to determine whether treatment with CD16 × 33 BiKE in combination with an ADAM17 inhibitor could prevent CD16 shedding (a novel inhibitory mechanism induced by NK cell activation) and overcome inhibition of class I MHC recognizing inhibitory receptors. Results: NK cell cytotoxicity and cytokine release were specifically triggered by the CD16 × 33 BiKE when cells were cultured with HL60 targets, CD33+ de novo and refractory AML targets. Combination treatment with CD16 × 33 BiKE and ADAM17 inhibitor resulted in inhibition of CD16 shedding in NK cells, and enhanced NK cell activation. Treatment of NK cells from double umbilical cord blood transplant (UCBT) recipients with the CD16 × 33 BiKE resulted in activation, especially in those recipients with cytomegalovirus reactivation. Conclusion: CD16 × 33 BiKE can overcome self-inhibitory signals and effectively elicit NK cell effector activity against AML. These in vitro studies highlight the potential of CD16 × 33 BiKE ± ADAM17 inhibition to enhance NK cell activation and specificity against CD33+ AML, which optimally could be applied in patients with relapsed AML or for adjuvant antileukemic therapy posttransplantation. Clin Cancer Res; 19(14); 3844–55. ©2013 AACR.

Improving Child and Parent Mental Health in Primary Care: A Cluster-Randomized Trial of Communication Skills Training

OBJECTIVE. We examined child and parent outcomes of training providers to engage families efficiently and to reduce common symptoms of a range of mental health problems and disorders. METHODS. Training involved three 1-hour discussions structured around video examples of family/provider communication skills, each followed by practice with standardized patients and self-evaluation. Skills targeted eliciting parent and child concerns, partnering with families, and increasing expectations that treatment would be helpful. We tested the training with providers at 13 sites in rural New York, urban Maryland, and Washington, DC. Children (5–16 years of age) making routine visits were enrolled if they screened “possible” or “probable” for mental disorders with the Strengths and Difficulties Questionnaire or if their provider said they were likely to have an emotional or behavioral problem. Children and their parents were then monitored for 6 months, to assess changes in parent-rated symptoms and impairment and parent symptoms. RESULTS. Fifty-eight providers (31 trained and 27 control) and 418 children (248 patients of trained providers and 170 patients of control providers) participated. Among the children, 72% were in the possible or probable categories. Approximately one half (54%) were white, 30% black, 12% Latino, and 4% other ethnicities. Eighty-eight percent (367 children) completed follow-up monitoring. At 6 months, minority children cared for by trained providers had greater reduction in impairment (−0.91 points) than did those cared for by control providers but no greater reduction in symptoms. Seeing a trained provider did not have an impact on symptoms or impairment among white children. Parents of children cared for by trained providers experienced greater reduction in symptoms (−1.7 points) than did those cared for by control providers. CONCLUSION. Brief provider communication training had a positive impact on parent mental health symptoms and reduced minority childrens impairment across a range of problems.

NK cell education after allogeneic transplantation: Dissociation between recovery of cytokine-producing and cytotoxic functions

Natural killer (NK) cells mediate GVL effects after allogeneic hematopoietic cell transplantation (allo-HCT) by the production of inflammatory cytokines and by direct target lysis. The acquisition of both functions was presumed to be developmentally linked, but this linkage remained unstudied after allo-HCT. We tested the cytokine production and degranulation of reconstituting NK cells after adult unrelated donor or umbilical cord blood grafting. Recipients of T cell-depleted transplants, receiving no immune suppression, showed diminished NK cell degranulation. In contrast, degranulation was normal or increased after T-cell replete transplants given with immune suppression. Strikingly, target cell-induced IFNγ production was markedly diminished in all transplant settings, especially with T cell-depleted or naive T cell-containing umbilical cord blood grafts, suggesting a role for T cells in NK education. Although degranulation was similar in the KIR(+) and KIR(-) populations that coexpressed NKG2A, target cell-induced IFNγ production was limited to the subset of NK cells expressing KIR inhibited by self-ligands. Thus, cytokine production and cytotoxic function do not consistently coexist in NK cells reconstituting after allo-HCT. Exposure to IL-15 rapidly increased target-inducible IFNγ production, indicative of IL-15s potential as a therapeutic tool to enhance NK cell function to protect against infection and relapse after allo-HCT.

Similar exposure to a tobacco-specific carcinogen in smokeless tobacco users and cigarette smokers

Smokeless tobacco has been proposed as a reduced risk substitute for smoking, but no large studies have investigated exposure to the powerful carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokeless tobacco users versus smokers. The purpose of this study was to carry out such a comparison. Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of NNK exposure, and cotinine, a biomarker of nicotine exposure, were quantified in the urine of 420 smokers and 182 smokeless tobacco users who were participants in studies designed to reduce their use of these products. The measurements were taken at baseline, before intervention. Levels of total NNAL per milliliter of urine were significantly higher in smokeless tobacco users than in smokers (P < 0.0001). When adjusted for age and gender, levels of total NNAL per milligram of creatinine were also significantly higher in smokeless tobacco users than in smokers (P < 0.001). Levels of cotinine per milliliter of urine and per milligram of creatinine were significantly higher in smokeless tobacco users than in smokers (P < 0.001). These results show similar exposures to the potent tobacco-specific carcinogen NNK in smokeless tobacco users and smokers. These findings do not support the use of smokeless tobacco as a safe substitute for smoking. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1567–72)

Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment (GPA)

PURPOSE Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. METHODS AND MATERIALS In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool (brainmetgpa.com) simplified GPA use. RESULTS The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. CONCLUSIONS This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.