The effect of imputed values on the distribution of the goodness-of-fit chi-square statistic

A method used to compensate for nonresponse is to impute missing values; that is, to replace each missing value with a respondent value selected from all observed values or from a subset of observed values. The imputation procedure used in this paper selects imputed values from the respondent data using simple random sampling with replacement within homogeneous subsets and replaces the missing values with these values to complete the data set. The empirical distribution of the goodness-of-fit chi-square statistic computed from the `completed' data set is compared to its asymptotic distribution and to the distribution of the traditional chi-square test statistic applied to the completed data set by ignoring the imputation.At nominal levels of five and ten percent, the asymptotic distribution of the goodness-of-fit chi-square statistic computed from the completed data set is shown to have a good empirical behavior at moderate sample sizes. When the imputed values are treated as actual responses and the imputation is ignored, the empirical levels of significance are much larger than the nominal levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26909/1/0000475.pd

Thin Melanoma with Nodal Involvement: Analysis of Demographic, Pathologic, and Treatment Factors with Regard to Prognosis.

BACKGROUND: Although only a small proportion of thin melanomas result in lymph node metastasis, the abundance of these lesions results in a relatively large absolute number of patients with a diagnosis of nodal metastases, determined by either sentinel lymph node (SLN) biopsy or clinical nodal recurrence (CNR). METHODS: Independent cohorts with thin melanoma and either SLN metastasis or CNR were identified at two melanoma referral centers. At both centers, SLN metastasis patients were included. At center 1, the CNR cohort included patients with initial negative clinical nodal evaluation followed by CNR. At center 2, the CNR cohort was restricted to those presenting in the era before the use of SLN biopsy. Uni- and multivariable analyses of melanoma-specific survival (MSS) were performed. RESULTS: At center 1, 427 CNR patients were compared with 91 SLN+ patients. The 5- and 10-year survival rates in the SLN group were respectively 88 and 84 % compared with 72 and 49 % in the CNR group (p \u3c 0.0001). The multivariate analysis showed age older than 50 years (hazard ratio [HR] 1.5; 95 % confidence interval [CI] 1.2-1.9), present ulceration (HR 1.9; 95 % CI 1.2-2.9), unknown ulceration (HR 1.6; 95 % CI 1.3-2.1), truncal site (HR 1.6; 95 % CI 1.2-2.2), and CNR (HR 3.3; 95 % CI 1.8-6.0) to be associated significantly with decreased MSS (p \u3c 0.01 for each). The center 2 cohort demonstrated remarkably similar findings, with a 5-year MSS of 88 % in the SLN (n = 29) group and 76 % in the CNR group (n = 39, p = 0.09). CONCLUSION: Patients with nodal metastases from thin melanomas have a substantial risk of melanoma death. This risk is lower among patients whose disease is discovered by SLN biopsy rather than CNR

Should tumor VEGF expression influence decisions on combining low-dose chemotherapy with antiangiogenic therapy? Preclinical modeling in ovarian cancer

Because of its low toxicity, low-dose (LD) chemotherapy is ideally suited for combination with antiangiogenic drugs. We investigated the impact of tumor vascular endothelial growth factor A (VEGF-A) expression on the efficacy of LD paclitaxel chemotherapy and its interactions with the tyrosine kinase inhibitor SU5416 in the ID8 and ID8-Vegf models of ovarian cancer. Functional linear models using weighted penalized least squares were utilized to identify interactions between Vegf, LD paclitaxel and antiangiogenic therapy. LD paclitaxel yielded additive effects with antiangiogenic therapy against tumors with low Vegf expression, while it exhibited antagonism to antiangiogenic therapy in tumors with high Vegf expression. This is the first preclinical study that models interactions of LD paclitaxel chemotherapy with antiangiogenic therapy and tumor VEGF expression and offers important lessons for the rational design of clinical trials

Statistical methods for building better biomarkers of chronic kidney disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/1/sim8091.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/2/sim8091_am.pd

Activating a collaborative innate-adaptive immune response to control breast and ovarian cancer metastasis

Many cancers recruit monocytes/macrophages and polarize them into tumor-associated macrophages (TAMs). TAMs promote tumor growth and metastasis and inhibit cytotoxic T cells. Yet, macrophages can also kill cancer cells after polarization by e.g., lipopolysaccharide (LPS, a bacteria-derived toll-like receptor 4 [TLR4] agonist) and interferon gamma (IFNγ). They do so via nitric oxide (NO), generated by inducible NO synthase (iNOS). Altering the polarization of macrophages could therefore be a strategy for controlling cancer. Here, we show that monophosphoryl lipid A (MPLA, a derivative of LPS) with IFNγ activated macrophages isolated from metastatic pleural effusions of breast cancer patients to kill the corresponding patients’ cancer cells in vitro. Importantly, intratumoral injection of MPLA with IFNγ not only controlled local tumor growth but also reduced metastasis in mouse models of luminal and triple negative breast cancers. Furthermore, intraperitoneal administration of MPLA with IFNγ reprogrammed peritoneal macrophages, suppressed metastasis, and enhanced the response to chemotherapy in the ID8-p53−/− ovarian carcinoma mouse model. The combined MPLA+IFNγ treatment reprogrammed the immunosuppressive microenvironment to be immunostimulatory by recruiting leukocytes, stimulating type I interferon signaling, decreasing tumor-associated (CD206+) macrophages, increasing tumoricidal (iNOS+) macrophages, and activating cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. MPLA and IFNγ are already used individually in clinical practice, so our strategy to engage the anti-tumor immune response, which requires no knowledge of unique tumor antigens, may be ready for near-future clinical testing

Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

SummaryBRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors

Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study

Abstract Introduction Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes. Methods We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables. Results In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen. Conclusions These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer

DR6 as a Diagnostic and Predictive Biomarker in Adult Sarcoma

The Death Receptor 6 (DR6) protein is elevated in the serum of ovarian cancer patients. We tested DR6 serum protein levels as a diagnostic/predictive biomarker in several epithelial tumors and sarcomas.DR6 gene expression profiles were screened in publically available arrays of solid tumors. A quantitative immunofluorescent western blot analysis was developed to test the serum of healthy controls and patients with sarcoma, uterine carcinosarcoma, bladder, liver, and pancreatic carcinomas. Change in DR6 serum levels was used to assay the ability of DR6 to predict the response to therapy of sarcoma patients.DR6 mRNA is highly expressed in all tumor types assayed. Western blot analysis of serum DR6 protein demonstrated high reproducibility (r = 0.97). Compared to healthy donor controls, DR6 serum levels were not elevated in patients with uterine carcinosarcoma, bladder, liver, or pancreatic cancers. Serum DR6 protein levels from adult sarcoma patients were significantly elevated (p<0.001). This was most evident for patients with synovial sarcoma. Change in serum DR6 levels during therapy correlated with clinical benefit from therapy (sensitivity 75%, and positive predictive value 87%).DR6 may be a clinically useful diagnostic and predictive serum biomarker for some adult sarcoma subtypes.Diagnosis of sarcoma can be difficult and can lead to improper management of these cancers. DR6 serum protein may be a tool to aid in the diagnosis of some sarcomatous tumors to improve treatment planning. For patients with advanced disease, rising DR6 levels predict non-response to therapy and may expedite therapeutic decision making and reduce reliance on radiologic imaging

Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18

<p>Abstract</p> <p>Background</p> <p>Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.</p> <p>Methods</p> <p>Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack <it>in vitro</it>. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated <it>in vivo </it>in mice bearing ID8-Vegf tumors.</p> <p>Results</p> <p>While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death <it>in vitro</it>. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy <it>in vivo </it>and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.</p> <p>Conclusion</p> <p>These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 <it>in vivo</it>.</p

A procedure for statistical analysis of the logit model on MTS

National Highway Traffic Safety Administration, Washington, D.C.http://deepblue.lib.umich.edu/bitstream/2027.42/411/2/46575.0001.001.pd