Search

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never‐smoking women. A case‐control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC‐MS/MS assays in plasma. The product‐substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable‐adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case‐control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34‐0.90; Ptrend =.03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34‐0.96; Ptrend =.04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never‐smoking women. [ABSTRACT FROM AUTHOR]

Background: Robust and reliable prognosis prediction models have not been developed and validated for Asian patients with breast cancer, a rapidly growing yet understudied population in the United States.Methods: We used longitudinal data from the Shanghai Breast Cancer Survival Study, a population-based prospective cohort study (n = 5042), to develop prediction models for 5- and 10-year disease-free survival (DFS) and overall survival (OS). The initial models considered age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the addition of modifiable lifestyle factors (physical activity, soy isoflavones intake, and postdiagnostic weight change) improved the models. All final models have been validated internally and externally in the National Cancer Database when applicable.Results: Our final models included age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status, PR status, 6-month postdiagnostic weight change, interaction between ER status and tamoxifen therapy, and interaction between age and TNM stage. The internal validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS, 10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity, 0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined.Conclusion: We developed prediction models for breast cancer prognosis from a large prospective study. Our prognostic models performed very well in women from the United States-particularly in Asian American women-and demonstrated high prediction accuracy and generalizability. [ABSTRACT FROM AUTHOR]

Background: Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness.Methods: A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables.Results: From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI.Conclusions: The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017;123:3781-3790. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Seborrheic keratoses ( SK) are the most common cutaneous neoplasm in humans. Given their numbers, a squamous cell carcinoma in situ ( SCCIS) arising from an SK would not be unexpected, although this occurrence has not been widely reported. Objective This study compares the immune status of patients with a SCCIS arising contiguously from SK ( SK/ SCCIS) and the number of daily medications taken by these patients. The biopsy tissue was evaluated for the presence of human papillomavirus DNA. Methods Over a 5-year period at our institution, 13 cases of SK/ SCCIS were diagnosed. For each case, age- and sex-matched control patients with a histologically diagnosed unremarkable SK were randomly selected. The number of patients taking immunosuppressing medications was determined from each group and compared statistically. In addition, polymerase chain reaction analysis of the 13 SK/ SCCIS biopsies was performed. Results Five of the 13 study patients took immunosuppressive medications compared to none of the 39 control patients ( P = 0.0005). None of the biopsies demonstrated the presence of human papillomavirus DNA by polymerase chain reaction. Conclusions Immunocompromised patients with SKs appear to carry a greater risk of these otherwise innocuous lesions developing an SCCIS, although given the small number of patients evaluated, further research into this possible association is warranted. [ABSTRACT FROM AUTHOR]

This trial was designed to assess efficacy and safety of erlotinib with sorafenib in the treatment of patients with advanced pancreatic adenocarcinoma. An exploratory correlative study analyzing pretreatment serum samples using a multivariate protein mass spectrometry-based test (VeriStrat®), previously shown to correlate with outcomes in lung cancer patients treated with erlotinib, was performed. Patients received sorafenib 400 mg daily along with erlotinib 150 mg daily with a primary endpoint of 8-week progression free survival ( PFS) rate. Pretreatment serum sample analysis by VeriStrat was done blinded to clinical and outcome data; the endpoints were PFS and overall survival ( OS). Difference between groups (by VeriStrat classification) was assessed using log-rank P values; hazard ratios ( HR) were obtained from Cox proportional hazards model. Thirty-six patients received study drug and were included in the survival analysis. Eight-week PFS rate of 46% (95% confidence interval ( CI): 0.32-0.67) did not meet the primary endpoint of a rate ≥70%. Thirty-two patients were included in the correlative analysis, and VeriStrat 'Good' patients had superior PFS (HR = 0.18, 95% CI: 0.06-0.57; P = 0.001) and OS (HR = 0.31 95% CI: 0.13-0.77, P = 0.008) compared to VeriStrat 'Poor' patients. Grade 3 toxicities of this regimen included fever, anemia, diarrhea, dehydration, rash, and altered liver function. This study did not meet the primary endpoint, and this combination will not be further pursued. In this small retrospective analysis, the proteomic classification was significantly associated with clinical outcomes and is being further evaluated in ongoing studies. [ABSTRACT FROM AUTHOR]

When primary endpoints of randomized trials are continuous variables, the analysis of covariance (ANCOVA) with pre-treatment measurements as a covariate is often used to compare two treatment groups. In the ANCOVA, equal slopes (coefficients of pre-treatment measurements) and equal residual variances are commonly assumed. However, random allocation guarantees only equal variances of pre-treatment measurements. Unequal covariances and variances of post-treatment measurements indicate unequal slopes and, usually, unequal residual variances. For non-normal data with unequal covariances and variances of post-treatment measurements, it is known that the ANCOVA with equal slopes and equal variances using an ordinary least-squares method provides an asymptotically normal estimator for the treatment effect. However, the asymptotic variance of the estimator differs from the variance estimated from a standard formula, and its property is unclear. Furthermore, the asymptotic properties of the ANCOVA with equal slopes and unequal variances using a generalized least-squares method are unclear. In this paper, we consider non-normal data with unequal covariances and variances of post-treatment measurements, and examine the asymptotic properties of the ANCOVA with equal slopes using the variance estimated from a standard formula. Analytically, we show that the actual type I error rate, thus the coverage, of the ANCOVA with equal variances is asymptotically at a nominal level under equal sample sizes. That of the ANCOVA with unequal variances using a generalized least-squares method is asymptotically at a nominal level, even under unequal sample sizes. In conclusion, the ANCOVA with equal slopes can be asymptotically justified under random allocation. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 9 (CDK9) is a well-characterized subunit of the positive transcription elongation factor b complex in which it regulates transcription elongation in cooperation with cyclin T. However, CDK9 also forms a complex with cyclin K, the function of which is less clear. Using a synthetic lethal RNA interference screen in human cells, we identified CDK9 as a component of the replication stress response. Loss of CDK9 activity causes an increase in spontaneous levels of DNA damage signalling in replicating cells and a decreased ability to recover from a transient replication arrest. This activity is restricted to CDK9-cyclin K complexes and is independent of CDK9-cyclin T complex. CDK9 accumulates on chromatin in response to replication stress and limits the amount of single-stranded DNA in cells under stress. Furthermore, we show that CDK9 and cyclin K interact with ataxia telangiectasia and Rad3-related protein and other checkpoint signalling proteins. These results reveal an unexpectedly direct role for CDK9-cyclin K in checkpoint pathways that maintain genome integrity in response to replication stress. [ABSTRACT FROM AUTHOR]

Aim Rapidly evolving pathogens may exert diversifying selection on genes involved in host immune defence including those encoding antimicrobial peptides (AMPs). Amphibian skin peptides are one important defence against chytridiomycosis, an emerging infectious disease caused by the chytrid fungus Batrachochytrium dendrobatidis ( Bd). We examined the population-level variation in this innate immune defence to understand its relationship with disease dynamics. Location Queensland, Australia. Methods We examined skin peptide defences in five geographically distinct populations of Australian green-eyed treefrogs, Litoria genimaculata. Skin peptide samples were collected from 52 frogs from three upland populations that previously declined as chytridiomycosis emerged, but subsequently recovered, and from 34 frogs in two lowland populations that did not decline. Historical samples of skin peptides preceding Bd emergence were not available from any population. Results In general, lowland populations had more effective peptide defences than upland populations. Peptide profiles were similar among populations, although relative amounts of peptides expressed differed significantly among populations and were more variable in the uplands. Infected frogs in upland populations carried a significantly higher infection burden compared to lowland populations. The presence of effective AMPs in the skin of L. genimaculata does not eliminate infection; however, more effective peptide defences may limit infection intensity and the progression of disease. Main conclusions The population bottleneck in upland populations caused by chytridiomycosis emergence did not appear to produce responses to selection for more effective peptide defences against chytridiomycosis compared to lowland populations of L. genimaculata. This does not exclude the possibility that current peptide defences have adapted in response to disease emergence. A suggestive ( P < 0.10) interaction between infection status and population indicates that in lowland populations, infected individuals tend to be those with lower relative intensities of AMPs, whereas in the upland populations, infected and uninfected individuals are similar. Thus, both the AMPs and the environment may act to mediate resistance to Bd infection. [ABSTRACT FROM AUTHOR]

Studies involving longitudinal binary responses are widely applied in the health and biomedical sciences research and frequently analyzed by generalized estimating equations (GEE) method. This article proposes an alternative goodness-of-fit test based on the nonparametric smoothing approach for assessing the adequacy of GEE fitted models, which can be regarded as an extension of the goodness-of-fit test of le Cessie and van Houwelingen ( Biometrics 1991; 47:1267-1282). The expectation and approximate variance of the proposed test statistic are derived. The asymptotic distribution of the proposed test statistic in terms of a scaled chi-squared distribution and the power performance of the proposed test are discussed by simulation studies. The testing procedure is demonstrated by two real data. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Patients with recurrent or metastatic HNC have a poor response and survival with currently available chemotherapy agents. Thus, new agents are needed. The authors report the results of a phase II trial of irinotecan and cisplatin in patients with metastatic or recurrent HNC.Methods: Patients were treated with irinotecan 65 mg/m2 IV over 90 minutes and cisplatin 30 mg/m2 were administered intravenously weekly for four weeks, followed by a two week rest. However, after 17 patients were treated with weekly irinotecan at a dose of 65 mg/m2, toxicity analysis demonstrated the poor tolerance of that dose in this patient population. Thus, the protocol was amended, and irinotecan was dose reduced to a starting dose of 50 mg/m2. Twenty-three additional patients were treated with this dose.Results: Forty patients were enrolled on study between February 2002 and April 2006, 17 patients at the first dose level and 23 patients at the amended dose level. Overall, 12 of 17 patients (71%) treated with irinotecan 65 mg/m2 experienced clinically significant grade 3 or 4 toxicity. Twelve patients required dose reductions. Toxicity was reduced but 17% of patients still experienced grade 3 or 4 toxicity on the lower irinotecan dose. The response rate was 35% for patients treated at irinotecan 65 mg/m2 and 22% for patients treated at 50 mg/m2. No complete responses were noted.Conclusions: The combination of irinotecan and cisplatin is efficacious in a poor prognosis group of patients but toxicity is substantial. [ABSTRACT FROM AUTHOR]

Background.The optimal drug schedule and sequencing of chemotherapy and radiation for organ preservation in head and neck cancer has yet to be determined. We undertook a phase II trial of a taxane-based induction chemotherapy (ICT) followed by a taxane-based concurrent chemoradiation (CCR) regimen in patients with resectable stage III or IV disease to determine the feasibility, toxicity, and overall efficacy. Methods.Forty-four patients with laryngeal or tongue base carcinomas were enrolled. All patients received 3 cycles of chemotherapy with paclitaxel 175 mg/m2 and carboplatin AUC (area under the curve) 6–7.5 over 30 minutes on days 1, 22, and 43. Responding patients went on to receive radiation (70 Gy/7 weeks) with cisplatin 75 mg/m2 IV on days 1, 22, and 43 and weekly paclitaxel 30 mg/m2 IV (n = 22). Because of hematologic toxicity, the concurrent regimen was changed to weekly carboplatin AUC 1 plus weekly paclitaxel 30 mg/m2 (n = 22). Results.Twenty-three patients with stage III and 21 patients with stage IV disease were enrolled. Median follow-up was 3.7 years. Acute toxicity of concurrent cisplatin and paclitaxel was excessive, with significant hematologic toxicity and 2 toxic deaths. Acute toxicities of concurrent carboplatin and paclitaxel were tolerable. No patients required permanent percutaneous gastrostomy tubes. The organ preservation rate was 83% (toxic deaths considered failures). Of 42 evaluable patients, 20 patients had complete responses (48%), 17 partial responses (41%), 3 minor responses (11%), 1 stable disease (2%), and 1 progressive disease (2%). Two-year local control, relapse-free survival, and overall survival were 82%, 77%, and 71%, respectively. Conclusion.There were no significant differences in relapse-free survival or organ preservation rates between concurrent regimens. Platinum and paclitaxel-based CCR is feasible after ICT and provides a high rate of organ preservation. Substitution of concurrent cisplatin to weekly carboplatin with paclitaxel and radiation has an improved toxicity profile. The ease of administration and low toxicity make this a regimen that is practical for use in the community setting. © 2007 Wiley Periodicals, Inc. Head Neck, 2007 [ABSTRACT FROM AUTHOR]

Although most investigators agree that lung dysfunction occurs rapidly in various pig-to-primate hyperacute lung rejection (HALR) models, the basic mechanisms mediating this phenomenon remain in question. Here we describe an immunohistochemical method for assessment of mechanisms driving HALR. Using an established model wherein piglet lungs are perfused ex vivo with human blood, six experimental groups (K76 COOH; FUT-175; K76 with FUT; anti-α-Gal column adsorption; column with FUT; and column with K76) and two control groups (unmodified human blood; autologous pig blood) were studied. Each lung was biopsied serially during perfusion, and assessed using an immunohistochemical technique, with vWF staining as an internal control to quantitate binding of human IgM, IgG, C3, C5b-9, properdin, and C1q. The effect of each treatment and subsequent lung perfusion on IgG and IgM anti-α-Gal titers(by ELISA) and on pig endothelial cell cytotoxicity were correlated with histologic findings. We found that [] the classical complement activation pathway was activated, as has been shown for other pig organs in primate or human blood environments []; alternative complement pathway activation is also seen, which has not been described for other organs in pig-to-primate models, but only in the context of classical pathway activation; and [] anti-Gal column absorption, pharmacologic inhibition of complement, or combination therapy each was associated with histologic evidence of partial protection, consistent with what would be predicted for each intervention. Further, immunohistologic differences correlated with physiologic outcomes [] and with antibody assay results, and revealed that treatments used were incompletely effective. Our data suggest that more complete inhibition of antibody- and complement-driven pathways than was achieved in these experiments will be necessary to prevent the antibody and complement-mediated facets of hyperacute lung rejection. This immunohistologic technique may also help us identify additional pathogenic mechanisms important to eventual clinical application of pig-to-human lung xenografts. [ABSTRACT FROM AUTHOR]

To comprehensively study extracellular small RNAs (sRNA) by sequencing (sRNA-seq), we developed a novel pipeline to overcome current limitations in analysis entitled, "Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER)". To demonstrate the power of this tool, sRNA-seq was performed on mouse lipoproteins, bile, urine and livers. A key advance for the TIGER pipeline is the ability to analyse both host and non-host sRNAs at genomic, parent RNA and individual fragment levels. TIGER was able to identify approximately 60% of sRNAs on lipoproteins and >85% of sRNAs in liver, bile and urine, a significant advance compared to existing software. Moreover, TIGER facilitated the comparison of lipoprotein sRNA signatures to disparate sample types at each level using hierarchical clustering, correlations, beta-dispersions, principal coordinate analysis and permutational multivariate analysis of variance. TIGER analysis was also used to quantify distinct features of exRNAs, including 5ʹ miRNA variants, 3ʹ miRNA non-templated additions and parent RNA positional coverage. Results suggest that the majority of sRNAs on lipoproteins are non-host sRNAs derived from bacterial sources in the microbiome and environment, specifically rRNA-derived sRNAs from Proteobacteria. Collectively, TIGER facilitated novel discoveries of lipoprotein and biofluid sRNAs and has tremendous applicability for the field of extracellular RNA. [ABSTRACT FROM AUTHOR]