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  • Wiley-Blackwell  (487,239)
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  • 1
    Publication Date: 2018-02-21
    Description: Purpose To assess the effect of pelvic lymph node dissection (PLND) extent on cancer-specific mortality (CSM) in prostate cancer (PCa) patients without lymph node invasion (LNI) treated with radical prostatectomy (RP). Methods Within the Surveillance, Epidemiology, and End results (SEER) database (2004–2014), we identified patients with D'Amico intermediate- or high-risk characteristics who underwent RP with PLND, without evidence of LNI. First, multivariable logistic regression models tested for predictors of more extensive PLND, defined as removed lymph node count (NRN) ≥75th percentile. Second, Kaplan-Meier analyses and multivariable Cox regression models tested the effect of NRN ≥75th percentile on CSM. Finally, survival analyses were repeated using continuously coded NRN. Results In 28 147 RP and PLND patients without LNI, 67.3% versus 32.7% exhibited D'Amico intermediate- or high-risk characteristics. The median NRN was 6 (IQR 3-10), the 75th percentile defined patients with NRN ≥11. Patients with NRN ≥11 had higher rate of cT2/3 stage (29.8 vs 26.1%), GS ≥8 (25.7 vs 22.4%), and respectively more frequently exhibited D'Amico high-risk characteristics (34.6 vs 32.1%). In multivariable logistic regression models predicting the probability of more extensive PLND (NRN ≥11), higher biopsy GS, higher cT stage, higher PSA, more recent year of diagnosis, and younger age at diagnosis represented independent predictors. At 72 months after RP, CSM-free rates were 99.5 versus 98.1% for NRN ≥11 and NRN ≤10, respectively and resulted in a HR of 0.50 ( P  = 0.01), after adjustment for all covariates. Similarly, continuously coded NRN achieved independent predictor status (HR: 0.955, P  = 0.01), where each additional removed lymph node reduced CSM risk by 4.5%. Conclusion More extensive PLND at RP provides improved staging information and consequently is associated with lower CSM in D'Amico intermediate- and high-risk PCa patients without evidence of LNI. Hence, more extensive PLND should be recommended in such individuals.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-21
    Description: In this communication, we present the phosphoproteome changes in an isogenic pair of colorectal cancer cell lines, viz., the poorly metastatic HCT-116 and the highly metastatic derivative E1, upon stathmin-1 knockdown. The aim was to better understand how the alterations of the phosphoproteins in these cells are involved in cancer metastasis. After the phospho-peptides were enriched using the TiO 2 HAMMOC approach, comparative proteomics analysis was carried out using SWATH-MS. Following bioinformatics analysis using MarkerView and OneOmics platforms, we identified a list of regulated phosphoproteins that may play a potential role in signaling, maintenance of cytoskeletal structure, and focal adhesion. Among these phosphoproteins, was the actin cytoskeleton regulator protein, vasodilator-stimulated phosphoprotein (VASP) where its change in phosphorylation status was found to be concomitant with stathmin-1 – associated roles in metastasis. We further showed that silencing of stathmin-1 altered the expression, subcellular localization and phosphorylation status of VASP, which suggested that it might be associated with remodeling of the cell cytoskeleton in colorectal cancer metastasis. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-21
    Description: Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time-to-event outcomes. For time-to-event outcomes, response is defined as a favorable event prior to the end of follow-up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time-to-event SPCD.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 4
    Publication Date: 2018-02-21
    Description: To estimate direct and indirect effects of an exposure on an outcome from observed data, strong assumptions about unconfoundedness are required. Since these assumptions cannot be tested using the observed data, a mediation analysis should always be accompanied by a sensitivity analysis of the resulting estimates. In this article, we propose a sensitivity analysis method for parametric estimation of direct and indirect effects when the exposure, mediator, and outcome are all binary. The sensitivity parameters consist of the correlations between the error terms of the exposure, mediator, and outcome models. These correlations are incorporated into the estimation of the model parameters and identification sets are then obtained for the direct and indirect effects for a range of plausible correlation values. We take the sampling variability into account through the construction of uncertainty intervals. The proposed method is able to assess sensitivity to both mediator-outcome confounding and confounding involving the exposure. To illustrate the method, we apply it to a mediation study based on the data from the Swedish Stroke Register (Riksstroke). An R package that implements the proposed method is available.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 5
    Publication Date: 2018-02-21
    Description: In a 2×2 crossover trial for establishing average bioequivalence (ABE) of a generic agent and a currently marketed drug, the recommended approach to hypothesis testing is the two one-sided test (TOST) procedure, which depends, among other things, on the estimated within-subject variability. The power of this procedure, and therefore the sample size required to achieve a minimum power, depends on having a good estimate of this variability. When there is uncertainty, it is advisable to plan the design in two stages, with an interim sample size reestimation after the first stage, using an interim estimate of the within-subject variability. One method and 3 variations of doing this were proposed by Potvin et al. Using simulation, the operating characteristics, including the empirical type I error rate, of the 4 variations (called Methods A, B, C, and D) were assessed by Potvin et al and Methods B and C were recommended. However, none of these 4 variations formally controls the type I error rate of falsely claiming ABE, even though the amount of inflation produced by Method C was considered acceptable. A major disadvantage of assessing type I error rate inflation using simulation is that unless all possible scenarios for the intended design and analysis are investigated, it is impossible to be sure that the type I error rate is controlled. Here, we propose an alternative, principled method of sample size reestimation that is guaranteed to control the type I error rate at any given significance level. This method uses a new version of the inverse-normal combination of p-values test, in conjunction with standard group sequential techniques, that is more robust to large deviations in initial assumptions regarding the variability of the pharmacokinetic endpoints. The sample size reestimation step is based on significance levels and power requirements that are conditional on the first-stage results. This necessitates a discussion and exploitation of the peculiar properties of the power curve of the TOST testing procedure. We illustrate our approach with an example based on a real ABE study and compare the operating characteristics of our proposed method with those of Method B of Povin et al.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 6
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    Publication Date: 2018-02-22
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 7
    Publication Date: 2018-02-06
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 8
    Publication Date: 2018-02-22
    Description: Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-HER2 drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. At first, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an anti-tumor effect in most of the HER2 -amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7 , as a tumor suppressor gene by inhibiting the activation of IGF-1R, were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, demonstrated a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and 3 cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2 -amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R -targeting therapy can overcome drug insensitiveness in HER2 -amplified gastric cancer. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 9
    Publication Date: 2018-02-22
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
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  • 10
    Publication Date: 2018-02-22
    Description: Aims Needle biopsy remains essential for diagnosis in assessment of liver disease, although there remains associated risk. Examination is largely limited to subjective evaluation and biopsies are not exploited to provide personalised prognostic information. Elastin is a durable component of fibrotic matrix in chronic disease, conferring resistance to remodelling and potentially influencing tissue biomechanics linked to portal hypertension. We hypothesised that elastin content was predictive of clinical outcome and so could be quantified to increase the beneficial information yield from a liver biopsy. Methods and results Elastin content in liver biopsies was determined by image analysis, technically validated in an independent centre, and correlated with outcome in patients with advanced (Ishak stage ≥ 5) chronic hepatitis C virus-related chronic liver disease. Elastin was robustly quantified in an operator- and laboratory-independent manner, with very strong correlation of elastin staining measured by two methods of image classification (r s = 0.873, p 〈 0.00001). Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virologic response, median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with hepatic elastin 〉3.4% progressed to a clinical outcome, compared to only 6 out of 15 (40%) with elastin 〈3.4%. The difference in time to outcome was significant. Conclusions We describe a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 11
    Publication Date: 2018-02-07
    Description: BACKGROUND Anaplastic thyroid cancer (ATC) is the rarest type of thyroid cancer and has the lowest overall survival. To the authors' knowledge, the impact of socioeconomic status and race/ethnicity has not yet been described. METHODS Data regarding 719 patients diagnosed with their first primary malignant ATC from January 1, 1998 to December 31, 2011 in the Surveillance, Epidemiology, and End Results program registries were examined. Differences in receipt of thyroidectomy, radiotherapy, and lymph node examination were examined by race/ethnicity. Survival also was examined by race/ethnicity. RESULTS Nearly 70% of patients were non-Hispanic white, and 55.4% of patients received treatment. Tumor size ( P  = .13), lymph node involvement ( P  = .60), and residence in high poverty neighborhoods ( P  = .08) did not vary by race/ethnicity. Nonwhite patients were more likely to receive no treatment (adjusted odds ratio, 0.29; 95% confidence interval [95% CI], 0.16-0.54). When receipt of radiotherapy was adjusted for, nonwhite patients had a higher risk of overall death (adjusted hazards ratio [aHR], 1.24; 95% CI, 1.01-1.54), although not disease-specific death (aHR, 1.14; 95% CI, 0.92-1.42). Patients living in areas of high poverty had lower overall survival (aHR, 1.54; 95% CI, 1.09-2.18) and disease-specific survival (aHR, 1.68; 95% CI, 1.19-2.36). CONCLUSIONS In this population-based study of patients with ATC, nonwhite patients were found to be less likely to receive treatment. Furthermore, nonwhite patients had poorer overall survival, and patients living in areas of high poverty had both worse overall and disease-specific survival. Racial/ethnic and socioeconomic disparities appear to exist in the treatment and survival of patients with ATC. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 12
    Publication Date: 2018-02-07
    Description: Multiple myeloma (MM) is the second most common hematologic malignancy and represents approximately 10% of all hematological neoplasms. Standard therapy consists of induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) or, if ASCT cannot be performed, standard doublet, triplet, or quadruplet, novel agent–containing induction treatment until progression. Although MM is still regarded as mostly incurable by current standards, the development of several novel compounds, combination therapies, and immunotherapy approaches has raised great hopes about transforming MM into an indolent, chronic disease and possibly achieving a cure for individual patients. Several new inhibitory and immunological agents have been approved or are under intensive investigation and may lead to new therapeutic options for patients with relapsed/refractory MM, for patients ineligible for ASCT, and for patients after ASCT. Especially in the field of immunotherapy, including monoclonal antibodies, checkpoint inhibition, and chimeric antigen receptor T cells, current advances are rapid and highly promising. This review aims to summarize the newest and most promising immunotherapeutic agents for MM, their clinical efficacy, their adverse event (AE) profiles, and the ways in which these AEs can best be overcome or avoided. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 13
    Publication Date: 2018-02-07
    Description: BACKGROUND The Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology-specific health-related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases. METHODS An international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) at baseline and fixed follow-up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF-36 and NRS pain score. Test-retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later. RESULTS A total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF-36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains. CONCLUSIONS The SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018 . © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society . This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 14
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    In: Cancer
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 15
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    In: Cancer
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 16
    Publication Date: 2018-02-07
    Description: The ethical and economic discussions regarding the extreme costs of many new cancer therapies are familiar. The authors have long held that changes in cancer care delivery also are an important strategy, yielding large benefits at potentially far lower costs. To put this into context, the authors performed an analysis to compare the overall survival of patients receiving a complex oncologic surgery, radical cystectomy, at high-volume and low-volume centers. Propensity score weighting was performed to simulate random allocation into high-volume versus low-volume centers, as would be the case in a prospective trial. On average, patients undergoing surgery at high-volume centers survived 15 months longer than those treated at low-volume centers (57.0 months vs 41.8 months). Although there certainly are caveats in contrasting the survival benefit of different care settings with anticancer agents, this differential clearly rivals or exceeds the benefit of many expensive, recently approved agents. As the debate regarding the costs of cancer therapies continues, it is worth remembering that investments in simple systems-based changes to improve cancer care delivery remain an important and likely cost-effective strategy with which to improve the survival of patients with cancer. Cancer 2018 . © 2018 American Cancer Society .
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    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 17
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 18
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    In: Cancer
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 19
    Publication Date: 2018-02-07
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 20
    Publication Date: 2018-02-07
    Description: Flurbiprofen (F) is a nonsteroidal anti-inflammatory drug (NSAID) used therapeutically as the racemate of ( R )-enantiomer and ( S )-enantiomer. The inversion of RF to SF and vice versa was investigated in C57Bl/6 and SJL mice and Dark Agouti and Lewis rats. The enzyme α-methylacyl-CoA racemase (AMACR) is involved in the chiral inversion pathway that converts members of the 2-arylpropionic acid NSAIDs from the R-enantiomer to the S-enantiomer. We studied C57Bl/6 mice deficient in AMACR postulating that they should show reduced inversion of RF to SF. In line with the data of others in mice, ( R )-inversion to ( S )-inversion was relatively high in both the C57Bl/6 and SJL mice (fraction inverted, F I  = 37.7% and 24.7%, respectively). In contrast, in AMACR deficient mice, there was no measurable peak for SF after administration of RF. The results in both rat strains (Dark Agouti and Lewis rats, F I  = 1.4% and 4.1%, respectively) confirm the low chiral inversion of the enantiomers of flurbiprofen in the rat, as observed by other authors in the Sprague-Dawley strain (〈5%). From the present results, we conclude that for the study of flurbiprofen enantiomers, the rat is more suitable than the mouse as a model for the human in which ( R )-inversion to ( S )-inversion is negligible.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 21
    Publication Date: 2018-02-22
    Description: Background Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. Objective We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC, and to directly compare these features to ulcerative colitis (UC). Methods This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC, and 5 controls with diarrhea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138, and FOXP3. Results Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, edematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs 92% for UC, p〈0.0001) and crypt distortion (23% for Ipi-AC vs 75% for UC, p=0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs 8.2 ± 4.2 for UC, p=0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells/mm 2 for Ipi-AC vs 1173.3 ± 1158.2 cells/mm 2 for UC, p=0.022), but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. Conclusions Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy. This article is protected by copyright. All rights reserved.
    Print ISSN: 0954-6820
    Electronic ISSN: 1365-2796
    Topics: Medicine
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  • 22
    Publication Date: 2018-02-22
    Description: ABSTRACT The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine or other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In comparison to EBV-negative tumors, EBV+ DLBCLs derived predominantly from IGVH -hypermutated CLL and exhibited CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal center DLBCL phenotype, EBV latency programs type II/III, and a very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoral B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2 -/- IL2γc -/- mice. Remarkably, the recipients’ impaired immunosurveillance favored the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients, but not from healthy donors. Eventually, these cells generated monoclonal tumors (mostly CLL-unrelated but also CLL-related) recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts exhibited indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and BCR signaling with ibrutinib in vivo . Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
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  • 23
    Publication Date: 2018-02-22
    Description: Quantification of magnetic resonance spectroscopy signals using the phantom replacement method requires an adequate correction of differences between the acquisition of the reference signal in the phantom and the measurement in vivo. Applying the principle of reciprocity, sensitivity differences can be corrected at low field strength by measuring the RF transmitter gain needed to obtain a certain flip angle in the measured volume. However, at higher field strength the transmit sensitivity may vary from the reception sensitivity, which leads to wrongly estimated concentrations. To address this issue, a quantification approach based on the principle of reciprocity for use at 3T is proposed and validated thoroughly. In this approach, the RF transmitter gain is determined automatically using a volume-selective power optimization and complemented with information from relative reception sensitivity maps derived from contrast-minimized images to correct differences in transmission and reception sensitivity. In this way, a reliable measure of the local sensitivity was obtained. The proposed method is used to derive in vivo concentrations of brain metabolites and tissue water in two studies with different coil sets in a total of 40 healthy volunteers. Resulting molar concentrations are compared with results using internal water referencing (IWR) and Electric REference To access In vivo Concentrations (ERETIC). With the proposed method, changes in coil loading and regional sensitivity due to B 1 inhomogeneities are successfully corrected, as demonstrated in phantom and in vivo measurements. For the tissue water content, coefficients of variation between 2% and 3.5% were obtained (0.6–1.4% in a single subject). The coefficients of variation of the three major metabolites ranged from 3.4–14.5%. In general, the derived concentrations agree well with values estimated with IWR. Hence, the presented method is a valuable alternative for IWR, without the need for additional hardware such as ERETIC and with potential advantages in diseased tissue. A quantification approach based on the phantom replacement method is implemented and validated in healthy volunteers. Using relative reception sensitivity maps and a volume-selective RF power optimization, a precise correction of coil loading and reception sensitivity differences between the acquisition of the reference signal in the phantom and the measurement in vivo is possible. The molal concentrations determined agree well with values derived using the tissue water signal as a reference, implying that the method presented is a valid alternative to internal water referencing in diseased tissue.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 24
    Publication Date: 2018-02-23
    Description: Pathologic differential diagnoses of pleuroparenchymal fibroelastosis (PPFE) include usual interstitial pneumonia (UIP) and pulmonary apical cap (PAC); however, there are no specific immunostaining makers to distinguish between these diseases. We performed immunohistochemistry using several pleural mesothelial cell-related markers, including cytokeratin-5/6, CAM5.2, WT-1, calretinin, desmin and podoplanin, for PPFE (n = 4), UIP (n = 10) and PAC (n = 3) lung sections. Among the examined markers, in PPFE and PAC lungs, podoplanin commonly showed positivity for spindle cells both in thickened pleura and subpleural fibroelastosis lesions; these cells were also stained with α-smooth muscle actin, a marker of myofibroblasts. However, even in elastic fibre-rich cases, UIP lungs did not show such podoplanin-positive myofibroblasts in pleura/subpleura and fibroblastic foci. These findings were also verified using immunofluorescence. By contrast, immunohistochemically as well as morphologically, the difference between PPFE and PAC was not apparent. The presence of podoplanin-positive myofibroblasts could be a pathologic hallmark of PPFE, suggesting a pathogenic process distinct from UIP but common to PAC. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 25
    Publication Date: 2018-02-22
    Description: Bordetella pertussis causes whooping cough. The predominant strains in Australia changed to single nucleotide polymorphism (SNP) cluster I (pertussis toxin promoter allele ptxP3/ pertactin gene allele prn2 ) from cluster II (non- ptxP3 /non- prn2 ). Cluster I were mostly responsible for the 2008–2012 Australian epidemic and were found to have higher fitness compared to cluster II using an in vivo mouse competition assay, regardless of host's immunisation status. This study aimed to identify proteomic differences that explain higher fitness in cluster I using iTRAQ, and high-resolution multiple reaction monitoring (MRM-hr). A few key differences in the whole cell and secretome were identified between the cluster I and II strain tested. In the whole cell, 9 proteins were upregulated (〉1.2 fold change, q〈0.05) and 3 were downregulated (〈0.8 fold change, q〈0.05) in cluster I. One downregulated protein was BP1569, a TLR2 agonist for Th1 immunity. In the secretome, 12 proteins were upregulated and one was downregulated which was Bsp22, a type III secretion system (T3SS) protein. Furthermore, there was a trend of downregulation in three T3SS effectors and other virulence factors. Three proteins were upregulated in both whole cell and supernatant: BP0200, Molybdate ABC transporter (ModB) and Tracheal colonisation factor A (TcfA). Important expression differences in lipoprotein, T3SS and transport proteins between the cluster I and II strains were identified. These differences may affect immune evasion, virulence and metabolism, and play a role in increased fitness of cluster I. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 26
    Publication Date: 2018-02-23
    Description: Childhood cancer is increasing in prevalence whilst survival rates are improving. The prevalence of adult survivors of childhood cancer is consequently increasing. Many survivors suffer long-term consequences of their cancer treatment. Whilst many of these are well documented, relatively little is known about the mental health of survivors of childhood cancer. This article aimed to describe the prevalence and spectrum of mental health problems found in adult survivors of childhood cancer using a systematic review methodology. Our review included 67 papers, describing a number of problems, including depression, anxiety, behavioural problems and drug misuse. Factors increasing the likelihood of mental health problems included treatment with high dose anthracyclines, cranial irradiation, diagnoses of sarcoma or central nervous system tumours and ongoing physical ill health. There were numerous limitations to the studies we found, including use of siblings of survivors as a control group, self-report methodology and lack of indications for prescriptions when prescribing data was used. This review has identified many mental health problems experienced by survivors of childhood cancer, however the exact incidence, prevalence and risk-factors for their development remain unclear. Further work to identify childhood cancer patients who are at risk of developing late mental health morbidity is essential. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 27
    Publication Date: 2018-02-23
    Description: Background Radiomic analysis is defined as computationally extracting features from radiographic images for quantitatively characterizing disease patterns. There has been recent interest in examining the use of MRI for identifying prostate cancer (PCa) aggressiveness in patients on active surveillance (AS). Purpose To evaluate the performance of MRI-based radiomic features in identifying the presence or absence of clinically significant PCa in AS patients. Study Type Retrospective. Subjects Model MRI/TRUS (transperineal grid ultrasound) fusion-guided biopsy was performed for 56 PCa patients on AS who had undergone prebiopsy. Field Strength/Sequence 3T, T 2 -weighted (T 2 w) and diffusion-weighted (DW) MRI. Assessment A pathologist histopathologically defined the presence of clinically significant disease. A radiologist manually delineated lesions on T 2 w-MRs. Then three radiologists assessed MRIs using PIRADS v2.0 guidelines. Tumors were categorized into four groups: MRI-negative–biopsy-negative (Group 1, N  = 15), MRI-positive–biopsy-positive (Group 2, N  = 16), MRI-negative–biopsy-positive (Group 3, N  = 10), and MRI-positive–biopsy-negative (Group 4, N  = 15). In all, 308 radiomic features (First-order statistics, Gabor, Laws Energy, and Haralick) were extracted from within the annotated lesions on T 2 w images and apparent diffusion coefficient (ADC) maps. The top 10 features associated with clinically significant tumors were identified using minimum-redundancy–maximum-relevance and used to construct three machine-learning models that were independently evaluated for their ability to identify the presence and absence of clinically significant disease. Statistical Tests Wilcoxon rank-sum tests with P  〈 0.05 considered statistically significant. Results Seven T 2 w-based (First-order Statistics, Haralick, Laws, and Gabor) and three ADC-based radiomic features (Laws, Gradient and Sobel) exhibited statistically significant differences ( P  〈 0.001) between malignant and normal regions in the training groups. The three constructed models yielded overall accuracy improvement of 33, 60, 80% and 30, 40, 60% for patients in testing groups, when compared to PIRADS v2.0 alone. Data Conclusion Radiomic features could help in identifying the presence and absence of clinically significant disease in AS patients when PIRADS v2.0 assessment on MRI contradicted pathology findings of MRI-TRUS prostate biopsies. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 28
    Publication Date: 2018-02-23
    Description: Background Clinical results of autologous osteochondral transplantation (AOT) for treatment of osteochondral lesions of the talus have been mixed. T1ρ imaging can be used to noninvasively detect early cartilage degeneration. Purpose or Hypothesis To quantitatively assess, by means of T1ρ imaging, changes over time in the biochemical health of grafted cartilage after AOT for osteochondral lesions of the talus. Study Type Retrosepctive case series. Population The study group comprised nine patients who underwent AOT for an osteochondral lesion of the talus and in whom T1ρ mapping was performed 1 and 2 years postoperatively. Field Strength/Sequence 3 Tesla. T1ρ-weighted turbo field echo. Assessment The mean T1ρ value of full-thickness cartilage at the repair site and that of full-thickness cartilage elsewhere in the same image (far-field cartilage) were determined. Clinical assessment was based on the American Orthopaedic Foot & Ankle Society (AOFAS) scale. Correlation between the T1ρ ratios (grafted-to-far-field cartilage T1ρ values) and clinical outcomes was examined. Statistical Tests Mixed effects model. Pearson correlation analysis. Results At 1 year, a significant difference existed between the mean T1ρ value of the grafted cartilage (57.0 ± 7.7 ms) and that of the far-field cartilage (41.8 ± 4.6 ms) ( P  〈 0.001). At 2 years, the mean T1ρ value of the grafted cartilage (49.1 ± 6.4 ms) was significantly lower than that at 1 year ( P  = 0.011). Moderate negative correlation was found between the 1-year T1ρ ratio and 1-year AOFAS score (r = −0.60) and between the 2-year T1ρ ratio and 2-year AOFAS score (r = −0.50). Data Conclusion Our observation of substantial restoration of the proteoglycan content of the grafted cartilage approximately 2 years after AOT for osteochondral lesions of the talus indicates that the content changes gradually and that the cartilage reparation process is slower than previously believed. Level of Evidence : 3 Technical Efficacy : Stage 3 J. Magn. Reson. Imaging 2018.
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  • 29
    Publication Date: 2018-02-23
    Description: Background Lung disease is the most frequent cause of morbidity and mortality in patients with cystic fibrosis (CF), and there is a shortage of sensitive biomarkers able to regionally monitor disease progression and to assess early responses to therapy. Purpose To determine the feasibility of noncontrast-enhanced multivolume MRI, which assesses intensity changes between expiratory and inspiratory breath-hold images, to detect and quantify regional ventilation abnormalities in CF lung disease, with a focus on the structure–function relationship. Study Type Retrospective. Population Twenty-nine subjects, including healthy young children ( n  = 9, 7–37 months), healthy adolescents ( n  = 4, 14–22 years), young children with CF lung disease ( n  = 10, 7–47 months), and adolescents with CF lung disease ( n  = 6, 8–18 years) were studied. Field Strength/Sequence 3D spoiled gradient-recalled sequence at 1.5T. Assessment Subjects were scanned during breath-hold at functional residual capacity (FRC) and total lung capacity (TLC) through noncontrast-enhanced MRI and CT. Expiratory-inspiratory differences in MR signal-intensity (Δ 1 H-MRI) and CT-density (ΔHU) were computed to estimate regional ventilation. MR and CT images were also evaluated using a CF-specific scoring system. Statistical Tests Quadratic regression, Spearman's correlation, one-way analysis of variance (ANOVA). Results Δ 1 H-MRI maps were sensitive to ventilation heterogeneity related to gravity dependence in healthy lung and to ventilation impairment in CF lung disease. A high correlation was found between MRI and CT ventilation maps (R 2  = 0.79, P  〈 0.001). Globally, Δ 1 H-MRI and ΔHU decrease with increasing morphological score (respectively, R 2  = 0.56, P  〈 0.001 and R 2  = 0.31, P  〈 0.001). Locally, Δ 1 H-MRI was higher in healthy regions (median 15%) compared to regions with bronchiectasis, air trapping, consolidation, and to segments fed by airways with bronchial wall thickening ( P  〈 0.001). Data Conclusion Multivolume noncontrast-enhanced MRI, as a nonionizing imaging modality that can be used on nearly any MRI scanner without specialized equipment or gaseous tracers, may be particularly valuable in CF care, providing a new imaging biomarker to detect early alterations in regional lung structure–function. Level of Evidence : 3 Technical Efficacy : Stage 3 J. Magn. Reson. Imaging 2018.
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  • 30
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    Wiley-Blackwell
    Publication Date: 2018-02-22
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
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  • 31
    Publication Date: 2018-02-23
    Description: Purpose To investigate the ability of simultaneous multislice triple-echo steady-state (SMS-TESS) imaging to provide quantitative maps of multiple tissue parameters, i.e., longitudinal and transverse relaxation times (T 1 and T 2 ), proton density (PD), and off-resonance (ΔB 0 ), in the human brain at 3T from a single scan. Methods TESS acquisitions were performed in 2D mode to reduce motion sensitivity and accelerated by an SMS excitation scheme (CAIPIRINHA) with SENSE reconstruction. SMS-acceleration factors (R) of 2 and 4 were evaluated. The in vitro and in vivo validation process included standard reference scans to analyze the accuracy of T 1 , T 2 , and ΔB 0 estimates, as well as single-slice TESS measurements. Results For R = 2, the quantification of T 1 , T 2 , PD, and ΔB 0 was overall reliable with marginal noise enhancement. T 1 and T 2 values were in good agreement with the reference measurements and single-slice TESS. For R = 4, the agreement of ΔB 0 with the standard reference was excellent and the determination of T 1 , T 2 , and PD was reproducible; however, increased variations in T 1 and T 2 values with respect to single-slice TESS were observed. Conclusion SMS-TESS has shown potential to offer rapid simultaneous T 1 , T 2 , PD, and ΔB 0 mapping of human brain tissues.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 32
    Publication Date: 2018-02-24
    Description: Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro-fibrotic response are partially effective, because of their side effects. Therefore, strategies that revert chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche in order to improve skeletal muscle regeneration after injury. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 33
    Publication Date: 2018-02-24
    Description: Fibrolamellar carcinoma (FLC) is a distinct and rare liver cancer typically occurring in young adults in the non-cirrhotic liver. Its rarity impedes evidence-based treatment guidelines derived from large clinical trials and thus case reports describing successful experimental treatments are an important instrument in improving FLC-patient care. We report one patient with end-stage FLC at time of diagnosis with a significant reduction in tumor mass and improvement of quality of life upon third-line palliative treatment with the mTOR inhibitor everolimus. This article is protected by copyright. All rights reserved.
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
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  • 34
    Publication Date: 2018-02-24
    Description: The bone morphogenetic protein (BMP) signaling pathway plays a central role during vasculature development. Mutations or dysregulation of the BMP pathway members have been linked to arteriovenous malformations. In the present study, we investigated the effect of the BMP modulators BMPER and twisted gastrulation protein homolog 1 (TWSG1) on arteriovenous specification during zebrafish development and analyzed downstream Notch signaling pathway in human endothelial cells. Silencing of bmper and twsg1b in zebrafish embryos by morpholinos resulted in a pronounced enhancement of venous ephrinB4a marker expression and concomitant dysregulated arterial ephrinb2a marker expression detected by in situ hybridization. As arteriovenous specification was disturbed, we assessed the impact of BMPER and TWSG1 protein stimulation on the Notch signaling pathway on endothelial cells from different origin. Quantitative real-time PCR and western blot analysis showed increased expression of Notch target gene HES, HEY1/2 and EPHRINB2. Consistently, silencing of BMPER in endothelial cells by siRNAs decreased Notch signaling and downstream effectors. BMP receptor antagonist DMH1 abolished BMPER and BMP4 induced Notch signaling pathway activation. In conclusion, we found that in endothelial cells BMPER and TWSG1 are necessary for regular Notch signaling activity and in zebrafish embryos BMPER and TWSG1 preserve arteriovenous specification to prevent malformations. This article is protected by copyright. All rights reserved.
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  • 35
    Publication Date: 2018-02-24
    Description: Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT)3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary end point was HCV RNA 〈15 IU/mL 12 weeks after end of treatment (SVR12). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm); 1 discontinued due to vomiting/cellulitis (16-week arm); and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). Conclusion : High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV–experienced people with GT3 infection and cirrhosis. ClinicalTrials.gov no: NCT02601573. This article is protected by copyright. All rights reserved.
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  • 36
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    Wiley-Blackwell
    Publication Date: 2018-02-24
    Print ISSN: 0018-019X
    Electronic ISSN: 1522-2675
    Topics: Chemistry and Pharmacology
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  • 37
    Publication Date: 2018-02-24
    Description: NK-cell enteropathy is a recently described clinically indolent condition characterized by atypical NK-cell infiltrates in the gastrointestinal mucosa that mimics malignant lymphoma. We report the case of a 69-year-old female who clinically had long-standing abdominal pain and recurrent mucosal ulcerations associated with atypical NK-cell infiltrates. The clinical, morphologic, and immunophenotypic findings in this case were diagnostic of NK-cell enteropathy. Review of the patient's prior biopsies demonstrated that this persisted without clinical progression for ten years—confirming the clinical indolent course. Recognition of NK-cell enteropathy is important to avoid over-diagnosing this benign condition as an aggressive lymphoma. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 38
    Publication Date: 2018-02-23
    Description: Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate. Preliminary data suggest that BV might improve outcomes after allogeneic stem cell transplantation (SCT) for Hodgkin lymphoma (HL) when used as pre-transplant salvage therapy. Between 2010 and 2014, 428 adult patients underwent an allogeneic SCT for classical HL at participating centres of the European Society for Blood and Marrow Transplantation. We compared the outcomes of 210 patients who received BV prior to allogeneic SCT with that of 218 patients who did not receive BV. The median follow-up for survivors was 41 months. Patients in the BV group were more heavily pre-treated (median pre-allograft treatment lines: 4 vs. 3). The two groups were comparable in terms of disease status, performance status, comorbidities, prior autologous SCT, type of donor, conditioning and in vivo T cell depletion. In multivariate analysis, pre-allograft BV had no impact on acute graft-versus-host disease (GVHD), non-relapse mortality, cumulative incidence of relapse, progression-free survival or overall survival (OS), but significantly reduced the risk of chronic GVHD (hazard ratio = 0·64; 95% confidence interval = 0·45–0·92; P  〈 0·02). Older age, poor performance status, use of pre-transplant radiotherapy and active disease at SCT adversely affected OS. Patients allografted for HL after prior exposure to BV do not have a superior outcome after allogeneic SCT except for a lower risk of chronic GVHD. However, BV may improve the outlook of allogeneic SCT by helping otherwise refractory patients to achieve a more favourable disease status, facilitating allotransplant success.
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
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  • 39
  • 40
    Publication Date: 2018-02-23
    Print ISSN: 0007-9235
    Electronic ISSN: 1542-4863
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of American Cancer Society.
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  • 41
    Publication Date: 2018-02-23
    Description: Based on their mechanisms-of-action, CD20 monoclonal antibodies (mAbs) are grouped into Type I [complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC)] and Type II [programmed cell death (PCD) and ADCC] mAbs. We generated 17 new hybridomas producing CD20 mAbs of different isotypes and determined unique heavy and light chain sequence pairs for 13 of them. We studied their epitope binding, binding kinetics and structural properties and investigated their predictive value for effector functions, i.e. PCD, CDC and ADCC. Peptide mapping and CD20 mutant screens revealed that 10 out of these 11 new mAbs have an overlapping epitope with the prototypic Type I mAb rituximab, albeit that distinct amino acids of the CD20 molecule contributed differently. Binding kinetics did not correlate with the striking differences in CDC activity among the mIgG2c mAbs. Interestingly, chimerization of mAb m1 resulted in a mAb displaying both Type I and II characteristics. PCD induction was lost upon introduction of a mutation in the framework of the heavy chain affecting the elbow angle, supporting that structural changes within this region can affect functional activities of CD20 mAbs. Together, these new CD20 mAbs provide further insights in the properties dictating the functional efficacy of CD20 mAbs.
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  • 42
    Publication Date: 2018-02-23
    Description: BACKGROUND Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti–PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018 . © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society . This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 43
    Publication Date: 2018-02-24
    Description: Immuno-proteomic screening has identified several tumor-associated auto-antibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53, and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times 〉1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. This article is protected by copyright. All rights reserved.
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  • 44
    Publication Date: 2018-02-23
    Description: BACKGROUND The Richmond Agitation-Sedation Scale (RASS) is commonly used to assess psychomotor activity; however, to the authors' knowledge, its minimal clinically important difference (MCID) has not been determined to date. The objective of the current study was to identify the MCID for RASS using 2 anchor-based approaches. METHODS The current study was a secondary analysis of a randomized controlled trial to compare the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium. The primary outcome was change in RASS (10-point numeric rating scale ranging from -5 [unarousable] to +4 [combative]) from baseline to 8 hours after treatment administration. The sensitivity-specificity and within-patient change methods were used to identify the MCID, with the anchor being patient comfort after the study intervention as perceived by caregivers and nurses. RESULTS A total of 90 patients were randomized and 58 (64%) received the study medication for restlessness/agitation (mean baseline RASS, 1.6). A total of 23 caregivers (61%) and 23 nurses (55%) perceived that the patient was more comfortable after treatment. Using the sensitivity-specificity method, the optimal RASS reduction was ≥4 points according to both caregivers (sensitivity of 61% and specificity of 80%; area under the curve, 0.71) and nurses (sensitivity of 73% and specificity of 84%; area under the curve, 0.78). The RASS cutoff value based on the within-patient change method was similar (-4.2 for caregivers and -4.0 for nurses). CONCLUSIONS For patients with persistent restlessness/agitation, a reduction of ≥4 points in RASS was considered to be the MCID for both nurses and caregivers. These preliminary findings may have implications for sample size calculation and the interpretation of treatment effect in future delirium trials. Cancer 2018 . © 2018 American Cancer Society .
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  • 45
    Publication Date: 2018-02-23
    Description: BACKGROUND The elevated risk for physical late effects in childhood cancer survivors (CCS) is well documented, but their risk for mental health problems is less well described. METHODS The authors assembled a cohort of all 5-year CCS who were diagnosed before age 18 years and treated in an Ontario pediatric cancer center between 1987 and 2008. Patients were matched to population controls and linked to health administration databases. The authors calculated rates of mental health care visits (family physician, psychiatrist, emergency department, hospitalization) and the risk for a severe mental health event (emergency department, hospitalization, suicide). Outcomes were compared using recurrent event and survival analyses. RESULTS Compared with 20,269 controls, 4117 CCS had a higher rate of mental health visits (adjusted relative rate [RR], 1.34; 95% confidence interval [CI], 1.12-1.52). Higher rates were associated with female gender (RR, 1.39; CI, 1.10-1.75; P = .006) and being diagnosed at ages 15 to 17.9 years (compared with ages 0-4 years: RR, 1.81; 95% CI, 1.17-2.80; P = .008). Cancer type, treatment intensity, and treatments targeting the central nervous system were not significant predictors. Survivors were at increased risk for a severe event compared with controls (adjusted hazard ratio, 1.13; 95% CI, 1.00-1.28; P = .045). CCS who were diagnosed with cancer at age 4 years or younger were at greatest risk: 16.3% (95% CI, 13.2%-19.8%) had experienced a severe event by age 28 years. CONCLUSIONS CCS experienced higher rates of mental health visits and a greater risk for a severe event than the general population. Survivors of adolescent cancer have a higher rate of mental health visits overall, whereas survivors of cancer before age 4 years have a markedly elevated risk of severe events. Cancer 2018 . © 2018 American Cancer Society .
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  • 46
    Publication Date: 2018-02-23
    Description: BACKGROUND T-cell–depleted, haploidentical transplantations (haplos) are commonly offered to patients who have high-risk, acute leukemia in the absence of a human leukocyte antigen (HLA) full-matched donor. METHODS To determine the effect of transplantation period, the authors divided 308 adults with de novo, acute leukemia who underwent T-cell–depleted haplo from 2005 to 2015 into 2 groups, according the year in which they underwent transplantation (2005-2011 [n = 191] and 2012-2015 [n = 117]). RESULTS The median age was 41 years in patients who underwent transplantation before 2012 and 46 years in those who underwent transplantation after 2012 ( P = .04). Most patients had acute myeloid leukemia (75% vs 69%; P = .26) and were in first complete remission (CR1) (55% vs 64%; P = .12) at the time of transplantation. The cumulative incidence of grade 2, 3, and 4 acute graft-versus-host disease (GvHD) and chronic GvHD were not different between the 2 groups (acute GvHD: 20% vs 22% cumulative incidence in patients who underwent haplo before and after 2012, respectively [ P = .67]; chronic GvHD: 19% vs 11% cumulative incidence, respectively; P = .12]. The 2-year relapse incidence was 20%, the nonrelapse mortality (NRM) rate was 48%, and no difference was observed over time (21% vs 19% [ P = .72] and 54% vs 38% [ P = .11] for patients who underwent haplo before and after 2012, respectively). The main cause of NRM was infection. Haplo after 2012 (hazard ratio [HR], 0.57; P = .01), younger age (HR, 0.82; P = .02), and receipt of a reduced-intensity conditioning (RIC) regimen (HR, 0.53; P = .01) were independently associated with lower NRM. The 2-year overall survival rate was 36% and improved after 2012 (29% vs 47% before 2012; P = .02); and it was higher for patients who underwent transplantation in CR1 (41% vs 29%; P = .01). In multivariate analysis, haplo after 2012 (HR, 0.54; P = .003) and receipt of a RIC regimen (HR, 0.54; P = .005) were independently associated with better overall survival. Similarly, leukemia-free survival and GvHD-free/relapse-free survival (GRFS) improved over time: the leukemia-free survival rate was 31% (25% vs 43% in the groups who underwent transplantation before and after 2012, respectively; P = .05), and the GRFS rate was 24% (19% vs 34%, respectively; P = .09). In addition, leukemia-free survival and GRFS improved among patients who received a RIC regimen. CONCLUSIONS The outcome of patients with acute leukemia who underwent T-cell–depleted haplo has improved over time. Cancer 2018 . © 2018 American Cancer Society .
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  • 47
    Publication Date: 2018-02-23
    Description: BACKGROUND The Bethesda System for Reporting Thyroid Cytopathology category of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) includes fine-needle aspiration (FNA) specimens that cannot straightforwardly be classified as benign or malignant. To determine whether morphological subcategorization based on atypia qualifiers and molecular testing could improve malignancy risk stratification of AUS/FLUS patients, this study assessed the correlation between these qualifiers and the molecular alterations commonly harbored by thyroid neoplasms. METHODS A total of 162 AUS/FLUS cases were subcategorized by atypia qualifiers (Hürthle cell changes, architectural atypia, and cytologic atypia [CyA]) and were tested for BRAF , N-H-KRAS , RET / PTC , and paired box 8 ( PAX8 )/peroxisome proliferator activated receptor γ ( PPARg ) mutations. RESULTS CyA was observed more frequently in mutation-positive AUS/FLUS (14 of 37 [37.84%]) than mutation-negative AUS/FLUS (20 of 125 [16.00%]; P 〈 .0084), and it specifically harbored the BRAF V600E point mutation. Malignancy was confirmed in the available follow-up. Conversely, although RAS was the most frequent mutation identified in AUS/FLUS FNA specimens (26 of 37 cases [70.27%]; P 〈 .0001), it was distributed across various AUS/FLUS subcategories and was not significantly associated with a specific atypia qualifier or malignant outcome according to the available follow-up. Rearrangements of both RET / PTC (n = 1) and PAX8 / PPARg (n = 3) were rarely retrieved in the FNA samples. CONCLUSIONS BRAF and RAS mutations are associated with different AUS/FLUS qualifiers and hence have different risks of malignancy. Consequently, a hybrid molecular and morphological subcategorization system could improve the malignancy risk stratification of thyroid FNA samples diagnosed as AUS/FLUS. Cancer Cytopathol 2018. © 2018 American Cancer Society .
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 48
    Publication Date: 2018-02-23
    Description: It is widely believed that selective packaging of nucleic acids, especially microRNAs, into exosomes secreted by the cancer cells not only ensures their growth and survival but also helps in the escape from immune surveillance. Keeping in view the fact that human cellular miR-2909 has emerged to regulate genes involved in oncogenesis and immunity, the present study was addressed to reveal the nature of miR-2909 expression within cancer cells of different tissue origin and its incorporation into exosomes secreted by these cells. Post-transcriptional modification, especially 3′-end adenylation and uridylation of miR-2909, exerts opposing effects that may contribute to direct its sorting into exosomes secreted by cancer cells. Our study also revealed that selective partitioning of adenosine kinase, between cancer cells and their secreted exosomes, may be responsible for the nature of post-transcriptional modification of miR-2909 observed within these cells.
    Print ISSN: 0263-6484
    Electronic ISSN: 1099-0844
    Topics: Biology , Medicine
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  • 49
    Publication Date: 2018-02-24
    Description: We previously reported a phase I clinical trial of a peptide vaccine ring finger protein 43 (RNF43) and 34-kDa translocase of the outer mitochondrial membrane (TOMM34) combined with uracil–tegafur (UFT)/LV for patients with metastatic colorectal cancer (CRC), and demonstrated the safety and immunological responsiveness of this combination therapy. In this study, we evaluated vaccination-induced immune responses to clarify the survival benefit of the combination therapy as adjuvant treatment. We enrolled 44 patients initially in an HLA-masked fashion. After the disclosure of HLA, 28 patients were in the HLA-A*2402-matched and 16 were in the unmatched group. In the HLA-matched group, 14 patients had positive CTL responses specific for the RNF43 and/or TOMM34 peptides after two cycles of treatment and 9 had negative responses; in the HLA-unmatched group, CTL responses were 10 positive, 2 negative. In the HLA-matched group, 3-year relapse-free survival (RFS) was significantly better in the positive CTL subgroup than in the negative-response subgroup. Patients with negative vaccination-induced CTL responses showed a significant trend towards shorter RFS than those with positive responses. Moreover, in the HLA-unmatched group, the positive CTL response subgroup showed an equally good 3-year RFS as in the HLA-matched group. In conclusion, vaccination-induced CTL response to peptide vaccination could predict survival in the adjuvant setting for stage III CRC. This article is protected by copyright. All rights reserved.
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  • 50
    Publication Date: 2018-02-24
    Description: Interaction of signal regulatory protein α (SIRPα) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRPα enhanced both the Ab-dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) in vitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. However, the effects of blocking Abs to human SIRPα in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRPα expressed on macrophages of immunodeficient mice. With the use of Rag2 −/− γ c −/− mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα-DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti–human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα-DKO mice. Our results thus suggest that the combination of Abs to human SIRPα with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRPα-DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 51
    Publication Date: 2018-02-24
    Description: Animal signals are inherently complex phenotypes with many interacting parts combining to elicit responses from receivers. The pattern of interrelationships between signal components reflects the extent to which each component is expressed, and responds to selection, either in concert with or independently of others. Furthermore, many species have complex repertoires consisting of multiple signal types used in different contexts, and common morphological and physiological constraints may result in interrelationships extending across the multiple signals in species’ repertoires. The evolutionary significance of interrelationships between signal traits can be explored within the framework of phenotypic integration, which offers a suite of quantitative techniques to characterize complex phenotypes. In particular, these techniques allow for the assessment of modularity and integration, which describe, respectively, the extent to which sets of traits covary either independently or jointly. Although signal and repertoire complexity are thought to be major drivers of diversification and social evolution, few studies have explicitly measured the phenotypic integration of signals to investigate the evolution of diverse communication systems. We applied methods from phenotypic integration studies to quantify integration in the two primary vocalization types (advertisement and aggressive calls) in the treefrogs Hyla versicolor , Hyla cinerea, and Dendropsophus ebraccatus . We recorded male calls and calculated standardized phenotypic variance–covariance ( P ) matrices for characteristics within and across call types. We found significant integration across call types, but the strength of integration varied by species and corresponded with the acoustic similarity of the call types within each species. H. versicolor had the most modular advertisement and aggressive calls and the least acoustically similar call types. Additionally, P was robust to changing social competition levels in H. versicolor . Our findings suggest new directions in animal communication research in which the complex relationships among the traits of multiple signals are a key consideration for understanding signal evolution. Signals, such as body parts, are complex structures that must be integrated to function properly, yet this integration also may limit the independent evolution of signal traits. We investigated how different signal traits were integrated across the repertoires of three treefrog species and found evidence for variation between species in the strength of integration that seemed to correspond with the similarity of different signal types.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 52
    Publication Date: 2018-02-24
    Description: Global change has the potential to affect river flow conditions which are fundamental determinants of physical habitats. Predictions of the effects of flow alterations on aquatic biota have mostly been assessed based on species ecological traits (e.g., current preferences), which are difficult to link to quantitative discharge data. Alternatively, we used empirically derived predictive relationships for species’ response to flow to assess the effect of flow alterations due to climate change in two contrasting central European river catchments. Predictive relationships were set up for 294 individual species based on (1) abundance data from 223 sampling sites in the Kinzig lower-mountainous catchment and 67 sites in the Treene lowland catchment, and (2) flow conditions at these sites described by five flow metrics quantifying the duration, frequency, magnitude, timing and rate of flow events using present-day gauging data. Species’ abundances were predicted for three periods: (1) baseline (1998–2017), (2) horizon 2050 (2046–2065) and (3) horizon 2090 (2080–2099) based on these empirical relationships and using high-resolution modeled discharge data for the present and future climate conditions. We compared the differences in predicted abundances among periods for individual species at each site, where the percent change served as a proxy to assess the potential species responses to flow alterations. Climate change was predicted to most strongly affect the low-flow conditions, leading to decreased abundances of species up to −42%. Finally combining the response of all species over all metrics indicated increasing overall species assemblage responses in 98% of the studied river reaches in both projected horizons and were significantly larger in the lower-mountainous Kinzig compared to the lowland Treene catchment. Such quantitative analyses of freshwater taxa responses to flow alterations provide valuable tools for predicting potential climate-change impacts on species abundances and can be applied to any stressor, species, or region. Our multidisciplinary study deals with the effects of climate-change-induced flow alterations on stream macroinvertebrates. Our approach links biological (i.e., macroinvertebrate sample data) and flow data (i.e., discharge) together and predicts potential changes in species abundances caused by flow alterations in two case-study catchments in Germany.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 53
    Publication Date: 2018-02-24
    Description: Sibling cannibalism—the killing and consumption of conspecifics within broods—carries a high risk of direct and inclusive fitness loss for parents and offspring. We reported previously that a unique vibrational behavior shown by the mother of the subsocial burrower bug, Adomerus rotundus (Heteroptera: Cydnidae), induced synchronous hatching. Maternal regulation may be one of the most effective mechanisms for preventing or limiting sibling cannibalism. Here, we tested the hypothesis that synchronous hatching induced by maternal vibration in A. rotundus prevents sibling cannibalism. Mothers and their mature egg masses were allocated to three groups: synchronous hatching by maternal vibration (SHmv), synchronous hatching by artificial vibration (SHav), and asynchronous hatching (AH). We then investigated the influence of each hatching strategy on the occurrence of sibling cannibalism of eggs and early-instar nymphs in the laboratory. No difference in the proportion of eggs cannibalized was observed among the three groups. However, the proportion of nymphs cannibalized was higher in the AH group than in the SHmv group. The difference in the number of days to first molting within clutch was significantly higher in the AH group than in the SHmv group. Junior nymphs were sometimes eaten by senior nymphs. However, immediately after molting, senior nymphs were at a high risk of being eaten by junior nymphs. Our results indicate that synchronous hatching of A .  rotundus is necessary to mitigate the risk of sibling cannibalism. Mother subsocial burrower bugs ( Adomerus rotundus ) use a unique vibrational behavior to induce synchronous hatching. We found that conditions lacking maternal hatching regulation facilitated asynchronous hatching and asynchronous molting and increased sibling cannibalism within a brood. Our results provide experimental evidence that synchronous hatching regulated by mother mitigates the risk of sibling cannibalism.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 54
    Publication Date: 2018-02-24
    Description: Ecological theory suggests that prey size should increase with predator size, but this trend may be masked by other factors affecting prey selection, such as environmental constraints or specific prey preferences of predator species. Owls are an ideal case study for exploring how predator body size affects prey selection in the presence of other factors due to the ease of analyzing their diets from owl pellets and their widespread distributions, allowing interspecific comparisons between variable habitats. Here, we analyze various dimensions of prey resource selection among owls, including prey size, taxonomy (i.e., whether or not particular taxa are favored regardless of their size), and prey traits (movement type, social structure, activity pattern, and diet). We collected pellets of five sympatric owl species ( Athene noctua , Tyto alba , Asio otus , Strix aluco, and Bubo bubo ) from 78 sites across the Mediterranean Levant. Prey intake was compared between sites, with various environmental variables and owl species as predictors of abundance. Despite significant environmental impacts on prey intake, some key patterns emerge among owl species studied. Owls select prey by predator body size: Larger owls tend to feed on wider ranges of prey sizes, leading to higher means. In addition, guild members show both specialization and generalism in terms of prey taxa, sometimes in contrast with the expectations of the predator–prey body size hypothesis. Our results suggest that while predator body size is an important factor in prey selection, taxon specialization by predator species also has considerable impact. We studied the roles of environmental gradients as well as various prey life history strategies on the diet of five sympatric owl species. When significant environmental factors were accounted for, we found a strong effect of prey selection by mass, although some owl species specialize on or avoid specific prey taxa.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 55
    Publication Date: 2018-02-24
    Description: Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 to 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn & eosin-stained tissue sections were assessed for numbers of TDLUs (“TDLU count”). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p=0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p〈0.0001). Postmenopausal IGFBP-3 was inversely associated with TDLU count among AA (RR T3vs.T1 =0.49, 95% CI=0.28-0.84, p-trend=0.04) and Caucasian (RR T3vs.T1 =0.64, 95% CI=0.42-0.98, p-trend=0.04) women. In premenopausal women, higher IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RR T3vs.T1 =1.33, 95% CI=1.02-1.75, p-trend=0.04), but not in AA (RR T3vs.T1 =0.65, 95% CI=0.42-1.00, p-trend=0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 56
    Publication Date: 2018-02-24
    Description: Immune homeostasis has been suggested to play an important role in the clinical evolution of chronic Chagas disease, however, the immunopathologic factors involved haven't been fully elucidated. Therefore, our study aimed to analyze the frequency of CD4 + CD25 + FoxP3 + cells, classic Th17 cells, alternative Th17 cells and IL-17 + B cells from peripheral blood of chronic cardiac patients after in vitro stimulation with Trypanosoma cruzi soluble EPI antigen. Patients were selected and classified according to clinical evaluation of cardiac involvement: mild, B1 (CARD1) (n = 20), and severe, C (CARD2) (n = 11). Patients with the indeterminate form of CD were included as the control group A (IND) (n = 17). Blood samples were collected and cultured in the presence of EPI antigen. Cells frequency and median fluorescence intensity (MFI) were obtained by flow cytometry. Our results showed that only CD4 + CD25 + FoxP3 + , CD4 + CD25 high FoxP3 + , CD4 + IL-17 + IFN-γ - and CD4 + IL-17 + IFN-γ + cells are more frequent in patients with severe cardiac disease, and correlate with worse global cardiac function. However, while indeterminate patients demonstrated a positive correlation between CD4 + CD25 + FoxP3 + and CD4 + IL-17 + IFN-γ - Th17 cells, this relationship was not observed in cardiac patients. IL-17 expression by Th17 cells and B cells correlated with disease progression. Altogether our results suggest that the clinical progression of Chagas cardiomyopathy involves worsening of inflammation and impairment of immunoregulatory mechanisms. This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 57
    Publication Date: 2018-02-23
    Description: To monitor the incidence rates of cancers, AIDS, cardiovascular diseases, and other chronic or infectious diseases, some global, national, and regional reporting systems have been built to collect/provide population-based data about the disease incidence. Such databases usually report daily, monthly, or yearly disease incidence numbers at the city, county, state, or country level, and the disease incidence numbers collected at different places and different times are often correlated, with the ones closer in place or time being more correlated. The correlation reflects the impact of various confounding risk factors, such as weather, demographic factors, lifestyles, and other cultural and environmental factors. Because such impact is complicated and challenging to describe, the spatiotemporal (ST) correlation in the observed disease incidence data has complicated ST structure as well. Furthermore, the ST correlation is hidden in the observed data and cannot be observed directly. In the literature, there has been some discussion about ST data modeling. But, the existing methods either impose various restrictive assumptions on the ST correlation that are hard to justify, or ignore partially or entirely the ST correlation. This paper aims to develop a flexible and effective method for ST disease incidence data modeling, using nonparametric local smoothing methods. This method can properly accommodate the ST data correlation. Theoretical justifications and numerical studies show that it works well in practice.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 58
    Publication Date: 2018-02-23
    Description: There is a global trend that the average onset age of many human complex diseases is decreasing, and the age of cancer patients becomes more spread out. The age effect on survival is nonlinear in practice and may have one or more important change-points at which the trend of the effect can be very different before and after these threshold ages. Identification of these change-points allows clinical researchers to understand the biologic basis for the complex relation between age and prognosis for optimal prognostic decision. This paper considers estimation of the potentially nonlinear age effect for general partly linear survival models to ensure a valid statistical inference on the treatment effect. A simple and efficient sieve maximum likelihood estimation method that can be implemented easily using standard statistical software is proposed. A data-driven adaptive algorithm to determine the optimal location and the number of knots for the identification of the change-points is suggested. Simulation studies are performed to study the performance of the proposed method. For illustration purpose, the method is applied to a breast cancer data set from the public domain to investigate the effect of onset age on the disease-free survival of the patients. The results revealed that the risk is highest among young patients and young postmenopausal patients, probably because of a change in hormonal environment during a certain phase of menopause.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 59
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    Wiley-Blackwell
    Publication Date: 2018-02-24
    Print ISSN: 1527-6465
    Electronic ISSN: 1527-6473
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  • 60
    Publication Date: 2018-02-25
    Description: Background Eczema affects ~20% of children but multiple different outcome measures have hampered research into the effectiveness of different treatments. Objectives To compare the change in scores and correlations within and between five measures of eczema severity: Patient Orientated Eczema Measure (POEM), Eczema Area Severity Index (EASI), Six Area Six Sign Atopic Dermatitis (SASSAD), Three Item Severity (TIS), and skin hydration (corneometry). Methods Data from a feasibility trial that randomised young children with eczema to one of four emollients were used. Participants were followed for three months (84 days). Descriptive statistics (by emollient over time) and Spearman's correlation coefficients comparing scores at each time-point and absolute change (between adjacent time-points) for each outcome measure were calculated. Results 197 children, mean age (SD) of 21.7 (12.8) months, were randomised. POEM and TIS appeared to capture a range of eczema severity at baseline but only POEM had close approximation to normal distribution. Mean POEM, EASI, SASSAD and TIS scores improved month-by-month, with POEM showing the greatest sensitivity (effect size 0.42). Correlations within POEM, EASI, SASSAD and TIS were moderate-to-good, decreasing over time. Correlations between measures were strongest for EASI, SASSAD and TIS. By contrast, corneometry scores were more variable, correlated less well over time, and were poorly correlated with the other measures. Conclusions Except for corneometry, all measures appear to change in relation to emollient use over time and correlate well with themselves. POEM demonstrated the greatest range of scores at baseline and change in eczema severity over the first 28 days. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 61
    Publication Date: 2018-02-25
    Description: Background Topical photodynamic therapy (PDT) is an approved treatment for actinic keratosis (AK). To enhance the efficacy of PDT for AKs, physical (ablative lasers and microneedling) and chemical (pro-differentiating drugs) pretreatments have been suggested. Objectives To compare the efficacy and safety of the combination of topical calcipotriol (CAL) before methylaminolevulinate (MAL)-PDT for AKs of the scalp versus conventional MAL-PDT in a randomized controlled-clinical trial. Materials and Methods Twenty patients with multiple AKs on the scalp were randomized to receive conventional MAL - PDT with previous curettage on one side of the scalp and CAL – assisted MAL-PDT applied once a day for fifteen days before the illumination with red light-emitting diode (37J/cm 2 ) on the other side. After three months, patients were evaluated for the clearance of AKs, side effects and histopathology before and after the procedure. Protoporphyrin IX (PpIX) fluorescence was measured before and after illumination on both sides. Results All twenty patients completed the study. Overall AK clearance was 92.07% and 82.04% for CAL-PDT and conventional PDT respectively (p〈 0.001). The AKs grade I showed similar response rate of 92.83% and 87.29% (p=0.055) respectively for CAL and MAL-PDT sides. However, AKs grade II showed more improvement on the CAL-PDT side (89.55%) compared with MAL-PDT (62.90%) (p〈0.001). Before illumination, PpIX fluorescence intensity was higher on the CAL-assisted side (p=0.048). The treatment was more painful on the CAL-PDT side, although well tolerated. The mean VAS score was 5.40±1.43 on the CAL-PDT side and 3.95±0.69 on the conventional MAL-PDT side (p=0.001). Side effects such as erythema (p=0.019), edema (p=0.002), crusts (p〈0.001) were more pronounced on the CAL-assisted side. Histopathological analyses were obtained from five patients and both sides showed improved keratinocyte atypia following PDT, with a slight more improvement on CAL- assisted side. Conclusion CAL-assisted PDT proved to be safe and more effective than conventional MAL-PDT for the treatment of AKs on the scalp. CAL pretreatment increased PpIX accumulation within the skin and may have enhanced the efficacy in this first human trial. As this is the first CAL-assisted PDT study in human skin, further and larger trials are needed to corroborate our findings. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 62
    Publication Date: 2018-02-24
    Description: Cell type classification and handling is a key issue for understanding biological systems. The advent of high multiplexing technologies increased the complexity of the classification process and new tools are needed to support the organization of this knowledge. I propose a classification based on both prime numbers and the fundamental theorem of arithmetic. As a not limiting example, I show the application of this method to unambiguously define any existing cell type using the CD nomenclature established by the Human Leukocyte Differentiation Antigens Workshops. This system allows for the unique identification of any possible combination of markers hence any cell population without previous knowledge and without the need to increment the system. This method can be the future basis of any database and ontology system dealing with cell types and beyond the biological field applies to the description of any entity characterized by a list of discrete qualities. © 2018 International Society for Advancement of Cytometry Prime numbers, the building blocks of all numbers, can be used as the building blocks for cell type classification.
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 63
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 64
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    Publication Date: 2018-02-24
    Description: Microfluidics is all the rage in developing the simple-structured, easily controlled and fast switched tools to diagnose diseases, test drugs and sort cells. The cover depicts a spark-generated microbubble sell-sorting process for microfluidic flow cytometry. Read the accompanying article by Zhao and You in the latest issue of Cytometry Part A Cover design by Bärbel Beran [ www.beran-design.de ].
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 65
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 66
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 67
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 68
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 69
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 70
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 71
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    Publication Date: 2018-02-24
    Electronic ISSN: 1552-4930
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  • 72
    Publication Date: 2018-02-24
    Description: Community assembly may not follow predictable successional stages, with a large fraction of the species pool constituted by potential pioneering species and successful founders defined through lottery. In such systems, priority effects may be relevant in the determination of trajectories of developing communities and hence diversity and assemblage structure at later advanced states. In order to assess how different founder species may trigger variable community trajectories and structures, we conducted an experimental study using subtidal sessile assemblages as model. We manipulated the identity of functionally different founders and initial colony size (a proxy of the time lag before the arrival of later species), and followed trajectories. We did not observe any effects of colony size on response variables, suggesting that priority effects take place even when the time lag between the establishment of pioneering species and late colonizers is very short. Late community structure at experimental panels that started either with the colonial ascidian Botrylloides nigrum , or the arborescent bryozoan Bugula neritina , was similar to control panels allowed natural assembling. In spite of high potential for fast space domination, and hence negative priority effects, B. nigrum suffered high mortality and did not persist throughout succession. Bugula neritina provided complex physical microhabitats through conspecific clustering that have enhanced larval settlement of late species arrivals, but no apparent facilitation was observed. Differently, panels founded by the encrusting bryozoan Schizoporella errata led to different and less diverse communities compared to naturally assembled panels, evidencing strong negative priority effects through higher persistence and space preemption. Schizoporella errata founder colonies inhibited further conspecific settlement, which may greatly relax intraspecific competition, allowing resource allocation to colony growth and space domination, thus reducing the chances for the establishment of other species. Community assembly may not always follow predictable trajectories and instead may be affected by priority effects. In order to investigate how founder species with different traits affect community trajectory and structure, we conducted a manipulative approach using sessile communities from shallow subtidal. We observed that communities founded by a colonial ascidian and an arborescent bryozoan that do not persist longer became similar to nonmanipulated natural communities. However, when founded by a encrusting bryozoan that is a good space monopolizing and resistant to predation, communities were different from nonmanipulated ones, holding a lower number of species and being dominated by such founder species.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 73
    Publication Date: 2018-02-24
    Description: Climate change alters the abiotic constraints faced by plants, including increasing temperature and water stress. These changes may affect flower development and production of flower rewards, thus altering plant–pollinator interactions. Here, we investigated the consequences of increased temperature and water stress on plant growth, floral biology, flower-reward production, and insect visitation of a widespread bee-visited species, Borago officinalis . Plants were grown for 5 weeks under three temperature regimes (21, 24, and 27°C) and two watering regimes (well-watered and water-stressed). Plant growth was more affected by temperature rise than water stress, and the reproductive growth was affected by both stresses. Vegetative traits were stimulated at 24°C, but impaired at 27°C. Flower development was mainly affected by water stress, which decreased flower number (15 ± 2 flowers/plant in well-watered plants vs. 8 ± 1 flowers/plant under water stress). Flowers had a reduced corolla surface under temperature rise and water stress (3.8 ± 0.5 cm 2 in well-watered plants at 21°C vs. 2.2 ± 0.1 cm 2 in water-stressed plants at 27°C). Both constraints reduced flower-reward production. Nectar sugar content decreased from 3.9 ± 0.3 mg/flower in the well-watered plants at 21°C to 1.3 ± 0.4 mg/flower in the water-stressed plants at 27°C. Total pollen quantity was not affected, but pollen viability decreased from 79 ± 4% in the well-watered plants at 21°C to 25 ± 9% in the water-stressed plants at 27°C. Flowers in the well-watered plants at 21°C received at least twice as many bumblebee visits compared with the other treatments. In conclusion, floral modifications induced by abiotic stresses related to climate change affect insect behavior and alter plant–pollinator interactions. Modifications on flower-reward production are considered as an indirect impact of climate changes which can disrupt the interactions between plants and pollinators. We investigated the consequences of temperature rise and water stress on plant growth, floral biology, flower-reward production, and insect visitation of a widespread bee-visited species, Borago officinalis . Reproductive traits were more affected than vegetative traits; particularly, flower-reward production decreased for stressed plants, and floral traits were modified, thus altering pollinator visitation behavior as stressed plants were two times less visited than non-stressed plants.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 74
    Publication Date: 2018-02-24
    Description: There is little direct evidence for effects of soil heterogeneity and root plasticity on the competitive interactions among plants. In this study, we experimentally examined the impacts of temporal nutrient heterogeneity on root growth and interactions between two plant species with very different rooting strategies: Liquidambar styraciflua (sweet gum), which shows high root plasticity in response to soil nutrient heterogeneity, and Pinus taeda (loblolly pine), a species with less plastic roots. Seedlings of the two species were grown in sandboxes in inter- and intraspecific combinations. Nutrients were applied in a patch either in a stable (slow-release) or in a variable (pulse) manner. Plant aboveground biomass, fine root mass, root allocation between nutrient patch and outside the patch, and root vertical distribution were measured. L. styraciflua grew more aboveground (40% and 27% in stable and variable nutrient treatment, respectively) and fine roots (41% and 8% in stable and variable nutrient treatment, respectively) when competing with P. taeda than when competing with a conspecific individual, but the growth of P. taeda was not changed by competition from L. styraciflua . Temporal variation in patch nutrient level had little effect on the species’ competitive interactions. The more flexible L. styraciflua changed its vertical distribution of fine roots in response to competition from P. taeda , growing more roots in deeper soil layers compared to its roots in conspecific competition, leading to niche differentiation between the species, while the fine root distribution of P. taeda remained unchanged across all treatments. Synthesis . L. styraciflua showed greater flexibility in root growth by changing its root vertical distribution and occupying space of not occupied by P. taeda . This flexibility gave L. styraciflua an advantage in interspecific competition. Liquidambar styraciflua showed greater flexibility in root growth by changing its root vertical distribution and occupying space not occupied by Pinus taeda . This flexibility gave L. styraciflua an advantage in interspecific competition.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 75
    Publication Date: 2018-02-24
    Description: DOI: 10.1002/pmic.201700391 In article number 1700391, Moon et al. performed a metaproteomic analysis of colonic samples from a mouse model of distal gut inflammation. The authors employed a T cell transfer model of colitis and directly compared wild-type, immunocompromised isogenic Rag1 −/− and the colitic Rag1 −/− T cell recipient mice to identify alterations in both host and gut microbial proteins associated with intestinal inflammation. Art designer: Judith Umaña Ayala
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 76
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    Wiley-Blackwell
    Publication Date: 2018-02-24
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 77
    Publication Date: 2018-02-24
    Description: Background Guidelines define docetaxel as a first-line therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). However, the role of docetaxel in non-metastatic castration-resistant prostate cancer (nmCRPC) has not been fully investigated. The aim of this retrospective study was to evaluate the potential role of docetaxel in nmCRPC. Clinical outcomes including overall survival were compared between CRPC patients who had docetaxel introduced while in nonmetastatic versus metastatic diseases. Methods A total of 98 CRPC patients had docetaxel therapy. Of these 46 patients received docetaxel for nmCRPC, and 52 had distant metastases. Clinical outcomes from the time of diagnosis of CRPC were compared retrospectively between groups. Results The median observation period after the diagnosis of CRPC in these patients was 42 months (range, 3-166). Overall survival (OS) was significantly longer in the nmCRPC group than in the mCRPC group (not reached vs 52.2 months, respectively, P  = 0.006). Multivariate analysis showed that longer time to CRPC, docetaxel use in nmCRPC, and use of abiraterone acetate and/or enzalutamide were significant predictors for improved OS ( P  = 0.04, 0.019 and 0.002, respectively). The incidence and profile of adverse events did not differ significantly between groups. Conclusions Earlier induction of docetaxel in nmCRPC patients may prolong OS. Further prospective studies in more patients will be required to confirm our findings.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 78
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    Wiley-Blackwell
    Publication Date: 2018-02-24
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 79
    Publication Date: 2018-02-24
    Description: Background Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. Methods In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. Results In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Conclusions Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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