Latent variables and route choice behavior

In the last decade, a broad array of disciplines has shown a general interest in enhancing discrete choice models by considering the incorporation of psychological factors affecting decision making. This paper provides insight into the comprehension of the determinants of route choice behavior by proposing and estimating a hybrid model that integrates latent variable and route choice models. Data contain information about latent variable indicators and chosen routes of travelers driving regularly from home to work in an urban network. Choice sets include alternative routes generated with a branch and bound algorithm. A hybrid model consists of measurement equations, which relate latent variables to measurement indicators and utilities to choice indicators, and structural equations, which link travelers' observable characteristics to latent variables and explanatory variables to utilities. Estimation results illustrate that considering latent variables (i.e., memory, habit, familiarity, spatial ability, time saving skills) alongside traditional variables (e.g., travel time, distance, congestion level) enriches the comprehension of route choice behavior

Once the shovel hits the ground : Evaluating the management of complex implementation processes of public-private partnership infrastructure projects with qualitative comparative analysis

Much attention is being paid to the planning of public-private partnership (PPP) infrastructure projects. The subsequent implementation phase – when the contract has been signed and the project ‘starts rolling’ – has received less attention. However, sound agreements and good intentions in project planning can easily fail in project implementation. Implementing PPP infrastructure projects is complex, but what does this complexity entail? How are projects managed, and how do public and private partners cooperate in implementation? What are effective management strategies to achieve satisfactory outcomes? This is the fi rst set of questions addressed in this thesis. Importantly, the complexity of PPP infrastructure development imposes requirements on the evaluation methods that can be applied for studying these questions. Evaluation methods that ignore complexity do not create a realistic understanding of PPP implementation processes, with the consequence that evaluations tell us little about what works and what does not, in which contexts, and why. This hampers learning from evaluations. What are the requirements for a complexity-informed evaluation method? And how does qualitative comparative analysis (QCA) meet these requirements? This is the second set of questions addressed in this thesis

A critical assessment of multifunctional polymers with regard to their potential use in structural applications

Multi Wall Carbon Nanotubes (MWCNTs) and Polyhedral Oligomeric Silsesquioxanes (POSS) are common additives to simultaneously enhance electrical conductivity and flame resistance. In the present work, the synergistic effect of the addition of MWCNTs and two different POSS compounds, DodecaPhenyl POSS (DPHPOSS) and Glycidyl POSS (GPOSS), on the mechanical behavior of multifunctional polymers subjected both to quasi-static as well as to fatigue loading was investigated. The results of the mechanical tests were discussed supported by Scanning Electron Microscope (SEM) and Energy Dispersive Spectroscopy (EDS) analyses. The results showed that the incorporation of MWCNTs in the resin containing GPOSS determines a slight decrease in the flexural modulus compared to the unfilled resin. The material filled with MWCNTs and DPHPOSS shows a higher reduction of the flexural modulus as compared to the other analyzed materials. The same trend was observed also for the flexural strength; more than 50% decrease of the flexural strength of the material filled with MWCNTs and DPHPOSS is detected. As far as the fatigue is concerned, it seems that the incorporation of the flame retardants led to an appreciable decrease in the fatigue life. The decrease in the mechanical properties of the nanofilled resin loaded with DPHPOSS is most likely due to the presence of aggregates of DPHPOSS crystals in the matrix. This hypothesis is confirmed by EDX analysis which shows that DPHPOSS forms some small aggregates, whereas GPOSS, being molecularly solubilized in the epoxy formulation, shows mechanical performance more similar to the sample loaded only with carbon nanotubes

Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab A Secondary Analysis of the HERA Trial

IMPORTANCE A number of studies suggest that response to antihuman epidermal growth factor receptor-2 (currently known as ERBB2, but referred to as HER2 in this study) agents differs by estrogen receptor (ER) level status. The clinical relevance of this is unknown. OBJECTIVE To determine the magnitude of trastuzumab benefit according to quantitative levels of ER and HER2 in the HERceptin Adjuvant (HERA) trial. DESIGN, SETTING, AND PARTICIPANTS The HERA trialwas an international, multicenter, randomized trial that included 5099 patients with early-stage HER2-positive breast cancer, randomized between 2001 and 2005 to receive either no trastuzumab or trastuzumab, after adjuvant chemotherapy. This is a secondary analysis of the HERA study. Local ER immunohistochemical (IHC) analyses, HER2 fluorescence in situ hybridization (FISH) ratio, and copy number results were available for 3037 patients (59.6%) randomized to observation and trastuzumab (1 or 2 years) (cohort 1). Transcript levels of ESR1 and HER2 genes were available for 615 patients (12.1%) (cohort 2). INTERVENTIONS Patients were randomized to receive either no trastuzumab or 1 year vs 2 years of trastuzumab. Endocrine therapy was given to patients with hormone receptor-positive disease as per local guidelines. MAIN OUTCOMES AND MEASURES Disease-free survival (DFS) and overall survival (OS)were the primary and secondary end points in the intent-To-Treat population (ITT). Analyses adjusting for crossover (censored and inverse probability weighted [IPW]) were also performed. Interactions among treatment, ER status, and HER2 amplification using predefined cutoffs were assessed in Cox proportional hazards regression models. RESULTS Median follow-up time was 8 years. Levels of FISH and HER2 copy numbers were significantly higher in ER-negative patients (P < .001). In cohort 1, for DFS and OS, a significant treatment effect was found for all ER, IHC, and FISH levels, except for the ER-positive/HER2 low FISH ratio (≥2 to <5) group (DFS: 3-way ITT P value for interaction = .07; censored = .02; IPW = .03; OS ITT P value for interaction = .007; censored = .04; IPW = .03). In cohort 2, consistent with cohort 1, a significant predictive effect of the ESR1 gene for both end points was also observed (DFS P value for interaction = .06; OS = .02), indicating that breast cancers with higher ESR1 levels also derive less benefit from trastuzumab. CONCLUSIONS AND RELEVANCE Patients with HER2-positive breast cancers that are ER-positive by IHC analyses with low FISH ratio (2 to <5), or with higher ESR1 levels derive significantly less benefit from adjuvant trastuzumab after chemotherapy. These data may explain heterogeneity in response to anti-HER2 agents in HER2-positive, ER-positive breast cancers as some may be more luminal-like than HER2 driven. ©Copyright 2016 American Medical Association. All rights reserved

Exploratory Analysis of Single-Gene Predictive Biomarkers in HERA DASL Cohort Reveals That C8A mRNA Expression Is Prognostic of Outcome and Predictive of Benefit of Trastuzumab.

Purpose The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2-positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs.Methods To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted. Disease-free survival (DFS) was used as the end point in a Cox regression model, with the interaction term between C8A mRNA and treatment as a categorical variable split on the cohort mean.Results A significant interaction between C8A mRNA and treatment was detected (P P = .73). In the C8A-high subgroup, patients receiving trastuzumab experienced a lower hazard of a DFS event by approximately 75% compared with those in the observation arm (hazard ratio [HR], 0.25; P P P P < .001).Conclusion C8A as a single-gene biomarker prognostic of DFS and predictive of a benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer if validated by additional studies. Understanding the advantage of overexpression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer

Exploratory analysis of single-gene predictive biomarkers in HERA DASL cohort reveals that C8A mRNA expression is prognostic of outcome and predictive of benefit of trastuzumab

Purpose The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2-positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs. Methods To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted. Disease-free survival (DFS) was used as the end point in a Cox regression model, with the interaction term between C8A mRNA and treatment as a categorical variable split on the cohort mean. Results A significant interaction between C8A mRNA and treatment was detected (P &lt; .001), indicating a predictive response to trastuzumab treatment. For the C8A-low subgroup (mRNA expression lower than the cohort mean), no significant treatment benefit was observed (P = .73). In the C8A-high subgroup, patients receiving trastuzumab experienced a lower hazard of a DFS event by approximately 75% compared with those in the observation arm (hazard ratio [HR], 0.25; P &lt; .001). A significant prognostic effect of C8A mRNA also was seen (P &lt; .001) in the observation arm, where the C8A-high group hazard of a DFS event was three times the respective hazard of the C8A-low group (HR, 3.27; P &lt; .001). C8A mRNA is highly prognostic in the Hungarian Academy of Science HER2+ gastric cancer cohort (HR, 1.72; P &lt; .001). Conclusion C8A as a single-gene biomarker prognostic of DFS and predictive of a benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer if validated by additional studies. Understanding the advantage of overexpression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer. © 2019 American Society of Clinical Oncology

Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) has been tested in advanced melanoma patients at various centers. We conducted a systematic review and meta-analysis to assess its efficacy on previously treated advanced metastatic cutaneous melanoma. The PubMed electronic database was searched from inception to 17 December 2018 to identify studies administering TIL-ACT and recombinant interleukin-2 (IL-2) following non-myeloablative chemotherapy in previously treated metastatic melanoma patients. Objective response rate (ORR) was the primary end point. Secondary end points were complete response rate (CRR), overall survival (OS), duration of response (DOR) and toxicity. Pooled estimates were derived from fixed or random effect models, depending on the amount of heterogeneity detected. Analysis was carried out separately for high dose (HD) and low dose (LD) IL-2. Sensitivity analyses were carried out. Among 1211 records screened, 13 studies (published 1988 - 2016) were eligible for meta-analysis. Among 410 heavily pretreated patients (some with brain metastasis), 332 received HD-IL-2 and 78 LD-IL-2. The pooled overall ORR estimate was 41% [95% confidence interval (CI) 35% to 48%], and the overall CRR was 12% (95% CI 7% to 16%). For the HD-IL-2 group, the ORR was 43% (95% CI 36% to 50%), while for the LD-IL-2 it was 35% (95% CI 25% to 45%). Corresponding pooled estimates for CRR were 14% (95% CI 7% to 20%) and 7% (95% CI 1% to 12%). The majority of HD-IL-2 complete responders (27/28) remained in remission during the extent of follow-up after CR (median 40 months). Sensitivity analyses yielded similar results. Higher number of infused cells was associated with a favorable response. The ORR for HD-IL-2 compared favorably with the nivolumab/ipilimumab combination following anti-PD-1 failure. TIL-ACT therapy, especially when combined with HD-IL-2, achieves durable clinical benefit and warrants further investigation. We discuss the current position of TIL-ACT in the therapy of advanced melanoma, particularly in the era of immune checkpoint blockade therapy, and review future opportunities for improvement of this approach