Dr Alexandre Vivot
email: alexandre.vivot@aphp.fr

Jacques Li

Jean-David Zeitoun

Samia Mourah

Perrine Crequit

Philippe Ravaud

Raphaël Porcher

Pharmacogenomic biomarkers as inclusion criteria in clinical trials of

Keywords: Clinical Trials, Biomarkers, Pharmacogenomics, Food and Drug Administration, Personalized Medicine

INTRODUCTION

In recent years oncology care has been completely transformed by the development and growth of molecular targeted therapies, [START_REF] De Bono | Translating cancer research into targeted therapeutics[END_REF] which has led to the concept of precision (or personalized or genomic) oncology. [START_REF] Schott | Genome Medicine in Cancer: What's in a Name?[END_REF][START_REF] Gonzalez De Castro | Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance[END_REF] A landmark example is imatinib, which has revolutionized the treatment of chronic myeloid leukemia. Other examples are vemurafenib for melanoma, trastuzumab and ado-trastuzumab for breast cancer, and crizotinib for lung cancer. These drugs need a pharmacogenomic biomarker to guide treatment decision-making [START_REF] Stegmeier | Targeted cancer therapies in the twenty-first century: lessons from imatinib[END_REF] because the indications for these drugs are biomarker-based (e.g., "unresectable or metastatic melanoma with BRAF V600E mutation" for vemurafenib). However, some targeted therapies, such as bevacizumab, do not require a biomarker assessment before prescription. This does not mean that no pharmacogenomic biomarker actually exists but that none has yet been validated or even found. Furthermore, some drugs, such as everolimus, may have one biomarker-based indication ("advanced hormone receptor-positive, HER2-negative breast cancer") and another nonbiomarker-based indication ("advanced renal cell carcinoma"). Currently, the label of 140 US Food and Drug Administration (FDA)-approved drugs mentions a pharmacogenomic biomarker, one-third indicated in oncology [START_REF] Vivot | Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs[END_REF] .

A drug that has been tested only in a biomarker-positive subpopulation would have an implicit requirement for genetic testing, [START_REF] Vivot | Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs[END_REF][START_REF]Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products[END_REF] and one may consider that a high-quality trial with only biomarkerpositive patients (i.e., an enriched trial) correspond to an acceptable level of evidence for targeted therapies. [START_REF] Wang | Clinical evidence supporting pharmacogenomic biomarker testing provided in US Food and Drug Administration drug labels[END_REF][START_REF] Simon | The role of nonrandomized trials in the evaluation of oncology drugs[END_REF] Nonetheless, if no clinical data are available for biomarker-negative patients, the use of a biomarker to restrict treatment to a subgroup of patients may not be relevant, as noted by several regulatory agencies. [START_REF]Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products[END_REF][START_REF]Haute autorité de santé. Companion diagnostic test associated with a targeted therapy: scientifix appeendix[END_REF][START_REF]Reflection paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection[END_REF] It may seem natural and logical to study a targeted drug in only patients with tumors harboring this target, and, therefore, the hallmark trial design for targeted therapy is an enriched design. This design increases the study power and therefore reduces the sample size and time to detect an effect [START_REF] Temple | Enrichment of clinical study populations[END_REF][START_REF] Sleijfer | Designing Transformative Clinical Trials in the Cancer Genome Era[END_REF] but does not provide information about the drug efficacy in biomarker-negative patients. Actually, considering the treatment effect to be null in biomarker-negative patients a priori means withdrawing treatment for some patients based on only preclinical data and the biological understanding of the drug mechanism of action and its target. Therefore, if the biomarker is not a perfect predictor of response (because of the test intrinsic qualities or because the treatment is also effective in some true negative patients), one may deny patients a treatment they would have otherwise benefitted from. [START_REF]Haute autorité de santé. Companion diagnostic test associated with a targeted therapy: scientifix appeendix[END_REF][START_REF] Messersmith | Targeting EGFR in Colorectal Cancer[END_REF][START_REF] Graf | Adaptive designs for subpopulation analysis optimizing utility functions[END_REF] We have several examples of this risk of denying some potential patients treatment. For example, some patients with HER2-negative tumors have benefitted from trastuzumab. [START_REF] Paik | HER2 Status and Benefit from Adjuvant Trastuzumab in Breast Cancer[END_REF] Indeed, 16 of 22 HER2-negative patients with HER-2 extracellular domain level > 15 ng/ml showed a clinical benefit, which led to the concept of "hidden" HER-2-positive breast cancer. [START_REF] Ardavanis | Trastuzumab plus Paclitaxel or Docetaxel in HER-2-Negative/HER-2 ECD-Positive Anthracycline-and Taxane-Refractory Advanced Breast Cancer[END_REF] Furthermore, contrary to expectations, the level of HER-2 did not predict clinical response and showed a U-shaped relationship, which suggested that trastuzumab could be effective in HER2-negative tumors. [START_REF] Tuma | Cancer Stem Cell Hypothesis and Trastuzumab in HER2-Negative Tumors[END_REF] Another example is cetuximab, the anti-EGFR drug, originally studied in only patients with EGFR-expressing tumors until it was found also beneficial for some patients with EGFR-negative tumors. [START_REF] Chung | Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry[END_REF][START_REF] Phelps | A Snapshot of Challenges and Solutions in Cancer Drug Development and Therapy[END_REF] Later, retrospective analyses of randomized clinical trial data revealed that only patients with RAS wild-type tumors benefitted from the treatment. [START_REF] Atreya | Expanded RAS: Refining the Patient Population[END_REF][START_REF] Amado | Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer[END_REF] The anti-EGFR therapies cetuximab and panitumumab are now restricted to patients with RAS wild-type tumors.

The emergence of targeted therapies has also transformed drug development. [START_REF] Phelps | A Snapshot of Challenges and Solutions in Cancer Drug Development and Therapy[END_REF][START_REF] Fridlyand | Considerations for the successful co-development of targeted cancer therapies and companion diagnostics[END_REF][START_REF] Zineh | Biomarkers in drug development and regulation: a paradigm for clinical implementation of personalized medicine[END_REF][START_REF] Parkinson | Making Personalized Cancer Medicine a Reality: Challenges and Opportunities in the Development of Biomarkers and Companion Diagnostics[END_REF][START_REF] Woodcock | The Prospects for "Personalized Medicine" in Drug Development and Drug Therapy[END_REF] The ideal goal in personalized medicine is the co-development of the drug and the biomarker (i.e., the biomarker is found in the early stages of drug development and both the drug and the biomarker test are developed concurrently). Nonetheless, for some drugs, the biomarker could have been discovered after the drug approval, and for other drugs, supplemental biomarkers could have been discovered after the discovery of the first one; hence, a targeted drug could have several pharmacogenomic biomarkers.

Both drug-target development and characteristics of clinical trials evaluating targeted therapiesespecially pharmacogenomic biomarkers used as inclusion criteria-are of crucial importance to understand how those drugs are studied.

We aimed to map the clinical trial development for oncology targeted therapies in order to assess the main characteristics of clinical trials involving oncology targeted therapies and their evolution after first FDA approval. We analyzed (i) the characteristics of oncology targeted therapies with pharmacogenomic testing required or recommended on their label; (ii) the characteristics of corresponding registered clinical trials, especially the use of an enrichment design; and (iii) the evolution of these characteristics over the drug development period.

METHODS

List of Drugs

On November 10, 2014, we extracted the list of oncology targeted therapies from the US National Cancer Institute website. [START_REF]Targeted Cancer Therapies[END_REF] We then selected drugs from the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling [START_REF]Genomics -Table of Pharmacogenomic Biomarkers in Drug Labeling[END_REF] for which the label required or recommended genetic testing, based on a previous work. [START_REF] Vivot | Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs[END_REF] We excluded drugs approved before 2005 because the International Committee of Medical Journal Editors required prospective registration of clinical trials as a precondition for publication in September 2004. [START_REF] Dickersin | The evolution of trial registries and their use to assess the clinical trial enterprise[END_REF] For each included drug, we searched ClinicalTrials.gov on November 10, 2014 using the name of drug as a keyword and extracted all retrieved studies without any additional limits.

Eligibility of Clinical Trials

Clinical trials were included if they were interventional clinical trials evaluating one included targeted drug as an experimental treatment (alone or combined with another drug). Two authors (AV and JL) independently assessed eligibility; any disagreements were resolved by consensus.

Data Extraction

Two authors (AV and JL) independently extracted data on biomarker-based criteria for including patients in clinical trials (i.e., enrichment) and, when appropriate, the names of the biomarkers. They compared all the data extracted and any disagreements were resolved by consensus. We considered studies in chronic myelogenous leukemia, a disease associated with Philadelphia chromosome, as being implicitly enriched on this biomarker because Philadelphia chromosome is part of this disease's definition. [START_REF] Kurzrock | Philadelphia Chromosome-Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics[END_REF] Other trial characteristics were extracted from ClinicalTrials.gov. The primary outcome was coded as overall survival or event-free survival (progression-free, disease-free or any event-free survival as defined in the trial registration) or time to progression, following this hierarchical and exclusive classification. To classify the diseases studied in each trial, we mapped the MeSH terms from ClinicalTrials.gov records to the list of diseases from the global burden of disease 2013 study. [START_REF] Gbd | Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study[END_REF] From the Drugs@FDA database and as previously described, [START_REF] Vivot | Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs[END_REF] we extracted the date of the drug approval, the date of the first label containing pharmacogenomic information, the first indication for the drug and, if different, the first indication for the drug with pharmacogenomic labeling, and the date the drug's sponsor submitted the application to the regulation agency. From the European Medicines Agency (EMA) website, we obtained the date of marketing authorization valid throughout the European Union and the date of submission of the application to the agency. We considered the first submission of an application to the FDA or EMA as a proxy for the end of drug development and the first approval of the drug by one agency as the start of drug marketing. Trials with a start date before the first submission of an application were classified as "before submission", trials with a start date after the drug approval by FDA or EMA application were classified as "after approval", and trials in between as "between submission and approval".

Statistical Analysis

We used only descriptive statistics. Continuous variables are presented as median and interquartile range (IQR) because most variables are not normally distributed and qualitative variables as frequencies (percentage). Analyses were performed with R version 3.1.0 (R Core Team, Vienna, Austria).

RESULTS

Included Drugs and Clinical Trials

The NCI listed 69 oncology targeted therapies, 22 also included in the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling and having a label requiring or recommending genetic testing. Nine drugs were approved before 2005 and were excluded. Everolimus was also excluded because this single drug represented more than half of trials and the majority corresponded to a new non-cancer indication (prevention of organ rejection). Thus, this single drug may need a separate evaluation. We included 12 drugs (detailed characteristics are displayed in Table S1). Overall, 935 studies corresponded to these drugs and were registered in ClinicalTrials.gov; we excluded 77 studies that did not fulfill inclusion criteria and therefore included 858 clinical trials (Figure S1).

Clinical Study Characteristics

Characteristics of the 858 included studies are in Table 1. Half of the studies (n=434, 51%) were enriched on the first biomarker mentioned in the drug label and 145 (17%) on another biomarker and 270 (31%) included patients without restriction for a pharmacogenomic biomarker. Industry was the lead sponsor for 334 studies (39%). The median sample size was 65 patients (Q1-Q3 = 35-154). The most frequent primary outcomes were response rate (37%), event-free survival (19%) and toxicity/dose finding (15%). Most studies (72%) started after the first FDA approval, and only 4% ended before approval. Overall, 497 studies (58%) assessed drug effects for the same disease as for the first approval. More than half of the studies (60%) were single-group studies. For all drugs, the first biomarker was present at approval and corresponded to the drug's target. Figure 1 displays the number of trials and of patients enrolled in enriched trials and in single-arm trials by phase. Enriched trials as well as single-arm trials represented a large proportion of trials and of patients, especially phase 3 trials, which typically enrolled many patients. shown by red and black vertical arrows, respectively. All drugs were tested in randomized trials restricted to the biomarker mentioned in the label (red areas). These trials could correspond to trials supporting drug approval and pharmacogenomic labeling. However, some drugs such as afatinib were also tested in non-enriched trials (green areas) and trials enriched on another biomarker (blue areas), whereas some drugs (e.g., dabrafenib) were tested almost exclusively in trials restricted to the biomarker mentioned in the label. [START_REF] Amado | Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer[END_REF] Of note, the first trials of afatinib and pertuzumab were not enriched on any biomarker. Vemurafenib was the only drug tested in biomarker-negative patients before FDA approval. After FDA approval, some drugs (e.g., vemurafenib, ado-trastuzumab) were tested in only one disease with trials enriched on the targeted biomarker. The most recent drugs (e.g., bosutinib, crizotinib) were obviously associated with a small number of trials after FDA approval.

Mapping of Clinical Trials Before and After FDA Approval

Dasatinib and nilotinib were associated with more trials of other diseases than approval indication.

Crizotinib was tested in biomarker-negative patients after FDA approval, after a post-marketing commitment of the FDA in its medical review. [START_REF]Center for drug evaluation and research[END_REF] Overall, among 237 trials started before FDA approval, 128 (54%) were enriched on the biomarker first mentioned in the label and 27 (11%) on another one, whereas among 614 trials started after FDA approval, 305 (50%) were enriched on the first biomarker and 117 (19%) on another biomarker.

Evolution of Biomarker and Disease Studied for Each Drug

Table 1 also displays the main characteristics of clinical trials across three periods of drug development: (i) before the first submission to the FDA or EMA, (ii) after this submission and before first approval by the FDA or EMA, and (iii) after approval. The share of industry-sponsored trials dropped from 73% before submission to 28% after approval. The proportion of trials enriched on the label biomarker and for the corresponding indication ranged from 4% with panitumumab-EGFR+ patients to 88% with ado-trastuzumab-HER-2+ patients. This proportion was still high (sometimes higher) after drug approval.

Figures 3 and4 show hive plots representing the mapping of the number of clinical trials for drugs, biomarkers and diseases. Multiple-disease trials are represented once for each studied disease, as are multiple-drugs trials. Two patterns of drugs seem to emerge: the first corresponds to drugs tested almost solely in biomarker-positive patients and with the same disease first described on the label (ado-trastuzumab, dabrafenib, vemurafenib) and the second includes drugs tested in trials enriched on other biomarkers, in treat-all trials or in other diseases (all other drugs). These patterns could be seen especially for recent drugs (e.g., ado-trastuzumab vs crizotinib). However, among the first group, dabrafenib and vemurafenib were tested with some other diseases but without expanding the biomarkers used to restrict trials. In the second group, dasatinib, lapatinib and nilotinb appear to be associated with the most diseases and biomarkers used in trials, resulting in very dense figures.

Afatinib and bosutinib were tested with many diseases, but as compared to the drugs in the second group, with a relatively small number of biomarkers. Among the 361 trials testing a drug in a disease different than the first indication, there was no enrichment for 219 trials (61%), enrichment on the biomarker described in the label for 48 trials (13%) , enrichment on a different biomarker for 87 trials (24%), and enrichment on multiple biomarkers for 7 trials (2%).

DISCUSSION

This mapping of clinical trials of targeted drugs with biomarker labeling shows a great diversity in the drug development of targeted drugs. Indeed, some targeted therapies have been tested with only one biomarker (which is the drug target) and in only one disease whereas others drugs have been tested with several biomarkers (which are not the drug's target) and in several diseases. Another finding of this study is that, although the efficacy of some drugs was studied both in biomarker-positive andnegative patients, most trials were enriched single-arm trials and several drugs were developed with only biomarker-positive patients included in trials. For those drugs, we have therefore no formal clinical evidence for restricting treatment to biomarker-positive patients.

The rationale to test or not a targeted therapy in others patient than the ones who are positive for the target biomarker (i.e., biomarker-negative patients or patients positive for another biomarker) depends on the strength of preclinical data and the rationale for drug targeting, [START_REF]Haute autorité de santé. Companion diagnostic test associated with a targeted therapy: scientifix appeendix[END_REF][START_REF] Sleijfer | Designing Transformative Clinical Trials in the Cancer Genome Era[END_REF] the relevance of which we do not discuss here. However, this point deserves careful consideration because of the risk of restricting drug indications to the wrong subpopulation-as it has been initially the case for cetuximab and EGFR expression before predictive role of RAS mutations have been shown-which need to be balanced against the ethics dilemma to expose biomarker-negative patients to a drug from which one thinks they will not derived benefit and strategic consideration about drug development from the drug's sponsor. Moreover, enrichment-only drug development reduces the number of patients exposed to the drug and therefore may also hinder the validity of drug safety evaluation. However, as compared with the number of investigational drugs to be tested in clinical trials, in some therapeutic areas, only a few patients may be eligible; thus, restricting trials to biomarker-positive patients could allow for biomarker-negative patients to be included in another trial, which more likely to be beneficial for them. Of note, at least one health authority agency (the French Haute Autorité de Santé) considered a drug to be targeted only with a high level of evidence of qualitative treatment-by-marker interaction (i.e., the treatment effective only in biomarker-positive patients) and recommended the randomize-all design with randomization stratified on biomarker results. [START_REF]Haute autorité de santé. Companion diagnostic test associated with a targeted therapy: scientifix appeendix[END_REF] Nearly one quarter (27%) of enriched trials used a biomarker other than the first one mentioned on the drug's label. For example, trametinib, a MEK kinase inhibitor, has also been studied in trials restricted to patients with KRAS mutations or HER-2 expression. Similarly, afatinib has been studied in several trials of HER-2-positive tumors although its first biomarker is EGFR. However, EGFR and HER-2 are both part of the ErbB family (ErbB-1 and ErbB-2, respectively) and afatinib has an affinity for HER-2. There are several reasons to test a drug with another biomarker than the first one. First, several post approval studies have attempted the discovery of response/resistance biomarkers and some of which are currently under clinical validation phase. Second, some included drugs are highly target selective drugs such as dabrafenib (which is a mutant BRAFV600 specific inhibitor) but others drugs do have affinity for other targets than the ones they were targeted for. This could explain the choice of biomarkers in some of those trials like crizotinib in ROS-1+ patients, dasatinib in PDGFR+ patients or nilotinib in KIT+ or PDGFRB+ patients. Another likely explanation of the differences in development schemes could be the differences between drugs developed to target a specific mutation: (dasatinib, nilotinib, afatinib, bosutinib, crizotinib, dabrafenib, vemurafenib, and trametinib) and drugs developed to target a molecular pathway (lapatinib, panitumumab, pertuzumab, ado-trastuzumab). Development may be more targeted for the former group than for the latter. However, dabrafenib and vemurafenib both displayed a targeted development scheme (i.e., a small network) whereas trametinib displayed a much less targeted development scheme (i.e., a wider network) although these three drugs were developed to target the BRAF V600 mutations. Overall, the disease-biomarker pairs were similar across drugs, so the disease-biomarker association may be more specific than the drug-biomarker association. Furthermore, several trials involved multiple biomarkers. These trials could test multiple biomarkers in one disease or with one drug, such as the AcSé (NCT02034981) or CREATE (Cross-tumoral Phase 2 with Crizotinib, NCT01524926) trials, and are called "basket" trials . [START_REF] Menis | New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response[END_REF] In contrast, "umbrella" trials such as NCI-MPACT [START_REF] Kummar | NCI mpact: National Cancer Institute molecular profiling-based assignment of cancer therapy [abstract[END_REF] or SHIVA [START_REF] Tourneau | Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial[END_REF] tested multiple biomarkers across a broad range of tumor types. [START_REF] Herbst | Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400[END_REF] In the open-label controlled, phase 2 SHIVA trial, patients with metastatic solid tumour refractory to standard of care and with a molecular alteration in PI3K/AKT/mTOR, RAF/MEK or hormone receptor pathways were randomized between matched molecularly targeted agent in a histology-agnostic way and treatment at physician's choice. There were no differences in primary outcome (progression-free survival, PFS) between the two groups: median PFS was 2.3 months (95% CI 1.7-3.8) in the experimental group versus 2.0 months (1.8-2.1) in the control group (hazard ratio 0.88, 95% CI 0.65-1.19, p=0.41). [START_REF] Tourneau | Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial[END_REF] These results suggest that relying solely on biomarker (i.e., without histology) to predict efficacy may not be yet possible in oncology.

Our results are consistent with a previous study of general oncology trials, finding that as compared with non-oncology trials, oncology trials were more often single-arm, open-label and nonrandomized, [START_REF] Hirsch | Characteristics of oncology clinical trials: Insights from a systematic analysis of clinicaltrials[END_REF] a pattern we also found for trials of targeted therapies. We did not specifically assess characteristics of pivotal trials in this study, but for the 55 oncology novel therapeutic agents approved by the FDA between 2005 and 2012, only half of the pivotal trials were randomized, 27% were double-blinded and only 16% had a clinical outcome as a primary end point, reflecting a lower level of evidence of studies for FDA approval in oncology as compared with non-oncology areas. [START_REF] Downing | Cinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012[END_REF] This finding could be explained in part by the high frequency of orphan drugs in oncology and the lower level of evidence for such drugs as compared with non-orphan oncology drugs. [START_REF] Kesselheim | Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer[END_REF] This relatively low level of evidence of trials could also be explained by the high number of indication (either the first or subsequent ones) approved under the accelerated approval process as pivotal studies supporting accelerated approvals are often early phase, non-randomized trials using surrogate endpoints. [START_REF] Hirsch | Characteristics of oncology clinical trials: Insights from a systematic analysis of clinicaltrials[END_REF][START_REF] Downing | Cinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012[END_REF] A study of pharmacogenomic information in drug labels approved by the EMA found that two thirds of pivotal trials for drugs with a biomarker-based indication have been conducted in only biomarkerpositive patients, [START_REF] Ehmann | Pharmacogenomic information in drug labels: European Medicines Agency perspective[END_REF] a pattern we also found in our study of all (not only pivotal) trials.

One strength of this study is the use of data from ClinicalTrials.gov. Because clinical trials take a long time to complete, studies with registration on clinical trial registries can provide information before the end of trials and therefore provide a preview of which studies are currently ongoing. However, the drawback is no access to the results of those trials. This study has several limitations. We used only US data (labels from the FDA and trials registered at clinicaltrials.gov) because we made the assumption that a US-centric view represents biomarker usage in targeted therapies trials. some trials may have been registered in another registry than clinicaltrials.gov but this would concern only trials conducted outside the United States because publication in ClinicalTrials.gov is mandatory for trials with at least one center in the United States). Some trials may have been conducted before trial registration was required and, thus, we excluded drugs approved before 2005. We analyzed data as provided by the trial's sponsor, which may suggest some errors in coding when the study was registered. Furthermore, we analyzed only targeted therapies with biomarker-based indications because we were interested in how targeted drugs that are restricted to biomarker-positive patients have been developed and especially if the development was targeted and how this might evolve after drug approval. Studying the use of biomarkers in clinical trials of targeted therapies without biomarker-based indication warrants further investigation

Conclusion

Oncology targeted therapies have undoubtedly set the stage for precision medicine, but the drugbiomarker-diseases network is actually more complex than it would seem at first glance. The rationale to test or not a targeted therapy in others patient than the ones who are positive for the target biomarker (i.e., biomarker-negative patients or patients positive for another biomarker) deserves careful consideration because of the risk of over-restricting drug indications and that of exposing patients to a drug which they are not likely to derive benefit from.

M a s k i n g

Type of study Efficacy 216 (25) 32 ( 18) 10 ( 18) 174

Figure 2

 2 Figure 2 displays for each drug, the number of trials by year and two characteristics of trials: (i) the use of a biomarker to restrict inclusion in the trial (treat-all patients, use of the same biomarker as the first one mentioned in the drug label, or use of another biomarker) and (ii) random assignment of treatment. Dates of first submission and first approval by the FDA or EMA (whichever came first) are

Figure 1 .

 1 Figure 1. Number of trials (left side) and of patients (right side) enrolled in trials registered on ClinicalTrials.gov by drug, 2005-2014. Top panel contrasts enriched trials (blue) vs non-enriched trials (violet). Bottom panel contrasts single-arm trials vs comparative trials.

Figure 2 .

 2 Figure 2. Cumulative number of trials registered on ClinicalTrials.gov by calendar time, 2005-2014. Cumulative number of trials stratified by use of enrichment design and randomization regrouped into 6 categories: non-randomized and randomized trials enriched on the same pharmacogenomics as mentioned in the label (dark and light red, respectively), non-randomized and randomized trials enriched on another pharmacogenomics (dark and light blue, respectively), and non-randomized and randomized non-enriched trials (dark and light green, respectively). Red areas represent trials restricted to the biomarker mentioned in the label; blue, trials enriched on another biomarker; and green, non-enriched trials. Lighter areas represent randomized trials, darker areas represent nonrandomized trials. The charts are sorted by number of trials. Vertical axes go up to 200 for the first row, 60 for the second, 40 for the third and 800 for the last row. Dates of first submission and first approval by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) are shown by red and black vertical arrows, respectively.

Figures 3 and 4 .

 4 Figures 3 and 4. Graphical representation (hive plots) of the disease-biomarker network in trials registered on ClinicalTrials.gov. Each hive plot represents a targeted therapy; within each plot, each trial is represented by a link between the biomarker used to restrict inclusion in the trial (vertical axis) and the disease studied (horizontal axis). The color of the link corresponds to the start year of the trial: green represents trials from 2002; yellow, studies from 2008; and red, trials from 2014; intermediate dates are represented by gradients between colors. Trials with treat-all design are linked to the group "None" in the vertical axis. Multiple-disease trials are represented once for each studied disease, and multiple-drug trials are represented once for each studied drug. Biomarker-indication pairs for which genetic testing is recommended or required are in bold and indicated below the drug name along with the proportion of corresponding trials.

a b a f a t i n i b b o s u t i n i b c r i z o t i n i b d a b r a f e n i b d a s a t i n i b l a p a t i n i b n i l o t i na t i n i b b o s u t i n i b c r i z o t i n i b d a b r a f e n i b d a s a t i n i b l a p a t i n i b n i l o t i n 3 No. of trials a d o -t r a s t u z u m a b a f a t i n i b b o s u t i n i b c r i z o t i n i b d a b r a f e n i b d a s a t i n i b l a p a t i n i b n i l o t i n i b p a n i t ut r a s t u z u m a b a f a t i n i b b o s u t i n i b c r i z o t i n i b d a b r a f e n i b d a s a t i n i b l a p a t i n i b n i l o t i n i b p a n i t u

 3 trials, phase 1/2 Non-enriched trials, phase 2 Non-enriched trials, phase trials, phase 2 Single-arm trials, phase 3 Comparative trials, phase 1/2 Comparative trials, phase 2 Comparative trials, phase 3

  Figure 1

  Figure 2

Table 1 .

 1 Main characteristics of included studies, overall and stratified by phase of drug development

				2. Between
			1. Before	submission and
		Overall	submission	approval	3. After approval
	No.*	858	182 (21.2)	55 (6.4)	614 (71.6)
	Phase
	1/2	116 (14)	15 ( 8)	4 ( 7)	97 (16)
	2	581 (68)	127 (70)	39 (71)	409 (67)
	3	161 (19)	40 (22)	12 (22)	108 (18)
	PGx used for enrichment
	No PGx	270 (31)	65 (36)	15 (27)	185 (30)
	Same as label PGx	434 (51)	93 (51)	35 (64)	305 (50)
	Other than label PGx	145

Table S1 .

 S1 Hodgkin's disease (Hodgkin) 12 : Kidney and other uriry organ cancers (Kidney) 13 : Leukemia ( Leukemia ) 14 : Liver cancer (Liver ) 15 : Malignt melanoma of skin (Melanoma) 16 : Mouth cancer (Mouth) 17 : Multiple myeloma (Myeloma) 18 : non cancer (Non -cancer) 19 : Non -Hodgkin lymphoma (NHL) 20 : Non-melanoma skin cancer (Skin ) 28:Trachea, bronchus, and lung cancers (Lung) 29:Uterine cancer (Uterus) List and main characteristics of included drugs (N = 12)

																									Figure 4
		Lapatinib HER2+ / Breast 102/220 (46%) SUPPLEMENTARY TABLE HER2 mutations HER2 -EGFR + HR + HR -ERB4 mut. KRAS mut. Multiple PGx PI3K/AKT act. PI3K wild-type	PDgFR mut. Multiple PGx PDGFRA + KIT mut. KIT +	Nilotinib Ph+ / Leukemia 61/102 (60%) Drugs with pharmacogenomic
																									biomarker in FDA Table N=140
												HER2 +
																									Ph +
															Drug							biomarker	Date of biomarker Labeling Indication of the first approval
							None ado-trastuzumab HER2+ B l a d d e r S N C B r e a s t bosutinib Ph+ crizotinib ALK+ afatinib EGFR mutations 12/07/2013 A n y 5 6 7 8 H e a d & N e c k 1 4 1 5 1 6 2 0 1 8 2 1 2 2 2 3 2 4 S t o m a c h 2 8 2 9 22/02/2013 None 04/09/2012 26/08/2011 Targeted therapies in NCI list N=69	Breast cancer Drugs with required or recommended S N C A n y G I S T L e u k e m i a M e l a n o m a N o n -c a n c e r Leukemia Trachea, bronchus, and lung cancers O t h e r n e o p l a s m s genetic testing and indicated in Trachea, bronchus, and lung cancers oncology N=33
	KRAS mut. NRAS wild-type BRAF wild-type PI3K wild-type BRAF mut. HR + HER2 -Multiple PGx dabrafenib dasatinib lapatinib nilotinib			Panitumumab BRAF mutations 29/05/2013 Drugs listed in both NCI list and DFA Table Screened EGFR+ / Colon-rectum 6/157 (4%) KRAS wt / Colon-rectum 40/157 (25%) HER3 -HR -Multiple PGx Ph+ 28/06/2006 (N = 22 drugs) HER2+ 13/03/2007 KRAS wild-type EGFR + BRAF mut. Ph+ 29/10/2007 Excluded (n=10) Malignant melanoma of skin Pertuzumab HER2+ / Breast Leukemia 35/61 (57%) Breast cancer Leukemia Excluded drugs (n=10)
						KRAS wild-type
												EGFR -panitumumab	EGFR+	27/09/2006	Colon and rectum cancers
											EGFR + pertuzumab		HER2+	08/06/2012	HER2 +	Breast cancer
												None trametinib				BRAF mutations 29/05/2013 Included (N=12 drugs)	Malignant melanoma of skin
										1 vemurafenib NRAS mut. G11 mut. GQ mut. HER2 -HR + Multiple PGx	2	/37 (78%) n o -r e c t u m E s o p h a g e H e a d & N e c k 8 9 1 4 1 2 1 6 2 0 1 8 Multiple PGx HR + HER2 -BRAF mut. DDR2 mut. EGFR mut. HR -CBF + HER2 + WT -KIT mut. KIT wild-type 2 1 2 2 2 3 2 4 None BRAF mutations 17/08/2011 C o l 2 5 L u n g 935 corresponding studies in 22/63 (35%) KRAS mut. Trametinib BRAF mut. / Melanoma B r e a s t 5 4 NRAS mut. Multiple PGx ClinicalTrials.gov	Dasatinib Malignant melanoma of skin S N C B r e a s t A n y E s o p h a g e O v a r y P a n c r e a s P r o s t a t e S t o m a c h L u n g C o l o n -r e c t u m Ph+ / Leukemia 54/181 (30%) 32/44 (72%) Vemurafenib BRAF mut. / Melanoma
											KRAS mut.									Ph +
								BRAF wild-type
																									BRAF mut.
																									None
																							B r e a s t A n y C e r v i x C o l o n -r e c t u m 8 L e u k e m i a L i v e r M e l	Figure 3 M y e l o m a M o u t h O v a r y P a n c r e a s P r o s t a t e T h y r o i d L u n g U t e r u s O t h e r n e o p l a s m s n a o m a 858 trials analyzed	None	A n y	S N C B r e a s t 4 6 9 1 0 1 9 1 2 L e u k e m i a 1 4 M e l a n o m a 1 6 1 7 1 8 1 9 2 0 O t h e r n e o p l a s m s 2 2 2 3 P r o s t a t e C o l o n -r e c t u m n o m a L e u k e m i a M e l a M y e l o m a T h y r o i d 2 6 L u n g 1 8
																									2002	2008	2014
																									2002	2008	2014
		1: Bladder cancer ( Bladder) 2 : Brain and nervous system cancers (SNC ) 3 : Breast cancer (Breast) 4 : Cancer, any (Any ) 5 : Cervical cancer (Cervix) 6 : Colon and rectum cancers (Colon-rectum) 7 : Esophageal cancer (Esophage) 8 : Gallbladder and biliary tract cancer	) n n i a k g d g r o o H y r i ( r u e s r e a h e s i d t o d n s ' n i a y k g d e n d o H i K 13 : Leukemia ( Leukemia ) : 1 1 : 2 1 r e v i L : 4 1 cancer (Liver ) e c a a n c e m r s ) a o n l M ( n i k s f o a m o n a l e m t n g i l a M : 5 1 16 : Mouth cancer (Mouth) ) a m o l e y M ( a m o l e y m e l p i t l u M : 7 1 18 : non cancer (Non -cancer)	(	K	e n d i	) y	28:Trachea, bronchus, and lung cancers (Lung) 21 : Other neoplasms (Other neoplasms ) ) y r a v O ( r e c n a c n a i r a v O : 2 21 : Other neoplasms (Other neoplasms ) 2 ) s a e r c n a P ( r e c n a c c i t a e r c n a P : 3 22 : Ovarian cancer (Ovary ) 2 ) e t a t s o r P ( r e c n a c e t a t s o r P : 4 23 : Pancreatic cancer (Pancreas ) 2 24 : Prostate cancer (Prostate ) 25 : Stomach cancer ( Stomach) ) r a l u c i t s e T ( r e c n a c r a l u c i t s e T : 6 25 : Stomach cancer ( Stomach) 2 26 : Testicular cancer (Testicular) 27 : Thyroid cancer (Thyroid) 27 : Thyroid cancer (Thyroid)
		9 : GIST																				19 : Non -Hodgkin lymphoma (NHL)	29:Uterine cancer (Uterus)
	1	0	:	e H	d a	a	d n	e N	c	k	c	c n a	e	r	(	e H	a	d	&	e N	c	k	)		20 : Non-melanoma skin cancer (Skin )

None

BRAF mut. 1: Bladder cancer ( Bladder) 2 : Brain and nervous system cancers (SNC ) 3 : Breast cancer (Breast) 4 : Cancer, any (Any) 5 : Cervical cancer (Cervix) 6 : Colon and rectum cancers (Colon-rectum) 7 : Esophageal cancer (Esophage) 8 : Gallbladder and biliary tract cancer 9 : GIST 10 : Head and Neck cancer (Head & Neck ) 11 :  Drugs approved before 2005 (n= 9 )  Everolimus (n= 1)  Drugs approved before 2005 (n= 9 )  Everolimus (n= 1) Excluded studies (n=77)  Not a clinical trial with a least one experimental arm with the included drug Figure S1. Flow diagram of the selection of drugs and corresponding trials.

ACKNOWLEDGEMENTS

A.V is supported by a French grant "Soutien pour la formation à la recherche translationnelle en cancérologie, édition 2014" with financial support from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan, 2014-2019. We thank Ignacio Atal (INSERM U1153, Paris, France) for providing the computer program to extract ClinicalTrials.gov data, Ludovic Trinquart (INSERM

SUPPLEMENTARY INFORMATION

Supplementary information is available at the Genetics in Medicine website. https://www.nature.com/articles/gim2015165 U1153, Paris, France) for suggesting the use of hive plots, Elise Diard (INSERM U1153, Paris, France) for help with artwork and Laura Smales (BioMedEditing, Toronto, Canada) for proofreading.


E Imbernon
email: imbernon@laas.fr

J-L Sanchez
email: sanchez@laas.fr

P Austin
email: austin@laas.fr

M Breil
email: breil@laas.fr

O Causse
email: causse@laas.fr

B Rousset
email: rousset@laas.fr

F Rossel
email: frossel@laas.fr

FLEXIBLE TECHNOLOGICAL PROCESS FOR FUNCTIONAL INTEGRATION

In this paper, a flexible technological process suitable for the development of complex integrated power structures based on the functional integration mode is presented. This technological process is based on a succession of basic technological steps corresponding to the fabrication of IGBT devices and compatible specific steps supporting more complex functions.

INTRODUCTION

In power electronics, semiconductor devices provide control and conversion of the electrical energy. The integration is a natural way allowing to increase performances and to decrease cost. The integrated solution of these functions can be hybrid or monolithic according to the power level required. Hybrid integration concerns high power applications. In the last ten years monolithic integration has been applied to power devices for application without high galvanic integration corresponding to the development of smart power devices. Now, numerous power conversion applications connected to the mains, such as household appliances, can benefit from advantages brought about by new power functions based on the functional integration concept [START_REF] Sanchez | Trends in design and technology for new power integrated devices based on Functional Integration[END_REF][START_REF] Pezzani | Functional Integration of power devices: a new approch[END_REF]. According to this concept the interactions between semiconductor layers in the bulk and MOS effects at the top surface allow to achieve new functionalities that could not be obtained by classical integration mode involving with devices isolated from each others. These new functionalities depend not only on the surface topology (layout design) but also in the sequencing and optimisation of the technological steps.

In order to achieve increasingly complex functions that are more complex than discrete power devices such as IGBT, or VDMOS transistor, it is essential to optimise new technological process. From a technological point of view unlike the set processes used by discrete power devices or integrated circuits (ICs) that only differ by the layout design, the fabrication of specific integrated functions requires the development of flexible processes composed of compatible technological steps.

SPECIFICITY OF FUNCTIONAL INTEGRATION 2.1 Why a flexible technological process ?

The design of new power functions based on a functional integration mode as the dual thyristor (fig. 1) requires the implementation of additional technological steps relative to currently produced discrete power devices such as Insulated Gate Bipolar Transistors (IGBT) and power MOS structures.

Optimisation of the self-fired blocking structure has shown that the blocking current corresponds to a resistance optimum per square of the P region under the cathode [START_REF] Breil | A new self-firing MOS-thyristor device : optimization of the turn-off performance and experimental results[END_REF]. This resistance per square is directly linked to the dose of implanted doping atoms that is, to the surface concentration for a given junction depth. However, this optimal dose leads to MOS transistor threshold voltages in excess of those encountered in most MOS gate controlled power devices. If one wishes to optimize the thyristor part and the control linked to the MOS transistors, one has to fabricate two types of Pwell with different doses. Usually this type of requirement is also taken into account whenever different threshold voltages have to be used on a same function. Moreover, specific functionalities, such as bidirectional blocking voltage, or passive components such as non linear capacitors or microcoils, can be implemented in the near future in order to achieve specific integrated functions for power applications. These functionalities depend not only on the surface topology (layout design) but also on the proper sequencing and optimisation of the various technological steps.

These examples show that the increased complexity of integrated structures with different optimization of the semiconducting layers leads to the development of a flexible technological process including optimized and compatible steps. Part or all of the optimized steps will then be used in the fabrication of a structure providing a specific electrical function.

Identification of building layers used in functional integration

Considering the last examples of monolithic structures based on the concept of functional integration, it has been observed that they were built up from the association of well-defined semiconductive cells. These various identified cells are defined by building layers reported in a schematic structure (fig. 2). We can define 4 types of MOS transistors enhanced and depleted N and P type, thyristors, diodes,… These cells are achieved using N, P and P + layers patterned by single sided or double sided lithography, or obtained by self aligned polysilicon gate materialised by silicon oxidation and polysilicon deposition.

Concerning NMOS devices, P wells with differents implanted doses allow to obtain differents threshold voltage. Depleted N and P MOS transistors are based on controlled ionic implantation doses in the channel.

Flexible technological process

This flexible process is based on a succession of technological steps corresponding to the fabrication of an IGBT type structure or MOSthyristor devices that constitutes the generic element in our design strategy. These basic steps are defined and optimized so as to include specific steps supporting more complex functions (Fig. 3). The design of process sequence must consider that the doping profiles change with every thermal cycle, and the total thermal cycle that impurities undergo must be taken into account. Indeed, the different implanted doses in Pwell and in the channels combined by an optimized thermal allow to differentiate the threshold voltage and to control the doping profile of the differents P regions.

a) Basic technological steps

The complete technological process includes thirty steps and seven layout levels. The starting silicon wafer is a lightly doped N --type substrate. The basic building layers are ordered as follows :

• N + cathode and P + regions on the backside

b) Specific technological steps

From these basic elements, new functionalities can achieved by developing specific technological steps. Preformed channels, for example, are obtained by controlled ionic implantation dose (boron on P type channels and phosphorus of N type) through the oxide and the polysilicon gate. They are then redistributed at a temperature of 950°C. Other building blocks will be integrated on the backside such as N + regions allowing the current to flow both ways (antiparallel diodes) and specific P + anodes referred to as semitransparent during fabrication of fast IGBTs.

New functionalities can be achieved using recent development in the field of microtechnology such as reactive ionic etching (RIE), deep etching, Chemical vapour deposition (CVD) low pressure chemical vapour deposition (LVCVD), thick resin deposition, electrochemical deposition, aluminium thermomigration and new assembly techniques. By mastering these techniques it will be able in the future to achieve isolation between power device and low voltage element, peripheral termination allowing bidirectional blocking voltage, variable integrated capacitance, microcoils, micro-transformers, microconverters and micro-coolers,…

Technological simulation process

To optimise the main technological steps, [2D] process simulations are needed. Simulation results compared with experimental ones from the points of view of physical (doping profiles) and electrical characteristics (MOS threshold voltages) allow determining the different physical parameters values of the models used and therefore optimisation of each technological step. Here, we present a straightforward example of ionic implantation of boron in an N type substrate followed by the thermal step needed to diffuse doping atoms (fig. 4).

EXPERIMENTAL RESULTS: fabrication of test vehicules 3.1 Structures

The first devices achieved with this technological process are the four types of enhanced and depleted N and P MOS transistors. This process fabrication includes 28 steps. The different implantation doses and energies shall be defined as a function of the final characteristics required and the thermal step that have been set. The set of twelve masks created for the fabrication of the devices is fully integrable into the more complex fabrication process permitting to achieve new power functions.

Technological characteristics

PMOS structures are obtained directly in the N substrate and the NMOS devices in two P well exhibiting different surface concentrations (1.10 17 at/cm 3 for one and 2,5.10 17 at/cm 3 for the other). The preformed channels of the depletion PMOS structures have been implanted using 120 keV energy and the doses varied from 2.10 12 to 3.5.10 1 2 at/cm 2 . Doses and energies for phosphorus implantation in depletion NMOS transistors defined as a function of the different P regions are listed in Tables 2 and3.

Electrical results

Electric tests of the devices obtained (Figs 5a and5b) have more particularly enabled us to characterize the threshold voltage. We have compared the threshold voltage values measured with those obtained by 2D electrical simulations. Threshold voltage values of PMOS structures correspond to the values found during simulation. Indeed, enhanced PMOS devices display a -1V threshold voltage corresponding to simulation (-0.8V), the simulated and measured results relative to the depletion PMOS device are listed in table 1.

Energy(keV)

120 Dose (at/cm 2 ) 2.10 12 2.5.10 12 3.10 12 2a and2b, the optimal implantation energy for the required operating mode. It can be seen that for the transistors fabricated in the less doped P well the optimal phosphorus implantation energy is in the vicinity of 180 keV whereas in the most doped P region it approximates 200 keV.

Optimisation of specific technological step

Control and integration of the flexible technological process in these various technologies will enable us to design specific power structures.

By way of example a new technological building block allowing for the fabrication of P + traversing vertical walls is presented. This technique uses deep trenches filled with highly boron doped polysilicon. The expected benefits relative to a conventional method (double diffusion of boron in the order of 300 hours at 1.300 °C for 300 µm thick wafers) are, one the one hand, low thermal constraints and on the other, smaller occupied silicon surfaces.

The first step consists in achieving trenches with a doted line topology that fully traverse the wafer through use of the deep RIE techniques.

The doted line is a succession of rectangle whose dimensions are 6 mm wide, 75 mm long spaced out 25 mm (fig 6). Trenches are then filled with highly boron doped polysilicon and thermal redistribution is then carried out to allow the impurities in the polysilicon to diffuse in the silicon volume. Diffusion recovery between two trenches equally permit to define a continuous traversing vertical P + wall. Figure 7 shows a top side of a full trench filled with polysilicon

CONCLUSION

In the concept of functional integration, functionality is derived from interactions between layers. Indeed, electrical characteristics depends on surface topology and of the physical characteristics of the different semiconducting layers. To achieve specific layer characteristics, a flexible technological process is needed. This process has been described based on a succession of basic technological steps and completed by specific steps. The first test vehicles featuring the four types of MOS structures that we have characterized have led to the first validation of the process against simulation. The optimisation of a specific technological step is presented. This new type of technological process will support new functions based on a functional integration mode.

Figure 1 :

 1 Figure 1: Dual thyristor principle cross section

Figure 2 :

 2 Figure 2: Various basic building layers

Figure 3 :

 3 Photoresist moulds electrochemichal

Figure 4 :

 4 Figure 4: P well doping profile: simulation and experiment

Figure 5 :

 5 Figure 5: Ids (Vds) characteristic of a depletion PMOS (a) and an enhanced NMOS (b) transistors

Figure 6 :

 6 Figure 6: Cross section of deep trenches

Figure 7 :

 7 Figure 7: View from the top part of the traversing 8 µm wide, 75 µm long and 300 µm deep trenches in a 300 µm thick wafer.

Table 1 :

 1 Simulated

	3.5.10 12

Table 2 :

 2 Simulated and measured results for depletion NMOS device fabricated in a P well with a maximum surface concentration of 1.10 17 at/cm

3

(a) and 2.5.10 17 at/cm

3 (b)


Julien Figeac

The Appropriation of Mobile TV through Television Preferences and Communication Networks

Introduction

Six years after the marketing of Mobile television (TV), few French people frequently use multimedia cell phones to watch the fifty-channel broadcast. Some users associate this service with their daily media practices. This choice can be explained by two factors. First, when the television at home is unavailable, teenagers can watch television programs by using mobile phone in their bedrooms. This factor explains the use of this service in residences. Second, many users adopt this service because they use public transportation systems to commute to their workplaces. In addition to listening to music or reading, these users want to be entertained by watching television when travelling. Television viewing is favored over the other forms of media consumption, and the users want to try this new entertainment tool to view their preferred media during their daily commutes.

In this article, we are interested in this second case because users must negotiate two important constraints to watch Mobile TV when commuting. First, their television programming must be adapted to mobile phone screens. For example, can a TV series fan watch the latest episodes by using his telephone? Will the size of the screen, lifespan of the battery and telephone network connection enable him to follow an episode under good conditions? Will these technical constraints encourage him to use Mobile TV less often, choosing shorter programs, such as news shows? Second, the television preferences must be adapted to travel constraints. The user must evaluate whether the duration of an episode corresponds to their trip time. Also, trips between two subway stations and transfers in public transportation are problems for telephone network connections that are linked to underground transport.

Several studies have dealt with these questions. These studies have shown that numerous constraints prevent users from viewing their preferred television programs on mobile phones and while travelling. The small screen size of mobile phones (Chipchase, Yanqing, & Yung, 2007), the short time slots in which they are used and the noise of urban environments [START_REF] Södergard | Mobile television: Technology and user experiences[END_REF] prompt users to select programs that are not their main television preference. These constraints, linked to Mobile TV, contribute to polarizing this televisual consumption towards the news because these programs can be watched over a short period of time (Knoche & Mc Carthy, 2005;[START_REF] Oksman | News in Mobiles: Comparing text, audio and video[END_REF]. This factor explains why television programs that are not based on a structure of intrigue are at the center of this televisual consumption [START_REF] Figeac | La configuration des pratiques d'information selon la logique des situations[END_REF]. These programs have neither a real beginning nor a real ending. They do not tell a story, and a user can watch the shows even if the beginning was missed. The viewer can stop watching the news whenever necessary without being frustrated in not knowing the end. Consequently, users tend to favor television content without a structure of intrigue because they can watch them for short moments during their trip. We conclude that the viewers choose their favorite television programs based on a narrative structure that is adapted to the utilization constraints related to daily commuting.

In this report, we describe how users show reflexivity in adopting Mobile TV and adapt their choice of television consumption to mobility constraints. We cannot be satisfied in saying that the viewers use this service to avoid being bored, from a desire to relax or out of simple curiosity or habit without any particular preference (O' Hara, Mitchell, & Vorbau, 2007). The users show reflexivity in selecting a TV program that can be watched on the small screens of their mobile phone over very short periods while commuting. The users denote a "focus, a suspension, a pause on what is happening" [START_REF] Hennion | Pragmatics of taste[END_REF] to select a specific television genre [START_REF] Corner | Meaning, genre and context: the problematics of "public knowledge" in the audience studies[END_REF] and to evaluate the selected TV program. Through this reflexivity, they evaluate which program is practical to watch in the current circumstances. They evaluate which television preferences are adapted to this new screen and which ones correspond to the mobility constraints. Thus, they review and renew their television preferences based on these evaluations.

Contrary to a structuralist vision of media practices, we will show in this article how users assume control of the renewal of their media practices and how the practical circumstances and the ecological dimension of daily activities intervene in this dynamic of media consumption. We will show how technical mediations also play an active role in the daily renewal of media practices. Indeed, the principal constraint of use encountered when travelling is phone network availability. We will show how users negotiate this constraint as opportunists by transforming it into a resource that enables them to explore new content and new forms of entertainment.

The Structuring Effects of an Invisible Technical Mediation

In this article, we study a specific usage constraint/resource: the availability of a phone network. The connectivity of the network is constraining because it makes the use of Mobile TV possible. The unavailability of the phone network can force users to switch off a program, particularly in underground public transport. This constraint is specific because it refers to "worked urban environments" [START_REF] Licoppe | Configurer l'accessibilité des voyageurs équipés à des services mobiles multimédia: Le cas des publicités "augmentées" par Bluetooth dans le métro parisien[END_REF] that access this mobile service usage.

To observe its effects on the appropriation of Mobile TV, we must refer to "ubiquitous computing" [START_REF] Weiser | The Computer for the Twenty-First Century[END_REF] because this work preceded, from a theoretical point of view, the current developments of this service. According to Weiser, technologies must be invisible: they must be embedded in usage environments and must work in the background of the user's awareness. This invisibility of technical mediation can be observed in the use of Mobile TV because the phone network waves are not perceptible to users. The mobile phone manages the connection to this invisible technical network. In addition to this invisibilization of technologies, "ambient intelligence" [START_REF] Dey | A conceptual framework and a toolkit for supporting the rapid prototyping of context-aware applications[END_REF] proposes to develop technologies that are able to determine by inference what a user does in a context or tries to do in order to offer the best-adapted service. Mobile services are not (yet) able to produce such opportunities of usage in proposing the relevant service to use in conjunction with the activity of the user, the type of phone network available, the force of the The Appropriation of Mobile TV through Television Preferences and Communication Networks 101 signal, the place, the time of day, etc. These adjustments must be made completely by the users. They must evaluate the media supports and the services available during their journey to determine which ones are relevant with regard to the practical circumstances. This path of research can be explored in the prolongation of ubiquitous computing by observing how users resort to various opportunities of usage offered to them while commuting. The objective is to locate how the invisible work of technologies comes to augment urban environments (Harrison & Dourish, 1996;[START_REF] Dourish | Re-Space-ing Place: "Place" and "Space" Ten Years On[END_REF]. The city can be divided into multiple territories, according to their technological equipment and the diversity of usage opportunities it produces. For example, railway stations form territories that are rich in opportunities because they are equipped with multiple communication networks: radio, telephone, GPS and, more recently, Wi-Fi hotspots. It thus becomes interesting to describe how users demarcate places (Harrison & Dourish, 1996;[START_REF] Dourish | Re-Space-ing Place: "Place" and "Space" Ten Years On[END_REF] in urban environments by territorializing their various media activities around the usage opportunities produced by technology. In this article, we will show how users demarcate places to use Mobile TV. Users who choose to watch Mobile TV rather than reading the press will evolve differently in their environments of mobility. The user who replaces reading the press with watching Mobile TV will move differently in urban environments. Indeed, he must evaluate the phone network reception in order to watch a televised program. To do so, the user will decode the graphic indicators of his mobile phone interface. Even if these indicators show the availability of Mobile TV at a precise moment, they do not provide any information on its availability during the trip. This technological resource does not enable the user to coordinate its use with the itinerary effectively, and the user must extract the indications that provide information on the (future) availability of Mobile TV from the urban environment. We will show that the indicators that the user will employ are the same as those that are used to follow the route (i.e., the name of the stations and place names). It is through the indicators that he will identify the places where it will be relevant to watch Mobile TV. Our observation point is thus the availability of the phone network to describe how users proceed to evaluate the connectivity of this technical mediation and, consequently, to evaluate the relevance of Mobile TV use in these practical circumstances. We will show how users demarcate places dedicated to the use of Mobile TV while describing how they index their television reception on the availability of this technical mediation. Through this double appropriation of Mobile TV and its territories of use, we will show how this service comes to supplement or to replace the media activities that the participants developed previously in their trajectory of utilization.

Methodology

The results we will present are extracted from a study in 2007 with a sample of 15 Mobile TV subscribers. This sample is primarily constituted of technophiles; i.e., users 25 to 35year-old college graduates with a professional occupation in a large French conglomeration (Paris). To observe their uses in situations of mobility, we conducted ethnographic observations by using camera glasses [START_REF] Relieu | The "glasscam" as an observational tool for studying screen-based mobile phone uses and management of parallel activities[END_REF]. The users filmed their journeys on public transportation for one week. Our video database is based on the round trips between their residences and their workplaces. It represents approximately 80 hours of recording.

These video recordings enabled us to describe how travel directs Mobile TV uses and, reciprocally, how the methods of using this service direct the means of travel in urban spaces. To show engagement in this form of multi-activity, we first described the movements of users in public transport: their bust and head movements, their directed regards and their quick glances [START_REF] Sudnow | Temporal parameters of interpersonal Observation[END_REF]. While describing how a user stops looking in the direction of his telephone screen to look at the platform or the name of a station, we will show how his attention is diverted from the activity of following his route to focus on the activity of television reception. Then, while describing how he once again looks at the screen, which was kept within glancing range, we recompose the sequential organization of this form of multi-activity. We show how the distribution of visual engagements between the uses and the itinerary takes the form of a succession of logical operations, prefaced by body positioning.

To describe engagement in this form of multi-activity, we then showed the participants the video recordings of their activities. The objective was to have them explain their intentions and their tactics in using the method of self-confrontation interviews [START_REF] Theureau | Le cours d'action: Analyse sémio-logique. Un essai d'une anthropologie cognitive située[END_REF].

This method was developed by ergonomists. It leads the user to discover the parameters, contained in the situational ecology, orienting his practices. Using the recordings, he can clarify his activities as he discovers them. The performativity of self-confrontation interviews constitutes a resource in understanding how media activities and television tastes are positioned. Interviews, questionnaires and logbooks are not very useful in understanding the ecological setting of media activities. The ethnographic observations are also too removed from the activities of the participants to make it possible to observe these settings. With these observations, it is not possible to understand how users articulate their reading of a newspaper and evaluating Mobile TV reception based on information from their mobile phone network indicators. Only the video recordings, coupled with self-confrontation interviews, show the action of these technological and ecological variables in the uses and in the reconfiguration of media activities.

The Reconfiguration of Media Activities as a Function of Communication Network Reception

The members of our sampling chose to watch Mobile TV while commuting, and they partially reconfigured their old media practices. We see this reconfiguration in examining the case of Linda, a 42-year-old receptionist. The ways in which she uses the media seem paradigmatic because the form of entertainment she chose was reading the newspaper, linked with watching television. To do this, she reorganized her media activities by alternating her reception of various media (press, radio and Mobile TV) according to phone and radio network receptivity. Indeed, during the 80 minutes between her residence and her workplace, she redirected her media activities four times, according to the reception or the unavailability of the telecommunication networks (see figure 8 at the end of this article). We now describe the sequential organization of her media practices. Ever since she has been able to watch television on her mobile phone, Linda does not perform the same ritual before crossing the threshold (Thibaut, 1994) of her residence because she no longer spends her

The Appropriation of Mobile TV through Television Preferences and Communication Networks 103 travel time reading. She relies on her new telephone to replace reading magazines with watching Mobile TV.

Even if she no longer takes magazines with her, she still reads while commuting. She now picks up the free daily newspapers that other passengers have left on the seats of the subway. Consequently, in the morning, she enters the underground train searching for a seat where there is a free daily newspaper (see figure 1).

Linda picks up "Matin Plus" before sitting down. Once she has found a newspaper, she does not read it immediately. She keeps it on her lap in order to read it later (Figure 2). In other words, she carries out a preparatory gesture [START_REF] Datchary | La multi-activité et ses appuis: L'exemple de la "présence obstinée" des messages dans l'environnement de travail[END_REF]: she keeps this media resource and thus shows her intention to use it at another time (during this trip or later at her workplace or at home). It is important to determine when and under what circumstances the reading of the daily newspaper will occur.

Once seated, she immediately uses her telephone to watch "Télématin" on TV channel France 2 (Figure 2). During the self-confrontation interview, she says that she continues watching television, an activity that she had started during breakfast with her husband and children. Furthermore, she likes to immediately watch Mobile TV because her favorite television program (the TV news show "Télématin") begins at the exact time she takes the subway. In regularly taking this route, she has learned that she will not be able to watch Mobile TV beyond fifteen minutes when the train runs beneath Paris. Consequently, she watches Mobile TV as soon as she sits down in the train because she likes this TV news program, and she knows that it will not be possible for her to use this mobile service afterwards. Figure 8 (at the end of this article) shows how this receptionist watched Mobile TV for 13 minutes between the moment she took the subway (8:00 a.m.) and the moment she no longer had access to the phone network, just after "Télématin". We would like to understand how this user anticipates the unavailability of the phone network to switch off the Mobile TV before using another media. How is this anticipation deployed in regards to the practical circumstances of which it takes advantage?

We will answer this question using the video recordings. We will describe the sequential organization of this transition between these two media activities; i.e., the end of Mobile TV reception and the beginning of reading the daily newspaper. We will show which elements of this usage situation the receptionist perceives as relevant in operating this transition and how this transition is indexed to the availability of the phone network.

How the Problems of Reception and Media Activities Form a Pragmatic Test

To answer these questions, we transcribed the video recording of her trip to work (Figure 8). Once seated in the underground, she watches the televised news while keeping a free daily newspaper on her lap.

The connection to the program lasts approximately 2 minutes 40 seconds between the moment she launched it (01:50:07) and the moment the TV news appears on the screen (04:31:09 ). Then she watches this program for one minute before losing the connection (05:27:27). She needs an additional minute to restore it (06:34:13). She watches it again for 4 minutes and 44 seconds before losing the connection with the Mobile TV once again (11:18:17).

This second disconnection occurs 30 seconds after the underground leaves the Bibliothèque François Mitterrand Station (we will call it "BNF") (10:49:74). During the selfconfrontation interview, she specifies: "Here, it cannot be picked up anymore (Mobile TV), so I listen to the radio". This statement proves that she had anticipated the unavailability of Mobile TV because she identified this area as a border area: "after the BNF, nothing can be picked up anymore." When she crosses this borderline on her way to the office, she says she stops using Mobile TV before launching the radio function of her mobile phone that she will listen to while reading a newspaper.

However, the transcription of this journey shows that she tries to connect once again to Mobile TV (11:35:06), even if the subway has left station BNF (10:49:74) for 45 seconds. In other words, she continued to attempt to access Mobile TV after she crossed this borderline. The launching of the connection lasts approximately one minute (12:17:10) until the moment she can watch the televised news again. She succeeds in watching it for seven

The Appropriation of Mobile TV through Television Preferences and Communication Networks 105 seconds before the program is cut off (12:25:91), as she could have predicted. Only after this final attempt does she decides to listen to the radio with the FM tuner of her mobile phone (12:55:20). She activates the radio to listen to it while she reads her free newspaper. She opens the daily newspaper 20 seconds later (13:18:69) when the train arrives at Austerlitz Station (13:26:12) and the Mobile TV reception has become impossible. In these practical circumstances, she consequently reactivates the reading activity that she had left on stand-by 13 minutes before (00:25:08) in a preparatory gesture.

With the transcription of this sequence, we understand better why she was hesitant during the self-confrontation interview: "It picks up often, in fact. It picks up until the BNF. From there, after passing the BNF, it does not pick up near Austerlitz. Nothing can be picked up anymore." She knows that a connection with Mobile TV will be difficult at the BNF station, but she is not completely certain. However, she is certain she cannot launch Mobile TV when she is in the following station, Austerlitz. Why is it so difficult for her to identify the exact moment when the phone network is no longer available? Also, why does she continue to try every day to restore connection to this service in an area where the phone network reception is difficult?

We will answer this question by showing that she does not try to optimize these transitions between Mobile TV, the radio and the newspaper, even if she has identified the border where she will be forced to change media activities. The imprecision of this border is not a problem for her. On the contrary, this imprecision enables her to test the technological mediations that connect her to media activities: she continues 1) to handle her telephone to test it, 2) to understand whether the connection problems are related to her telephone or the phone networks, 3) to determine whether the telephone operator has deployed the Mobile TV network in this area, 4) to check if this service is usable in the underground systems in Paris and 5) to reevaluate the borders between Paris (where Mobile TV is unavailable in underground systems) and the suburb where she lives (and where this service can be consulted in overland transport). We now describe how she tests these technological mediations, which frame her media activities, before showing in the last part how this test leads her to requalify the locations of her media practices [START_REF] De Certeau | The Practice of Everyday Life[END_REF]Harrison & Dourish, 1996;[START_REF] Dourish | Re-Space-ing Place: "Place" and "Space" Ten Years On[END_REF].

At Time T of Network Indicators

Users can evaluate the intensity of the phone network with two indicators that are posted on mobile phone screens. The first indicates the type of phone networks to which the telephone is connected (e.g. EDGE, 3G, 3G+). The second indicates the signal intensity of this phone network. Using the video recordings, we can observe that Linda is connected to Mobile TV when these indicators show her that this service is available. When she is in an area where she knows from experience that Mobile TV reception is unavailable, she will try to launch this service if these indicators show her that the phone network is (temporarily) available. During the self-confrontation interview, she noted that she had identified that Mobile TV was unavailable between the BNF and the Austerlitz Stations. The phone network indicators, located at the top left of the screen (Figure 3), clearly indicated the loss of the signal to her when the TV news stopped (11:18:17). Just afterwards (11:32:45; Figure 4), these indicators showed her that the network was available again. Consequently, she tried to connect to Mobile TV (11:35:36) even if she knew that this service was usually unavailable at this location. This graphic information made connection to the service relevant under these circumstances.

Loss of reception.

When the service stopped after this last connection, the indicators showed that the phone networks were unavailable (12:25:91; Figure 5). The indicators contributed to

The Appropriation of Mobile TV through Television Preferences and Communication Networks 107 dissuading her from using Mobile TV, and encouraged her to read a newspaper and use the radio function on her mobile phone. These indicators provide support to evaluate under which circumstances she can (or cannot) watch Mobile TV. However, they indicate to users that reception is not possible once the service is blocked, the program is stopped or the image is immobilized. This information appears too late to allow users to anticipate the unavailability of Mobile TV. The limit of these indicators is to reveal instantaneous information, relating the telephone signal reception to a precise moment without specifying the degree of receptivity of the signal in the upcoming minutes. This information would be useful for a user who would like to watch Mobile TV in the subway. An indicator could provide this information to the user if his trip was traced, the orientation of his journey predictable, his stops in the stations anticipated and the speed of his movements were calculated to indicate how long he will be in an area where Mobile TV is available. No technological mediation can fulfill this function (legally).

Loss of reception. Figure 5:

Consequently, users must seek other resources to anticipate the telephone signal reception to evaluate whether it is practical to start watching Mobile TV under particular circumstances. To anticipate the connectivity of this invisible technical mediation, environmental indicators that provide information on the telephone signal fluctuations are identified by the users.

In Light of an Invisible Technical Mediation

In addition to the indications given by network indicators, users seek indicators in the surrounding environment to help anticipate the availability of the phone network at moment T + 1. The users attribute the information given by the telephone interface to their location.

A large amount of information can be used to identify a location. Categorizing all of the architectural elements and other indicators that make it possible for a user to know their location during their daily commute is difficult. It is not possible for us to identify the vari-ous indicators by which Linda identifies station BNF. However, she can identify the places where she will be able to watch Mobile TV and to define the borders of where she must use another media by using the indicators. It is possible to isolate one of the parameters that enables her to identify the places of use for Mobile TV. The person who often takes the same route can move while watching Mobile TV. She manages her activities using the perceptible light around the screen of her telephone.

Like all users, Linda thinks that connection to Mobile TV is possible when public transport runs above ground. On the other hand, she thinks that the connection is interrupted when transport moves underground. Consequently, she relies on this indication, formed by light variations, in order to direct her media activities: J.F.: "And there you are watching TV…" L.:

"Exactly, there the RER is outside, so I start watching TV."

If we take another look at her last connection to Mobile TV in light of this indicator, it appears that she begins this use (11:35:36) when the underground has been above ground for more than ten seconds (11:23:22). However, when the connection with the TV news program is established (12:17:10), the train has just entered a tunnel (12:16:22). Consequently, when the reception of this program stopped seven seconds later, this indicator dissuaded her from attempting the connection again because the train had moved underground. This example illustrates how external light is used as an indicator, which is both relevant and problematic, regarding phone network availability. This example shows how variations in luminosity between the light of day and the semi-obscurity of tunnels can influence the deployment of various uses. When the user is focused on reception, he can easily locate these variations. In this example, Linda does not move her eyes from her telephone screen. She does not need to look outside to find her location because she can identify, through the rays that light the underground train, her departure from the BNF station. She sees in these light variations an indicator showing phone network availability. This supplements information given by network indicators, enabling her to anticipate Mobile TV connectivity at the precise moment T + 1; i.e., when the RER train heads above ground.

This example also shows how the information that users extract from external light is problematic. The fact that the RER moved above ground supplemented the information delivered by the network indicators, leading her into error because she could not watch the program for more than seven seconds. For this reason, the participants test the phone network availability every day because no indicator enables them to precisely anticipate these interruptions in connection. Uncertainty involved in the appropriation of Mobile TV shows us that the logic behind utilization proceeds from indications extracted from the situational ecology. However, these indications direct the course of action towards a model that differs from Gibson's theory of perception [START_REF] Gibson | The ecological approach to visual perception[END_REF]. For Gibson, the information given by an affordance directs the single activity of a person who is moving. Consequently, the light rays of an affordance overlap a coupling of perception and action without the mediation of reflexivity being necessary; e.g., when a door handle is grasped.

In this case, variations in luminosity in the underground train direct two activities at the same time. The participants make use of these variations to exploit various uses and choose their itinerary. Luminosity transmits information on the phone network availability

The Appropriation of Mobile TV through Television Preferences and Communication Networks 109

for the person who intends to manage these two activities simultaneously in an urban environment. This indicator is not useful for a user who is in a stopped train because the information from telephone network indicators is sufficient. The relevance of this indicator comes from this mode of involvement for this form of multi-activity. This indicator gives information to the participants who manage their journey on a peripheral level of attention around the Mobile TV screen on which they are focused. The light gives information to the user who awaits its appearance because he makes use of it as a reference mark that prefaces the orientation of its uses. Consequently, Mobile TV reception is embedded as a form of multi-activity because the indicators used to manage it are also used to manage the journey.

The Appropriation of Mobile TV Creates New Forms of Mobility

We described the commuting of a participant between her residence and her workplace.

Because she has started watching Mobile TV, she does not wait for the underground train in the same station as that where she returns home in the evening. Before using this service, she waited for the underground train on the Boulainvilliers station platform. During this wait, she read a newspaper or a magazine. She let the trains that went in other directions of the underground line pass and took the one that stopped at her destination. When she started using Mobile TV, she reconsidered her itinerary because the telephone network and the radio network were unavailable in this station. Now she enters the first train that stops at this station, no matter what underground line it serves. Then, she makes an intermediate stop in another station to take another train that stops at her destination. She selected this intermediate stop according to Mobile TV availability. Because the phone network is available in the above ground stations, she chose to change trains at the Champs de Mars station near the Eiffel Tower. This station offers a beautiful view of Paris, and she can take advantage of the panorama while watching her favorite television program (Figure 7).

Consequently, she thought of taking this initiative once she had the opportunity to watch Mobile TV. To use this service, she reconsidered her itinerary by modifying her habits. She reconfigured her trip around her attachment to television programs and phone network availability. This itinerary leads to increased mobility [START_REF] Licoppe | Emergent Uses of a Location-aware Multiplayer Game: The Interactional Consequences of Mediated Encounters[END_REF] through the use of new technologies. The journey is no longer calculated according to a purely strategic logic of connecting two destinations as quickly as possible. This search for performance is secondary compared to the pleasure felt watching television because she is entertained during the time spent in transport. This pleasure is why she now reorganizes her commuting time around the requirements that must be met in order to watch Mobile TV.

Linda stands near the arrival and departure board. Her engagement in this form of multi-activity made these two communication networks, the phone network and the transport system, converge at this particular place. The place where she stops to watch Mobile TV (Figures 6 and7) is closely linked to this form of multi-activity. She stands near the arrival and departure board to be able to keep an eye on the arrival of the train (Figure 6). Through her preoccupation with the activity, which she will soon focus on (entering the train), she defines the temporal horizon of the activity of reception in this intermediate place. This example shows how the activities of reception and commuting overlap to form a multi-activity because the control of the first activity interferes with controlling the second and vice versa. As we have seen, the uses of Mobile TV modify the choice of the intermediate stations and the way in which these places are used. It is interesting to see how these places will retroactively affect the uses of this service: […] But it is not only because of that. It is also because the station is outside, and the weather is nice. So I can watch TV while soaking up the sun." J.F.: "And that is why you turned and faced the landscape?" L.:

"Yes, it is. Here, facing the sun, facing the landscape, the Seine river… In spite of the noise of cars and the train…".

She appropriated this place (Harrison & Dourish, 1996;[START_REF] Dourish | Re-Space-ing Place: "Place" and "Space" Ten Years On[END_REF] because it allowed her "to watch TV facing the sun […], facing the landscape, the Seine river… In spite of the noise of cars and the train…". Consequently, she did not choose this place only because the communication networks were accessible but also for its atmosphere [START_REF] Thibaud | Les mobilisations de l'auditeur-baladeur: une sociabilité publicative[END_REF]. She said during the interview that the perception of the sunshine in this place appears to her, retrospectively, as the main reason she left the underground to continue watching TV on the platform: "the weather is nice and all, and what's more, I could watch TV." This example shows that the atmosphere of the places where Mobile TV is used is important in understanding its appropriation. Light is not only an indicator of phone network reception. The bright sunlight illuminates this place [START_REF] Chelkoff | L'espace public, modes sensibles: Le regard sur la ville[END_REF]. The sunlight makes it prominent on a practical level and makes it conspicuous on a subjective level as a place of exposure, allowing her "to get some sun".

It is necessary to show how technical mediations converge with the atmosphere of the places so that they can be suitable as places to use Mobile TV. If it is relevant to continue the paradigm of increased mobility while describing how the uses of information and communication technologies transform urban mobility, it is also necessary to describe how the emotional tonalities [START_REF] Thibaud | Les mobilisations de l'auditeur-baladeur: une sociabilité publicative[END_REF] of urban environments influence the uses of these technologies. These emotional tonalities do not have a direct impact on the televisual content choices. However, they enter into forming media tastes because they induce pleasures, which bind a user to a media practice and affect his value judgments: to appreciate Ruquier's television program "facing the sun, facing the landscape, the Seine… In spite of the noise of cars and the train… ".

Conclusion

Throughout these descriptions, we have shown how the uses of Mobile TV are linked to daily commuting. We have described how a user redefines her itinerary in public transport to watch Laurent Ruquier's program. As an opportunist, she exploits the availability of the phone network in stopping at the stations where Mobile TV reception is possible. She adapts to this constraint in preserving her old media practices to be used during the temporal interstices in which Mobile TV reception is not possible. This technical mediation partially structures her new itinerary by directing her towards certain stations, defining the phases and places (Harrison & Dourish, 1996;[START_REF] Dourish | Re-Space-ing Place: "Place" and "Space" Ten Years On[END_REF] where the uses of the various media become relevant. But these mediations fulfill this function if the user gives them this capacity, i.e., if he exploits them as an opportunist to renew his media activities during his journeys.

The video recordings show how this opportunist attachment with television preferences is carried out like a performance. The problems of Mobile TV reception do not form simple constraints. Even if it is considered to be prejudicial, it pushes the users to refer to their mobile phones and the environments where they wish to use them. It is through this referral process and the answers obtained that the appropriation of Mobile TV becomes a performance. As part of the mobile phone network, indicators do not enable them to effectively manage connections to Mobile TV. The users seek indicators that show the availability of the phone network in the urban environments. They exploit the name of the stations and the light variations to delimit and identify the places where Mobile TV reception is reliable. These ecological supports cannot be reduced to simple resources, exploited on a procedural level, in the prolongation of the situated action approach. The performance aspect is because the light of day is perceived differently through a new function. In the same way, the places, the distances between the stations and all this information that can make commuting unpleasant by their recurrence are exploited as invaluable indicators to direct the use of Mobile TV. Multi-activity [START_REF] Datchary | La multi-activité et ses appuis: L'exemple de la "présence obstinée" des messages dans l'environnement de travail[END_REF] is used to explain this embedding of the indications in the joint control of the uses and the activity of commuting. It is true that our method, based on video recordings, contributes to involving the participant in this state of concern. The user partly records what he sees with camera glasses. He is aware that the researcher can see from the recordings what he was looking at. Consequently, this method incites him to focus his attention on his telephone instead of looking around him and staring at the passengers. This method can amplify the performance engaged in this form of multi-activity. It can encourage users to quickly divide their attention between the media.

Through the concept of multi-activity, we have tried to highlight pragmatic methods of this performance. It seems to be a state of concern [START_REF] Datchary | La multi-activité et ses appuis: L'exemple de la "présence obstinée" des messages dans l'environnement de travail[END_REF] and a state of continual vigilance. In situations of mobility, the user never isolates himself from the surrounding world. He is vigilant, according to the two meanings of [START_REF] Goffman | Relations in Public: Micro-Studies of the Public Order[END_REF]: 1) to preserve his physical integrity in relation to others and 2) to preserve the normality of his physical appearance. To manage his engagement in this multi-activity, the user remains in a state of awareness to perceive the external signals that can lead him in directing his activity.

Even if the researcher's methodology has a real effect on the practices observed, we can still conclude this study with the following idea: this state of awareness, characteristic of the various forms of multi-activity, shows that the use of Mobile TV must be referenced to the peripheral activities occurring around its use. It is interesting to describe this performance, which consists of carrying out certain activities differently, particularly those that require little attention, such as media activities or cultural attachments. Through the study of Mobile TV uses, we can describe this performance of opportunistic attachment to television programs. This opportunism characterizes a form of attachment in which practical circumstances and technical mediations prompt users to select certain media preferences. This form of attachment is specific because there are not that many people using these services. Today, users have many different media preferences, which are constantly increasing with the growth of media. Consequently, to understand the adoption of new media and complementarities between various media, it is interesting to observe which media preferences they will select according to the utilization opportunities produced by new technologies and new services.

The Appropriation of Mobile TV through Television Preferences and Communication Networks 113

Linda's trip between her residence and her workplace Figure 8:

Figure 1 :

 1 Linda watches "Télématin".

Figure 6 :

 6 Linda is about to watch Laurent Ruquier's program.

  stop at the Champ-de-Mars station. In fact, I could have continued to the BNF station, but I preferred to stop. The weather is nice and all. And what's more, I could The Appropriation of Mobile TV through Television Preferences and Communication Networks 111 watch TV.