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Background: In France, approximately 40% of women, including menopausal women, do not participate in cervical cancer screening. Many studies and meta-analyses have shown that self-sampling devices for high-risk human papillomavirus (HR-HPV) testing are valuable tools to increase participation. The success of self-sampling screening strategies depends on several factors, including the manner and circumstances in which the women are invited to participate. The acceptability and effectiveness of these strategies should be evaluated before further implementation. Objectives: The primary objective is to evaluate the uptake of cervical cancer screening in under-screened women, based on a direct offer of a vaginal self-sampling device by a midwife. Design: RIDECA is an interventional research project located in the South of France. Methods and Analysis: Six hundred women aged 50–65 with no cervical smear or HR-HPV test for 3 years or more will be recruited at two sites. The device will be offered to enrolled women to utilize at home and return to the Montpellier Hospital laboratory for HR-HPV testing. Completion of self-sampling by women who have accepted the device and follow-up of those with positive HR-HPV DNA tests will be monitored. During recruitment, participants will complete questionnaires on their socio-economic environment and motivational factors based on the psychosocial I-Change model. Semi-structured interviews will be conducted with a sub-group to identify barriers and levers to participation. Statistical analyses will be conducted for the full research sample and for each recruitment site. Ethics: The project was approved by the Ethical Research Committee Ile de France VI and by the French Data Protection Authority. Discussion: The results will provide useful information on the effectiveness (acceptability, efficiency) of this outreach strategy and identify barriers and levers that facilitate its implementation. Registration: ClinicalTrials.gov (NCT04716127), January 20, 2021. Plain language summary: Can we improve postmenopausal women's adherence to cervical cancer screening by using vaginal self-sampling and a direct approach by a midwife? Why is this study being done? In France, 40% of women, especially postmenopausal women, do not participate in cervical cancer screening. We already know that vaginal self-collection with HPV testing is highly accepted by women and increases their participation in screening. Different strategies have been proposed as the most appropriate approach to utilize when offering the vaginal self-sampling option to women. What are the researchers doing? The study, set up in the Occitania region of France, is still ongoing and is targeting women aged 50–65 who have not been screened for cervical cancer. The aim of the study is to assess whether reaching women in their everyday environment and offering them a vaginal self-collection device during an educational session with a midwife improves their adherence to and participation in cervical cancer screening. To answer these questions, we will recruit six hundred women aged 50–65 who have not been screened for cervical cancer for three years or more at two sites: - In the department of Hérault, where midwives will approach women visiting a mobile breast cancer screening unit, - in the department of Aude, where a midwife can easily arrange appointments for interested women, following an information campaign. Participants who agree to take part will receive a self-sampling kit to use at home and return to the laboratory for HR-HPV testing. During recruitment, we will also use questionnaires and interviews to assess women's socio-economic situation and motivations for participating (or not) in cervical cancer screening. What are the expected results? This study will allow us to assess women's adherence to this "direct" "face-to-face" cervical screening strategy and the potential influence of socio-economic and motivational factors on adherence. Through gaining these vital insights, we hope to identify the barriers and levers that will facilitate its implementation. [ABSTRACT FROM AUTHOR]

In adults, monocytes and neutrophils play important roles in the hyperinflammatory responses characteristic of severe forms of SARS-CoV-2 infection. We assessed leukocyte activation in 55 children attending the emergency department for acute fever between March 2020 and September 2021. The following markers were analyzed by flow cytometry: CD169 and HLA-DR on monocytes, CD64 and CD16 on neutrophils, and CD38 on lymphocytes TCD8. Fifteen of the children had SARS-CoV-2 infection, 15 had bacterial infections, and 15 had inflammatory diseases. We observed overexpression of CD169 on monocytes and CD38 on T lymphocytes in all patients with a diagnosis of SARS-CoV-2, while overexpression of CD64 on neutrophils was observed with bacterial infections and inflammatory diseases. There was a decrease in the expression of HLA-DR on monocytes in the bacterial infection and inflammatory pathology groups. Leukocyte analysis identifies distinct activation patterns in children during SARS-CoV-2 infections, bacterial infections, and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Controversy encompasses content that draws diverse perspectives, along with positive and negative feedback on a specific event, resulting in the formation of distinct user communities. we explore the explainability of controversy through the lens of SHAP (SHapley Additive exPlanations) method, aiming to provide a fair assessment of the individual contributions of different text features of tweets to controversy detection. We conduct an analysis of topic discussions on Twitter from a community perspective, investigating the role of text in accurately classifying tweets into their respective communities. To achieve this, we introduce a SHAP-based pipeline designed to quantify the influence of impactful text features on the predictions of three tweet classifiers. Text content alone offers interesting controversy detection accuracy. It can contain predictive features for controversy detection. For instance, negative connotations, pejorative tendencies and positive qualifying adjectives tend to impact the controversy model detection. [ABSTRACT FROM AUTHOR]

The search for hereditary bleeding disorders (HBD) prior to invasive procedures in children is primarily based on personal and family bleeding history. Although several scores are available, they have only been evaluated in specific situations or in adults. Our monocentric retrospective study aimed to analyze the association between clinical history and four scores (HEMSTOP, PBQ, ISTH-BAT, TOSETTO) and the diagnosis of MHC in children referred to the University Hospital of Montpellier for hemostasis investigations. A total of 117 children were retrospectively included in the study. Of these, 57 (49%) were diagnosed with HBD, with 30 having primary bleeding disorders and 27 having coagulation disorders. The diagnosis of HBD was significantly associated with gingival bleeding, which was present in 30% of HBD patients. In our population, only the HEMSTOP score showed an association with the diagnosis of HBD, but it was positive in only 48% of patients. By including gingival bleeding as a factor, we modified the HEMSTOP score, which increased its sensitivity from 0.45 to 0.53. When examining primary bleeding disorders, the modified HEMSTOP score, with the inclusion of gingival bleeding, enables us to diagnose 63% of patients (see Fig. 1). Conclusion: Therefore, gingival bleeding should be considered a useful factor in bleeding history for HBD diagnosis. Adding this symptom to a screening score such as HEMSTOP improves its sensitivity. To confirm our findings, a prospective study is required. Trial registration: Study registration number: NCT05214300. What is Known: • Screening for hereditary bleeding disorder diseases is a necessity and a challenge in children. • Minor disorders of primary hemostasis are the most common, but often escape standard coagulation tests. What is New: • Gingival bleeding is a frequent symptom that is easy to investigate and may point to a primary hemostasis disorder. • Adding the gingival bleeding item to a routine screening score such as HEMSTOP improves sensitivity. [ABSTRACT FROM AUTHOR]

HE4 and CA-125 are used for epithelial ovarian cancer (EOC) screening, diagnosis, and follow-up. Our objective was to study HE4 and CA-125 kinetics in patients treated for recurrent EOC. Serum samples were prospectively collected before the first chemotherapy cycle and every 3 months until disease progression. Data from 89/101 patients could be analyzed. At baseline, the median CA-125 and HE4 concentrations were 210 IU/L (7-10,310) and 184 pM (31-4,836). Among the 12 patients (13%) with normal CA-125 (<35 IU/L) concentration, eight had HE4 concentration ≥75 pM, and among the 16 patients with normal HE4 concentration (18%), 12 had increased CA-125 concentration. The median nadir concentrations were 31 IU/L (3-8,744) for CA-125 and 75 pM (20-4,836) for HE4. The median times to nadir were 14 (0-130) weeks for CA- 125 and 12 (0-52) weeks for HE4. In multivariate analysis, CA-125 and HE4 nadir concentrations (<35 IU/L, HR 0.35, 95% CI: 0.17-0.72 and<75 pM, HR 0.40, 95% CI: 0.20-0.79) and time to CA-125 and HE4 nadir (>14 weeks, HR 0.37, 95% CI: 0.20-0.70 and >12 weeks, HR 0.43, 95% CI: 0.23-0.83) were prognostic factors of progression-free survival. More investigations on HE4 kinetics could help to better monitor patients with CA-125 concentration within normal values. [ABSTRACT FROM AUTHOR]

Progesterone (P4) is essential for pregnancy. A controlled ovarian stimulation (COS) leads to a iatrogenic luteal defect that indicates a luteal phase support (LPS) at least untilpregnancy testday.SomeclinicianscontinuetheLPSuntilweek8or later, when P4 is mainly secreted by syncytiotrophoblast cells.Measuring serum P4 on pregnancy test day after a fresh embryo transfer could help to identify women who might benefit from prolonged LPS. In women with LPS based on P4 administered by the rectal route, P4 concentration on pregnancy test day was significantly higher in patients with ongoing pregnancy than in patients with abnormal pregnancy.This monocentric retrospective study used data on 99 consecutive cycles of COS, triggered with human chorionic gonadotropin, followed by fresh embryo transfer resulting in a positive pregnancy test (>100 IU/L) (fromNovember 2020 toNovember 2022). Patients undergoing preimplantation genetic screening or with ectopic pregnancy were excluded. All patients received standard luteal phase support (i.e.micronized vaginal progesterone 600mg per day for 15 days). The primary endpoint was P4 concentration at day 15 after oocyte retrieval (pregnancy test day) inwomen with ongoing pregnancy for >12 weeks and in patients with miscarriage before week 12 of pregnancy.The median P4 concentration [range] at pregnancy test day was higher in women with ongoing pregnancy than inwomen with miscarriage (55.9 ng/mL [11.6; 290.6] versus 18.1 ng/mL [8.3; 140.9], p = 0.002). A P4 concentration =16.5 ng/mL at pregnancy test day was associatedwithhigherongoingpregnancyrate(OR=12.5,95%CI3.61-43.33, p <0.001). A P4 concentration =16.5 ng/mL at pregnancy test day was significantly associated with higher live birth rate (OR=11.88, 95%CI 3.30-42.71, p <0.001). After COS and fresh embryo transfer, the risk of miscarriage is higher in women who discontinue luteal support after 15 days, as recommended, but with P4 concentration <16.5 ng/mL. The benefit of individualized prolonged luteal phase support should be evaluated. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype and lacks specific targeted therapeutic agents. The current mechanistic evidence from cell‐based studies suggests that the matricellular protein SPARC has a tumor‐promoting role in TNBC; however, data on the clinical relevance of SPARC expression/secretion by tumor and stromal cells in TNBC are limited. Here, we analyzed by immunohistochemistry the prognostic value of tumor and stromal cell SPARC expression in 148 patients with non‐metastatic TNBC and long follow‐up (median: 5.4 years). We also quantified PD‐L1 and PD‐1 expression. We detected SPARC expression in tumor cells (42.4%), cancer‐associated fibroblasts (CAFs; 88.1%), tumor‐associated macrophages (77.1%), endothelial cells (75.2%) and tumor‐infiltrating lymphocytes (9.8%). Recurrence‐free survival was significantly lower in patients with SPARC‐expressing CAFs. Multivariate analysis showed that SPARC expression in CAFs was an independent prognostic factor. We also detected tumor and stromal cell SPARC expression in TNBC cytosols, and in patient‐derived xenografts and cell lines. Furthermore, we analyzed publicly available single‐cell mRNA sequencing data and found that in TNBC, SPARC is expressed by different CAF subpopulations, including myofibroblasts and inflammatory fibroblasts that are involved in tumor‐related processes. We then showed that fibroblast‐secreted SPARC had a tumor‐promoting role by inhibiting TNBC cell adhesion and stimulating their motility and invasiveness. Overall, our study demonstrates that SPARC expression in CAFs is an independent prognostic marker of poor outcome in TNBC. Patients with SPARC‐expressing CAFs could be eligible for anti‐SPARC targeted therapy. [ABSTRACT FROM AUTHOR]

Purpose: A joint modeling approach is recommended for analysis of longitudinal health-related quality of life (HRQoL) data in the presence of potentially informative dropouts. However, the linear mixed model modeling the longitudinal HRQoL outcome in a joint model often assumes a linear trajectory over time, an oversimplification that can lead to incorrect results. Our aim was to demonstrate that a more flexible model gives more reliable and complete results without complicating their interpretation. Methods: Five dimensions of HRQoL in patients with esophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 were analyzed. Joint models assuming linear or spline-based HRQoL trajectories were applied and compared in terms of interpretation of results, graphical representation, and goodness of fit. Results: Spline-based models allowed arm-by-time interaction effects to be highlighted and led to a more precise and consistent representation of the HRQoL over time; this was supported by the martingale residuals and the Akaike information criterion. Conclusion: Linear relationships between continuous outcomes (such as HRQoL scores) and time are usually the default choice. However, the functional form turns out to be important by affecting both the validity of the model and the statistical significance. Trial registration: This study is registered with ClinicalTrials.gov, number NCT00861094. [ABSTRACT FROM AUTHOR]

The recurrence of non-metastatic endometrial carcinoma (EC) (6 to 21%) might be due to disseminated tumor cells. This feasibility study investigated whether circulating tumor cells (CTCs) were detectable in blood samples from the peripheral and ovarian veins of 10 patients undergoing laparoscopic resection of stage I-II EC between July 2019 and September 2021. CTCs were detected using the CellSearch® system (i) preoperatively (T0) in peripheral blood, (ii) after ovary suspensory ligament pediculation in ovarian vein blood (T1), and (iii) before colpotomy in peripheral blood (T2). CTCs were detected only in ovarian vein samples in 8/10 patients. The CTC median number did not differ with patient age (37 (min-max: 0–91) in <70-year-old vs. 11 (0–65) in ≥70 year-old women, p = 0.59), tumor grade (15 (0–72) for grade 1 vs. 15 (0–91) for grade 2, p = 0.97), FIGO stage (72 (27–91) vs. 2 (0–65) vs. 3 (0–6]) for stage IA, B, and II, respectively; p = 0.08), and tumor size (40 (2–72) for size < 30 mm vs. 4 (0–91) for size ≥ 30 mm, p = 0.39). Estrogen receptor-positive CTCs and CTC clusters were identified. The prognostic and therapeutic values of CTCs released during EC surgery need to be determined. [ABSTRACT FROM AUTHOR]

Expressed opinions on social media frequently cause a controversy. Controversial content refers to content that attracts different opinions and interrogations, implying interaction between communities. Its automatic identification remains a challenging task. Most of the existing approaches rely on the graph structure of discussion and/or the content of messages but did not deeply explore the recent advances on Graph Neural Network (gnn) to predict if a discussion is controversial or not. This paper aims to combine both user interactions present in the graph structure of a discussion and the discussion text features to detect controversy. We rely on sampling techniques to reduce the size of large graphs and augment the graph training set if needed. Our proposed approach relies then on gnn techniques to encode the initial (or sampled) graph in an embedding vector before performing a graph classification task. We propose two controversy detection strategies. The first one is based on a hierarchical graph representation learning to take advantage of hierarchical relationships that could exist between users. The second one is based on the attention mechanism, which allows each user node to give more or less importance to its neighbors when computing node embeddings. We present different experiments conducted with data sources collected from both Reddit and Twitter to show the applicability of our approach to different social networks. Conducted experiments show the positive impact of combining textual features and structural information in terms of performance and accuracy. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcomes such as health-related quality of life (HRQoL) are increasingly used as endpoints in randomized cancer clinical trials. However, the patients often drop out so that observation of the HRQoL longitudinal outcome ends prematurely, leading to monotone missing data. The patients may drop out for various reasons including occurrence of toxicities, disease progression, or may die. In case of informative dropout, the usual linear mixed model analysis will produce biased estimates. Unbiased estimates cannot be obtained unless the dropout is jointly modeled with the longitudinal outcome, for instance by using a joint model composed of a linear mixed (sub)model linked to a survival (sub)model. Our objective was to investigate in a clinical trial context the consequences of using the most frequently used linear mixed model, the random intercept and slope model, rather than its corresponding joint model. Methods: We first illustrate and compare the models on data of patients with metastatic pancreatic cancer. We then perform a more formal comparison through a simulation study. Results: From the application, we derived hypotheses on the situations in which biases arise and on their nature. Through the simulation study, we confirmed and complemented these hypotheses and provided general explanations of the bias mechanisms. Conclusions: In particular, this article reveals how the linear mixed model fails in the typical situation where poor HRQoL is associated with an increased risk of dropout and the experimental treatment improves survival. Unlike the joint model, in this situation the linear mixed model will overestimate the HRQoL in both arms, but not equally, misestimating the difference between the HRQoL trajectories of the two arms to the disadvantage of the experimental arm. [ABSTRACT FROM AUTHOR]

Background: Patient-reported outcomes such as health-related quality of life (HRQoL) are increasingly used as endpoints in randomized cancer clinical trials. However, the patients often drop out so that observation of the HRQoL longitudinal outcome ends prematurely, leading to monotone missing data. The patients may drop out for various reasons including occurrence of toxicities, disease progression, or may die. In case of informative dropout, the usual linear mixed model analysis will produce biased estimates. Unbiased estimates cannot be obtained unless the dropout is jointly modeled with the longitudinal outcome, for instance by using a joint model composed of a linear mixed (sub)model linked to a survival (sub)model. Our objective was to investigate in a clinical trial context the consequences of using the most frequently used linear mixed model, the random intercept and slope model, rather than its corresponding joint model. Methods: We first illustrate and compare the models on data of patients with metastatic pancreatic cancer. We then perform a more formal comparison through a simulation study. Results: From the application, we derived hypotheses on the situations in which biases arise and on their nature. Through the simulation study, we confirmed and complemented these hypotheses and provided general explanations of the bias mechanisms. Conclusions: In particular, this article reveals how the linear mixed model fails in the typical situation where poor HRQoL is associated with an increased risk of dropout and the experimental treatment improves survival. Unlike the joint model, in this situation the linear mixed model will overestimate the HRQoL in both arms, but not equally, misestimating the difference between the HRQoL trajectories of the two arms to the disadvantage of the experimental arm. [ABSTRACT FROM AUTHOR]

Introduction: Poor responder patients remain a challenge in assisted reproductive technologies. The "short agonist stop" (SAS) stimulation protocol uses a double stimulation (flare up effect with the gonadotropinreleasing hormone (GnRH) agonist (GnRH-a) then gonadotropins) associated with a less strenuous blockage (discontinuation of GnRH-a) to favor follicular recruitment in order to obtain a better ovarian response. This study aims to compare the number of oocytes obtained after a SAS stimulation protocol with those obtained after the previous stimulation protocol, in the same women, with poor ovarian response (POR) diagnosed according to the POSEIDON criteria. Design: This therapeutic observational retrospective cohort from 2018 to 2022, with a case-control evaluation compared with the same patients' previous performance, included women with POR undergoing IVF with SAS stimulation protocol. The primary outcome was the number of total oocytes recovered and secondary outcomes were the numbers of mature oocytes, total embryos observed at day 2 and usable cleaved embryos and blastocysts (day 5/6). Results: 63 patients with SAS and previous cycles were included. In the SAS group, the mean number of oocytes was significantly higher: 7.3 vs 5.7, p=0.018 in comparison with the previous attempt. So was the number of mature oocytes (5.8 vs 4.1, p=0.032) and the total mean number of embryos obtained at day 2 (4.1 versus 2.7, p=0.016). The SAS stimulation generated 84 usable embryos: 57 cleaved embryos and 27 blastocysts. The mean number of usable embryos was similar in both groups (1.64 vs 1.31, respectively, p=0.178). In total, out of 63 patients, after the SAS protocol, and subsequent embryo transfers (fresh and frozen, n=54), 9 patients had ongoing pregnancies and no miscarriage occurred. The cumulative ongoing pregnancy rate (cOPR) after the SAS protocol was 14.3% (9/63) per oocyte pick-up and 16.7% (9/54) per transfer. Conclusion: SAS stimulation is a short and original protocol strengthening the therapeutic arsenal of poor responders, that may offer promising results for those patients with low prognosis and previous failed IVF. Results must be confirmed with a randomized controlled trial. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancers (TBNCs) represent 10–20% of all breast cancers. TNBCs are more frequent in younger women, and present more aggressive features and poorer prognosis. Few specific therapeutics are available for TNBC treatment and it is crucial to better characterize TNBC biology in order to discover new therapeutic targets. In this study, we focused on the immune tumor microenvironment, particularly on macrophages that have been less studied in the context of TNBC. Macrophages are very plastic cells; their phenotype and function can change depending upon environmental conditions. Therefore, we used four macrophage markers to quantify the macrophage infiltrate (CD68, IRF8, CD163, and CD206) in tumors from 285 patients with TNBC. We demonstrated for the first time that a population of macrophages, defined by CD206 expression, delineates a subgroup of TNBCs that may have a better prognosis. These results could help to refine the patients' prognosis and develop new therapeutic strategies. Background: Triple-negative breast cancers (TNBCs) have a worse prognosis, but might respond to immunotherapies. Macrophages are plastic cells that can adopt various phenotypes and functions. Although they are a major immune population in TNBCs, the relationship between tumor-associated macrophages (TAMs) and TNBC progression has been rarely explored, with controversial results. Methods: We evaluated the prognostic impact of TAMs, quantified by immunohistochemistry with anti-CD68, -IRF8, -CD163, and -CD206 antibodies, in a well-described cohort of 285 patients with non-metastatic TNBC. Results: CD68 (p = 0.008), IRF8 (p = 0.001), and CD163 (p < 0.001) expression positively correlated with higher tumor grade, while CD206 was associated with smaller tumor size (p < 0.001). All macrophage markers were associated with higher tumor-infiltrating lymphocyte numbers and PD-L1 expression. Univariate survival analyses reported a significant positive correlation between CD163+ or CD206+ TAMs and relapse-free survival (respectively: HR = 0.52 [0.28–0.97], p = 0.027, and HR = 0.51 [0.31–0.82], p = 0.005), and between CD206+ TAMs and overall survival (HR = 0.54 [0.35–0.83], p = 0.005). In multivariate analysis, there was a trend for an association between CD206+ TAMs and relapse-free survival (HR = 0.63 [0.33–1.04], p = 0.073). Conclusions: These data suggest that CD206 expression defines a TAM subpopulation potentially associated with favorable outcomes in patients with TNBC. CD206 expression might identify an immune TNBC subgroup with specific therapeutic options. [ABSTRACT FROM AUTHOR]

Changes in health‐related quality of life (HRQoL) over time are not necessarily homogeneous within a population of interest. Our study aim was twofold: to determine homogeneous patient subpopulations distinguished by HRQoL trajectories, and to identify the particular patient profile associated with each subpopulation. To classify patients according to HRQoL dimension scores, we compared mixtures of linear mixed models (LMMs) classically applied to scores defined by the EORTC procedure, and mixtures of random effect cumulative models (CMs) applied to scores treated as ordinal variables. A simulation study showed that the mixture of LMMs overestimated the number of subpopulations and was less able to correctly classify patients than the mixture of CMs. Considering HRQoL scores as ordinal rather than continuous variables is relevant when classifying patients. The mixture of CMs for ordinal scores is able to identify homogeneous subpopulations and their associated trajectories. The application focused on changes over time in HRQoL data (collected using the EORTC QLQ‐C30 questionnaire) from 132 breast cancer patients from the Moral study. Once the classification is obtained only from HRQoL scores, class membership was then explained through a logistic regression model, given a large panel of variables collected at baseline. Analysis of data revealed that deterioration over time of role functioning and insomnia was closely related to patient anxiety: anxiety at baseline is a prognostic factor for a poor level and/or a deterioration over time of HRQoL. For functional dimensions, large tumor size and high education level were associated with worse HRQoL scores. [ABSTRACT FROM AUTHOR]

Purpose: Health-related quality of life (HRQoL) is an important endpoint in cancer clinical trials. Analysis of HRQoL longitudinal data is plagued by missing data, notably due to dropout. Joint models are increasingly receiving attention for modelling longitudinal outcomes and the time-to-dropout. However, dropout can be informative or non-informative depending on the cause. Methods: We propose using a joint model that includes a competing risks sub-model for the cause-specific time-to-dropout. We compared a competing risks joint model (CR JM) that distinguishes between two causes of dropout with a standard joint model (SJM) that treats all the dropouts equally. First, we applied the CR JM and SJM to data from 267 patients with advanced oesophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 to analyse HRQoL data in the presence of dropouts unrelated and related to a clinical event. Then, we compared the models using a simulation study. Results: We showed that the CR JM performed as well as the SJM in situations where the risk of dropout was the same whatever the cause. In the presence of both informative and non-informative dropouts, only the SJM estimations were biased, impacting the HRQoL estimated parameters. Conclusion: The systematic collection of the reasons for dropout in clinical trials would facilitate the use of CR JMs, which could be a satisfactory approach to analysing HRQoL data in presence of both informative and non-informative dropout. Trial registration: This study is registered with ClinicalTrials.gov, number NCT00861094. [ABSTRACT FROM AUTHOR]

Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure–toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug–drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies. [ABSTRACT FROM AUTHOR]

In patients with metastatic breast cancer (MBC), brain metastases (BM) are associated with high morbidity and mortality. However, there is no validated serum biomarker that accurately predicts BM occurrence in these patients, and the role of serum biomarkers for prognosis remains unclear. Here, we evaluated the association of neurofilament light chain (NfL), ubiquitin C‐terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP) and tau serum levels with BM presence and prognosis in patients with MBC. In serum samples from patients with MBC with (n = 100) and without BM (n = 47), we measured the biomarker serum levels using single molecule array (Simoa) technology (Neurology‐4‐Plex assay). To evaluate their accuracy to identify patients with BM, we determined the receiver operating characteristic curve and the area under the curve (AUC) for each biomarker and calculated their sensitivity and specificity. The median serum levels of NfL, UCHL1, tau and GFAP were significantly higher in patients with BM. The AUC for GFAP (0.82, 95% confidence interval [CI] 0.75‐0.88) was significantly higher than those of the other biomarkers considered independently. Using the medians as cutoff values, elevated serum levels of NfL, UCHL1, tau and GFAP were associated with BM in univariate analysis, but only high GFAP levels in multivariate analysis (odd ratio 23.4, 95% CI 6.8‐80.5, P <.001). Elevated serum GFAP levels were independently associated with poor outcome. GFAP outperforms NfL, UCHL1 and tau as diagnostic and prognostic factor of BM in patients with MBC. These results must now be validated in an independent cohort of patients. What's new? Patients with metastatic breast cancer (MBC) are highly susceptible to brain metastases. While predictive factors have been identified, including younger age and biological features, biomarkers to screen for risk of brain metastases in MBC patients are lacking. Here, the authors investigated associations between the presence of brain metastasis and different biomarkers associated with neuronal damage, including tau, neurofilament light chain (NfL), ubiquitin C‐terminal hydrolase L1 (UCHL1), and glial fibrillary acidic protein (GFAP). Serum GFAP outperformed NfL, UCHL1, and tau as a diagnostic biomarker of brain metastases. Serum GFAP levels correlated with number of brain metastases and associated symptoms and with prognosis. [ABSTRACT FROM AUTHOR]

Background: The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.Methods: FOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3 + 3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, α = 5%, β = 20%, p0 = 35% and p1 = 50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150-180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.Discussion: FOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.Trial Registration: EudraCT: 2018-003541-42 ; ClinicalTrials.gov: NCT03828799 . [ABSTRACT FROM AUTHOR]

The authors reflect on the relationship between cancer and systemic sclerosis (SSc) by examining the results of a Canadian cohort study that focused on synchronous diseases. Other topics include the close temporal relationship between anti-RNA polymerase III antibodies (ARNAP) and cancer, and the environmental factors for cancer like tobacco and dietary factors.

In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second‐line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first‐line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression‐free (PFS), overall (OS) survival and toxicity (NCI‐CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty‐three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35‐77), 59.7% men. The median treatment duration was 16.1 weeks (2.1‐61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8‐85.0; 44/59 patients). After a median follow‐up of 23.3 months (0.6‐23.6), median PFS was 3.5 months (95%CI: 2.4‐3.8) and median OS 7.9 months (95%CI: 5.1‐10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0‐1 toxicities (HR = 0.55, 95%CI: 0.33‐0.92, P =.020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed. What's new? Despite extensive investigation into gemcitabine‐based combination therapies for pancreatic cancer, significant need remains for novel strategies with improved clinical benefit. A promising approach is the triplet combination gemcitabine, trastuzumab, and erlotinib, which the present pilot multicenter phase II trial identifies as an effective strategy for disease control and survival when used as a first‐line regimen. In particular, pancreatic cancer patients with grade 2 or worse cutaneous toxicity showed superior progression‐free survival compared to patients with grade 0‐1 cutaneous toxicities. In multivariate analyses, progression‐free and overall survival were correlated EGFR and HER2, while HER2 expression was linked to tumor response. [ABSTRACT FROM AUTHOR]

Purpose: Health-related quality of life (HRQoL) is assessed by self-administered questionnaires throughout the care process. Classically, two longitudinal statistical approaches were mainly used to study HRQoL: linear mixed models (LMM) or time-to-event models for time to deterioration/time until definitive deterioration (TTD/TUDD). Recently, an alternative strategy based on generalized linear mixed models for categorical data has also been proposed: the longitudinal partial credit model (LPCM). The objective of this article is to evaluate these methods and to propose recommendations to standardize longitudinal analysis of HRQoL data in cancer clinical trials. Methods: The three methods are first described and compared through statistical, methodological, and practical arguments, then applied on real HRQoL data from clinical cancer trials or published prospective databases. In total, seven French studies from a collaborating group were selected with longitudinal collection of QLQ-C30. Longitudinal analyses were performed with the three approaches using SAS, Stata and R software. Results: We observed concordant results between LMM and LPCM. However, discordant results were observed when we considered the TTD/TUDD approach compared to the two previous methods. According to methodological and practical arguments discussed, the approaches seem to provide additional information and complementary interpretations. LMM and LPCM are the most powerful methods on simulated data, while the TTD/TUDD approach gives more clinically understandable results. Finally, for single-item scales, LPCM is more appropriate. Conclusion: These results pledge for the recommendation to use of both the LMM and TTD/TUDD longitudinal methods, except for single-item scales, establishing them as the consensual methods for publications reporting HRQoL. [ABSTRACT FROM AUTHOR]

While the utility of circulating cell‐free DNA (cfDNA) in cancer screening and early detection have recently been investigated by testing genetic and epigenetic alterations, here, an original approach by examining cfDNA quantitative and structural features is developed. First, the potential of cfDNA quantitative and structural parameters is independently demonstrated in cell culture, murine, and human plasma models. Subsequently, these variables are evaluated in a large retrospective cohort of 289 healthy individuals and 983 patients with various cancer types; after age resampling, this evaluation is done independently and the variables are combined using a machine learning approach. Implementation of a decision tree prediction model for the detection and classification of healthy and cancer patients shows unprecedented performance for 0, I, and II colorectal cancer stages (specificity, 0.89 and sensitivity, 0.72). Consequently, the methodological proof of concept of using both quantitative and structural biomarkers, and classification with a machine learning method are highlighted, as an efficient strategy for cancer screening. It is foreseen that the classification rate may even be improved by the addition of such biomarkers to fragmentomics, methylation, or the detection of genetic alterations. The optimization of such a multianalyte strategy with this machine learning method is therefore warranted. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) has a worse prognosis compared with other breast cancer subtypes, and biomarkers to identify patients at high risk of recurrence are needed. Here, we investigated the expression of human epidermal receptor (HER) family members in TNBC and evaluated their potential as biomarkers of recurrence.Methods: We developed Time Resolved-Förster Resonance Energy Transfer (TR-FRET) assays to quantify HER1, HER2 and HER3 in formalin-fixed paraffin-embedded (FFPE) tumour tissues. After assessing the performance and precision of our assays, we quantified HER protein expression in 51 TNBC specimens, and investigated the association of their expression with relapse-free survival.Results: The assays were quantitative, accurate, and robust. In TNBC specimens, HER1 levels ranged from ≈4000 to more than 2 million receptors per cell, whereas HER2 levels varied from ≈1000 to 60,000 receptors per cell. HER3 expression was very low (less than 5500 receptors per cell in all samples). Moderate HER2 expression was significantly associated with higher risk of recurrence (HR = 3.93; P = 0.003).Conclusions: Our TR-FRET assays accurately quantify HER1, HER2 and HER3 in FFPE breast tumour specimens. Moderate HER2 expression may represent a novel prognostic marker in patients with TNBC. [ABSTRACT FROM AUTHOR]

Health-related quality of life (HRQoL) data are measured via patient questionnaires, completed by the patients themselves at different time points. We focused on oncology data gathered through the use of European Organization for Research and Treatment of Cancer questionnaires, which decompose HRQoL into several functional dimensions, several symptomatic dimensions, and the global health status (GHS). We aimed to perform a global analysis of HRQoL and reduce the number of analyses required by using a two-step approach. First, a structural equation model (SEM) was used for each time point; in these models, the GHS is explained by two latent variables. Each latent variable is a factor that summarizes, respectively, the functional dimensions and the symptomatic dimensions to the global measurement. This is achieved through the maximization of the likelihood of each SEM using the EM algorithm, which has the advantage of giving an estimation of the subject-specific factors and the influence of additional explanatory variables. Then, to consider the longitudinal aspect, the GHS variable and the two factors were concatenated for each patient visit at which the questionnaire was completed. The GHS and the two factors estimated in the first step can then be explained by additional explanatory variables using a linear mixed model. [ABSTRACT FROM AUTHOR]

We examined whether 66 germline single‐nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD‐12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose‐intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin‐based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40–38.23], pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32–0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34–0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease‐free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT. What's new? May germline variants in genes encoding DNA repair and detoxification enzymes predict response to preoperative capecitabine‐based chemoradiotherapy in rectal cancer? In response, the authors analyzed 66 germline variants of 10 candidate genes. Among them, ERCC1 rs10412761 and ERCC2 rs1799787 are associated with tumor response in patients treated with preoperative capecitabine‐based chemoradiotherapy. For the first time, they described a predictive effect of XPA rs3176683 that may identify patients who benefit from adding oxaliplatin to capecitabine‐based chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Today, social media is increasingly used by patients to openly discuss their health. Mining automatically such data is a challenging task because of the non-structured nature of the text and the use of many abbreviations and the slang terms. Our goal is to use Patient Authored Text to build a French Consumer Health Vocabulary on breast cancer field, by collecting various kinds of non-experts' expressions that are related to their diseases and then compare them to biomedical terms used by health care professionals. We combine several methods of the literature based on linguistic and statistical approaches to extract candidate terms used by non-experts and to link them to expert terms. We use messages extracted from the forum on 'cancerdusein.org' and a vocabulary dedicated to breast cancer elaborated by the Institut National Du Cancer. We have built an efficient vocabulary composed of 192 validated relationships and formalized in Simple Knowledge Organization System ontology. [ABSTRACT FROM AUTHOR]

Background: The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan.Methods: Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice.Results: Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies.Conclusion: Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity. [ABSTRACT FROM AUTHOR]

Background: In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation.Methods: AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed.Results: AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years).Conclusions: AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup. [ABSTRACT FROM AUTHOR]

Abstract: The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS‐independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1‐mediated BCR phosphorylation on Tyr177, which is important for maintaining β‐catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient‐derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC. [ABSTRACT FROM AUTHOR]

Background: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined.Methods: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results.Results: In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD.Conclusions: The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data. [ABSTRACT FROM AUTHOR]

Background: The use of health-related quality of life (HRQoL) as an endpoint in cancer clinical trials is growing rapidly. Hence, research into the statistical approaches used to analyze HRQoL data is of major importance, and could lead to a better understanding of the impact of treatments on the everyday life and care of patients. Amongst the models that are used for the longitudinal analysis of HRQoL, we focused on the mixed models from item response theory, to directly analyze raw data from questionnaires.Methods: We reviewed the different item response models for ordinal responses, using a recent classification of generalized linear models for categorical data. Based on methodological and practical arguments, we then proposed a conceptual selection of these models for the longitudinal analysis of HRQoL in cancer clinical trials.Results: To complete comparison studies already present in the literature, we performed a simulation study based on random part of the mixed models, so to compare the linear mixed model classically used to the selected item response models. As expected, the sensitivity of the item response models to detect random effects with lower variance is better than that of the linear mixed model. We then used a cumulative item response model to perform a longitudinal analysis of HRQoL data from a cancer clinical trial.Conclusions: Adjacent and cumulative item response models seem particularly suitable for HRQoL analysis. In the specific context of cancer clinical trials and the comparison between two groups of HRQoL data over time, the cumulative model seems to be the most suitable, given that it is able to generate a more complete set of results and gives an intuitive illustration of the data. [ABSTRACT FROM AUTHOR]

Introduction. A new longitudinal statistical approach was compared to the classical methods currently used to analyze health-related quality-of-life (HRQoL) data. The comparison was made using data in patients with metastatic pancreatic cancer. Methods. Three hundred forty-two patients from the PRODIGE4/ACCORD 11 study were randomly assigned to FOLFIRINOX versus gemcitabine regimens. HRQoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30. The classical analysis uses a linear mixed model (LMM), considering an HRQoL score as a good representation of the true value of the HRQoL, following EORTC recommendations. In contrast, built on the item response theory (IRT), our approach considered HRQoL as a latent variable directly estimated from the raw data. For polytomous items, we extended the partial credit model to a longitudinal analysis (longitudinal partial credit model [LPCM]), thereby modeling the latent trait as a function of time and other covariates. Results. Both models gave the same conclusions on 11 of 15 HRQoL dimensions. HRQoL evolution was similar between the 2 treatment arms, except for the symptoms of pain. Indeed, regarding the LPCM, pain perception was significantly less important in the FOLFIRINOX arm than in the gemcitabine arm. For most of the scales, HRQoL changes over time, and no difference was found between treatments in terms of HRQoL. Discussion. The use of LMM to study the HRQoL score does not seem appropriate. It is an easy-to-use model, but the basic statistical assumptions do not check. Our IRT model may be more complex but shows the same qualities and gives similar results. It has the additional advantage of being more precise and suitable because of its direct use of raw data. [ABSTRACT FROM AUTHOR]

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France ( n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients ( n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing. [ABSTRACT FROM AUTHOR]

Background: Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.Methods: We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.Results: EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome.Conclusions: High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting. [ABSTRACT FROM AUTHOR]

Health-related quality of life is often an endpoint in oncology clinical trials. The European Organization for Research and Treatment of Cancer (EORTC) developed the cancer-specific quality of life questionnaire (QLQ-C30), which includes five functions, nine symptoms, and a global health status. These questionnaires are completed by the patients themselves throughout the process of care. The recommended approaches for processing EORTC QLQ-C30 data are usually descriptive and graphic. Our aim was to develop a user-written command that provided an automatic descriptive analysis of EORTC QLQ-C30 data, consisting of profile plots per visit and longitudinal plots per functional and symptom scale. [ABSTRACT FROM AUTHOR]

Purpose: Longitudinal analysis of health-related quality of life (HRQoL) remains unstandardized and compromises comparison of results between trials. In oncology, despite available statistical approaches, results are poorly used to change standards of care, mainly due to lack of standardization and the ability to propose clinical meaningful results. In this context, the time to deterioration (TTD) has been proposed as a modality of longitudinal HRQoL analysis for cancer patients. As for tumor response and progression, we propose to develop RECIST criteria for HRQoL. Methods: Several definitions of TTD are investigated in this paper. We applied this approach in early breast cancer and metastatic pancreatic cancer with a 5-point minimal clinically important difference. In breast cancer, TTD was defined as compared to the baseline score or to the best previous score. In pancreatic cancer (arm 1: gemcitabine with FOLFIRI.3, arm 2: gemcitabine alone), the time until definitive deterioration (TUDD) was investigated with or without death as event. Results: In the breast cancer study, 381 women were included. The median TTD was influenced by the choice of the reference score. In pancreatic cancer study, 98 patients were enrolled. Patients in Arm 1 presented longer TUDD than those in Arm 2 for most of HRQoL scores. Results of TUDD were slightly different according to the definition of deterioration applied. Conclusion: Currently, the international ARCAD group supports the idea of developing RECIST for HRQoL in pancreatic and colorectal cancer with liver metastasis, with a view to using HRQoL as a co-primary endpoint along with a tumor parameter. [ABSTRACT FROM AUTHOR]

Background Health-Related Quality of Life (HRQoL) is an important endpoint in oncology clinical trials aiming to investigate the clinical benefit of new therapeutic strategies for the patient. However, the longitudinal analysis of HRQoL remains complex and unstandardized. There is clearly a need to propose accessible statistical methods and meaningful results for clinicians. The objective of this study was to compare three strategies for longitudinal analyses of HRQoL data in oncology clinical trials through a simulation study. Methods The methods proposed were: the score and mixed model (SM); a survival analysis approach based on the time to HRQoL score deterioration (TTD); and the longitudinal partial credit model (LPCM). Simulations compared the methods in terms of type I error and statistical power of the test of an interaction effect between treatment arm and time. Several simulation scenarios were explored based on the EORTC HRQoL questionnaires and varying the number of patients (100, 200 or 300), items (1, 2 or 4) and response categories per item (4 or 7). Five or 10 measurement times were considered, with correlations ranging from low to high between each measure. The impact of informative missing data on these methods was also studied to reflect the reality of most clinical trials. Results With complete data, the type I error rate was close to the expected value (5%) for all methods, while the SM method was the most powerful method, followed by LPCM. The power of TTD is low for single-item dimensions, because only four possible values exist for the score. When the number of items increases, the power of the SM approach remained stable, those of the TTD method increases while the power of LPCM remained stable. With 10 measurement times, the LPCM was less efficient. With informative missing data, the statistical power of SM and TTD tended to decrease, while that of LPCM tended to increase. Conclusions To conclude, the SM model was the most powerful model, irrespective of the scenario considered, and the presence or not of missing data. The TTD method should be avoided for single-item dimensions of the EORTC questionnaire. While the LPCM model was more adapted to this kind of data, it was less efficient than the SM model. These results warrant validation through comparisons on real data. [ABSTRACT FROM AUTHOR]

Internet health forums are a rich textual resource with content generated through free exchanges among patients and, in certain cases, health professionals. We tackle the problem of retrieving clinically relevant information from such forums, with relevant topics being defined from clinical auto-questionnaires. Texts in forums are largely unstructured and noisy, calling for adapted preprocessing and query methods. We minimize the number of false negatives in queries by using a synonym tool to achieve query expansion of initial topic keywords. To avoid false positives, we propose a new measure based on a statistical comparison of frequent co-occurrences in a large reference corpus (Web) to keep only relevant expansions. Our work is motivated by a study of breast cancer patients' health-related quality of life (QoL). We consider topics defined from a breast-cancer specific QoLquestionnaire. We quantify and structure occurrences in posts of a specialized French forum and outline important future developments. [ABSTRACT FROM AUTHOR]

The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate the proteome. We describe here an approach based on a large-scale intracellular expression and selection of antibody fragments in eukaryotic cells, so-called intrabodies, and the subsequent identification of their natural target within living cell. Starting from a phenotypic trait, this integrated system allows the identification of new therapeutic targets together with their companion inhibitory intrabody. We applied this system in a model of allergy and inflammation. We first cloned a large and highly diverse intrabody library both in a plasmid and a retroviral eukaryotic expression vector. After transfection in the RBL-2H3 rat basophilic leukemia cell line, we performed seven rounds of selection to isolate cells displaying a defect in FcεRI-induced degranulation. We used high throughput sequencing to identify intrabody sequences enriched during the course of selection. Only one intrabody was common to both plasmid and retroviral selections, and was used to capture and identify its target from cell extracts. Mass spectrometry analysis identified protein RGD1311164 (C12orf4), with no previously described function. Our data demonstrate that RGD1311164 is a cytoplasmic protein implicated in the early signaling events following FcεRI-induced cell activation. This work illustrates the strength of the intrabody-based in-cell selection, which allowed the identification of a new player in mast cell activation together with its specific inhibitor intrabody. [ABSTRACT FROM AUTHOR]

Assessment of KRAS status is mandatory in patients with metastatic colorectal cancer (mCRC) before applying targeted therapy. We describe here a blinded prospective study to compare KRAS and BRAF mutation status data obtained from the analysis of tumor tissue by routine gold-standard methods and of plasma DNA using a quantitative PCR-based method specifically designed to analyze circulating cell-free DNA (cfDNA). The mutation status was determined by both methods from 106 patient samples. cfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For the seven tested KRAS point mutations, the method exhibited 98% specificity and 92% sensitivity with a concordance value of 96%. Mutation load, expressed as the proportion of mutant alleles in cfDNA, was highly variable (0.5-64.1%, median 10.5%) among mutated samples. CfDNA was detected in 100% of patients with mCRC. This study shows that liquid biopsy through cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer. [ABSTRACT FROM AUTHOR]

Background It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs). Methods In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP). Results Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP, we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome. Conclusions Our data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors. [ABSTRACT FROM AUTHOR]

Background The occurrence of response shift (RS) in longitudinal health-related quality of life (HRQoL) studies, reflecting patient adaptation to disease, has already been demonstrated. Several methods have been developed to detect the three different types of response shift (RS), i.e. recalibration RS, 2) reprioritization RS, and 3) reconceptualization RS. We investigated two complementary methods that characterize the occurrence of RS: factor analysis, comprising Principal Component Analysis (PCA) and Multiple Correspondence Analysis (MCA), and a method of Item Response Theory (IRT). Methods Breast cancer patients (n = 381) completed the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires at baseline, immediately following surgery, and three and six months after surgery, according to the "then-test/post-test" design. Recalibration was explored using MCA and a model of IRT, called the Linear Logistic Model with Relaxed Assumptions (LLRA) using the then-test method. Principal Component Analysis (PCA) was used to explore reconceptualization and reprioritization. Results MCA highlighted the main profiles of recalibration: patients with high HRQoL level report a slightly worse HRQoL level retrospectively and vice versa. The LLRA model indicated a downward or upward recalibration for each dimension. At six months, the recalibration effect was statistically significant for 11/22 dimensions of the QLQ-C30 and BR23 according to the LLRA model (p ⩽ 0.001). Regarding the QLQ-C30, PCA indicated a reprioritization of symptom scales and reconceptualization via an increased correlation between functional scales. Conclusions Our findings demonstrate the usefulness of these analyses in characterizing the occurrence of RS. MCA and IRT model had convergent results with then-test method to characterize recalibration component of RS. PCA is an indirect method in investigating the reprioritization and reconceptualization components of RS. [ABSTRACT FROM AUTHOR]

To identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment. [ABSTRACT FROM AUTHOR]