Mass Spectrometry as a Highly Sensitive Method for Specific Circulating Tumor DNA Analysis in NSCLC:A Comparison Study

Simple Summary We compared the UltraSEEK (TM) Lung Panel on the MassARRAY (R) System (Agena Bioscience) with the FDA-approved Cobas (R) EGFR Mutation Test v2 for the detection of EGFR mutations in liquid biopsies of NSCLC patients, accompanied with preanalytical sample assessment using the novel Liquid IQ (R) Panel. For the detection of relevant predictive mutations using the UltraSEEK (TM) Lung Panel, an input of over 10 ng showed 100% concordance with Cobas (R) EGFR Mutation Test v2 and detection of all tissue confirmed mutations. In case of lower ccfDNA input, the risk of missing clinically relevant mutations should be considered. The use of a preanalytical ccfDNA quality control assay such as the Liquid IQ (R) Panel is recommended to confidently interpret results, avoiding bias induced by non-specific genomic DNA and low input of specific tumoral ccfDNA fragments. Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared the FDA-approved Cobas (R) EGFR Mutation Test v2 with the UltraSEEK (TM) Lung Panel on the MassARRAY (R) System on detection of EGFR mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ (R) Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas (R) and UltraSEEK (TM) tests. Liquid IQ (R) analysis was initially validated (n = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ (R) results were applied to harmonize ccfDNA input for the Cobas (R) and UltraSEEK (TM) tests for 63 NSCLC patients. The overall concordance between the Cobas (R) and UltraSEEK (TM) tests was 86%. The Cobas (R) test detected more EGFR exon19 deletions and L858R mutations, while the UltraSEEK (TM) test detected more T790M mutations. A 100% concordance in both the clinical (n = 137) and harmonized (n = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ (R) Panel. The Cobas (R) and UltraSEEK (TM) tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

Facteurs pronostiques des tumeurs épithéliales de l'ovaire, traitées par chimiothérapie (apport des dosages sériques du CA 125)

MONTPELLIER-BU Médecine (341722104) / SudocMONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Longitudinal associations between parental autonomy support and educational adjustment during adolescence: The mediating role of self-concept clarity

Educational adjustment, which includes multiple dimensions such as school engagement, performance, and belonging, may be especially important during educational transitions. Indeed, successful educational adjustment relates to an array of positive outcomes, such as higher well-being and later educational attainment (Upadyaya & Salmela-Aro, 2013). Most studies investigate individual differences in educational adjustment by comparing adolescents to other adolescents (for meta-analyses, see MacCann et al., 2020; Robson et al., 2020; Wu et al., 2021). Predictors of the differences in educational adjustment between adolescents include emotional intelligence, self-regulation, and academic self-concept. Additionally, extant empirical studies revealed that parents play a key role in successful educational adjustment notably through their expectations and their supportive behaviors (for meta-analyses, see Barger et al., 2019 and Pinquart & Ebeling, 2020). More specifically, extant empirical studies suggest that parental autonomy support is a positive predictor of educational adjustment (for a meta-analysis, see Vasquez et al., 2016; Ratelle et al., 2021). In contrast, parental psychological control was found to be negatively associated with educational adjustment concurrently, and longitudinally (Albert Sznitman et al., 2022; Yau et al., 2021). Yet, differences between adolescents regarding educational adjustment are fairly stable over time, and more research is needed to understand the antecedents of change over time in educational adjustment that occur at an individual level. The first objective of this study is to examine within-person processes by examining fluctuations in individual adolescents’ educational adjustment, which allows to better understand how parenting behaviors relate to each adolescent’s change over time in educational adjustment. Examining within-person bidirectional processes between parental behaviors, namely parental autonomy support and psychological control, and educational adjustment will allow us to test the direction of the associations between these parental behaviors and educational adjustment. The second objective of this study is to examine self-concept clarity as a mediator in these associations. Self-concept clarity refers to a clearly and confidently defined individual self-concept (Campbell et al., 1996). Self-concept clarity also reflects the internal consistency and temporal stability of this self-concept. Of note, self-concept clarity is considered an aspect of autonomy and identity, and is akin to the construct of authenticity (Schwartz et al., 2017). According to Self-Determination Theory (Ryan and Deci, 2017), autonomy supportive parents promote optimal child development, including educational adjustment, by satisfying their basic psychological need for autonomy (i.e., feelings of agency and authenticity). Parental autonomy support includes parental consideration of youth’s perspective and emotions, giving informative rather than evaluative feedback, and giving choices of possible actions (Mageau & Joussemet, 2023). Conversely, SDT suggests that parental psychological control can lead to autonomy frustration. Parental psychological control refers to parental behaviors that force youth to feel, act, or think in specific ways, notwithstanding their own perspective (e.g., using threats, inducing guilt; Mageau et al., 2015). According to SDT, levels of autonomy satisfaction vary within individuals (Ryan & Ryan, 2019). Thus, this theory applies to within-person processes and suggests that within-person changes in parental autonomy support and psychological control should relate to within-person changes in educational adjustment. In addition to educational adjustment, parental autonomy support fosters positive identity development among youth (Ratelle & Guay, 2023). More specifically, autonomy support may promote higher self-concept clarity. According to SDT, parental autonomy support facilitates the development of a clearly defined self because it allows youth to develop an authentic inner compass, which reflects their self-guiding schemas (e.g., values, interests, and goals; Assor, 2017; Assor et al., 2020). This inner compass guides youth's actions and helps them make decisions congruent with their true self. Autonomy support may facilitate identity formation through youth satisfaction of psychological need for autonomy, which promotes career identity exploration and commitment. Conversely, parental control is associated with autonomy frustration, which may hinder identity development, including career identity exploration (Ratelle & Guay, 2023). Although most extant studies examined how parental autonomy support or psychological control predicts youth educational adjustment or identity development, these links are most likely bidirectional. According to the vigilant care model, parents may increase their levels of controlling behaviors and display lower levels of autonomy support when they perceive that their youth experience difficulties in their psychological or educational adjustment (Omer et al., 2016). Similarly, parents may react to lower educational adjustment or self-concept clarity with higher levels of controlling behaviors because they do not know how to help their youth with identity development or because they are ego-involved and wish to promote their youth achievements to increase their own self-esteem (Ratelle & Guay, 2023). Providing empirical support for SDT, several empirical studies suggest that the quality of parent-youth relationships is associated with higher self-concept clarity and more broadly, identity development during adolescence (Hertel, 2017; Albert Sznitman et al., 2022). Moreover, one study examined and found bidirectional and positive associations between the quality of parent-child relationship and self-concept clarity using a within-person research design (i.e., Becht et al., 2017). Additional empirical evidence suggests that the relations between parental behaviors and educational adjustment are also bidirectional (Ahn et al., 2022; Cimon-Paquet et al., 2023; Kiuru et al., 2020). Nonetheless, the processes underlying the bidirectional associations between parenting and educational adjustment are still unclear. According to SDT, through satisfaction with psychological needs, autonomy support may promote higher self-concept clarity, which, in turn, may foster educational adjustment within youth as they develop clearer goals and career identities. Relatedly, empirical research showed that higher self-concept clarity relates to higher educational adjustment during adolescence (Van der Aar et al., 2022). Grounded in Self-Determination Theory (Ryan & Deci, 2017), the aim of the current study is to examine the within-person longitudinal and bidirectional links between parental autonomy support, parental psychological control, and educational adjustment during school transitions. The second objective of this study is to examine self-concept clarity as a potential mediator of the links between parental behaviors and educational attainment

Cancer immune contexture and immunotherapy

International audienceThe immune contexture that characterizes the density, the location, the organization and the functional orientation of tumor-infiltrating immune cells in cancers has a clinical impact on patient's outcome. It is, in great part, shaped by the malignant cells, as in a given cancer type, tumors presenting different oncogenic processes have different immune contextures. Moreover, the immune contexture in metastatic sites reflects that of the corresponding primary tumors. Finally, the components forming the immune contexture represent targets and markers of efficient anti-cancer immunotherapies

Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies

International audienceTumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

International audienceThe outcome of tumors results from genetic and epigenetic modifications of the transformed cells and also from the interactions of the malignant cells with their tumor microenvironment (TME), which includes immune and inflammatory cells. For a given cancer type, the composition of the immunological TME is not homogeneous. Heterogeneity is found between different cancer types and also between tumors from patients with the same type of cancer. Some tumors exhibit a poor infiltration by immune cells, and others are highly infiltrated by lymphocytes. Among the latter, the architecture of the TME, with the localization of immune cells in the invasive front and the center of the tumor, the presence of tumor-adjacent organized lymphoid aggregates, and the type of inflammatory context, determines the prognostic impact of the infiltrating cells. The description and the understanding of the immune and inflammatory landscape in human tumors are of paramount importance at different levels of patient's care. It completes the mutational, transcriptional, and epigenetic patterns of the malignant cells and open paths to understand how tumor cells shape their immune microenvironment and are shaped by the immune reaction. It provides prognostic and theranostic markers, as well as novel targets for immunotherapies

Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression

International audienceWe introduce the Microenvironment Cell Populations-counter (MCP-counter) method, which allows the robust quantification of the absolute abundance of eight immune and two stromal cell populations in heterogeneous tissues from transcriptomic data. We present in vitro mRNA mixture and ex vivo immunohistochemical data that quantitatively support the validity of our method's estimates. Additionally, we demonstrate that MCP-counter overcomes several limitations or weaknesses of previously proposed computational approaches. MCP-counter is applied to draw a global picture of immune infiltrates across human healthy tissues and non-hematopoietic human tumors and recapitulates microenvironment-based patient stratifications associated with overall survival in lung adenocarcinoma and colorectal and breast cancer