EGFR mutation-positive NSCLC: factors to consider when deciding first-line therapy

International audienceIntroduction: Advanced non-small-cell lung cancers with EGFR mutation belong to the models of solid tumors which revealed the concept of oncogene addiction. For that reason, first, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are the major anti-cancer drugs used in this indication. Translational research is currently focused on induced mechanisms of resistance and aims to define the best first therapeutic option and the best multiline strategy.Areas covered: EGFR TKIs, alone or in combination, i.e. anti-angiogenic drugs or chemotherapy, have demonstrated their ability to improve median PFS and OS in large randomized phase 3 trials. All these combinations, now available in first-line for EGFR mutated advanced NSLC, need to integrate multiple factors like patients characteristics (age, co-morbidities, eligibility to platinum-based chemotherapy), presence of brain metastasis at diagnosis, and type of EGFR mutation. This review has 2 aims: (1) to discuss the current knowledge of therapies available in non pre-treated EGFR-mutated NSCLC; (2) to propose the best therapeutic option according to multiple parameters, either clinical or biological.Expert commentary: In 2020, we can affirm that osimertinib the first choice for patients with EGFR-mutated NSCLC. However, this has to be balanced with patient characteristics, type of EGFR mutation and new therapeutic options

Pembrolizumab for the treatment of colorectal cancer

International audienceIntroduction: Colorectal cancer (CRC) is one of the most frequent and lethal cancers in the world, and therapies are still insufficient. Immune checkpoint inhibitors (ICI) in metastatic CRC (mCRC) have not revolutionized treatment to the extent that they have in melanoma or renal carcinoma. Their use is limited to a molecular niche of mCRC with microsatellite instability (MSI). This review summarizes clinical data published with pembrolizumab in mCRC and also tries to identify potential new strategies. Areas covered: This paper focuses on pembrolizumab in mCRC. We screened all trials on PubMed and ClinicalTrials.gov and describe the most significant ones in our opinion. Expert opinion: Pembrolizumab seems to be effective in tumors with MSI-high status. It defines a new horizon for therapeutic strategy called 'agnostic' medicine. For microsatellite stable (MSS) colorectal cancers, the future challenge will be to successfully redraw the immune microenvironment to make it immunogenic with new therapeutic combinations, including IC

Impact of chemotherapy on lung cancer cells and their microenvironment, evaluated in tridimensional multicellular tumor spheroids

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Acute Ulceronecrotic Gastritis With Cytomegalovirus Reactivation: Uncommon Toxicity of Immune Checkpoint Inhibitors in Microsatellite Instability–High Metastatic Colorectal Cancer

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Carcinoembryonic Antigen Increase in a Patient with Colon Cancer Who Have Achieved Complete Remission and Negative 18F-FDG PET/CT: Don’t Forget the Thyroid!

International audienceSerum carcinoembryonic antigen (CEA) is a tumor marker especially used to follow a patient with colorectal cancer. However, it is non-specific and could be increased in several cancers and some benign conditions. We report the case of a 70-year-old man followed since 2014 for a left colon adenocarcinoma with the persistence of an increased CEA. There was no evidence of recurrence, but a right lobar thyroid nodule without a significantly increased uptake was incidentally discovered on the CT scan of 18F-fluorodeoxyglucose (18F-FDG) PET/CT. We suspected a medullary thyroid carcinoma (MTC) explaining the persistent elevation of CEA. Plasma calcitonin levels were 47 ng/L (N < 10). Fine needle aspiration cytology found atypia of undetermined significance and the patient was reluctant to undergo surgery without any further exploration. We performed a 18Ffluorodihydroxyphenylalanine (18F-FDOPA) PET/CT preoperatively which revealed a punctiform focus of the right thyroid lobe corresponding to a pT1aN1aMxR0 medullary thyroid carcinoma, histopathologically confirmed. This case highlights that despite the potential usefulness of 18F-FDG PET/CT in case of an unknown source of elevated CEA this imaging may be falsely negative as in the case of MTC and should lead to further explorations

Infectious viral load in unvaccinated and vaccinated individuals infected with ancestral, Delta or Omicron SARS-CoV-2

Infectious viral load (VL) expelled as droplets and aerosols by infected individuals partly determines transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RNA VL measured by qRT-PCR is only a weak proxy for infectiousness. Studies on the kinetics of infectious VL are important to understand the mechanisms behind the different transmissibility of SARS-CoV-2 variants and the effect of vaccination on transmission, which allows guidance of public health measures. In this study, we quantified infectious VL in individuals infected with SARS-CoV-2 during the first five symptomatic days by in vitro culturability assay in unvaccinated or vaccinated individuals infected with pre-variant of concern (pre-VOC) SARS-CoV-2, Delta or Omicron BA.1. Unvaccinated individuals infected with pre-VOC SARS-CoV-2 had lower infectious VL than Delta-infected unvaccinated individuals. Full vaccination (defined as &gt;2 weeks after receipt of the second dose during the primary vaccination series) significantly reduced infectious VL for Delta breakthrough cases compared to unvaccinated individuals. For Omicron BA.1 breakthrough cases, reduced infectious VL was observed only in boosted but not in fully vaccinated individuals compared to unvaccinated individuals. In addition, infectious VL was lower in fully vaccinated Omicron BA.1-infected individuals compared to fully vaccinated Delta-infected individuals, suggesting that mechanisms other than increased infectious VL contribute to the high infectiousness of SARS-CoV-2 Omicron BA.1. Our findings indicate that vaccines may lower transmission risk and, therefore, have a public health benefit beyond the individual protection from severe disease

Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy

International audienceBackground: Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies.Methods: To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3'RNA sequencing, real-time PCR, flow cytometry and confocal microscopy.Results: We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level.Conclusions: This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment

Additional file 1 of Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy

Supplementary Figure S1: Number of genes regulated specifically and in common by CaPa and CaGe treatments. A) Left, vendiagramm showing the number of genes upregulated in common or specifically after CaPa or CaGe treatment. A) Right, vendiagramm showing the number of genes downregulated in common or specifically after CaPa or CaGe treatment. B-D) Hallmark gene sets pathways enrichment of genes specifically regulated by CaPa (B), by CaGe (C) and in common between CaPa and CaGe (D) (GSEA, Human MSigDB v2023.2.Hs updated October 2023)(Subramanian, Tamayo, et al. (2005, PNAS)

First experimental assessment of protein intrinsic disorder involvement in an RNA virus natural adaptive process.

Intrinsic disorder (ID) in proteins is defined as a lack of stable structure in physiological conditions. Intrinsically disordered regions (IDRs) are highly abundant in some RNA virus proteomes. Low topological constraints exerted on IDRs are expected to buffer the effect of numerous deleterious mutations and could be related to the remarkable adaptive potential of RNA viruses to overcome resistance of their host. To experimentally test this hypothesis in a natural pathosystem, a set of four variants of Potato virus Y (PVY; Potyvirus genus) containing various ID degrees in the Viral genome-linked (VPg) protein, a key determinant of potyvirus adaptation, was designed. To estimate the ID contribution to the VPg-based PVY adaptation, the adaptive ability of the four PVY variants was monitored in the pepper host (Capsicum annuum) carrying a recessive resistance gene. Intriguingly, the two mutants with the highest ID content displayed a significantly higher ability to restore infection in the resistant host, whereas the less intrinsically disordered mutant was unable to restore infection. The role of ID on virus adaptation may be due either to a larger exploration of evolutionary pathways or the minimization of fitness penalty caused by resistance-breaking mutations. This pioneering study strongly suggests the positive impact of ID in an RNA virus adaptive capacity