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Papers by catherine butori

Annales de Dermatologie et de Vénéréologie - FMC, 2021

Introduction L’association ipilimumab (IPI)+nivolumab (NIVO) offre un taux de réponse et de guéri... more Introduction L’association ipilimumab (IPI)+nivolumab (NIVO) offre un taux de réponse et de guérison supérieur aux anti-PD1 en monothérapie mais expose à des événements indésirables immunitaires (EII) plus fréquents. La COVID-19 a tué plus de 3M de personnes. Comme les patients atteints de cancers sont particulièrement exposés aux formes sévères/mortelles, la vaccination est recommandée. Il n’existe pas de données testant la relation entre vaccination et développement/exacerbation des EII au cours du traitement par ICI. Nous rapportons un cas de myopathie nécrosante survenue 10jours après la vaccination contre la COVID-19 chez un patient atteint d’un mélanome avancé traité par IPI+NIVO. Matériel et méthodes Un homme de 43 ans était inclus en 2015 dans l’essai adjuvant EORTC MK-3475 (pembrolizumab vs. placebo) pour un mélanome stade IIIb. E n 02/2021 une récidive ganglionnaire lombo-aortique, non opérable survenait. Malgré un statut BRAF (+) et une levée d’aveugle révélant qu’il avait reçu le pembrolizumab (sans EII à l’époque), un traitement par IPI+NIVO était alors débuté. Il recevait sa 1ère et 2e injection les 25/02 et 19/03/21. Le 12/03, il recevait sa 1ère dose de vaccin COVID-19 (Pfizer/BioNTech), sans réaction immédiate. Le 22/03 il développait un tableau associant: myalgies, faiblesse musculaire des membres, dysphagie, dyspnée, dysphonie et diplopie bilatérale avec rhabdomyolyse (CK 12647 U/L). Le bilan immunologique revenait négatif. L’ENMG décrivait un syndrome myogène. L’IRM musculaire révélait un aspect de myosite (muscles rotateurs du cou/de la cuisse) et l’histologie retrouvait un aspect de myopathie inflammatoire avec nécrose multifocale de myocytes et infiltrat inflammatoire à prédominance macrophagique. Le diagnostic de myopathie nécrosante grade IV était retenu. L’immunothérapie était arrêtée et une corticothérapie (bolus puis per os) permettait une amélioration progressive. Le patient est toujours sous corticothérapie orale, la surveillance oncologique montre à ce jour une réponse partielle. La 2e injection du vaccin n’a pas été faite d’autant plus que les IgG étaient fortement positives. Discussion Des myosites secondaires aux ICI, au COVID-19 et de façon plus anecdotique à la vaccination ont été rapportées. Ici, l’association temporelle étroite de la bi-ICI et du diagnostic de myopathie suggère que la myopathie est un EII et que la vaccination a contribué au développement de la myopathie par un effet de boost immunitaire. Le scénario inverse ne peut être exclu. Parce que de plus en plus de patients traités par ICI seront vaccinés dans les prochains mois, les cliniciens doivent être conscients de cette association potentielle du vaccin COVID-19 et de l’exacerbation des EII. Des données prospectives de pharmacovigilance sont nécessaires.

The Lancet Respiratory Medicine, 2020

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Journal of Clinical Oncology, 2017

e20632 Background: The use in routine clinical practice of the EGFR tyrosine kinase inhibitors is... more e20632 Background: The use in routine clinical practice of the EGFR tyrosine kinase inhibitors is limited to patients with advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have known EGFR mutations. Currently, patient care has to respond to several imperatives to make it broadly available to all patients; fast and accurate detection of EGFR mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. The possibility to obtain EGFR testing results in less than few hours in a large number of pathology laboratories is recently guaranteed by the Idylla system. Methods: We evaluated the Idylla system (Biocartis) for the detection of EGFR mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 18 patients with lung adenocarcinoma and compared these results with those obtained by the Therascreen EGFR Pyro assay (Qiagen)-ISO 15189 accredi...

Journal of Clinical Oncology, 2019

e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In v... more e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The ...

Cancers, Jan 13, 2018

With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 c... more With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 clinical trials, better understanding of the interplay of PD-L1 and tumor-associated immune cells (TAICs) could assist clinicians in stratifying these patients for immunotherapy. One hundred and one patients with LADCs, stratified by age, were included for analysis of PD-L1 expression and density of TAICs expressing CD4, CD8, and CD33, by using multiplex chromogenic immunohistochemistry (IHC) assays and automated digital quantification. The CD4⁺/CD8⁺ ratio was significantly higher in elderly patients. In patients <75 years, the density of CD4⁺, CD8⁺, and PD-L1 in TAICs showed a positive significant correlation with PD-L1 expression in tumor cells (TCs), while a lower correlation was observed in the elderly population. In the latter, a high CD4⁺/CD8⁺ ratio, and combined PD-L1 expression ≥1% TCs with a low CD8⁺ density, low CD33⁺ density, and a high CD4⁺ density correlated to worse overa...

Cancers, Jan 29, 2018

Lung cancer is the major cause of death from cancer in the world and its incidence is increasing ... more Lung cancer is the major cause of death from cancer in the world and its incidence is increasing in women. Despite the progress made in developing immunotherapies and therapies targeting genomic alterations, improvement in the survival rate of advanced stages or metastatic patients remains low. Thus, urgent development of effective therapeutic molecules is needed. The discovery of novel therapeutic targets and their validation requires high quality biological material and associated clinical data. With this aim, we established a biobank dedicated to lung cancers. We describe here our strategy and the indicators used and, through an overall assessment, present the strengths, weaknesses, opportunities and associated risks of this biobank.

Oncotarget, Jan 28, 2017

Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lun... more Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lung cancer who have known mutations. Currently, patient care has to respond to several imperatives to make these inhibitors broadly available to all patients; fast and accurate detection of mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. We evaluated the Idylla™ EGFR Mutation Assay (Biocartis) for the detection of mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 55 patients with lung adenocarcinoma and compared these results with those obtained by a pyrosequencing ISO-15189 accredited laboratory method. The comparison was made on both whole surgical tumor sections and on three artificially constructed small biopsies (∼1 mm) from the same FFPE blocks. Cost-effectiveness and turnaround time comparison between the two methods was performed. On bo...

Cancers, Jan 13, 2018

The identification of certain genomic alterations (, , , ) or immunological markers (PD-L1) in ti... more The identification of certain genomic alterations (, , , ) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological sample...

Revue Francophone des Laboratoires, 2017

Les biobanques ou centres de ressources biologiques (CRB) sont les maillons essentiels de la rech... more Les biobanques ou centres de ressources biologiques (CRB) sont les maillons essentiels de la recherche translationnelle. Ces structures bénéficient de financements publics récurrents afin d'établir des collections d'échantillons biologiques utilisées dans le cadre de projets de recherche. Plus de 100 biobanques ont été développées sur le territoire national au sein des hôpitaux universitaires et des centres de lutte contre le cancer. Le développement de nouvelles techniques et de nouvelles méthodes d'analyses dans la recherche médicale bouleversent les pratiques et soulèvent de nouveaux défis scientifiques et organisationnels dans la collecte, la transformation et la conservation des échantillons. Relever ces défis devient un enjeu primordial pour les biobanques. La mise en place d'une stratégie dynamique pour anticiper les besoins des utilisateurs est nécessaire et repose sur de nouveaux modes de fonctionnement. Cet article décrit les enjeux à court et à moyen terme pour les biobanques françaises et propose des éléments d'organisation pour y répondre. Biobanque-centre de ressources biologiques-enjeuxmodèle économique, indicateurs.

Nature communications, Jan 19, 2017

Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decis... more Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through αvβ6 and α9β1 engagement, rather than α5β1. Moreover, αvβ6-driven migration occurs independently of latent TGF-β activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour-stroma interface that govern the collective mod...

Oncotarget, Jan 15, 2017

Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circul... more Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circulating tumor cells (CTCs) for MET status assessment in NSCLC patients. We used two platforms for CTC capture, and assessed MET expression in CTCs and matched-bronchial biopsies in patients with advanced-stage III/IV lung adenocarcinoma. Baseline peripheral blood was collected from 256 advanced-stage III/IV NSCLC patients from Genentech clinical trials, and from 106 patients with advanced-stage III/IV lung adenocarcinoma treated at the Department of Pneumology, Pasteur Hospital, Nice. CTCs were enriched using CellSearch (Genentech), or ISET technologies (Pasteur Hospital). MET expression was evaluated by immunofluorescence on CellSearch, and by immunocytochemistry on ISET-enriched CTCs and on matched FFPE tissue sections (Pasteur Hospital). CTCs were detected in 83 of 256 (32%) patients evaluated on CellSearch, with 30 samples (12%) exhibiting ≥ 5 CTCs/7.5 ml blood. On ISET, CTC were obser...

Cancer Research, 2016

Background: Although small cell lung carcinomas (SCLC) show an initial response to treatment, pat... more Background: Although small cell lung carcinomas (SCLC) show an initial response to treatment, patients rapidly suffer disease recurrence and become refractory to chemotherapy. Despite intensive research, the prognosis of SCLC remains poor, and therefore new strategies to improve outcome are urgently needed. Blockade of immune checkpoints PD-1/PD-L1 with monoclonal antibodies has recently emerged as a new therapeutic tool in oncology. Due to the difficulty in obtaining adequate tissue in diseases such as SCLC for PD-L1 expression assessment, we investigated the usefulness of circulating tumor cells (CTCs) detection as a non-invasive method to evaluate PD-L1 status in SCLC patients. Materials and Methods: CTC capture and PD-L1 expression was evaluated in a cohort of 18 SCLC patients for whom resected tissue specimens were available and were positive for CTCs, as detected by using the filtration-based ISET platform (Rarecells Diagnostics, Paris, France). PD-L1 expression was evaluated ...

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Dec 26, 2016

PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell... more PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell carcinoma. However, the expression pattern of PD-L1 and the presence of CD8(+) and PD-1(+) tumor-infiltrating T cells in the basaloid variant of squamous cell carcinoma remain unknown. immunohistochemistry analysis of PD-L1 expression, with three recently validated monoclonal antibodies used in clinical trials (clones SP142, SP263, and 28-8), and detection of CD8(+) and PD-1(+) tumor-infiltrating T cells was performed on whole-tissue sections from 56 patients following surgery for basaloid squamous cell carcinoma. Data were correlated to clinicopathological parameters and outcome. Fair to poor concordance was observed between the SP142 vs SP263 clones, and SP142 vs 28-8 (κ range, 0.018-0.412), while the 28-8 and SP263 demonstrated a strong correlation in both the tumor cell and immune cell compartments (κ=0.883, and κ=0.721). Expression of PD-L1 correlated with a high content of CD8(+) ...

Oncotarget, 2016

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic a... more In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid Oncotarget 30462 www.impactjournals.com/oncotarget tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib. Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Cancer medicine, Jun 6, 2016

Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMP... more Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMPs) both as isolated circulating tumor cells (iCTCs) and circulating tumor microemboli (CTMs), but their clinical significance remains unknown. The aim of this work was to evaluate the prognostic impact in metastatic cutaneous melanoma of CTMs and iCTCs identified by a cytomorphological approach using the isolation by size of tumor cell (ISET) method. We characterized the phenotype of CTCs using anti-PS100, anti-SOX10, anti-CD10, and anti-TRF2 antibodies. 128 MMPs and 37 control healthy individuals with benign nevi were included in this study. Results were compared to the follow-up of patients. 109/128 (85%) MMPs showed CTCs, 44/128 (34%) with 2 to 6 CTMs and 65/128 (51%) with 4 to 9 iCTCs. PS100 expression was homogeneous in iCTCs and heterogeneous in CTMs. SOX10, CD10, and TRF2 were mainly expressed in CTMs. None of the control subjects demonstrated circulating malignant tumor cells. Ov...

Annals of Oncology, 2015

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in... more Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/ 06).

Diagnostic Pathology, 2010

Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently... more Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently treated if rapid identification of the causative fungus is obtained. We report a case of fatal necrotic pneumonia caused by combined pulmonary invasive mucormycosis and aspergillosis in a 66 year-old renal transplant recipient. Aspergillus was first identified during the course of the disease by cytological examination and culture (A. fumigatus) of bronchoalveolar fluid. Hyphae of Mucorales (Rhizopus microsporus) were subsequently identified by culture of a tissue specimen taken from the left inferior pulmonary lobe, which was surgically resected two days before the patient died. Histological analysis of the lung parenchyma showed the association of two different filamentous mycoses for which the morphological features were evocative of aspergillosis and mucormycosis. However, the definitive identification of the associative infection was made by polymerase chain reaction (PCR) performed on deparaffinized tissue sections using specific primers for aspergillosis and mucormycosis. This case demonstrates that discrepancies between histological, cytological and mycological analyses can occur in cases of combined mycotic infection. In this regard, it shows that PCR on selected paraffin blocks is a very powerful method for making or confirming the association of different filamentous mycoses and that this method should be made available to pathology laboratories.

Biopreservation and Biobanking, 2011

Annales de Dermatologie et de Vénéréologie - FMC, 2021

Introduction L’association ipilimumab (IPI)+nivolumab (NIVO) offre un taux de réponse et de guéri... more Introduction L’association ipilimumab (IPI)+nivolumab (NIVO) offre un taux de réponse et de guérison supérieur aux anti-PD1 en monothérapie mais expose à des événements indésirables immunitaires (EII) plus fréquents. La COVID-19 a tué plus de 3M de personnes. Comme les patients atteints de cancers sont particulièrement exposés aux formes sévères/mortelles, la vaccination est recommandée. Il n’existe pas de données testant la relation entre vaccination et développement/exacerbation des EII au cours du traitement par ICI. Nous rapportons un cas de myopathie nécrosante survenue 10jours après la vaccination contre la COVID-19 chez un patient atteint d’un mélanome avancé traité par IPI+NIVO. Matériel et méthodes Un homme de 43 ans était inclus en 2015 dans l’essai adjuvant EORTC MK-3475 (pembrolizumab vs. placebo) pour un mélanome stade IIIb. E n 02/2021 une récidive ganglionnaire lombo-aortique, non opérable survenait. Malgré un statut BRAF (+) et une levée d’aveugle révélant qu’il avait reçu le pembrolizumab (sans EII à l’époque), un traitement par IPI+NIVO était alors débuté. Il recevait sa 1ère et 2e injection les 25/02 et 19/03/21. Le 12/03, il recevait sa 1ère dose de vaccin COVID-19 (Pfizer/BioNTech), sans réaction immédiate. Le 22/03 il développait un tableau associant: myalgies, faiblesse musculaire des membres, dysphagie, dyspnée, dysphonie et diplopie bilatérale avec rhabdomyolyse (CK 12647 U/L). Le bilan immunologique revenait négatif. L’ENMG décrivait un syndrome myogène. L’IRM musculaire révélait un aspect de myosite (muscles rotateurs du cou/de la cuisse) et l’histologie retrouvait un aspect de myopathie inflammatoire avec nécrose multifocale de myocytes et infiltrat inflammatoire à prédominance macrophagique. Le diagnostic de myopathie nécrosante grade IV était retenu. L’immunothérapie était arrêtée et une corticothérapie (bolus puis per os) permettait une amélioration progressive. Le patient est toujours sous corticothérapie orale, la surveillance oncologique montre à ce jour une réponse partielle. La 2e injection du vaccin n’a pas été faite d’autant plus que les IgG étaient fortement positives. Discussion Des myosites secondaires aux ICI, au COVID-19 et de façon plus anecdotique à la vaccination ont été rapportées. Ici, l’association temporelle étroite de la bi-ICI et du diagnostic de myopathie suggère que la myopathie est un EII et que la vaccination a contribué au développement de la myopathie par un effet de boost immunitaire. Le scénario inverse ne peut être exclu. Parce que de plus en plus de patients traités par ICI seront vaccinés dans les prochains mois, les cliniciens doivent être conscients de cette association potentielle du vaccin COVID-19 et de l’exacerbation des EII. Des données prospectives de pharmacovigilance sont nécessaires.

The Lancet Respiratory Medicine, 2020

HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Journal of Clinical Oncology, 2017

e20632 Background: The use in routine clinical practice of the EGFR tyrosine kinase inhibitors is... more e20632 Background: The use in routine clinical practice of the EGFR tyrosine kinase inhibitors is limited to patients with advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have known EGFR mutations. Currently, patient care has to respond to several imperatives to make it broadly available to all patients; fast and accurate detection of EGFR mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. The possibility to obtain EGFR testing results in less than few hours in a large number of pathology laboratories is recently guaranteed by the Idylla system. Methods: We evaluated the Idylla system (Biocartis) for the detection of EGFR mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 18 patients with lung adenocarcinoma and compared these results with those obtained by the Therascreen EGFR Pyro assay (Qiagen)-ISO 15189 accredi...

Journal of Clinical Oncology, 2019

e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In v... more e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The ...

Cancers, Jan 13, 2018

With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 c... more With underrepresentation of elderly patients with lung adenocarcinoma (LADC) in anti-PD-1/PD-L1 clinical trials, better understanding of the interplay of PD-L1 and tumor-associated immune cells (TAICs) could assist clinicians in stratifying these patients for immunotherapy. One hundred and one patients with LADCs, stratified by age, were included for analysis of PD-L1 expression and density of TAICs expressing CD4, CD8, and CD33, by using multiplex chromogenic immunohistochemistry (IHC) assays and automated digital quantification. The CD4⁺/CD8⁺ ratio was significantly higher in elderly patients. In patients <75 years, the density of CD4⁺, CD8⁺, and PD-L1 in TAICs showed a positive significant correlation with PD-L1 expression in tumor cells (TCs), while a lower correlation was observed in the elderly population. In the latter, a high CD4⁺/CD8⁺ ratio, and combined PD-L1 expression ≥1% TCs with a low CD8⁺ density, low CD33⁺ density, and a high CD4⁺ density correlated to worse overa...

Cancers, Jan 29, 2018

Lung cancer is the major cause of death from cancer in the world and its incidence is increasing ... more Lung cancer is the major cause of death from cancer in the world and its incidence is increasing in women. Despite the progress made in developing immunotherapies and therapies targeting genomic alterations, improvement in the survival rate of advanced stages or metastatic patients remains low. Thus, urgent development of effective therapeutic molecules is needed. The discovery of novel therapeutic targets and their validation requires high quality biological material and associated clinical data. With this aim, we established a biobank dedicated to lung cancers. We describe here our strategy and the indicators used and, through an overall assessment, present the strengths, weaknesses, opportunities and associated risks of this biobank.

Oncotarget, Jan 28, 2017

Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lun... more Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lung cancer who have known mutations. Currently, patient care has to respond to several imperatives to make these inhibitors broadly available to all patients; fast and accurate detection of mutations by a sensitive and specific standardized cost-effective method, easy-to-implement in settings with limited expertise in molecular diagnostics. We evaluated the Idylla™ EGFR Mutation Assay (Biocartis) for the detection of mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples from a series of 55 patients with lung adenocarcinoma and compared these results with those obtained by a pyrosequencing ISO-15189 accredited laboratory method. The comparison was made on both whole surgical tumor sections and on three artificially constructed small biopsies (∼1 mm) from the same FFPE blocks. Cost-effectiveness and turnaround time comparison between the two methods was performed. On bo...

Cancers, Jan 13, 2018

The identification of certain genomic alterations (, , , ) or immunological markers (PD-L1) in ti... more The identification of certain genomic alterations (, , , ) or immunological markers (PD-L1) in tissues or cells has led to targeted treatment for patients presenting with late stage or metastatic lung cancer. These biomarkers can be detected by immunohistochemistry (IHC) and/or by molecular biology (MB) techniques. These approaches are often complementary but depending on, the quantity and quality of the biological material, the urgency to get the results, the access to technological platforms, the financial resources and the expertise of the team, the choice of the approach can be questioned. The possibility of detecting simultaneously several molecular targets, and of analyzing the degree of tumor mutation burden and of the micro-satellite instability, as well as the recent requirement to quantify the expression of PD-L1 in tumor cells, has led to case by case development of algorithms and international recommendations, which depend on the quality and quantity of biological sample...

Revue Francophone des Laboratoires, 2017

Les biobanques ou centres de ressources biologiques (CRB) sont les maillons essentiels de la rech... more Les biobanques ou centres de ressources biologiques (CRB) sont les maillons essentiels de la recherche translationnelle. Ces structures bénéficient de financements publics récurrents afin d'établir des collections d'échantillons biologiques utilisées dans le cadre de projets de recherche. Plus de 100 biobanques ont été développées sur le territoire national au sein des hôpitaux universitaires et des centres de lutte contre le cancer. Le développement de nouvelles techniques et de nouvelles méthodes d'analyses dans la recherche médicale bouleversent les pratiques et soulèvent de nouveaux défis scientifiques et organisationnels dans la collecte, la transformation et la conservation des échantillons. Relever ces défis devient un enjeu primordial pour les biobanques. La mise en place d'une stratégie dynamique pour anticiper les besoins des utilisateurs est nécessaire et repose sur de nouveaux modes de fonctionnement. Cet article décrit les enjeux à court et à moyen terme pour les biobanques françaises et propose des éléments d'organisation pour y répondre. Biobanque-centre de ressources biologiques-enjeuxmodèle économique, indicateurs.

Nature communications, Jan 19, 2017

Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decis... more Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through αvβ6 and α9β1 engagement, rather than α5β1. Moreover, αvβ6-driven migration occurs independently of latent TGF-β activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour-stroma interface that govern the collective mod...

Oncotarget, Jan 15, 2017

Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circul... more Given the difficulty in obtaining adequate tissue in NSCLC, we investigated the utility of circulating tumor cells (CTCs) for MET status assessment in NSCLC patients. We used two platforms for CTC capture, and assessed MET expression in CTCs and matched-bronchial biopsies in patients with advanced-stage III/IV lung adenocarcinoma. Baseline peripheral blood was collected from 256 advanced-stage III/IV NSCLC patients from Genentech clinical trials, and from 106 patients with advanced-stage III/IV lung adenocarcinoma treated at the Department of Pneumology, Pasteur Hospital, Nice. CTCs were enriched using CellSearch (Genentech), or ISET technologies (Pasteur Hospital). MET expression was evaluated by immunofluorescence on CellSearch, and by immunocytochemistry on ISET-enriched CTCs and on matched FFPE tissue sections (Pasteur Hospital). CTCs were detected in 83 of 256 (32%) patients evaluated on CellSearch, with 30 samples (12%) exhibiting ≥ 5 CTCs/7.5 ml blood. On ISET, CTC were obser...

Cancer Research, 2016

Background: Although small cell lung carcinomas (SCLC) show an initial response to treatment, pat... more Background: Although small cell lung carcinomas (SCLC) show an initial response to treatment, patients rapidly suffer disease recurrence and become refractory to chemotherapy. Despite intensive research, the prognosis of SCLC remains poor, and therefore new strategies to improve outcome are urgently needed. Blockade of immune checkpoints PD-1/PD-L1 with monoclonal antibodies has recently emerged as a new therapeutic tool in oncology. Due to the difficulty in obtaining adequate tissue in diseases such as SCLC for PD-L1 expression assessment, we investigated the usefulness of circulating tumor cells (CTCs) detection as a non-invasive method to evaluate PD-L1 status in SCLC patients. Materials and Methods: CTC capture and PD-L1 expression was evaluated in a cohort of 18 SCLC patients for whom resected tissue specimens were available and were positive for CTCs, as detected by using the filtration-based ISET platform (Rarecells Diagnostics, Paris, France). PD-L1 expression was evaluated ...

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, Dec 26, 2016

PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell... more PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell carcinoma. However, the expression pattern of PD-L1 and the presence of CD8(+) and PD-1(+) tumor-infiltrating T cells in the basaloid variant of squamous cell carcinoma remain unknown. immunohistochemistry analysis of PD-L1 expression, with three recently validated monoclonal antibodies used in clinical trials (clones SP142, SP263, and 28-8), and detection of CD8(+) and PD-1(+) tumor-infiltrating T cells was performed on whole-tissue sections from 56 patients following surgery for basaloid squamous cell carcinoma. Data were correlated to clinicopathological parameters and outcome. Fair to poor concordance was observed between the SP142 vs SP263 clones, and SP142 vs 28-8 (κ range, 0.018-0.412), while the 28-8 and SP263 demonstrated a strong correlation in both the tumor cell and immune cell compartments (κ=0.883, and κ=0.721). Expression of PD-L1 correlated with a high content of CD8(+) ...

Oncotarget, 2016

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic a... more In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid Oncotarget 30462 www.impactjournals.com/oncotarget tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib. Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Cancer medicine, Jun 6, 2016

Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMP... more Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMPs) both as isolated circulating tumor cells (iCTCs) and circulating tumor microemboli (CTMs), but their clinical significance remains unknown. The aim of this work was to evaluate the prognostic impact in metastatic cutaneous melanoma of CTMs and iCTCs identified by a cytomorphological approach using the isolation by size of tumor cell (ISET) method. We characterized the phenotype of CTCs using anti-PS100, anti-SOX10, anti-CD10, and anti-TRF2 antibodies. 128 MMPs and 37 control healthy individuals with benign nevi were included in this study. Results were compared to the follow-up of patients. 109/128 (85%) MMPs showed CTCs, 44/128 (34%) with 2 to 6 CTMs and 65/128 (51%) with 4 to 9 iCTCs. PS100 expression was homogeneous in iCTCs and heterogeneous in CTMs. SOX10, CD10, and TRF2 were mainly expressed in CTMs. None of the control subjects demonstrated circulating malignant tumor cells. Ov...

Annals of Oncology, 2015

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in... more Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/ 06).

Diagnostic Pathology, 2010

Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently... more Immunocompromised patients who develop invasive filamentous mycotic infections can be efficiently treated if rapid identification of the causative fungus is obtained. We report a case of fatal necrotic pneumonia caused by combined pulmonary invasive mucormycosis and aspergillosis in a 66 year-old renal transplant recipient. Aspergillus was first identified during the course of the disease by cytological examination and culture (A. fumigatus) of bronchoalveolar fluid. Hyphae of Mucorales (Rhizopus microsporus) were subsequently identified by culture of a tissue specimen taken from the left inferior pulmonary lobe, which was surgically resected two days before the patient died. Histological analysis of the lung parenchyma showed the association of two different filamentous mycoses for which the morphological features were evocative of aspergillosis and mucormycosis. However, the definitive identification of the associative infection was made by polymerase chain reaction (PCR) performed on deparaffinized tissue sections using specific primers for aspergillosis and mucormycosis. This case demonstrates that discrepancies between histological, cytological and mycological analyses can occur in cases of combined mycotic infection. In this regard, it shows that PCR on selected paraffin blocks is a very powerful method for making or confirming the association of different filamentous mycoses and that this method should be made available to pathology laboratories.

Biopreservation and Biobanking, 2011