Publications by authors named "Arnaud Uguen"

124 Publications

N3 (> 6 cm) squamous cell carcinoma of the head and neck: outcomes and predictive factors in 104 patients.

Acta Otorhinolaryngol Ital 2021 Jun;41(3):221-229

Oncology Department, University Hospital, Brest, France.

Objective: To report outcome and predictive factors in patients with N3 (> 6 cm) non-metastatic locally advanced head and neck squamous cell carcinoma (LAHNSCC) treated with a conservative approach or with initial surgery.

Methods: 104 patients were included: 69 treated with radiotherapy (RT) ± chemotherapy (CT) and 35 with nodal surgery with or without primary tumour resection, which was completed in 30 patients by adjuvant RT ± CT. Positron-emission tomography-computed tomography (PET-CT) guided surveillance after RT ± CT was standard.

Results: Two-year overall survival (OS) and locoregional control (LRC) were 39.4% and 37.5%, respectively. In univariate analysis, body mass index (BMI), performance status (PS), p16 status and haemoglobin value influenced OS and disease-free survival (DFS). In multivariate analysis, p16 positive status and BMI ≥ 25 remained independent prognostic factors for better OS (p = 0.023) and DFS (p = 0.002). Only under/normal weight remained an independent and adverse significant prognostic factor in multivariate analysis for regional control (RC). Patients treated with primary RT ± CT had slightly better 2-year OS (43.5% 33.3%, p = 0.31).

Conclusions: Patients with N3 LAHNSCC have poor prognosis, but long term LRC is achievable, especially in overweight patients and those with a good PS.
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http://dx.doi.org/10.14639/0392-100X-N1437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283407PMC
June 2021

Each RET Break-Apart Fluorescence In Situ Hybridization Probe Requires Proper Interpretation Criteria.

Authors:
Arnaud Uguen

J Thorac Oncol 2021 Jul;16(7):e55

Lymphocytes B and Auto-Immunity, UMR 1227, CHRU Brest, INSERM, Brest University, Brest, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.03.021DOI Listing
July 2021

The prognostic significance of PD-L1 expression on tumor and immune cells in Merkel cell carcinoma.

J Cancer Res Clin Oncol 2021 Sep 11;147(9):2569-2578. Epub 2021 Jun 11.

Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France.

Introduction: The aim of this study was to evaluate prognostic factors in patients with non-metastatic Merkel cell carcinoma (MCC), with a particular focus on immunological markers such as TILs subtyping (CD3, CD8, CD68, FoxP3, PD-L1 and PD-1) and MCPyV.

Methods: Patients treated for a non-metastatic MCC with oncologic surgical resection followed or not by adjuvant radiotherapy between 01/2007 and 12/2018 were analyzed. Local and regional control (LC, RC), distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated. Clinical variables analyzed included age, gender, performance status, comorbidity, tumor size, location and presentation type, extension, oncologic resection and adjuvant radiotherapy. Pathological variables analyzed included type of tumor-infiltrating lymphocytes, CD3, CD8, CD68, PD-L1 expression on immune cells and tumors cells, PD-1, FoxP3 and MCPyV, assessed with immunohistochemistry (IHC).

Results: 77 patients were included. After a median follow-up of 18 months (range 0.2-144), the 1-year LC, RC, DMFS and OS were 83%, 60%, 82% and 75%, respectively. In multivariate analysis, a percentage of PD-L1 expression by immune cells ≥ 1% was significantly correlated with improvement of RC (p = 0.012), DMFS (p = 0.003) and OS (p = 0.006). Adjuvant radiotherapy significantly improved DMFS (p = 0.021) and OS (0.041) rates. There was a correlation between the presence of MCPyV + and the expression of PD-L1 on IC (p = 0.05) and TC (p = 0.03).

Conclusion: PD-L1 expression by immune and tumor cells in non-metastatic MCC seems to significantly improve outcome in patients who did not received PD-1/PD-L1 inhibitors. Prospective studies are needed to confirm our hypothesis.
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http://dx.doi.org/10.1007/s00432-021-03676-6DOI Listing
September 2021

Incidental Finding of a Parotid Basal Cell Adenoma With High Tracer Uptake on 68Ga-DOTATOC PET/CT.

Clin Nucl Med 2021 Jul;46(7):e381-e383

Oto-Rhino-Laryngology Department, University Hospital Morvan.

Abstract: A 67-year-old man was referred to our department to undergo a 68Ga-DOTATOC PET/CT during the systematic follow-up of a small intestine neuroendocrine tumor. PET revealed an incidental focal increased uptake of 68Ga-DOTATOC matching with a left intraparotid lesion on the combined contrast-enhanced CT, suggestive of a benign salivary tumor. An MRI was performed to characterize this lesion, and finally, the patient underwent surgery. Histological analysis confirmed the presence of a basal cell adenoma.
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http://dx.doi.org/10.1097/RLU.0000000000003564DOI Listing
July 2021

MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories.

Hum Pathol 2021 May 19;114:99-109. Epub 2021 May 19.

CHU de la Martinique, Service d'anatomie et Cytologie Pathologiques, Fort-de-France, F-97261, France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, 29200, France. Electronic address:

Targetable kinase fusions are extremely rare (<1%) in colorectal cancers (CRCs), making their diagnosis challenging and often underinvestigated. They have been shown particularly frequently among MSI-High, BRAF/KRAS/NRAS wild-type CRCs with MLH1 loss (MLH1 MSI-High wild-type). We searched for NTRK1, NTRK2, NTRK3, ALK, ROS1, BRAF, RET, and NRG1 kinase fusions in CRCs using methods easy-to-implement in pathology laboratories: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and fully automated real-time PCR targeted analyses. RNA-sequencing analyses were used for confirmation. Among 84 selected MLH1 deficient (IHC) CRCs cases, MLH1 MSI-High wild-type CRCs consisted first in 19 cases after Idylla™ analyses and finally in 18 cases (21%) after RNA-sequencing (detection of one additional KRASG12D mutation). FISH (and when relevant, IHC) analyses concluded in 5 NTRK1, 3 NTRK3, 1 ALK, 2 BRAF, and 2 RET FISH positive tumors. ALK and NTRK1 rearranged tumors were IHC positive, but pan-TRK IHC was negative in the 3 NTRK3 FISH positive tumors. RNA-sequencing analyses confirmed 12 of 13 fusions with only one false positive RET FISH result. Finally, 12/18 (67%) of MLH1 MSI-High wild-type CRCs contained targetable kinase fusions. Our study demonstrates the feasibility, but also the cost-effectiveness, of a multistep but rapid diagnostic strategy based on nonsequencing methods to identify rare and targetable kinase fusions in patients with advanced CRCs, as well as the high prevalence of these kinase fusions in MLH1 MSI-High wild-type CRCs. Nevertheless, confirmatory RNA-sequencing analyses are necessary in case of low FISH positive nuclei percentage to rule out FISH false-positive results.
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http://dx.doi.org/10.1016/j.humpath.2021.05.006DOI Listing
May 2021

[How to test for NTRK gene fusions: A practical approach for pathologists].

Ann Pathol 2021 Jul 9;41(4):387-398. Epub 2021 Apr 9.

Service d'anatomie et cytologie pathologiques, Hôpital Saint-Joseph, 75014 Paris, France.

The recent availability of targeted anti-TRK therapies represents a new opportunity to treat patients with advanced cancers harboring NTRK gene fusions. In this article, we present an update on the practical modalities of implementing a "NTRK testing" to search for these fusions in view of the performances and availability of the different testing methods and the epidemiological characteristics of the tumors liable to present the NTRK1, NTRK2 or NTRK3 gene fusions.
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http://dx.doi.org/10.1016/j.annpat.2021.03.005DOI Listing
July 2021

PD-L1 expression in recurrent head and neck squamous cell carcinoma.

Eur Arch Otorhinolaryngol 2021 Apr 1. Epub 2021 Apr 1.

Radiation Oncology Department, University Hospital Morvan, 2 avenue Foch, 29200, Brest, France.

Purpose: To evaluate the Programmed Cell Death Ligand (PD-L1) expression at diagnosis and relapse in patients with head and neck carcinoma (HNSCC) treated with radio(chemo)therapy.

Methods: PD-L1 immunohistochemistry was performed in tumor cells (TC) and immune cells (IC) in 44 patients and scored as 0 = 0%, 1 =  < 5%, 2 = 6-49% or 3 =  ≥ 50% cells.

Results: PD-L1 expression on TC before RT was scored as 0, 1, 2 and 3 in 28, 4, 8 and 4 patients, respectively. In 10 patients, IC did not show any PD-L1 expression; while in 8, 16, and 10 patients, PD-L1 expression was scored 1, 2 and 3, respectively. At relapse, 7/36 patients had a PD-L1 expression positivation in TC, while the opposite was observed in 6 patients. Overall, survival at 2 years was higher in patients with PD-L1 expression (90% versus 62.5%, p = 0.032).

Conclusion: PD-L1 expression may vary throughout the course of the disease. A re-evaluation of PD-L1 expression on biopsies at the time of recurrence should be recommended.
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http://dx.doi.org/10.1007/s00405-021-06777-7DOI Listing
April 2021

Fluorescent In Situ Hybridization Must be Preferred to pan-TRK Immunohistochemistry to Diagnose NTRK3-rearranged Gastrointestinal Stromal Tumors (GIST).

Appl Immunohistochem Mol Morphol 2021 Mar 22. Epub 2021 Mar 22.

Department of Pathology Cytogenetics Unit, Department of Genetics, CHRU Brest Registre des cancers digestifs du Finistère EA7479 SPURBO, Université de Bretagne Occidentale Ouest Pathologie Univ Brest, Inserm, CHU de Brest, LBAI, Brest Departement of Pathology, CHU Rennes Ouest Pathologie, Rennes Ouest Pathologie, Quimper, France.

Tyrosine kinase inhibitors have revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Nevertheless, some GISTs do not contain any targetable KIT or PDGFRA mutations classically encountered in this field. Novel approved therapies targeting TRK chimeric proteins products of NTRK genes fusions consist in a promising approach to treat some patients with GISTs lacking any identified driver oncogenic mutation in KIT, PDGFRA or BRAF genes. Thus, an adequate testing strategy permitting to diagnose the rare NTRK-rearranged GISTs is required. In this work, we studied about the performances of pan-TRK immunohistochemistry (IHC) and NTRK1/2/3 fluorescent in situ hybridization in a series of 39 GISTs samples. Among 22 patients with GISTs lacking KIT or PDGFRA mutations, BRAFV600E IHC permitted to diagnose 2/22 (9%) BRAFV600E-mutated GISTs and, among the 20 KIT, PDGFRA, and BRAF wild type tumors, 1/20 (5%), NTRK3-rearranged tumor was diagnosed using NTRK3 fluorescent in situ hybridization. Pan-TRK IHC using EPR17341 and A7H6R clones was negative in this NTRK3-rearranged sample. Pan-TRK IHC was frequently positive in NTRK not rearranged tumors without (24 samples analyzed) or with (15 samples analyzed) KIT or PDGFRA mutations with major discrepancies between the 2 IHC clones (intraclass correlation coefficient of 0.3042). Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.
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http://dx.doi.org/10.1097/PAI.0000000000000933DOI Listing
March 2021

Digital Pathology Slides-based Measurement of Tumor Cells and Lymphocytes Within Cytology Samples Supports the Relevance of the Separation by Size of Nonhematological Tumor and Hematological Nontumor Cells in Liquid Biopsies.

Authors:
Arnaud Uguen

Appl Immunohistochem Mol Morphol 2021 Mar 12. Epub 2021 Mar 12.

Department of Pathology, CHRU Brest Inserm U1227 LBAI, Brest, France.

Filtration by size is one method used to study circulating tumor cells in blood samples. Filtration-migration ability is highly dependent of the size of cell nucleus. This implies to search for the appropriate nucleus size able to separate between hematological nucleated and nonhematological nucleated blood cells to maximize circulating tumor cell isolation. Digitalized cytology slides [May-Grünwald Giemsa (MGG) stained and immunocytochemistry (ICC) slides] from various cancer metastases served for manual measurements of nuclei about tumor cells and adjacent lymphocytes to determine the diameters the more able to separate between tumor cells and lymphocytes. Among 2022 cells analyzed (1067 tumor cells and 955 lymphocytes) on MGG stained slides, the mean diameter of tumor cells nuclei was 14.77 µm whereas the mean diameter of lymphocytic nuclei was 6.47 µm (P<0.001). In ICC slides, about 6583 cells (4753 tumor cells and 1830 lymphocytes), the mean diameter of tumor cells nuclei was 9.28 µm whereas the mean diameter of lymphocytic nuclei was 4.95 µm (P<0.001). Areas under the receiver operating characteristic curves analyses concluded that diameters of 9.37 µm and 6 µm separated the best between tumor cells and lymphocytes in MGG and ICC slides, respectively. Measuring manually the diameters of the smallest tumor cells in ICC slides, we established more than 99% of tumor cells had diameters superior to 8 µm. The sizes differences between tumor cells and lymphocytes support the relevance of the filtration by size to isolate blood circulating nonhematological tumor cells. The existence of small tumor cells with sizes overlapping with those of lymphocytes is worth to optimize the threshold to separate between tumor cells and hematological cells.
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http://dx.doi.org/10.1097/PAI.0000000000000931DOI Listing
March 2021

Detection of in virtual slides requires high resolution digitalisation.

Authors:
Arnaud Uguen

J Clin Pathol 2021 Feb 10. Epub 2021 Feb 10.

Pathology, CHU Brest, Brest, Bretagne, France

To diagnose (HP) infection and its related mucosal injuries requires the histopathological analysis of gastric biopsies. The move from glass slides interpretation towards digital pathology implies technical choices to maintain the performances of histopathological diagnosis. The intra-rater agreement in assessing gastritis diagnostic criteria between glass slides, low resolution and high resolution digital slides in the subject of the present study. One hundred gastric biopsies were re-assessed by a single digestive pathologist on glass slides and digitalised slides at low resolution (ie, x20 magnification and single focus without z-stack) and high resolution (ie, x40 magnification with seven focus levels and z-stack) about the criteria of the updated Sydney system and the detection of HP. Inter-analyses agreement were very good (Kappa values>0.81) for every criteria but slightly inferior (ie, Kappa values<0.9) comparing glass slides interpretations with low resolution digital slides-based ones. Indeed, some HP infections were misdiagnosed using x20 magnification histochemical stained digitalised slides (p<0.05). At the opposite, anti-HP immunohistochemistry slides and/or x40 magnification digitalisation permitted to maintain almost perfect concordance in diagnosis (Kappa value>0.9). As mentioned in current guidelines, a high resolution x40 magnification digitalisation must be favoured in order to avoid some misdetection of microorganisms as HP.
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http://dx.doi.org/10.1136/jclinpath-2020-207378DOI Listing
February 2021

Breast cancer tumor heterogeneity has only little impact on the estimation of the Oncotype DX® recurrence score using Magee Equations and Magee Decision Algorithm™.

Hum Pathol 2021 02 24;108:51-59. Epub 2020 Nov 24.

CHRU Brest, Department of Pathology, Brest, F-29220, France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France. Electronic address:

Oncotype DX® assay is used to guide therapeutic decisions in early-stage invasive breast carcinoma but remains expensive. Magee Equations (MEs) and Magee Decision Algorithm (MDA) predict the Oncotype DX® recurrence score (RS) on the basis of histopathological parameters. The influence of intratumor heterogeneity on MEs and MDA remains uncertain. We compared Ki-67, estrogen and progesterone receptors, and human erb-b2 receptor tyrosine kinase 2 (HER2) status on tissue microarray cores with the corresponding findings on the whole slides to calculate MEs scores and to decide if Oncotype DX® testing was required as per MDA in two sets of 175 and 59 tumors, without and with Oncotype DX® results, respectively. Agreements in the interpretation of Ki-67, estrogen and progesterone receptors, and HER2 status were very good between limited areas and whole-slide analyses. This resulted also in very good agreements about the results of MEs and MDA. For 7 of 175 (4%) and 3 of 59 (5.1%) cases, MEs and MDA results in different tumor areas would have changed the indication to perform or not perform Oncotype DX® assays. Oncotype DX® RSs were significantly correlated with MEs and MDA results, but among cases initially predicted to have an RS ≤25 using MDA, 3 of 34 cases (8.8%) had in fact an RS >25. Tumor heterogeneity appears to have little impact on the estimation of the Oncotype DX® RS using MEs and MDA and would have permitted to avoid half of Oncotype DX® assays in our series. Caution is nevertheless required in discarding Oncotype DX® assay in cases with ME scores >18 associated with low mitotic activity.
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http://dx.doi.org/10.1016/j.humpath.2020.11.006DOI Listing
February 2021

HER2 Mutated and Nonmutated Non-small Cell Lung Carcinomas Can Harbor Heterogeneous HER2 Gene Amplification and HER2 Protein Expression.

Appl Immunohistochem Mol Morphol 2021 04;29(4):321-326

Department of Pathology, CHRU Brest.

Molecular analyses have become mandatory for treatment choices in patients with advanced non-small cell lung cancers (NSCLC). Among them, HER2 gene mutation, HER2 gene amplification, and HER2 protein expression consist in potential targets of various treatments. Tumor heterogeneity and overlapping of molecular alterations may cause dilemmas in treatment choices but to date there are few that reported about HER2 with discrepant data. We led a retrospective study evaluating HER2 protein expression and HER2 gene/chromosome 17 copy number variations across different tumor areas and samples from patients with advanced NSCLC harboring HER2 gene mutations and other oncogenic mutations. Among patients with HER2-mutated (10 patients) and nonmutated lung adenocarcinomas (10 patients), we observed frequent heterogeneous HER2 protein expression with no correlation with HER2 gene copy number variations. HER2 gene amplification was observed in 6 patients (3 HER2-mutated and 3 HER2-nonmutated), but with intrasample heterogeneity in 2 cases and intersample heterogeneity in another case. Our small case series emphasizes the potential overlapping and spatial heterogeneity of HER2 alterations in NSCLC, which must be taken into account as a limitation in building predictive strategies accompanying the development of anti-HER2 therapeutic strategies in patients with advanced NSCLC.
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http://dx.doi.org/10.1097/PAI.0000000000000879DOI Listing
April 2021

Evaluation of , and mutational status and microsatellite instability in early colorectal carcinomas invading the (pT1): towards an in-house molecular prognostication for pathologists?

J Clin Pathol 2020 Nov 9;73(11):741-747. Epub 2020 Apr 9.

Pathology, CHRU de Brest, Brest, France

Aim: We aimed to study the prognostic value of , , mutations and microsatellite stable (MSS)/instable (MSI) in the field of colorectal cancer invading the (ie, pT1 colorectal cancer (CRC)).

Methods: We led a case-control study in tumour samples from 60 patients with pT1 CRC with (20 cases) and without (40 cases) metastatic evolution (5 years of follow-up) which were analysed for , , mutations (Idylla testing and next generation sequencing, NGS) and MSS/MSI status (Idylla testing and expression of mismatch repair (MMR) proteins using immunohistochemistry).

Results: mutations were encountered in 11/20 (55%) cases and 21/40 (52.5%) controls (OR=1.11 (0.38 to 3.25), p=0.8548), mutations in 1/20 (5%) cases and 3/40 (7.5%) controls (OR=3.08 (0.62 to 15.39), p=0.1698) and mutations in 3/20 (15%) cases and 6/40 (15%) controls (OR=1.00 (0.22 to 4.5), p=1.00). A MSI status was diagnosed in 3/20 (15%) cases and 5/40 (12.5%) controls (OR=1.2353 (0.26 to 5.79), p=0.7885). Beyond the absence of significant association between the metastatic evolution and any of the studied molecular parameters, we observed a very good agreement between methods analysing and mutations (Kappa value of 0.849 (0.748 to 0.95) between Idylla and NGS) and MSS/MSI (Idylla)-proficient MMR/deficient MMR (immunohistochemistry) status (Kappa value of 1.00).

Conclusion: Although being feasible using the fully automated Idylla method as well as NGS, the molecular testing of and MSS/MSI status does not seem useful for prognostic purpose in the field of pT1 CRC.
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http://dx.doi.org/10.1136/jclinpath-2020-206496DOI Listing
November 2020

KRAS and BRAF Double Mutations and Functional Classes of BRAF Mutations in Non-small-cell Lung Cancers.

Clin Lung Cancer 2020 07 28;21(4):e240-e242. Epub 2020 Feb 28.

Department of Pathology, CHRU Brest, Brest, France; Inserm U1053 BaRITOn, Bordeaux, France. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2020.02.018DOI Listing
July 2020

EPR17341 and A7H6R pan-TRK Immunohistochemistry Result in Highly Different Staining Patterns in a Series of Salivary Gland Tumors.

Appl Immunohistochem Mol Morphol 2020 10;28(9):719-724

CHRU Brest, Department of Pathology, Brest.

Patients with NTRK-rearranged tumors can be now treated using anti-TRK-targeted therapies making NTRK testing important for treatment choices in patients with advanced cancers. Pan-TRK immunohistochemistry (IHC) could be a valuable premolecular screening strategy in this field. The choice of 1 IHC method or another requires to investigate for intermethod comparison. A high frequency of pan-TRK positive tumors among salivary gland tumors makes these tumors particularly appropriate for such a technical study. In this work, we studied the intermethod agreement for 2 pan-TRK IHC methods (using A7H6R and EPR17341 clones) in a file of salivary gland tumors of different subtypes. Among 71 tumors, pan-TRK IHC was diagnosed as positive (ie, H score ≥5) in 23 and 18 cases using EPR17341 and A7H6R clones, respectively, with a good intermethod agreement in terms of positive/negative result (κ, 0.70) but only a moderate agreement considering the H score values themselves (intraclass correlation coefficient of 0.5399). Beyond the intensity of staining and the percentages of stained cells, major differences were also observed between the location and type of cells stained in positive cases between the 2 clones. The single NTRK-rearranged case in our series (ie, a NTRK3-rearranged salivary secretory carcinoma) was positive with the 2 pan-TRK antibodies. Future studies including molecularly proven NTRK-rearranged tumors remain required to further study and compare the performances of different pan-TRK clones in the screening of NTRK-rearranged cancers but it is now obvious that the staining patterns of A7H6R and EPR17341 clones are not strictly identical.
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http://dx.doi.org/10.1097/PAI.0000000000000825DOI Listing
October 2020

PD-L1 Copy Number Variation Does Not Correlate With PD-L1 Expression or Response to Anti-PD-1 Immunotherapy In Patients With Advanced Melanomas.

Appl Immunohistochem Mol Morphol 2020 02;28(2):161-165

Department of Pathology, CHRU Brest.

Predicting the response to PD-1/PD-L1 immune checkpoint blockade in patients with metastatic melanoma remains challenging. In this study, we have investigated for the relationships between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. We studied the formalin-fixed paraffin-embedded tumor samples of 36 patients with metastatic melanoma using PD-L1 immunohistochemistry (IHC) and PD-L1/chromosome 9 fluorescent in situ hybridization (FISH). PD-L1 IHC was positive in 3 patients (8.33%, with >5% stained tumor cells) and PD-L1 FISH test revealed 5 (13.8%) PD-L1 amplifications, 8 (22.2%) PD-L1 gains, and 2 (5.5%) PD-L1 losses. Among 14 responders and 13 nonresponders to anti-PD-1 immunotherapy, we concluded that there was no significant relationship between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. In our study, the determination of PD-L1 expression using IHC and PD-L1 copy number using FISH was insufficient to predict the response to PD-1/PD-L1 immune checkpoint blockade in patients with advanced melanomas.
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http://dx.doi.org/10.1097/PAI.0000000000000712DOI Listing
February 2020

Reconsidering the turnaround times for V600 mutation analysis in non-small-cell lung cancer: a molecular diagnosis in one day is achievable for rapid treatment choices.

Authors:
Arnaud Uguen

Curr Oncol 2019 Aug 1;26(4):e595-e596. Epub 2019 Aug 1.

chru Brest, Department of Pathology Brest, France, inserm U1053 bariton, Bordeaux, France.

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http://dx.doi.org/10.3747/co.26.4779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726278PMC
August 2019

Testing for fusions in patients with advanced // wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy.

J Clin Pathol 2020 Feb 10;73(2):116-119. Epub 2019 Sep 10.

Department of Pathology, CHRU Brest, Brest, France

Beyond targeted therapy for patients with -mutated melanomas and immunotherapy in patients lacking mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring fusions. fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using fluorescent in situ hybridisation (FISH), we searched for fusions in 74 samples of 66 patients with advanced // wild-type melanomas. We identified 2/66 (3%) patients with fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'- FISH signals. As a result, we conclude that FISH in patients with advanced // wild-type melanomas is a valuable and easy-to-perform test to diagnose fusions and to identify patients who could benefit of anti-MEK targeted therapy.
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http://dx.doi.org/10.1136/jclinpath-2019-206026DOI Listing
February 2020

PD-L1 Immunohistochemistry-Discrepant Results Between Synchronous Tumor Samples May Cause More Treatment Choice Dilemmas Than Molecular Heterogeneity in Patients With Advanced Non-Small Cell Lung Cancers.

Appl Immunohistochem Mol Morphol 2020 07;28(6):437-443

Department of Pathology, CHRU Brest, Brest.

Biomarker analyses have become mandatory for treatment choices in patients with advanced non-small cell lung cancers. PD-L1 expression for immunotherapy as well as oncogenic molecular alterations for targeted therapies must be analyzed in tumor samples. Intersample heterogeneity may cause dilemmas in treatment choices when faced with discrepant biomarker results. We led a retrospective study evaluating the potential impact on guideline-based therapeutic decisions of biomarker analyses performed in several synchronous tumor samples per patient. We collected retrospective data about patients with advanced non-small cell lung cancers, and synchronous tumor paired samples were analyzed for PD-L1 immunohistochemistry (IHC) and oncogene molecular statuses. Among 34 patients, none had a discrepant result between paired samples with respect to oncogene molecular statuses. At the opposite, intersample-discrepant PD-L1 IHC results may have caused treatment choice dilemmas for 6 (17.6%) patients discussing first-line therapy options (ie, immune checkpoint inhibitor therapy versus other systemic therapy with regard to the threshold of ≥50% PD-L1 IHC-positive tumor cells). In addition, for 6 (17.6%) other patients, different PD-L1 IHC results may have also influenced the choice of one therapy or another in second-line therapy (ie, with regard to the threshold of ≥1% PD-L1 IHC-positive tumor cells). In our case series, discrepant results with regard to PD-L1 IHC between paired tumor samples could generate more treatment choice dilemmas than the molecular heterogeneity of oncogenic drivers.
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http://dx.doi.org/10.1097/PAI.0000000000000768DOI Listing
July 2020

Foci of Programmed Cell Death-Ligand 1 (PD-L1)-positive Tumor Areas With Tumor-infiltrating Leukocytes (TILs) Evocative of a PD-1/PD-L1-related Adaptive Immune Resistance are Frequent in Merkel Cell Carcinoma.

Appl Immunohistochem Mol Morphol 2020 01;28(1):17-22

Departments of Pathology.

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis have revolutionized the treatment of patients with Merkel cell carcinoma (MCC). To date, no biomarker conditions access to these ICIs in MCC. We compared the tumor microenvironment of PD-L1 and PD-L1 areas in a case series of MCC searching for foci evocative of PD-1/PD-L1 adaptive immune resistance. Among 58 tumors studied on digitalized serial tissue sections, 11 (19%) were concluded as "PD-L1 tumors" [≥1% positive tumor cells (TCs) using PD-L1 immunohistochemistry in the whole tumor slide]. In addition, among the remaining 47 (81%) "PD-L1 tumors," we nevertheless also identified "PD-L1 FOV" (ie, "field of view" of about 3 mm² containing ≥1% positive TCs) in 22 (38%) additional tumors. Comparison between paired "PD-L1 field of view (FOV)" and "PD-L1 FOV" within tumors, and between "PD-L1 tumors" and "PD-L1 tumors", revealed correlations between PD-L1 positivity and the abundance of tumor-infiltrating leukocytes, arguing for areas of PD-1/PD-L1-related adaptive immune resistance at least in some foci of "PD-L1 tumors" and also in "PD-L1 tumors." Tumor heterogeneity consists in a challenge searching for biomarkers able to predict the response/nonresponse to ICIs. Progress in digital pathology and multiplex immunolabeling may permit to overcome this challenge by better analyzing the interactions between TCs and immune and nonimmune non-TCs in the same tissue section. This approach of tumor heterogeneity may contribute to elucidate and to predict why some patients respond impressively to ICIs, whereas others do not.
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http://dx.doi.org/10.1097/PAI.0000000000000792DOI Listing
January 2020

[A NTRK1-rearranged mammary carcinoma].

Ann Pathol 2020 Jan 26;40(1):42-45. Epub 2019 Jun 26.

CHRU Brest, service d'anatomie et cytologie pathologiques, 29220 Brest, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2019.05.009DOI Listing
January 2020

Microsatellite instability diagnosis using the fully automated Idylla platform: feasibility study of an in-house rapid molecular testing ancillary to immunohistochemistry in pathology laboratories.

J Clin Pathol 2019 Dec 23;72(12):830-835. Epub 2019 Jun 23.

Pathology, CHRU Brest, Brest, France

Aim: To study the performances of the Idylla MSI Assay in the diagnosis of microsatellite instability (MSI) or microsatellite stability (MSS).

Methods: We selected 12 tumour samples previously tested for MSI focusing on cases with discrepant results between MLH1, PMS2, MSH2 and MSH6 immunohistochemistry and microsatellite molecular analyses (five cases) or doubtful immunohistochemistry (two cases). Idylla MSI Assay was compared with retrospective immunohistochemistry and molecular results.

Results: Idylla MSI Assay showed an almost perfect concordance with microsatellite analysis results previously obtained (only one case with not fully conclusive analysis due to sample exhaustion). The full molecular analysis took less than 150 min per sample and revealed no mutation in any of the seven microsatellite sequences in five MSS samples and four to six mutated ones in seven MSI-High samples.

Conclusion: At the era when the determination of MSI/MSS status is becoming important for rapid treatment choices, the Idylla MSI Assay consists of a valuable easy-to-perform diagnostic tool that allows, complementary to MLH1, PMS2, MSH2 and MSH6 immunohistochemistry, the diagnosis of MSI/MSS status in a single day.
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http://dx.doi.org/10.1136/jclinpath-2019-205935DOI Listing
December 2019

Avoiding non-contributive molecular results in cancer samples: proposal of a score-based approach for sample choice.

Pathology 2019 Aug 18;51(5):524-528. Epub 2019 Jun 18.

CHRU Brest, Department of Pathology, Brest, France; Inserm U1053 BaRITOn, Bordeaux, France. Electronic address:

Mutational analyses have become crucial for therapeutic choices in patients with advanced lung cancer, colorectal cancer and melanoma. Short turnaround times for molecular analyses are necessary to match the patient's therapeutic management. Non-contributive molecular analyses may increase the delay in reaching a relevant mutational status. We attempted to identify criteria in samples associated with non-contributive molecular results to better anticipate them and select samples with contributive analyses. We compared several criteria such as cancer type, sample type, organ of origin and percentage of tumour cells between samples with non-contributive or contributive EGFR, KRAS, NRAS and BRAF mutation analyses. Among two sets of 3367 and 554 tumour samples analysed in 2015-2017 and 2018, respectively, 11.7% and 15.7% of sample analyses were non-contributive for at least one oncogene. Lung cancer and melanoma cancer subtypes [odds ratio (OR)=7.2], cytological (OR=1.8) or bone samples (OR=8.5) and a percentage of tumour cells ≤20% (OR=41.4) were significantly associated with non-contributive results. By combining these parameters in a scoring system, we were able to predict the contributive or non-contributive result of a molecular analysis with sensitivity and specificity higher than 80% in a validation set of samples. Predicting the contributive or non-contributive result of a molecular analysis is feasible in samples on the basis of simple features. A combination of these features could be used to better choose samples to analyse in order to reduce the rate of non-contributive molecular results and related treatment delays and costs in patients with advanced cancers.
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http://dx.doi.org/10.1016/j.pathol.2019.03.008DOI Listing
August 2019

Histopathological factors help to predict lymph node metastases more efficiently than extra-nodal recurrences in submucosa invading pT1 colorectal cancer.

Sci Rep 2019 06 6;9(1):8342. Epub 2019 Jun 6.

CHRU Brest, Service d'anatomie et cytologie pathologiques, Brest, F-29200, France.

The therapeutic management of patients with endoscopic resection of colorectal cancer invading the submucosa (i.e. pT1 CRC) depends on the balance between the risk of cancer relapse and the risk of surgery-related morbidity and mortality. The aim of our study was to report on the histopathological risk factors predicting lymph node metastases and recurrences in an exhaustive case series comprising every pT1 CRC (of adenocarcinoma subtype only) diagnosed in Finistère (France) during 5-years. For 312 patients with at least 46 months follow-up included in the digestive cancers registry database, histopathological factors required for risk stratification in pT1 CRC were reviewed. Patients were treated by endoscopic resection only (51 cases), surgery only (138 cases), endoscopic resection followed by surgery (102 cases) or transanal resection (21 cases). Lymph node metastases were diagnosed in 19 patients whereas 15 patients had an extra-nodal recurrence (7 local recurrences only, 4 distant metastases only and 4 combining local and distant recurrences). Four patients with distant metastases died of their cancer. Poor tumor differentiation, vascular invasion and high grade tumor budding on HES slides were notably identified as strong risk-factors of lymph node metastases but the prediction of extra-nodal recurrences (local, distant and sometimes fatal) was less obvious, albeit it was more frequent in patients treated by transanal resection than with other treatment strategies. Beyond good performances in predicting lymph node metastases and guiding therapeutic decision in patients with pT1 CRC, our study points that extra-nodal recurrence of cancer is more difficult to predict and requires further investigations.
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http://dx.doi.org/10.1038/s41598-019-44894-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554401PMC
June 2019

Spitz Tumors With NTRK1 Fusions: TRK-A and pan-TRK Immunohistochemistry as Ancillary Diagnostic Tools.

Authors:
Arnaud Uguen

Am J Surg Pathol 2019 10;43(10):1438-1439

CHRU Brest Department of Pathology, Brest.

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http://dx.doi.org/10.1097/PAS.0000000000001294DOI Listing
October 2019

Screening for NTRK-rearranged Tumors Using Immunohistochemistry: Comparison of 2 Different pan-TRK Clones in Melanoma Samples.

Appl Immunohistochem Mol Morphol 2020 03;28(3):194-196

Department of Pathology, CHRU Brest, Brest.

NTRK-rearranged tumors could be treated using promising anti-TRK-targeted therapies in patients with advanced cancers including melanomas. Different targeted therapies are being developed together with different screening strategies including pan-TRK immunohistochemistry (IHC) as first-line screening strategies. In this technical study, we compared 2 pan-TRK IHC (using A7H6R and EPR17341 clones) in tumor samples of patients with advanced melanomas. IHC-positive cases were studied using NTRK1, NTRK2, and NTRK3 fluorescent in situ hybridization tests. Among 300 melanoma samples, 4 samples were positive using A7H6R IHC, but none using EPR17341. None of the 4 samples were NTRK-rearranged using fluorescent in situ hybridization. Different staining was also noted in nontumor kidney tissue, whereas an NTRK1-rearranged tumor used as positive control was strongly stained with both A7H6R and EPR17341 clones. Future studies including more numerous NTRK-rearranged tumors are required to further study and compare the performances of different pan-TRK clones in the screening of NTRK-rearranged cancers.
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http://dx.doi.org/10.1097/PAI.0000000000000708DOI Listing
March 2020

Retroperitoneal Pelvic Solitary Fibrous Tumor With High Tracer Uptake in 68Ga-DOTATOC PET/CT: A Rare Differential Diagnosis of Paraganglioma.

Clin Nucl Med 2019 May;44(5):e370-e371

Nuclear Medicine, University Hospital of Brest, Brest, France.

We report the case of a 27-year-old woman referred to our department for the characterization of a 7 × 6-cm left ischio-anal fossa mass by Ga-DOTATOC PET/CT. Several diagnoses were previously mentioned, in particular, myxoid sarcoma but also pelvic paraganglioma. Urinary methoxylated derivates and blood chromogranin A tests were negative. PET/CT showed a high Ga-DOTATOC uptake of the mass that was strongly consistent with paraganglioma diagnosis. Histopathological analysis surprisingly revealed a solitary fibrous tumor without aggressive criteria.
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http://dx.doi.org/10.1097/RLU.0000000000002540DOI Listing
May 2019

Decalcification can cause the failure of BRAF molecular analyses and anti-BRAFV600E VE1 immunohistochemistry.

Pathol Int 2019 Apr 7;69(4):219-223. Epub 2019 Mar 7.

CHRU Brest, Department of Pathology, Brest, F-29220, France.

BRAF mutation detection is worthwhile for the management of patients with some advanced cancers. The tumor samples are sometimes difficult to analyze using DNA-based molecular methods because of poor tumor DNA quality or quantity. Anti-BRAFV600E VE1 immunohistochemistry (IHC) has been proposed as a valuable ancillary tool to analyze some "molecularly challenging" tumor samples. In this technical study, we focused on its application in the field of decalcified tumor samples. We selected four patients with known BRAFV600E-mutated cancer (3 metastatic melanomas and 1 hairy cell leukemia) and paired non-decalcified/decalcified tumor samples. Molecular analyses failed in the four decalcified samples (3 bone metastases and 1 osteo-medullar biopsy) with non-contributive mutation status. Whereas non-decalcified tumor samples were all positive using anti-BRAFV600E VE1 IHC, the four decalcified samples were concluded negative. Because decalcified tumor samples are difficult to analyze from a molecular point of view, it is tempting to use IHC instead of DNA-based methods searching for BRAFV600E mutations in these samples. Nevertheless, the decalcification process may also cause false-negative results using VE1 IHC. Decalcified samples require specific and optimized IHC and molecular protocols and quality controls.
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http://dx.doi.org/10.1111/pin.12784DOI Listing
April 2019

[Meningeal melanoma arising from a preexisting meningeal melanocytoma: A clinical, pathological and cytogenetic study about one case].

Ann Pathol 2019 Sep 26;39(5):352-356. Epub 2019 Feb 26.

Service d'anatomie et cytologie pathologiques, CHRU de Brest, 29220 Brest, France. Electronic address:

Meningeal melanocytic tumors are rare. We report an exceptional case of transformation of a meningeal melanocytoma in a malignant melanoma. The course of the disease extents from 61-years to 85-years and ends with the death of the patient. Besides histopathological and immunohistochemical data, we also report the array CGH study of the melanocytoma and melanoma components suggesting the malignant transformation from whole chromosome gains in the melanocytoma to additional segmental aberrations in the malignant melanoma. Beyond the rarity of this tumor subtype, this case report highlights the potential interest of molecular analyses for diagnostic and prognostic purposes in the field of meningeal melanocytic tumors.
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http://dx.doi.org/10.1016/j.annpat.2019.01.010DOI Listing
September 2019

About concomitant KRAS and other molecular alterations in non-small cell lung cancers.

Hum Pathol 2019 05 20;87:115-116. Epub 2019 Feb 20.

CHRU Brest, Service d'anatomie et cytologie pathologiques, Brest, F-29200, France; Inserm U1053 BaRITOn, Bordeaux, F-33076, France. Electronic address:

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http://dx.doi.org/10.1016/j.humpath.2019.01.003DOI Listing
May 2019
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