Publications by authors named "Cécile Badoual"

158 Publications

Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.

Mod Pathol 2021 Sep 16. Epub 2021 Sep 16.

Hôpital européen Georges Pompidou, Université de Paris, F-75006, Paris, Department of Pathology, F-75015, Paris, France.

Low-grade oncocytic renal tumor (LOT) is an emerging provisional entity, described as rare solid renal oncocytic/eosinophilic tumor sharing diffuse CK7 and negative CD117 immunoprofile. The links between LOT and other eosinophilic chromophobe like-renal cell carcinomas (RCC) are currently discussed. We sequenced tumoral DNA with a next generation sequencing panel for kidney cancer and carried out immunohistochemical analyses with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies in a series of ten cases of LOT (9 females, 1 male; mean age at surgery: 66 years, 42.3 to 83.4) retrospectively diagnosed from a cohort of 272 tumors initially classified as chromophobe RCC (CHRCC). All LOT were single, without known hereditary predisposition, classified stage pT1 (70%), pT2 (20%) or pT3a (10%). Morphological features were similar to previous descriptions and clinical behavior was indolent for the six cases with available follow-up. We identified genetic variations in mTOR pathway related genes in 80% of cases, MTOR (7 cases) or TSC1 (1 case). Expression of FOXI1 was absent in all cases. In 9 LOT, 4EBP1-P and S6K-P were overexpressed, suggesting mTOR pathway activation.Our data highlights the major role of mTOR pathway in tumorigenesis of LOT mostly due to activating MTOR gene variations. Absence of FOXI1 expression is a strong argument to distinguish LOT from eosinophilic CHRCC and to bring them closer to other recently described FOXI1 negative eosinophilic-CHRCC like with MTOR/TSC mutations. Altogether, our data argue to consider LOT as a distinct entity with a favorable clinical outcome. However, in case of metastasis, an accurate diagnosis of LOT would be essential for the patient's management and could allow targeted therapy.
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http://dx.doi.org/10.1038/s41379-021-00906-7DOI Listing
September 2021

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.

Genome Med 2021 Jul 14;13(1):113. Epub 2021 Jul 14.

Centre de Recherche des Cordeliers, Inserm UMRS-1138, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors, Paris, France.

Background: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.

Methods: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed.

Results: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients.

Conclusions: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.
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http://dx.doi.org/10.1186/s13073-021-00931-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281651PMC
July 2021

Is sexual harassment and psychological abuse among medical students a fatality? A 2-year study in the Paris Descartes School of Medicine.

Med Teach 2021 Apr 21:1-9. Epub 2021 Apr 21.

Faculty of Health, School of Medicine, Université de Paris, Paris, France.

Introduction: An observatory of sexual harassment and psychological abuse was set up at one of France's largest schools of medicine to both quantify and reduce sexual harassment or psychological abuse of medical students.

Methods: Over a 2-year period, we described the evolution of sexual harassment and psychological abuse and explored for associated factors. Moreover, a qualitative analysis using an inductive approach was performed from students' verbatim.

Results: 2795 responses were collected. Sexual harassment was reported in 7% and psychological abuse in 15%, at baseline, and decreased after the observatory was set up. Women had higher odds of being a victim of sexual harassment. Older students reported less often psychological abuse and being a witness of sexual harassment. Surgery departments were associated with up to 5.7-fold increased odds of sexual harassment. Surgery and pediatrics departments were associated with a 2-fold increased odds of psychological abuse. Qualitative analysis revealed four categories: humiliation, the feeling of inferiority, sexual harassment, and manifestations of violence.

Conclusion: During clerkships, factors associated with higher odds of sexual harassment and psychological abuse were female gender, younger age, and departments of surgery. Setting up such an observatory may contribute to reduce this burden and provide a useful tool to raise awareness.
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http://dx.doi.org/10.1080/0142159X.2021.1910225DOI Listing
April 2021

Histological Severity Risk Factors Identification in Juvenile-Onset Recurrent Respiratory Papillomatosis: How Immunohistochemistry and AI Algorithms Can Help?

Front Oncol 2021 8;11:596499. Epub 2021 Mar 8.

INSERM-U970, PARCC, Université de Paris, Paris, France.

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a condition characterized by the repeated growth of benign exophytic papilloma in the respiratory tract. The course of the disease remains unpredictable: some children experience minor symptoms, while others require multiple interventions due to florid growth. Our study aimed to identify histologic severity risk factors in patients with JoRRP. Forty-eight children from two French pediatric centers were included retrospectively. Criteria for a severe disease were: annual rate of surgical endoscopy ≥ 5, spread to the lung, carcinomatous transformation or death. We conducted a multi-stage study with image analysis. First, with Hematoxylin and eosin (HE) digital slides of papilloma, we searched for morphological patterns associated with a severe JoRRP using a deep-learning algorithm. Then, immunohistochemistry with antibody against p53 and p63 was performed on sections of FFPE samples of laryngeal papilloma obtained between 2008 and 2018. Immunostainings were quantified according to the staining intensity through two automated workflows: one using machine learning, the other using deep learning. Twenty-four patients had severe disease. For the HE analysis, no significative results were obtained with cross-validation. For immunostaining with anti-p63 antibody, we found similar results between the two image analysis methods. Using machine learning, we found 23.98% of stained nuclei for medium intensity for mild JoRRP vs. 36.1% for severe JoRRP ( = 0.041); and for medium and strong intensity together, 24.14% for mild JoRRP vs. 36.9% for severe JoRRP ( = 0.048). Using deep learning, we found 58.32% for mild JoRRP vs. 67.45% for severe JoRRP ( = 0.045) for medium and strong intensity together. Regarding p53, we did not find any significant difference in the number of nuclei stained between the two groups of patients. In conclusion, we highlighted that immunochemistry with the anti-p63 antibody is a potential biomarker to predict the severity of the JoRRP.
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http://dx.doi.org/10.3389/fonc.2021.596499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982831PMC
March 2021

CXCR6 deficiency impairs cancer vaccine efficacy and CD8 resident memory T-cell recruitment in head and neck and lung tumors.

J Immunother Cancer 2021 03;9(3)

Université de Paris, PARCC, INSERM U970, 75006 Paris, France

Background: Resident memory T lymphocytes (T) are located in tissues and play an important role in immunosurveillance against tumors. The presence of T prior to treatment or their induction is associated to the response to anti-Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) immunotherapy and the efficacy of cancer vaccines. Previous work by our group and others has shown that the intranasal route of vaccination allows more efficient induction of these cells in head and neck and lung mucosa, resulting in better tumor protection. The mechanisms of in vivo migration of these cells remains largely unknown, apart from the fact that they express the chemokine receptor CXCR6.

Methods: We used -deficient mice and an intranasal tumor vaccination model targeting the Human Papillomavirus (HPV) E7 protein expressed by the TC-1 lung cancer epithelial cell line. The role of CXCR6 and its ligand, CXCL16, was analyzed using multiparametric cytometric techniques and Luminex assays.Human biopsies obtained from patients with lung cancer were also included in this study.

Results: We showed that CXCR6 was preferentially expressed by CD8 T after vaccination in mice and also on intratumoral CD8 T derived from human lung cancer. We also demonstrate that vaccination of Cxcr6-deficient mice induces a defect in the lung recruitment of antigen-specific CD8 T cells, preferentially in the T subsets. In addition, we found that intranasal vaccination with a cancer vaccine is less effective in these -deficient mice compared with wild-type mice, and this loss of efficacy is associated with decreased recruitment of local antitumor CD8 T. Interestingly, intranasal, but not intramuscular vaccination induced higher and more sustained concentrations of CXCL16, compared with other chemokines, in the bronchoalveolar lavage fluid and pulmonary parenchyma.

Conclusions: This work demonstrates the in vivo role of CXCR6-CXCL16 axis in the migration of CD8 resident memory T cells in lung mucosa after vaccination, resulting in the control of tumor growth. This work reinforces and explains why the intranasal route of vaccination is the most appropriate strategy for inducing these cells in the head and neck and pulmonary mucosa, which remains a major objective to overcome resistance to anti-PD-1/PD-L1, especially in cold tumors.
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http://dx.doi.org/10.1136/jitc-2020-001948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949477PMC
March 2021

Facing new challenges to informed consent processes in the context of translational research: the case in CARPEM consortium.

BMC Med Ethics 2021 03 2;22(1):21. Epub 2021 Mar 2.

Centre de Recherche Des Cordeliers (UMRS 1138), INSERM, Sorbonne Université, Université de Paris, Team ETREs, 75006, Paris, France.

Background: In the context of translational research, researchers have increasingly been using biological samples and data in fundamental research phases. To explore informed consent practices, we conducted a retrospective study on informed consent documents that were used for CARPEM's translational research programs. This review focused on detailing their form, their informational content, and the adequacy of these documents with the international ethical principles and participants' rights.

Methods: Informed consent forms (ICFs) were collected from CARPEM investigators. A content analysis focused on information related to biological samples and data treatment (context of sampling and collect, aims, reuse, consent renewal), including the type of consent. An automatic assessment of the readability of the ICFs were performed with the IT program "Flesch Score".

Results: 29 ICFs from 25 of 49 studies were analyzed after selection criteria were applied. Three types of consent were identified: 11 broad consents, six specific consents, and two opt-out consents. The Flesch Scores showed that most of the documents were too complex to be fully understood by most of the potential research participants. Most of the biological samples were collected during the healthcare routine, but the information content about secondary use of biological samples varied between ICFs. All documents mentioned personal data treatment but information about their reuse was not standardized in the ICFs.

Conclusions: Our review of current IC procedures of CARPEM showed that practices could be improved considering new translational research methods. "Old fashion written ICFs" should be adapted to the translational research approach, to better respect individual rights and international research ethics principles. In this context, theoretically, a digital tool allowing dynamic information and consent of participants, through an electronic interactive platform may be a good way to promote more active participation in research. Nevertheless, its feasibility in the complex environment of biological samples and data research remains to prove. The way of a combination of a broad consent followed by dynamic information may be alternatively tested.
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http://dx.doi.org/10.1186/s12910-021-00592-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927247PMC
March 2021

Episomal HPV16 responsible for aggressive and deadly metastatic anal squamous cell carcinoma evidenced in peripheral blood.

Sci Rep 2021 Feb 25;11(1):4633. Epub 2021 Feb 25.

Laboratoire de virologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, 20-40 rue Leblanc, 75015, Paris, France.

Archival tissue samples collected longitudinally from a patient who died from HPV16-induced high-grade anal intraepithelial squamous cell carcinoma with vertebral HPV16-positive metastasis were retrospectively analyzed by the Capture-HPV method (Capt-HPV) followed by Next-Generation Sequencing (NGS). Full length nucleotide sequences of the same HPV16 were identified from the initial and second anal biopsy samples, from plasma sample and from vertebral metastasis biopsy. Remarkably, HPV was episomal in each sample. The HPV genome sequence was closest to the HPV16 Qv18158E variant subtype (A1 lineage) exhibiting base substitutions and deletions in 7 and 2 HPV loci, respectively. In conclusion, the powerful Capt-HPV followed by NGS allows evidencing the detailed cartography of tumoral and circulating HPV DNA, giving rise to a unique and unexpected episomal virus molecular status in a context of aggressive carcinoma, underlying the importance of HPV status and its association with clinical features for further prospective studies.
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http://dx.doi.org/10.1038/s41598-021-84110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907240PMC
February 2021

Impact of integrating objective structured clinical examination into academic student assessment: Large-scale experience in a French medical school.

PLoS One 2021 14;16(1):e0245439. Epub 2021 Jan 14.

Université de Paris, Faculté de Médecine, Paris, France.

Purpose: Objective structured clinical examinations (OSCE) evaluate clinical reasoning, communication skills, and interpersonal behavior during medical education. In France, clinical training has long relied on bedside clinical practice in academic hospitals. The need for a simulated teaching environment has recently emerged, due to the increasing number of students admitted to medical schools, and the necessity of objectively evaluating practical skills. This study aimed at investigating the relationships between OSCE grades and current evaluation modalities.

Methods: Three-hundred seventy-nine 4th-year students of University-of-Paris Medical School participated to the first large-scale OSCE at this institution, consisting in three OSCE stations (OSCE#1-3). OSCE#1 and #2 focused on cardiovascular clinical skills and competence, whereas OSCE#3 focused on relational skills while providing explanations before planned cholecystectomy. We investigated correlations of OSCE grades with multiple choice (MCQ)-based written examinations and evaluations of clinical skills and behavior (during hospital traineeships); OSCE grade distribution; and the impact of integrating OSCE grades into the current evaluation in terms of student ranking.

Results: The competence-oriented OSCE#1 and OSCE#2 grades correlated only with MCQ grades (r = 0.19, P<0.001) or traineeship skill grades (r = 0.17, P = 0.001), respectively, and not with traineeship behavior grades (P>0.75). Conversely, the behavior-oriented OSCE#3 grades correlated with traineeship skill and behavior grades (r = 0.19, P<0.001, and r = 0.12, P = 0.032), but not with MCQ grades (P = 0.09). The dispersion of OSCE grades was wider than for MCQ examinations (P<0.001). When OSCE grades were integrated to the final fourth-year grade with an incremental 10%, 20% or 40% coefficient, an increasing proportion of the 379 students had a ranking variation by ±50 ranks (P<0.001). This ranking change mainly affected students among the mid-50% of ranking.

Conclusion: This large-scale French experience showed that OSCE designed to assess a combination of clinical competence and behavioral skills, increases the discriminatory capacity of current evaluations modalities in French medical schools.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808634PMC
June 2021

[To beat the heart must not stop].

Authors:
Cécile Badoual

Ann Pathol 2021 Feb 9;41(1). Epub 2021 Jan 9.

Service d'anatomo-pathologie, hôpital européen G.-Pompidou, 20-40, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833171PMC
February 2021

[Last one for this year].

Authors:
Cécile Badoual

Ann Pathol 2020 11;40(6):425

Service d'anatomo-pathologie, hôpital européen Georges-Pompidou, université de Paris, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.10.002DOI Listing
November 2020

HPV Detection in Head and Neck Squamous Cell Carcinomas: What Is the Issue?

Front Oncol 2020 15;10:1751. Epub 2020 Sep 15.

Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France.

Besides classic tobacco and alcohol risk factors, human papillomavirus (HPV) plays a role in the development of a subset of head and neck squamous cell carcinomas (HNSCCs), and notably oropharynx squamous cell carcinomas (OPSCCs). HPV-induced OPSCCs have a different biological behavior and a better prognosis compared to non-HPV-induced OPSCCs and the eighth-edition TNM classification now separates these two entities. Therefore, determining the HPV status of patients with OPSCC is now essential for treatment, prognosis, and development of clinical trials. In this review, after reminding essential steps of HPV implication in the cell cycle, we describe the existing tools that are currently feasible in routine practice according to facilities available in health structures, with their benefits and drawbacks: HPV PCR, E6/E7 mRNA RT-PCR, E6/E7 mRNA hybridization, HPV DNA hybridization, and P16 immunochemistry. Besides these traditional HPV detection tools, novel diagnostic approaches are being evaluated for HPV-induced OPSCC "ultrastaging." E6 humoral response and ddPCR-detecting HPVct DNA are two techniques performed on blood and are therefore non-invasive. Baseline E6 humoral levels could have a prognostic value, and HPVct DNA could be helpful for HPV OPSCC recurrence monitoring. At last, next-generation sequencing (NGS)-based "capture HPV" is a technique feasible on biopsies and circulating DNA material. It helps characterize HPV integration status and sites, and it could define prognostic subgroups in HPV-induced OPSCC. These novel precision detection tools could be further integrated in the care of patients with HPV-induced OPSCC.
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http://dx.doi.org/10.3389/fonc.2020.01751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523032PMC
September 2020

Juvenile-Onset Recurrent Respiratory Papillomatosis Aggressiveness: In Situ Study of the Level of Transcription of HPV E6 and E7.

Cancers (Basel) 2020 Oct 1;12(10). Epub 2020 Oct 1.

Department of Pathology, European Hospital Georges-Pompidou, Assistance Publique-Hôpitaux de Paris, F-75015 Paris, France.

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a condition related to HPV 6 and 11 infection which is characterized by the repeated growth of benign exophytic papilloma in the respiratory tract. Disease progression is unpredictable: some children experience minor symptoms, while others require multiple interventions due to florid growth. The aim of this study was to explore the biomarkers of JoRRP severity on a bicentric cohort of forty-eight children. We performed a CISH on the most recent sample of papilloma with a probe targeting the mRNA of the and genes of HPV 6 and 11 and an immunostaining with p16 antibody. For each patient HPV RNA CISH staining was assessed semi-quantitatively to define two scores: 1+, defined as a low staining extent, and 2+, defined as a high staining extent. This series contained 19 patients with a score of 1+ and 29 with a score of 2+. Patients with a score of 2+ had a median of surgical excision (SE) per year that was twice that of patients with a score of 1+ (respectively 6.1 versus 2.8, = 0.036). We found similar results with the median number of SE the first year. Regarding p16, all patients were negative. To conclude, HPV RNA CISH might be a biomarker which is predictive of disease aggressiveness in JoRRP, and might help in patient care management.
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http://dx.doi.org/10.3390/cancers12102836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601884PMC
October 2020

[Vaccination against papillomavirus : outstanding issues].

Rev Prat 2020 Jan;70(1):104-108

Inserm U970, PARCC, Paris, France.

Vaccination against papillomavirus: outstanding issues. Human papillomavirus or HPV are oncogenic viruses involved in many cancers. It is estimated that around 5% of cancers worldwide are linked to HPV infection. Cancers of the cervix, vagina, vulva, anus, penis and throat (tonsil) are virally induced in proportions ranging from 35 to almost 100%. These cancers are not all easily detected and the detection of lesions is not always simple and effective. Prophylactic anti-HPV vaccination is recognized for its effectiveness in the prevention of cervical cancers, its place in the prevention of other induced HPV cancers remains debated.
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January 2020

[Thanks for this commitment].

Authors:
Cécile Badoual

Ann Pathol 2020 07;40(4):249

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http://dx.doi.org/10.1016/j.annpat.2020.07.001DOI Listing
July 2020

High expression of spliced X-Box Binding Protein 1 in lung tumors is associated with cancer aggressiveness and epithelial-to-mesenchymal transition.

Sci Rep 2020 06 23;10(1):10188. Epub 2020 Jun 23.

Paris Descartes University, Paris, France.

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor growth and aggressiveness. Endoplasmic Reticulum (ER) stress has been documented in most major cancers, and the ability to tolerate persistent ER stress through an effective unfolded protein response enhances cancer cell survival, angiogenesis, metastasis, drug resistance and immunosuppression. The ER stress sensor IRE1α contributes to tumor progression through XBP1 mRNA splicing and regulated IRE1α-dependent decay of mRNA and miRNA. The aim of this study was to perform a molecular characterization of series of tumor samples to explore the impact of intratumoral IRE1 signaling in non-small cell lung cancer characteristics. To monitor IRE1 splicing activity, we adopted a fragment length analysis to detect changes in the length of the XBP1 mRNA before and after splicing as a method for measuring sXBP1 mRNA levels in tumors because sXBP1 mRNA is not probed by standard transcriptomic analyses. We demonstrate for the first time that XBP1 splicing is a valuable marker of lung cancer aggressiveness, and our results support a model in which IRE1 downstream signaling could act as a regulator of Epithelial to Mesenchymal Transition (EMT). Our findings study highlights the role of IRE1α downstream signaling in non-small cell lung cancer and opens a conceptual framework to determine how IRE1α endoribonuclease activity shapes the EMT program.
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http://dx.doi.org/10.1038/s41598-020-67243-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311525PMC
June 2020

Curative anticoagulation prevents endothelial lesion in COVID-19 patients.

J Thromb Haemost 2020 09 30;18(9):2391-2399. Epub 2020 Jul 30.

Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France.

Background: Coronavirus disease-2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders.

Objectives: To explore the coagulopathy and endothelial dysfunction in COVID-19 patients.

Methods: The study analyzed clinical and biological profiles of patients with suspected COVID-19 infection at admission, including hemostasis tests and quantification of circulating endothelial cells (CECs).

Results: Among 96 consecutive COVID-19-suspected patients fulfilling criteria for hospitalization, 66 were tested positive for SARS-CoV-2. COVID-19-positive patients were more likely to present with fever (P = .02), cough (P = .03), and pneumonia at computed tomography (CT) scan (P = .002) at admission. Prevalence of D-dimer >500 ng/mL was higher in COVID-19-positive patients (74.2% versus 43.3%; P = .007). No sign of disseminated intravascular coagulation were identified. Adding D-dimers >500 ng/mL to gender and pneumonia at CT scan in receiver operating characteristic curve analysis significantly increased area under the curve for COVID-19 diagnosis. COVID-19-positive patients had significantly more CECs at admission (P = .008) than COVID-19-negative ones. COVID-19-positive patients treated with curative anticoagulant prior to admission had fewer CECs (P = .02) than those without. Interestingly, patients treated with curative anticoagulation and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers had even fewer CECs (P = .007).

Conclusion: Curative anticoagulation could prevent COVID-19-associated coagulopathy and endothelial lesion.
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http://dx.doi.org/10.1111/jth.14968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323356PMC
September 2020

[Tomorrow belongs to us].

Authors:
Cécile Badoual

Ann Pathol 2020 06;40(3):185

Service d'anatomo-pathologie, hôpital européen G.-Pompidou, 20-40, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.05.004DOI Listing
June 2020

HPV Involvement in the Tumor Microenvironment and Immune Treatment in Head and Neck Squamous Cell Carcinomas.

Cancers (Basel) 2020 Apr 25;12(5). Epub 2020 Apr 25.

Department of Otolaryngology and Head and Neck Surgery, CHU Saint-Pierre, 1000 Brussels, Belgium.

Head and neck squamous cell carcinomas (HNSCC) are one of the most prevalent cancers worldwide. Active human papillomavirus (HPV) infection has been identified as an important additional risk factor and seems to be associated with a better prognosis in non-drinker and non-smoker young patients with oropharyngeal SCC. The better response of the immune system against the HPV-induced HNSCC is suspected as a potential explanation for the better prognosis of young patients. To further assess this hypothesis, our review aims to shed light the current knowledge about the impact of HPV infection on the immune response in the context of HNSCC, focusing on the innate immune system, particularly highlighting the role of macrophages, Langerhans and myeloid cells, and on the adaptative immune system, pointing out the involvement of T regulatory, T CD8 and T CD4 lymphocytes. In addition, we also review the preventive (HPV vaccines) and therapeutic (checkpoint inhibitors) strategies against HPV-related HNSCC, stressing the use of anti-CTLA4, PD-L1, PD-L2 antibodies alone and in combination with other agents able to modulate immune responses.
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http://dx.doi.org/10.3390/cancers12051060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281394PMC
April 2020

A prospective multicentre REFCOR study of 470 cases of head and neck Adenoid cystic carcinoma: epidemiology and prognostic factors.

Eur J Cancer 2020 05 11;130:241-249. Epub 2020 Mar 11.

Sorbonne University, APHP, Department of ENT-Head and Neck Surgery, Tenon Hospital, 4 Rue de La Chine, 75020, Paris, France. Electronic address:

Background: Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC.

Patients And Methods: A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software.

Results: Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age ≥65 years (hazard ratio [HR] = 1.67), BMI<16.5 (HR = 2.62), and lymph node invasion cN (HR = 2.08).

Conclusion: Age, BMI and N stage are the three main clinical prognostic factors determining EFS identified in this prospective series of patients with ACC. Such findings open new research perspectives on the influence of these components on initial patient care.
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http://dx.doi.org/10.1016/j.ejca.2020.01.023DOI Listing
May 2020

The Microenvironment of Head and Neck Cancers: Papillomavirus Involvement and Potential Impact of Immunomodulatory Treatments.

Head Neck Pathol 2020 Jun 2;14(2):330-340. Epub 2020 Mar 2.

Department of Pathology, European Georges Pompidou Hospital, APHP, Paris University, 20 rue Leblanc, 75015, Paris, France.

Cancer progression can be understood as the result of deregulation of tumors' immune microenvironments. Recent studies of the alterations of microenvironments highlight their significant influence on the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). It is necessary to better characterize tumor-infiltrating lymphocytes by focusing, in particular, on the tumor escape mechanisms from immune surveillance. One of the best described tumor immune system evasion mechanisms is the expression of co-stimulation molecules that constitute so-called "immune checkpoints". These molecules regulate the immune response by either activating or inhibiting its effects. The programmed cell death 1 (PD-1) surface protein is an inhibitory co-stimulation molecule that induces exhaustion of activated T-lymphocytes (TLs, T cells) through binding with its ligands, PD-L1 and PD-L2. Half of HNSCCs exhibit PD-L1 expression with higher expression identified in human papillomavirus (HPV) positive tumors. Numerous studies have shown differences between the microenvironments of HPV+ and HPV- cancers. Notably, infiltrations of exhausted CD4+ PD1+ and CD8+ PD1+ T cells are far higher in the microenvironment of HPV+ tumors. The FDA has approved the use of molecules that target PD-1 for the treatment of HNSCC. The first results of clinical trials with anti-PD-1 blockers in HNSCC show improved patient survival, particularly long-term survival without recurrence. However, discordant results were sometimes observed, and improvements in defining cellular predictive markers are necessary. With the development of immunotherapies, pathologists play a role in the selection of patients who are eligible for specific treatments and assessment of their prognosis in greater detail. An automated, quantitative in situ imaging system that integrates both multispectral imaging and automated slide scanning could be developed in pathology laboratories. The evaluation of PD-L1 expression has only been used to stratify the administration of first-line immunotherapy. The validation of these tests and their routine interpretation is essential. No specific recommendation is adopted for HPV+ HNSCC.
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http://dx.doi.org/10.1007/s12105-020-01147-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235119PMC
June 2020

Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival.

Mol Oncol 2020 06 10;14(6):1207-1223. Epub 2020 Mar 10.

Centre de Recherche des Cordeliers, Inserm, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors laboratory, France.

Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well annotated with histologic, molecular and clinical data of patients. Targeted next-generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioid-like and sarcomatoid-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2, and LATS2 were more frequent in nonepithelioid MPM and positively associated with the S.score. BAP1, NF2, TERT promoter, TP53, and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2, and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.
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http://dx.doi.org/10.1002/1878-0261.12651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266286PMC
June 2020

[Study of the Human Papillomavirus (HPV) prevalence in head and neck carcinomas in a French monocentric cohort of 372 patients].

Ann Pathol 2020 Sep 18;40(5):401-410. Epub 2020 Feb 18.

Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France; Inserm U970, université Paris Descartes Sorbonne Paris, 75015 Paris, France; Équipe labellisée ligue contre le cancer, 75013 Paris, France.

Introduction: French data about HPV role in head and neck carcinomas are sparse, although French patients are mostly heavy smokers. In this series of oropharyngeal et non-oropharyngeal tumors, we aimed to determine what were the clinicopathological features associated with HPV and evaluate survival of patients according to HPV status.

Methods: Three hundred and seventy-two cases of head and neck squamous cell carcinomas were reviewed and clinicopathological data were detailed. For each case, we performed a HPV PCR and an immunostaining against p16 protein (paraffin embedded tissues).

Results: The series contained 90% of heavy smokers and 36% of tumors were located in oropharynx. HPV DNA was detected in 46% of oropharyngeal carcinomas and 16% of non-oropharyngeal carcinomas. Genotype 16 was the most frequently detected (84%). Clinicopathological features significantly associated with HPV DNA were: oropharyngeal location; absence of tobacco smoking; nodal involvement; poorly-differentiated non-keratinizing histology; positive p16 immunostaining. HPV infection was significantly associated with a longer survival for oropharyngeal carcinomas. It was not the case for non-oropharyngeal carcinomas.

Conclusion: In this French series with lot of heavy smokers, under half of carcinomas are HPV induced. Clinicopathological features and survival data associated with HPV infection are the same as those classically described in literature.
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http://dx.doi.org/10.1016/j.annpat.2020.01.005DOI Listing
September 2020

[2020 back to the future].

Authors:
Cécile Badoual

Ann Pathol 2020 Jan;40(1)

Service d'anatomo-pathologie, hôpital européen G Pompidou, AP-HP, Paris, université de Paris, 20, rue Leblanc, 75015 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2020.01.001DOI Listing
January 2020

HPV circulating tumoral DNA quantification by droplet-based digital PCR: A promising predictive and prognostic biomarker for HPV-associated oropharyngeal cancers.

Int J Cancer 2020 08 18;147(4):1222-1227. Epub 2019 Dec 18.

Laboratoire de Virologie, Hôpital Européen Georges Pompidou, and Assistance Publique - Hôpitaux de Paris, Paris, France.

We aimed to determine whether pretherapeutic assessment of HPV circulating tumoral DNA (HPV ctDNA) by droplet-based digital PCR (ddPCR) could constitute a predictive and prognostic biomarker for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). A mono-institutional prospective biomarker study on 66 patients with p16+/HPV16-positive oropharyngeal squamous cell carcinoma (OPSCC) was conducted in European Georges Pompidou Hospital, Paris, France. Blood samples were collected at the time of diagnosis before any treatment. Optimized digital PCR assays were used to quantify HPV16 ctDNA. Forty-seven (71%) patients showed a positive pretherapeutic HPV ctDNA at time of diagnosis. Interestingly, the quantity of HPV16 ctDNA at baseline, as assessed by ddPCR, was significantly correlated with the T/N/M status or OPSCC stages according to the 2018 new staging criteria for high-risk human papillomavirus (HR HPV) related OPSCC from American Joint Committee on Cancer (AJCC). Moreover, all recurrences and the majority (83%) of death reported events occurred in patients with positive HPV16 ctDNA at baseline. Finally, when posttreatment blood samples were available (n = 6), the kinetic of pretreatment/posttreatment HPV16 ctDNA was clearly associated with treatment success or failure. HPV ctDNA monitoring by ddPCR could constitute a useful and noninvasive dynamic biomarker to select HR HPV-related OPSCC patients eligible for potential treatment de-escalation and to monitor treatment response.
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http://dx.doi.org/10.1002/ijc.32804DOI Listing
August 2020

Carbonic anhydrase 9 immunohistochemistry as a tool to predict or validate germline and somatic VHL mutations in pheochromocytoma and paraganglioma-a retrospective and prospective study.

Mod Pathol 2020 01 5;33(1):57-64. Epub 2019 Aug 5.

Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015, Paris, France.

The development of pheochromocytomas and paragangliomas is strongly linked to the presence of germline mutations in more than 15 predisposing genes. Among them, germline and somatic VHL mutations account for ~10% of all cases. In contrast with SDHA and SDHB immunohistochemistries that are routinely used to validate SDHx gene mutations, there is no such tool available for VHL mutations. The aim of this study was to evaluate whether CA9 immunostaining could be used as a tool to predict the presence or validate the pathogenicity of VHL gene mutations in paraganglioma. Immunohistochemistry for CA9 was performed on 207 tumors. A retrospective series of 100 paragangliomas with known mutation status for paraganglioma susceptibility genes was first investigated. Then, a prospective series of 107 paragangliomas was investigated for CA9 immunostaining followed by germline and/or somatic genetic testing of all paraganglioma susceptibility genes by next-generation sequencing. Cytosolic CA9 protein expression was heterogeneous in the different samples. However, we observed that a membranous CA9 staining was almost exclusively observed in VHL-related cases. Forty two of 48 (88%) VHL-mutated samples showed a CA9 membranous immunostaining. Positive cells were either isolated, varying from 1 or 2 cells (5% of cases) to 10-20 cells per tumor block (35% of cases), grouped in areas of focal positivity representing between 1 and 20% of the tissue section (35% of cases), or widely distributed on 80-100% of the tumor sections (25% of samples). In contrast, 142/159 (91%) of non-VHL-mutated tumors presented no membrane CA9 localization. Our results demonstrate that VHL gene mutations can be predicted or validated reliably by an easy-to-perform and low-cost immunohistochemical procedure. CA9 immunohistochemistry on paragangliomas will improve the diagnosis of VHL-related disease, which is important for the surveillance and therapeutic management of paraganglioma patients, and in case of germline mutation, their family members.
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http://dx.doi.org/10.1038/s41379-019-0343-4DOI Listing
January 2020

Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance.

Gastric Cancer 2020 01 2;23(1):73-81. Epub 2019 Jul 2.

Université de Paris, PARCC, INSERM, 75015, Paris, France.

Background: The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown.

Methods: Circulating natural killer (NK) cells, CD4 and CD8 T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56 cells (NK), CD8, and FoxP3 (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples.

Results: Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4 and CD8 T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8 T cells, but not NK or FoxP3 cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8 TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8 TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039).

Conclusion: Diffuse/mixed-type AGC has lower rates of CD8 TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.
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http://dx.doi.org/10.1007/s10120-019-00983-3DOI Listing
January 2020

Chromogenic In Situ Hybridization as a Tool for HPV-Related Head and Neck Cancer Diagnosis.

J Vis Exp 2019 06 14(148). Epub 2019 Jun 14.

Department of Pathology, Georges Pompidou European Hospital, Assistance publique - Hôpitaux de Paris (APHP), Paris Descartes University; Paris Cardiovascular Research Center (PARCC), Institut national de la santé et de la recherche médicale (Inserm) U970;

Human papillomavirus (HPV) infection is a major risk factor for a subtype of oropharyngeal squamous cell carcinoma (OPSCC), which tends to be associated with a better outcome than alcohol- and tobacco-related OPSCC. Chromogenic in situ hybridization (CISH) of HPV viral RNA could allow the semiquantitative evaluation of viral transcripts of the oncogenic proteins E6 and E7 and an in situ visualization with a good spatial resolution. This technique allows the diagnosis of an active infection with the visualization of HPV transcription in the tumoral HPV-infected cells. An advantage of this technique is the avoidance of contamination from nonneoplastic HPV-infected cells adjacent to the tumor. Overall, its good diagnosis performances have it considered to be the gold standard for active HPV infection identification. Since E6 and E7 viral protein interaction with cell proteins pRb and p53 is mandatory for cell transformation, HPV RNA CISH is functionally relevant and acutely reflects active oncogenic HPV infection. This technique is clinically relevant as well since "low" or "high" HPV transcription levels helped the identification of two prognosis groups among HPV-related p16-positive head and neck cancer patients. Here we present the protocol for manual HPV RNA CISH performed on formalin-fixed paraffin-embedded (FFPE) slides with a kit obtained from the manufacturer. Instead of chromogenic revelation, RNA in situ hybridization may also be performed with fluorescent revelation (RNA FISH). It may also be combined with conventional immunostaining.
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http://dx.doi.org/10.3791/59422DOI Listing
June 2019

[An intriguing immunohistochemical expression profile for an adenosquamous carcinoma].

Ann Pathol 2019 Dec 26;39(6):444-446. Epub 2019 Jun 26.

Service d'anatomie et de cytologie pathologiques de l'hôpital européen Georges-Pompidou, AP-HP, 20, rue Leblanc, 75015 Paris, France; PARCC équipe 10, unité Inserm U970, 75015 Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2019.04.008DOI Listing
December 2019

The integrity of the FOG-2 LXCXE pRb-binding motif is required for small intestine homeostasis.

Exp Physiol 2019 07 14;104(7):1074-1089. Epub 2019 May 14.

Division of Innovative Therapies, UMR E007, Institute of Biology François Jacob, CEA, Université Paris Sud, Université Paris-Saclay, Fontenay aux Roses, France.

New Findings: What is the central question of this study? Do Fog2 mice present a defect of small intestine homeostasis? What is the main finding and its importance? The importance of interactions between FOG-2 and pRb in adipose tissue physiology has previously been demonstrated. Here it is shown that this interaction is also intrinsic to small intestine homeostasis and exerts extrinsic control over mouse metabolism. Thus, this association is involved in maintaining small intestine morphology, and regulating crypt proliferation and lineage differentiation. It therefore affects mouse growth and adaptation to a high-fat diet.

Abstract: GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. We have shown that GATA-1 and FOG-2 contain an LXCXE pRb-binding motif. Interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation, whereas the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Fog2-knock-in mice have defective pRb binding and are resistant to obesity, due to efficient white-into-brown fat conversion. Our aim was to investigate the pathophysiological impact of FOG-2-pRb interaction on the small intestine and mouse growth. Histological analysis of the small intestine revealed architectural changes in Fog2 mice, including villus shortening, with crypt expansion and a change in muscularis propria thickness. These differences were more marked in the proximo-distal part of the small intestine and were associated with an increase in crypt cell proliferation and disruption of the goblet and Paneth cell lineage. The small intestine of the mutants was unable to adapt to a high-fat diet, and had significantly lower plasma lipid levels on such a diet. Fog2 mice displayed higher levels of glucose-dependent insulinotropic peptide release, and lower levels of insulin-like growth factor I release on a regular diet. Their intestinal lipid absorption was impaired, resulting in restricted weight gain. In addition to the intrinsic effects of the mutation on adipose tissue, we show here an extrinsic relationship between the intestine and the effect of FOG-2 mutation on mouse metabolism. In conclusion, the interaction of FOG-2 with pRb coordinates the crypt-villus axis and controls small intestine homeostasis.
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http://dx.doi.org/10.1113/EP087369DOI Listing
July 2019

HPV detection and genotyping of head and neck cancer biopsies by molecular testing with regard to the new oropharyngeal squamous cell carcinoma classification based on HPV status.

Pathology 2019 Jun 17;51(4):421-425. Epub 2019 Apr 17.

Laboratoire de virologie, Hôpital Européen Georges Pompidou, and Assistance Publique - Hôpitaux de Paris, Paris, France; Faculté de Médecine Paris Descartes, Université Paris Descartes (Paris V), Sorbonne Paris Cité, Paris, France. Electronic address:

Recently, both the World Health Organization/International Agency for Research on Cancer (WHO/IARC) and the American Joint Committee on Cancer (AJCC) have classified oropharyngeal squamous cell carcinoma (OPSCC) on the basis of HPV status. For this purpose, the WHO/IARC recommended direct molecular HPV testing. In practice, formalin-fixed, paraffin-embedded (FFPE) biopsy specimens are frequently the only available samples. We herein compared in parallel two commercially available molecular assays that were first designed for cervical HPV detection and genotyping: Inno-Lipa HPV Genotyping Extra II (IL) and Anyplex II HPV28 (AP28). A total of 55 samples were tested. By IL assay, chosen as reference assay, 27 (49.1%) biopsies were positive for HPV16, 10 (18.2%) were positive for HPV but negative for HPV16, and 18 (32.7%) were negative for HPV. A valid result with AP28 was obtained for 51 biopsy samples (92.7%). Among 37 HPV positive samples by IL, 33 (89.2%) were positive by AP28. The agreement between both assays was good (Cohen's κ = 0.78). Among the six discrepancies between assays, always associated with low HPV16 viral load, four biopsies positive for HPV16 by IL could not be detected by AP28. Taken together, these observations demonstrate that both assays could be used in routine HPV detection and genotyping on FFPE biopsy samples of head and neck tumours.
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http://dx.doi.org/10.1016/j.pathol.2019.02.002DOI Listing
June 2019
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