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1. Clinicopathological factors associated with sentinel lymph node detection in non-small-cell lung cancer

Author

Christophe Wollbrett, Joseph Seitlinger, Florent Stasiak, Juliette Piccoli, Arthur Streit, Joelle Siat, Guillaume Gauchotte, and Stéphane Renaud

Subjects
Sentinel lymph node, Near-infrared fluorescence, Indocyanine green, Electromagnetic navigation bronchoscopy, Non-small-cell lung cancer, Surgery, RD1-811, Anesthesiology, RD78.3-87.3
Abstract

Abstract Background Mapping of the pulmonary lymphatic system by near-infrared (NIR) fluorescence imaging might not always identify the first lymph node relay. The aim of this study was to determine the clinicopathologic factors allowing the identification of sentinel lymph nodes (SLNs) by NIR fluorescence imaging in thoracic surgery for non-small-cell lung cancer (NSCLC). Methods We conducted a retrospective review of 92 patients treated for suspected or confirmed cN0 lung cancer with curative intent who underwent an intraoperative injection of indocyanine green (ICG) either by direct peritumoral injection or by endobronchial injection using electromagnetic navigational bronchoscopy (ENB). After exclusion of patients for technical failure, benign disease and metastasis, we analyzed the clinicopathologic findings of 65 patients treated for localized-stage NSCLC, comparing the group with identification of SLNs (SLN-positive group) with the group without identification of SLNs (SLN-negative group). Results Forty-eight patients (73.8%) were SLN-positive. Patients with SLN positivity were more frequently female (50%) than the SLN-negative patients were (11.8%) (p = 0.006). The mean value of diffusing capacity for carbon monoxide (DLCO) was lower among the patients in the SLN-negative group (64.7% ± 16.7%) than the SLN-positive group (77.6% ± 17.2%, p 75% (HR = 4.92, 95% CI: 1.27–24.7; p = 0.03) and female sex (HR = 5.55, 95% CI: 1.25–39.33; p = 0.04) were independently associated with SLN detection. Conclusions At a time of resurgence in the use of the sentinel lymph node mapping technique in the field of thoracic surgery, this study enabled us to identify, using multivariate analysis, two predictive factors for success: DLCO > 75% and female sex. Larger datasets are needed to confirm our results.

Published
2024
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2. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author

Julien Broséus, Sébastien Hergalant, Julia Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos-Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan H. Bernhart, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Elise Chapiro, Florence Nguyen-Khac, Céline Chery, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie-Christine Béné, Catherine Thieblemont, Peter Lichter, Ole Ammerpohl, Jean-Louis Guéant, ICGC MMML-Seq Consortium, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, and Stephan Stilgenbauer

Subjects
Science
Abstract

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Published
2023
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3. MicroRNAs miR-16 and miR-519 control meningioma cell proliferation via overlapping transcriptomic programs shared with the RNA-binding protein HuR

Author

Sébastien Hergalant, Jean-Matthieu Casse, Abderrahim Oussalah, Rémi Houlgatte, Déborah Helle, Fabien Rech, Laurent Vallar, Jean-Louis Guéant, Jean-Michel Vignaud, Shyue-Fang Battaglia-Hsu, and Guillaume Gauchotte

Subjects
miR-16, miR-519, microRNA, HuR, proliferation, tumorigenesis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionMeningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma.MethodsA cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data. ResultsIn tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P6-fold; 79.6% of target genes). DiscussionThese results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition.

Published
2023
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4. The dural angioleiomyoma harbors frequent GJA4 mutation and a distinct DNA methylation profile

Author

Arnault Tauziède-Espariat, Thibaut Pierre, Michel Wassef, David Castel, Florence Riant, Jacques Grill, Alexandre Roux, Johan Pallud, Edouard Dezamis, Damien Bresson, Sandro Benichi, Thomas Blauwblomme, Djallel Benzohra, Guillaume Gauchotte, Celso Pouget, Sophie Colnat-Coulbois, Karima Mokhtari, Corinne Balleyguier, Frédérique Larousserie, Volodia Dangouloff-Ros, Nathalie Boddaert, Marie-Anne Debily, Lauren Hasty, Marc Polivka, Homa Adle-Biassette, Alice Métais, Emmanuèle Lechapt, Fabrice Chrétien, Felix Sahm, Philipp Sievers, Pascale Varlet, and the RENOCLIP-LOC

Subjects
Dural angioleiomyoma, GJA4, DNA methylation profile, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.

Published
2022
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5. What is the appropriate 'first lymph node' in the era of segmentectomy for non-small cell lung cancer?

Author

Joseph Seitlinger, Florent Stasiak, Juliette Piccoli, Gabriele Maffeis, Arthur Streit, Christophe Wollbrett, Joelle Siat, Guillaume Gauchotte, and Stéphane Renaud

Subjects
sentinel lymph node, lung cancer, segmentectomy, fluorescence guided surgery, electromagnetic navigational bronchoscopy, lung resection, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionThe place of segmentectomy in the management of lung cancer is shifting following the inspiring results of the Japanese JCOG0802 trial. I n this study, authors suggested that performing segmentectomy would require in an optimal way an intraoperative confirmation of pN0 tumor with a frozen section. Our objective was to determine whether the proposed technique, i.e. adjacent lymph node analysis, is consistent with the results of our study on sentinel lymph node (SLN) detection using fluorescence.MethodsThis is a retrospective, observational, single center study. Eighty-one patients with suspected localized stage NSCLC (IA to IIA) were included between December 2020 and March 2022. All patients received an intra-operative injection of indocyanine green (ICG) directly in the peritumoral area or by electromagnetic navigational bronchoscopy (ENB). The SLN was then assessed by using an infrared fluorescence camera.ResultsIn our cohort, SLN was identified in 60/81 patients (74.1%). In 15/60 patients with identified SLN (25%), NIR-guided SLN was concordant with the suggestions of JCOG0802 study. A retrospective SLN pathological analysis was performed in 43 patients/60 cases with identified SLN (71.2%), including 37 cases of malignant disease. Occult micro-metastases were found in 4 patients out of 37 SLN analyzed, leading to a 10.8% upstaging with NIR-guided SLN analysis.DicussionAt the time of segmentectomies, ICG technique allowed the identification of the SLN in a high percent of cases and in some areas usually out of the recommended stations for lymph node dissection.

Published
2023
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6. Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature

Author

Stephanos Finitsis, Valerie Bernier, Isabelle Buccheit, Olivier Klein, Serge Bracard, Francois Zhu, Guillaume Gauchotte, and René Anxionnat

Subjects
Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Chronic encapsulated intracerebral hematomas (CEIHs) are a rare, late complication of radiosurgery for intracranial AVM. We present 5 cases treated mostly by surgical excision and review the literature. Methods Patients (age 39, 42, 36, 31, 62) presented with headache, paresthesia, hemiparesis or were asymptomatic. CEIHs presented 10 to 13 years (median 12 years) post radiosurgery. Three patients had demonstrated early radiation induced changes post radiosurgery. Angiographic cure, assessed with DSA, was present in all cases except 1 case with a small nidus remnant. MRI demonstrated mixed lesions with a solid enhancing part, organized hematoma and extensive surrounding edema while three cases had also a cystic component. Results Excision of the CEIHs with complete or partial removal of the capsule was performed in 4 patients and resulted in marked clinical improvement. One patient was managed conservatively with administration of steroids as surgery was judged excessively hazardous with eventual stabilization of his symptoms. Conclusions CEIHs are rare, late complications of radiosurgery for cranial AVM. They may be asymptomatic or provoke symptoms and may be preceded by early radiation induced changes. Complete removal of CEIHS is an effective treatment. Because of the long latency period of CEIHs, patients who had radiosurgery for brain AVMs should be followed by MRI at least 10 years even after complete obliteration.

Published
2020
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7. Use of static and dynamic [18F]-F-DOPA PET parameters for detecting patients with glioma recurrence or progression

Author

Timothée Zaragori, Merwan Ginet, Pierre-Yves Marie, Véronique Roch, Rachel Grignon, Guillaume Gauchotte, Fabien Rech, Marie Blonski, Zohra Lamiral, Luc Taillandier, Laëtitia Imbert, and Antoine Verger

Subjects
[18F]-F-DOPA, Glioma, Recurrence, Dynamic analysis, Amino-acid PET, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Static [18F]-F-DOPA PET images are currently used for identifying patients with glioma recurrence/progression after treatment, although the additional diagnostic value of dynamic parameters remains unknown in this setting. The aim of this study was to evaluate the performances of static and dynamic [18F]-F-DOPA PET parameters for detecting patients with glioma recurrence/progression as well as assess further relationships with patient outcome. Methods Fifty-one consecutive patients who underwent an [18F]-F-DOPA PET for a suspected glioma recurrence/progression at post-resection MRI, were retrospectively included. Static parameters, including mean and maximum tumor-to-normal-brain (TBR) ratios, tumor-to-striatum (TSR) ratios, and metabolic tumor volume (MTV), as well as dynamic parameters with time-to-peak (TTP) values and curve slope, were tested for predicting the following: (1) glioma recurrence/progression at 6 months after the PET exam and (2) survival on longer follow-up. Results All static parameters were significant predictors of glioma recurrence/progression (accuracy ≥ 94%) with all parameters also associated with mean progression-free survival (PFS) in the overall population (all p < 0.001, 29.7 vs. 0.4 months for TBRmax, TSRmax, and MTV). The curve slope was the sole dynamic PET predictor of glioma recurrence/progression (accuracy = 76.5%) and was also associated with mean PFS (p < 0.001, 18.0 vs. 0.4 months). However, no additional information was provided relative to static parameters in multivariate analysis. Conclusion Although patients with glioma recurrence/progression can be detected by both static and dynamic [18F]-F-DOPA PET parameters, most of this diagnostic information can be achieved by conventional static parameters.

Published
2020
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8. Myeloperoxydase and CD15 With Glycophorin C Double Staining in the Evaluation of Skin Wound Vitality in Forensic Practice

Author

Guillaume Gauchotte, Agathe Bochnakian, Philippe Campoli, Emilie Lardenois, Muriel Brix, Etienne Simon, Sophie Colomb, Laurent Martrille, and Pierre-Antoine Peyron

Subjects
CD15, myeloperoxidase (MPO), glycophorin, vitality, wound datation, histology, Medicine (General), R5-920
Abstract

BackgroundThe determination of skin wound vitality based on tissue sections is a challenge for the forensic pathologist. Histology is still the gold standard, despite its low sensitivity. Immunohistochemistry could allow to obtain a higher sensitivity. Upon the candidate markers, CD15 and myeloperoxidase (MPO) may allow to early detect polymorphonuclear neutrophils (PMN). The aim of this study was to evaluate the sensitivity and the specificity of CD15 and MPO, with glycophorin C co-staining, compared to standard histology, in a series of medicolegal autopsies, and in a human model of recent wounds.MethodsTwenty-four deceased individuals with at least one recent open skin wound were included. For each corpse, a post-mortem wound was performed in an uninjured skin area. At autopsy, a skin sample from the margins of each wound and skin controls were collected (n = 72). Additionally, the cutaneous surgical margins of abdominoplasty specimens were sampled as a model of early intravital stab wound injury (scalpel blade), associated with post-devascularization wounds (n = 39). MPO/glycophorin C and CD15/glycophorin C immunohistochemical double staining was performed. The number of MPO and CD15 positive cells per 10 high power fields (HPF) was evaluated, excluding glycophorin C—positive areas.ResultsWith a threshold of at least 4 PMN/10 high power fields, the sensitivity and specificity of the PMN count for the diagnostic of vitality were 16 and 100%, respectively. With MPO/glycophorin C as well as CD15/glycophorin C IHC, the number of positive cells was significantly higher in vital than in non-vital wounds (p < 0.001). With a threshold of at least 4 positive cells/10 HPF, the sensitivity and specificity of CD15 immunohistochemistry were 53 and 100%, respectively; with the same threshold, MPO sensitivity and specificity were 28 and 95%.ConclusionWe showed that combined MPO or CD15/glycophorin C double staining is an interesting and original method to detect early vital reaction. CD15 allowed to obtain a higher, albeit still limited, sensitivity, with a high specificity. Confirmation studies in independent and larger cohorts are still needed to confirm its accuracy in forensic pathology.

Published
2022
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9. Initial PCV Chemotherapy Followed by Radiotherapy Is Associated With a Prolonged Response But Late Neurotoxicity in 20 Diffuse Low-Grade Glioma Patients

Author

Marie Blonski, Tiphaine Obara, Cyril Brzenczek, Celso Pouget, Céline Dillier, Mylène Meyer, Laura Lavigne, Natacha Forthoffer, Aurélie Broussois, Guillaume Gauchotte, Marie-Hélène Baron, Fabien Rech, Sophie Mézières, Yann Gaudeau, Antoine Verger, Guillaume Vogin, René Anxionnat, Jean-Marie Moureaux, and Luc Taillandier

Subjects
diffuse low-grade glioma, quality of life, neurocognition, neurotoxicity, kinetics, surgery, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundStudy RTOG 9802 in high-risk diffuse low-grade gliomas (DLGGs) showed the potential synergistic effect on survival of the procarbazine, CCNU, and vincristine (PCV) radiotherapy (RT) combination. Limited data on long-term neurocognitive impact and quality of life (QoL) have yet been reported.Patients and MethodsWe described a monocentric series of patients treated at first line by the combination of PCV immediately followed by RT between January 01, 1982 and January 01, 2017. Radiological data were collected and included volume, velocity of diametric expansion (VDE), and MRI aspects. Long-term neurocognitive and QoL were analyzed.ResultsTwenty patients fulfilled the eligibility criteria. The median response rate was 65.1% (range, 9.6%–99%) at the time of maximal VDE decrease corresponding to a median volume reduction of 79.7 cm3 (range, 3.1 to 174.2 cm3), which occurred after a median period of 7.2 years (range, 0.3–21.9) after the end of RT. An ongoing negative VDE was measured in 13/16 patients after the end of RT, with a median duration of 6.7 years (range, 9 months–21.9 years). The median follow-up since radiological diagnosis was 17.5 years (range, 4.8 to 29.5). Estimated median survival was 17.4 years (95% CI: 12; NR). After a long-term follow-up, substantial neurotoxicity was noticed with dementia in six progression-free patients (30%), leading to ventriculo-peritoneal shunt procedures in three, and premature death in five. Thirteen patients (65%) were unable to work with disability status. Successive longitudinal neurocognitive assessments for living patients showed verbal episodic memory deterioration.ConclusionsPCV-RT combination seems to have not only an oncological synergy but also a long-term neurotoxic synergy to consider before initial therapeutic decision.

Published
2022
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10. Adult Diffuse Low-Grade Gliomas: 35-Year Experience at the Nancy France Neurooncology Unit

Author

Tiphaine Obara, Marie Blonski, Cyril Brzenczek, Sophie Mézières, Yann Gaudeau, Celso Pouget, Guillaume Gauchotte, Antoine Verger, Guillaume Vogin, Jean-Marie Moureaux, Hugues Duffau, Fabien Rech, and Luc Taillandier

Subjects
diffuse low-grade glioma, prognosis, survival, quality of life, surgery, chemotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

BackgroundTo report survival, spontaneous prognostic factors, and treatment efficacy in a French monocentric cohort of diffuse low-grade glioma (DLGG) patients over 35 years of follow-up.MethodsA monocentric retrospective study of 339 patients diagnosed with a new DLGG between 01/01/1982 and 01/01/2017 was created. Inclusion criteria were patient age ≥18 years at diagnosis and histological diagnosis of WHO grade II glioma (according to 1993, 2007, and 2016 WHO classifications). The survival parameters were estimated using the Kaplan-Meier method with a 95% confidence interval. Differences in survival were tested for statistical significance by the log-rank test. Factors were considered significant when p ≤ 0.1 and p ≤ 0.05 in the univariate and multivariate analyses, respectively.ResultsA total of 339 patients were included with a median follow-up of 8.7 years. The Kaplan-Meier median overall survival was 15.7 years. At the time of radiological diagnosis, Karnofsky Performance Status score and initial tumor volume were significant independent prognostic factors. Oncological prognostic factors were the extent of resection for patients who underwent surgery and the timing of radiotherapy for those concerned. In this study, patients who had delayed radiotherapy (provided remaining low grade) did not have worse survival compared with patients who had early radiotherapy. The functional capabilities of the patients were preserved enough so that they could remain independent during at least three quarters of the follow-up.ConclusionThis large monocentric series spread over a long time clarifies the effects of different therapeutic strategies and their combination in the management of DLGG.

Published
2020
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11. PET imaging of 68Ga-NODAGA-RGD, as compared with 18F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma

Author

Sibel Isal, Julien Pierson, Laetitia Imbert, Alexandra Clement, Charlotte Collet, Sophie Pinel, Nicolas Veran, Aurélie Reinhard, Sylvain Poussier, Guillaume Gauchotte, Steeven Frezier, Gilles Karcher, Pierre-Yves Marie, and Fatiha Maskali

Subjects
68Ga-NODAGA-RGD, 18F-FDG, PET, αvβ3 integrin, Glioblastoma, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract

Abstract Background Tracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma. Methods Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD. Results Both tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density. Conclusions 68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

Published
2018
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12. Multiorgan and Vascular Tropism of SARS-CoV-2

Author

Cédric Hartard, Ahlam Chaqroun, Nicla Settembre, Guillaume Gauchotte, Benjamin Lefevre, Elodie Marchand, Charles Mazeaud, Duc Trung Nguyen, Laurent Martrille, Isabelle Koscinski, Sergueï Malikov, and Evelyne Schvoerer

Subjects
SARS-CoV-2, viral quasispecies, ultra-deep sequencing, Microbiology, QR1-502
Abstract

Although the respiratory tract is the main target of SARS-CoV-2, other tissues and organs are permissive to the infection. In this report, we investigated this wide-spectrum tropism by studying the SARS-CoV-2 genetic intra-host variability in multiple tissues. The virological and histological investigation of multiple specimens from a post-mortem COVID-19 patient was performed. SARS-CoV-2 genome was detected in several tissues, including the lower respiratory system, cardio-vascular biopsies, stomach, pancreas, adrenal gland, mediastinal ganglion and testicles. Subgenomic RNA transcripts were also detected, in favor of an active viral replication, especially in testicles. Ultra-deep sequencing allowed us to highlight several SARS-CoV-2 mutations according to tissue distribution. More specifically, mutations of the spike protein, i.e., V341A (18.3%), E654 (44%) and H655R (30.8%), were detected in the inferior vena cava. SARS-CoV-2 variability can contribute to heterogeneous distributions of viral quasispecies, which may affect the COVID-19 pathogeny.

Published
2022
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13. Permanently Hypoxic Cell Culture Yields Rat Bone Marrow Mesenchymal Cells with Higher Therapeutic Potential in the Treatment of Chronic Myocardial Infarction

Author

Yihua Liu, Xiaoxi Yang, Pablo Maureira, Aude Falanga, Vanessa Marie, Guillaume Gauchotte, Sylvain Poussier, Frederique Groubatch, Pierre-Yves Marie, and Nguyen Tran

Subjects
Hypoxic preconditioning, Mesenchymal stem cells, Chronic myocardial infarction, Myocardial viability, Angiogenesis, Physiology, QP1-981, Biochemistry, QD415-436
Abstract

Background: The mismatch between traditional in vitro cell culture conditions and targeted chronic hypoxic myocardial tissue could potentially hamper the therapeutic effects of implanted bone marrow mesenchymal stem cells (BMSCs). This study sought to address (i) the extent of change to BMSC biological characteristics in different in vitro culture conditions and (ii) the effectiveness of permanent hypoxic culture for cell therapy in treating chronic myocardial infarction (MI) in rats. Methods: rat BMSCs were harvested and cultured in normoxic (21% O2, n=27) or hypoxic conditions (5% O2, n=27) until Passage 4 (P4). Cell growth tests, flow cytometry, and Bio-Plex assays were conducted to explore variations in the cell proliferation, phenotype, and cytokine expression, respectively. In the in vivo set-up, P3-BMSCs cultured in normoxia (n=6) or hypoxia (n=6) were intramyocardially injected into rat hearts that had previously experienced 1-month-old MI. The impact of cell therapy on cardiac segmental viability and hemodynamic performance was assessed 1 month later by 2-Deoxy-2[18F]fluoro-D-glucose (18F-FDG) positron emission tomography (PET) imaging and pressure-volume catheter, respectively. Additional histomorphological examinations were conducted to evaluate inflammation, fibrosis, and neovascularization. Results: Hypoxic preconditioning significantly enhanced rat BMSC clonogenic potential and proliferation without altering the multipotency. Different profiles of inflammatory, fibrotic, and angiogenic cytokine secretion were also documented, with a marked correlation observed between in vitro and in vivo proangiogenic cytokine expression and tissue neovessels. Hypoxic-preconditioned cells presented a beneficial effect on the myocardial viability of infarct segments and intrinsic contractility. Conclusion: Hypoxic-preconditioned BMSCs were able to benefit myocardial perfusion and contractility, probably by modulating the inflammation and promoting angiogenesis.

Published
2017
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15. Fatal massive pulmonary thromboembolism and concomitant pulmonary trophoblastic embolism associated with exaggerated placental site reaction: a case study

Author

Guillaume Gauchotte, Elodie Marchand, Hervé Sartelet, Antoine Kimmoun, and Héloïse Pina

Subjects
Disseminated intravascular coagulation, Pathology, medicine.medical_specialty, Fetus, Lung, Trophoblastic embolism, Gestational trophoblastic disease, business.industry, Exaggerated placental site, Case study, Histopathology, Autopsy, Case Report, medicine.disease, Pathology and Forensic Medicine, Exaggerated Placental Site, Pulmonary embolism, medicine.anatomical_structure, Embolism, embryonic structures, medicine, business, reproductive and urinary physiology
Abstract

Pulmonary embolism is a major cause of maternal morbidity during pregnancy. Beside the frequently encountered thromboembolism, trophoblastic cell embolism has also been reported in a few case reports. This phenomenon may be symptomless in physiological gestational process but is more pronounced in contexts of preeclampsia or gestational trophoblastic disease. It was exceptionally reported to be associated with death. Here, we report the case of a 15-year-old girl, who experienced dyspnea followed by cardiac arrests and disseminated intravascular coagulation. Echocardiography showed a massive proximal pulmonary embolism. Abdominal sonography revealed that she was 11 weeks pregnant. Autopsy confirmed the presence of multiple clot emboli in the proximal pulmonary arteries. Additionally, the histopathological examination showed a massive syncytiotrophoblastic embolism in the lung microcirculation. Microscopic examination of the uterus revealed an exaggerated placental site reaction. In conclusion, this exhaustive post-mortem study describes a previously unreported association between exaggerated placental site reaction and pulmonary trophoblastic embolism, with fatal issue. Forensic pathologists should be aware that a large sampling of the lungs and uterus and examination of both placenta and fetus are needed to achieve this diagnosis. This case study emphasizes the need for further work elucidating pathways of trophoblast deportation.

Published
2021

16. Sentinel Lymph Node in Non-Small Cell Lung Cancer: Assessment of Feasibility and Safety by Near-Infrared Fluorescence Imaging and Clinical Consequences

Author

Florent Stasiak, Joseph Seitlinger, Arthur Streit, Christophe Wollbrett, Juliette Piccoli, Joelle Siat, Guillaume Gauchotte, and Stéphane Renaud

Subjects
Medicine (miscellaneous), lung tumors, occult micrometastases, sentinel lymph node, near-infrared fluorescence, indocyanine green, electromagnetic navigation bronchoscopy
Abstract

Occult micrometastases can be missed by routine pathological analysis. Mapping of the pulmonary lymphatic system by near-infrared (NIR) fluorescence imaging can identify the first lymph node relay. This sentinel lymph node (SLN) can be analyzed by immunohistochemistry (IHC), which may increase micrometastasis detection and improve staging. This study analyzed the feasibility and safety of identifying SLNs in thoracic surgery by NIR fluorescence imaging in non-small cell lung cancer (NSCLC). This was a prospective, observational, single-center study. Eighty adult patients with suspected localized stage NSCLC (IA1 to IIA) were included between December 2020 and May 2022. All patients received an intraoperative injection of indocyanine green (ICG) directly in the peri tumoural area or by electromagnetic navigational bronchoscopy (ENB). The SLN was then assessed using an infrared fluorescence camera. SLN was identified in 60 patients (75%). Among them, 36 SLNs associated with a primary lung tumor were analyzed by IHC. Four of them were invaded by micrometastases (11.1%). In the case of pN0 SLN, the rest of the lymphadenectomy was cancer free. The identification of SLNs in thoracic surgery by NIR fluorescence imaging seems to be a feasible technique for improving pathological staging.

Published
2022
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17. The Implementation of DNA Methylation Profiling into a Multistep Diagnostic Process in Pediatric Neuropathology: A 2-Year Real-World Experience by the French Neuropathology Network

Author

Melanie, Pages, Emmanuelle, Uro-Coste, Carole, Colin, David, Meyronet, Guillaume, Gauchotte, Claude-Alain, Maurage, Audrey, Rousseau, Catherine, Godfraind, Karima, Mokhtari, Karen, Silva, Dominique, Figarella-Branger, Pascale, Varlet, On Behalf Of The Renoclip-Loc Network, GHU Paris Psychiatrie et Neurosciences, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), HAL-SU, Gestionnaire, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Laboratoire de Neuropathologie Raymond Escourolle

Subjects
0301 basic medicine, Oncology, tumor classification, Cancer Research, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathology, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, molecular pathology, Internal medicine, medicine, Copy-number variation, Medical diagnosis, Grading (tumors), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, DNA methylation, business.industry, Molecular pathology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Methylation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Dna methylation profiling, 030104 developmental biology, copy-number variation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, pediatric CNS tumors, integrated diagnosis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery
Abstract

Simple Summary Supported by the “easy-to-use” and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts—including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH—62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ “classifier” and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. Abstract DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores

Published
2021
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18. Late complications of radiosurgery for cerebral arteriovenous malformations: report of 5 cases of chronic encapsulated intracerebral hematomas and review of the literature

Author

François Zhu, Isabelle Buccheit, Olivier Klein, Serge Bracard, Guillaume Gauchotte, Stephanos Finitsis, René Anxionnat, and Valérie Bernier

Subjects
Adult, Intracranial Arteriovenous Malformations, Male, lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, medicine.medical_treatment, lcsh:R895-920, Radiosurgery, Asymptomatic, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Hematoma, Edema, medicine, Humans, Effective treatment, Radiology, Nuclear Medicine and imaging, Cerebral Hemorrhage, business.industry, Research, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cerebral arteriovenous malformations, Radiation therapy, Hemiparesis, Oncology, 030220 oncology & carcinogenesis, Chronic Disease, Female, Radiology, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Chronic encapsulated intracerebral hematomas (CEIHs) are a rare, late complication of radiosurgery for intracranial AVM. We present 5 cases treated mostly by surgical excision and review the literature. Methods Patients (age 39, 42, 36, 31, 62) presented with headache, paresthesia, hemiparesis or were asymptomatic. CEIHs presented 10 to 13 years (median 12 years) post radiosurgery. Three patients had demonstrated early radiation induced changes post radiosurgery. Angiographic cure, assessed with DSA, was present in all cases except 1 case with a small nidus remnant. MRI demonstrated mixed lesions with a solid enhancing part, organized hematoma and extensive surrounding edema while three cases had also a cystic component. Results Excision of the CEIHs with complete or partial removal of the capsule was performed in 4 patients and resulted in marked clinical improvement. One patient was managed conservatively with administration of steroids as surgery was judged excessively hazardous with eventual stabilization of his symptoms. Conclusions CEIHs are rare, late complications of radiosurgery for cranial AVM. They may be asymptomatic or provoke symptoms and may be preceded by early radiation induced changes. Complete removal of CEIHS is an effective treatment. Because of the long latency period of CEIHs, patients who had radiosurgery for brain AVMs should be followed by MRI at least 10 years even after complete obliteration.

Published
2020

19. Integration of dynamic parameters in the analysis of 18F-FDopa PET imaging improves the prediction of molecular features of gliomas

Author

Timothée Zaragori, Luc Taillandier, Véronique Roch, Antoine Verger, Merwan Ginet, Zohra Lamiral, Pierre-Yves Marie, Guillaume Gauchotte, Fabien Rech, Marie Blonski, Laetitia Imbert, Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pathologie [CHRU Nancy], Service de Neurochirurgie [CHRU Nancy], Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), and Service de Neuro-Oncologie [CHRU Nancy]

Subjects
Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Standardized uptake value, Newly diagnosed, 18F-FDopa PET, Independent predictor, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Glioma, Diagnosis, medicine, Dynamic analysis, Radiology, Nuclear Medicine and imaging, neoplasms, business.industry, Area under the curve, General Medicine, Metabolic tumor volume, Pet imaging, medicine.disease, IDH mutation, 3. Good health, Idh mutation, WHO 2016 classification, 030220 oncology & carcinogenesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Purpose: 18F-FDopa PET imaging of gliomas is routinely interpreted with standardized uptake value (SUV)-derived indices. This study aimed to determine the added value of dynamic 18F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas.Methods: We retrospectively included 58 patients having undergone an 18F-FDopa PET for establishing the initial diagnosis of gliomas, whose molecular features were additionally characterized according to the WHO 2016 classification. Dynamic parameters, involving time-to-peak (TTP) values and curve slopes, were tested for the prediction of glioma types in addition to current static parameters, i.e., tumor-to-normal brain or tumor-to-striatum SUV ratios and metabolic tumor volume (MTV).Results: There were 21 IDH mutant without 1p/19q co-deletion (IDH+/1p19q−) gliomas, 16 IDH mutants with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 IDH wildtype (IDH−) gliomas. Dynamic parameters enabled differentiating the gliomas according to these molecular features, whereas static parameters did not. In particular, a longer TTP was the single best independent predictor for identifying (1) IDH mutation status (area under the curve (AUC) of 0.789, global accuracy of 74% for the criterion of a TTP ≥ 5.4 min) and (2) 1p/19q co-deletion status (AUC of 0.679, global accuracy of 69% for the criterion of a TTP ≥ 6.9 min). Moreover, the TTP from IDH− gliomas was significantly shorter than those from both IDH+/1p19q− and IDH+/1p19q+ (p ≤ 0.007).Conclusion: Prediction of the molecular features of newly diagnosed gliomas with 18F-FDopa PET and especially of the presence or not of an IDH mutation, may be obtained with dynamic but not with current static uptake parameters.

Published
2020
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20. Rapid fully-automated assay for routine molecular diagnosis of BRAF mutations for personalized therapy of low grade gliomas

Author

François Doz, Marie Rouyer, Agnès Leroux, Guillaume Gauchotte, Jean-Louis Merlin, Pascal Chastagner, Pascale Varlet, Marie-Sophie Merlin, Pauline Gilson, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Service d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Curie [Paris], Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Oncology, medicine.medical_specialty, business.industry, Hematology, Automated real-time PCR, 3. Good health, BRAF, [SPI.AUTO]Engineering Sciences [physics]/Automatic, 03 medical and health sciences, 0302 clinical medicine, Fully automated, 030220 oncology & carcinogenesis, Internal medicine, Pediatrics, Perinatology and Child Health, molecular diagnosis, medicine, Low-Grade Glioma, Personalized therapy, business, low grade glioma, neoplasms, 030215 immunology
Abstract

International audience; Background: BRAF mutation analysis is important to personalize the management with low-grade gliomas (LGG) in children and adults, with therapeutic and prognostic impacts. In recurrent tumors, targeted therapies such as BRAF inhibitors had been reported to induce disease stabilization and significant radiographic responses. This highlights the potential interest of BRAF mutation to stratify patients for targeted therapy. Standard operating procedures (SOP) for BRAF V600E mutation detection can be time-consuming and consequently delay treatment choice in patients with acute deterioration. Here, we evaluated IdyllaTM fully automated PCR (FA-PCR) assay for the rapid determination of BRAF mutational status in children and adult LGG.Methods: Formalin-fixed and paraffin-embedded (FFPE) samples from three histological LGG subtypes (ganglioglioma, pleomorphic xantoastrocytoma, and dysembryoplastic neuroepithelial tumor) with previous SOP-characterized BRAF mutational status were re-analyzed using the FA-PCR. Overall concordance with the mutational status determined using SOP, as well as sensitivity and specificity of FA-PCR technique were assessed.Results: All 14 samples gave interpretable results with FA-PCR. Overall concordance of BRAF mutational status between FA-PCR and SOP was 100%. Sensitivity and specificity were 100%.Conclusion: This study confirms the reliability of FA-PCR for BRAF mutations analysis in children and adult LGG. Considering the short time to results enabled by FA-PCR, providing results in less than 90 minutes, this technique represents an interesting option for the molecular diagnosis of LGG and personalization of treatment.

Published
2020
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21. Metastatic glioblastoma cells in brain biopsy rinse fluid

Author

Julien Broséus, Delphine Gérard, Carole Humbert, Guillaume Gauchotte, Jean-François Lesesve, Fabien Rech, Service d'Hématologie Biologique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Neurochirurgie [CHRU Nancy], Département d’Anatomie et Cytologie Pathologiques [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Male, Pathology, medicine.medical_specialty, Histology, Biopsy, Cytodiagnosis, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, Pathology and Forensic Medicine, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Aphasia, Cytology, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Aphasia, Broca, medicine.diagnostic_test, business.industry, Brain biopsy, Brain, General Medicine, medicine.disease, Frontal Lobe, 030220 oncology & carcinogenesis, medicine.symptom, Glioblastoma, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience

Published
2019
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22. PDTM-24. PINEOBLASTOMA SEGREGATES INTO MOLECULAR SUBTYPES WITH DISTINCT CLINICOPATHOLOGIC FEATURES: REPORT FROM THE RARE BRAIN TUMOUR CONSORTIUM

Author

Bryan Li, Alexandre Vasiljevic, Christelle Dufour, Ben Ho, Eugene Hwang, Sridharan Gururangan, Jordan Hansford, Annie Laquerriere, Marie-Bernadette Delisle, Jason Fangusaro, Fabien Forest, Nobusawa Sumihito, Helen Toledano, Diane Birks, Xing Fan, Maryam Fouladi, Amar Gajjar, Guillaume Gauchotte, Lindsey Hoffman, Chris Jones, Delphine Loussouarn, Karima Mokhtari, Scott Pomeroy, Audrey Rousseau, Gino Somers, Michael Taylor, David S Ziegler, Mei Lu, Cynthia Hawkins, Richard Grundy, Anne Jouvet, Eric Bouffet, D Ashley Hill, and Annie Huang

Subjects
Cancer Research, Oncology, Pediatric Tumors, Neurology (clinical)
Abstract

BACKGROUND Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Overall survival rates are estimated at 50–70%, with younger patients (< 5 years old) faring much worse (15–40%) despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. METHODS We collected tumor tissue from 93 PB cases diagnosed at their referring centres. We undertook global DNA methylation profiling and performed multiple orthogonal consensus clustering analyses to elucidate PB subgroups. Chromosomal copy number alterations were determined using Conumee and GISTIC2, and whole exome or targeted sequencing was completed. Clinical data was analyzed with correlative statistical methods and outcomes were measured by Kaplan-Meier survival estimates. RESULTS PB comprise five epigenetic groups, designated 1, 2, 3, 4A, and 4B. Deleterious, mutually exclusive alterations affecting miRNA biogenesis pathway members (DICER1, DROSHA, and DGCR8) were observed in 12/21 group 1 and 11/11 group 2 samples. Group 4A was characterized by recurrent RB1 loss and gain of the oncogenic miR-17/92, and group 4B by recurrent gain or amplification of MYC. These groups also exhibit distinct clinical features. PB groups 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent outcome (5-year OS of 71.9–100%). Group 4A and 4B were restricted to much younger children (median age 1.3–1.4 years) and had dismal prognoses (5-year OS 37.5% and 28.6%, respectively). CONCLUSIONS PB divides into five groups with distinct genetic and clinical profiles. These findings will have important implications for precise patient stratification and form the foundation for preclinical studies of biology-informed therapies.

Published
2019

23. Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

Author

Celso Pouget, Sébastien Hergalant, Emilie Lardenois, Stéphanie Lacomme, Rémi Houlgatte, Catherine Carpentier, Caroline Dehais, Fabien Rech, Luc Taillandier, Marc Sanson, Romain Appay, Carole Colin, Dominique Figarella‐Branger, Shyue‐Fang Battaglia‐Hsu, Guillaume Gauchotte, Christine Desenclos, H. Sevestre, Philippe Menei, A. Rousseau, T. Cruel, S. Lopez, M.I. Mihai, A. Petit, R. Seizeur, I. Quintin‐Roué, C. Adam, F. Parker, S. Eimer, H. Loiseau, L. Bekaert, F. Chapon, D. Ricard, C. Godfraind, T. Khallil, D. Cazals‐Hatem, T. Faillot, C. Gaultier, M. C Tortel, I. Carpiuc, P. Richard, W. Lahiani, H. Aubriot‐Lorton, F. Ghiringhelli, C‐A Maurage, E. Le Rhun, E. M. Gueye, F. Labrousse, F. Ducray, D. Meyronet, O. Chinot, L. Bauchet, V. Rigau, P. Beauchesne, M. Campone, D. Loussouarn, D. Fontaine, F. Vandenbos‐Burel, A. Le. Floch, P. Roger, C. Blechet, M. Fesneau, A. Carpentier, A. Idbaih, J. Y. Delattre, K. Mokhtari, F. Bielle, S. Hamdi, M. Polivka, S. Milin, P. Colin, M. D. Diebold, D. Chiforeanu, E. Vauleon, O. Langlois, A. Laquerriere, F. Forest, M. J. Motso‐Fotso, M. Andraud, G. Runavot, B. Lhermitte, G. Noel, S. Gaillard, C. Villa, N. Desse, C. Rousselot‐Denis, I. Zemmoura, E. Cohen‐Moyal, E. Uro‐Coste, F. Dhermain, Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurochirurgie [CHRU Nancy], Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de neurologie [CHRU Nancy], OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
0301 basic medicine, Male, Proliferation index, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 0302 clinical medicine, Research Articles, Aged, 80 and over, Brain Neoplasms, General Neuroscience, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Middle Aged, Prognosis, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Microglial cell activation, Ki-67, Immunohistochemistry, Female, France, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Adult, IDH1, Mitotic index, Oligodendroglioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Postsynaptic specialization, Pathology and Forensic Medicine, 03 medical and health sciences, Young Adult, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Glioma, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Mitotic Index, Humans, Aged, [INFO.INFO-DB]Computer Science [cs]/Databases [cs.DB], Gene Expression Profiling, medicine.disease, Minichromosome Maintenance Complex Component 6, 030104 developmental biology, Ki-67 Antigen, Mutation, biology.protein, Cancer research, Neurology (clinical), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery, Gene Deletion
Abstract

International audience; Anaplastic oligodendroglioma (AO), IDH‐mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high‐grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki‐67, in a large series of IDHmut+/1p19qcodel AO included in the POLA (“Prise en charge des Oligodendrogliomes Anaplasiques”) French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labelling indices (LI) of MCM6 and Ki‐67 were obtained via computer‐assisted color image analyses on immunostained AO tissues of the cohort (n=220). Furthermore, a subgroup of AO (n=68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki‐67 (≥ 15%) correlated with shorter overall survival, both in univariate (P=0.013 and P=0.004, respectively) and multivariate analyses (P=0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki‐67). MCM6 and Ki‐67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro‐neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta‐amyloid binding, and postsynaptic specialization.In conclusion, the overexpression of MCM6 and/or Ki‐67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy‐to‐use and cost‐effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down‐regulated immune response and lower microglial cells activation, and bears pro‐neural phenotype.

Published
2019
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24. Développement et mise en place d’un compte rendu standardisé d’anatomopathologie pour les tumeurs pulmonaires à l’aide d’une application de saisie et d’export des données : l’application PELICAN

Author

Luc Taillandier, Stéphanie Lacomme, Joëlle Siat, Dominique Clauzon, Sandra Lomazzi, Jean-Michel Vignaud, Clémence Yguel, Guillaume Gauchotte, Emilie Lardenois, Département d’Anatomie et Cytologie Pathologiques [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénieur Consultant, Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Service de Chirurgie Thoracique [CHRU Nancy], Service de neurologie [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Philosophy, [SDV]Life Sciences [q-bio], Humanities, 3. Good health, Pathology and Forensic Medicine
Abstract

Resume Introduction L’application PELICAN (« partager efficacement en laboratoire les informations des comptes rendus anatomopathologiques ») est un outil permettant de generer des comptes rendus standardises et de creer des bases de donnees utilisables a visee scientifique. Cette application est utilisee dans notre laboratoire depuis 2014 en neuropathologie tumorale. L’objectif de ce travail etait de l’etendre a un autre type de tumeur, le cancer du poumon. Materiel et methodes Le contenu des comptes rendus etait au prealable defini a l’aide de divers referentiels (Societe francaise de pathologie, institut national du cancer, classification OMS 2015, …). Une double codification SNOMED et ADICAP etait utilisee. L’application PELICAN est un fichier Microsoft Excel comportant un logiciel specifiquement developpe pour les laboratoires, ecrit en Visual Basic pour Applications, et respectant la norme CDA-R2. Resultats Apres etablissement du cahier des charges, une beta-version a ete installee en fevrier 2018. Diverses mises a jour ont ensuite ete realisees, la version 3.19 ayant ete installee en juillet 2018. La quasi-totalite des pieces d’exerese fait ainsi aujourd’hui l’objet d’un compte-rendu genere par l’application PELICAN. Un total de 56 comptes-rendus a ete valide au moment de la redaction de cet article. Par rapport aux comptes rendus classiques, le temps medical de generation du compte rendu est globalement le meme, voire diminue, le temps de secretariat etant quant a lui fortement diminue. Conclusion L’application PELICAN est un outil simple, d’utilisation facile, permettant de generer des comptes rendus standardises en pathologie pulmonaire, alimentant une base de donnees facilement exploitable sur le plan statistique.

Published
2019
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25. PET imaging of 68Ga-NODAGA-RGD, as compared with 18F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma

Author

Pierre-Yves Marie, Sophie Pinel, Fatiha Maskali, Julien Pierson, Sibel Isal, Sylvain Poussier, Guillaume Gauchotte, Aurélie Reinhard, Laetitia Imbert, Charlotte Collet, Steeven Frezier, Alexandra Clément, Gilles Karcher, Nicolas Veran, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)

Subjects
lcsh:Medical physics. Medical radiology. Nuclear medicine, 0301 basic medicine, Biodistribution, Rodent, lcsh:R895-920, Integrin, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, biology.animal, medicine, Radiology, Nuclear Medicine and imaging, Integrin binding, Fluorodeoxyglucose, biology, business.industry, Cell growth, αvβ3 integrin, Pet imaging, medicine.disease, 68Ga-NODAGA-RGD, 18F-FDG, 030104 developmental biology, PET, 030220 oncology & carcinogenesis, biology.protein, Cancer research, business, Glioblastoma, medicine.drug
Abstract

International audience; BackgroundTracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma.MethodsNude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD.ResultsBoth tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density.Conclusions68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

Published
2018
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26. Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma

Author

Dominique Figarella-Branger, Franck Bielle, Clovis Adam, Louis Royer-Perron, Guillaume Gauchotte, David Meyronet, Aurélie Bruno, Chiara Villa, Amithys Rahimian, Blandine Boisselier, Carole Soussain, Fabrice Chrétien, Khê Hoang-Xuan, Caroline Houillier, Sandrine Eimer, Mailys Daniau, Frederic Davi, Karima Mokhtari, Karim Labreche, Justine Guegan, Pierre de la Grange, Agusti Alentorn, Marc Polivka, Audrey Rousseau, Frédéric Lemoine, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], GenoSplice, Ltd, GenoSplice technology, GenoSplice [Paris], iCONICS, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Anatomopathologie [Le Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hospices civils de Lyon, hôpital neurologique Pierre-Wertheimer, Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Pathologie [Hôpital Foch], Hôpital Foch [Suresnes], Centre Hospitalier Sainte Anne [Paris], Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Département de Pathologie Cellulaire et Tissulaire [CHU Angers] (Laboratoire d’Histopathologie-Cytopathologie), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital René HUGUENIN (Saint-Cloud), This work is part of the national program Cartes d’Identité des Tumeurs (CIT) funded and developed by the Ligue nationale contre le cancer, the Institut National du Cancer, Association pour la recherche sur les tumeurs cérébrales (ARTC), Cancéropôle Île-de-France 'Emergence 2015-1' (2015-1-EMERG-05-INSERM 6-1), Ligue nationale contre le cancer (Comité du Val d’Oise, R14044DD), Ligue Nationale contre le cancer 'Recherche épidemiologique' (N° PRE2015.LNCC), Fondation pour la Recherche Médicale (FDT20140930968), and the program 'Investissements d’avenir' ANR-10-IAIHU-06, and the Institut National du Cancer (INCa) (Réseau Expert National LOC, Lymphomes Oculo-Cérébraux). This study was supported by the Lymphomes Oculo-Cérébraux (LOC) study group network (Réseau national de centres experts des lymphomes primitifs du système nerveux central), We would like to thank the French LOC Network investigators. Specimens from Marseille were retrieved from the AP-HM tumor bank AC 2013-1786, ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Incubateur et Pépinière d'Entreprises Paris-Salpêtrière (iPEPS-ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Cancer Research, Oncogene Proteins, Fusion, MESH: Central Nervous System Neoplasms, Fusion gene, Central Nervous System Neoplasms, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Middle Aged, medicine.diagnostic_test, Primary central nervous system lymphoma, RNA sequencing, ETV6-IgH, MESH: Follow-Up Studies, Middle Aged, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Survival Rate, Oncology, fusion gene, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Female, Lymphoma, Large B-Cell, Diffuse, MESH: Biomarkers, Tumor, Haploinsufficiency, Immunoglobulin Heavy Chains, MESH: Immunoglobulin Heavy Chains, MESH: Proto-Oncogene Proteins c-ets, MESH: Survival Rate, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Prognosis, 03 medical and health sciences, primary CNS lymphoma, medicine, Biomarkers, Tumor, Humans, Survival rate, MESH: Humans, Proto-Oncogene Proteins c-ets, medicine.disease, MESH: Male, Lymphoma, haploinsufficiency, Repressor Proteins, ETV6, 030104 developmental biology, Cancer research, Immunoglobulin heavy chain, MESH: Lymphoma, Large B-Cell, Diffuse, Neurology (clinical), MESH: Female, Fluorescence in situ hybridization, Follow-Up Studies, MESH: Oncogene Proteins, Fusion
Abstract

International audience; Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq).Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion.Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion.Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.

Published
2018
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27. EMBR-17. PINEOBLASTOMA SEGREGATES INTO MOLECULAR SUBTYPES WITH DISTINCT CLINICOPATHOLOGIC FEATURES: REPORT FROM THE RARE BRAIN TUMOR CONSORTIUM

Author

Anne Jouvet, Xing Fan, Annie Laquerrière, Guillaume Gauchotte, Richard Grundy, Eugene Hwang, Jason Fangusaro, Michael D. Taylor, Gino R. Somers, Maryam Fouladi, Alexandre Vasiljevic, Fabien Forest, Christelle Dufour, Helen Toledano, Karima Mokhtari, Amar Gajjar, David S. Ziegler, Scott L. Pomeroy, Ben Ho, Marie-Bernadette Delisle, Eric Bouffet, Jordan R. Hansford, Lindsey M. Hoffman, Mei Lu, Sridharan Gururangan, Audrey Rousseau, Delphine Loussouarn, Bryan K. Li, Diane K. Birks, Cynthia Hawkins, Nobusawa Sumihito, Chris Jones, Annie Huang, and Joseph D. Norman

Subjects
Pineoblastoma, Cancer Research, Pathology, medicine.medical_specialty, business.industry, Brain tumor, Methylation, Brain tumor childhood, medicine.disease, Painful Bladder Syndrome, Abstracts, Oncology, medicine, Neurology (clinical), business
Abstract

Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Outcomes remain dismal with long-term survival rates between 10–40% despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. We undertook global methylation profiling of 75 PB cases, and discovered that PBs comprise four molecular sub-types, designated groups 1 to 4 with characteristic copy number alterations and mutational patterns. Molecular sub-groups of PB also exhibited distinct clinical features and survival outcomes. While PBs group 1–3 arose in older children (median ages 5.2–12.6 years), group 4 PB was restricted to much younger children (median age 1.4 years). Group 4 PB exhibited the highest incidence of metastases (53%) and had the worst 5-year event-free survival (EFS) and overall survival (OS), respectively 7.7% and 16.7%. In contrast, group 2 patients had a 5-year EFS and OS of 100%, while group 1 and 3 had intermediate outcomes (68.1%, 53.3% respectively). These findings demonstrate significant clinical and molecular heterogeneity in PB and underscore the critical need to define mechanisms underlying PB, so that precise patient stratification and selection of biology-informed therapies can be undertaken in future clinical trials.

Published
2018

28. A high 18 F-FDOPA uptake is associated with a slow growth rate in diffuse grade II-III gliomas

Author

Sophie Planel, Marie Blonski, Gilles Karcher, Sibel Isal, Antoine Verger, Fabien Rech, Pierre-Yves Marie, Guillaume Gauchotte, Luc Taillandier, Mohammad B. Chawki, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Service de Neuro-Oncologie [CHRU Nancy], Département de neuroradiologie diagnostique et thérapeutique [CHRU Nancy], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and Maquin, Didier

Subjects
business.industry, Standardized uptake value, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Brain tissue, 030218 nuclear medicine & medical imaging, Idh mutation, 03 medical and health sciences, 0302 clinical medicine, 18f fdopa, Isocitrate dehydrogenase, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, Radiology, Nuclear Medicine and imaging, Slow Growth Rate, business, Nuclear medicine, 030217 neurology & neurosurgery
Abstract

International audience; Objective: In diffuse Grade II–III gliomas, a high 3,4-dihydroxy-6-(18F)-fluoro-L-phenylalanine (18F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUVmax)/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18F-FDOPA uptake in diffuse Grade II–III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year.Methods: 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II–III gliomas (17 with IDH mutation) were retrospectively included. All had a 18F-FDOPA PET, quantified with SUVmax ratio, along with a serial MRI enabling VDE determination.Results: SUVmax ratio was above 1.8 in 5 patients (25%) all of whom had a VDE

Published
2018
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29. Interactions between glioma and pregnancy: insight from a 52-case multicenter series

Author

Guillaume Gauchotte, Mélanie Pagès, Fabrice Chrétien, Thierry Lesimple, M. Lopes, Stéphanie Cartalat-Carel, Philippe Menei, Catherine Miquel, Patrick Beauchesne, Philippe Colin, Luc Taillandier, Johan Pallud, Marc Zanello, Jean Stecken, Marc Debouverie, Denys Fontaine, Luc Bauchet, Didier Frappaz, Catherine Oppenheim, Emmanuel Jouanneau, Sophie Peeters, Pascale Varlet, Elisabeth Moyal, Jean-Sébastien Guillamo, Laurence Bozec, Christophe Deroulers, Olivier De Witte, Jean-Yves Delattre, Laurent Capelle, Hugues Duffau, Hospices Civils de Lyon (HCL), Service de Neurophysiologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, medicine.medical_specialty, Malignancy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Glioma, medicine, Humans, Retrospective Studies, [PHYS]Physics [physics], Brain Neoplasms, Vaginal delivery, Obstetrics, business.industry, Pregnancy Outcome, Retrospective cohort study, General Medicine, medicine.disease, Survival Analysis, 3. Good health, Surgery, Natural history, Tumor progression, 030220 oncology & carcinogenesis, Disease Progression, Gestation, Female, business, Pregnancy Complications, Neoplastic, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

OBJECTIVEThe goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk.METHODSIn this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma.RESULTSFor gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal.CONCLUSIONSWhen a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management.■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Published
2018
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30. Impact of uterine balloon tamponade on the use of invasive procedures in severe postpartum hemorrhage

Author

Olivier Morel, E. Gauchotte, Guillaume Gauchotte, E. Perdriolle-Galet, Manuela de la Torre, Catherine Lamy, Service d'Obstétrique et de Gynécologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Anatomie Pathologique [CHRU Nancy], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and BIRKER, Juliette

Subjects
Adult, medicine.medical_specialty, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Uterotonic, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Severity of Illness Index, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Medicine, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Uterine Balloon Tamponade, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, Uterine Hemorrhage, business.industry, Postpartum Hemorrhage, Obstetrics and Gynecology, Retrospective cohort study, Interventional radiology, General Medicine, medicine.disease, Hemostatic technique, 3. Good health, Surgery, Treatment Outcome, Anesthesia, Female, Tamponade, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Introduction The aim of this study was to assess the impact of tamponade when uterotonic agents fail, on the need for surgery or interventional radiology. Material and methods All women who received sulprostone for postpartum hemorrhage were retrospectively compared over two periods [December 2008 to December 2010 without use of tamponade (period 1) and June 2011 to June 2013 with use of tamponade (period 2)] in the case of sulprostone failure (STROBE compliant retrospective cohort study). During period 2, interventional radiology or surgery was used only in the case of tamponade failure. Results 165 women were included (74 for period 1, 91 for period 2). The rate of interventional radiology or surgery significantly decreased from period 1 (21 of 74 women, 28.4%) to period 2 (six of 91 women, 6.6%, p = 0.0003). The rate of assumed failure of uterotonic agents was higher for period 2: 22 of 74 women (29.7%) during period 1, and 41 of 91 (45.1%, p = 0.0439) during period 2. The success rate of tamponade was 92.1% (35 of 38 women). Conclusions Although the efficacy of tamponade should be viewed in the light of its widespread use, our findings confirm that tamponade significantly reduces the need for interventional radiology or surgery for postpartum hemorrhage treatment.

Published
2017
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31. Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Author

Luc Bauchet, Eric Bord, Valérie Rigau, Johan Pallud, Bertrand Muckenstrum, Guillaume Gauchotte, Louis-Marie Terrier, Walid Farah, Patrick François, Isabelle Filipiak, Bertrand Debono, Phong Dam Hieu, Bernard Irthum, Audrey Rousseau, Pierre-Hugues Roche, Catherine Godfraind, Pierre-Jean Le Reste, Marie-Bernadette Delisle, Agnès Caille, Philippe Metellus, Stéphane Velut, Alain Czorny, Anne-Marie Bergemer-Fouquet, Philippe Menei, D. Liguoro, Michel Wager, Marie-Hélène Aubriot-Lorton, Emmanuel Mandonnet, Pascale Varlet, Jimmy Voirin, Serge Milin, Sonia Zouaoui, Kevin Janot, Ilyess Zemmoura, Hugues Loiseau, Jacques Guyotat, Marc Zanello, Philippe Cornu, Evelyne Emery, Aymeric Amelot, Vincent Lubrano, Guillaume Lot, Fabien Almairac, Dominique Figarella-Branger, Anne Vital, Emmanuelle Uro-Coste, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [CHU Dijon], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Kastler Brossel (LKB (Lhomond)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cellules souches leucémiques et thérapeuthiques, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Sorbonne Paris Cité (USPC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Archimedes Pharma®, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), CIC 1415, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Francois Rabelais [Tours], Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [Rouen], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de neurochirurgie [CHU de Dijon], Université Catholique de Louvain (UCL)-Clinique Saint-Luc, Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Département de Neurochirurgie [CHU Toulouse], Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Clinical Investigations, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Ganglioglioma, cerebral malignancy, surgery, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Progression-free survival, Pathological, Survival rate, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Intracranial pressure, Brain Neoplasms, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Anaplastic Ganglioglioma, Disease Progression, Female, Neurology (clinical), Radiology, prognosis, business, 030217 neurology & neurosurgery, anaplastic ganglioglioma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; Background - Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods - Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results - Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions - We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Published
2017
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32. Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma

Author

Jean-Louis Guéant, Amandine Luc, Charlène Vigouroux, Shyue-Fang Battaglia-Hsu, Jean-Matthieu Casse, Stéphanie Lacomme, Christophe Paris, Jean-Michel Vignaud, Lydia Brochin, Guillaume Gauchotte, Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Interactions Gènes-Risques environnementaux et Effets sur la Santé (INGRES), Université de Lorraine (UL), and Centre de Ressources Biologiques - [Nancy] (CRB Nancy)

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Cancer Research, Pathology, medicine.medical_specialty, Lung Neoplasms, RNA-binding protein, Kaplan-Meier Estimate, Methylation, ELAV-Like Protein 1, Carcinoma, Non-Small-Cell Lung, microRNA, Biomarkers, Tumor, medicine, Carcinoma, Humans, Lung cancer, ComputingMilieux_MISCELLANEOUS, Aged, Neoplasm Staging, Aged, 80 and over, biology, MCM6, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Minichromosome Maintenance Complex Component 6, [STAT]Statistics [stat], Protein Transport, Oncology, Ki-67, Cancer research, biology.protein, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined.Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR.Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p0.0001 and p0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p0.0001), but only miR519 correlated inversely to HuR expression (p=0.01).While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC.

Published
2015
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33. Evidence for BRAF V600E and H3F3A K27M double mutations in paediatric glial and glioneuronal tumours

Author

Dominique Figarella-Branger, François Labrousse, Anh Tuan Nguyen, Emmanuelle Uro-Coste, Laetitia Padovani, Isabelle Nanni-Metellus, Catherine Miquel, Anne Jouvet, Catherine Godfraind, Carole Colin, Claude-Alain Maurage, Pascale Varlet, Emmanuelle Lechapt-Zalcman, Guillaume Gauchotte, Karen Silva, Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Transfert d’Oncologie Biologique, APHM, Hôpital Nord, Hôpital Nord [CHU - APHM], Service de Radiothérapie, APHM, Hôpital de la Timone, Marseille, Institut de Pathologie, Centre de Biologie Pathologie Génétique, CS 70001, CHRU de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Service de Neuropathologie [Hôpital Sainte-Anne, Paris], Hôpital Sainte Anne, Université Paris Descartes - Paris 5 (UPD5), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), nserm U823, Institut Albert-Bonniot, Département de Pathologie, Université Joseph-Fourier, Grenoble, Institut National de la Santé et de la Recherche Médicale (INSERM), Hypoxie, physiopathologies cérébrovasculaire et tumorale (CERVOxy), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Service d’Anatomie Pathologique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Pathologie et de Neuropathologie Est, Hospices civils de Lyon, Lyon, Franc, Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Inserm, U837, Université Lille – Nord-de-France, Lille, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Neuropathologie, Hôpital Sainte-Anne, Université Paris Descartes - Paris 5 ( UPD5 ), Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hypoxie, physiopathologies cérébrovasculaire et tumorale ( CERVOxy ), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales ( ISTCT ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Anatomie Pathologique [Caen], Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)

Subjects
Pathology, medicine.medical_specialty, Histology, [ SDV ] Life Sciences [q-bio], business.industry, [SDV]Life Sciences [q-bio], Pathology and Forensic Medicine, BRAF V600E, Text mining, Neurology, Physiology (medical), DNA Mutational Analysis, Mutation (genetic algorithm), Cancer research, Medicine, Neurology (clinical), business, ComputingMilieux_MISCELLANEOUS
Abstract

CERVOXY COLL; International audience

Published
2015
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34. Predictors of respiratory epithelial adenomatoid hamartomas of the olfactory clefts in patients with nasal polyposis

Author

Fabien Arous, Jean Michel Vignaud, Phi-Linh Nguyen-Thi, Guillaume Gauchotte, Roger Jankowski, D.T. Nguyen, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Epidémiologie et Evaluations Cliniques [CHRU Nancy] (Pôle S2R), Service de Pathologie [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Médecine [Nancy], and Université de Lorraine (UL)

Subjects
Adult, Male, medicine.medical_specialty, Hamartoma, [SDV]Life Sciences [q-bio], Nasal Surgical Procedures, Nose Neoplasms, Respiratory Tract Diseases, Disease, Respiratory Mucosa, Logistic regression, Gastroenterology, Risk Assessment, Statistics, Nonparametric, Cohort Studies, Tertiary Care Centers, Age Distribution, Nasal Polyps, Predictive Value of Tests, Reference Values, Internal medicine, medicine, Humans, In patient, Prospective Studies, Respiratory system, Sex Distribution, Prospective cohort study, Pathological, Asthma, business.industry, Incidence, Confounding, Biopsy, Needle, Middle Aged, medicine.disease, Prognosis, Immunohistochemistry, Olfactory Bulb, 3. Good health, Surgery, Logistic Models, Treatment Outcome, Otorhinolaryngology, Multivariate Analysis, Female, business
Abstract

Objectives/Hypothesis To look for predictors of respiratory epithelial adenomatoid hamartomas (REAH) development in patients operated for nasal polyposis (NP) by adjusting on confounding factors. Study Design Prospective study. Methods One hundred and six patients with NP, endoscopically operated between September 2009 and March 2012 on the ethmoidal labyrinths and olfactory clefts, were enrolled in this study. Clinical data was collected 1 day prior to surgery by using a standard grid without knowledge of any histological features. Patients were then divided into two groups based on operative and pathological reports: with and without REAH in the olfactory cleft (REAH-OC). The multivariate logistic regression model was used to assess independent factors linked to the presence of REAH-OC in patients with NP. Results The mean duration of NP disease in patients with REAH-OC was about 13.95 ± 10.8 years versus 5.7 ± 5.6 years in patients without REAH-OC (P

Published
2014
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35. P17.09PCV CHEMOTHERAPY IMMEDIATELY FOLLOWED BY RADIOTHERAPY IN DIFFUSE LOW GRADE GLIOMAS - ABOUT A SERIES OF 12 PATIENTS

Author

C. Lacroix, Guillaume Gauchotte, Luc Taillandier, Marie Blonski, T. Bastogne, Jean-Marie Moureaux, M. Ben Abdallah, P. Manceau, P. Nguyen Thi-Lambert, and K. Hassani

Subjects
Cancer Research, medicine.medical_specialty, Vincristine, Chemotherapy, Temozolomide, business.industry, medicine.medical_treatment, Procarbazine, medicine.disease, Chemotherapy regimen, Surgery, Radiation therapy, Poster Presentations, Oncology, Quality of life, medicine, Neurology (clinical), Radiology, business, Stroke, medicine.drug
Abstract

INTRODUCTION: PCV (procarbazine, CCNU, vincristine) chemotherapy was the first association evaluated in diffuse low grade gliomas (DLGGs). Impact of temozolomide and PCV was previously assessed on growth kinetics. Nevertheless, there are no data concerning the growth kinetics of DLGGs after PCV immediately followed by radiotherapy. METHODS: We retrospectively selected patients with histological diagnosis of DLGGs from a french neuro-oncological center (Nancy) who benefited from PCV chemotherapy immediately followed by conventional radiotherapy. Clinical, neuroimaging (kinetics), pathological and molecular data were recorded. RESULTS: Twelve patients with a median age at diagnosis of 37,9 years (range 24 to 56) were selected. The median follow-up was 17,9 years (range 12,6 to 22,31). The median number of PCV cycles was 5 (range 2 to 6). The median time between the end of PCV chemotherapy and the beginning of the radiotherapy was 2,6 months (range 1 to 5). The median dose of radiotherapy was 54 Gy (range 54 to 60). During the follow-up period, 3 patients died and 3 patients presented anaplastic transformation (median time to transformation 12 years, range 11,8 to 14). The median survival was 18 years (range 12,6 to “not reached”). 2 patients developed severe neurocognitive deficits (dementia) and 1 patient presented a postradiation stroke. 10 DLGG patients had IDH1 R132H mutation, 5 patients showed a surexpression of P53 and 5 expressed alpha-internexin. Before treatment combining PCV and radiotherapy, the median spontaneous growth kinetics was 4,03 mm per year (range 2,32 to 11,26). After the combined treatment, the growth kinetics remain negative in 10 patients with a median of -1,72mm/year (range -5,36 to 1,92). The median duration of negative kinetics was 8,8 years (range 0 to 16,6). CONCLUSIONS: Despite this limited series, we reported growth kinetics data on the synergy of PCV and radiotherapy in DLGGs. The prolonged response seems longer than previous data obtained with PCV alone (median of 2,7 years). Specific neurocognitive and quality of life data will be collected.

Published
2014

36. BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer

Author

Marius Ilie, Elodie Long-Mira, Xavier Hébuterne, Paul Hofman, Jean-Philippe Merlio, Jean-François Emile, Guillaume Gauchotte, Jean-Michel Vignaud, Hugues Begueret, Jérôme Mouroux, Véronique Hofman, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Human Biobank CHUN, Hôpital Pasteur [Nice] (CHU), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], L'Association pour la Recherche contre le Cancer (ARC), Service de Chirurgie thoracique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de pathologie [Hôpital Haut Lévêque], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service de gastroentérologie, and Hôpital l'Archet

Subjects
Oncology, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, endocrine system diseases, Colorectal cancer, [SDV]Life Sciences [q-bio], Population, DNA Mutational Analysis, Adenocarcinoma, medicine.disease_cause, Sensitivity and Specificity, Pathology and Forensic Medicine, symbols.namesake, BRAFV600E mutation, Internal medicine, medicine, Biomarkers, Tumor, Humans, skin and connective tissue diseases, education, neoplasms, Aged, Sanger sequencing, Aged, 80 and over, education.field_of_study, business.industry, Antibodies, Monoclonal, Middle Aged, Thoracic Neoplasms, medicine.disease, Prognosis, targeted therapy, digestive system diseases, 3. Good health, enzymes and coenzymes (carbohydrates), Monoclonal, immunohistochemistry, Cancer research, Mutation testing, symbols, Immunohistochemistry, Female, KRAS, business, Colorectal Neoplasms, V600E, metastatic colorectal carcinoma
Abstract

The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non-BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients.

Published
2014
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37. Primary Cerebral Alveolar Echinococcosis: Mycology to the Rescue

Author

Marie Machouart, Gérald Umhang, Franck Boué, Thierry May, François Goehringer, Anne Debourgogne, Guillaume Gauchotte, Sandrine Henard, Stress, Immunité, Pathogènes (SIMPA), Université de Lorraine (UL), Service de Parasitologie-Mycologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Microbiology (medical), Male, Pathology, medicine.medical_specialty, Echinococcosis, Hepatic, Biopsy, Foxes, Strains, Alveolar echinococcosis, Case Reports, Biology, Polymerase Chain Reaction, Serology, X ray computed, Echinococcosis, medicine, Molecular diagnostic techniques, Humans, Favorable outcome, Brain Diseases, Microscopy, Ribosomal DNA, medicine.diagnostic_test, Histocytochemistry, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Multilocularis, 3. Good health, Tomography x ray computed, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Diagnostic Techniques, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tomography, X-Ray Computed
Abstract

A case of primary cerebral alveolar echinococcosis with a favorable outcome is reported. A universal fungal PCR enabled this diagnosis, while the initial serological analysis remained noncontributive.

Published
2014
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38. CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features

Author

Jean-Louis Guéant, Christelle Clément-Duchêne, Rania Elakoum, Marie-Pierre Wissler, Jean-Michel Vignaud, Abderrahim Oussalah, Guillaume Gauchotte, Farès Namour, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Male, Protein-Arginine N-Methyltransferases, Lung Neoplasms, CARM1, PRMT1, [SDV]Life Sciences [q-bio], Cell, Proliferation, Neuromedin B receptor, Biology, Biochemistry, Cytokeratin, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Humans, RNA, Small Interfering, Lung cancer, Aged, Neoplasm Staging, Regulation of gene expression, Cell growth, Keratin-8, Keratin-7, Cancer, General Medicine, medicine.disease, Survival Analysis, Gene Expression Regulation, Neoplastic, Receptors, Bombesin, Repressor Proteins, medicine.anatomical_structure, siRNA, Cancer research, Female
Abstract

International audience; CARM1 and PRMT1 are 2 Protein Arginine Methyl Transferases (PRMT) dysregulated in cancer. CARM1 function is contradictory and depicted as facilitating proliferation or differentiation. PRMT1 is required for cell proliferation. CARM1 and PRMT1 cooperate for gene regulation. We report that CARM1 and PRMT1 are significantly overexpressed in 60 patients with Non-Small Cell Lung Carcinomas (NSCLC). CARM1 and PRMT1 correlated in healthy but not tumor tissue. Their levels of expression in tumor tissue were proportional to their levels of expression in the counterpart healthy tissue. Only CARM1 expression was found to be correlated with tumor differentiation and neither CARM1 nor PRMT1 expression was correlated with survival. Accordingly, CARM1 and PRMT1 are overexpressed in 2 NSCLC cell lines, A549 and H1299. Targeting PRMT1 with siRNA reduced proliferation, by decreasing cell growth and inhibiting soft agar colony formation, and promoted differentiation, by increasing the epithelial markers cytokeratin 7 and 8 and decreasing Neuromedin B receptor, which binds a mitogenic factor. siCARM1 yielded similar consequences but the conditions with siCARM1 reflected inhibition of both CARM1 and PRMT1. Together these results suggest that CARM1 and PRMT1 are involved in proliferation in lung cancer with no hierarchy of one protein over the other. The fact that CARM1 targeting suppresses PRMT1 in addition to CARM1 reinforces the functional importance of CARM1/PRMT1 interaction.

Published
2014
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39. Does surgery of the olfactory clefts modify the sense of smell?

Author

Guillaume Gauchotte, Phi-Linh Nguyen-Thi, Roger Jankowski, Duc Trung Nguyen, Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)

Subjects
Adult, Male, Natural Orifice Endoscopic Surgery, Olfactory system, medicine.medical_specialty, Hamartoma, [SDV]Life Sciences [q-bio], Nasal Surgical Procedures, Olfaction, Hospitals, University, 03 medical and health sciences, Nasal Polyps, 0302 clinical medicine, Ethmoid Sinus, Eosinophilic, medicine, otorhinolaryngologic diseases, Humans, Immunology and Allergy, Prospective Studies, 030223 otorhinolaryngology, Prospective cohort study, Asthma, business.industry, Ethmoidectomy, Histology, General Medicine, Middle Aged, medicine.disease, Olfactory Bulb, Surgery, Smell, Treatment Outcome, Otorhinolaryngology, 030220 oncology & carcinogenesis, Female, business
Abstract

Background The olfactory outcome after surgery of polyps in the olfactory clefts (OCs) is unknown. This study was designed to (1) investigate the relationship between clinical characteristics and the presence of the respiratory epithelial adenomatoid hamartoma (REAH) in the OCs and (2) assess the olfactory outcome after surgery in the OC for either eosinophilic polyps (EP) or REAH in patients with ethmoidectomy for nasal polyposis (NP). Methods Seventy-four patients with NP having undergone nasalization procedure were enrolled in this prospective study. The OCs were systematically examined during endoscopic surgery. Small polyps or edematous mucosa of the OC were systematically biopsied. Moderate or big polyps in the OC were removed after nasalization of the ethmoidal labyrinths. The distinction between REAH and EP relied on histopathological examinations. The olfactory function was measured with standardized odor threshold and identification tests 1 day before and 6 weeks after surgery. Results There was a close relationship between the presence of REAH-OC and the duration of NP disease (p = 0.0009), asthma (p = 0.004), and previous surgery (p = 0.0006). Before surgery, 90.6% of patients with REAH-OC were hypo-anosmic in contrast with one-half of patients having EP-OC (p = 0.0003). Predictors of poor olfactory outcomes after surgery were long-standing nasal symptoms (p = 0.027), history of previous surgery (p = 0.01), and history of previous middle turbinates resection (p = 0.0006). Polyp histology and surgery of the OC were not predictors of poor olfactory outcomes. Conclusion The resection of REAH or EP of the OC in patients with NP does not worsen but instead can improve the sense of smell after surgery.

Published
2013
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40. Decreased vitamin B12 availability induces ER stress through impaired SIRT1-deacetylation of HSF1

Author

Carole Arnold, Shyue-Fang Battaglia-Hsu, Pooya S, Rose Ghemrawi, Guillaume Gauchotte, Jean-Louis Guéant, Lorentz S, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), and University of KwaZulu-Natal (UKZN)

Subjects
Cancer Research, Thapsigargin, [SDV]Life Sciences [q-bio], Immunology, Biological Availability, HSF1, Endoplasmic Reticulum, Epigenesis, Genetic, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, 0302 clinical medicine, SIRT1, Heat Shock Transcription Factors, Sirtuin 1, Cell Line, Tumor, Animals, RNA, Small Interfering, 030304 developmental biology, Methionine synthase activity, acetylation, Cell Proliferation, 0303 health sciences, biology, ATF6, Chimera, Endoplasmic reticulum, Biological Transport, Cell Biology, Transfection, vitamin B12, Endoplasmic Reticulum Stress, Cell biology, DNA-Binding Proteins, Vitamin B 12, chemistry, biology.protein, Unfolded protein response, Original Article, methylation, Signal transduction, ER stress, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, Molecular Chaperones, Signal Transduction, Transcription Factors
Abstract

International audience; Vitamin B12 (cobalamin) is a key determinant of S-adenosyl methionine (SAM)-dependent epigenomic cellular regulations related to methylation/acetylation and its deficiency produces neurodegenerative disorders by elusive mechanisms. Sirtuin 1 deacetylase (SIRT1) triggers cell response to nutritional stress through endoplasmic reticulum (ER) stress. Recently, we have established a N1E115 dopaminergic cell model by stable expression of a transcobalamin-oleosin chimera (TO), which impairs cellular availability of vitamin B12, decreases methionine synthase activity and SAM level, and reduces cell proliferation. In contrast, oleosin-transcobalamin chimera (OT) does not modify the phenotype of transfected cells. Presently, the impaired cellular availability of vitamin B12 in TO cells activated irreversible ER stress pathways, with increased P-eIF-2α, P-PERK, P-IRE1α, ATF6, ATF4, decreased chaperon proteins and increased pro-apoptotic markers, CHOP and cleaved caspase 3, through reduced SIRT1 expression and consequently greater acetylation of heat-shock factor protein 1 (HSF1). Adding either B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 dramatically reduced the activation of ER stress pathways in TO cells. Conversely, impairing SIRT1 and HSF1 by siRNA, expressing a dominant negative form of HSF1, or adding a SIRT1 inhibitor led to B12-dependent ER stress in OT cells. Addition of B12 abolished the activation of stress transducers and apoptosis, and increased the expression of protein chaperons in OT cells subjected to thapsigargin, a strong ER stress stimulator. AdoX, an inhibitor of methyltransferase activities, produced similar effects than decreased B12 availability on SIRT1 and ER stress by a mechanism related to increased expression of hypermethylated in cancer 1 (HIC1). Taken together, these data show that cellular vitamin B12 has a strong modulating influence on ER stress in N1E115 dopaminergic cells. The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.

Published
2013
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41. Sclerosing nodular lesions of the gastrointestinal tract containing large numbers of IgG4 plasma cells

Author

Guillaume Gauchotte, Abbas Agaimy, Runjan Chetty, Bruno Märkl, and Stefano Serra

Subjects
Male, Pathology, medicine.medical_specialty, Gastrointestinal Diseases, Population, Plasma Cells, Inflammation, Plasma cell, Biology, Granuloma, Plasma Cell, Pathology and Forensic Medicine, Autoimmune Diseases, Fibrosis, Colon, Sigmoid, medicine, Humans, Intestinal Mucosa, education, Cecum, Autoimmune disease, education.field_of_study, Gastrointestinal tract, Sclerosis, Stomach, Middle Aged, medicine.disease, medicine.anatomical_structure, Granuloma, Immunoglobulin G, Immunohistochemistry, Female, medicine.symptom
Abstract

Summary Background Hyalinised fibrous nodules have been encountered within the gastrointestinal tract (GIT) and been labelled as reactive nodular fibrous tumours. Several have a history of abdominal surgery and/or sepsis that acts as a precipitating cause for the fibrosis. Recently, much attention has been focused on IgG4 related fibrosing lesions that are typically associated with a high population of IgG4 positive plasma cells and tissue fibrosis. There may be attendant elevated serum IgG4 levels and associated autoimmune disease. Methods We present four patients with well-circumscribed fibrous nodular lesions occurring in the GIT Tissue was formalin fixed after microwave antigen retrieval and H&E stains and immunohistochemistry were performed. IgG4/ IgG ratios were calculated from the three high power fields containing the densest concentration of positive plasma cells. Results The patients were two females (45 and 56 years) and two males (47 and 60 years) who presented with gastric (2 cases), caecal and sigmoid flexure involvement. One case had four lesions while the other three cases were solitary nodules. Two patients had coexistent autoimmune disease. All lesions were nodular and composed of paucicellular, hyalinised fibrous tissue associated with chronic inflammation. In all lesions the plasma cell population was strongly IgG4 positive. Conclusions This paper describes unique, well-circumscribed sclerosing nodules containing IgG4 positive plasma cells within the bowel wall that may cause mucosal polypoid lesions. It is possible that these lesions may be related to the spectrum of IgG4 related sclerosing disease or belong to a separate subset of inflammatory reactive conditions that are rich in IgG4 plasma cells.

Published
2011

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