Publications by authors named "Florence Renaud"

45 Publications

Limited Resection Versus Pancreaticoduodenectomy for Duodenal Gastrointestinal Stromal Tumors? Enucleation Interferes in the Debate: A European Multicenter Retrospective Cohort Study.

Ann Surg Oncol 2021 Apr 10. Epub 2021 Apr 10.

Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, CHU de Lille, Lille, France.

Background: The optimal surgical procedure for duodenal gastrointestinal stromal tumors (D-GISTs) remains poorly defined. Pancreaticoduodenectomy (PD) allows for a wide resection but is associated with a high morbidity rate.

Objectives: The aim of this study was to compare the short- and long-term outcomes of PD versus limited resection (LR) for D-GISTs and to evaluate the role of tumor enucleation (EN).

Methods: In this retrospective European multicenter cohort study, 100 patients who underwent resection for D-GIST between 2001 and 2013 were compared between PD (n = 19) and LR (n = 81). LR included segmental duodenectomy (n = 47), wedge resection (n = 21), or EN (n = 13). The primary objective was to evaluate disease-free survival (DFS) between the groups, while the secondary objectives were to analyze the overall morbidity and mortality, radicality of resection, and 5-year overall survival (OS) and recurrence rates between groups. Furthermore, the short- and long-term outcomes of EN were evaluated.

Results: Baseline characteristics were comparable between the PD and LR groups, except for a more frequent D2 tumor location in the PD group (68.3% vs. 29.6%; p = 0.016). Postoperative morbidity was higher after PD (68.4% vs. 23.5%; p < 0.001). OS (p = 0.70) and DFS (p = 0.64) were comparable after adjustment for D2 location and adjuvant therapy rate. EN was performed more in American Society of Anesthesiologists (ASA) stage III/IV patients with tumors < 5 cm and was associated with a 5-year OS rate of 84.6%, without any disease recurrences.

Conclusions: For D-GISTs, LR should be the procedure of choice due to lower morbidity and similar oncological outcomes compared with PD. In selected patients, EN appears to be associated with equivalent short- and long-term outcomes. Based on these results, a surgical treatment algorithm is proposed.
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http://dx.doi.org/10.1245/s10434-021-09862-7DOI Listing
April 2021

Adalimumab and myositis: A case report and review of the French and international Pharmacovigilance Databases.

Neuromuscul Disord 2020 11 20;30(11):915-920. Epub 2020 Sep 20.

Centre régional de PharmacoVigilance, service de pharmacologie médicale, CHU Lille, 1, place de Verdun, F-59000 Lille, France.

TNFα inhibitors, including adalimumab, are widely used in inflammatory rheumatologic and bowel diseases. Well-known adverse effects include: opportunistic infections, immunogenicity and new inflammatory manifestations. Myositis is an inflammatory disease, which manifests with muscle symptoms and can be life-threatening. Little is known about drug-induced myositis. We aimed to describe a case of myositis induced by adalimumab and reviewed national and international pharmacovigilance databases for other cases until 01/02/2019. This was a 63 years old woman with Crohn's disease, who developed muscle weakness, and rhabdomyolysis 3 months after starting adalimumab. Diagnosis of myositis was suspected and confirmed with electromyography and muscle biopsy. Improvement in muscle symptoms was observed after stopping adalimumab and starting corticosteroids. Muscular adverse effects are well-known and usually benign with adalimumab. However, five cases of myositis during treatment with adalimumab were registered in French PharmacoVigilance Database (FPVD) with muscle symptoms observed 3 months to 7 years after starting adalimumab. In VigiBase, 90 cases of myositis associated with adalimumab with some similar characteristics were registered. When a patient treated with adalimumab complains of muscular symptoms, inflammatory myopathies should be considered. This adverse effect should be mentioned in a 'Summary of Product Characteristics' to alert healthcare professionals.
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http://dx.doi.org/10.1016/j.nmd.2020.09.026DOI Listing
November 2020

Extended myositis-specific and -associated antibodies profile in systemic sclerosis: A cross-sectional study.

Joint Bone Spine 2021 01 9;88(1):105048. Epub 2020 Jul 9.

Univ. Lille, U1286 - Infinite - Institute for Translational Research in Inflammation, 59000 Lille, France; Inserm, U1286, 59000 Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), 59000 Lille, France. Electronic address:

Objective: In systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), auto-antibodies are used in daily practice as potent biomarkers of clinical phenotypes. This study aimed at estimating the prevalence of myositis-specific (MSA) and myositis-associated (MAA) auto-antibodies in a well-characterised SSc patients cohort using two different immunoblot assays, and studying their clinical associations.

Methods: In this cross-sectional study, the sera of 300 consecutive patients were tested at the same time with myositis antibodies Euroimmun® and D-tek® immunoblot assays.

Results: Prevalence of MSA/MAA, MSA and MAA were 17.0%, 8.0% and 9.7%, respectively. When combining results of both tests, anti-PM/Scl 100 were found in 5.0% (95% confidence interval 2.8; 8.1); anti-PM/Scl 75 and anti-TIF1γ in 3.7% (1.8; 6.5); anti-Ku 3.0% (1.4; 5.6); anti-MDA5 in 1.3% (0.4; 3.4); anti-Mi-2 β, anti-NXP2, anti-PL-7 and anti-SRP in 0.7% (0.08; 2.4); anti-EJ and anti-PL-12 in 0.3% (0.01; 1.8) of patients. No reactivity against SAE1, Jo-1 or OJ was observed. Anti-PM/Scl 75 antibodies were associated with interstitial lung disease (80% vs. 42%) and myositis (27% vs. 3%); anti-Ku antibodies were associated with myositis (33% vs. 3%).

Conclusion: In this cross-sectional study of 300 SSc patients, the prevalence of MSA/MAA, MSA and MAA using immunoblot assays were 17.0%, 8.0% and 9.7%, respectively. MAA positivity was associated with ILD and myositis, but this study did not highlight any clinical associations with MSA positivity.
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http://dx.doi.org/10.1016/j.jbspin.2020.06.021DOI Listing
January 2021

Confirmation of risk of cancer in blepharocheilodontic syndrome.

Genet Med 2020 10 2;22(10):1727-1728. Epub 2020 Jun 2.

Université de Lille, EA7364 RADEME, Lille, France.

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http://dx.doi.org/10.1038/s41436-020-0849-7DOI Listing
October 2020

The amount of signet ring cells is significantly associated with tumour stage and survival in gastric poorly cohesive tumours.

J Surg Oncol 2020 Jun 9;121(7):1084-1089. Epub 2020 Mar 9.

Unit of General and Upper GI Surgery, Università degli studi di Verona, Verona, Italy.

Background And Objectives: The aim of this study was to evaluate whether the amount of signet ring cells (SRCs) affects clinicopathological characteristics and prognosis of poorly cohesive (PC) gastric tumours.

Study Design: One hundred seventy-three patients with PC tumours treated at three European centres from 2004 to 2014 were reclassified in three categories: (a) pure SRC cancers (SRC1) (≥90% SRCs); (b) PC carcinoma with SRC component (SRC2) (>10%, <90% SRCs); (c) PC carcinoma not otherwise specified (SRC3) (≤10% SRCs).

Results: The percentage of SRCs was inversely related to the pT stage (Spearman's ρ = -0.174, P < .001) and the number of positive nodes coded as a continuous variable (P = .009). Five year cancer-related survival was significantly higher (58%, 95% confidence interval [CI]: 36%-75%) in SRC1 compared with SRC2 (39%, 95% CI: 28%-50%) and SRC3 (38%, 95% CI: 22%-53%), (P = .048). In multivariable analysis, the impact of PC categories on cancer-related survival was significant when controlling for sex, age, pT, pN, and curativity (hazard ratio [HR] of sSRC2 vs SRC1 = 2.08, 95% CI: 1.01-4.29, P = .046; HR of SRC3 vs SRC1 = 2.38, 95% CI: 1.05-5.41, P = .039).

Conclusion: The percentage of SRCs was inversely related to tumour aggressiveness, with long-term survival significantly higher in SRC1 compared with SRC2 and SRC3 tumours.
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http://dx.doi.org/10.1002/jso.25885DOI Listing
June 2020

[Hereditary gastric cancer: Challenges for the pathologist in 2020].

Ann Pathol 2020 Apr 5;40(2):95-104. Epub 2020 Mar 5.

Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.

Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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http://dx.doi.org/10.1016/j.annpat.2020.02.007DOI Listing
April 2020

Multicystic peritoneal mesothelioma: a systematic review of the literature.

Pleura Peritoneum 2019 Sep 25;4(3):20190024. Epub 2019 Sep 25.

Claude Huriez University Hospital, Lille, France.

Multicystic peritoneal mesothelioma (MCPM) is a particularly rare and benign neoplasm that arises from the peritoneum in reproductive aged females. Its etiopathogenesis is still unclear. The current prevailing theory supports the idea that the tumor is the result of an excessive inflammatory process. Because of a lack of clinical and imaging presentation, the diagnosis is intricate, and heavily relies on case reports and short studies. A histological analysis with immunohistochemistry is required for a definitive diagnosis. To date, there is no standard treatment recommended for MCPM. However, some studies suggest proceeding with a cytoreductive surgery and a hyperthermic intraperitoneal chemotherapy combining CISPLATIN and DOXORUBICIN, due to a high incidence of recurrence rate after medical treatment or surgery alone and potential malignant transformation.
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http://dx.doi.org/10.1515/pp-2019-0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812218PMC
September 2019

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation.

Hum Mutat 2020 01 15;41(1):17-37. Epub 2019 Sep 15.

Department of translational medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.

Calcium (Ca ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca entry, storage, and release. Store-operated Ca entry (SOCE) is a major mechanism controlling extracellular Ca entry, and mainly relies on the accurate interplay between the Ca sensor STIM1 and the Ca channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.
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http://dx.doi.org/10.1002/humu.23899DOI Listing
January 2020

Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant.

Brain Pathol 2020 01 14;30(1):179-190. Epub 2019 Aug 14.

Institute of Pathology, Centre de Biologie Pathologie, Lille University Hospital, Lille, F-59000, France.

Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.
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http://dx.doi.org/10.1111/bpa.12768DOI Listing
January 2020

The role of trait emotional intelligence in quality of life, anxiety and depression symptoms after surgery for esophageal or gastric cancer: A French national database FREGAT.

Psychooncology 2019 04 27;28(4):799-806. Epub 2019 Feb 27.

Affective and Cognitive Sciences, University Lille, UMR CNRS 9193-SCALab, Villeneuve d'Ascq Cedex, France.

Objective: The main objective was to test the indirect effects of emotional competence (EC) after diagnosis (T1) on the health-related quality of life (HRQoL) after surgery (T2) of esogastric cancer patients via fewer anxiety and depression symptoms (T2).

Methods: Data were collected from 30 French centers via the clinicobiological database French EsoGastric Tumors (FREGAT). Two hundred and twenty-eight participants completed a self-reported questionnaire at T1 and T2, assessing their EC (Profile of Emotional Competence (PEC)), HRQoL (EORTC Quality of Life Questionnaire-Core (QLQ-C30)), and anxiety and depression symptoms (Hospital Anxiety and Depression Scale (HADS)). Regression analyses were used to test the direct effects of intrapersonal and interpersonal EC on their anxiety/depression symptoms and HRQoL at T1 and T2. The PROCESS Macro in SPPS v.22 with bootstrap methods was used to test the indirect effects of intrapersonal and interpersonal EC at T1 on HRQoL at T2 via anxiety and depression symptoms.

Results: EC predicted fewer anxiety and depression symptoms of patients at T1 and T2 and better HRQoL at T1. EC at T1 also predicted a better HRQoL at T2 via fewer anxiety and depression symptoms at T2.

Conclusions: Patients who tended to use their EC in daily life could be more effective in regulating the emotional impact of the cancer diagnosis and surgery. This explains why they reported fewer anxiety and depression symptoms, which in turn enabled a better perceived HRQoL after surgery. Therefore, reinforcing the use of patients' EC in daily life following their diagnosis could decrease their emotional distress and, in this way, improve their HRQoL in the preoperative and postoperative stages.
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http://dx.doi.org/10.1002/pon.5023DOI Listing
April 2019

Prevalence of Eosinophilic Esophagitis in Adolescents With Esophageal Atresia.

J Pediatr Gastroenterol Nutr 2019 07;69(1):52-56

Institut de Pathologie, CHU Lille.

Background And Objective: Eosinophilic esophagitis (EoE) is an increasingly recognized childhood disease. Esophageal atresia (EA) is the most frequent congenital malformation of the esophagus. Recently, cases of EoE occurring in patients with EA have been reported, although the exact prevalence of EoE in EA remains unknown. The aim is to investigate the prevalence of EoE among EA in adolescents and to describe these patients' characteristics.

Methods: Systematic upper gastrointestinal endoscopies with multistage esophageal biopsies were prospectively performed in 63 adolescents with EA. A standardized form was used to collect clinical and endoscopic data. Diagnosis of EoE was made as ≥15 intraepithelial eosinophils/high power field, whatever the response on proton pump inhibitors therapy.

Results: Six patients (9.5%) presented an EoE (17-100 eosinophils/high power field). An atopic condition was reported more frequently in the eosinophil ≥15 group than in patients with no EoE (66% vs 16%; P = 0.014). Except for chest pain, symptoms and endoscopic features were similar in patients with EoE and patients with no EoE.

Conclusion: In our series of 63 patients born with EA, mainly distal tracheoesophageal fistula, the prevalence of EoE is increased, and therefore should be considered in adolescents with EA.
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http://dx.doi.org/10.1097/MPG.0000000000002261DOI Listing
July 2019

Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status.

JAMA Oncol 2019 Apr;5(4):551-555

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique 938 and Site de Recherche Intégré contre le Cancer, Cancer United Research Associating Medicine University and Society, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, Sorbonne Université, Paris, France.

Importance: Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR).

Objective: To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR.

Design, Setting, And Participants: This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat.

Main Outcomes And Measures: The primary outcome was positive predictive value.

Results: Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable).

Conclusions And Relevance: Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.
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http://dx.doi.org/10.1001/jamaoncol.2018.4942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459114PMC
April 2019

Safety of Islet Autotransplantation After Pancreatectomy for Adenocarcinoma.

Transplantation 2019 01;103(1):177-181

Department of Endocrine Surgery, CHU Lille, Lille, France.

Background: Total pancreatectomy with intraportal islet autotransplantation (TPIAT) rather than partial pancreatectomy could represent a major shift in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC) when risks of postoperative pancreatic fistula are well identified. This approach provides a theoretical risk of tumor cell dissemination when islet cells are transplanted into the portal vein. Our objective was to explore the safety of TPIAT in PDAC in a mouse preclinical model of subcutaneous xenotransplantation of human cells isolated from pancreatic specimen during partial pancreatectomy performed for PDAC.

Methods: Patients requiring pancreatectomy for PDAC were prospectively included. Immunocompromised mice were transplanted with pancreatic cells isolated from the nonmalignant part of the surgical specimen (experimental group). Results were compared with pancreatic tumor implants (control group). Pancreatic grafts were explanted at 6 weeks for histological analyses.

Results: Nine patients were included, and 31 mice were transplanted. In the experimental group, explants were microscopically devoid of tumor cell, and no metastasis was observed. In the control group, all explants were composed of tumor.

Conclusions: We report in a preclinical model the absence of local and distant spreading of malignant cells after pancreatic islets xenograft isolated from PDAC patients. These data supports the oncological safety of TPIAT as valuable alternative to partial pancreatectomy for PDAC patients with a high risk of postoperative pancreatic fistula.
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http://dx.doi.org/10.1097/TP.0000000000002419DOI Listing
January 2019

Salvage Surgery for Esophageal Cancer: How to Improve Outcomes?

Ann Surg Oncol 2018 May 7;25(5):1277-1286. Epub 2018 Feb 7.

Department of Digestive and Oncological Surgery, Centre Hospitalier Régional Universitaire, University Hospital Claude Huriez, Lille Cedex, France.

Background: Locoregional recurrence rates after definitive chemoradiotherapy (dCRT) for locally advanced esophageal cancer (EC) are high. Salvage surgery (SALV) is considered the best treatment option in case of persistent or recurrent disease for operable patients, but SALV has been associated with increased morbidity and mortality. The aim of this study is to identify factors linked to outcomes after SALV to better select candidates and to optimize perioperative care.

Study Design: We retrospectively analyzed data from 308 consecutive SALV patients from a large multicenter European cohort. Univariate and multivariate analyses were performed to identify factors associated with in-hospital postoperative morbidity, anastomotic leakage (AL), and overall survival (OS).

Results: The in-hospital postoperative mortality and morbidity rates were 8.4 and 34.7%, respectively. Squamous cell histology (p = 0.040) and radiation dose ≥ 55 Gy (p = 0.047) were independently associated with major morbidity. The AL rate was 12.7%, and cervical anastomosis was independently associated with AL (p = 0.002). OS at 5 years was 34.0%. Radiation dose ≥ 55 Gy (p = 0.003), occurrence of postoperative complications (p = 0.006), ypTNM stage 3 (p = 0.019), and positive surgical margins (p < 0.001) were linked to poor prognosis.

Conclusions: SALV is a valuable option for patients with persistent or recurrent disease after dCRT and offers long-term survival. Factors such as radiation dose and anastomosis location identified here will help to optimize outcomes after SALV, which may be considered a standard treatment in the EC therapeutic armamentarium.
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http://dx.doi.org/10.1245/s10434-018-6365-1DOI Listing
May 2018

The FREGAT biobank: a clinico-biological database dedicated to esophageal and gastric cancers.

BMC Cancer 2018 02 6;18(1):139. Epub 2018 Feb 6.

Department of Gastrointestinal Oncology, Oscar Lambret Center, Univ. Lille, F-59000, Lille, France.

Background: While the incidence of esophageal and gastric cancers is increasing, the prognosis of these cancers remains bleak. Endoscopy and surgery are the standard treatments for localized tumors, but multimodal treatments, associated chemotherapy, targeted therapies, immunotherapy, radiotherapy, and surgery are needed for the vast majority of patients who present with locally advanced or metastatic disease at diagnosis. Although survival has improved, most patients still present with advanced disease at diagnosis. In addition, most patients exhibit a poor or incomplete response to treatment, experience early recurrence and have an impaired quality of life. Compared with several other cancers, the therapeutic approach is not personalized, and research is much less developed. It is, therefore, urgent to hasten the development of research protocols, and consequently, develop a large, ambitious and innovative tool through which future scientific questions may be answered. This research must be patient-related so that rapid feedback to the bedside is achieved and should aim to identify clinical-, biological- and tumor-related factors that are associated with treatment resistance. Finally, this research should also seek to explain epidemiological and social facets of disease behavior.

Methods: The prospective FREGAT database, established by the French National Cancer Institute, is focused on adult patients with carcinomas of the esophagus and stomach and on whatever might be the tumor stage or therapeutic strategy. The database includes epidemiological, clinical, and tumor characteristics data as well as follow-up, human and social sciences quality of life data, along with a tumor and serum bank.

Discussion: This innovative method of research will allow for the banking of millions of data for the development of excellent basic, translational and clinical research programs for esophageal and gastric cancer. This will ultimately improve general knowledge of these diseases, therapeutic strategies and patient survival. This database was initially developed in France on a nationwide basis, but currently, the database is available for worldwide contributions with respect to the input of patient data or the request for data for scientific projects.

Trial Registration: The FREGAT database has a dedicated website ( www.fregat-database.org ) and is registered on the Clinicaltrials.gov site, number NCT 02526095 , since August 8, 2015.
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http://dx.doi.org/10.1186/s12885-018-3991-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801889PMC
February 2018

Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement.

Virchows Arch 2018 Mar 1;472(3):461-468. Epub 2018 Feb 1.

Service d'Endocrinologie, Hôpital Huriez, CHRU de Lille, 59037, Lille, France.

Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.
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http://dx.doi.org/10.1007/s00428-018-2303-7DOI Listing
March 2018

[FREGAT: French clinico-biological database dedicated to esogastric cancers].

Ann Pathol 2017 Dec 28;37(6):457-466. Epub 2017 Nov 28.

UMR-S 1172-JPARC-centre de recherche Jean-Pierre-Aubert neurosciences et cancer, University Lille, 59000 Lille, France; Inserm, UMR-S 1172, 59000 Lille, France; SIRIC OncoLille, 59000 Lille, France; Service de chirurgie oncologique et digestive, hôpital Huriez, university Lille, CHRU, 59000 Lille, France.

Even though esogastric cancers are estimated at 1.5 million new cases worldwide with an expected 2.11 million new cases by 2025, prognosis remains poor and research is unsatisfactory compared to other cancers. There is an urgent need to intensify research via innovative and ambitious programs to improve patient's survival and quality of life. Incidence of esogastric cancers is particularly high in France, and the creation of a national clinicobiological database prospectively collecting epidemiological, human and social, clinical, pathological, biological data, sustained by biobanks of blood and tissues, is a critical point to improve research and care for these cancers considering all determinants of the disease with a more integrated approach. FREGAT clinicobiological database, funded and labeled by the French NCI in 2012, gathers the vast majority of university hospitals and cancer centers in France. This research relies on preexisting networks ensuring its efficacy and quality. Beyond significant increase of inclusions opened since January 2015, the establishment of public multiprivate industrial partnerships and creation of numerous French and European scientific projects, make FREGAT a decisive tool for research on esogastric cancers.
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http://dx.doi.org/10.1016/j.annpat.2017.10.005DOI Listing
December 2017

Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/β-catenin pathway.

Biochem J 2017 11 1;474(22):3733-3746. Epub 2017 Nov 1.

Univ. Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences and Cancer, Lille F-59000, France

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to proliferation, migration and invasion, and on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT-PCR were used to identify proteins and signalling pathways involved. MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of β-catenin expression, localization and activity and decreased expression of several of its target genes. xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/β-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.
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http://dx.doi.org/10.1042/BCJ20170348DOI Listing
November 2017

Discrepancy Between Clinical and Pathologic Nodal Status of Esophageal Cancer and Impact on Prognosis and Therapeutic Strategy.

Ann Surg Oncol 2017 Dec 25;24(13):3911-3920. Epub 2017 Sep 25.

Department of Digestive and Oncological Surgery, Univ.Lille, Claude Huriez University Hospital, Lille, France.

Background: The impact of discrepancies between clinical (c) and pathologic (p) stages of esophageal cancer remains a poorly understood issue. This study aimed to compare the prognosis of patient groups treated by primary surgery including clinical N0/pathologic N0 (cN0pN0), clinical N0/pathologic N+ (cN0pN+), clinical N+/pathologic N0 (cN+pN0), and clinical N+/pathologic N+ (cN+pN+).

Methods: Data were collected from 30 European centers during the years 2000 to 2010. Among 2944 recruited patients, 1554 patients receiving primary surgery met the inclusion criteria including 613 cN0pN0, 403 cN0pN+, 220 cN+pN0, and 318 cN+pN+ patients. Analyses with adjustment of the propensity score were used to compensate for differences in baseline characteristics.

Results: Clinical T stages 3 and 4 were increased in cN+pN+ (73.0%), cN0pN+ (49.6%), and cN+pN0 (51.8%) compared with cN0pN0 (32.8%). Compared with cN0pN0, cN+pN+ and cN0pN+ showed an increase in the proportion of adenocarcinoma histologic subtype, poor tumor differentiation, pathologic T3 and T4 stages, and R1/2 resection margin. Adjusted 5-year overall survival (hazard ratio [HR] 3.12; 95% confidence interval [CI] 2.57-3.78; P < 0.001) and event-free survival (HR 2.87; 95% CI 2.39-3.45; P < 0.001) were significantly reduced in cN0pN+ compared with cN0pN0. No significant differences in 5-year overall survival or event-free survival between cN0pN+ and cN+pN+ were observed. Regression analysis identified an association of distal tumor location, advanced clinical T stage, and poor tumor differentiation with pN+ disease.

Conclusions: This large multicenter study showed that cN0pN+ has a prognosis similar to that of cN+pN+ and worse than that of cN0pN0. Patients with clinical N0 disease but risk factors for pathologic N+ disease may benefit from neoadjuvant therapy before surgery.
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http://dx.doi.org/10.1245/s10434-017-6088-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670185PMC
December 2017

Combination of galectin-3, CK19 and HBME-1 immunostaining improves the diagnosis of thyroid cancer.

Oncol Lett 2017 Oct 4;14(4):4183-4189. Epub 2017 Aug 4.

Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, B-7000 Mons, Belgium.

Currently, fine-needle aspiration is the most frequently used pre-operative technique for diagnosis of malignant thyroid tumors, however, pathologists are unable to reach efficient and accurate differential diagnoses between benign and malignant thyroid nodules. To aid in resolving this issue, immunohistochemistry for galectins (gal)-1, -3, -7, -8, cytokeratin 19 (CK19), Hector Battifora Mesothelial Epitope-1 (HBME-1) and thyroid peroxidase (TPO) was performed on two tissue microarrays composed of 66 follicular adenomas (FA) and 66 papillary carcinomas (PC). The identification of optimal cut-off levels and the diagnostic value of single immunomarkers or combinations were evaluated using the receiver operating characteristic curve analysis. Signal intensities for gal-1, gal-3, CK19 and HBME-1 were significantly greater in PC compared with FA (P<0.001). Conversely, expression levels of TPO were significantly increased in FA compared with PC (P<0.001). Gal-3 and CK19 appeared to be the most sensitive markers (97 and 98%, respectively), whereas galectin-1 was the most specific (97%). The combination of gal-3, CK19 and HBME-1 acted as the most efficient and informative marker panel reaching the greatest specificity (97%) and sensitivity (95%) for the diagnosis of PCs. The findings suggest that this combination of markers may improve the reliability of diagnosis of thyroid cancer.
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http://dx.doi.org/10.3892/ol.2017.6719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592881PMC
October 2017

Survival Benefit of Neoadjuvant Treatment in Clinical T3N0M0 Esophageal Cancer: Results From a Retrospective Multicenter European Study.

Ann Surg 2017 11;266(5):805-813

*Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland †UniversityLille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille, France ‡Department of Digestive Surgery, Haut-Lévêque University Hospital, Bordeaux, France §UniversityLille, Department of Pathology, University Hospital, Lille, France ¶UniversityLille, UMR-S 1172 - JPARC - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France ||Inserm, UMR-S 1172, Lille, France **UniversityLille, Department of Biostatistics, University Hospital, Lille, France ††SIRIC (Site de Recherche Intégrée en Cancérologie) OncoLille, France ‡‡Department of Digestive Surgery, Cavale Blanche University Hospital, Brest, France §§Department of General and Digestive Surgery, Hautepierre University Hospital, Strasbourg, France ¶¶Department of General and Digestive Surgery, Purpan University Hospital, Toulouse, France ||||Department of Digestive Surgery, Saint-Antoine University Hospital, Paris, France ***Department of Digestive Surgery, Edouard Herriot University Hospital, Lyon, France †††Department of Digestive and Hepatobiliary Surgery, Pontchaillou University Hospital, Rennes, France.

Background: Based on current guidelines, clinical T3N0M0 esophageal tumors may or may not receive neoadjuvant treatment, according to their perception as locally advanced (cT3) or early-stage tumors (stage II). The study aim was to assess the impact of neoadjuvant treatment upon survival for cT3N0M0 esophageal cancer patients, with subgroup analyses by histological type (squamous cell carcinoma vs adenocarcinoma) and type of neoadjuvant treatment (chemotherapy vs radiochemotherapy).

Methods: Data from patients operated on for esophageal cancer in 30 European centers were collected. Among the 382 of 2944 patients with clinical T3N0M0 stage at initial diagnosis (13.0%), we compared those treated with primary surgery (S, n = 193) versus with neoadjuvant treatment plus surgery (NS, n = 189).

Results: The S and NS groups were similar regarding their demographic and surgical characteristics. In-hospital postoperative morbidity and mortality rates were comparable between groups. Patients were found to be pN+ in 64.2% versus 42.9% in the S and NS groups respectively (P < 0.001), pN2/N3 in 35.2% versus 21.2% (P < 0.001), stage 0 in 0% versus 16.4% (P < 0.001), and R0 in 81.3% versus 89.4% of cases (P = 0.026). Median overall and disease-free survivals were significantly better in the NS group, 38.4 versus 27.9 months (P = 0.007) and 31.6 versus 27.5 months (P = 0.040), respectively, and this difference remained for both histological types. Radiotherapy did not offer a benefit compared with chemotherapy alone (P = 0.687). In multivariable analysis, neoadjuvant treatment was an independent favorable prognostic factor (HR 0.76, 95% CI 0.58-0.99, P = 0.044).

Conclusion: Neoadjuvant treatment offers a significant survival benefit for clinical T3N0M0 esophageal cancer.
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http://dx.doi.org/10.1097/SLA.0000000000002402DOI Listing
November 2017

Are Thoracotomy and/or Intrathoracic Anastomosis Still Predictors of Postoperative Mortality After Esophageal Cancer Surgery?: A Nationwide Study.

Ann Surg 2017 11;266(5):854-862

*Department of Digestive and Oncological Surgery, University Lille, Claude Huriez University Hospital, Lille, France †University Lille, UMR-S 1172 - JPARC - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France ‡Inserm, UMR-S 1172, Lille, France §Department of Digestive and Oncological Surgery, E. Herriot University Hospital, Lyon, France ¶Claude Bernard Lyon 1 University, Lyon, France ||SIRIC OncoLille, Lille, France **Hox-Com Analytiques, Paris, France ††Department of Pathology, UniversityLille, Centre de Biologie et de Pathologie, University Hospital, Lille, France ‡‡Department of biostatistics, UniversityLille, University Hospital, Lille, France.

Background: Intrathoracic (vs cervical) anastomosis and a thoracotomy (vs absence) have previously been associated with increasing postoperative mortality (POM). Recent improvements in surgical practices and perioperative management may have changed these dogmas.

Objectives: The aim of this study was to evaluate the impact of performing intrathoracic anastomosis and/or thoracotomy on POM after esophageal cancer surgery in recent years.

Methods: All consecutive patients who underwent esophageal cancer surgery with reconstruction between 2010 and 2012 in France were included (n = 3286). Patients with a thoracoscopic approach were excluded (n = 4). We compared 30-day POM between patients having received intrathoracic (vs cervical) anastomosis and between those having received a thoracotomy or not. Multivariate analyses and propensity score matching were used to adjust for confounding factors.

Results: Patients had either cervical (n = 548) or intrathoracic (n = 2738) anastomosis. Thirty-day POM was higher after cervical anastomosis (8.8% vs 4.9%, P < 0.001). Having received a thoracotomy (n = 3061) was associated with a decreased risk of 30-day POM (5.3% vs 9.3%, P = 0.011). After adjustment for confounding factors, cervical anastomosis was associated with 30-day POM [odds ratio (OR) 1.71; 95% confidence interval (CI) 1.05-2.77); P = 0.032], whereas performing a thoracotomy was not associated with 30-day POM (OR 0.97; 95% CI 0.51-1.84; P = 0.926).

Conclusions: Nowadays, intrathoracic anastomosis provides a lower 30-day POM rate compared to cervical anastomosis, and performing a thoracotomy is not associated with POM. Systematic anastomosis neck placement or thoracotomy avoidance is not a relevant argument anymore to decrease POM.
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http://dx.doi.org/10.1097/SLA.0000000000002401DOI Listing
November 2017

Galectin-1 is a diagnostic marker involved in thyroid cancer progression.

Int J Oncol 2017 Sep 4;51(3):760-770. Epub 2017 Jul 4.

Laboratory of Human Anatomy and Experimental Oncology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium.

Fine-needle aspiration (FNA) is the most commonly used pre-operative technique for diagnosis of malignant thyroid tumor. However, many benign lesions, with indeterminate diagnosis following FNA, are referred to surgery. Based on multifunctionality of the endogenous galectin-1, we aimed to assess its status for early diagnosis of thyroid cancer. Immunohistochemistry for galectin-1 and -3 was performed on a clinical series of 69 cases of thyroid lesions. Galectin-1 expression was further examined in two additional tissue microarrays (TMA) composed of 66 follicular adenomas and 66 papillary carcinomas in comparison to galectin-3 and cytokeratin-19 (CK19). In addition, a knockdown of galectin-1 in papillary (TPC-1) and anaplastic (8505C) thyroid cancer cell lines was achieved by lentiviral transduction for in vitro experiments. A murine orthotopic thyroid cancer model was used to investigate tumor growth and metastatic ability. Immunohistochemical analyses of galectin-1 and -3 in the series of 69 cases of thyroid lesions revealed that galectin-1 was completely absent in the epithelial compartment of all benign thyroid lesions. Levels of both galectins significantly increased in the cytoplasmic compartment of malignant thyroid cells. Galectin-1 expression in the TMA yielded an excellent specificity (97%), while galectin-3 and CK19 presented a higher sensitivity (>97%) in discriminating benign from malignant thyroid lesions. In vitro experiments revealed that migration was negatively affected in TPC-1 galectin-1 knockdown (KD) cells, and that proliferation and invasion capacity of 8505C cells decreased after galectin-1 KD. Moreover, an orthotopic mouse model displayed a lower rate of tumor development with galectin-1 KD thyroid anaplastic cancer cells than in the control. Our findings support the introduction of galectin-1 as a reliable diagnostic marker for thyroid carcinomas. Its involvement in cell proliferation, migration, invasion and tumor growth also intimate functional involvement of galectin-1 in the progression of thyroid carcinoma, suggesting its potential as a therapeutic target.
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http://dx.doi.org/10.3892/ijo.2017.4065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564411PMC
September 2017

Galectin-3 is a non-classic RNA binding protein that stabilizes the mucin MUC4 mRNA in the cytoplasm of cancer cells.

Sci Rep 2017 03 6;7:43927. Epub 2017 Mar 6.

Univ. Lille, UMR-S 1172 - JPARC - Jean-Pierre Aubert Research Center, F-59000 Lille, France.

Pancreatic cancer cells express high levels of MUC1, MUC4 and MUC16 mRNAs that encode membrane-bound mucins. These mRNAs share unusual features such as a long half-life. However, it remains unknown how mucin mRNA stability is regulated. Galectin-3 (Gal-3) is an endogenous lectin playing important biological functions in epithelial cells. Gal-3 is encoded by LGALS3 which is up-regulated in pancreatic cancer. Despite the absence of a RNA-recognition motif, Gal-3 interacts indirectly with pre-mRNAs in the nucleus and promotes constitutive splicing. However a broader role of Gal-3 in mRNA fate is unexplored. We report herein that Gal-3 increases MUC4 mRNA stability through an intermediate, hnRNP-L which binds to a conserved CA repeat element in the 3'UTR in a Gal-3 dependent manner and also controls Muc4 mRNA levels in epithelial tissues of Gal3 mice. Gal-3 interacts with hnRNP-L in the cytoplasm, especially during cell mitosis, but only partly associates with protein markers of P-Bodies or Stress Granules. By RNA-IP plus RNA-seq analysis and imaging, we demonstrate that Gal-3 binds to mature spliced MUC4 mRNA in the perinuclear region, probably in hnRNP-L-containing RNA granules. Our findings highlight a new role for Gal-3 as a non-classic RNA-binding protein that regulates MUC4 mRNA post-transcriptionally.
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http://dx.doi.org/10.1038/srep43927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338267PMC
March 2017

Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of "thyroid-checked" controls.

Eur J Med Genet 2017 Mar 9;60(3):178-184. Epub 2017 Jan 9.

Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France. Electronic address:

A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4-14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of "thyroid-checked" controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.
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http://dx.doi.org/10.1016/j.ejmg.2017.01.001DOI Listing
March 2017

Is Centralization Needed for Esophageal and Gastric Cancer Patients With Low Operative Risk?: A Nationwide Study.

Ann Surg 2016 Nov;264(5):823-830

*Univ.Lille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille, France†Univ.Lille, UMR-S 1172 - JPARC - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France‡Inserm, UMR-S 1172, F-59000 Lille, France§Department of Digestive and Oncological Surgery, E. Herriot University Hospital, Lyon, France¶Claude Bernard Lyon 1 University, Lyon, France||SIRIC OncoLille, France**Hox-Com Analytiques, Paris, France††UniversityLille, Department of Pathology, Centre de Biologie et de Pathologie, University Hospital, Lille, France.

Objective: To investigate the impact of center volume on postoperative mortality (POM) according to patient condition.

Background: Centralization has been shown to improve POM in esophageal and, to a lesser extent, gastric cancer surgery; however, the benefit of centralization for patients with low operative risk is questionable.

Methods: All consecutive patients who underwent esophageal or gastric cancer surgery between 2010 and 2012 in France were included (N = 11,196). The 30-day POM was compared in terms of the center volume (low: <20 cases per year, intermediate: 20-39, high: 40-59, and very high: ≥60) and stratified according to the Charlson score (0, 1-2, ≥3). The consistency across the esophageal (n = 3286) and gastric (n = 7910) subgroups, and variations between 30-day and 90-day POM were analyzed.

Results: Low-volume centers treated 64.2% of patients. A linear decrease in 30-day and 90-day POM was observed with increasing center volume, with rates of 5.7% and 10.2%, 4.3% and 7.9%, 3.3% and 6.7%, and 1.7% and 3.6% in low, intermediate, high, and very high-volume centers, respectively (P < 0.001). Comparing low and very high-volume centers, 30-day POM was 4.0% versus 1.1% for Charlson 0 (P = 0.001), 7.5% versus 3.4% for Charlson 1 to 2 (P < 0.001), and 14.7% versus 3.7% for Charlson ≥3 (P = 0.003) patients. A similar linear decrease was observed in the esophageal and gastric cancer subgroups. Between the low and very high-volume centers, an almost 70% reduction in the relative risk of POM was systematically observed, independent of Charlson score or tumor location.

Conclusions: To improve POM, esophageal and gastric cancer surgery should be centralized, irrespective of the patient's comorbidity or tumor location.
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http://dx.doi.org/10.1097/SLA.0000000000001768DOI Listing
November 2016

Esophageal Adenocarcinoma: Impact of a Large Hiatal Hernia on Outcomes After Surgery.

Ann Surg 2016 Nov;264(5):862-870

*Univ.Lille, Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille, France†Univ.Lille, URM-S 1172 - JPArc - Centre de Recherche, Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France‡Inserm, UMR-S 1172, Lille, France§Univ.Lille, Department of Pathology, Centre de Biologie et Pathologie, University Hospital, Lille, France¶SIRIC ONCOLille, Lille, France||Univ.Lille, Department of Radiology, Claude Huriez University Hospital, University Hospital, Lille, France**Department of Gastrointestinal Oncology, Oscar Lambret Center, Lille, France††Department of Radiation Oncology, Oscar Lambret Center, Lille, France.

Objective: To evaluate complete tumor resection rate (primary objective), 30-day postoperative outcomes, and survival (secondary objectives) in patients with a hiatal hernia (HH) ≥5 cm (HH group) compared with those who did not have a HH or presented with a HH <5 cm (control group).

Background: HH is a risk factor for esophageal and junctional adenocarcinoma (EGJA). Its impact on the outcomes after EGJA surgery is unknown.

Methods: Among 367 patients who underwent surgery for EGJA, a HH was searched for on computerized tomography scan and barium swallow, with comparison between the HH (n = 42) and control (n = 325) groups.

Results: In the HH group, EGJAs exhibited higher rates of incomplete resection (50.0% vs 4.0%; P < 0.001), of pN3 stages (28.5% vs 10.1%; P = 0.002), and lower median survival (20.9 vs 41.0 mos; P = 0.001). After adjustment, a HH ≥5 cm was a predictor of incomplete resection (odds ratio 21.0, 95% confidence interval 9.4-46.8, P < 0.001) and a poor prognostic factor (hazard ratio 1.6, 95% confidence interval 1.1-2.5, P = 0.025). In the HH group, 30-day mortality was significantly higher in patients who received neoadjuvant radiotherapy (20.0% vs 0%; P = 0.040), which was related to greater cardiac and pulmonary toxicity.

Conclusions: For the first time, we showed that a HH ≥5 cm is associated with a poor prognosis in patients who had surgery for EGJA, linked to greater incomplete resection and lymph node involvement. Neoadjuvant radiotherapy was associated with a significant toxicity in patients with a HH ≥5 cm.
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http://dx.doi.org/10.1097/SLA.0000000000001769DOI Listing
November 2016

Regulation of cellular quiescence by YAP/TAZ and Cyclin E1 in colon cancer cells: Implication in chemoresistance and cancer relapse.

Oncotarget 2016 Aug;7(35):56699-56712

University Lille, Inserm, CHU Lille, UMR-S1172-JPARC-Jean-Pierre Aubert Research Center, F-59000, Lille, France.

Our aim was to decipher the role and clinical relevance of the YAP/TAZ transcriptional coactivators in the regulation of the proliferation/quiescence balance in human colon cancer cells (CCC) and survival after 5FU-based chemotherapy. The prognostic value of YAP/TAZ on tumor relapse and overall survival was assessed in a five-year follow-up study using specimens of liver metastases (n = 70) from colon cancer patients. In 5FU-chemoresistant HT29-5F31 and -chemosensitive HCT116 and RKO CCC, a reversible G0 quiescent state mediated by Cyclin E1 down-regulation was induced by 5FU in 5F31 cells and recapitulated in CCC by either YAP/TAZ or Cyclin E1 siRNAs or the YAP inhibitor Verteporfin. Conversely, the constitutive active YAPdc-S127A mutant restricted cellular quiescence in 5FU-treated 5F31 cells and sustained high Cyclin E1 levels through CREB Ser-133 phosphorylation and activation. In colon cancer patients, high YAP/TAZ level in residual liver metastases correlated with the proliferation marker Ki-67 (p < 0.0001), high level of the YAP target CTGF (p = 0.01), shorter disease-free and overall survival (p = 0.008 and 0.04, respectively). By multivariate analysis and Cox regression model, the YAP/TAZ level was an independent factor of overall (Hazard ratio [CI 95%] 2.06 (1.02-4.16) p = 0.045) and disease-free survival (Hazard ratio [CI 95%] 1.98 (1.01-3.86) p = 0.045). Thus, YAP/ TAZ pathways contribute to the proliferation/quiescence switch during 5FU treatment according to the concerted regulation of Cyclin E1 and CREB. These findings provide a rationale for therapeutic interventions targeting these transcriptional regulators in patients with residual chemoresistant liver metastases expressing high YAP/TAZ levels.
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http://dx.doi.org/10.18632/oncotarget.11057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302946PMC
August 2016

BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy.

J Clin Oncol 2016 09 5;34(25):3023-30. Epub 2016 Jul 5.

Sébastien Héritier, Mohamed-Aziz Barkaoui, Jean Miron, and Jean Donadieu, French Reference Center for Langerhans Cell Histiocytosis, Trousseau Hospital; Sébastien Héritier, Sabah Boudjemaa, Guy Leverger, and Jean Donadieu, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris; Sylvie Fraitag, Despina Moshous, and Christine Bodemer, Necker Hospital, Assistance Publique-Hôpitaux de Paris; Michel Peuchmaur and Brigitte Lescoeur, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris; Michel Peuchmaur, Université Paris Diderot, Sorbonne Paris Cité; Hélène Pacquement, Institut Curie Medical Center; Guy Leverger, Université Pierre et Marie Curie; Fleur Cohen-Aubart and Julien Haroche, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris; Roger Lacave, Tenon Hospital, Assistance Publique-Hôpitaux de Paris; Valérie Taly, Institut National de la Santé et de la Recherche Médicale, Unités Mixte de Recherche S1147, Centre National de la Recherche Scientifique SNC 5014, Université Paris Sorbonne Cité, Paris; Sébastien Héritier, Jean-François Emile, Zofia Hélias-Rodzewicz, and Jean Donadieu, Université de Versailles Saint-Quentin-en-Yvelines, Université Paris-Saclay; Jean-François Emile, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt; Caroline Thomas and Anne Moreau, Centre Hospitalo-Universitaire de Nantes, Nantes; Florence Renaud, Centre Hospitalier Régional Universitaire, Université de Lille; Anne Lambilliotte and Françoise Mazingue, Centre Hospitalo-Universitaire de Lille, Lille; Catherine Chassagne-Clément, Centre Léon Bérard; Frédérique Dijoud, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon; Kamila Kebaili, Institut d'Hémato-Oncologie Pediatrique, Lyon; Valérie Rigau, Gui de Chauliac Hospital; Eric Jeziorski, Hôpital Arnaud de Villeneuve, Montpellier; Geneviève Plat, Centre Hospitalo-Universitaire de Toulouse, Toulouse; Nathalie Aladjidi, Centre Hospitalo-Universit

Purpose: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined.

Patients And Methods: BRAF(V600E) mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae.

Results: Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAF(V600E) mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAF(V600E) more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001).

Conclusion: In children with LCH, BRAF(V600E) mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.
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http://dx.doi.org/10.1200/JCO.2015.65.9508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321082PMC
September 2016

SALL4 expression in gestational trophoblastic tumors: a useful tool to distinguish choriocarcinoma from placental site trophoblastic tumor and epithelioid trophoblastic tumor.

Hum Pathol 2016 08 8;54:121-6. Epub 2016 Apr 8.

Department of Pathology, Lille University Hospital CHRU, 59037 Lille Cedex, France. Electronic address:

SALL4 has important functions in embryonic stem cells. The aim of this study was to investigate SALL4 expression in gestational trophoblastic neoplasia. We hypothesized that it could help to distinguish choriocarcinoma, the presumed most primitive form of gestational trophoblastic neoplasia, from placental site trophoblastic tumor and epithelioid trophoblastic tumor, which would be more differentiated variants. This study included 31 gestational trophoblastic neoplasias: 19 choriocarcinomas, 9 placental site trophoblastic tumors, 1 epithelioid trophoblastic tumor, and 2 mixed tumors comprising a placental site trophoblastic tumor and an epithelioid trophoblastic tumor. Unlike usual markers of gestational trophoblastic neoplasia (p63, human chorionic gonadotrophin and human placental lactogen), SALL4 was expressed in 100% of choriocarcinomas and it was not detected in any placental site trophoblastic tumor and epithelioid trophoblastic tumor. However, the proportion of positive cells varied in a wide range, from 10% to 70%, reflecting the fact that SALL4 was specifically present in mononuclear cells consistent with neoplastic cytotrophoblast. So, SALL4 may be helpful in the differential diagnosis of gestational trophoblastic neoplasias.
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http://dx.doi.org/10.1016/j.humpath.2016.03.012DOI Listing
August 2016