Publications by authors named "Anne Couvelard"

216 Publications

Treatment outcomes of advanced digestive well-differentiated grade 3 NETs.

Endocr Relat Cancer 2021 Jun 1. Epub 2021 Jun 1.

J Cros, Pathology, Beaujon Hospital - Paris Diderot University - INSERM U1149, Clichy, France.

There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1=74; L2=52) included alkylating-based (n=32), etoposide-platinum (n=22) or adenocarcinoma-like chemotherapy (n=20), somatostatin analogs (n=21), targeted therapies (n=22) and liver-directed therapies (n=7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI [1.5-12.2]; p=0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (p<0.001 and p=0.008, respectively). The longest median PFS were obtained with adenocarcinoma-like chemotherapy (16.5 months [9.0-24.0]) and targeted therapies (12.0 months [8.2-15.8]), while the shortest PFS were observed with somatostatin analogues (6.2 months [3.8-8.5]) and etoposide-platinum chemotherapy (7.2 months [5.2-9.1]). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 [1.61-8.44], p=0.002) and alkylating-based chemotherapies (multivariable HR 1.95 [1.01-3.78], p=0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.
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http://dx.doi.org/10.1530/ERC-21-0109DOI Listing
June 2021

Pathogenic ATM Variant-Harbouring Well-Differentiated Aggressive Type 1 Gastric Neuroendocrine Tumour with High-grade Features (G3 NET): a New Addition to the Clinical and Pathological Spectrum of Gastric Neuroendocrine Neoplasms.

Endocr Pathol 2021 May 21. Epub 2021 May 21.

Département de Pathologie, Hôpital Bichat, AP-HP, 46 Rue Henri Huchard, 75018, Paris, France.

Gastric type 1 neuroendocrine tumours are considered to have low rates of proliferation and a good prognosis. We report here a patient with an aggressive well-differentiated high-grade gastric neuroendocrine tumour (gastric grade 3 NET), in a context of autoimmune gastritis. Consistent with grade 3 disease, the tumour had a Ki-67 proliferation index of 30%. Targeted next-generation sequencing identified variants of four genes, including a pathogenic ATM variant underlying the differentiation and metastatic potential of the tumour. Liver metastasis was diagnosed during follow-up, and the patient died after 6 years, due to disease progression.
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http://dx.doi.org/10.1007/s12022-021-09681-2DOI Listing
May 2021

Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumors.

Endocr Relat Cancer 2021 Jun 11;28(7):457-466. Epub 2021 Jun 11.

Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital, Clichy, France.

A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK to 100 (IQR 56-180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.
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http://dx.doi.org/10.1530/ERC-21-0034DOI Listing
June 2021

Serotonin immunoreactive pancreatic neuroendocrine neoplasm associated with main pancreatic duct dilation: a recognizable entity with excellent long-term outcome.

Eur Radiol 2021 May 11. Epub 2021 May 11.

Université de Paris, INSERM U1149 "centre de recherche sur l'inflammation," CRI, F-75018, Paris, France.

Objectives: Dilatation of the main pancreatic duct (MPD) is rare in pancreatic neuroendocrine neoplasm (panNEN) and may be due to different mechanisms. We compared the imaging and pathological characteristics as well as the outcome after resection of positive (S+) and negative (S-) serotonin immunoreactive panNENs causing MPD dilatation.

Methods: This retrospective study included patients with panNEN, with MPD dilatation (≥ 4 mm) on preoperative CT/MRI and resected between 2005 and 2019. Clinical, radiological, and pathological features were compared between S+ and S- panNENs. Imaging features associated with S+ panNEN were identified using logistic regression analysis. The diagnostic performance of imaging for the differentiation of S+ and S- panNENs was assessed by ROC curve analysis. Recurrence-free survival (RFS) was compared between the two groups.

Results: The final population of 60 panNENs included 20/60 (33%) S+ panNENs. S+ panNENs were smaller (median 12.5 mm vs. 33 mm; p < 0.01), more frequently hyperattenuating/intense on portal venous phase at CT/MRI (95% vs. 25%, p < 0.01), and presented with more fibrotic stroma on pathology (60.7 ± 16% vs. 40.7 ± 12.8%; p < 0.01) than S- panNENs. Tumor size was the only imaging factor associated with S+ panNEN on multivariate analysis. A tumor size ≤ 20 mm had 95% sensitivity and 90% specificity for the diagnosis of S+ panNEN. Among 52 patients without synchronous liver metastases, recurrence occurred in 1/20 (5%) with S+ panNEN and 18/32 (56%) with S- panNEN (p < 0.01). Median RFS was not reached in S+ panNENs and was 31.3 months in S- panNENs (p < 0.01).

Conclusions: In panNENs with MPD dilatation, serotonin positivity is associated with smaller size, extensive fibrotic stroma, and better long-term outcomes.

Key Points: • S+ panNENs showed a higher percentage of fibrotic stroma, higher microvessel density, and lower proliferation index (Ki-67) compared to S- panNENs. • Radiologically, S+ panNENs causing dilatation of the MPD were characterized by a small size (< = 20 mm) and a persistent enhancement on portal phase on both CT and MRI. • Patients with S+ panNENs presented with longer RFS when compared to those with S- panNENs.
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http://dx.doi.org/10.1007/s00330-021-08007-4DOI Listing
May 2021

Prevalence and prognosis of microsatellite instability in oesogastric adenocarcinoma, NORDICAP 16-01.

Clin Res Hepatol Gastroenterol 2021 Jul 20;45(4):101691. Epub 2021 Apr 20.

Service de gastro entérologie, Hôpital Saint Louis, AP-HP, Paris, France.

Background: The prevalence and prognosis association of microsatellite instability (MSI) in oesogastric junction and gastric adenocarcinoma (OGC) have been reported with conflicting results.

Methods: Patients with OGC from 2010 to 2015 were enrolled in this retrospective multicenter study. MSI was determined by genotyping. MLH1 promoter methylation and BRAFV600E mutation were screened in the MSI tumors.

Results: Among 315 tumors analyzed, 39 (12.4%) were of the MSI phenotype. Compared to MSS tumors, MSI tumors were more frequent in patients >70 years (17% vs 9%, p=0.048) and in gastric antral primary (20% versus 5% in junction tumor and 12% in fundus tumor. Among 29 MSI tumors analyzed, 28 had a loss of MLH1 protein expression and 27 had MLH1 promotor hypermethylation. None had a BRAF V600E mutation. The 4-year cumulative incidence of recurrence for patients with resected tumor was significantly lower in dMMR tumors versus pMMR tumors (17% versus 47%, p=0.01). For the patients with unresectable tumor the median overall survival was 11 months in MSS group and 14 months in MSI group (p=0.24).

Conclusion: MSI prevalence in OGC was 12.4%, associated with antral localization and advanced age. Patients with MSI tumors had a lower cumulative incidence of recurrence after surgery. MSI phenotype was mainly associated with loss of MLH1 protein expression, MLH1 promotor hypermethylation and had no BRAFV600E mutation.
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http://dx.doi.org/10.1016/j.clinre.2021.101691DOI Listing
July 2021

Cytomegalovirus proctitis as a complication of COVID-19 with immunosuppressive treatments.

IDCases 2021 5;24:e01111. Epub 2021 Apr 5.

Infectious Diseases Department, AP-HP Bichat Claude-Bernard Hospital, 75018, Paris, France.

We report a case of reactivated biopsy-proven cytomegalovirus proctitis complicating the course of severe COVID-19 pneumonia treated with dexamethasone, anakinra and lopinavir/ritonavir. No other contributing factor was found than iatrogenic immunosuppression and COVID-19 immune dysregulation. We draw attention to the immunosuppressive risk when treating severe COVID-19 pneumonia with immunomodulators.
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http://dx.doi.org/10.1016/j.idcr.2021.e01111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020601PMC
April 2021

Pancreatic Ductal Adenocarcinoma Arising in Young and Old Patients Displays Similar Molecular Features.

Cancers (Basel) 2021 Mar 11;13(6). Epub 2021 Mar 11.

INSERM U1149, Inflammation Research Center, Beaujon Hospital, 92110 Clichy, France.

Pancreatic ducal adenocarcinoma is classically diagnosed in the 7th decade, but approximately 10% of patients are diagnosed under 55 years (y.o.). While the genomic and transcriptomic landscapes of late-onset tumors (LOT) have been described, little is known about early-onset tumors (EOT). Ageing is known to impact DNA methylation and proteome integrity through carbonylation-related oxidative damages. We therefore aimed to assess the global molecular features of EOT. We compared 176 EOT (≤55 y.o.) and 316 LOT (≥70 y.o.) from three distinct surgical cohorts at the clinical/genomic/epigenomic/transcriptomic level. Furthermore, we assessed oxidative stress responses and oxidative proteome damages using 2D gel electrophoresis followed by mass spectrometry protein identification. There was no consistent clinical difference between EOT and LOT across the three cohorts. The mutational landscape of key driver genes and the global methylation profile were similar in the two groups. LOT did display age-related features such as enriched DNA repair gene signatures and upregulation of oxidative stress defenses together with increased proteome carbonylation. However, these age-related differences were more preeminent in non-tumor tissues while tumor proteome and proteome damages were fairly comparable. In conclusion, this multi-omics comparison showed that EOT harbor a comparable molecular profile to that of LOT.
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http://dx.doi.org/10.3390/cancers13061234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999057PMC
March 2021

Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Université de Paris, Department of Gastroenterology-Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), 92110 Clichy, France.

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rb) or the absence of very intense p53 staining (p53) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, = 0.040; LCNEC vs. SCNEC, < 0.001). The ORR was significantly higher in NEN presenting with Rb (63% vs. 42%, = 0.025) and p16 (66% vs. 35%, = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11-15.53, = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.
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http://dx.doi.org/10.3390/cancers13040643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915900PMC
February 2021

Bariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells.

Nat Commun 2021 01 4;12(1):110. Epub 2021 Jan 4.

Université de Paris, Inserm U1149, Centre de Recherche sur l'inflammation, Paris, France.

Glucagon-Like Peptide-1 (GLP-1) undergoes rapid inactivation by dipeptidyl peptidase-4 (DPP4) suggesting that target receptors may be activated by locally produced GLP-1. Here we describe GLP-1 positive cells in the rat and human stomach and found these cells co-expressing ghrelin or somatostatin and able to secrete active GLP-1 in the rats. In lean rats, a gastric load of glucose induces a rapid and parallel rise in GLP-1 levels in both the gastric and the portal veins. This rise in portal GLP-1 levels was abrogated in HFD obese rats but restored after vertical sleeve gastrectomy (VSG) surgery. Finally, obese rats and individuals operated on Roux-en-Y gastric bypass and SG display a new gastric mucosa phenotype with hyperplasia of the mucus neck cells concomitant with increased density of GLP-1 positive cells. This report brings to light the contribution of gastric GLP-1 expressing cells that undergo plasticity changes after bariatric surgeries, to circulating GLP-1 levels.
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http://dx.doi.org/10.1038/s41467-020-20301-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782689PMC
January 2021

CT-Based Radiomics Analysis to Predict Malignancy in Patients with Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas.

Cancers (Basel) 2020 Oct 23;12(11). Epub 2020 Oct 23.

Service De Radiologie, Assistance Publique-Hôpitaux De Paris, APHP. Nord, Hôpital Beaujon, 92110 Clichy, France.

To assess the performance of CT-based radiomics analysis in differentiating benign from malignant intraductal papillary mucinous neoplasms of the pancreas (IPMN), preoperative scans of 408 resected patients with IPMN were retrospectively analyzed. IPMNs were classified as benign (low-grade dysplasia, = 181), or malignant (high grade, = 128, and invasive, = 99). Clinicobiological data were reported. Patients were divided into a training cohort (TC) of 296 patients and an external validation cohort (EVC) of 112 patients. After semi-automatic tumor segmentation, PyRadiomics was used to extract radiomics features. A multivariate model was developed using a logistic regression approach. In the training cohort, 85/107 radiomics features were significantly different between patients with benign and malignant IPMNs. Unsupervised clustering analysis revealed four distinct clusters of patients with similar radiomics features patterns with malignancy as the most significant association. The multivariate model differentiated benign from malignant tumors in TC with an area under the ROC curve (AUC) of 0.84, sensitivity (Se) of 0.82, specificity (Spe) of 0.74, and in EVC with an AUC of 0.71, Se of 0.69, Spe of 0.57. This large study confirms the high diagnostic performance of preoperative CT-based radiomics analysis to differentiate between benign from malignant IPMNs.
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http://dx.doi.org/10.3390/cancers12113089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690711PMC
October 2020

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass.

Cell Rep 2020 10;33(4):108270

Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Orders of Eagles Diabetes Research Center, Iowa City, IA 52242, USA; Veterans Affairs Health Care System, Iowa City, IA 52242, USA; Obesity Research & Education Initiative, University of Iowa, Iowa City, IA 52242, USA. Electronic address:

The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.
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http://dx.doi.org/10.1016/j.celrep.2020.108270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660289PMC
October 2020

PD-1/PD-L1 expression in anal squamous intraepithelial lesions.

Oncotarget 2020 Sep 29;11(39):3582-3589. Epub 2020 Sep 29.

AP-HP, Service de Gastroentérologie et Proctologie, Hôpital Bichat-Claude Bernard, F-75018 Paris, France.

Introduction: Studies have shown that the PD-1/PD-L1 immunomodulatory pathway slows down anti-tumor immunity in a number of cancers. The description of the expression of these molecules has never been performed in anal low-grade/high grade squamous intra-epithelial lesions (LSIL/HSIL respectively).

Materials And Methods: Patients followed in the AIN3 cohort were routinely sampled. For each selected sample, an immunohistochemical study was performed with anti-CD8, PD-1, PD-L1 antibodies. The presence and distribution of CD8+ lymphocytes, and the presence of PD-1+ lymphocytes and PD-L1+ epithelial cells were assessed. The comparison of these characteristics was performed between the HSIL and LSIL groups.

Results: 33 patients were included and 78 samples selected (60 HSIL and 18 LSIL). CD8+ lymphocytes were observed more frequently in HSIL versus LSIL in the lamina propria or intra epithelial (respectively 90% vs. 60%, = 0.01; and 62% vs. 33%, = 0.04). PD-1+ lymphocytes were observed more frequently in HSIL versus LSIL (41% vs 11%, = 0.03). There was no difference between HSIL and LSIL for PD-L1+ epithelial cells.

Conclusions: Anal dysplastic lesions are accompanied by an inflammatory lymphocytic infiltrate expressing CD8 and PD-1, more frequent in high-grade lesions. These results highlight the involvement of the PD-1/PD-L1 pathway in the natural history of anal dysplasia.
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http://dx.doi.org/10.18632/oncotarget.27756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533075PMC
September 2020

O-positive blood type is associated with prolonged recurrence-free survival following curative resection of pancreatic neuroendocrine tumors.

Pancreatology 2020 Dec 30;20(8):1718-1722. Epub 2020 Sep 30.

Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon University Hospital (APHP), Clichy, France; Université de Paris, France; INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France. Electronic address:

Background: The ABO blood group may influence the development and progression of cancer. In particular, the prognosis of patients with blood type O is better for pancreatic adenocarcinoma, although this has not been extensively explored in pancreatic neuroendocrine tumors (PanNET).

Objective: To assess the influence of the ABO and Rhesus blood types on the risk of recurrence in patients who underwent curative intent PanNET surgical resection.

Methods: All consecutive patients operated on for well-differentiated panNET in an expert center from 2003 to 2018 were retrospectively included. Blood group, Rhesus system, demographic and clinical data were collected. The primary endpoint was recurrence free survival (RFS). Factors associated with RFS were explored using Cox proportional hazard models.

Results: Overall, 300 patients (male 43%) were included, median age 54 years old (IQR 45-64). The ABO blood group distribution was similar to that of the French population. There was no association between blood group and tumor features. The median postoperative follow-up was 43.9 months (17.0-77.8). The 5- and 10-year RFS rates were 85 ± 4% and 71 ± 13% in O RhD + patients, versus 72 ± 4% and 63 ± 6% otherwise, respectively (p = 0.035). The O RhD + blood group was associated with a decreased risk of recurrence (HR 0.34, 95% CI [0.15-0.75]), p = 0.007 in multivariable analysis adjusted for age, ki67, functioning syndrome, resection margins, tumor size, lymph node status, oncogenetic syndrome.

Conclusions: After curative-intent surgical resection for PanNET, patients with a non-O RhD + blood group may have an increased risk of recurrence and could benefit from closer follow-up.
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http://dx.doi.org/10.1016/j.pan.2020.09.014DOI Listing
December 2020

Critical appraisal of MGMT in digestive NET treated with alkylating agents.

Endocr Relat Cancer 2020 10;27(10):R391-R405

Centre of Research on Inflammation, INSERM U1149, Paris, France.

The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.
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http://dx.doi.org/10.1530/ERC-20-0227DOI Listing
October 2020

Correction to: Prediction of pancreatic neuroendocrine tumour grade with MR imaging features: added value of diffusion-weighted imaging.

Eur Radiol 2020 Nov;30(11):6387

Department of Radiology, University Hospitals Paris Nord Val de Seine, Beaujon, Clichy, Hauts-de-Seine, France.

The original version of this article, published on 19 August 2016, unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s00330-020-06947-xDOI Listing
November 2020

Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model.

Sci Rep 2020 04 30;10(1):7393. Epub 2020 Apr 30.

Inserm UMRS 1149, UFR de Médecine Paris Diderot, Université de Paris, AP-HP, Paris, France.

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.
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http://dx.doi.org/10.1038/s41598-020-64425-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192900PMC
April 2020

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 05 28;52(5):473-492. Epub 2020 Mar 28.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France. Electronic address:

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).

Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.

Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.

Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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http://dx.doi.org/10.1016/j.dld.2020.02.011DOI Listing
May 2020

Could pancreatic grade 3 neuroendocrine tumors really behave similarly to neuroendocrine carcinomas following resection?

HPB (Oxford) 2020 05 26;22(5):792. Epub 2020 Mar 26.

Université de Paris, France; INSERM U1149, Centre of Research on Inflammation, France; Department of Pathology, ENETS Centre of Excellence, Bichat/Beaujon Hospital, Clichy, Paris, France.

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http://dx.doi.org/10.1016/j.hpb.2020.03.009DOI Listing
May 2020

Histopathological Revision for Gastroenteropancreatic Neuroendocrine Neoplasms in Expert Centers: Does It Make the Difference?

Neuroendocrinology 2021 11;111(1-2):170-177. Epub 2020 Mar 11.

Department of Endocrinology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Background: The correct histopathological diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is crucial for treatment selection and prognostication. It is also very challenging due to limited experience in nonexpert centers. Revision of pathology is standard of care for most patients who are referred to NEN expert centers.

Objectives: To describe the clinical impact of histopathological revision for GEP-NEN patients referred to an expert center.

Methods: Retrospective multicenter analysis of all GEP-NENs receiving a histopathological revision in 6 European NEN expert centers (January 2016 to December 2016) to evaluate the impact on patient management.

Results: 175 patients were included and 14.7% referred for a second opinion. Histological samples were 69.1% biopsies, 23.4% surgical specimens, and 7.5% endoscopic resections. Histopathological changes due to revision included first assessment of Ki67 in 8.6% of cases, change in grading in 11.4% (3.4% G1 to G2; 5.7% G2 to G1; 0.6% G2 to G3; 1.7% G3 to G2), definition of tumor invasion in 10.8%, additional immunohistochemical staining in 2.3%, diagnosis of mixed adenoneuroendocrine carcinoma in 3.4%, exclusion of NEN in 3.4%, first diagnosis of NEN in 2.3%, and tumor differentiation for G3 in 1.7%. The revision had a clinical impact in 36.0% of patients, leading to a new therapeutic indication in 26.3%. The indication to then perform a new imaging test occurred in 21.1% and recommendation to follow-up with no further treatment in 6.3%.

Conclusions: Histopathological revision in expert centers for NENs can change the diagnosis, with a significant clinical impact in about one third of patients.
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http://dx.doi.org/10.1159/000507082DOI Listing
March 2020

[Inherited tumor syndromes of gastroenteropancreatic and thoracic neuroendocrine neoplasms].

Ann Pathol 2020 Apr 5;40(2):120-133. Epub 2020 Feb 5.

Département de biologie et pathologie médicales, institut Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif cedex, France. Electronic address:

About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.
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http://dx.doi.org/10.1016/j.annpat.2020.01.002DOI Listing
April 2020

Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.

Neuroendocrinology 2021 3;111(1-2):158-169. Epub 2020 Feb 3.

Department of Pathology, ENETS Centre of Excellence, Beaujon-Bichat Hospitals, AP-HP, Paris, France.

Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity.

Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity).

Results: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations.

Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours.
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http://dx.doi.org/10.1159/000506292DOI Listing
February 2020

[Gastric metastasis of merkel cell carcinoma: Review of the literature and histopathological differential diagnoses].

Ann Pathol 2020 Jul 16;40(4):300-305. Epub 2019 Dec 16.

Service d'anatomie et cytologie pathologiques, centre hospitalier Montbéliard-Belfort, 12, rue Docteur Flamand, 25200 Montbéliard, France.

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http://dx.doi.org/10.1016/j.annpat.2019.11.002DOI Listing
July 2020

[Acinic cell carcinoma: an unsuspected malignancy of the nasal cavity].

Ann Pathol 2020 Jan 10;40(1):24-27. Epub 2019 Dec 10.

Département de pathologie, hôpital Bichat-Claude Bernard, Assistance publique-hôpitaux de Paris (AP-HP), 75018, Paris, France.

Acinic cell carcinoma (ACC) is a low grade malignant tumor of the salivary glands. Primary ACC affects most frequently the parotid gland and can rarely arise in the minor salivary glands of the oral cavity, pharynx and larynx. It is extremely rare in the nasal cavity; to our knowledge only 18 cases of primary ACC of the nasal cavity are reported in the English-written literature. Herein we report a case of acinic cell carcinoma of the nasal cavity, describe the clinical, radiological and microscopic features of this uncommon presentation and finally provide a discussion in the light of relevant literature.
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http://dx.doi.org/10.1016/j.annpat.2019.11.003DOI Listing
January 2020

hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status.

Cancers (Basel) 2019 Nov 18;11(11). Epub 2019 Nov 18.

Institut national de la santé et de la recherche médicale (INSERM) U1149, Inflammation research center, Beaujon's Hospital, 92110 Clichy, France.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status.
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http://dx.doi.org/10.3390/cancers11111808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896053PMC
November 2019

Chemotherapy in Resected Neuroendocrine Carcinomas of the Digestive Tract: A National Study from the French Group of Endocrine Tumours.

Neuroendocrinology 2020 21;110(5):404-412. Epub 2019 Aug 21.

Department of Medical Oncology, Saint-Antoine Hospital, Paris, France.

Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy.

Objectives: We aimed to evaluate the effect of neoadjuvant +/- adjuvant and adjuvant therapy in this indication.

Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity.

Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/- adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death.

Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.
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http://dx.doi.org/10.1159/000502825DOI Listing
February 2021

Clinicopathological and Molecular Study of Peritoneal Carcinomatosis Associated with Non-Small Cell Lung Carcinoma.

Pathol Oncol Res 2020 Oct 12;26(4):2795-2800. Epub 2019 Aug 12.

Assistance Publique - Hôpitaux de Paris, département de pathologie, Hôpital Bichat-Claude Bernard, Paris, France.

To retrospectively characterize the molecular features of Non-Small Cell Lung Carcinomas (NSCLC) with peritoneal carcinomatosis (PC), clinicopathological data of 12 patients diagnosed with NSCLC and PC between 2007 and 2016 were collected. Immunohistochemistry and Next Generation Sequencing (NGS) were performed on cases with available material. PC was the initial presentation of NSCLC in 17% of the cases. Overall, patients with PC displayed a poor median survival of 12 weeks. Histology was adenocarcinoma in 11 cases. 37.5% of cases showed PD-L1 immunostaining positivity (50% cut-off). ALK and ROS1 immunostainings were negative. Using NGS, we identified 17 molecular alterations in 9 genes (TP53, KRAS, STK11, BRAF, EGFR, DDR2, ERBB4, SMAD4, CTNNB1) in 88.9% of adenocarcinomas. To the best of our knowledge, 5 of these variants are not referenced in the literature. In conclusion, PC might be the initial presentation of NSCLC. Molecular profiling of our cases did not find any effective targetable alteration, except from high PD-L1 expression.
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http://dx.doi.org/10.1007/s12253-019-00713-1DOI Listing
October 2020

Lesion-by-lesion correlation between uptake at FDG PET and the Ki67 proliferation index in resected pancreatic neuroendocrine tumors.

Dig Liver Dis 2019 12 23;51(12):1720-1724. Epub 2019 Jul 23.

Department of Gastroenterology and Pancreatology, ENETS Centre of Excellence, Beaujon Hospital, APHP, Clichy, France; Université de Paris, Paris, France; INSERM U1149, Beaujon Hospital, Clichy, France.

Background: Ki67 proliferation index and tumor uptake on 18fluorodeoxyglucose positron-emitting tomography (FDG-PET) could be correlated in pancreatic neuroendocrine tumors (PanNET), but the evaluation of the former is subject to tumor heterogeneity.

Aims: Explore the correlation between Ki67 and FDG-PET uptake at the lesion scale in PanNET.

Methods: We identified target lesions ≥10 mm in patients operated on for a PanNET and/or associated metastases with preoperative FDG-PET and without neoadjuvant treatment. We assessed the lesion-by-lesion correlation between Ki67 and the tumor-to-liver SUVmax ratio (SUVmax T/L), and between pathological grade (G) and metabolic grade (mG) (mG1, SUVmax T/L ≤ 1, mG2, SUVmax T/L 1-2.3 and mG3, SUVmax T/L > 2.3).

Results: Twenty-one patients underwent pancreatic (n = 12), liver (n = 2) or combined surgery (n = 7). Overall, 36 target lesions (21 primary PanNET, 13 liver metastases and 2 lymph-node metastases) were identified, of median Ki67 4%. Ki67 correlated with SUVmax T/L (r = 0.55, p < 0.001). Median SUVmax T/L was 0.76, 1.41 and 2.67 for lesions G1, G2 and G3, respectively (p = 0.005). Median Ki67 was 1, 4 and 25 for lesions mG1, mG2 and mG3, respectively (p = 0.005).

Conclusions: Uptake on FDG-PET could predict the pathological grade of PanNET lesions. Hence, FDG-PET could supplement pathological evaluation of tumor biological aggressiveness and could guide the choice of the most relevant lesions to biopsy.
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http://dx.doi.org/10.1016/j.dld.2019.06.022DOI Listing
December 2019

Endoscopic, transanal, laparoscopic, and transabdominal management of rectal neuroendocrine tumors.

Best Pract Res Clin Endocrinol Metab 2019 10 9;33(5):101293. Epub 2019 Jul 9.

Department of Pancreatology and Gastroenterology, ENETS Centre of Excellence, AP-HP, Beaujon Hospital, Clichy, France; Université de Paris, France; INSERM UMR1149, Paris, France.

Rectal neuroendocrine tumors (RNET) are rare tumors but their prevalence is constantly increasing due to a prolonged survival and rising incidence related to a growing number of colonoscopies and improved knowledge. Their main prognostic determinant is tumor stage. While most RNET are localized, their management should be tailored depending on the presence or absence of the factors predictive of lymph-node metastases including tumor size, endoscopic aspect, T stage, grade and lymphovascular invasion. Endoscopic ultrasonography is the most relevant technique for locoregional assessment. Low-risk RNET can be treated using advanced endoscopic resection techniques or transanal endoscopic microsurgery, in expert centers because they require technicity and experience. Conversely, radical surgery with lymphadenectomy should be proposed in the presence of any pejorative factor. The long-term evolution of RNET remains to be specified, and prospective studies should be conducted in order to determine the relevance of the current management strategies.
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http://dx.doi.org/10.1016/j.beem.2019.101293DOI Listing
October 2019