Publications by authors named "Jean-Yves Scoazec"

438 Publications

Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma.

Cancers (Basel) 2022 Jun 14;14(12). Epub 2022 Jun 14.

Department of Dermatology, Gustave Roussy, 114 rue Edouard-Vaillant, 94800 Villejuif, France.

We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this "experimental" sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition.
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http://dx.doi.org/10.3390/cancers14122937DOI Listing
June 2022

Diagnostic Challenges and Pitfalls of Mammary Pleomorphic Adenoma Illustrated by a Case Report.

Int J Surg Pathol 2022 May 29:10668969221102552. Epub 2022 May 29.

Department of Pathology, 46657Gustave Roussy, Villejuif, France.

Mammary pleomorphic adenoma is a biphasic tumor, characterized by epithelial-myoepithelial components with myxochondroid stroma, resembling the prototypic pleomorphic adenoma of the salivary glands. We report the multiple diagnostic pitfalls raised by a mammary pleomorphic adenoma, initially diagnosed as mucinous carcinoma on fine-needle aspiration (FNA) cytology and invasive carcinoma on needle core biopsy. The final diagnosis was made on the surgical specimen. As the term "pleomorphic" suggests, this tumor can present various phenotypes, some of which might be misleading on both FNA cytology or needle core biopsy. Rearrangements in and genes have not been detected in our patient. Mammary pleomorphic adenoma is considered a benign tumor, despite rare local recurrence and malignant behavior. Its correct identification, despite the difficulties, is essential to avoid unnecessary aggressive treatment.
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http://dx.doi.org/10.1177/10668969221102552DOI Listing
May 2022

Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies.

J Immunother Cancer 2022 May;10(5)

Department of Medecine, Institut Bergonié, Bordeaux, France

Background: Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles.

Methods: Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration.

Results: Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of , CD27, and in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of in the tumors of responders. Analysis of three independent data sets confirmed that high expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment.

Conclusions: Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of , and gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.
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http://dx.doi.org/10.1136/jitc-2021-003890DOI Listing
May 2022

Screening for Prognostic Biomarkers in Metastatic Adrenocortical Carcinoma by Tissue Micro Arrays Analysis Identifies P53 as an Independent Prognostic Marker of Overall Survival.

Cancers (Basel) 2022 Apr 29;14(9). Epub 2022 Apr 29.

Department of Endocrine Oncology, Gustave Roussy, 94805 Villejuif, France.

Advanced adrenocortical carcinoma (ACC) has poor but heterogeneous prognosis. Apart from Ki67 index, no prognostic or predictive biomarker has been validated in advanced ACC, so far. We aimed at analyzing expression of a large panel of proteins involved in known altered pathways in ACC (cell cycle, Wnt/ß-catenin, methylation) to identify and prioritize potential prognostic or predictive parameters metastatic ACC population. We conducted a retrospective multicentric study. Overall survival (OS) and partial response according to RECIST 1.1 were primary endpoints. TMA was set up and 16 markers were analyzed. Modified ENSAT and GRAS parameters were characterized for prognostic adjustment. Results: We included 66 patients with a mean age at metastatic diagnosis of 48.7 ± 15.5 years. Median survival was 27.8 months. After adjustment to mENSAT-GRAS parameters, p53 and PDxK were prognostic of OS. No potential biomarker has been identified as predictive factor of response. We identified for the first time P53 as an independent prognostic marker of metastatic adrenocortical carcinoma after mENSAT-GRAS parameter adjustment. Prognostic impact of Wnt/ß-catenin alterations was not confirmed in this cohort of metastatic ACC.
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http://dx.doi.org/10.3390/cancers14092225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099575PMC
April 2022

Recurrent IgG4 cholangitis after liver transplantation: Back to the future.

Dig Liver Dis 2022 May 3. Epub 2022 May 3.

Université Claude Bernard Lyon 1, Lyon, France; Hospices civils de Lyon, Hôpital Edouard Herriot, Service d'Anatomie Pathologique, Lyon, France.

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http://dx.doi.org/10.1016/j.dld.2022.04.010DOI Listing
May 2022

Targeting genome integrity dysfunctions impedes metastatic potency in non-small cell lung cancer circulating tumor cell-derived explants.

JCI Insight 2022 Jun 8;7(11). Epub 2022 Jun 8.

Gustave Roussy, Paris-Saclay University, "Circulating Tumor Cells" Translational Platform, CNRS UMS3655 - INSERM US23 AMMICA, Villejuif, France.

DNA damage and genomic instability contribute to non-small cell lung cancer (NSCLC) etiology and progression. However, their therapeutic exploitation is disappointing. CTC-derived explants (CDX) offer systems for mechanistic investigation of CTC metastatic potency and may provide rationale for biology-driven therapeutics. Four CDX models and 3 CDX-derived cell lines were established from NSCLC CTCs and recapitulated patient tumor histology and response to platinum-based chemotherapy. CDX (GR-CDXL1, GR-CDXL2, GR-CDXL3, GR-CDXL4) demonstrated considerable mutational landscape similarity with patient tumor biopsy and/or single CTCs. Truncal alterations in key DNA damage response (DDR) and genome integrity-related genes were prevalent across models and assessed as therapeutic targets in vitro, in ovo, and in vivo. GR-CDXL1 presented homologous recombination deficiency linked to biallelic BRCA2 mutation and FANCA deletion, unrepaired DNA lesions after mitosis, and olaparib sensitivity, despite resistance to chemotherapy. SLFN11 overexpression in GR-CDXL4 led to olaparib sensitivity and was in coherence with neuroendocrine marker expression in patient tumor biopsy, suggesting a predictive value of SLFN11 in NSCLC histological transformation into small cell lung cancer (SCLC). Centrosome clustering promoted targetable chromosomal instability in GR-CDXL3 cells. These CDX unravel DDR and genome integrity-related defects as a central mechanism underpinning metastatic potency of CTCs and provide rationale for their therapeutic targeting in metastatic NSCLC.
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http://dx.doi.org/10.1172/jci.insight.155804DOI Listing
June 2022

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer.

Nat Commun 2022 04 13;13(1):1985. Epub 2022 Apr 13.

Aix Marseille Univ, CNRS, IBDM, Marseille, France.

Neuronal nerve processes in the tumor microenvironment were highlighted recently. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via conventional histological preparations. Here, we employ three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in a murine model of pancreatic ductal adenocarcinoma (PDAC). Our results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing sympathetic nerves within tumors plus an active, localized sprouting of axon terminals into non-neoplastic lesions and tumor periphery. Ablation of the innervating sympathetic nerves increases tumor growth and spread. This effect is explained by the observation that sympathectomy increases intratumoral CD163 macrophage numbers, which contribute to the worse outcome. Altogether, our findings provide insights into the mechanisms by which the sympathetic nervous system exerts cancer-protective properties in a mouse model of PDAC.
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http://dx.doi.org/10.1038/s41467-022-29659-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007988PMC
April 2022

Diagnostic Pitfall: a Low-Grade EC-Cell Neuroendocrine Tumor Arising in a Rectal Duplication Cyst.

Endocr Pathol 2022 06 17;33(2):327-329. Epub 2022 Mar 17.

Département de Biologie Et Pathologie Médicales, Service de Pathologie, Gustave Roussy Cancer Campus, 114 rue Edouard Vaillant, 94805, Villejuif, France.

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http://dx.doi.org/10.1007/s12022-022-09713-5DOI Listing
June 2022

The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies.

Cancer Discov 2022 05;12(5):1266-1281

Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Abstract: MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered "ready for routine use." Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies-56% of them within early clinical trials-mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA).

Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171.
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http://dx.doi.org/10.1158/2159-8290.CD-21-1136DOI Listing
May 2022

-Associated Inflammatory Polyp of the Colon: First Report of a Sporadic Case.

Int J Surg Pathol 2022 Mar 8:10668969221085819. Epub 2022 Mar 8.

Gustave Roussy Cancer Campus, Département de Biologie et Pathologie Médicales, Service de Pathologie morphologique, Villejuif, France.

"Juvenile-like (hyperplastic/inflammatory) mucosal polyp" is a term proposed for rare benign mesenchymal lesions of the gastro-intestinal tract so far reported only in patients with type 1 neurofibromatosis (NF1). We report here a first sporadic case of -associated mucosal inflammatory polyp of the colon. The diagnosis was made in a 53-year old female patient with a large polypoid tumor of the cecum. The lesion was predominantly mucosal, made of fibroblast-like cells associated with inflammatory infiltrates rich in eosinophils and containing entrapped, distorted epithelial glands, responsible for the juvenile-like appearance. Whole exome sequencing showed a pathogenic variant of . The patient had no evidence of NF1; no mutation was detected in normal tissues. Our observation may support the existence of juvenile-like inflammatory polyps associated with alterations, either germline or somatic. This justifies to test in difficult-to-classify gastrointestinal mesenchymal tumors.
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http://dx.doi.org/10.1177/10668969221085819DOI Listing
March 2022

De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells.

Mol Cancer 2022 03 4;21(1):65. Epub 2022 Mar 4.

Laboratory of the « Genome Dynamics in the Immune System », Équipe Labellisée La Ligue Contre Le Cancer, Université de Paris, Université Paris Saclay, INSERM UMR 1163, Institut Imagine, Paris, France.

Background: Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion.

Methods: We performed CRISPR/Cas9-mediated genome editing of the NPM-ALK chromosomal translocation in primary human activated T lymphocytes.

Results: Both CD4+ and CD8+ NPM-ALK-edited T lymphocytes showed rapid and reproducible competitive advantage in culture and led to in vivo disease development with nodal and extra-nodal features. Murine tumors displayed the phenotypic diversity observed in ALK+ ALCL patients, including CD4+ and CD8+ lymphomas. Assessment of transcriptome data from models and patients revealed global activation of the WNT signaling pathway, including both canonical and non-canonical pathways, during ALK+ ALCL lymphomagenesis. Specifically, we found that the WNT signaling cell surface receptor ROR2 represented a robust and genuine marker of all ALK+ ALCL patient tumor samples.

Conclusions: In this study, ab initio modeling of the ALK+ ALCL chromosomal translocation in mature T lymphocytes enabled the identification of new therapeutic targets. As ROR2 targeting approaches for other cancers are under development (including lung and ovarian tumors), our findings suggest that ALK+ ALCL cases with resistance to current therapies may also benefit from ROR2 targeting strategies.
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http://dx.doi.org/10.1186/s12943-022-01520-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895835PMC
March 2022

Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy.

Cancer Cell 2022 03 3;40(3):318-334.e9. Epub 2022 Feb 3.

Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

Recruitment of lymphocytes into tumors is critical for anti-tumor immunity and efficacious immunotherapy. We show in murine models that tumor-associated high endothelial venules (TA-HEVs) are major sites of lymphocyte entry into tumors at baseline and upon treatment with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB). TA-HEV endothelial cells (TA-HECs) derive from post-capillary venules, co-express MECA-79 HEV sialomucins and E/P-selectins, and are associated with homing and infiltration into tumors of various T cell subsets. Intravital microscopy further shows that TA-HEVs are the main sites of lymphocyte arrest and extravasation into ICB-treated tumors. Increasing TA-HEC frequency and maturation increases the proportion of tumor-infiltrating stem-like CD8 T cells, and ameliorates ICB efficacy. Analysis of tumor biopsies from 93 patients with metastatic melanoma reveals that TA-HEVs are predictive of better response and survival upon treatment with anti-PD-1/anti-CTLA-4 combination. These studies provide critical insights into the mechanisms governing lymphocyte trafficking in cancer immunity and immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2022.01.002DOI Listing
March 2022

Posttransplant immune-mediated cholangiopathies.

Curr Opin Gastroenterol 2022 03;38(2):98-103

Institut Gustave Roussy, Département de pathologie, Villejuif and Université Paris Saclay, France.

Purpose Of Review: Liver transplantation (LT) is the treatment of end-stage chronic liver diseases, mainly decompensated cirrhosis and hepatocellular carcinoma. Biliary complications can be schematically classified into macroscopic versus microscopic lesions. Immune-related cholangiopathies include rejection, graft-versus-host disease (GVHD) and recurrence of pre-LT auto-immune biliary diseases, i.e. primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Here, we review the various types of posttransplant immune-related cholangiopathies, and discuss their clinical implications, especially diagnostic issues.

Recent Findings: Recurrence of PBC and PSC after LT is increasingly well described in large cohorts and long-term follow-up. In this setting, the preventive effect of ursodeoxycholic acid on PBC recurrence, as well as the deleterious role of tacrolimus are now well documented. In addition, the significant negative impact of recurrent PBC on survival after LT has recently been demonstrated. With respect to rejection-associated biliary injury, a growing body of evidence is emerging on the role of anti-HLA antibody-mediated rejection.

Summary: Immune-mediated cholangiopathies occurring after LT can be divided in two main nosologic groups: biliary lesions due to recurrence of PBC or PSC, or in the context of rejection, either acute or chronic, T-cell- or antibody-mediated. GVHD is very rare. Final diagnosis is strongly based on clinical context (indication for LT, delay since transplantation, biological abnormalities, imaging) but also and to an even greater extent on biopsy of liver graft. Clinico-pathological discussions are recommended, hearing in mind that diseases can be intertwined.
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http://dx.doi.org/10.1097/MOG.0000000000000815DOI Listing
March 2022

TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth.

Commun Biol 2022 01 12;5(1):42. Epub 2022 Jan 12.

Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings confirm TWIST1 as promising therapeutic target in NB.
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http://dx.doi.org/10.1038/s42003-021-02958-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755726PMC
January 2022

Drug-induced bile duct injury: new agents, new mechanisms.

Curr Opin Gastroenterol 2022 03;38(2):83-88

Department of Pathology, Gustave Roussy Cancer Campus, Villejuif.

Purpose Of Review: Drug-induced bile duct injury can be caused by a long list of agents. In most cases, damage is because of T-cell-mediated idiosyncratic reactions. Recently, a number of new agents, including not only drugs but also herbal supplements, have been incriminated and new mechanisms of bile duct injury have emerged. This review will focus on these new data.

Recent Findings: New members of drug families already known to be responsible for bile duct injury have been incriminated. New players have been identified, such as herbal supplements, like kratom, and recreational drugs, such as ketamine used outside the medical setting. Anticytokine monoclonal antibodies are rarely involved. In contrast, antineoplastic treatments are of growing concern, especially immune checkpoint inhibitors, which induce immune-related adverse effects because of the excessive stimulation of the immune system and its lack of regulation.

Summary: Two patterns of bile duct injury are recognized. Drug-induced small-duct cholangiopathies target the smaller bile ducts; acute injuries eventually progress to chronic disease in the form of the vanishing bile duct syndrome. Drug-induced sclerosing cholangitis target large bile ducts, with a protracted chronic course; the onset of symptoms may be delayed after drug discontinuation; potentially severe, life-threatening complications can occur.
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http://dx.doi.org/10.1097/MOG.0000000000000813DOI Listing
March 2022

Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.

Cancer Discov 2022 04;12(4):1128-1151

Laboratoire de Pathologie Clinique et Expérimental, FHU OncoAge et Biobanque BB-0033-00025, CHU de Nice, Université Côte d'Azur, Nice, France.

Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies.

Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0999DOI Listing
April 2022

Case Report: Response to Immunotherapy, Can Radiotherapy Be a Troublemaker?

Front Immunol 2021 4;12:745146. Epub 2021 Nov 4.

Early Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France.

Immunotherapy has dramatically changed the treatment landscape for several tumor types. However, the impact of previous radiotherapy (RT) on response to immunotherapy is still unknown. We report the case of a 58-year-old female diagnosed with a squamous anal cell carcinoma previously treated with RT and having a dissociated response to anti-PD1 agent. An extensive analysis of the immune contexture performed on the tissue collected from both previously RT-treated and RT-untreated lesions confirmed differences on immune microenvironment, highlighting the potential impact of radiotherapy on the immune response.
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http://dx.doi.org/10.3389/fimmu.2021.745146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600981PMC
December 2021

A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma.

Clin Cancer Res 2022 02 16;28(3):518-525. Epub 2021 Nov 16.

Gustave Roussy, INSERM U981, Villejuif France.

Purpose: Less than 50% of patients with melanoma respond to anti-programmed cell death protein 1 (anti-PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8 T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti-PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti-PD-1 therapy.

Experimental Design: PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory = 66 and validation = 71) of samples from patients with melanoma treated with anti-PD-1±anti-CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8 cells density, and NanoString RNA signature, were also evaluated.

Results: A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71-0.77). Progression-free and overall survival were significantly longer in patients with high PLA values ( = 0.00019 and < 0.0001, respectively).

Conclusions: The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti-PD-1 efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1229DOI Listing
February 2022

Long Term Efficacy and Assessment of Tumor Response of Transarterial Chemoembolization in Neuroendocrine Liver Metastases: A 15-Year Monocentric Experience.

Cancers (Basel) 2021 Oct 26;13(21). Epub 2021 Oct 26.

Gustave Roussy, Département d'Anesthésie, Chirurgie et Interventionnel (DACI), F-94805 Villejuif, France.

Background: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival.

Methods: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003-2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan-Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS.

Results: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90-139 months). Median TTP and TTUP were 19.3 months (95%CI 16.3-22.3) and 26.2 months (95%CI 22.3-33.1), respectively. Median OS was 5.3 years (95%CI 4.2-6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6-89.8) than in non-responders (39.6 months; 95%CI = 32.8-60.2; < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS.

Conclusion: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.
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http://dx.doi.org/10.3390/cancers13215366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582443PMC
October 2021

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Nat Genet 2021 11 18;53(11):1553-1563. Epub 2021 Oct 18.

Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.
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http://dx.doi.org/10.1038/s41588-021-00928-6DOI Listing
November 2021

Erratum à l’article « Tumeur à cellules fusiformes : infection ou néoplasie ? ».

Ann Pathol 2021 Sep;41(5):505

Service de pathologie morphologique, département de biologie et pathologie médicales, Gustave-Roussy Cancer Campus, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2021.08.001DOI Listing
September 2021

PAX3-NCOA1 alveolar rhabdomyosarcoma of the tongue: A rare entity with challenging diagnosis and management.

Pediatr Blood Cancer 2021 11 23;68(11):e29288. Epub 2021 Aug 23.

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Alveolar rhabdomyosarcoma (ARMS) is associated with PAX3/PAX7-FOXO1 fusion, which confers specific clinic and biologic characteristics with inferior outcomes. A minority of tumors still histologically classified as "true" ARMS lack the canonical PAX-FOXO1 fusion but have new molecular alterations. We present the first case of PAX3-NCOA1 ARMS with clinical data and follow-up in a two-year-old girl with ARMS of the tongue and nodal extension, treated with chemotherapy, hemi glossectomy, lymph node dissection, and brachytherapy to conserve oral function and limit long-term sequelae. Given the rarity of such variant fusion in ARMS, international collaboration is required to evaluate its prognostic value.
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http://dx.doi.org/10.1002/pbc.29288DOI Listing
November 2021

Therapeutic potential of the human endogenous retroviral envelope protein HEMO: a pan-cancer analysis.

Mol Oncol 2022 04 11;16(7):1451-1473. Epub 2021 Oct 11.

CNRS UMR 9196, Laboratory of Molecular Physiology and Pathology of Endogenous and Infectious Retroviruses, Gustave Roussy, University Paris-Saclay, Villejuif, France.

Human endogenous retroviruses represent approximately 8% of our genome. Most of these sequences are defective except for a few genes such as the ancestral retroviral HEMO envelope gene (Human Endogenous MER34 ORF), recently characterized by our group. In this study, we characterized transcriptional activation of HEMO in primary tumors from The Cancer Genome Atlas (TCGA) and in metastatic tumors from a Gustave Roussy cohort. Pan-cancer detection of the HEMO protein in a series of patient samples validated these results. Differential gene expression analysis in various TCGA datasets revealed a link between HEMO expression and activation of Wnt/β-catenin signaling, in particular in endometrial cancer. Studies on cell models led us to propose that the Wnt/β-catenin pathway could act as an upstream regulator of this retroviral endogenous sequence in tumor condition. Characterization of transcriptomic profiles of both HEMO and HEMO tumors suggested that activation of HEMO is negatively associated with immune response signatures. Taken together, these results highlight that HEMO, as an endogenous retroviral envelope protein specifically expressed in tumors, represents a promising tumor biomarker and therapeutic target.
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http://dx.doi.org/10.1002/1878-0261.13069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978518PMC
April 2022

Prognostic factors of metastatic neuroendocrine carcinoma under first-line treatment with platinum etoposide with a focus on NEC score and Rb expression: Results from the multicentre RBNEC study of the Groupe d'Etude des Tumeurs Endocrines (GTE) and the ENDOCAN-RENATEN network.

Eur J Cancer 2021 07 3;152:100-115. Epub 2021 Jun 3.

Oncologie endocrinienne, Département d'imagerie, Gustave Roussy, Villejuif, F-94805, France.

Introduction And Aim: Neuroendocrine carcinomas (NECs) are aggressive malignant diseases. Platinum-etoposide (PE) combination is the standard first-line treatment, whatever the primary location. The NEC score and also retinoblastoma protein (Rb) status have been suggested to be predictive/prognostic factors in NEC. The primary objective of our multicentric retrospective study was to evaluate the prognostic relevance of the NEC score and Rb status, assessed by immunohistochemistry in PE-treated patients with metastatic NEC.

Methods: Seven centres participated. The inclusion criteria were NEC, whatever the primary site, metastatic stage, first-line treatment with PE and tissue samples available. Rb status was determined centrally.

Results: We report multicentric data from 185 metastatic patients (37% women, median age 63). There were 108 small-cell NECs (SCNECs, 58.4%), 50 large-cell NECs (LCNECs, 27%) and 27 not otherwise specified NECs (nosNECs, 14.6%). The primary sites were the thorax (37%), gastroenteropancreatic sites (38%), unknown (15%) and other (9%). The mean Ki-67 index was 76% (range 20-100). Rb status was interpretable in 122 cases. Rb expression was lost in 74% of the cases: 84% of SCNEC vs. 60% and 63% of LCNEC and nosNEC, respectively (p = 0.016). Objective response was seen in 70% of SCNEC, 45% of LCNEC and 48% of nosNEC (p < 0.001) and in 62% of Rb-negative tumours vs. 46% of Rb-positive tumours (p = 0.3). There was no difference in median progression-free survival or overall survival (OS) as per Rb status. Age, NEC score and response to chemotherapy were the main factors associated with OS in our cohort.

Conclusion: In our series, Rb status had no prognostic impact in PE-treated metastatic patients with NEC, whereas age, NEC score and response to chemotherapy were the main factors associated with OS.
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http://dx.doi.org/10.1016/j.ejca.2021.04.030DOI Listing
July 2021

FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin.

Dig Liver Dis 2021 07 12;53(7):824-829. Epub 2021 May 12.

Hepato-gastroenterology department, Centre Hospitalier de Saint-Malo, Saint-Malo F-35403, France.

Background: Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen.

Methods: The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled.

Main Inclusion Criteria Are: NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.
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http://dx.doi.org/10.1016/j.dld.2021.04.016DOI Listing
July 2021

Response to systemic therapy in fumarate hydratase-deficient renal cell carcinoma.

Eur J Cancer 2021 07 8;151:106-114. Epub 2021 May 8.

Department of Medical Oncology, Gustave Roussy, Villejuif, France; Réseau National de Référence pour Cancers Rares de l'Adulte PREDIR labellisé par l'INCa, Hôpital Bicêtre, AP-HP, Le Kremlin Bicêtre, France. Electronic address:

Purpose: Fumarate hydratase-deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population.

Methods: We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan-Meier method.

Results: Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received "other antiangiogenics" (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for "other antiangiogenics," and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0-95.0).

Conclusions: We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.
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http://dx.doi.org/10.1016/j.ejca.2021.04.009DOI Listing
July 2021

Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium.

Eur J Cancer 2021 06 20;150:53-62. Epub 2021 Apr 20.

Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. Electronic address:

Purpose: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation.

Experimental Design: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry.

Results: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased.

Conclusions: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS.

Gov Identifier: NCT2813135.
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http://dx.doi.org/10.1016/j.ejca.2021.03.032DOI Listing
June 2021

[Spindle cell tumor: Infection or neoplasm?]

Ann Pathol 2021 Jul 18;41(4):418-421. Epub 2021 Apr 18.

Service de pathologie morphologique, département de biologie et pathologie médicales, Gustave-Roussy Cancer Campus, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2021.03.010DOI Listing
July 2021

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

NPJ Breast Cancer 2021 Apr 16;7(1):41. Epub 2021 Apr 16.

Gustave Roussy Cancer Campus, Villejuif, France.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
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http://dx.doi.org/10.1038/s41523-021-00252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052407PMC
April 2021

Perspectives in pathomics in head and neck cancer.

Curr Opin Oncol 2021 05;33(3):175-183

INSERM U1030, Molecular Radiotherapy and Therapeutic Innovation, Gustave Roussy Cancer Campus, Paris-Saclay University.

Purpose Of Review: Pathology is the cornerstone of cancer care. Pathomics, which represents the use of artificial intelligence in digital pathology, is an emerging and promising field that will revolutionize medical and surgical pathology in the coming years. This review provides an overview of pathomics, its current and future applications and its most relevant applications in Head and Neck cancer care.

Recent Findings: The number of studies investigating the use of artificial intelligence in pathology is rapidly growing, especially as the utilization of deep learning has shown great potential with Whole Slide Images. Even though numerous steps still remain before its clinical use, Pathomics has been used for varied applications comprising of computer-assisted diagnosis, molecular anomalies prediction, tumor microenvironment and biomarker identification as well as prognosis evaluation. The majority of studies were performed on the most frequent cancers, notably breast, prostate, and lung. Interesting results were also found in Head and Neck cancers.

Summary: Even if its use in Head and Neck cancer care is still low, Pathomics is a powerful tool to improve diagnosis, identify prognostic factors and new biomarkers. Important challenges lie ahead before its use in a clinical practice, notably the lack of information on how AI makes its decisions, the slow deployment of digital pathology, and the need for extensively validated data in order to obtain authorities approval. Regardless, pathomics will most likely improve pathology in general, including Head and Neck cancer care in the coming years.
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http://dx.doi.org/10.1097/CCO.0000000000000731DOI Listing
May 2021
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