Publications by authors named "Nicolas Girard"

246 Publications

Optimal delineation of the clinical target volume for thymomas in the post-resection setting: a multi-center study.

Radiother Oncol 2021 Oct 18. Epub 2021 Oct 18.

Department of Radiation Oncology (Maastro Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.

Background: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyse the difference in CTV delineation between radiation oncologists (RTO) and surgeons.

Methods: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed.

Results: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm, p=0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34±0.21) and high mean HD of 4.5 (± 2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm, p<0.001). A mean volume of 18.9 (±38.1) cm was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm was included in RTO's delineations, but not in the joint delineations.

Conclusions: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favouring the surgeons' judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice.
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http://dx.doi.org/10.1016/j.radonc.2021.10.007DOI Listing
October 2021

Thymic tumours and their special features.

Eur Respir Rev 2021 Dec 20;30(162). Epub 2021 Oct 20.

Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France

Thymic tumours are rare thoracic malignancies, that may be aggressive and difficult to treat. The pillars of the management include pathological review, consideration of differential diagnoses, staging and multidisciplinary discussion. Assessment of resectability is key to drive the treatment sequencing. Association with autoimmune diseases, especially myasthenia gravis, is observed, which impacts the oncological management. Networks are being built at the national and international levels. This article provides an overview of the most recent findings in the diagnosis, staging, histology, and management strategies of thymic tumours.
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http://dx.doi.org/10.1183/16000617.0394-2020DOI Listing
December 2021

A Real-World Study of Patients with Advanced Non-squamous Non-small Cell Lung Cancer with EGFR Exon 20 Insertion: Clinical Characteristics and Outcomes.

Target Oncol 2021 Oct 18. Epub 2021 Oct 18.

Institut Régional du Cancer de Montpellier, Montpellier, France.

Background: In Europe, few data regarding the characteristics of EGFR exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available.

Objective: Using a large real-world cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring EGFR exon 20ins.

Patients And Methods: The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (EGFR) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring EGFR exon 20ins, common EGFR mutations, other EGFR mutations, and wild-type EGFR. Survival parameters were estimated by the Kaplan-Meier method in these four groups.

Results: Out of 9435 nsqNSCLC patients tested for EGFR, 1549 (16.4%) had a mutation, including 61 with EGFR exon 20ins (3.9% of all mutated EGFR). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0-1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval [CI] 22.3-32.4) months, the median real-world overall survival was 24.3 (19.1-32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6-37.5) in patients with common EGFR mutation (n = 1049) (p = 0.049) and 19.6 (95% CI 18.6-20.5) in patients with wild-type EGFR (n = 7866) (p = 0.2).

Conclusions: This large national study in nsqNSCLC patients confirms that EGFR exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type EGFR, but worse than common EGFR mutations, highlighting the need for advancements for this rare population.
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http://dx.doi.org/10.1007/s11523-021-00848-9DOI Listing
October 2021

Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global non-interventional study (UpSwinG).

Lung Cancer 2021 Sep 21;162:9-15. Epub 2021 Sep 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan. Electronic address:

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.

Methods: In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).

Results: At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.

Conclusion: Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.009DOI Listing
September 2021

Unravelling the Puzzle of Anthranoid Metabolism in Living Plant Cells Using Spectral Imaging Coupled to Mass Spectrometry.

Metabolites 2021 Aug 25;11(9). Epub 2021 Aug 25.

Centre National de la Recherche Scientifique, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, CEDEX, F-67401 Illkirch, France.

Vismione H (VH) is a fluorescent prenylated anthranoid produced by plants from the Hypericaceae family, with antiprotozoal activities against malaria and leishmaniosis. Little is known about its biosynthesis and metabolism in plants or its mode of action against parasites. When VH is isolated from , it is rapidly converted into madagascine anthrone and anthraquinone, which are characterized by markedly different fluorescent properties. To locate the fluorescence of VH in living plant cells and discriminate it from that of the other metabolites, an original strategy combining spectral imaging (SImaging), confocal microscopy, and non-targeted metabolomics using mass spectrometry, was developed. Besides VH, structurally related molecules including madagascine (Mad), emodin (Emo), quinizarin (Qui), as well as lapachol (Lap) and fraxetin (Fra) were analyzed. This strategy readily allowed a spatiotemporal characterization and discrimination of spectral fingerprints from anthranoid-derived metabolites and related complexes with cations and proteins. In addition, our study validates the ability of plant cells to metabolize VH into madagascine anthrone, anthraquinones and unexpected metabolites. These results pave the way for new hypotheses on anthranoid metabolism in plants.
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http://dx.doi.org/10.3390/metabo11090571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472718PMC
August 2021

[Establishing at a shared and common educational assessment at Curie Institute].

Bull Cancer 2021 Sep 20. Epub 2021 Sep 20.

Hôpital Institut Curie, département de soins de supports, 26, rue d'Ulm, 75005 Paris, France.

The Institut Curie initiated a therapeutic patient education activity in 2011 by creating several programs. Coordinated and animated by different multidisciplinary teams, these functioned autonomously, with a different initial educational assessment for each one. This organization broke up the patient's educational pathway, and the educational offer, which sometimes proved to be redundant, most often corresponding to the needs shared by all cancer patients. The transversal therapeutic education unit allowed the creation of a single educational pathway per patient. It was necessary to imagine a common initial educational assessment. How can we move from eight specific educational assessments to a single educational assessment? After the harmonization of the different workshops, we moved from seven programs with several workshops to one program with eight themes and 26 workshops. Then several working groups led to the creation of a common, unique framework for the initial educational assessment. In seven months, a total of 119 unique educational assessments were carried out. The majority of those who wanted to undertake an educational process were women (96%). 7% had localized breast cancer, and 66% were undergoing treatment. Each workshop chosen corresponded to a need identified during the assessment. The themes mostly requested were nutrition, communication, and pain. Several advantages have been felt in the implementation of this educational assessment: single entry for the patient reinforced therapeutic alliance, transversal reading of the patient's educational needs. What remains to be done is to train therapeutic education practitioners about this global vision.
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http://dx.doi.org/10.1016/j.bulcan.2021.04.023DOI Listing
September 2021

European and US Real-World Treatment Patterns in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Retrospective Medical Record Review.

Drugs Real World Outcomes 2021 Sep 17. Epub 2021 Sep 17.

Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD, USA.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line (1L) therapy for EGFR mutation-positive (EGFRm) advanced/metastatic non-small cell lung cancer (NSCLC).

Objective: Our objective was to describe real-world treatment patterns and T790M testing practices in patients with 1L disease progression (Europe/USA) following treatment with first- or second-generation EGFR-TKIs.

Methods: This was a retrospective, non-interventional medical record review of patients with EGFRm locally advanced/metastatic NSCLC from routine clinical practice (EGFR-TKI initiation: 1 January 2015 to 31 December 2017; follow-up: last available medical record). Endpoints were demographic/clinical characteristics, incidence of central nervous system (CNS) metastases/leptomeningeal disease, second-line (2L) treatment, T790M mutation testing, and osimertinib treatment prevalence.

Results: Among 469 patients, 73% (n = 341/469) progressed on 1L EGFR-TKI treatment. Of those who progressed, 74% (n = 252/341) were tested for T790M, with 50% (n = 126/252) testing positive; 75% (n = 94/126) of T790M-positive patients received osimertinib (mostly 2L). Of the patients with progression, 24% (n = 83/341) did not receive 2L treatment, and 88% (n = 73/83) of these patients died. At diagnosis of advanced disease, 9% of patients (n = 41) had CNS metastases; at EGFR-TKI initiation, 14% of patients (n = 68) had CNS metastases. Over the study period, 11% of patients (n = 42) developed CNS metastases not detected at NSCLC diagnosis.

Conclusions: Rates of resistance mutation testing and subsequent utilization of recommended 2L therapies could be improved. As more targeted therapies are developed, it will be crucial to improve the molecular testing rates to ensure patients receive appropriate, effective, and timely treatment.
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http://dx.doi.org/10.1007/s40801-021-00261-8DOI Listing
September 2021

Central Nervous System Metastases in Thymic Epithelial Tumors: A Brief Report of Real-World Insight From RYTHMIC.

J Thorac Oncol 2021 Aug 26. Epub 2021 Aug 26.

Thoracic Cancer Unit, Gustave Roussy, Villejuif, France; Paris-Saclay University, Orsay, France. Electronic address:

Thymic epithelial tumors (TETs) are rare malignancies ranging from indolent thymoma A to aggressive thymic carcinomas (TCs). Brain metastases are extremely infrequent for TETs and have only been described in case reports or small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically review every TET case and prospectively includes all consecutive patients discussed by national or regional tumor boards. We analyzed patients with TETs and central nervous system (CNS) metastasis during their cancer history from this large French registry. In an 8-year period, 2909 patients were included in the database, including 248 TCs (8.5%). A total of 14 patients had CNS metastases, five (36%) at diagnosis and nine (64%) at relapse. Among them, 12 patients (86%) had a diagnosis of TC and two (14%) had thymoma A and B3. Surgical biopsies were performed, and the histologic subtype for non-TC tumors was centrally confirmed. Median overall survival was 22 months (95% confidence interval [CI]: 9.8-34.2), with longer, albeit not significant, overall survival when CNS metastases were present at diagnosis versus relapse (not reached versus 17 mo; p = 0.29); median progression-free survival was 13 versus 8 months (p = 0.06), respectively. A higher risk of death (hazard ratio = 5.34, 95% CI: 1.3-21.9, p = 0.02) and relapse (hazard ratio = 1.89, 95% CI: 0.9-3.7, p = 0.06) was observed for patients suffering from TC with brain metastases compared with those without CNS extension. CNS disease was extremely rare in our TET cohort (0.48%), reported at both diagnosis and progression, present primarily in TC, with prevalence rising to 4.9%.
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http://dx.doi.org/10.1016/j.jtho.2021.08.008DOI Listing
August 2021

PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients.

Clin Lung Cancer 2021 Jul 20. Epub 2021 Jul 20.

Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Université Paris-Saclay, Orsay, France.

Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival.
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http://dx.doi.org/10.1016/j.cllc.2021.07.008DOI Listing
July 2021

Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study.

J Clin Oncol 2021 Oct 2;39(30):3391-3402. Epub 2021 Aug 2.

Janssen R&D, Spring House, PA.

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.

Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.

Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.

Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with Exon20ins mutations after progression on platinum-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.21.00662DOI Listing
October 2021

Prognostic value of inflammatory response biomarkers using peripheral blood and [18F]-FDG PET/CT in advanced NSCLC patients treated with first-line chemo- or immunotherapy.

Lung Cancer 2021 09 20;159:45-55. Epub 2021 Jul 20.

Department of Nuclear Medicine, Institut Curie, 92210 Saint-Cloud, France; Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm, Institut Curie, 91401, Orsay, France.

Objectives: We aimed to compare the prognostic value of inflammatory biomarkers extracted from pretreatment peripheral blood and [18F]-FDG PET for estimating outcomes in non-small cell lung cancer (NSCLC) patients treated with first-line immunotherapy (IT) or chemotherapy (CT).

Materials And Methods: In this retrospective multicenter study, we evaluated 111 patients with advanced NSCLC who underwent baseline [18F]-FDG PET/CT before IT or CT between 2016 and 2019. Several blood inflammatory indices were evaluated: derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP) and systemic immune-inflammation index (SII). FDG-PET inflammatory parameters were extracted from lymphoid tissues (BLR and SLR: bone marrow or spleen-to-Liver SUVmax ratios). Association with survival and relationships between parameters were evaluated using Cox prediction models and Spearman's correlation respectively.

Results: Overall, 90 patients were included (IT:CT) (51:39pts). Median PFS was 8.6:6.6 months and median OS was not reached:21.2 months. In the IT cohort, high dNLR (>3), high SII (≥1,270) and high SLR (0.77) were independent statistically significant prognostic factors for one-year progression-free survival (1y-PFS) and two-year overall survival (2y-OS) on multivariable analysis. In the CT cohort, high BLR (≥0.80) and high dNLR (>3) were associated with shorter 1y-PFS (HR 2.2, 95% CI 1.0-4.9) and 2y-OS (HR 3.4, 95CI 1.1-10.3) respectively, on multivariable analysis. Finally, BLR significantly but moderately correlated with most blood-based inflammatory indices (CRP, PLR and SII) while SLR was only associated with CRP (p < 0.01 for all).

Conclusion: In advanced NSCLC patients undergoing first-line IT or CT, pretreatment blood and inflammatory factors evaluating the spleen or bone marrow on [18F]-FDG PET/CT provided prognostic information for 1y-PFS and 2y-OS. These biomarkers should be further evaluated for potential clinical application.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.024DOI Listing
September 2021

CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract.

Genes Chromosomes Cancer 2021 Nov 21;60(11):723-732. Epub 2021 Jul 21.

EA4340 Research Unit, University of Versailles SQY, Boulogne, France.

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.
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http://dx.doi.org/10.1002/gcc.22981DOI Listing
November 2021

["Fortuitous discovery of a thymoma"].

Rev Prat 2021 02;71(2):173-176

Institut du thorax Curie-Montsouris, hôpital Institut Curie, Paris, France.

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February 2021

Oligometastases for Clinicians: Size Matters.

J Clin Oncol 2021 Aug 16;39(24):2643-2646. Epub 2021 Jun 16.

Institut du Thorax Curie-Montsouris, Paris, France.

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http://dx.doi.org/10.1200/JCO.21.00445DOI Listing
August 2021

Lymph Node Dissection in Thymoma: Is it worth it?

Lung Cancer 2021 07 21;157:156-162. Epub 2021 May 21.

Department of Thoracic Surgery, Lung and Heart-Lung Transplantation, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France; National Expert Center for Thymic Malignancies, Réseau Tumeurs THYMiques et Cancer (RYTHMIC), Lyon, France.

Objectives: Lymph node dissection (LND) and nodal metastases in thymomas remain controversial and understudied. The aim of our study was to evaluate the incidence of nodal metastasis and the short term outcomes of systematic LND in thymomas.

Material And Methods: From December 2017 to September 2020, we performed 54 LND conducted according to the International Thymic Malignancy Interest Group (ITMIG) lymph node map. This group was compared to a historical control group of 55 patients who underwent surgery in our center from January 2015 to November 2017.

Results: LND was performed in 72 % and in 5 % of the cases in the study cohort group and historical control group, respectively. The number of lymph nodes retrieved was significantly higher in the study cohort group (3.89 per patient vs. 1.62, p = 0.0021). In the whole population studied, nodal metastases were found in 3 patients (2.8 % of all patients) with 5.6 % in the cohort study group vs. 0 % in the control group (p = 0.12). Patients with nodal metastasis had larger tumors (> 7 cm), and a higher histology grade (B2 and B3). There was a trend towards higher risk of laryngeal nerve palsy in the cohort study group (9.3 % vs. 1.8 %, p = 0.11).

Conclusion: Systematic LND increases the number of lymph node harvested and detects more lymph node metastases, which remains infrequent in thymomas. The impact of LND and the true prognostic significance of lymph node metastases remains controversial. Given the potential complications, LND or sampling should not be perfomed in small, encapsulated and low grade thymomas.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.022DOI Listing
July 2021

Management of thymoma associated autoimmune pure red cell aplasia: Case report and systematic review of the literature.

Lung Cancer 2021 07 11;157:131-146. Epub 2021 May 11.

Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Laboratoire Facultaire de Médecine Factuelle de l'Université Libre de Bruxelles, Belgium. Electronic address:

Pure red cell aplasia (PRCA) is a rare paraneoplastic syndrome observed in 2-5 % of thymomas. Literature reports great variability in its management. Based on an illustrative clinical case, we present a systematic literature review whose main objective is to evaluate the therapeutic management of PRCA. The literature search was performed based on the PICO method in the Medline and Scopus databases. The reference clinical case concerns a 51-year-old woman with stage IVa thymoma. After initial response to chemotherapy, a locoregional progression occurred with PRCA development that responded favorably under second line chemotherapy. The patient finally died in a context of bicytopenia with febrile neutropenia. The systematic review covers 135 articles published between 1950 and 2019. Thymectomy alone or in combination with other therapies showed a 31 % complete remission (CR) rate for PRCA of, whereas none was reported with anti-tumor treatments without thymectomy. Among immunomodulatory therapies, cyclosporin gave the highest percentage of CR (74 %). Finally, the combination of thymectomy and immunomodulatory treatments showed a CR rate of 45 %. Thymectomy appeared to be the most effective anti-tumor treatment for PRCA. Immunomodulatory therapies, particularly cyclosporine, are shown effective, but the risk of infectious complications must be considered. The optimal place of anti-tumor and immunomodulatory therapies against PRCA has yet to be determined.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.010DOI Listing
July 2021

Impact of COVID-19 on the management of patients with thoracic cancers in a tertiary referral center.

Lung Cancer 2021 07 8;157:79-84. Epub 2021 May 8.

Institut Curie, Paris, France; Université Paris Saclay, Université Versailles Saint Quentin, Unité de Formation et de Recherche Simone Veil - Santé, Montigny le Bretonneux, France. Electronic address:

Introduction: Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has spread worldwide in 2020 leading the World Health Organization to declare a pandemic. Patients with thoracic cancers have been reported at higher risk to develop severe disease, and die from COVID-19. In this setting, clinical practice recommendations for the management of patients were published. We report here how these guidelines were implemented in a routine practice setting.

Methods: We retrospectively collected the characteristics, treatment regimen and modification, as well as COVID-19 status and death for all patients with thoracic malignancies scheduled for an appointment at Institute Curie from March 23 to April 17 2020.

Results: A total of 339 patients were included. Treatment strategy was modified for a total of 110 (32 %) patients because of COVID-19; these modifications were in accordance with guidelines for 92 % of patients. The majority of dose modifications were related to immune checkpoint inhibitors, for which switch to flat dosing every 4-6 weeks was made. A total of 5 (1.5 %) patients were diagnosed with COVID-19 disease, 1 of whom died from disease complication.

Conclusion: Our study provides a unique insight in the decision making for patients with thoracic malignancies in the setting of COVID-19 outbreak, showing how guidelines were implemented in the clinic, and what may be optimized in the clinical practice of thoracic oncology in the future.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105127PMC
July 2021

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival.

NPJ Precis Oncol 2021 Apr 28;5(1):33. Epub 2021 Apr 28.

American Society of Clinical Oncology (ASCO), Alexandria, VA, USA.

The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E-05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E-04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients' treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).
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http://dx.doi.org/10.1038/s41698-021-00171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080819PMC
April 2021

[Rheumatic immune adverse events related to immune checkpoint inhibitors-(IrAEs related to ICI)].

Bull Cancer 2021 Jun 24;108(6):643-653. Epub 2021 Apr 24.

Centre hospitalier Lyon Sud-hospices civils de Lyon, service de rhumatologie, centre expert des métastases et d'oncologie osseuse secondaire (CEMOS), 69310 Pierre Bénite, France; Université de Lyon, Inserm UMR 1033-LYOS, 69003 Lyon, France; Institut de cancérologie des hospices Civils de Lyon, ImmuCare (Immunology cancer research), 69310 Pierre Bénite, France. Electronic address:

New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (<20mg per day). Dose should be adjusted according to severity. The use of disease modifying anti-rheumatic drugs (DMARDs), either conventional and/or biological should be very cautious and result from a shared decision between oncologist and rheumatologist to best manage dysimmunitary complications without hampering the antitumor efficacy of ICI.
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http://dx.doi.org/10.1016/j.bulcan.2021.01.016DOI Listing
June 2021

High and synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.

Oncotarget 2021 Apr 13;12(8):859-872. Epub 2021 Apr 13.

Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France.

Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., , , and . We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.
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http://dx.doi.org/10.18632/oncotarget.27930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057272PMC
April 2021

Tertiary Lymphoid Structure-B Cells Narrow Regulatory T Cells Impact in Lung Cancer Patients.

Front Immunol 2021 8;12:626776. Epub 2021 Mar 8.

Sorbonne Université, UMRS 1135, Faculté de Médecine Sorbonne Université, Paris, France.

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment is associated with better clinical outcome in many cancers. In non-small cell lung cancer (NSCLC), we have previously showed that a high density of B cells within TLS (TLS-B cells) is positively correlated with tumor antigen-specific antibody responses and increased intratumor CD4 T cell clonality. Here, we investigated the relationship between the presence of TLS-B cells and CD4 T cell profile in NSCLC patients. The expression of immune-related genes and proteins on B cells and CD4 T cells was analyzed according to their relationship to TLS-B density in a prospective cohort of 56 NSCLC patients. We observed that tumor-infiltrating T cells showed marked differences according to TLS-B cell presence, with higher percentages of naïve, central-memory, and activated CD4 T cells and lower percentages of both immune checkpoint (ICP)-expressing CD4 T cells and regulatory T cells (Tregs) in the TLS-B tumors. A retrospective study of 538 untreated NSCLC patients showed that high TLS-B cell density was even able to counterbalance the deleterious impact of high Treg density on patient survival, and that TLS-B Treg patients had the best clinical outcomes. Overall, the correlation between the density of TLS-B tumors with early differentiated, activated and non-regulatory CD4 T cell cells suggest that B cells may play a central role in determining protective T cell responses in NSCLC patients.
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http://dx.doi.org/10.3389/fimmu.2021.626776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983944PMC
September 2021

RADIORYTHMIC: Phase III, Opened, Randomized Study of Postoperative Radiotherapy Versus Surveillance in Stage IIb/III of Masaoka Koga Thymoma after Complete Surgical Resection.

Clin Lung Cancer 2021 Sep 4;22(5):469-472. Epub 2021 Feb 4.

Thoracic Oncology, Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France. Electronic address:

Introduction: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway.

Patients And Methods: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers.

Results: The first patient will be enrolled in January 2021, with results expected in 2028.
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http://dx.doi.org/10.1016/j.cllc.2021.01.020DOI Listing
September 2021

Intergroupe francophone de cancérologie thoracique, Société de pneumologie de langue française, and Société d'imagerie thoracique statement paper on lung cancer screening.

Diagn Interv Imaging 2021 Apr 26;102(4):199-211. Epub 2021 Feb 26.

Université de Paris, F-75006 Paris, France; Department of Radiology, Groupe Hospitalier Bichat-Claude-Bernard, Assistance publique-Hôpitaux de Paris, 75018 Paris, France.

Following the American National Lung Screening Trial results in 2011 a consortium of French experts met to edit a statement. Recent results of other randomized trials gave the opportunity for our group to meet again in order to edit updated guidelines. After literature review, we provide here a new update on lung cancer screening in France. Notably, in accordance with all international guidelines, the experts renew their recommendation in favor of individual screening for lung cancer in France as per the conditions laid out in this document. In addition, the experts recommend the very rapid organization and funding of prospective studies, which, if conclusive, will enable the deployment of lung cancer screening organized at the national level.
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http://dx.doi.org/10.1016/j.diii.2021.01.012DOI Listing
April 2021

Micronodular thymic carcinoma with lymphoid hyperplasia: relevance of immunohistochemistry with a small panel of antibodies for diagnosis-a RYTHMIC study.

Virchows Arch 2021 Oct 24;479(4):741-746. Epub 2021 Feb 24.

Department of Pathology, AP-HP.5, University of Paris, Paris, France.

Micronodular thymic carcinoma with lymphoid hyperplasia (MNTCLH) is a rare form of thymic carcinoma. We present the experience of RYTHMIC, the French national network devoted to the treatment of thymic epithelial tumors through multidisciplinary tumor boards with a review of all tumors by pathologists for classification and staging. Six cases of MNTCLH were diagnosed during a review of 1007 thymic epithelial tumors. Histologically, epithelial cells with atypia and mitoses formed micronodules that were surrounded by an abundant lymphoid background with follicles. There was neither obvious fibro-inflammatory stroma nor necrosis. Spindle cells areas were common. Initial diagnosis was micronodular thymoma in two cases, cellular atypia being overlooked, eclipsed by the micronodular pattern. Immunohistochemistry with a panel of five antibodies showed that cytokeratins (AE1-AE3) and p63-positive epithelial cells also expressed CD5 and that there was no TdT-positive cells within the tumors. CD20 highlighted the lymphoid hyperplasia. Additionally epithelial cells also expressed CD117 and diffusely Glut 1. Twenty-seven micronodular thymomas with lymphoid stroma diagnosed during the same period did not show the CD5 and CD117 positivities seen in MNTCLH and contained TdT-positive lymphocytes. Three of the 6 patients with MNTCLH had adjuvant radiotherapy. Three patients with follow-up information were alive without recurrence at 38, 51, and 95 months. Our study shows that immunohistochemistry, such as that used in the RYTHMIC network with a small panel of antibodies, may easily help to confirm the correct diagnosis of MNTCLH, a rare and low-aggressive form of thymic carcinoma, and avoid the misdiagnosis of micronodular thymoma.
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http://dx.doi.org/10.1007/s00428-021-03044-2DOI Listing
October 2021

Proton Beam Therapy for Thymic Carcinoma with Pericardial Involvement.

Int J Part Ther 2021 16;7(3):65-70. Epub 2020 Nov 16.

Department of Radiation Oncology, Institut Curie, Paris, France.

Purpose: Thymic malignancies are the most common anterior mediastinal tumors. Advanced thymic carcinoma treatment relies on chemotherapy and definitive radiation therapy when possible. However, pericardial involvement is problematic for radiation therapy treatment planning owing to significant cardiac radiation exposure. We report the first case of definitive proton beam therapy (PBT) for an advanced thymic carcinoma with pericardial invasion.

Materials And Methods: We report the case of a 69-year-old patient treated with definitive radiation therapy for a stage IVB thymic carcinoma with pericardial invasion. Mean doses delivered to critical organs at risk were compared between deep inspiration breath-hold (DIBH) volumetric modulated arc therapy (VMAT) and DIBH-PBT.

Results: When compared to DIBH-VMAT, DIBH-PBT reduced the mean doses delivered to the heart by 3.72 Gy (19.0% dose reduction), to the right lung by 5.9 Gy (41.7% dose reduction), to the left lung by 3.63 Gy (19.0% dose reduction), and to the esophagus by 3.57 Gy (21.3% dose reduction). Despite an early mediastinal relapse after 3.0 months, our patient is still alive after a 14-month follow-up, without any radiation-induced cardiac adverse events and is undergoing pembrolizumab-based immunotherapy.

Conclusion: Proton beam therapy is an option for definitive irradiation of thymic malignancies invading the pericardium; in this situation, PBT reduces doses to the heart and may help to reduce cardiotoxicity when compared with photon techniques.
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http://dx.doi.org/10.14338/IJPT-20-00023.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886270PMC
November 2020

Biphasic Calcium Phosphate Microparticles Mixed With Autologous Blood: Application for the Reconstruction of a Large Mandibular Bone Defect in a Dog.

J Vet Dent 2020 Dec 19;37(4):201-209. Epub 2021 Feb 19.

560854Azurvet Veterinary Referal Center, Saint Laurent du Var, France.

Large mandibular bone defects can be difficult to treat in dogs, with a high risk of mal or nonunion due to instability and risk of infection. This case report describes the use of autologous clotted blood mixed with biphasic calcium phosphate microparticles to fill a defect in a nonunion fracture and promote bone regeneration in a dog using a 2-stage surgical approach. This new method was designed and tried in a dog with a chronic, unstable mandibular fracture associated with a large sequestrum. Initial treatment involved debridement of the lesion, then the oral wound and oral vestibule were reconstructed in 2 layers. Four weeks later a second stage surgery allowed placement of a pre-contoured maxillofacial plate to bridge the defect, which was filled with a blood/biphasic calcium phosphate compound implant. Cone-beam computed tomography was used prior to the initial surgery for preoperative planning and 3-D printing of a mandibular template for plate contouring. CT was subsequently used to document the healing process, using a bone density measurement tool to assess bone regeneration. Radiographic evidence suggestive of osseointegration was observed within 6 months with effective filling of the defect and restoration of alveolar ridge continuity. A return to normal and atraumatic occlusion was considered excellent. Cone-beam computed tomography was found useful to document radiographic evidence of osseointegration, bone regrowth and remodeling. This case report is to serve as a proof-of-concept study and should be followed by a prospective evaluation.
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http://dx.doi.org/10.1177/0898756421990909DOI Listing
December 2020

The Use of Biphasic Calcium Phosphate Substitute (BCP) in Mandibular Defects in Dogs: Use of CBCT to Evaluate Bone Healing.

J Vet Dent 2020 Dec 8;37(4):210-219. Epub 2021 Feb 8.

Azurvet Veterinary Referal Center, Saint Laurent du Var, France.

This study aimed to assess the use of cone beam computed tomography (CBCT) to follow-up bone healing of mandibular bone defects in dogs, filled with a combination of autologous blood and millimetric BCP granules. CBCT was performed ≥4 weeks postoperatively. CBCT gray-scale values were measured from multiplanar reconstructions of the defects and compared to that of normal contralateral mandibular bone and to pure BCP/blood composite time 0 (T0) value. Other parameters, determined by affecting grades according to specific criteria included: bone ridge margin restoration; biomaterial homogeneity; bone-biomaterial interface. Results: 8 dogs with 14 defects were included. Median age was 7.2 years (1-15 years). Follow-up CBCT was performed 1 to 7.5 months postoperatively (mean 3.3 months). Defect CBCT gray-scale values at follow-up were significantly greater than T0 (p < 0.05). Ratios of maximum and minimum densities of the defects to contralateral mandibular bone followed a linear correlation with time (p < 0.05). The bone ridge margin was adequately restored in all the defects and significantly correlated with time (p = 0.03). Biomaterial homogeneity was fair to good in 11 defects and significantly correlated with the bone ridge margin parameter (p = 0.05) and time (p = 0.006). There was no significant correlation with the bone-material interface. The latter was satisfactory in 12 defects and significantly correlated with time (p = 0.01) but not with the other parameters. The biomaterial was more homogeneous in smaller defects and with increasing time. CBCT allowed effective assessment of bone healing via the measurement of CBCT gray-scale values and assessment of multiple radiological variables.
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http://dx.doi.org/10.1177/0898756421989120DOI Listing
December 2020

Contribution of resident and circulating precursors to tumor-infiltrating CD8 T cell populations in lung cancer.

Sci Immunol 2021 Jan;6(55)

PSL Research University, Institut Curie Research Center, INSERM U932, Paris, France.

Tumor-infiltrating lymphocytes (TILs), in general, and especially CD8 TILs, represent a favorable prognostic factor in non-small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations remain poorly understood. Using a combination of single-cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8 TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxtatumor tissue (tissue-resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late-differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, ontogeny, and functional organization in primary NSCLC.
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http://dx.doi.org/10.1126/sciimmunol.abd5778DOI Listing
January 2021
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