432 results on '"Emile JF"'
Search Results
2. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX
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Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, JF, Van Laethem, JL, Allard, MA, Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, JF, Van Laethem, JL, and Allard, MA
- Abstract
Background The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use. Patients and methods According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data. Results Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients. Conclusion Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients. © 2017 Elsevier Ltd
- Published
- 2017
3. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial
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Taieb, J., Tabernero, J., Mini, E., Subtil, Fabien, Folprecht, G., Van Laethem, JL., Thaler, J., Bridgewater, J., Peterson, LN., Blons, H., Collette, L., Van Cutsem, E., Rougier, P., Salazar, R., Bedenne, L., Emile, JF., Laurent-Puig, P., Lepage, C., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] - Published
- 2014
4. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial
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Taieb, J, Tabernero, J, Mini, E, Subtil, F, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Petersen, L, Blons, H, Collette, L, Van Cutsem, E, Rougier, P, Salazar, R, Bedenne, L, Emile, J, Laurent-Puig, P, Lepage, C, Bidoli, P, Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C, Bidoli P, Taieb, J, Tabernero, J, Mini, E, Subtil, F, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Petersen, L, Blons, H, Collette, L, Van Cutsem, E, Rougier, P, Salazar, R, Bedenne, L, Emile, J, Laurent-Puig, P, Lepage, C, Bidoli, P, Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C, and Bidoli P
- Abstract
Background: Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). Methods: For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patieNts with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Findings: Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/. BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We note
- Published
- 2014
5. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset
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Blons, H, Emile, J, Le Malicot, K, Julié, C, Zaanan, A, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Nørgård-Petersen, L, Van Cutsem, E, Lepage, C, Zawadi, M, Salazar, R, Laurent-Puig, P, Taieb, J, Bidoli, P, Blons H, Emile JF, Le Malicot K, Julié C, Zaanan A, Tabernero J, Mini E, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Nørgård-Petersen L, Van Cutsem E, Lepage C, Zawadi MA, Salazar R, Laurent-Puig P, Taieb J, Bidoli P, Blons, H, Emile, J, Le Malicot, K, Julié, C, Zaanan, A, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Nørgård-Petersen, L, Van Cutsem, E, Lepage, C, Zawadi, M, Salazar, R, Laurent-Puig, P, Taieb, J, Bidoli, P, Blons H, Emile JF, Le Malicot K, Julié C, Zaanan A, Tabernero J, Mini E, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Nørgård-Petersen L, Van Cutsem E, Lepage C, Zawadi MA, Salazar R, Laurent-Puig P, Taieb J, and Bidoli P
- Abstract
Background: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. Patients and methods: We analyzed the pronostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. Results: KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). Conclusion: KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors
- Published
- 2014
6. Infections à cytomégalovirus post-transfusionnelles : incidence et moyens de prévention
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Fretz C, Andreu G, Janot C, Emile Jf, Huart Jj, Girard M, Gluckman E, Brossard Y, Marinière Am, and Bierling P
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Gynecology ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Congenital cytomegalovirus infection ,medicine ,General Medicine ,Viral disease ,medicine.disease ,business ,medicine.disease_cause ,Herpesviridae - Published
- 1991
7. PARTIAL INTERFERON g RECEPTOR SIGNALING IN A PATIENT WITH BACILLE CALMETTE-GUERIN AND MYCOBACTERIUM ABSCESSUM INFECTION
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Döffinger, R, Jouanguy, E, Dupuis, S, Fondanèche, Mc, Stephan, Jl, Emile, Jf, LAMHAMEDI CHERRADI, S, Altare, F, Pallier, A, BARCENAS MORALES, G, Meinl, E, Krause, C, Pestka, S, Schreiber, Rd, Novelli, Francesco, and Casanova, Jl
- Published
- 2000
8. Rituximab plus CHOP (R-CHOP) overcomes bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL)
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UCL, Mounier, N., Briere, J, Gisselbrecht, C., Emile, JF, Lederlin, P., Sebban, C., Berger, F., Bosly, André, Morel, Priscilla, Tilly, H., Bouabdallah, R., Reyes, F., Gaulard, P., Coiffier, B., UCL, Mounier, N., Briere, J, Gisselbrecht, C., Emile, JF, Lederlin, P., Sebban, C., Berger, F., Bosly, André, Morel, Priscilla, Tilly, H., Bouabdallah, R., Reyes, F., Gaulard, P., and Coiffier, B.
- Abstract
In diffuse large B-cell lymphoma (DLBCL), the combination of rituximab and CHOP (cyclophosphamide, doxorubicine, vincristine, prednisone; R-CHOP) has been shown to be more effective than CHOP for the treatment of elderly patients. Bcl-2 protein expression has been associated with poor prognosis in patients with DLBCL. To establish whether or not rituximab reduces bcl-2-assoclated treatment failure, we studied bcl-2 protein expression and clinical outcome in patients included in the Groupe d'Etude des Lymphomes de l'Adulte LNH-98-5 trial. Patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks. Of the 399 patients included, 292 with histologically proven DLBCL had material available for bcI-2 study. Tumors were considered positive when at least 50% of tumor cells expressed bcl-2 protein. There were 193 (66%) bcl-2(+) patients and 99 (34%) bcl-2 patients. The response rates for R-CHOP and CHOP were, respectively, 78% and 60% (P = .01) in bcl-2(+) patients and 76% and 73% (P = .7) in bcl-2- patients. At a median of 2 years of follow-up, R-CHOP was significantly associated with a better overall survival than CHOP in bcl-2(+) patients (67% +/- 9% versus 48% +/- 11%, P = .004). In bcl-2- patients there was no statistically significant difference ( 72% +/- 12% versus 67% +/- 14%, P = .6). In addition, R-CHOP was associated with significantly better event-free survival than CHOP in bcl-2(+) patients (58% +/- 10% versus 32% +/- 10%, P < .001) but not in bcl-2- patients (60% +/- 13% versus 40% +/- 15%, P = .13). Multivariate analysis confirmed the significant benefit for survival and event-free survival of R-CHOP in bcl-2(+) patients. These results suggest that rituximab is able to prevent chemotherapy failure in patients with bcl-2 protein overexpression. (C) 2003 by The American Society of Hematology.
- Published
- 2003
9. Apport de la biopsie hépatique chez les enfants atteints de sida
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Lacaille, F, primary, Emile, JF, additional, Fournet, JC, additional, Brousse, N, additional, and Blanche, S, additional
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- 1998
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10. Venoocclusive disease after liver transplantation as part of the process of cellular rejection with endothelial predilection
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Sebagh, M., primary, Debette, M., additional, Samuel, D., additional, Emile, JF., additional, Bismuth, H., additional, and Reynes, M., additional
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- 1998
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11. Histiocytoses: données physiopathogéniques récentes
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Emile, JF, primary and Brousse, N, additional
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- 1996
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12. CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas [see comments]
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Emile, JF, primary, Boulland, ML, additional, Haioun, C, additional, Kanavaros, P, additional, Petrella, T, additional, Delfau-Larue, MH, additional, Bensussan, A, additional, Farcet, JP, additional, and Gaulard, P, additional
- Published
- 1996
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13. Histiocytose langerhansienne
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Thomas, C, primary, Donnadieu, J, additional, Emile, JF, additional, and Brousse, N, additional
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- 1996
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14. Physiçologie de la réponse immunitaire humorale thymo-dépendante
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Emile, JF, primary and Brousse, N, additional
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- 1992
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15. Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study.
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Copie-Bergman C, Gaulard P, Leroy K, Briere J, Baia M, Jais JP, Salles GA, Berger F, Haioun C, Tilly H, Emile JF, Banham AH, Mounier N, Gisselbrecht C, Feugier P, Coiffier B, and Molina TJ
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- 2009
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16. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.
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Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P, and Lièvre, Astrid
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- 2008
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17. Langerhans cell histiocytosis in adults. Report of 274 patients from the International Registry
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Danesino, C., Egeler, M., Bernstrand, C., Juli, E., Lukina, E., Emile, Jf, Grois, N., Mcclain, K., Catherine Klersy, Genereau, T., Girschikofsky, M., and Arico, M.
18. IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts.
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Rottman M, Soudais C, Vogt G, Renia L, Emile JF, Decaluwe H, Gaillard JL, Casanova JL, Rottman, Martin, Soudais, Claire, Vogt, Guillaume, Renia, Laurent, Emile, Jean-François, Decaluwe, Hélène, Gaillard, Jean-Louis, and Casanova, Jean-Laurent
- Abstract
Background: Interferon-gamma receptor 1 (IFN-gammaR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-gammaR1 deficiency.Methods and Findings: We demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1+/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1-/- recipients. However, Ifngr1-/- mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-gammaR1-deficient humans, infected Ifngr1-/- mice displayed very high serum IFN-gamma levels before HSCT. The administration of a recombinant IFN-gamma-expressing AAV vector to Ifngr1-/- naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-gamma depletion in infected Ifngr1-/- mice in vivo allowed subsequent engraftment.Conclusions: High serum IFN-gamma concentration is both necessary and sufficient for graft rejection in IFN-gammaR1-deficient mice, inhibiting the development of heterologous, IFN-gammaR1-expressing, haematopoietic cell lineages. These results confirm that IFN-gamma is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-gammaR1-deficient patients through IFN-gamma depletion from the blood. They further raise the possibility that depleting IFN-gamma may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor. [ABSTRACT FROM AUTHOR]- Published
- 2008
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19. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial
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John Bridgewater, Eric Van Cutsem, Josef Thaler, Côme Lepage, Lone Petersen, Jean-Luc Van Laethem, Fabien Subtil, Josep Tabernero, Julien Taieb, Laurence Collette, Philippe Rougier, Pierre Laurent-Puig, Enrico Mini, Jean-François Emile, Hélène Blons, Laurent Bedenne, Ramon Salazar, Gunnar Folprecht, Taieb, J, Tabernero, J, Mini, E, Subtil, F, Folprecht, G, Van Laethem, J, Thaler, J, Bridgewater, J, Petersen, L, Blons, H, Collette, L, Van Cutsem, E, Rougier, P, Salazar, R, Bedenne, L, Emile, J, Laurent-Puig, P, Lepage, C, Bidoli, P, Meiler, Johannes (Beitragende*r), Trarbach, Tanya (Beitragende*r), Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem JL, Thaler J, Bridgewater J, Petersen LN, Blons H, Collette L, Van Cutsem E, Rougier P, Salazar R, Bedenne L, Emile JF, Laurent-Puig P, Lepage C, PETACC-8 Study Investigator, and Biasco G
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Male ,Oncology ,Organoplatinum Compounds ,Colorectal cancer ,stage III ,Medizin ,medicine.disease_cause ,Antineoplastic Combined Chemotherapy Protocols ,cetuximab ,Infusions, Intravenous ,oxaliplatinum ,education.field_of_study ,Cetuximab ,Exons ,Middle Aged ,Intention to Treat Analysis ,3. Good health ,Oxaliplatin ,colon cancer ,Chemotherapy, Adjuvant ,Colonic Neoplasms ,5-FLUOROURACIL ,Female ,Drug Eruptions ,Fluorouracil ,KRAS ,medicine.drug ,Adult ,Diarrhea ,Mucositis ,medicine.medical_specialty ,phase 3 trial ,Bevacizumab ,Perforation (oil well) ,Population ,Adenocarcinoma ,open-label ,Antibodies, Monoclonal, Humanized ,Disease-Free Survival ,Proto-Oncogene Proteins p21(ras) ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Humans ,education ,neoplasms ,Aged ,Neoplasm Staging ,fluouracil ,leucovorin ,(PETACC-8) ,business.industry ,medicine.disease ,digestive system diseases ,ras Proteins ,FOLFOX4 ,business - Abstract
Summary Background Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). Methods For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene ( KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Findings Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2–3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85–1·29; p=0·66), and in patients with KRAS exon 2/ BRAF wild-type (n=984, HR 0·99; 95% CI 0·76–1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82–1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [ vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. Interpretation The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. Funding Federation Francophone de Cancerologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.
- Published
- 2014
20. Indeterminate DC histiocytosis is distinct from LCH and often associated with other hematopoietic neoplasms.
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Ozkaya N, Melloul Benizri S, Venkataraman G, Karai LJ, Fraitag S, Razanamahery J, Pittaluga S, Battistella M, Pack S, Le Pelletier F, Xi L, Moreau A, Lee I, Hélias-Rodzewicz Z, Donadieu J, Haroche J MD, PhD, Raffeld M, Jaffe ES, and Emile JF
- Abstract
Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis (LCH)), but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (IQR: 44-80 years) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated non-histiocytic hematopoietic neoplasm ('secondary' IDCH) while 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ('mixed' histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)-phenotype, mirroring the signature of normal indeterminate cells and conventional dendritic cell type 2. Mutational analysis revealed frequent KRAS (13/32; 41%), and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNAseq analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2 and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in four individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not impact outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH., (Copyright © 2024 American Society of Hematology.)
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- 2024
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21. Tuberculosis in otherwise healthy adults with inherited TNF deficiency.
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Arias AA, Neehus AL, Ogishi M, Meynier V, Krebs A, Lazarov T, Lee AM, Arango-Franco CA, Yang R, Orrego J, Corcini Berndt M, Rojas J, Li H, Rinchai D, Erazo-Borrás L, Han JE, Pillay B, Ponsin K, Chaldebas M, Philippot Q, Bohlen J, Rosain J, Le Voyer T, Janotte T, Amarajeeva K, Soudée C, Brollo M, Wiegmann K, Marquant Q, Seeleuthner Y, Lee D, Lainé C, Kloos D, Bailey R, Bastard P, Keating N, Rapaport F, Khan T, Moncada-Vélez M, Carmona MC, Obando C, Alvarez J, Cataño JC, Martínez-Rosado LL, Sanchez JP, Tejada-Giraldo M, L'Honneur AS, Agudelo ML, Perez-Zapata LJ, Arboleda DM, Alzate JF, Cabarcas F, Zuluaga A, Pelham SJ, Ensser A, Schmidt M, Velásquez-Lopera MM, Jouanguy E, Puel A, Krönke M, Ghirardello S, Borghesi A, Pahari S, Boisson B, Pittaluga S, Ma CS, Emile JF, Notarangelo LD, Tangye SG, Marr N, Lachmann N, Salvator H, Schlesinger LS, Zhang P, Glickman MS, Nathan CF, Geissmann F, Abel L, Franco JL, Bustamante J, Casanova JL, and Boisson-Dupuis S
- Subjects
- Adult, Female, Humans, Male, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Homozygote, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells immunology, Induced Pluripotent Stem Cells cytology, Inflammation immunology, Interferon-gamma immunology, Loss of Function Mutation, Lung cytology, Lung drug effects, Macrophages, Alveolar cytology, Macrophages, Alveolar drug effects, Macrophages, Alveolar immunology, Macrophages, Alveolar microbiology, Macrophages, Alveolar pathology, Mycobacterium tuberculosis immunology, Phenotype, Reactive Oxygen Species metabolism, Receptors, Tumor Necrosis Factor, Type I deficiency, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I metabolism, Respiratory Burst, Tumor Necrosis Factor Inhibitors pharmacology, Adolescent, Young Adult, Macrophages cytology, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Macrophages pathology, Tuberculosis, Pulmonary immunology, Tuberculosis, Pulmonary microbiology, Tuberculosis, Pulmonary genetics, Tumor Necrosis Factors deficiency, Tumor Necrosis Factors genetics
- Abstract
Severe defects in human IFNγ immunity predispose individuals to both Bacillus Calmette-Guérin disease and tuberculosis, whereas milder defects predispose only to tuberculosis
1 . Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFNγ. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Guérin disease and tuberculosis3 . Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents., (© 2024. The Author(s).)- Published
- 2024
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22. Clinical phenotype of adult-onset systemic histiocytosis harboring BRAF in-frame deletions.
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Papo M, Razanamahéry J, Da Silva M, Hélias-Rodzewicz Z, Potapenko V, Bota S, Leguy-Seguin V, Dominique S, Lhote R, Moyon Q, Taïeb D, Abrassart T, Campana M, Keo V, Rivière E, Lucidarme O, Cohen-Aubart F, Amoura Z, Haroche J, and Emile JF
- Subjects
- Humans, Adult, Male, Female, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis diagnosis, Middle Aged, Sequence Deletion, Age of Onset, Proto-Oncogene Proteins B-raf genetics, Phenotype
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- 2024
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23. Surgery for Infrarenal Retroperitoneal Node Metastases from Colon Cancer.
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Dulac AS, Genova P, Benoit O, Neuzillet C, Hajjam ME, Emile JF, Peschaud F, and Lupinacci RM
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- Humans, Male, Female, Aged, Retrospective Studies, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local surgery, Lymph Node Excision methods, Aged, 80 and over, Lymph Nodes pathology, Lymph Nodes surgery, Disease-Free Survival, Colonic Neoplasms pathology, Colonic Neoplasms surgery, Colonic Neoplasms mortality, Retroperitoneal Neoplasms surgery, Retroperitoneal Neoplasms mortality, Retroperitoneal Neoplasms pathology, Retroperitoneal Neoplasms secondary, Lymphatic Metastasis
- Abstract
Purpose: Treatment of retroperitoneal lymph node metastases (RPN) from colon cancer (CC) is a therapeutic challenge. Available evidence supporting a curative approach is weak and uncertainties remain concerning the extent of the dissection, the optimal timing for surgery, and the role of adjuvant radiotherapy. We report the outcomes of a curative intent strategy in a recent monocentric series of patients., Methods: We did a retrospective review of all curative intent surgical treatment of RPN from CC performed consecutively in a French university hospital from June 2015 to April 2021. Demographics, clinicopathological, and molecular characteristics were evaluated. We describe recurrence-free and overall survival and factors related to recurrence., Results: Records from 18 patients were reviewed. The median age was 69 years. Most of the patients were male (55%), ASA 1-2 (94%), had a left-sided primary colon cancer (73%), and had metachronous RPN (62%). Thirteen patients (72%) experienced recurrence. Recurrence was often limited to RPN (27%) or liver (22%). Four patients underwent a second surgery for RPN recurrence. Median disease-free and overall survival were 22 months and 50 months after RPN surgery. We did not find any factor associated with recurrence. Short-term recurrence (< 6 months) was associated with shorter overall survival (0.031)., Conclusion: The current results suggest that RPN resection is feasible and associated with long survival in selected patients. Further studies evaluating the benefit of curative strategies including radical surgery for patients with potentially resectable RPN are warranted., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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24. Misdiagnosis of Hodgkin disease as histiocytosis is associated with adverse consequences.
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Emile JF, Pluchart C, Azoulay LD, Quere B, Venton G, Filhon B, Maria A, Cabrera Q, Cohen-Aubart F, Schleinitz N, Donadieu J, and Haroche J
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- 2024
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25. Machine learning evaluation of immune infiltrate through digital tumour score allows prediction of survival outcome in a pooled analysis of three international stage III colon cancer cohorts.
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Lecuelle J, Truntzer C, Basile D, Laghi L, Greco L, Ilie A, Rageot D, Emile JF, Bibeau F, Taïeb J, Derangere V, Lepage C, and Ghiringhelli F
- Subjects
- Humans, Prognosis, Female, Male, Aged, Middle Aged, Retrospective Studies, Machine Learning, Colonic Neoplasms mortality, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Neoplasm Staging
- Abstract
Background: T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables., Methods: We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression., Findings: CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS., Interpretation: In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination., Funding: This research received no external funding., Competing Interests: Declaration of interests JT has received honoraria as a speaker and/or in an advisory role from AMGEN, Astellas, Astra Zeneca, BMS, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi and Servier. CL has received honoraria as a speaker and/or in an advisory role from AMGEN, AAA-Novartis, Takeda, Deciphera, Pierre Fabre, Servier. FG's institution has received grants or contracts from Astra, consulting fees from Roche, AMGEN and MSD, honoraria as a speaker from Merck and support for attending meetings and/or travel from AMGEN. FB has received honoraria for lectures, speakers, presentations, manuscript writing or educational events from MSD, Pierre Fabre, Sanofi, BMS, Incyte, Servier and Astellas and support for attending meetings and/or travel from AMGEN, Pierre Fabre and MSD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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26. Human inherited CCR2 deficiency underlies progressive polycystic lung disease.
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Neehus AL, Carey B, Landekic M, Panikulam P, Deutsch G, Ogishi M, Arango-Franco CA, Philippot Q, Modaresi M, Mohammadzadeh I, Berndt MC, Rinchai D, Le Voyer T, Rosain J, Momenilandi M, Martin-Fernandez M, Khan T, Bohlen J, Han JE, Deslys A, Bernard M, Gajardo-Carrasco T, Soudée C, Le Floc'h C, Migaud M, Seeleuthner Y, Jang MS, Nikolouli E, Seyedpour S, Begueret H, Emile JF, Le Guen P, Tavazzi G, Julia Colombo CN, Marzani FC, Angelini M, Trespidi F, Ghirardello S, Alipour N, Molitor A, Carapito R, Mazloomrezaei M, Rokni-Zadeh H, Changi-Ashtiani M, Brouzes C, Vargas P, Borghesi A, Lachmann N, Bahram S, Crestani B, Fayon M, Galode F, Pahari S, Schlesinger LS, Marr N, Bogunovic D, Boisson-Dupuis S, Béziat V, Abel L, Borie R, Young LR, Deterding R, Shahrooei M, Rezaei N, Parvaneh N, Craven D, Gros P, Malo D, Sepulveda FE, Nogee LM, Aladjidi N, Trapnell BC, Casanova JL, and Bustamante J
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- 2024
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27. FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial.
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Tougeron D, Dahan L, Evesque L, Le Malicot K, El Hajbi F, Aparicio T, Bouché O, Bonichon Lamichhane N, Chibaudel B, Angelergues A, Bodere A, Phelip JM, Mabro M, Kaluzinski L, Petorin C, Breysacher G, Rinaldi Y, Zaanan A, Smith D, Gouttebel MC, Perret C, Etchepare N, Emile JF, Sanfourche I, Di Fiore F, Lepage C, Artru P, and Louvet C
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Camptothecin analogs & derivatives, Camptothecin therapeutic use, Camptothecin administration & dosage, Camptothecin adverse effects, Adult, Esophageal Neoplasms drug therapy, Esophageal Neoplasms pathology, Progression-Free Survival, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Leucovorin therapeutic use, Leucovorin administration & dosage, Leucovorin adverse effects, Adenocarcinoma drug therapy, Fluorouracil therapeutic use, Fluorouracil administration & dosage, Esophagogastric Junction pathology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal administration & dosage
- Abstract
Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited., Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma., Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy., Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023., Main Outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators., Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%)., Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.
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- 2024
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28. ALK-Positive Histiocytosis-A Distinct Histiocytic Entity Deserving Recognition.
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Kemps PG, Picarsic JL, and Emile JF
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- Female, Humans, Male, Biopsy, Case Reports as Topic, Anaplastic Lymphoma Kinase metabolism, Anaplastic Lymphoma Kinase genetics, Histiocytosis diagnosis, Histiocytosis pathology
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- 2024
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29. Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis).
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Pegoraro F, Papo M, Cohen-Aubart F, Peyronel F, Lugli G, Trambusti I, Baulier G, de Menthon M, Le Scornet T, Oziol E, Ferreira-Maldent N, Hermine O, Faucher B, Koschel D, Straetmans N, Abisror N, Terrier B, Lifermann F, Razanamahery J, Allenbach Y, Keraen J, Bulifon S, Hervier B, Buccoliero A, Charlotte F, Monzani Q, Boussouar S, Shor N, Tondo A, Barete S, Idbaih A, Tazi A, Sieni E, Amoura Z, Emile JF, Vaglio A, and Haroche J
- Abstract
Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH., Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival., Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAF
V600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432)., Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAFV600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH., Funding: None., Competing Interests: AI reports research grants from Transgene, Sanofi, and Nutritheragene; consulting fees from Novocure, LeoPharma, Polytone Laser, and Novartis; honoraria from Novocure and Neurologies; travel funding from LeoPharma, Novocure, and Carthera. BT report consulting fees and honoraria from GSK, AstraZeneca, CSL Vifor, Boehringer Ingelheim, and Novartis; advisory board activity for Amgen., (© 2024 The Author(s).)- Published
- 2024
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30. Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.
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Schubert C, Schiffmann I, Farschtschi SC, Emile JF, and Friese MA
- Subjects
- Humans, Mutation, Protein Kinase Inhibitors adverse effects, Mitogen-Activated Protein Kinase Kinases, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Histiocytosis drug therapy, Histiocytosis chemically induced, Histiocytosis pathology, Azetidines, Piperidines
- Abstract
Objectives: Histiocytic disorders are pathologic expansions of myeloid cells in multiple organs, including the CNS. They share activation of the MAP kinase pathway due to either BRAF
V600E variant or other variants in the RAS-RAF-MEK-ERK pathway. The rarity and heterogeneity of the disease only enable therapy through pathophysiologic considerations., Methods: We present 2 histiocytosis cases without BRAF sequence variants that affect the CNS, one with Erdheim-Chester disease and the other with an unspecified histiocytosis, and their diagnostic and therapeutic challenges., Results: In both cases, comprehensive analysis of the RAS-RAF-MEK-ERK signaling pathway secured the diagnosis. Treatment with the MEK inhibitor cobimetinib brought the disease to a complete halt. However, side effects such as thrombosis and serous macular edema made it necessary to reduce cobimetinib dosage. Low-dose cobimetinib maintenance medication was successful in preventing recurrence of histiocytic disease., Discussion: CNS involvement of histiocytic disorders can lead to detrimental neurologic symptoms. MEK inhibitors are effective treatment options for some of these patients. Since side effects are common, according to our cases we propose a low-dose treatment of 20 mg per day to balance treatment effects with side effects., Classification of Evidence: This case report provides Class IV evidence. This is a single observational study without controls.- Published
- 2024
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31. Complete remission after a single bisphosphonate infusion in isolated bone Langerhans cell histiocytosis lesion: a case report and a narrative review of the literature.
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Kachaner A, Seror R, Aubart FC, Henry J, Lazure T, Emile JF, Mariette X, and Bitoun S
- Abstract
Langerhans cell histiocytosis (LCH) is a rare disease with limited treatment options. We present a case involving a 57-year-old woman afflicted with an isolated LCH bone osteolytic lesion. A single bisphosphonate infusion significantly alleviated pain, and follow-up scans via CT, PET-CT, and MRI revealed a substantial recalcification of the lesion. Conducting an extensive literature review, we identified 46 cases documenting the efficacy of bisphosphonates in the context of LCH. These findings have raised interest in bisphosphonate infusion as a simple therapeutic alternative in similar situations, with benefits in terms of bone recalcification and pain control for individuals with LCH., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
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- 2024
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32. CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
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Moulin C, Beaupain B, Suarez F, Bertrand Y, Beaussant SC, Fischer A, Durin J, Ranta D, Espéli M, Bachelerie F, Bellanné-Chantelot C, Molina T, Emile JF, Balabanian K, Deback C, and Donadieu J
- Subjects
- Humans, Adult, Herpesvirus 4, Human, Syndrome, Receptors, CXCR4, Papillomavirus Infections complications, Papillomavirus Infections epidemiology, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections epidemiology, Warts complications, Warts epidemiology, Warts diagnosis, Agammaglobulinemia, Lymphoma, Carcinoma, Primary Immunodeficiency Diseases
- Abstract
Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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33. Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.
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Jiang L, Qin J, Dai Y, Zhao S, Zhan Q, Cui P, Ren L, Wang X, Zhang R, Gao C, Zhou Y, Cai S, Wang G, Xie W, Tang X, Shi M, Ma F, Liu J, Wang T, Wang C, Svrcek M, Bardier-Dupas A, Emile JF, de Mestier L, Bachet JB, Nicolle R, Cros J, Laurent-Puig P, Wei M, Song B, Jing W, Guo S, Zheng K, Jiang H, Wang H, Deng X, Chen H, Tian Q, Wang S, Shi S, Jin G, Yin T, Fang H, Chen S, and Shen B
- Subjects
- Humans, Proteomics, Biomarkers, Tumor metabolism, Prospective Studies, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal genetics, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism
- Abstract
Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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34. Radiofrequency Combined with Intratumoral Immunotherapy: Preclinical Results and Safety in Metastatic Colorectal Carcinoma.
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Seguin J, El Hajjam M, Legagneux J, Diakhaby S, Mignet N, Boudy V, Toussaint B, Peschaud F, Emile JF, Capron C, and Malafosse R
- Abstract
Radiofrequency ablation (RFA) of cancer induces an anti-tumor immunity, which is insufficient to prevent recurrences. In mice, RFA-intratumoral immunotherapy by granulocyte-macrophage colony-stimulating factor (GM-CSF) and Bacillus Calmette-Guerin resulted in complete metastases regression. Infectious risk in human needs replacement of live vaccines. Intratumoral purified protein derivatives (PPD) have never been tested in digestive cancers, and the safety of intratumoral immunotherapy after RFA has not yet been validated in human models. We investigated the therapeutic efficacy of combined radiofrequency ablation (RFA) and intratumoral immunotherapy (ITI) using an immune-muco-adherent thermogel (IMT) in a mouse model of metastatic colorectal cancer (CRC) and the safety of this approach in a pig model. Intratumoral stability of the immunogel was assessed using magnetic resonance imaging (MRI) and bioluminescent imaging. Seventy-four CT26 tumor-bearing female BALB/c mice were treated with RFA either alone or in combination with intratumoral IMT. Regression of distant metastasis and survival were monitored for 60 days. Six pigs that received liver radiofrequency and intralesional IMT injections were followed for 15 days. Experimental gel embolisms were treated using an intravascular approach. Pertinent rheology of IMT was confirmed in tumors, by the signal stability during 3 days in MRI and 7 days in bioluminescence imaging. In mice, the abscopal effect of RFA-intratumoral immunotherapy resulted in regression of distant lesions completed at day 16 vs. a volume of 350 ± 99.3 mm
3 in the RFA group at day 25 and a 10-fold survival rate at 60 days. In pigs, injection of immunogel in the liver RFA area was safe after volume adjustment without clinical, hematological, and liver biology disorder. Flow cytometry showed an early increase in CD3 TCRγδ+T cells at D7 ( p < 0.05) and a late decrease in CD29+ -CD8 T cells at D15 ( p < 0.05), reflecting the inflammation status changes. Systemic GM-CSF release was not detectable. Experimental caval and pulmonary thermogel embolisms were treated by percutaneous catheterism and cold serum infusion. RFA-intratumoral immunotherapy as efficient and safe mini-invasive interventional oncology is able to improve ablative treatment of colorectal liver metastases., Competing Interests: M.E.H., J.S., J.L., B.T., F.P., J.F.E. and C.C. report no conflicts of interest. N.M., V.B. and R.M., regarding activities related to the present article, are no remunerated consultants for Imisca and report no other conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.- Published
- 2024
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35. Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection.
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Hamza A, Masliah-Planchon J, Neuzillet C, Lefèvre JH, Svrcek M, Vacher S, Bourneix C, Delaye M, Goéré D, Dartigues P, Samalin E, Hilmi M, Lazartigues J, Girard E, Emile JF, Rigault E, Dangles-Marie V, Rioux-Leclercq N, de la Fouchardière C, Tougeron D, Casadei-Gardini A, Mariani P, Peschaud F, Cacheux W, Lièvre A, and Bièche I
- Subjects
- Humans, Class I Phosphatidylinositol 3-Kinases genetics, Mutation, Papillomavirus Infections complications, Papillomavirus Infections genetics, Phosphatidylinositol 3-Kinases genetics, Prognosis, Anus Neoplasms genetics, Anus Neoplasms pathology, Anus Neoplasms surgery, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell surgery, Carcinoma, Squamous Cell pathology, Proctectomy
- Abstract
The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)
KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials., (© 2023 UICC.)- Published
- 2024
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36. [Isolated liver involvement in Langerhans cell histiocytosis: A case report].
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Allaume P, Meneyrol E, Bernard G, Houssel-Debry P, Emile JF, and Turlin B
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- Aged, Humans, Liver pathology, Rare Diseases, Histiocytosis, Langerhans-Cell diagnosis
- Abstract
Langerhans cell histiocytosis (LCH) is a disease whose physiopathology remains unclear, involving both inflammatory processes and clonal proliferation. It is observable at any given age, although about ten times more frequent in children than adults. Hepatic involvement is not rare, mostly part of a systemic disease, and linked to a poor prognosis. We report here a case of LCH with solitary hepatic involvement in a 74 year-old patient. This case demonstrated molecular anomaly of the MAPK pathway, BRAF N486_P490del. Through this observation, we precise the epidemiological and histological aspects and diagnostic criteria of this rare disease., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2024
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37. Colony stimulating factor-1 (CSF-1) signalling is predictive of response to immune checkpoint inhibitors in advanced non-small cell lung cancer.
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Takam Kamga P, Mayenga M, Sebane L, Costantini A, Julie C, Capron C, Parent F, Seferian A, Guettier C, Emile JF, and Giroux Leprieur E
- Subjects
- Humans, Immune Checkpoint Inhibitors therapeutic use, Leukocytes, Mononuclear, Macrophage Colony-Stimulating Factor, Prospective Studies, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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38. Antitumoral effect of local injection of TLR-9 agonist emulsified in Lipiodol with systemic anti-PD-1 in a murine model of colorectal carcinoma.
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Grindel AL, Fretellier N, Soares M, Bouzakher N, Millot Maysounabe V, Santus R, Bawa O, Wintrebert M, Couquelet C, Robert P, Emile JF, and Capron C
- Subjects
- Male, Animals, Mice, Ethiodized Oil therapeutic use, Toll-Like Receptor 9, Emulsions therapeutic use, Disease Models, Animal, Immunologic Factors therapeutic use, Carcinoma, Hepatocellular pathology, Liver Neoplasms therapy, Chemoembolization, Therapeutic, Colorectal Neoplasms drug therapy
- Abstract
Introduction: Local treatments of cancer, including transarterial chemoembolization, could enhance responses to systemic immune checkpoint inhibitors such as anti-PD-1 antibodies. Lipiodol, a radiopaque oil, is widely used for transarterial chemoembolization as a tumor-targeting drug carrier and could be used in emulsion with immunomodulators. This study aimed at evaluating the antitumoral effect of intra-tumoral injection of Lipiodol-immunomodulator emulsions combined with systemic anti-PD-1 therapy in a murine model of colorectal carcinoma., Method: Mice (male BALB/c) with anti-PD-1-resistant subcutaneous CT26 tumors were injected with immunomodulators, emulsified or not with Lipiodol (N=10-12/group)., Results: The TLR-9 agonist CpG displayed antitumor effects, while Poly I:C and QS21 did not. The Lipiodol-CpG emulsion appeared to be stable and maintained CpG within tumors for a longer time. Repeated intra-tumoral injections, combined with anti-PD-1, induced responses towards the tumor as well as to a distant metastatic-like nodule. This treatment was associated with an increase in proliferative CD8+ T cells and of IFN-γ expression, a decrease in proliferative regulatory T cells but also, surprisingly, an increase in myeloid derived suppressor cells., Conclusions: Local administration of CpG emulsified with Lipiodol led to an effective antitumoral effect when combined to systemic anti-PD-1 therapy. Lipiodol, apart from its radiopaque properties, is an efficient drug-delivery system. The formulated oil-in-water emulsion allows efficient loading and control release of CpG, which induces favorable immune modifications in this murine tumor model., Competing Interests: MS, RS, MW, CCo, PR, NF and VM were Guerbet’s employees at the time of study execution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Guerbet. The funder had the following involvement in the study: study design, data collection and analysis, decision to publish, and preparation of the manuscript., (Copyright © 2024 Grindel, Fretellier, Soares, Bouzakher, Millot Maysounabe, Santus, Bawa, Wintrebert, Couquelet, Robert, Emile and Capron.)
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- 2024
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39. Lung transplantation as a rescue option in childhood critical pulmonary Langerhans cell histiocytosis.
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Heritier S, Donadieu J, Leger PL, De Tersant M, Della Vallee V, Barkaoui MA, Le Louet S, Tazi A, Taytard J, Corvol H, Helias-Rodzevicz Z, Emile JF, Fadel E, Fabre D, Feuillet S, and Nathan N
- Subjects
- Humans, Lung, Lung Transplantation, Histiocytosis, Langerhans-Cell surgery
- Published
- 2024
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40. Histiocytic neoplasm subtypes differ in their MAP2K1 mutational type.
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Emile JF, Hélias-Rodzewicz Z, Durham BH, Héritier S, da Silva M, Younas K, Cohen-Aubart F, Abdel-Wahab O, Diamond EL, Donadieu J, and Haroche J
- Subjects
- Humans, Mutation, MAP Kinase Kinase 1, Neoplasms
- Published
- 2023
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41. Specific blood monocyte distribution in histiocytoses correlates with vascular involvement and disease activity.
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Razanamahery J, Samson M, Guy J, Racine J, Row C, Greigert H, Nicolas B, Francois S, Emile JF, Cohen-Aubart F, Audia S, Haroche J, and Bonnotte B
- Subjects
- Humans, Monocytes, Histiocytosis
- Published
- 2023
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42. Cardiac involvement resolution is frequent and associated with improved outcome in Erdheim-Chester disease.
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Azoulay LD, Bravetti M, Cohen-Aubart F, Emile JF, Charlotte F, Amoura Z, Cluzel P, and Haroche J
- Published
- 2023
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43. Sinonasal and ear manifestations of Erdheim-Chester disease.
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Drouillard M, Trunet S, Hervochon R, Azoulay LD, Amoura Z, Cohen-Aubart F, Emile JF, Tankéré F, and Haroche J
- Subjects
- Humans, Retrospective Studies, Proto-Oncogene Proteins B-raf genetics, Mutation, Erdheim-Chester Disease complications, Erdheim-Chester Disease diagnostic imaging
- Abstract
To calculate the prevalence of sinonasal and ear involvement in an Erdheim-Chester disease (ECD) population, to describe the different ear, nose and throat (ENT) manifestations and to study the association between ENT involvement, other organ involvement, and BRAF mutations. We led a retrospective monocentric study in the national referral center for ECD. One hundred and sixty-two patients with ECD and ENT data were included between January 1, 1980 and December 31, 2020. Ear and nose clinical and radiological findings were noted. We described and studied the prevalence of ENT involvement in ECD population. The association between sinonasal and ear involvement, other organ involvement, and BRAF mutations was calculated. The prevalence of ENT manifestations is around 45%. No clinical rhinologic or otologic signs were specific to ECD. Sinus imaging was abnormal in 70% of cases. A bilateral maxillary sinus frame osteosclerosis was highly specific of ECD. Associations were found between the sinus MRI imaging type and BRAF status, central nervous system involvement, cerebellum involvement and xanthelasma. Sinonasal or ear involvement is frequent in ECD and has specific imaging features for sinuses. Trial registration: #2011-A00447-34., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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44. Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability: A Randomized Clinical Trial.
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Taïeb J, Bouche O, André T, Le Malicot K, Laurent-Puig P, Bez J, Toullec C, Borg C, Randrian V, Evesque L, Corbinais S, Perrier H, Buecher B, Di Fiore F, Gallois C, Emile JF, Lepage C, Elhajbi F, and Tougeron D
- Abstract
Importance: Only 1 randomized clinical trial has shown the superiority of immune checkpoint inhibitors in patients with deficient mismatch repair and/or microsatellite instability (dMMR/MSI) metastatic colorectal cancer (mCRC) in the first-line setting., Objectives: To determine whether avelumab (an anti-programmed cell death ligand 1 antibody) improves progression-free survival (PFS) compared with standard second-line chemotherapy in patients with dMMR/MSI mCRC., Design, Setting, and Participants: The SAMCO-PRODIGE 54 trial is a national open-label phase 2 randomized clinical trial that was conducted from April 24, 2018, to April 29, 2021, at 49 French sites. Patients with dMMR/MSI mCRC who experienced progression while receiving standard first-line therapy were included in the analysis., Interventions: Patients were randomized to receive standard second-line therapy or avelumab every 2 weeks until progression, unacceptable toxic effects, or patient refusal., Main Outcome and Measures: The primary end point was PFS according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1, evaluated by investigators in patients with mCRC and confirmed dMMR and MSI status who received at least 1 dose of treatment (modified intention-to-treat [mITT] population)., Results: A total of 122 patients were enrolled in the mITT population. Median age was 66 (IQR, 56-76) years, 65 patients (53.3%) were women, 100 (82.0%) had a right-sided tumor, and 52 (42.6%) had BRAF V600E-mutated tumors. There was no difference in patients and tumor characteristics between treatment groups. No new safety concerns in either group were detected, with fewer treatment-related adverse events of at least grade 3 in the avelumab group than in the chemotherapy group (20 [31.7%] vs 34 [53.1%]; P = .02). After a median follow-up of 33.3 (95% CI, 28.3-34.8) months, avelumab was superior to chemotherapy with or without targeted agents with respect to PFS (15 [24.6%] vs 5 [8.2%] among patients without progression; P = .03). Rates of PFS rates at 12 months were 31.2% (95% CI, 20.1%-42.9%) and 19.4% (95% CI, 10.6%-30.2%) in the avelumab and control groups, respectively, and 27.4% (95% CI, 16.8%-39.0%) and 9.1% (95% CI, 3.2%-18.8%) at 18 months. Objective response rates were similar in both groups (18 [29.5%] vs 16 [26.2%]; P = .45). Among patients with disease control, 18 (75.7%) in the avelumab group compared with 9 (19.1%) in the control group had ongoing disease control at 18 months., Conclusions: The SAMCO-PRODIGE 54 phase 2 randomized clinical trial showed, in patients with dMMR/MSI mCRC, better PFS and disease control duration with avelumab over standard second-line treatment, with a favorable safety profile., Trial Registration: ClinicalTrials.gov Identifier: NCT03186326.
- Published
- 2023
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45. Childhood-onset Erdheim-Chester disease in the molecular era: clinical phenotypes and long-term outcomes of 21 patients.
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Pegoraro F, Mazzariol M, Trambusti I, Bakhshi S, Mallick S, Dunkel IJ, van den Bos C, Tezol Ö, Shan S, Ocak S, Giordano F, De Fusco C, Gaspari S, Buccoliero AM, Coniglio ML, Buti E, Romagnani P, Picarsic J, Donadieu J, Diamond EL, Emile JF, Sieni E, Haroche J, and Vaglio A
- Subjects
- Humans, Child, Phenotype, Erdheim-Chester Disease diagnostic imaging, Erdheim-Chester Disease genetics
- Published
- 2023
- Full Text
- View/download PDF
46. H syndrome treated with Tocilizumab: two case reports and literature review.
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Jacquot R, Jouret M, Valentin MG, Richard M, Jamilloux Y, Rousset F, Emile JF, Haroche J, Steinmüller L, Zekre F, Phan A, Belot A, and Seve P
- Subjects
- Female, Humans, Adult, Child, Preschool, Fever, Nucleoside Transport Proteins genetics, Hearing Loss, Sensorineural, Contracture, Histiocytosis diagnosis, Histiocytosis drug therapy, Histiocytosis genetics
- Abstract
H syndrome is a rare autosomal recessive genetic disorder characterized by the following clinical features: cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, hyperglycemia, fixed flexion contractures of the toe joints, and the proximal interphalangeal joints. In rare cases, autoinflammatory and lymphoproliferative manifestations have also been reported. This disorder is due to loss-of-function mutations in SLC29A3 gene, which encode the equilibrative nucleoside transporter ENT3. This deficiency leads to abnormal function and proliferation of histiocytes. H syndrome is part of the R-group of histiocytosis. We report two different cases, one was diagnosed in adulthood and the other in childhood. The first case reported is a 37-year-old woman suffering from H syndrome with an autoinflammatory systemic disease that begins in adulthood (fever and diffuse organ's infiltration) and with cutaneous, articular, auditory, and endocrinological manifestations since childhood. The second case reported is a 2-year-old girl with autoinflammatory, endocrine, and cutaneous symptoms (fever, lymphadenopathy, organomegaly, growth delay, and cutaneous hyperpigmentation). Homozygous mutations in SLC29A3 confirmed the diagnosis of H syndrome in both cases. Each patient was treated with Tocilizumab with a significant improvement for lymphoproliferative, autoinflammatory, and cutaneous manifestations. Both cases were reported to show the multiple characteristics of this rare syndrome, which can be diagnosed either in childhood or in adulthood. In addition, an overview of the literature suggested Tocilizumab efficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author AB declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Jacquot, Jouret, Valentin, Richard, Jamilloux, Rousset, Emile, Haroche, Steinmüller, Zekre, Phan, Belot and Seve.)
- Published
- 2023
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47. H syndrome mimicking Erdheim Chester disease: new entity and therapeutic perspectives.
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Lequain H, Gerfaud-Valentin M, Emile JF, Gangloff YG, Boursier G, Deligny C, Le Guenno G, Tantot J, Valantin J, Savey L, Bachmeyer C, Jamilloux Y, Schaeffer L, Leblanc P, and Sève P
- Subjects
- Humans, Erdheim-Chester Disease diagnosis, Erdheim-Chester Disease drug therapy, Erdheim-Chester Disease genetics, Histiocytosis
- Published
- 2023
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48. PU.1 is a useful nuclear marker to distinguish between histiocytosis and histiocyte-rich tumours.
- Author
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Ungureanu IA, Cohen-Aubart F, Héritier S, Haroche J, Donadieu J, and Emile JF
- Subjects
- Humans, Histiocytes pathology, Histiocytosis diagnosis, Histiocytosis pathology, Histiocytosis, Langerhans-Cell diagnosis, Histiocytosis, Langerhans-Cell pathology, Histiocytosis, Sinus metabolism, Histiocytosis, Sinus pathology, Erdheim-Chester Disease pathology, Hematologic Neoplasms pathology
- Abstract
Aims: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis., Methods and Results: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes., Conclusion: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2023
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49. Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.
- Author
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Azoulay LD, Bravetti M, Cohen-Aubart F, Emile JF, Seilhean D, Plu I, Charlotte F, Waintraub X, Carrat F, Amoura Z, Cluzel P, and Haroche J
- Subjects
- Humans, Female, Male, Retrospective Studies, Prevalence, Magnetic Resonance Imaging, Erdheim-Chester Disease complications, Erdheim-Chester Disease epidemiology, Erdheim-Chester Disease genetics, Cardiac Tamponade epidemiology, Cardiac Tamponade etiology, Pericarditis epidemiology, Pericarditis complications
- Abstract
Aims: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series., Methods and Results: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]., Conclusion: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival., Competing Interests: Conflict of interest: F.C.-A. and J.H. are investigators (F.C.-A. being the principal investigator) in an academic study on the efficacy of cobimetinib for treating histiocytoses (COBRAH, NCT 04007848). X.W. reports personal fees from Abbot, Medtronic, Biosense Webster, Volta and Boston, and travel funding from Biotronik and Boston. None of the other authors have any conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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50. Molecular and clinicopathologic characterization of pediatric histiocytoses.
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Hélias-Rodzewicz Z, Donadieu J, Terrones N, Barkaoui MA, Lambilliotte A, Moshous D, Thomas C, Azarnoush S, Pasquet M, Mansuy L, Aladjidi N, Jeziorski E, Marec-Berard P, Gilibert-Yvert M, Spiegel A, Saultier P, Pellier I, Pagnier A, Pertuisel S, Poiree M, Bodet D, Millot F, Isfan F, Stephan JL, Leruste A, Rigaud C, Filhon B, Carausu L, Reguerre Y, Kieffer I, Brichard B, Ben Jannet R, Bakari M, Idbaih A, Bodemer C, Cohen-Aubart F, Haroche J, Tazi A, Boudjemaa S, Fraitag S, Emile JF, and Heritier S
- Subjects
- Humans, Child, Proto-Oncogene Proteins B-raf genetics, Mutation, Exons, Histiocytosis, Langerhans-Cell genetics, Erdheim-Chester Disease genetics
- Abstract
The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAF
V600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)- Published
- 2023
- Full Text
- View/download PDF
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