72 results on '"Schlageter MH"'
Search Results
2. Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells
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Dubois, C, primary, Schlageter, MH, additional, de Gentile, A, additional, Guidez, F, additional, Balitrand, N, additional, Toubert, ME, additional, Krawice, I, additional, Fenaux, P, additional, Castaigne, S, additional, and Najean, Y, additional
- Published
- 1994
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3. Prospective external validation of biomarkers to predict acute graft-versus-host disease severity.
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Robin M, Porcher R, Michonneau D, Taurines L, de Fontbrune FS, Xhaard A, Oriano B, Sutra Del Galy A, Peffault de Latour R, Socié G, and Schlageter MH
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- Algorithms, Biomarkers, Humans, Prospective Studies, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute graft-versus-host disease (GVHD) is still the major contributor to comorbidities and mortality after allogeneic hematopoietic stem cell transplantation. The use of plasmatic biomarkers to predict early outcomes has been advocated in the past decade. The purpose of this prospective noninterventional study was to test the ability of panels including 7 biomarkers (Elafin, HGF, IL2RA, IL8, REG3, ST2, and TNFRI), to predict day 28 (D28) complete response to steroid, D180 overall survival, and D180 nonrelapse mortality (NRM). Using previous algorithms developed by the Ann Arbor/MAGIC consortium, 204 patients with acute GVHD were prospectively included and biomarkers were measured at GVHD onset for all of them. Initial GVHD grade and bilirubin level were significantly associated with all those outcomes. After adjustment on clinical variables, biomarkers were associated with survival and NRM. In addition to clinical variables, biomarkers slightly improved the prediction of overall survival and NRM (concordance and net reclassification indexes). The potential benefit of adding biomarkers panel to clinical parameters was also investigated by decision curve analyses. The benefit of adding biomarkers to clinical parameters was however marginal for the D28 nonresponse and mortality endpoints., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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4. Revisiting Diagnostic performances of serum erythropoïetin level and JAK2 mutation for polycythemias: analysis of a cohort of 1090 patients with red cell mass measurement.
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Maslah N, Ravdan O, Drevon L, Verger E, Belkhodja C, Chomienne C, Cassinat B, Kiladjian JJ, Giraudier S, and Schlageter MH
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- Alleles, Amino Acid Substitution, Clinical Decision-Making, Disease Management, Erythrocyte Indices, Erythrocyte Volume, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Plasma Volume, Polycythemia Vera diagnosis, Polycythemia Vera epidemiology, Sensitivity and Specificity, Erythropoietin blood, Janus Kinase 2 genetics, Mutation, Polycythemia Vera blood, Polycythemia Vera genetics
- Abstract
We assessed the diagnostic performances of erythropoietin and JAK2 mutations in 1,090 patients with suspected polycythemia who were referred for red cell mass (RCM) measurement. In patients with a high haematocrit and/or haemoglobin level, a low erythropoietin level (<=3·3 mUI/ml) and JAK2 mutation showed comparable positive predictive value (PPV) for true polycythemia (RCM>=125%), 92·1% and 90% respectively. A very-low erythropoietin level (<=1·99 mUI/ml) had a PPV of 100% for polycythemia vera (PV) diagnosis. We confirmed the correlations between RCM, erythropoietin and JAK2 variant allelic frequency in PV patients. This study prompts the need to revisit the role of EPO in PV diagnostic criteria., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2022
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5. Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups.
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Robin M, Porcher R, Orvain C, Bay JO, Barraco F, Huynh A, Charbonnier A, Forcade E, Chantepie S, Bulabois C, Yakoub-Agha I, Detrait M, Michonneau D, Turlure P, Raus N, Boyer F, Suarez F, Vincent L, Guyen SN, Cornillon J, Villate A, Dupriez B, Cassinat B, Rolland V, Schlageter MH, Socié G, and Kiladjian JJ
- Subjects
- Humans, Nitriles, Prospective Studies, Pyrazoles, Pyrimidines, Transplantation Conditioning, Unrelated Donors, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Primary Myelofibrosis therapy
- Abstract
This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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6. Anemia and hemodilution: analysis of a single center cohort based on 2,858 red cell mass measurements.
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Drevon L, Maslah N, Soret-Dulphy J, Dosquet C, Ravdan O, Vercellino L, Belkhodja C, Parquet N, Brignier AC, Schlageter MH, Cassinat B, Kiladjian JJ, Chomienne C, and Giraudier S
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- Cohort Studies, Erythrocyte Volume, Hematocrit, Humans, Anemia, Hemodilution
- Published
- 2021
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7. Analytical validation of eight methods of thyroglobulin measurement in fine-needle aspiration washouts.
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Boux de Casson F, Beloeil R, Gauchez AS, Oris C, Leban M, Schlageter MH, Moineau MP, Dufour-Rainfray D, Bach-Ngohou K, Chikh K, and Moal V
- Subjects
- Biopsy, Fine-Needle, Female, Humans, Male, Thyroid Neoplasms pathology, Neoplasm Proteins metabolism, Thyroglobulin metabolism, Thyroid Neoplasms metabolism
- Abstract
Background: Thyroglobulin (Tg) assay in washout fluids of fine needles, after cervical lymph nodes aspiration, is used for detecting metastases from differentiated thyroid carcinomas. Assay methods are the same as for Tg in serum. However, with non-serum samples, methods require extensive validation to notably check for the absence of matrix effect. This study fits this context. Our objectives were to assess analytic performances, in washout fluid, of eight different Tg assay methods and to compare them to validated data in serum., Methods: Eleven medical laboratories participated in this study. The matrix tested was phosphate-buffer saline containing 1% bovine serum albumin (PBS-1% BSA). Samples used were dilutions, in this buffer, of Certified Reference Material (CRM 457). We verified, for all methods, the limit of detection, precision, linearity, trueness and accuracy., Results: In PBS-1% BSA, the functional sensitivities (FS) were comparable to those expected for serum. All the methods were linear. The relative biases of trueness were between -24.5 and 10.2% around 1 µ g/L. Total analytical error was ≤40% near the functional sensitivity values., Conclusion: No quantitatively important matrix effect was observed. All the methods showed their ability to measure Tg in PBS-1% BSA, over the concentration range of interest, with acceptable total analytical error. We validated the functional sensitivity value as a decision threshold in thyroidectomized patients after treatment and with low concentrations of serum Tg.
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- 2021
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8. Pitfalls in CALR exon 9 mutation detection: A single-center experience in 571 positive patients.
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Verger E, Maslah N, Schlageter MH, Chomienne C, Kiladjian JJ, Giraudier S, and Cassinat B
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- DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Polymerase Chain Reaction, Calreticulin genetics, Exons, Hematologic Neoplasms genetics, Mutation, Myeloproliferative Disorders genetics, Neoplasm Proteins genetics
- Abstract
Introduction: The pathogenesis of myeloproliferative neoplasms (MPNs) is closely related to the acquisition of specific molecular alterations in JAK2, MPL, or CALR genes, the presence of which represent major diagnostic criteria in the WHO classification. The CALR exon 9 insertions and deletions are very heterogeneous, and their detection mainly relies on polymerase chain reaction (PCR) fragment length analysis., Methods: We report on the rare nonclassical profiles that we observed among the 1382 patients analyzed by PCR fragment length analysis. In difficult cases, we tested germline DNA and performed NGS analysis., Results: We faced some troubling results because of the presence of several unexpected peaks. Our investigations showed that they resulted from a mix of isolated or double somatic mutations combined with germline alterations which could be misleading for a correct diagnosis. The precise interpretation of such difficult cases is mandatory as a misinterpretation could lead to the prescription of cytoreductive drugs to nondiseased persons or to an absence of treatment in true MPN patients., Conclusion: Our observations showed that every mutation should be verified by direct Sanger sequencing, and we show that sometimes it may be necessary to study germline DNA and to complement with NGS analysis to precisely interpret the molecular alterations., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
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9. The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.
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Su A, Ling F, Vaganay C, Sodaro G, Benaksas C, Dal Bello R, Forget A, Pardieu B, Lin KH, Rutter JC, Bassil CF, Fortin G, Pasanisi J, Antony-Debré I, Alexe G, Benoist JF, Pruvost A, Pikman Y, Qi J, Schlageter MH, Micol JB, Roti G, Cluzeau T, Dombret H, Preudhomme C, Fenouille N, Benajiba L, Golan HM, Stegmaier K, Lobry C, Wood KC, Itzykson R, and Puissant A
- Subjects
- Animals, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy, Proto-Oncogene Proteins c-myc biosynthesis, U937 Cells, Folic Acid metabolism, Methylenetetrahydrofolate Reductase (NADPH2) metabolism, Neoplasms drug therapy, Neoplasms metabolism
- Abstract
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH
3 -THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies. SIGNIFICANCE: Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3 -THF supplementation thus represents a low-risk intervention to enhance their effects. See related commentary by Marando and Huntly, p. 1791 . This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)- Published
- 2020
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10. Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease.
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Giannoni L, Morin F, Robin M, Peyneau M, Schlageter MH, Desmier D, Pagliuca S, Sutra Del Galy A, Sicre de Fontbrune F, Xhaard A, Dhedin N, Moins-Teisserenc H, Peffault de Latour R, Socié G, and Michonneau D
- Subjects
- Humans, Remission Induction, Retrospective Studies, Steroids, Graft vs Host Disease drug therapy, Intestinal Diseases
- Abstract
Almost one-half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in preclinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells, and skews effector T cells toward regulatory T cells. Gastrointestinal steroid-refractory (SR)-GVHD is a protein-losing enteropathy that might represent the optimal setting in which to use AAT. Here we analyze the outcomes of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD. The overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. The median time to best response was 21 days (range, 6 to 26 days). At day 56 after AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year overall survival was 48% (95% confidence interval, 26% to 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment, whereas fecal loss was elevated. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T cells decreased during AAT treatment. This retrospective analysis supports a previous report of AAT as a promising agent in the management of gut SR-GVHD and should prompt its evaluation at an earlier stage., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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11. Paraneoplastic neutrophilic leukaemoid reaction in a patient with melanoma: association between tumour volume and leucocytosis.
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Fredeau L, Bohelay G, Shourick J, Piver D, Guyot A, Schlageter MH, Caux F, and Maubec E
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- Humans, Leukocytosis etiology, Tumor Burden, Leukemoid Reaction, Leukocyte Disorders, Melanoma, Paraneoplastic Syndromes etiology
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- 2020
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12. Synergistic effects of PRIMA-1 Met (APR-246) and 5-azacitidine in TP53 -mutated myelodysplastic syndromes and acute myeloid leukemia.
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Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, Aubin P, Naoui N, Schlageter MH, Bally C, Miekoutima E, Rahmé R, Lehmann-Che J, Ades L, Fenaux P, Cassinat B, and Giraudier S
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- Aza Compounds, Azacitidine pharmacology, Bridged Bicyclo Compounds, Heterocyclic, Humans, Quinuclidines, Tumor Suppressor Protein p53 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Abstract
Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine (AZA). PRIMA-1
Met (APR-246,APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. Here we show that low doses of APR on its own or in combination with AZA reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with AZA in TP53 -mutated myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) cell lines and in TP53 -mutated primary cells from MDS/AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53 -mutated MDS/AML may be better targeted by the addition of APR-246 to conventional treatments., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
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13. Masked polycythemia vera: analysis of a single center cohort of 2480 red cell masses.
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Maslah N, Soret J, Dosquet C, Vercellino L, Belkhodja C, Schlageter MH, Cassinat B, Kiladjian JJ, Chomienne C, and Giraudier S
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- Cohort Studies, Erythrocyte Volume, Humans, Polycythemia Vera diagnosis, Polycythemia Vera genetics
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- 2020
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14. Next-generation sequencing for JAK2 mutation testing: advantages and pitfalls.
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Maslah N, Verger E, Schlageter MH, Miclea JM, Kiladjian JJ, Giraudier S, Chomienne C, and Cassinat B
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- Amino Acid Substitution, Cell Line, Tumor, DNA Mutational Analysis methods, Female, Humans, Janus Kinase 2 metabolism, Male, Real-Time Polymerase Chain Reaction methods, Exons, Hematologic Neoplasms genetics, High-Throughput Nucleotide Sequencing methods, Janus Kinase 2 genetics, Mutation, Missense, Myeloproliferative Disorders genetics
- Abstract
The JAK2
V617F mutation is part of the major criteria for diagnosis of myeloproliferative neoplasms (MPN). Allele-specific quantitative PCR (qPCR) is the most prevalent method used in laboratories but with the advent of next-generation sequencing (NGS) techniques, we felt necessary to evaluate this approach for JAK2 mutations testing. Among DNA samples from 427 patients analyzed by qPCR and NGS, we found an excellent concordance between both methods when allelic burden was superior to 2% (the detection limit of our NGS assay). Only one sample among 298 was found negative by NGS while allelic burden by qPCR was 3%. Because NGS detection limit is higher, sensitivity was lower as exemplified by 21 samples found negative whereas qPCR measured allelic burdens between 0.1 and 1%. Importantly, quantitative data of samples found positive by both techniques were highly correlated (R2 = 0.9477). We also evaluated 40 samples tested for JAK2 exon 12 mutations by HRM. The concordance with NGS was of 100%. Using NGS, the full coding region of JAK2 was analyzed leading to identification of several variants outside of exon 12 and 14 which were previously described or not. Interestingly, we found one somatic mutation (c.1034A>T p.H345L) which induced constitutive activation of the JAK/STAT pathway leading to an increased proliferation of BaF/3 cells with low-dose EPO. This study showed that NGS is a robust method highly correlated to qPCR, although less sensitive, but providing the opportunity to identify other JAK2 variants with potential impact on disease initiation or evolution.- Published
- 2019
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15. Prognostic Biomarkers Used for Localised Prostate Cancer Management: A Systematic Review.
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Lamy PJ, Allory Y, Gauchez AS, Asselain B, Beuzeboc P, de Cremoux P, Fontugne J, Georges A, Hennequin C, Lehmann-Che J, Massard C, Millet I, Murez T, Schlageter MH, Rouvière O, Kassab-Chahmi D, Rozet F, Descotes JL, and Rébillard X
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- Chemotherapy, Adjuvant methods, Genomics methods, Humans, Male, Neoplasm Grading, Neoplasm Recurrence, Local, Predictive Value of Tests, Prostate-Specific Antigen blood, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology, Prostatic Neoplasms surgery, Biomarkers, Tumor blood, Prognosis, Prostatectomy methods, Prostatic Neoplasms metabolism
- Abstract
Context: Prostate cancer stratification is based on tumour size, pretreatment PSA level, and Gleason score, but it remains imperfect. Current research focuses on the discovery and validation of novel prognostic biomarkers to improve the identification of patients at risk of aggressive cancer or of tumour relapse., Objective: This systematic review by the Intergroupe Coopérateur Francophone de Recherche en Onco-urologie (ICFuro) analysed new evidence on the analytical validity and clinical validity and utility of six prognostic biomarkers (PHI, 4Kscore, MiPS, GPS, Prolaris, Decipher)., Evidence Acquisition: All available data for the six biomarkers published between January 2002 and April 2015 were systematically searched and reviewed. The main endpoints were aggressive prostate cancer prediction, additional value compared to classical prognostic parameters, and clinical benefit for patients with localised prostate cancer., Evidence Synthesis: The preanalytical and analytical validations were heterogeneous for all tests and often not adequate for the molecular signatures. Each biomarker was studied for specific indications (candidates for a first or second biopsy, and potential candidates for active surveillance, radical prostatectomy, or adjuvant treatment) for which the level of evidence (LOE) was variable. PHI and 4Kscore were the biomarkers with the highest LOE for discriminating aggressive and indolent tumours in different indications., Conclusions: Blood biomarkers (PHI and 4Kscore) have the highest LOE for the prediction of more aggressive prostate cancer and could help clinicians to manage patients with localised prostate cancer. The other biomarkers show a potential prognostic value; however, they should be evaluated in additional studies to confirm their clinical validity., Patient Summary: We reviewed studies assessing the value of six prognostic biomarkers for prostate cancer. On the basis of the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the prognostic parameters currently used by clinicians., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2018
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16. Successful Treatment of Differentiated Thyroid Carcinoma with Transaxillary Robotic Surgery and Radioiodine: The First European Experience.
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Balay MA, Aidan P, Schlageter MH, Georges O, Meas T, Bechara M, Toubert ME, Faugeron I, Monpeyssen H, and Chougnet CN
- Abstract
Objectives: Transaxillary robotic thyroidectomy surgery (TARS) has been reported to be a safe approach in patients with differentiated thyroid carcinoma, and oncological responses are promising., Study Design: This study aimed to evaluate the oncological outcomes of TARS followed by radioiodine (RAI) therapy in patients with differentiated thyroid carcinoma. Between 2011 and 2016, patients treated for differentiated thyroid carcinoma by TARS in a single institution, followed by RAI, were retrospectively included. The oncological response was performed according to the 2015 American Thyroid Association (ATA) guidelines 6-12 months later and at the last available visit., Results: A total of 42 patients (30 females) were included, with a median tumor size of 20 mm (12 cases of N1a and 5 cases of N1b on initial pathology report). According to ATA classification of recurrence risk after surgery, 17 and 25 patients were classified as low and intermediate risk, respectively. After RAI, all patients had a normal posttherapeutic whole body scan (except 1 patient, who had pathological lymph node uptake), but no unusual uptake was seen. At the 6- to 12-month evaluation ( n = 37), 24 patients had excellent response, 8 had indeterminate response, and 5 had incomplete response (2 biological and 3 structural); no distant metastasis was found. At the last evaluation (median follow-up 15.9 months), 35 patients had no evidence of disease and 1 patient had a structural incomplete response. In total, a second open surgery was necessary for 3 patients to treat persistent lymph nodes (all intermediate risk)., Conclusion: In this study, TARS followed by RAI therapy seems to be curative, even for patients with lymph node metastases, after good preoperative staging. More studies are required to confirm the findings.
- Published
- 2018
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17. Graft-Versus-Host Disease in Adolescents and Young Adults (15-24 Years Old) After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia in First Complete Remission.
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Vignon M, Andreoli A, Dhédin N, Lengliné E, Masson E, Robin M, Granier C, Larghero J, Schlageter MH, de Latour RP, Socié G, and Boissel N
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- Acute Disease, Adolescent, Adult, Child, Chronic Disease, Cyclosporine therapeutic use, Graft vs Host Disease prevention & control, Humans, Immunosuppressive Agents therapeutic use, Incidence, Intestinal Diseases prevention & control, Methotrexate therapeutic use, Mortality, Proportional Hazards Models, Quality of Life, Remission Induction, Severity of Illness Index, Skin Diseases prevention & control, Survival Rate, Transplantation, Homologous, Young Adult, Graft vs Host Disease epidemiology, Hematopoietic Stem Cell Transplantation, Intestinal Diseases epidemiology, Leukemia, Myeloid, Acute therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Skin Diseases epidemiology
- Abstract
Purpose: Adolescents and young adults (AYAs) with cancer are a unique group of patients in terms of disease incidence and biology, outcome, and psychosocial needs. This study aims to correlate the risk of graft-versus-host disease (GvHD) and age in a population of children and young adults with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT) in first complete remission (CR)., Methods: We analyzed the outcome of 153 consecutive children (<15 years), AYAs (15-24 years), and adults (25-35 years) with lymphoblastic or myeloid acute leukemia in first CR who underwent HSCT with matched donors after myeloablative conditioning. GvHD prophylaxis was methotrexate and cyclosporine A (CsA) in all patients., Results: The cumulative incidence of grade II-IV acute GvHD (aGvHD) was significantly higher in AYA patients than in children (subdistribution hazard ratio (SHR), 2.04, p = 0.005) or adults (SHR 1.59, p = 0.048). Both gut and skin aGvHD occurred more frequently in AYA patients. Increasing CsA blood levels with age could not fully account for this difference. No difference in terms of grade III-IV aGvHD was observed. Chronic GvHD was more frequent in AYAs (SHR 2.81, p = 0.007) and adults (SHR 2.31, p = 0.033) than in children. No difference in terms of nonrelated mortality and overall survival was observed among the age subgroups., Conclusion: Since GvHD occurrence is strongly correlated to quality of life, specific attention should be paid to AYAs undergoing HSCT. Further studies should investigate the reasons for the excess of GvHD observed in this population.
- Published
- 2017
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18. Thyroglobulin assay in fluids from lymph node fine needle-aspiration washout: influence of pre-analytical conditions.
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Casson FB, Moal V, Gauchez AS, Moineau MP, Sault C, Schlageter MH, and Massart C
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- Biopsy, Fine-Needle, Humans, Lymphatic Metastasis, Sensitivity and Specificity, Thyroid Neoplasms diagnosis, Biomarkers, Tumor analysis, Lymph Nodes pathology, Specimen Handling standards, Thyroglobulin analysis, Thyroid Neoplasms pathology
- Abstract
The aim of this study was to evaluate the pre-analytical factors contributing to uncertainty in thyroglobulin measurement in fluids from fine-needle aspiration (FNA) washout of cervical lymph nodes. We studied pre-analytical stability, in different conditions, of 41 samples prepared with concentrated solutions of thyroglobulin (FNA washout or certified standard) diluted in physiological saline solution or buffer containing 6% albumin. In this buffer, over time, no changes in thyroglobulin concentrations were observed in all storage conditions tested. In albumin free saline solution, thyroglobulin recovery rates depended on initial sample concentrations and on modalities of their conservation (in conventional storage tubes, recovery mean was 56% after 3 hours-storage at room temperature and 19% after 24 hours-storage for concentrations ranged from 2 to 183 μg/L; recovery was 95%, after 3 hours or 24 hours-storage at room temperature, for a concentration of 5,656 μg/L). We show here that these results are due to non-specific adsorption of thyroglobulin in storage tubes, which depends on sample protein concentrations. We also show that possible contamination of fluids from FNA washout by plasma proteins do not always adequately prevent this adsorption. In conclusion, non-specific adsorption in storage tubes strongly contributes to uncertainty in thyroglobulin measurement in physiological saline solution. It is therefore recommended, for FNA washout, to use a buffer containing proteins provided by the laboratory.
- Published
- 2017
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19. Relevance of serum biomarkers associated with melanoma during follow-up of anti-CTLA-4 immunotherapy.
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Felix J, Cassinat B, Porcher R, Schlageter MH, Maubec E, Pages C, Baroudjian B, Homyrda L, Boukouaci W, Tamouza R, Bagot M, Caignard A, Toubert A, Lebbé C, and Moins-Teisserenc H
- Subjects
- Adult, Aged, Antibodies blood, Biomarkers, Tumor blood, CTLA-4 Antigen immunology, Cohort Studies, Female, Follow-Up Studies, Histocompatibility Antigens Class I blood, Histocompatibility Antigens Class I immunology, Humans, Ipilimumab, Male, Melanoma drug therapy, Melanoma mortality, Middle Aged, Monitoring, Physiologic methods, Neoplasm Staging, Skin Neoplasms drug therapy, Skin Neoplasms mortality, Survival Analysis, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Immunotherapy methods, L-Lactate Dehydrogenase blood, Melanoma diagnosis, S100 Calcium Binding Protein beta Subunit blood, Skin Neoplasms diagnosis
- Abstract
Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4 immunotherapy used in advanced melanoma, is an effective immunotherapy alone or combined with other agents but with few predictive biomarkers of response. Here, we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA antibodies and LDH as serum biomarkers of response and survival in a cohort of 77 advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and LDH at baseline and at weeks 3 and 6 correlated to a better response and survival. After multivariate analysis LDH maintained its independence at baseline and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment monitoring after the first two doses of ipilimumab (W6). In addition, higher sMICA serum levels at baseline were associated with less frequency of irAEs., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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20. pVAX14DNA-mediated add-on immunotherapy combined with arsenic trioxide and all-trans retinoic acid targeted therapy effectively increases the survival of acute promyelocytic leukemia mice.
- Author
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Patel S, Guerenne L, Gorombei P, Omidvar N, Schlageter MH, Alex AA, Ganesan S, West R, Adès L, Mathews V, Krief P, Pla M, Fenaux P, Chomienne C, and Padua RA
- Subjects
- Animals, Arsenic Trioxide, DNA administration & dosage, Disease Models, Animal, Immunotherapy, Mice, Adjuvants, Immunologic administration & dosage, Arsenicals therapeutic use, Leukemia, Promyelocytic, Acute therapy, Oxides therapeutic use, Tretinoin therapeutic use
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- 2015
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21. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations.
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Verger E, Cassinat B, Chauveau A, Dosquet C, Giraudier S, Schlageter MH, Ianotto JC, Yassin MA, Al-Dewik N, Carillo S, Legouffe E, Ugo V, Chomienne C, and Kiladjian JJ
- Subjects
- Adolescent, Adult, Alleles, Aspirin therapeutic use, Clonal Evolution drug effects, Clone Cells drug effects, DNA Mutational Analysis, DNA-Binding Proteins genetics, Dioxygenases, Female, Follow-Up Studies, Genes, p53, Humans, Hydroxyurea therapeutic use, Interferon-alpha adverse effects, Isocitrate Dehydrogenase genetics, Male, Middle Aged, Off-Label Use, Polyethylene Glycols adverse effects, Proto-Oncogene Proteins genetics, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Remission Induction, Repressor Proteins genetics, Thrombocythemia, Essential blood, Thrombocythemia, Essential genetics, Thrombocythemia, Essential pathology, Young Adult, Calreticulin genetics, Interferon-alpha therapeutic use, Mutation, Polyethylene Glycols therapeutic use, Thrombocythemia, Essential drug therapy
- Abstract
Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy., (© 2015 by The American Society of Hematology.)
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- 2015
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22. The spectrum of neutrophilic dermatoses associated with monoclonal gammopathy: Association with IgA isotype and inflammatory profile.
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Szalat R, Monsel G, Le Goff W, Battistella M, Bengouffa D, Schlageter MH, Bouaziz JD, Arnulf B, Vignon M, Lesnik P, Saussine A, Malphettes M, Lazareth A, Vignon-Pennamen MD, Bagot M, Brouet JC, Fermand JP, Rybojad M, and Asli B
- Subjects
- Adult, Aged, Aged, 80 and over, Cell Adhesion Molecules blood, Chemokines blood, Cytokines blood, Female, Humans, Male, Middle Aged, Neutrophils, Paraproteinemias diagnosis, Retrospective Studies, Skin Diseases diagnosis, Immunoglobulin A immunology, Immunoglobulin Isotypes immunology, Paraproteinemias complications, Paraproteinemias immunology, Skin Diseases complications, Skin Diseases immunology
- Abstract
Background: Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome., Objective: We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg., Methods: We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules., Results: This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1., Limitations: This is a retrospective study from a single institution with a limited number of participants., Conclusion: Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2015
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23. DNA-mediated adjuvant immunotherapy extends survival in two different mouse models of myeloid malignancies.
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Le Pogam C, Patel S, Gorombei P, Guerenne L, Krief P, Omidvar N, Tekin N, Bernasconi E, Sicre F, Schlageter MH, Chopin M, Noguera ME, West R, Abu A, Mathews V, Pla M, Fenaux P, Chomienne C, and Padua RA
- Subjects
- Animals, Antibodies blood, Base Sequence, Cancer Vaccines immunology, Gene Expression Regulation, Neoplastic, Genes, ras, Immunologic Memory drug effects, Interferon-gamma immunology, Interferon-gamma metabolism, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute immunology, Leukemia, Promyelocytic, Acute metabolism, Leukemia, Promyelocytic, Acute pathology, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Transgenic, Molecular Sequence Data, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes immunology, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Neoplasms, Experimental genetics, Neoplasms, Experimental immunology, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Receptors, Retinoic Acid genetics, Receptors, Retinoic Acid metabolism, Retinoic Acid Receptor alpha, Signal Transduction drug effects, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Time Factors, Tumor Burden drug effects, Vaccination, Vaccines, DNA immunology, Adjuvants, Immunologic pharmacology, Cancer Vaccines pharmacology, Leukemia, Promyelocytic, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Neoplasms, Experimental drug therapy, Tretinoin pharmacology, Vaccines, DNA pharmacology
- Abstract
We have previously shown that a specific promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) DNA vaccine combined with all-trans retinoic acid (ATRA) increases the number of long term survivors with enhanced immune responses in a mouse model of acute promyelocytic leukemia (APL). This study reports the efficacy of a non-specific DNA vaccine, pVAX14Flipper (pVAX14), in both APL and high risk myelodysplastic syndrome (HR-MDS) models. PVAX14 is comprised of novel immunogenic DNA sequences inserted into the pVAX1 therapeutic plasmid. APL mice treated with pVAX14 combined with ATRA had increased survival comparable to that obtained with a specific PML-RARA vaccine. Moreover, the survival advantage correlated with decreased PML-RARA transcript levels and increase in anti-RARA antibody production. In HR-MDS mice, pVAX14 significantly improved survival and reduced biomarkers of leukemic transformation such as phosphorylated mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1. In both preclinical models, pVAX14 vaccine significantly increased interferon gamma (IFNγ) production, memory T-cells (memT), reduced the number of colony forming units (CFU) and increased expression of the adapter molecule signalling to NF-κB, MyD88. These results demonstrate the adjuvant properties of pVAX14 providing thus new approaches to improve clinical outcome in two different models of myeloid malignancies, which may have potential for a broader applicability in other cancers.
- Published
- 2015
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24. Evaluation of a new thyroglobulin sensitive assay in patients with differentiated thyroid cancer.
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Schlageter MH, Toubert ME, Meas T, Bouhassira E, Faugeron I, Vimont V, Thomas E, Theimer C, and Chomienne C
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Thyroid Neoplasms pathology, Biomarkers, Tumor analysis, Thyroglobulin analysis, Thyroid Neoplasms metabolism
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- 2015
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25. Ovarian reserve in breast cancer: assessment with anti-Müllerian hormone.
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Hamy AS, Porcher R, Cuvier C, Giacchetti S, Schlageter MH, Coussieu C, Gronier H, Feugeas JP, Adoui N, Lacorte JM, Poirot C, Habdous M, and Espié M
- Subjects
- Adolescent, Adult, Amenorrhea chemically induced, Antineoplastic Agents adverse effects, Female, Humans, Menstruation drug effects, Ovariectomy, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Anti-Mullerian Hormone blood, Breast Neoplasms complications, Breast Neoplasms drug therapy, Ovarian Reserve drug effects, Ovary drug effects
- Abstract
Anti-Müllerian hormone (AMH) levels fall during chemotherapy. Treatment-induced amenorrhoea is a reversible phenomenon, but few data are available on long-term AMH changes in breast cancer. The aim of the study was to describe serum AMH levels before, during and in the long term after chemotherapy, and to show a potential AMH recovery. Between May 2010 and June 2011, we selected 134 women aged 18-43 years at the time of breast cancer diagnosis who received chemotherapy between 2005 and 2011, and had not undergone an oophorectomy or had previous cytotoxic treatment. The AMH levels were assessed before, during and 4 months to 5.5 years after the end of chemotherapy. During chemotherapy, AMH was undetectable in 69% of women. After chemotherapy, a significant increase in AMH was found, with an average magnitude of +1.2% per month (95% credibility interval: 0.7 to 1.6). Older age and 12 months of amenorrhoea were found to be associated with a lower AMH recovery rate, whereas baseline AMH and number of chemotherapy cycles were not. The process of AMH changes during and after chemotherapy is dynamic, and shows recovery after ovarian injury. Caution should be exercised in interpreting individual AMH assessment in this context., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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26. Automated two-site immunofluorescent assay for the measurement of serum chromogranin A.
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Popovici T, Moreira B, Schlageter MH, and Bories PN
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- Biomarkers, Tumor blood, Humans, Neuroendocrine Tumors blood, Reproducibility of Results, Chromogranin A blood, Fluorescent Antibody Technique methods
- Abstract
Objectives: Chromogranin A (CgA) is the best-characterized biological marker common to neuroendocrine tumours and is therefore recommended for their diagnosis. The measurement of serum CgA is of great importance for reaching an early diagnosis and thus reducing the delay before treatment is instigated. The Kryptor CgA assay is the first fully automated assay available. The aim of this study was to evaluate its analytical performance., Design and Methods: The imprecision and linearity of the Kryptor CgA assay were evaluated. This assay was compared with the Cis Bio CgA RIA assay in 78 serum samples. Its clinical utility was assessed in serum from 229 patients., Results: The study performed on imprecision of Kryptor measurements showed intra- and inter-run CVs ≤ 5%. The study of linearity showed a satisfactory recovery rate for CgA concentrations up to 1200 μg/L. The Kryptor and RIA assays agreed well on the basis of the cut-off values provided by the two manufacturers. The Bland and Altman plot of the values obtained (range: 20-5560 μg/L) provided a mean difference of -10.1 μg/L (SD: 116). The clinical sensitivities of Kryptor CgA for diagnosis of pheochromocytoma and paraganglioma (n 20) and gastroenteropancreatic NETs (n 17) were respectively 100 and 94%., Conclusions: The Kryptor assay for CgA shows reliable analytical and clinical characteristics and allows a fast delivery of results., (© 2013.)
- Published
- 2014
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27. Hypoxia imaging of uterine cervix carcinoma with (18)F-FETNIM PET/CT.
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Vercellino L, Groheux D, Thoury A, Delord M, Schlageter MH, Delpech Y, Barré E, Baruch-Hennequin V, Tylski P, Homyrda L, Walker F, Barranger E, and Hindié E
- Subjects
- Adult, Aged, Disease-Free Survival, Female, Fluorodeoxyglucose F18, Humans, Middle Aged, Uterine Cervical Neoplasms pathology, Hypoxia diagnostic imaging, Imaging, Three-Dimensional, Multimodal Imaging, Nitroimidazoles, Positron-Emission Tomography, Tomography, X-Ray Computed, Uterine Cervical Neoplasms diagnostic imaging
- Abstract
Purpose: Our aims were to assess the feasibility of imaging hypoxia in cervical carcinoma with (18)F-fluoroerythronitroimidazole ((18)F-FETNIM) and to compare (18)F-FETNIM uptake with metabolic uptake of (18)F-FDG., Patients and Methods: We included 16 patients with cervical carcinoma. After imaging with FDG, (18)F-FETNIM PET/CT was performed and tumor-to-muscle (T/M) ratio uptake was assessed. (18)F- FETNIM uptake was correlated to FDG uptake and osteopontin (OPN), a marker of hypoxia, and patients' outcomes., Results: All tumors were detected by (18)F-FDG PET. (18)F-FETNIM T/M ratios ranged from 1.3 to 5.4. There was no significant correlation between (18)F-FETNIM and (18)F-FDG uptake. High (18)F-FETNIM uptake (T/M > 3.2) was associated with reduced progression-free survival (log-rank = 0.002) and overall survival (log-rank = 0.02). Osteopontin ranged from 39 to 662 μg/L (median, 102.5 μg/L). Patients with OPN greater than 144 μg/L had reduced progression-free survival compared with those with OPN less than 144 μg/L (log-rank = 0.03). We found no significant correlation between (18)F-FETNIM uptake and OPN blood levels., Conclusions: Our preliminary results showed that a high uptake of (18)F-FETNIM was associated with a worse progression-free and overall survival.
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- 2012
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28. Coexistence of a myeloproliferative disorder and secondary polycythemia in the same patient.
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Kouroupi E, Cassinat B, Schlageter MH, Dosquet C, Kiladjian JJ, and Chomienne C
- Subjects
- Aged, 80 and over, Comorbidity, Drug Resistance, Erythropoiesis drug effects, Erythropoietin blood, Humans, Hydroxyurea pharmacology, Hydroxyurea therapeutic use, Janus Kinase 2 genetics, Male, Mutation, Missense, Phlebotomy, Point Mutation, Polycystic Kidney, Autosomal Dominant complications, Polycystic Kidney, Autosomal Dominant diagnostic imaging, Polycythemia Vera drug therapy, Polycythemia Vera genetics, Ultrasonography, Polycythemia etiology, Polycythemia Vera complications
- Published
- 2012
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- View/download PDF
29. Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy.
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Blanchard P, Quero L, Pacault V, Schlageter MH, Baruch-Hennequin V, and Hennequin C
- Subjects
- Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Biomarkers, Tumor immunology, Carcinoma, Squamous Cell therapy, Chemoradiotherapy, Enzyme-Linked Immunosorbent Assay, Esophageal Neoplasms therapy, Female, Humans, Male, Middle Aged, Prognosis, Proto-Oncogene Proteins p21(ras), Retrospective Studies, Survival Analysis, Adenocarcinoma immunology, Antibodies, Neoplasm blood, Carcinoma, Squamous Cell immunology, Esophageal Neoplasms immunology, Proto-Oncogene Proteins immunology, Tumor Suppressor Protein p53 immunology, ras Proteins immunology
- Abstract
Background: P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma., Methods: Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted., Results: Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT., Conclusions: Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.
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- 2012
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30. When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group).
- Author
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Cassinat B, de Botton S, Kelaidi C, Ades L, Zassadowski F, Guillemot I, Schlageter MH, Raffoux E, Harousseau JL, Legrand O, Escoffre-Barbe M, Reman O, Gardembas M, Himberlin C, Cahn JY, Guyotat D, Bouscary D, Parry A, Rousselot P, Baruchel A, Dombret H, Chevret S, Fenaux P, and Chomienne C
- Subjects
- Humans, Leukemia, Promyelocytic, Acute genetics, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Leukemia, Promyelocytic, Acute pathology, Oncogene Proteins, Fusion genetics
- Abstract
10-20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARalpha transcript detection by RQ-PCR in 260 consecutive APL patients (n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARalpha mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARalpha NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.
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- 2009
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31. Therapy-resistant anaemia in congenital nephrotic syndrome of the Finnish type--implication of EPO, transferrin and transcobalamin losses.
- Author
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Toubiana J, Schlageter MH, Aoun B, Dunand O, Vitkevic R, Bensman A, and Ulinski T
- Subjects
- Anemia blood, Anemia etiology, Blood Transfusion, Erythropoietin administration & dosage, Erythropoietin blood, Female, Hematinics administration & dosage, Hematinics blood, Humans, Infant, Newborn, Nephrectomy, Nephrotic Syndrome complications, Nephrotic Syndrome congenital, Nephrotic Syndrome genetics, Transcobalamins analysis, Transferrin analysis, Anemia therapy, Erythropoietin urine, Hematinics urine, Nephrotic Syndrome therapy, Transcobalamins urine, Transferrin urine
- Abstract
Congenital nephrotic syndrome of the Finnish type (CNF) is due to NPHS1 mutation and is responsible for a variety of urinary protein losses. We report the case of a 4-month-old girl with a particularly severe form (proteinuria approximately 150 g/l) of CNF. She developed severe non-regenerative anaemia requiring bi-monthly blood transfusions despite daily EPO (600 UI/kg) and iron supplementation. Epoetin pharmacokinetics revealed a urinary loss of 27% of the given dose within the first 24 h after IV injection. However, plasma levels remained increased after 24 h (228 UI/l). Plasma transferrin and transcobalamin levels were undetectable. Atransferrinaemia and atranscobalaminaemia seem to be responsible for disturbed erythropoiesis.
- Published
- 2009
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32. Auer rods and differentiation in acute promyelocytic leukemia.
- Author
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Zassadowski F, Ades L, Schlageter MH, Chevret S, Guillemot I, Fenaux P, Chomienne C, and Cassinat B
- Subjects
- Antineoplastic Agents pharmacology, Cell Differentiation drug effects, Cells, Cultured, Follow-Up Studies, Humans, Prognosis, Tretinoin pharmacology, Inclusion Bodies pathology, Leukemia, Promyelocytic, Acute pathology
- Published
- 2008
- Full Text
- View/download PDF
33. Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome.
- Author
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Lapillonne H, Leclerc A, Ulinski T, Balu L, Garnier A, Dereuddre-Bosquet N, Watier H, Schlageter MH, and Deschênes G
- Subjects
- B-Lymphocytes cytology, B-Lymphocytes immunology, Child, Female, Flow Cytometry, Humans, Killer Cells, Natural cytology, Killer Cells, Natural immunology, Male, Nephrotic Syndrome drug therapy, Proteinuria drug therapy, Proteinuria immunology, Recurrence, Remission Induction, Steroids therapeutic use, Thymus Gland cytology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Nephrotic Syndrome immunology, T-Lymphocytes cytology, T-Lymphocytes immunology, Thymus Gland immunology
- Abstract
Steroid-sensitive nephrotic syndrome (SSNS) is classically thought to be a T-cell disorder. The aim of this study was to examine whether or not thymus homeostasis was affected in SSNS. Mature and naive T cell recent thymic emigrants were quantified in the peripheral blood of nephrotic patients and controls. Because the generation of new T cells by the thymus ultimately depends on hematopoietic stem cells, CD34+ cells were also included in the study. Nineteen patients with SSNS during relapse, 13 with SSNS during proteinuria remission, and 18 controls were studied. Cell-surface markers (CD3, CD4, CD8, CD19, CD16, CD56, CD45RA, CD62L, CD34, and CD38) were analyzed by flow cytometric analysis. T-cell rearrangement excision circles (TRECs) were quantified in CD2+ cells by real-time polymerase chain reaction. Stroma cell-derived factor-1 (SDF-1) genotype and metalloproteinase-9 (MMP-9) plasma levels were also determined. Mature T cells (CD4+ and CD8+), circulating naive T cells (CD62L+ and CD3+ CD62L+), and recent thymic emigrants (CD45RA+) as well as TRECs, that measure thymus production, had a similar level in the three groups of patients. Conversely, CD34+ hematopoietic stem cells displayed a two-fold increase in SSNS patients during relapse either compared with controls or SSNS patients at remission. In addition, compared with controls, SSNS patients at remission displayed (1) a decrease in CD19+ cells (B cells) and (2) an increase in CD16CD56+ cells [natural killer (NK) cells]. In conclusion, thymus homeostasis is not significantly affected in nephrotic patients. Hematopoietic stem-cell mobilization at proteinuria relapse, as well as changes in B and NK cells during remission, suggest that SSNS might be due to a general disturbance of hematopoietic and immune cell trafficking.
- Published
- 2008
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34. Mutations in exon 12 of JAK2 are mainly found in JAK2 V617F-negative polycythaemia vera patients.
- Author
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Kouroupi E, Zoi K, Parquet N, Zoi C, Kiladjian JJ, Grigoraki V, Vainchenker W, Lellouche F, Marzac C, Schlageter MH, Dosquet C, Scott LM, Fenaux P, Loukopoulos D, Chomienne C, and Cassinat B
- Subjects
- Adolescent, Adult, Aged, Erythrocyte Count, Exons, Female, Humans, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Janus Kinase 2 genetics, Mutation genetics, Polycythemia Vera genetics
- Published
- 2008
- Full Text
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35. Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients.
- Author
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Schlumberger M, Hitzel A, Toubert ME, Corone C, Troalen F, Schlageter MH, Claustrat F, Koscielny S, Taieb D, Toubeau M, Bonichon F, Borson-Chazot F, Leenhardt L, Schvartz C, Dejax C, Brenot-Rossi I, Torlontano M, Tenenbaum F, Bardet S, Bussière F, Girard JJ, Morel O, Schneegans O, Schlienger JL, Prost A, So D, Archambeaud F, Ricard M, and Benhamou E
- Subjects
- Adult, Biomarkers blood, Carcinoma, Papillary, Follicular therapy, Female, Follow-Up Studies, Humans, Iodine Radioisotopes, Male, Middle Aged, Neoplasm Recurrence, Local blood, Neoplasm Recurrence, Local diagnostic imaging, Prospective Studies, Radionuclide Imaging, Remission Induction, Sensitivity and Specificity, Thyroid Neoplasms therapy, Carcinoma, Papillary, Follicular blood, Carcinoma, Papillary, Follicular diagnostic imaging, Chemistry, Clinical methods, Thyroglobulin analysis, Thyroglobulin blood, Thyroid Neoplasms blood, Thyroid Neoplasms diagnostic imaging
- Abstract
Background: Serum thyroglobulin (Tg) is the marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease., Aim: The goal of the study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T4 treatment and after TSH stimulation., Methods: Thyroid cancer patients who had no evidence of persistent disease after initial treatment (total thyroidectomy and radioiodine ablation) were studied at 3 months on L-T4 treatment (Tg1) and then at 9-12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up., Results: Thirty recurrences were detected among 944 patients. A control 131I total body scan had a low sensitivity, a low specificity, and a low clinical impact. Assuming a common cutoff for all Tg assays at 0.9 ng/ml, sensitivity ranged from 19-40% and 68-76% and specificity ranged from 92-97% and 81-91% for Tg 1 and Tg2, respectively. Using assays with a functional sensitivity at 0.2-0.3 ng/ml, sensitivity was 54-63% and specificity was 89% for Tg1. Using the two methods with a lowest functional sensitivity at 0.02 and 0.11 ng/ml resulted in a higher sensitivity for Tg1 (81% and 78%), but at the expense of a loss of specificity (42% and 63%); finally, for these two methods, using an optimized functional sensitivity according to receiver operating characteristic curves at 0.22 and 0.27 ng/ml resulted in a sensitivity at 65% and specificity at 85-87% for Tg1., Conclusion: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T4 treatment and may be used to study the trend in serum Tg without performing any TSH stimulation. Serum Tg determination obtained after TSH stimulation still permits a more reliable assessment of cure and patient's reassurance.
- Published
- 2007
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36. Frequent antibody production against RARalpha in both APL mice and patients.
- Author
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Robin M, Andreu-Gallien J, Schlageter MH, Bengoufa D, Guillemot I, Pokorna K, Robert C, Larghero J, Rousselot P, Raffoux E, Dombret H, Fenaux P, Pla M, Charron D, Padua RA, and Chomienne C
- Subjects
- Animals, Antibodies, Antineutrophil Cytoplasmic blood, Antibodies, Antinuclear blood, Antineoplastic Agents therapeutic use, Autoantibodies blood, Enzyme-Linked Immunosorbent Assay, Humans, Leukemia, Experimental drug therapy, Leukemia, Experimental immunology, Leukemia, Promyelocytic, Acute drug therapy, Mice, Retinoic Acid Receptor alpha, Time Factors, Tretinoin therapeutic use, Autoantibodies biosynthesis, Leukemia, Promyelocytic, Acute immunology, Receptors, Retinoic Acid immunology
- Abstract
In an acute promyelocytic leukemia (APL)-transplantable mouse model, we previously reported the presence of antibodies recognizing PML-RARalpha and RARalpha in the sera of ATRA-treated mice. To evaluate this immune response, we determined the prevalence of anti-RARalpha antibodies in a cohort of 48 APL mice, treated by ATRA (n = 24) or by placebo pellets (n = 24), and in a preliminary subset of 9 patients with APL using a specific enzyme-linked immunosorbent assay (ELISA). In APL mice, significantly higher antibody levels were observed at the latest time points (day 48 to 58 levels superior to day 15 to 18 or day 28 to 38 levels). Antibody levels were higher in ATRA-treated mice than in placebo-treated mice and were also predictive of better survival. In the patients with APL, anti-RARalpha antibodies were detected at diagnosis and after maintenance therapy, reminiscent of the ATRA-treated APL mice. Antinuclear or antineutrophil cytoplasmic autoantibodies were also detected. These data reveal for the first time that in patients with APL an immune response may be detected at diagnosis and enhanced after maintenance therapy.
- Published
- 2006
- Full Text
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37. Management of Graves' disease during pregnancy: the key role of fetal thyroid gland monitoring.
- Author
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Luton D, Le Gac I, Vuillard E, Castanet M, Guibourdenche J, Noel M, Toubert ME, Léger J, Boissinot C, Schlageter MH, Garel C, Tébeka B, Oury JF, Czernichow P, and Polak M
- Subjects
- Adult, Autoantibodies blood, Female, Humans, Immunoglobulins, Thyroid-Stimulating, Pregnancy, Prospective Studies, Receptors, Thyrotropin blood, Thyroid Gland physiology, Thyroxine blood, Antithyroid Agents therapeutic use, Fetus physiology, Graves Disease drug therapy, Pregnancy Complications drug therapy, Thyroid Gland diagnostic imaging, Ultrasonography, Prenatal
- Abstract
Background: Fetuses from mothers with Graves' disease may experience hypothyroidism or hyperthyroidism due to transplacental transfer of antithyroid drugs (ATD) or anti-TSH receptor antibodies, respectively. Little is known about the fetal consequences. Early diagnosis is essential to successful management. We investigated a new approach to the fetal diagnosis of thyroid dysfunction and validated the usefulness of fetal thyroid ultrasonograms., Methods: Seventy-two mothers with past or present Graves' disease and their fetuses were monitored monthly from 22 wk gestation. Fetal thyroid size and Doppler signals, and fetal bone maturation were determined on ultrasonograms, and thyroid function was evaluated at birth. Thyroid function and ATD dosage were monitored in the mothers., Results: The 31 fetuses whose mothers were anti-TSH receptor antibody negative and took no ATDs during late pregnancy had normal test results. Of the 41 other fetuses, 30 had normal test results at 32 wk, 29 were euthyroid at birth, and one had moderate hypothyroidism on cord blood tests. In the remaining 11 fetuses, goiter was visualized by ultrasonography at 32 wk, and fetal thyroid dysfunction was diagnosed and treated; there was one death, in a late referral, and 10 good outcomes with normal or slightly altered thyroid function at birth. The sensitivity and specificity of fetal thyroid ultrasound at 32 wk for the diagnosis of clinically relevant fetal thyroid dysfunction were 92 and 100%, respectively., Conclusion: In pregnant women with past or current Graves' disease, ultrasonography of the fetal thyroid gland by an experienced ultrasonographer is an excellent diagnostic tool. This tool in conjunction with close teamwork among internists, endocrinologists, obstetricians, echographists, and pediatricians can ensure normal fetal thyroid function.
- Published
- 2005
- Full Text
- View/download PDF
38. Targeted immunotherapy in acute myeloblastic leukemia: from animals to humans.
- Author
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Robin M, Schlageter MH, Chomienne C, and Padua RA
- Subjects
- Animals, Dendritic Cells immunology, Humans, Leukemia, Myeloid, Acute immunology, Vaccines, DNA immunology, Immunotherapy, Leukemia, Myeloid, Acute therapy
- Abstract
Immunity against acute myeloid leukemia (AML) is demonstrated in humans by the graft-versus-leukemia effect in allogeneic hematopoietic stem cell transplantation. Specific leukemic antigens have progressively been discovered and circulating specific T lymphocytes against Wilms tumor antigen, proteinase peptide or fusion-proteins produced from aberrant oncogenic chromosomal translocations have been detected in leukemic patients. However, due to the fact that leukemic blasts develop various escape mechanisms, antileukemic specific immunity is not able to control leukemic cell proliferation. The aim of immunotherapy is to overcome tolerance and boost immunity to elicit an efficient immune response against leukemia. We review different immunotherapy strategies tested in preclinical animal models of AML and the human trials that spurred from encouraging results obtained in animal models, demonstrate the feasibility of immunotherapy in AML patients.
- Published
- 2005
- Full Text
- View/download PDF
39. Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells.
- Author
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Larghero J, Gervais N, Cassinat B, Rain JD, Schlageter MH, Padua RA, Chomienne C, and Rousselot P
- Subjects
- Case-Control Studies, Cell Proliferation drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Erythroid Precursor Cells drug effects, Erythropoietin pharmacology, Farnesyltranstransferase, Humans, Polycythemia Vera drug therapy, Alkyl and Aryl Transferases antagonists & inhibitors, Erythropoiesis drug effects, Polycythemia Vera pathology, Quinolones pharmacology
- Abstract
Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.
- Published
- 2005
- Full Text
- View/download PDF
40. PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia.
- Author
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Padua RA, Larghero J, Robin M, le Pogam C, Schlageter MH, Muszlak S, Fric J, West R, Rousselot P, Phan TH, Mudde L, Teisserenc H, Carpentier AF, Kogan S, Degos L, Pla M, Bishop JM, Stevenson F, Charron D, and Chomienne C
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cancer Vaccines pharmacology, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Neoplasm Proteins drug effects, Neoplasm Proteins genetics, Oncogene Proteins, Fusion drug effects, Oncogene Proteins, Fusion genetics, Tretinoin pharmacology, Vaccines, DNA pharmacology, Cancer Vaccines immunology, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute prevention & control, Neoplasm Proteins immunology, Oncogene Proteins, Fusion immunology, Vaccines, DNA immunology
- Abstract
Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.
- Published
- 2003
- Full Text
- View/download PDF
41. Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.
- Author
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Anglicheau D, Flamant M, Schlageter MH, Martinez F, Cassinat B, Beaune P, Legendre C, and Thervet E
- Subjects
- Adult, Biological Availability, Dose-Response Relationship, Drug, Drug Interactions, Female, Glucocorticoids administration & dosage, Glucocorticoids pharmacokinetics, Humans, Immunosuppressive Agents blood, Kidney Transplantation, Male, Methylprednisolone administration & dosage, Methylprednisolone pharmacokinetics, Middle Aged, Retrospective Studies, Tacrolimus blood, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents pharmacokinetics, Tacrolimus administration & dosage, Tacrolimus pharmacokinetics
- Abstract
Background: Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation., Methods: We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment., Results: The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level., Conclusions: We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.
- Published
- 2003
- Full Text
- View/download PDF
42. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients.
- Author
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Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, Legendre C, and Daly AK
- Subjects
- Adult, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Osmolar Concentration, Predictive Value of Tests, Cytochrome P-450 Enzyme System genetics, Immunosuppressive Agents administration & dosage, Kidney Transplantation, Polymorphism, Genetic, Tacrolimus administration & dosage
- Abstract
Background: Tacrolimus pharmacokinetic characteristics vary greatly among individuals. Tacrolimus is a substrate of cytochrome p450 (CYP), of subfamily CYP3A. CYP3A activity is the sum of the activities of the family of CYP3A genes, including CYP3A5. Subjects with the CYP3A5*1/*1 genotype express large amounts of CYP3A5. Heterozygotes (genotype CYP3A5*1/*3) also express the enzyme. We postulated that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations., Methods: CYP3A5 genotype was evaluated in 80 renal transplant recipients and correlated with the daily tacrolimus dose and concentration-to-dose ratio., Results: The frequency of the homozygous CYP3A5*1 genotype (CYP3A5*1/*1) was 5%, and 11% of subjects were heterozygous (CYP3A5*1/*3). The mean doses required to obtain the targeted concentration-to-dose ratio were significantly lower in patients with the CYP3A5*1/*1 genotype., Conclusions: Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.
- Published
- 2003
- Full Text
- View/download PDF
43. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients.
- Author
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Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, Beaune P, Legendre C, and Thervet E
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology, Adult, Dose-Response Relationship, Drug, Exons, Female, Genotype, Graft Survival, Haplotypes, Humans, Kidney drug effects, Male, Middle Aged, Models, Genetic, Polymorphism, Genetic, Protein Structure, Secondary, Genes, MDR genetics, Genes, MDR physiology, Immunosuppressive Agents therapeutic use, Kidney Transplantation methods, Polymorphism, Single Nucleotide, Tacrolimus therapeutic use
- Abstract
The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.
- Published
- 2003
- Full Text
- View/download PDF
44. Primary Sjögren's syndrome associated agranulocytosis: a benign disorder?
- Author
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Coppo P, Sibilia J, Maloisel F, Schlageter MH, Voyer AL, Gouilleux-Gruart V, Goetz J, Desablens B, Tribout B, and Lassoued K
- Subjects
- Adult, Aged, Agranulocytosis drug therapy, Agranulocytosis immunology, Antibodies, Antinuclear analysis, Antirheumatic Agents therapeutic use, Bone Marrow Examination methods, Female, Granulocyte Colony-Stimulating Factor blood, Granulocyte Colony-Stimulating Factor therapeutic use, Humans, Methotrexate therapeutic use, Middle Aged, Neutropenia etiology, Pregnancy, Sjogren's Syndrome drug therapy, Sjogren's Syndrome immunology, Steroids administration & dosage, Treatment Outcome, Agranulocytosis complications, Sjogren's Syndrome complications
- Abstract
Objective: To report on an uncommon association of agranulocytosis in primary Sjögren's syndrome (SS)., Methods: The clinical, haematological, and immunological features of seven patients with primary SS associated with a chronic (>6 months) agranulocytosis, and the outcome of the patients, were analysed., Results: Patients were white women with an unexplained agranulocytosis. They all had non-erosive arthritis and three had a thrombocytopenia or Evan's syndrome. In three patients, transient or durable expansion of T lymphocytes was present in the peripheral blood or in the bone marrow, but evolved independently from neutrophil counts. There was no paroxysmal nocturnal haemoglobinuria clone or antibodies to neutrophil surface antigens. In vitro bone marrow culture was normal (four patients) or showed a decrease in colony forming unit-granulocyte monocyte (CFU-GM) and colony forming unit-erythroblast (CFU-E) (one patient). Serum levels of soluble Fas ligand (sFasL) were normal, and granulocyte-colony stimulating factor (G-CSF) concentrations were either normal or raised. One patient was treated with steroids associated with intravenous immunoglobulins and achieved a lasting response. Two other patients were treated with steroids and methotrexate, with poor efficacy. Short courses of subcutaneous G-CSF produced a transient and mild response in all three patients. Complete recovery of the neutrophils occurred temporarily during pregnancy in two patients. After a mean follow up of 34.8 months (range 6-139) all patients were alive and none developed serious infections., Conclusion: A subset of patients with primary SS and non-destructive arthritis may develop a chronic but well tolerated agranulocytosis that is usually poorly responsive to steroids and oral methotrexate.
- Published
- 2003
- Full Text
- View/download PDF
45. Is the thrombopoietin assay useful for differential diagnosis of thrombocytopenia? Analysis of a cohort of 160 patients with thrombocytopenia and defined platelet life span.
- Author
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Gouin-Thibault I, Cassinat B, Chomienne C, Rain JD, Najean Y, and Schlageter MH
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Child, Diagnosis, Differential, Female, Humans, Indium Radioisotopes, Male, Middle Aged, Thrombocytopenia blood, Thrombocytopenia etiology, Thrombopoietin isolation & purification, Blood Platelets pathology, Thrombocytopenia diagnosis, Thrombopoietin blood
- Abstract
Background: Thrombopoietin (TPO), the major hormone controlling platelet production, has been measured in thrombocytopenias with discordant results. The aim of our work was to assess the value of the TPO assay for differential diagnosis of thrombocytopenias in a large cohort of patients classified according to the results of their platelet isotopic study., Methods: We measured TPO (R&D Systems) in serum of 160 thrombocytopenic patients referred to our department for platelet life span isotopic studies. We classified patients as follows: (a) idiopathic or autoimmune thrombocytopenia group (ITP; patients with increased platelet destruction and shortened platelet life span; n = 67); (b) pure genetic thrombocytopenia group (patients with decreased platelet production, normal platelet life span, and without bone marrow aplasia; n = 55); (c) bone marrow aplasia group (BM; patients with decreased platelet production, normal platelet life span, and bone marrow aplasia; n = 13)., Results: In patients with pure genetic thrombocytopenia, TPO (median, 55 ng/L) was not different from TPO in patients with ITP (median, 58 ng/L) or controls (n = 54; median, 51 ng/L). Only in patients with bone marrow aplasia was TPO significantly higher (median, 155 ng/L) and negatively correlated to the platelet count (r(2) = 0.5014)., Conclusions: Although the median serum TPO is increased in thrombocytopenia with decreased platelet production from bone marrow aplasia, it does not differentiate patients with pure genetic thrombocytopenia from those with ITP.
- Published
- 2001
46. Intermethod discordance for alpha-fetoprotein measurements in Fanconi anemia.
- Author
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Cassinat B, Darsin D, Guardiola P, Toubert ME, Rain JD, Gluckman E, and Schlageter MH
- Subjects
- Adolescent, Adult, Anemia, Aplastic blood, Anemia, Aplastic diagnosis, Antibodies, Heterophile blood, Child, Child, Preschool, Diagnosis, Differential, Electrophoresis, Agar Gel, Female, Humans, Immunoassay methods, Infant, Lectins, Male, Middle Aged, Protein Isoforms blood, Quality Control, Fanconi Anemia diagnosis, alpha-Fetoproteins analysis
- Abstract
Background: The significantly higher serum alpha-fetoprotein (AFP) in patients with Fanconi anemia (FA) than in non-FA aplastic patients has potential diagnostic utility, but the increase is method-dependent. The aim of this study was to compare five AFP assays on FA and non-FA samples and to investigate possible explanations for FA-specific discrepancies., Methods: Two methods available in our laboratory (Kryptor and IMx) were compared on 59 FA and 27 non-FA patient samples. Kryptor, Immulite, Elecsys, Immuno-I, and Elsa-2 methods were then compared on 14 FA and 14 non-FA patient samples. The AFP glycosylation profile was analyzed by electrophoretic separation in a lectin-containing gel., Results: With all six methods, AFP values were significantly higher in FA than in non-FA patients, but the diagnostic precision and optimal cutoff values varied. Indeed, two methods reached 100% sensitivity and specificity, but in other methods, one or both of these parameters were significantly <100%. Neither heterophilic antibodies nor a specific glycosylation profile was detected in FA samples., Conclusions: AFP results are method-dependent in FA. New methods must be evaluated before use in differential diagnosis of aplastic patients.
- Published
- 2001
47. Evaluation of total PSA assay on vitros ECi and correlation with Kryptor-PSA assay.
- Author
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Cassinat B, Wacquet M, Toubert ME, Rain JD, and Schlageter MH
- Subjects
- Antibodies, Monoclonal immunology, Follow-Up Studies, Half-Life, Humans, Luminescent Measurements, Male, Sensitivity and Specificity, Adenocarcinoma blood, Biomarkers, Tumor blood, Fluorescent Antibody Technique, Indirect instrumentation, Fluorescent Dyes analysis, Immunoenzyme Techniques instrumentation, Neoplasm Proteins blood, Organometallic Compounds analysis, Prostate-Specific Antigen blood, Prostatic Neoplasms blood
- Abstract
Background: An increasing number of multiparametric immuno-analysers for PSA assays are available. As different immuno-assays may vary in their analytical quality and their accuracy for the follow-up of patients, expertise is necessary for each new assay., Methods: The PSA assay on the Vitros-ECi analyser has been evaluated and compared with the PSA assay from the Kryptor analyser., Results: Variation coefficients were 0.91 to 1.98% for within-run assays, and 4.2% to 5.4% for interassay (PSA levels = 0.8 microgram/L to 33.6 micrograms/L). Dilution tests showed 93 to 136% recovery until 70 micrograms/L PSA. Functional sensitivity was estimated at 0.03 microgram/L. Equimolarity of the test was confirmed. Correlation of PSA levels measured with Vitros-ECi and Kryptor analysers displayed a correlation coefficient r2 of 0.9716. The half-lives and doubling times of PSA were similar using both methods., Conclusion: Vitros-ECi PSA assay meets the major criteria for the management of prostate cancer patients.
- Published
- 2001
48. All trans retinoic acid abrogates spontaneous monocytic growth in juvenile chronic myelomonocytic leukaemia.
- Author
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Cambier N, Menot ML, Schlageter MH, Balitrand N, Leblanc T, Bordigoni P, Rohrlich P, Lamagnère JP, Donadieu J, Herbelin C, Puissant C, Gourand F, Baruchel A, and Chomienne C
- Subjects
- Cell Differentiation drug effects, Cell Proliferation drug effects, Child, Female, Granulocyte Precursor Cells metabolism, Humans, Leukemia, Myelomonocytic, Chronic drug therapy, Leukemia, Myelomonocytic, Chronic pathology, Male, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Granulocyte Precursor Cells pathology, Leukemia, Myelomonocytic, Chronic physiopathology, Tretinoin pharmacology
- Abstract
Introduction: All trans retinoic acid, the active metabolite of vitamin A, exerts profound effects on cell differentiation. On normal myeloid progenitors, retinoids switch the differentiation program of granulo-macrophagic progenitors towards the granulocytic lineage and consequently reduce CFU-M colony formation. Bone marrow and peripheral blood mononuclear cells from children with Juvenile Chronic Myelomonocytic Leukaemia show typical spontaneous monocytic growth. We questioned whether in this disease, retinoids could switch myelomonocytic growth and inhibit the abnormal CFU-M colony proliferation., Methods: Ten JCML samples were studied in the presence of ATRA in methyl cellulose colony assay, before (CFU-C) or after (pre-CFU) liquid suspension culture., Results: In vitro characteristics of JCML such as spontaneous monocytic growth in the absence of growth factor was noted in all patients. In the presence of leucocyte-conditioned medium, nine samples showed only CFU-M growth and one sample CFU-GM growth. Incubation with ATRA inhibited CFU-M colony formation in nine cases. Enhancement of granulocytic differentiation (CFU-G) was noted in nine cases. ATRA also inhibited CD34+ JCML monocytic growth and GM-CSF hypersensitivity., Conclusion: These data suggest that, in JCML progenitors, retinoid pathways are functional and inhibition of immature monocytic progenitors cells may be achieved with retinoids, without impeding granulocytic cell growth.
- Published
- 2001
- Full Text
- View/download PDF
49. Constitutive elevation of serum alpha-fetoprotein in Fanconi anemia.
- Author
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Cassinat B, Guardiola P, Chevret S, Schlageter MH, Toubert ME, Rain JD, and Gluckman E
- Subjects
- Adolescent, Adult, Biological Assay, Biomarkers, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Fanconi Anemia blood, alpha-Fetoproteins analysis
- Abstract
The diagnosis of Fanconi anemia (FA) is based on the association of congenital malformations, bone marrow failure syndrome, and hypersensitivity to chromosomal breaks induced by cross-linking agents. In the absence of typical features, the diagnosis is not easy to establish because there is no simple and cost-effective test; thus, investigators must rely on specialized analyses of chromosomal breaks. Because we observed elevated serum alpha-fetoprotein (sAFP) levels in FA patients, we investigated this parameter as a possible diagnostic tool. Serum AFP levels from 61 FA patients and 27 controls with acquired aplastic anemia or other inherited bone marrow failure syndromes were analyzed using a fluoroimmunoassay based on the TRACE technology. Serum AFP levels were significantly more elevated (P <.0001) in FA than in non-FA aplastic patients. In the detection of FA patients among patients with bone marrow failure syndromes, this assay had a sensitivity of 93% and a specificity of 100%. This elevation was not explained by liver abnormalities. Levels of sAFP were unchanged during at least 4 years of follow-up, and allogeneic bone marrow transplantation did not modify sAFP levels. Three of 4 FA patients with mosaicism as well as 5 of 6 FA patients with myelodysplastic syndrome were detected by this test. Heterozygous parents of FA patients had normal sAFP levels. Measurement of sAFP levels with this automated, cost-effective, and reproducible fluoroimmunoassay could be proposed for the preliminary diagnosis of FA whenever this disorder is suspected.
- Published
- 2000
50. Serum carcinoembryonic antigen, cancer antigen 125, cancer antigen 15-3, squamous cell carcinoma, and tumor-associated trypsin inhibitor concentrations during healthy pregnancy.
- Author
-
Schlageter MH, Larghero J, Cassinat B, Toubert ME, Borschneck C, and Rain JD
- Subjects
- Female, Humans, Reference Values, Antigens, Neoplasm blood, Biomarkers, Tumor blood, CA-125 Antigen blood, Carcinoembryonic Antigen blood, Mucin-1 blood, Pregnancy blood, Serpins, Trypsin Inhibitor, Kazal Pancreatic blood
- Published
- 1998
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