Publications by authors named "Bertrand Favier"

31 Publications

Cemiplimab removed from reimbursable drugs in France.

Eur J Cancer 2021 May 1;149:11-13. Epub 2021 Apr 1.

Service de Dermatologie, Centre Léon Bérard, Lyon, France.

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http://dx.doi.org/10.1016/j.ejca.2021.02.041DOI Listing
May 2021

Chlamydia-infected Macrophages mediate Interleukin-23 and Tumor Necrosis Factor-driven Reactive Arthritis in SKG Mice.

Arthritis Rheumatol 2021 Jan 16. Epub 2021 Jan 16.

Univ. Grenoble Alpes, GREPI TIMC-IMAG, UMR 5525, 38000, Grenoble, France.

Objective: ZAP-70 BALB/c (SKG) mice develop reactive arthritis (ReA) after Chlamydia muridarum (Cmu) infection. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells taking up Cmu drive arthritis.

Methods: Female SKG, Il17a-deficient SKG and BALB/c mice were genitally infected with Cmu or Cmu Luciferase. Cmu dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-TNF, anti-IL-23p19 were administered after infection or arthritis onset. Hspa5, Tgtp1, Il23a, Il17a, Il12b and Tnf expression was compared in SKG and BALB/c mice.

Results: One-week post infection, macrophages and neutrophils infiltrated the uterus; both carried Cmu DNA to the spleen. Cmu load was higher in SKG than BALB/c. Macrophage depletion reduced Cmu load and prevented arthritis. Compared with BALB/c, expression of Il23a and Il17a was increased in SKG uterine and splenic neutrophils. Anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was over-expressed in SKG joints within one-week post infection and persisted. TNF inhibition during infection or at arthritis onset suppressed arthritis. Endoplasmic reticulum stress was constitutively increased in SKG joints but was induced, with immunity-related GTPase, by Cmu infection in uterus.

Conclusion: The load of Cmu is higher in SKG than BALB/c mice. While proinflammatory IL-23 produced by neutrophils contributes to the initiation of Cmu-mediated ReA, macrophage depletion reduces Cmu dissemination to other tissues, tissue burden, and arthritis. TNF inhibition suppresses arthritis. Our data suggest that enhanced bacterial dissemination in SKG macrophages drives TNF production required for persistent arthritis.
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http://dx.doi.org/10.1002/art.41653DOI Listing
January 2021

Permeation measurement of 27 chemotherapy drugs after simulated dynamic testing on 15 surgical and examination gloves: A knowledge update.

J Oncol Pharm Pract 2020 Aug 26:1078155220950423. Epub 2020 Aug 26.

Laboratoire de Biochimie et de Pharmaco-toxicologie, Centre Hospitalier Lyon-Sud - HCL, Pierre Bénite, France.

Purpose: Exposure to anticancer drugs is one of the known risks for people working in specialist oncology units. Wearing gloves is a vital form of personal protection. The aim of this study was to assess, in close to real use dynamic conditions, the permeability of 15 surgical and examination gloves made from different materials when exposed to 27 anticancer drugs included in the list from international Guides and Recommendations.

Methods: Gloves were tested by using controlled dynamic conditions replicating flexion and extension movements that mimic typical clinical applications. Tests were performed at 37°C or at 43°C for 30 min and anticancer drugs were tested at the highest concentration used in clinical practice. To determine the permeation rate, the quantification of anticancer drugs was performed with selective and sensitive analytical methods such as inductively coupled plasma-mass spectroscopy and liquid chromatography-mass spectrometry.

Results: All the gloves met the EN 16523-1 European standard (1000 ng/(min.cm)). The penetration rate of busulfan, carmustine and thiotepa exceeded the ASTM D-6978-05 American standard (10 ng/(min.cm)) with several surgical and/or examination gloves. This standard was met in all of cases when double gloving was used. Breakage of several nitrile gloves was observed in relation with the excipient used by drugs suppliers.

Conclusions: Permeation is a complex multifactorial phenomenon. However, we have suggested that the thickness of the glove and three physicochemical parameters (molecular weight, topological polar surface area and hydrogen bond donor) of the drug were the main parameters affecting permeation.
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http://dx.doi.org/10.1177/1078155220950423DOI Listing
August 2020

Semi-automated fact-checking of nucleotide sequence reagents in biomedical research publications: The Seek & Blastn tool.

PLoS One 2019 1;14(3):e0213266. Epub 2019 Mar 1.

Molecular Oncology Laboratory, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Nucleotide sequence reagents are verifiable experimental reagents in biomedical publications, because their sequence identities can be independently verified and compared with associated text descriptors. We have previously reported that incorrectly identified nucleotide sequence reagents are characteristic of highly similar human gene knockdown studies, some of which have been retracted from the literature on account of possible research fraud. Because of the throughput limitations of manual verification of nucleotide sequences, we developed a semi-automated fact checking tool, Seek & Blastn, to verify the targeting or non-targeting status of published nucleotide sequence reagents. From previously described and unknown corpora of 48 and 155 publications, respectively, Seek & Blastn correctly extracted 304/342 (88.9%) and 1066/1522 (70.0%) nucleotide sequences and a predicted targeting/ non-targeting status. Seek & Blastn correctly predicted the targeting/ non-targeting status of 293/304 (96.4%) and 988/1066 (92.7%) of the correctly extracted nucleotide sequences. A total of 38/39 (97.4%) or 31/79 (39.2%) Seek & Blastn predictions of incorrect nucleotide sequence reagent use were correct in the two literature corpora. Combined Seek & Blastn and manual analyses identified a list of 91 misidentified nucleotide sequence reagents, which could be built upon through future studies. In summary, incorrect nucleotide sequence reagents represent an under-recognized source of error within the biomedical literature, and fact checking tools such as Seek & Blastn may help to identify papers and manuscripts affected by these errors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213266PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396917PMC
December 2019

[Intravenous chemotherapy at home: A pediatric monocentric experience].

Bull Cancer 2018 Feb 1;105(2):155-161. Epub 2018 Feb 1.

Centre Léon-Bérard, hospitalisation à domicile pédiatrique, IHOPe, 1, place du Pr-J.-Renaut, 69373 Lyon cedex 08, France; ESPPéRA, ERRSPP Rhône-Alpes, 1, place du Pr-J.-Renaut, 69373 Lyon cedex 08, France.

Introduction: Our home care unit (HCU) developed the administration of IV chemotherapy at home for some pediatric oncologic patients.

Methods: We conducted a retrospective monocentric analysis, leading to identify patients with at least one sequence of chemotherapy at home in 2015.

Results: Two hundred and forty four sequences of home chemotherapy have been administered in 2015. We identified two situations for home IV chemotherapy. Pediatric oncologist of day hospital prescribes the sequence. The chemotherapy is delivered at hospital for the first day. HCU takes over for the next days at home. For a sequence replacing a conventional hospitalization, the attending physician examines the patient, and confirm the clinical validation. The pediatric oncologist of HCU checks lab exams, and prescribes the chemotherapy. For both situations, IV chemotherapy is prepared by our hospital pharmacy, delivers at home or at day hospital, and HCU team manages home material and organizes hospitalization.

Conclusions: This kind of organization allows setting up home IV CT for more and more patients. It allows to limit daily hospitalization for some patients living far from the hospital, and whose therapies lead to several hospitalizations.
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http://dx.doi.org/10.1016/j.bulcan.2017.10.026DOI Listing
February 2018

Histone H3.3 regulates mitotic progression in mouse embryonic fibroblasts.

Biochem Cell Biol 2017 08 1;95(4):491-499. Epub 2017 Feb 1.

f Université de Lyon, Institut de Génomique Fonctionnelle de Lyon, CNRS UMR 5242, Ecole normale supérieur de Lyon, Université Claude Bernard Lyon 1, 46 Allée d'Italie, F-69364 Lyon, France.

H3.3 is a histone variant that marks transcription start sites as well as telomeres and heterochromatic sites on the genome. The presence of H3.3 is thought to positively correlate with the transcriptional status of its target genes. Using a conditional genetic strategy against H3.3B, combined with short hairpin RNAs against H3.3A, we essentially depleted all H3.3 gene expression in mouse embryonic fibroblasts. Following nearly complete loss of H3.3 in the cells, our transcriptomic analyses show very little impact on global gene expression or on the localization of histone variant H2A.Z. Instead, fibroblasts displayed slower cell growth and an increase in cell death, coincident with large-scale chromosome misalignment in mitosis and large polylobed or micronuclei in interphase cells. Thus, we conclude that H3.3 may have an important under-explored additional role in chromosome segregation, nuclear structure, and the maintenance of genome integrity.
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http://dx.doi.org/10.1139/bcb-2016-0190DOI Listing
August 2017

Kininogen Cleavage Assay: Diagnostic Assistance for Kinin-Mediated Angioedema Conditions.

PLoS One 2016;11(9):e0163958. Epub 2016 Sep 29.

GREPI EA7408, Université Grenoble Alpes, Grenoble, France.

Background: Angioedema without wheals (AE) is a symptom characterised by localised episodes of oedema presumably caused by kinin release from kininogen cleavage. It can result from a hereditary deficiency in C1 Inhibitor (C1Inh), but it can present with normal level of C1Inh. These forms are typically difficult to diagnose although enhanced kinin production is suspected or demonstrated in some cases.

Objectives: We wanted to investigate bradykinin overproduction in all AE condition with normal C1Inh, excluding cases with enhanced kinin catabolism, and to propose this parameter as a disease biomarker.

Methods: We retrospectively investigated high molecular weight kininogen (HK) cleavage pattern, using gel electrophoresis and immunorevelation. Plasma samples were drawn using the same standardised procedure from blood donors or AE patients with normal C1Inh conditions, normal kinin catabolism, and without prophylaxis.

Results: Circulating native HK plasma concentrations were similar in the healthy men (interquartile range: 98-175μg/mL, n = 51) and in healthy women (90-176μg/mL, n = 74), while HK cleavage was lower (p<0.001) in men (0-5%) than women (3-9%). Patients exhibited lower native HK concentration (p<10-4; 21-117μg/mL, n = 31 for men; 0-84μg/mL, n = 41 for women) and higher HK cleavage (p<10-4; 10-30% and 14-89%, respectively) than healthy donors. Pathological thresholds were set at: <72μg/mL native HK, >14.4% HK cleavage for men; <38μg/mL; native HK, >33.0% HK cleavage for women, with >98% specificity achieved for all parameters. In plasma from patients undergoing recovery two months after oestrogen/progestin combination withdrawal (n = 13) or two weeks after AE attack (n = 2), HK cleavage was not fully restored, suggesting its use as a post-attack assay.

Conclusion: As a diagnostic tool, HK cleavage can offer physicians supportive arguments for kinin production in suspected AE cases and improve patient follow-up in clinical trials or prophylactic management.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042432PMC
September 2016

Discovery of benzo[e]pyridoindolones as kinase inhibitors that disrupt mitosis exit while erasing AMPK-Thr172 phosphorylation on the spindle.

Oncotarget 2015 Sep;6(26):22152-66

INSERM UJF U823 Institut Albert Bonniot, Team 5, BP 170, Grenoble Cedex 9, France.

Aurora kinases play an essential role in mitotic progression and are attractive targets in cancer therapy. The first generation of benzo[e]pyridoindole exhibited powerful aurora kinase inhibition but their low solubility limited further development. Grafting a pyperidine-ethoxy group gives rise to a hydrosoluble inhibitor: compound C5M.C5M could efficiently inhibit the proliferation of cells from different origins. C5M prevented cell cycling, induced a strong mitotic arrest then, cells became polyploid and finally died. C5M did not impair the spindle checkpoint, the separation of the sister chromatids and the transfer of aurora B on the mid-zone. C5M prevented histone H3 phosphorylation at mitotic entry and erased AMPK-Thr172 phosphorylation in late mitosis. With this unique profile of inhibition, C5M could be useful for understanding the role of phospho-Thr172-AMPK in abscission and the relationship between the chromosomal complex and the energy sensing machinery.C5M is a multikinase inhibitor with interesting preclinical characteristics: high hydro-solubility and a good stability in plasma. A single dose prevents the expansion of multicellular spheroids. C5M can safely be injected to mice and reduces significantly the development of xenograft. The next step will be to define the protocol of treatment and the cancer therapeutic field of this new anti-proliferative drug.
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http://dx.doi.org/10.18632/oncotarget.4158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673153PMC
September 2015

Transferability of health cost evaluation across locations in oncology: cluster and principal component analysis as an explorative tool.

BMC Health Serv Res 2014 Nov 18;14:537. Epub 2014 Nov 18.

Background: The transferability of economic evaluation in health care is of increasing interest in today's globalized environment. Here, we propose a methodology for assessing the variability of data elements in cost evaluations in oncology. This method was tested in the context of the European Network of Excellence "Connective Tissues Cancers Network".

Methods: Using a database that was previously aimed at exploring sarcoma management practices in Rhône-Alpes (France) and Veneto (Italy), we developed a model to assess the transferability of health cost evaluation across different locations. A nested data structure with 60 final factors of variability (e.g., unit cost of chest radiograph) within 16 variability areas (e.g., unit cost of imaging) within 12 objects (e.g., diagnoses) was produced in Italy and France, separately. Distances between objects were measured by Euclidean distance, Mahalanobis distance, and city-block metric. A hierarchical structure using cluster analysis (CA) was constructed. The objects were also represented by their projections and area of variability through correlation studies using principal component analysis (PCA). Finally, a hierarchical clustering based on principal components was performed.

Results: CA suggested four clusters of objects: chemotherapy in France; follow-up with relapse in Italy; diagnosis, surgery, radiotherapy, chemotherapy, and follow-up without relapse in Italy; and diagnosis, surgery, and follow-up with or without relapse in France. The variability between clusters was high, suggesting a lower transferability of results. Also, PCA showed a high variability (i.e. lower transferability) for diagnosis between both countries with regard to the quantities and unit costs of biopsies.

Conclusion: CA and PCA were found to be useful for assessing the variability of cost evaluations across countries. In future studies, regression methods could be applied after these methods to elucidate the determinants of the differences found in these analyses.
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http://dx.doi.org/10.1186/s12913-014-0537-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241216PMC
November 2014

Administration of anticancer drugs: exposure in hospital nurses.

Clin Ther 2014 Mar 5;36(3):401-7. Epub 2014 Mar 5.

Hospices Civils de Lyon, Groupement Hospitalier Sud, Chemotherapy Targeting in Oncology Laboratory-University Claude Bernard Lyon, Faculty of Pharmacy, Toxicology Laboratory, Lyon, France.

Background: Even though anticancer drugs are prepared in dedicated pharmaceutical units, nurses remain exposed to cytotoxic agents during administration to patients.

Objective: The aim of this study was to assess this occupational exposure during the intravenous line-purging procedure at the patient's bedside before administration in oncology departments.

Methods: This prospective study was conducted over a 4-week period in the hematology and oncology departments at a university hospital. Amounts of doxorubicin and cyclophosphamide on the surface of nurses' gloves were measured after the intravenous line purge of the infusion bag and the connection to the patient. For this purpose, gloves were washed with sterile water, following a validated procedure. Quantification of the 2 drugs into the water was performed using LC-MS/MS.

Results: After 59 chemotherapy administrations, 30.5% of gloves were contaminated. Despite extremely low volumes of contamination (0.08-6.28 µL), amounts collected ranged from 190 to 2500 ng per pair of gloves that tested positive for doxorubicin (median, 1600 ng) and from 130 to 32,600 ng with cyclophosphamide (median, 2700 ng).

Conclusions: The intravenous line purge preceding antineoplastic infusion bag administration is a potential source of contamination in nurses. Contaminations appear to be invisible but frequent (in >30% of cases). Therefore, intravenous line purging performed under appropriately safe conditions should be mandated in pharmaceutical units dedicated to injectable-drug preparation. This measure should be included as a standard hospital practice as a matter of urgency.
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http://dx.doi.org/10.1016/j.clinthera.2014.01.016DOI Listing
March 2014

Contact system activation in patients with HAE and normal C1 inhibitor function.

Immunol Allergy Clin North Am 2013 Nov 14;33(4):513-33. Epub 2013 Sep 14.

University Joseph Fourier, GREPI/AGIM CNRS FRE 3405, Grenoble, France; French Reference Centre for Angioedema, CREAK, Grenoble, France.

In addition to hereditary angioedema (HAE) with C1 inhibitor (C1INH) deficiency, a type of HAE with dominant inheritance and normal C1INH function (HAE with normal C1INH) has been described. This relates to contact phase activation with exaggerated kinin formation, and mutations in the coagulation factor XII gene have been identified in some affected families, but the cause of the disease has remained elusive in a majority of families. Several triggering factors are responsible for developing kinin forming system, with participation of endothelium and mast cell component. Angioedema conditions meet the accumulation of kinins with failed kinin catabolism.
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http://dx.doi.org/10.1016/j.iac.2013.07.007DOI Listing
November 2013

Enzymatic assays for the diagnosis of bradykinin-dependent angioedema.

PLoS One 2013 5;8(8):e70140. Epub 2013 Aug 5.

Centre de Référence des Angioedèmes à Kinines, CREAK, Grenoble, France.

Background: The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE.

Methods: The plasma amidase assays are performed using the Pro-Phe-Arg-p-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays.

Results: Spontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol⋅min(-1)⋅mL(-1), area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol·min(-1)⋅mL(-1), AUC 91.0%, sensitivity 87.0% and specificity 81.2%).

Conclusion: The amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK-related and -unrelated AE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070140PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734293PMC
March 2014

Hereditary angioedema caused by the p.Thr309Lys mutation in the F12 gene: a multifactorial disease.

J Allergy Clin Immunol 2013 Oct 10;132(4):986-9.e1-5. Epub 2013 Jul 10.

Allergy Department, Hospital Universitario La Paz, Madrid, Spain; Hospital La Paz Health Research Institute (IdiPAZ), Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2013.04.032DOI Listing
October 2013

Cost effectiveness of pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous stem cell transplantation in patients with lymphoma and myeloma: an economic evaluation of the PALM Trial.

Appl Health Econ Health Policy 2013 Apr;11(2):129-38

Department Cancer and Environment, Cancer Centre Léon Bérard, University of Lyon, GATE Lyon-St Etienne, UMR-CNRS 5824, 28 rue Laënnec, 69373, Lyon Cedex 08, France.

Background: Use of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) filgrastim accelerates neutrophil recovery following myelosuppressive chemotherapy. Since filgrastim requires multiple daily administrations, forms of rhG-CSF with a longer half life, including pegfilgrastim, have been developed. Pegfilgrastim is safe and effective in supporting neutrophil recovery and reducing febrile neutropenia after conventional chemotherapy. Pegfilgrastim has also been successfully used to support patients undergoing peripheral blood stem cell (PBSC) transplantation for haematological malignancies. To our knowledge, no cost-effectiveness analysis (CEA) of pegfilgrastim in this setting has been published yet.

Objective: We undertook a CEA to compare a single injection of pegfilgrastim versus repeated administrations of filgrastim in patients who had undergone PBSC transplantation for lymphoma or myeloma. The CEA was set in France and covered a period of 100 ± 10 days from transplant.

Methods: The CEA was designed as part of an open-label, multicentre, randomized phase II trial. Costs were assessed from the hospital's point of view and are expressed in 2009 euros. Costs computation focused on inpatient, outpatient, and home care. Costs in the two arms of the study were compared using the Mann-Whitney test. When differences were statistically significant, multiple regression analyses were performed in order to identify cost drivers. Incremental cost-effectiveness ratios (ICER) were calculated for the major endpoints of the trial; i.e., duration of febrile neutropenia (absolute neutrophil count [ANC] <0.5 × 10(9)/L and temperature ≥38 °C), duration of neutropenia (ANC <1.0 × 10(9)/L and ANC <0.5 × 10(9)/L), duration of thrombopenia (platelets <50 × 10(9)/L and <20 × 10(9)/L), and days with a temperature ≥38 °C). Uncertainty around the ICER was captured by a probabilistic analysis using a non-parametric bootstrap method.

Results: 151 patients were enrolled at ten French centres from October 2008 to September 2009. The mean total cost in the pegfilgrastim arm of the study (n = 74) was 25,024 (SD 9,945). That in the filgrastim arm (n = 76) was 28,700 (SD 20,597). Pegfilgrastim strictly dominated filgrastim for days of febrile neutropenia avoided, days of neutropenia (ANC <1.0 × 10(9)/L) avoided, days of thrombopenia (platelets <20 × 10(9)/L) avoided, and days with temperature ≥38 °C) avoided. Pegfilgrastim was less costly and less effective than filgrastim for the number of days with ANC <0.5 × 10(9)/L avoided and the number of days with platelets <50.0 × 10(9)/L avoided. Taking uncertainty into account, the probabilities that pegfilgrastim strictly dominated filgrastim were 67 % for febrile neutropenia, 86 % for neutropenia (ANC <1.0 × 10(9)/L), 59 % for thrombopenia (platelets <20 × 10(9)/L), 86 % for temperature ≥38 °C, 32 % for neutropenia (ANC <0.5 × 10(9)/L), and 43 % for thrombopenia (platelets <50 × 10(9)/L). Conversely, the probability that filgrastim strictly dominated pegfilgrastim for neutropenia (ANC <0.5 × 10(9)/L) is 5 %.

Conclusion: This study found no evidence that the use of pegfilgrastim is associated with greater cost in lymphoma and myeloma patients after high-dose chemotherapy and PBSC transplantation.
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http://dx.doi.org/10.1007/s40258-013-0011-7DOI Listing
April 2013

Paclitaxel and cetuximab combination efficiency after the failure of a platinum-based chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma.

Anticancer Drugs 2012 Oct;23(9):996-1001

Department of Medical Oncology, University of Lyon, France.

The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m) and TXL (60-80 mg/m) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23-53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1-4.7 months] and the median OS was 7.6 months [95% CI; 5.3-9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.
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http://dx.doi.org/10.1097/CAD.0b013e32835507e5DOI Listing
October 2012

First-line endocrine therapy alone could be a reasonable treatment option for hormone-positive, HER2-positive metastatic breast cancer.

Bull Cancer 2012 Feb;99(2):E18-25

Centre Léon-Bérard, Department of Medical Oncology, 28, rue Laennec, 69008 Lyon, France.

Purpose: The treatment strategy for hormone receptor-positive (ER+) HER2-positive (HER2+) metastatic breast cancer has been modified since several randomized trials have proven the effectiveness of anti-HER2 targeted therapy. Previously validated clinical practice guidelines recommending the use of endocrine therapy alone in first line might be changed.

Methods: This study focused on the outcomes of women with ER+ HER2+ metastatic breast cancer receiving first-line endocrine therapy alone at the Léon-Bérard Centre, Lyon, France.

Results: Of 290 patients with ER+ HER2+ tumors, 32 (11%) met the criteria for inclusion. The median age was 54 years (29-79 years). Eighteen patients (56%) had only bone and/or soft tissue metastases. Most patients (n = 21; 65%) had only one metastatic site. Fifteen (47%) had histological grade III disease. The median progression free survival (PFS) was 8.2 months (95% CI: 0.1-16.3) and the median overall survival (OS) was 48 months (95% CI: 22.9-72.9). The overall response rate was 25% (95% CI: 11-49%), including one patient with complete response and seven with partial responses. Ten patients (31%) had stable disease. After failure of endocrine therapy, all patients received trastuzumab. The median PFS after first-line chemotherapy was 8.4 months (95% CI: 5.1-11.8). We identified a group of 10 patients with good prognostic factor (tumor grade < 3 tumors and no visceral metastases), for whom median PFS was 15.5 months (95% CI: 7-23).

Conclusions: Our result suggests that first-line endocrine therapy is a viable therapeutic option for a selected population of metastatic breast cancer patients with HER2-positive tumors. Genomic and transcriptomic signature could help to identify tumors that remain dependant of estrogen-signaling pathway.
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http://dx.doi.org/10.1684/bdc.2011.1537DOI Listing
February 2012

Chemotherapy for metastatic breast cancer. Comparison of clinical practice and cost of drugs in two cohorts of patients: 1994-1998 and 2003-2006.

Breast Cancer Res Treat 2011 Jul 24;128(1):187-95. Epub 2010 Dec 24.

Department of Pharmacy, Centre Léon Bérard, Lyon, 69008, France.

Although new chemotherapeutic drugs for metastatic breast cancer (MBC) have been approved over the past decade, it is unclear whether this has changed the overall outcome of patients. This study assessed the clinical and economic impacts of these drugs. We retrospectively studied MBC patients receiving chemotherapy in our institution over two time periods, 1994-1998 and 2003-2006. Patient characteristics and outcomes, and treatment characteristics and costs (€, 2008) were compared. Three hundred and one patients were identified, 149 patients in the first cohort and 152 in second one. The median number of lines of chemotherapy was similar in the two cohorts (three lines). The median costs of chemotherapy per patient nearly doubled over time, from 6,272 € in the 1994-1998 cohort to 13,035 € in the 2003-2006 cohort (P < 0.001). No survival difference was observed between the two groups, with a 3-year survival rate estimated to 41% in the 1994-1998 cohort and 44% in the 2003-2006 cohort (P = 0.52). In multivariate analysis, prognostic factors associated with longer overall survival were single metastatic site (HR 0.48; P < 10⁻³), bone metastases (HR = 0.67; P = 0.007) and positive hormone receptors (HR 0.56; P = 0.0002). New chemotherapeutic agents induced a significant cost increase over time. The limited size and heterogeneity of our cohort do not allow any conclusion concerning their impact on survival.
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http://dx.doi.org/10.1007/s10549-010-1311-3DOI Listing
July 2011

Paclitaxel is effective in relapsed head and neck squamous cell carcinoma: a retrospective study of 66 patients at a single institution.

Anticancer Drugs 2010 Jun;21(5):553-8

Université de Lyon, Centre Léon Bérard, Lyon, France.

The standard first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma is cisplatin-based chemotherapy, but taxanes can also be beneficial after progression or in patients not eligible for cisplatin. The objective of this retrospective study was to evaluate paclitaxel in this population. We reviewed 66 patients who were treated with paclitaxel at a single institution (Lyon, France) between January 2003 and November 2008. Paclitaxel was administered as first, second or more line of treatment; alone or in combination with carboplatin or cetuximab; every 3 weeks (175 mg/m(2)) or weekly (80 mg/m(2)). Forty-six (70%) patients received paclitaxel as first-line therapy after relapse and 26 (39%) patients as monotherapy. The objective response rate was 30% [95% confidence interval (CI): 20-43%]; 37% (95% CI: 23-52%) in the first line after relapse, and 20% (95% CI: 4-48%) in the second line. Rates were 19% (95% CI: 7-39%) after monotherapy and 36% (95% CI: 20-55%) after combination with carboplatin. Two of the six patients receiving cetuximab had a partial response. The overall survival of all patients was 7.2 months (95% CI: 5.2-8.8). Paclitaxel can be used in symptomatic patients. Although no improvement of overall survival can be expected, paclitaxel treatment is safe and achieves interesting response rates.
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http://dx.doi.org/10.1097/CAD.0b013e3283388e60DOI Listing
June 2010

Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution.

Anticancer Drugs 2010 Jan;21(1):113-9

Department of Medicine, Unité INSERM, Centre Léon Bérard, Lyon, France.

Trabectedin was recently approved for patients failing doxorubicin, the standard treatment for advanced/metastatic sarcoma. This retrospective study aimed to compare trabectedin efficacy between compassionate use in unselected patients and clinical trials. From May 1999 to January 2006, 92 patients were treated at the Centre Léon Bérard, either in phase II studies or on a named patient compassionate basis. All cases were retrospectively analyzed to assess trabectedin efficacy in terms of response, progression-free, and overall survival.The objective response rate was 10% (N=9): 4% (N=2) for patients treated in compassionate use program and 16% (N=7) for those in clinical trials (P=0.18); 26 (28%) patients had stable disease for at least 6 months, 11 (23%) in the compassionate group and 15 (33%) in clinical trials. Median progression-free and overall survivals were, respectively, 2.2 [95% confidence interval (CI): 1.9-3.6] and 8.9 (95% CI: 6.4-14.2) months for all patients, 2.3 (95% CI: 1.9-4.3) and 10.4 (95% CI: 6.9-24.2) months for patients in clinical trials and 1.8 (95% CI: 1.4-3.4) and 6.4 (95% CI: 3.3-14.2) months for patients under compassionate treatment. In this retrospective analysis, the reported grade 3-4 toxicities were increased transaminase (34 patients, 37%) and neutropenia (38 patients; 42%). Higher efficacy was observed in phase II studies than with compassionate treatment, but no significant difference remained after adjustment in multivariate analysis for performance status, a well-established prognosis factor. The safety and tolerability of trabectedin shown in clinical trials is confirmed for patients in real-life situation treated in compassionate use programs, but its benefit is higher for patients with performance status 0-1.
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http://dx.doi.org/10.1097/CAD.0b013e328333057bDOI Listing
January 2010

Bevacizumab and paclitaxel for breast cancer patients with central nervous system metastases: a case series.

Clin Breast Cancer 2009 May;9(2):118-21

Department of Medical Oncology, Centre Leon Berard, Laennec, France.

Central nervous system (CNS) metastases are a major concern in patients with stage IV breast cancer. Recent studies have shown the efficacy of anti-vascular endothelial growth factor drugs on brain tumors, in particular glioblastoma, but none has explored their efficacy and tolerance in breast cancer patients with CNS metastases. We report 4 cases of patients with CNS metastases treated with bevacizumab and paclitaxel. All but 1 had previous whole-brain radiation therapy, performance status 0-2, and radiographic evidence of progressive CNS metastases. Patients received paclitaxel 80 mg/m2 on days 1, 8, and 15, and bevacizumab 10 mg/kg on days 1 and 15. Response was evaluated according to the World Health Organization criteria. Three patients had brain metastases, and 1 had meningeal lesions. Only 1 patient was chemotherapy-naive. Significant antitumor activity was observed, with 1 complete response and 3 partial responses in the CNS metastases. With a mean follow-up of 9 months, duration of response was 11, 10, 8, and 6 months. No patient had extra-CNS progression. This observed antitumor activity suggests efficiency of the combination of bevacizumab and paclitaxel and warrants further evaluation of this combination as an alternative option for the treatment of multiple CNS metastases in breast cancer.
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http://dx.doi.org/10.3816/CBC.2009.n.021DOI Listing
May 2009

Benzo[e]pyridoindoles, novel inhibitors of the aurora kinases.

Cell Cycle 2009 Mar 18;8(5):765-72. Epub 2009 Mar 18.

INSERM: U823 Institut Albert Bonniot, Université Joseph Fourier, La Tronche, France.

Aurora kinases are serine/threonine protein kinases that are involved in cancer development and are important targets for cancer therapy. By high throughput screening of a chemical library we found that benzo[e]pyridoindole derivatives inhibited Aurora kinase. The most potent compound (compound 1) was found to be an ATP competitive inhibitor, which inhibited in vitro Aurora kinases at the nanomolar range. It prevented, ex vivo, the phosphorylation of Histone H3, induced mitosis exit without chromosome segregation, known phenomena observed upon Aurora B inactivation. This compound was also shown to affect the localization of Aurora B, since in the presence of the inhibitor the enzyme was delocalized on the whole chromosomes and remained associated with the chromatin of newly formed nuclei. In addition, compound 1 inhibited the growth of different cell lines derived from different carcinoma. Its IC(50) for H358 NSCLC (Non Small Cancer Lung Cells), the most sensitive cell line, was 145 nM. Furthermore compound 1 was found to be efficient towards multicellular tumor spheroid growth. It exhibited minimal toxicity in mice while it had some potency towards aggressive NSCLC tumors. Benzo[e]pyridoindoles represent thus a potential new lead for the development of Aurora kinase inhibitors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325905PMC
http://dx.doi.org/10.4161/cc.8.5.7879DOI Listing
March 2009

[Continuous training program for technicians handling antineoplastic drugs and occupational exposure risk].

Bull Cancer 2008 Sep;95(9):821-2

Service de pharmacie, hôpital d'instruction des armées Desgenettes, 108, boulevard Pinel, 69003 Lyon, France.

Training and regular evaluation of technicians involved in the preparation of antineoplastic agents seems essential to reduce occupational exposure. In this way, a continuous training program was established. Technicians were asked to prepare a safe simulated liquid cytotoxic drug with a fluorescein solution (10 mg/L). After, occupational exposure with this solution was simulated. Ultra-violet light (365 nm) was employed to determine surface contamination. This continuous training program is tested and validated with pharmacy technicians. All people handling these drugs (physicians, nurses, pharmacy staff) can use this program. Short mandatory training courses are stimulating and well appreciated.
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http://dx.doi.org/10.1684/bdc.2008.0706DOI Listing
September 2008

Combination of rituximab with chemotherapy in diffuse large B-cell lymphoma. Evaluation in daily practice before and after approval of rituximab in this indication.

Hematol Oncol 2008 Sep;26(3):139-47

Service d'Hématologie Clinique, Centre Léon Bérard, Lyon, France.

Randomized trials have demonstrated improved outcome from adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with diffuse large B-cell lymphoma (DLBCL). This retrospective study compared the outcomes of 224 patients with DLBCL treated in our institution before (Period 1, 1996-2002) and after (Period 2, 2002-2005) approval of rituximab in this indication to evaluate the impact of the drug in daily practice in unselected patients receiving different types of chemotherapy. We treated 131 patients in Period 1 versus 93 in Period 2 (median follow-up, 75 and 29 months, respectively) with no difference in patient characteristics between the two periods. Event-free and overall survivals (EFS and OS) were significantly improved in Period 2 for elderly patients and a significant shift in the selection of regimens was observed at the time when rituximab became available. More patients received the CHOP regimen in Period 2 than in Period 1 (82 vs. 57%, p < 0.007) with CHOP being substituted for epirubicin-based regimens. In younger patients treated mostly with the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) these differences were not observed, suggesting that combination of rituximab with dose-dense chemotherapy may deserve further evaluation in this age group.
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http://dx.doi.org/10.1002/hon.850DOI Listing
September 2008

Activation of classical pathway of complement cascade by soluble oligomers of prion.

Cell Microbiol 2007 Dec;9(12):2870-9

Laboratoire d'Adaptation et Pathogenèse des Microorganismes, UMR5163 CNRS-UJF, Institut Jean Roget, BP170, 38042 Grenoble cedex 9, France.

Mice defective for C1q complement factor show enhanced resistance to peripheral prion inoculation, and previous work demonstrated a direct interaction between C1q and conformationally modified PrP. However, the nature and physiological consequences of this interaction remain uncharacterized. PrP amino acids 141-159 has been identified as a potential C1q binding site; we show, by both surface plasmon resonance (SPR) spectroscopy and ELISA, that C1q and its globular region bind to PrP mutagenized in the region of interest with comparable efficiency to that of wild-type protein. To test PrP's ability to activate complement, soluble oligomers of the PrP constructs were made. Only PrP and mutagenized PrP oligomers activate the classical complement cascade while PrP monomer and the C-terminal domain, both in oligomeric and in monomeric form, failed to induce activation. This suggests that a conformational change in PrP, which occurs both when PrP is bound to an SPR sensor chip and when it undergoes oligomerization, is requisite for PrP/C1q interaction and activation of the complement cascade. We propose that C1q may act as a natural sensor for prions, leading to activation of the classical complement cascade, which could result in local inflammation and subsequent recruitment of the immune cells that prions initially infect.
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http://dx.doi.org/10.1111/j.1462-5822.2007.01002.xDOI Listing
December 2007

Permeability of 13 different gloves to 13 cytotoxic agents under controlled dynamic conditions.

Am J Health Syst Pharm 2006 Mar;63(6):547-56

Clinical Chemistry Department, University Hospital St. Luc, Université Catholique de Louvain, 10 Hippocrate Avenue, B-1200 Brussels, Belgium.

Purpose: The permeability of 13 different gloves to 13 cytotoxic agents under controlled dynamic conditions is described.

Methods: Thirteen cytotoxic agents were prepared at the highest concentrations normally encountered by pharmacy personnel. Four glove types--neoprene, natural rubber latex, nitrile, and vinyl--were exposed to the cytotoxic agents for 15, 30, and 60 minutes. Tests were conducted using the middle finger of each glove. Linearity, reproducibility, and sensitivity were evaluated for each drug tested. Assays were run using liquid chromatographic tandem mass spectrometry (LC/MS/MS) and high-performance liquid chromatography with ultraviolet light (HPLC-UV). Permeability testing was conducted using an original system designed to evaluate dynamic constraints, such as rubbing, stretching, and tension.

Results: Linearity by LC/MS/MS and HPLC-UV was confirmed at concentrations up to 1000 ng/mL for all drugs. Most glove materials were permeable at rates below ASTM recommendations over the one-hour testing period. Vinyl was the most permeable material. Carmustine permeated the widest variety of materials. Due to the high sensitivity of the analytic methods, all materials displayed low but significant permeability for at least one drug after one hour. Higher resistance to permeation was recorded for all neoprene, some natural rubber latex, and one nitrile glove.

Conclusion: Neoprene, natural rubber latex, and nitrile gloves displayed the highest resistance to permeation of the 13 cytotoxic agents studied. Additional factors, such as duration of exposure, glove thickness, and drug liposolubility and molecular weight, also affected permeability.
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http://dx.doi.org/10.2146/ajhp050197DOI Listing
March 2006

Contamination of syringe plungers during the sampling of cyclophosphamide solutions.

J Oncol Pharm Pract 2005 Mar;11(1):1-5

Pharmacy Department, Centre Régional de Lutte Contre le Cancer Léon Bérard, 28 rue Laennec, 69373 Lyon Cedex 08, France.

The presence of cytotoxic agents in the urine of operators and in their environment has been demonstrated. The pharmacokinetics of the urinary elimination of cyclophosphamide suggests that these drugs are absorbed cutaneously during handling. In the framework of a more general study on the contamination of hospital environment, the present study addresses the possible presence of cytotoxic agents on the plungers of syringes. The report is based on results indicating that the bacterial contamination of a plunger may result in the contamination of the solution being sampled. The study was divided into two phases. The first phase consisted in measuring the contamination of the plungers of eight syringes used for handling cyclophosphamide. Cyclophosphamide was analysed by gas chromatography-mass spectrometry with a detection limit of 0.1 ng/ml. The aim of the second phase was to localize the contamination on the plunger and thus determine the amount of drug that comes into contact with the gloves of the operators. The contamination was quantified by measuring the activity of metastable technetium. The results of the first phase showed that all the plungers were contaminated with cyclophosphamide amounts varying from 3.7 to 445.7 ng. The second phase showed that the infiltration of liquid onto the plunger depended on the solution being sampled. Almost no infiltration was seen with labelled water, but contamination appeared after the first sampling of a cyclophosphamide solution, then increased as a function of the number of times the plunger was pushed in and out. These results indicate that cyclophosphamide solutions infiltrate onto the plungers of syringes. They suggest that the general procedure for handling cytotoxic agents should be modified, and a regular replacement of syringes should be enforced. They also partly explain why the gloves of 50-90% operators are contaminated after a single preparation. The contamination seems to depend on the type of solution sampled and the number of samplings. Initial investigations by the manufacturer of the syringes had shown that the acid pH of cyclophosphamide solutions may affect the lubricant of the joint. Our study demonstrates that the contamination of plungers is one of the sources of environmental contamination for health workers handling antineoplastic agents, even in the absence of manipulation errors. More generally, these results demonstrate that the exposure of operators cannot be clearly described unless all existing sources of contamination in their environment are identified. The implementation of suitable procedures should thus take into account all possible sources of contamination, including technical facilities such as the use of a safety cabinet or an isolator.
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http://dx.doi.org/10.1191/1078155205jp147oaDOI Listing
March 2005

[Analysis of cyclophosphamide in the urine of antineoplastic drugs handlers].

Bull Cancer 2003 Oct;90(10):905-9

Service pharmacie, Centre régional de lutte contre le cancer Léon-Bérard, 28, rue Laennec, 69008 Lyon.

The first study in which amounts of cyclophosphamide were found in the urine of nurses handling cytotoxic drugs using gas chromatography was published in 1984. We carried out a similar investigation on six pharmacy technicians involved in the preparation of antineoplastic agents (25,000 doses per year) but the analysis was performed with a more sensitive method: gas chromatography-mass spectrometry (LOQ = 0.1 ng/ml). Cyclophosphamide was found in two urine samples (out of 104) from two different workers. The rates detected were just above the limit of quantification. No correlation was found between the amounts of cyclophosphamide handled and the urinary excretion. The mean urinary levels measured in this study are lower than those reported by other investigators. In addition, only 1.9% of the collected samples are positive to cyclophosphamide. The drug was detected for two different technicians during two different sampling periods, suggesting that pollution is not repeated. No relationship could be seen between urinary detection of cyclophosphamide and individual or general work in the cytotoxic preparation unit. As supported by recent datas, transdermal resorption seems to be the most important way of incorporation. Further investigations are necessary to prove this hypothesis if we want to prevent occupational exposure of people handling these drugs.
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October 2003

Hair follicle stem cells.

J Investig Dermatol Symp Proc 2003 Jun;8(1):28-38

Department of Dermatology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

The workshop on Hair Follicle Stem Cells brought together investigators who have used a variety of approaches to try to understand the biology of follicular epithelial stem cells, and the role that these cells play in regulating the hair cycle. One of the main concepts to emerge from this workshop is that follicular epithelial stem cells are multipotent, capable of giving rise not only to all the cell types of the hair, but also to the epidermis and the sebaceous gland. Furthermore, such multipotent stem cells may represent the ultimate epidermal stem cell. Another example of epithelial stem cell and transit amplifying cell plasticity, was the demonstration that adult corneal epithelium, under the influence of embryonic skin dermis could form an epidermis as well as hair follicles. With regards to the location of follicular epithelial stem cells, immunohistochemical and ultrastructural data was presented, indicating that cells with stem cell attributes were localized to the prominent bulge region of developing human fetal hair follicles. Finally, a new notion was put forth concerning the roles that the bulge-located stem cells and the hair germ cells played with respect to the hair cycle.
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http://dx.doi.org/10.1046/j.1523-1747.2003.12169.xDOI Listing
June 2003