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Petit-Jean E.,Paul Strauss Cancer Center | Buclin T.,University of Lausanne | Guidi M.,University of Lausanne | Guidi M.,University of Geneva | And 6 more authors.
Therapeutic Drug Monitoring | Year: 2015

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure. © 2014 Wolters Kluwer Health, Inc. All rights reserved.


Antoni D.,Paul Strauss Cancer Center | Clavier J.-B.,Paul Strauss Cancer Center | Pop M.,Paul Strauss Cancer Center | Schumacher C.,Paul Strauss Cancer Center | And 2 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To retrospectively evaluate the prognostic factors and survival of a series of 777 patients with brain metastases (BM) from a single institution. Methods and Materials: Patients were treated with surgery followed by whole-brain radiation therapy (WBRT) or with WBRT alone in 16.3% and 83.7% of the cases, respectively. The patients were RPA (recursive partitioning analysis) class I, II, and III in 11.2%, 69.6%, and 18.4% of the cases, respectively; RPA class II-a, II-b, and II-c in 8.3%, 24.8%, and 66.9% of the cases, respectively; and with GPA (graded prognostic assessment) scores of 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 in 35%, 27.5%, 18.2%, and 8.6% of the cases, respectively. Results: The median overall survival (OS) times according to RPA class I, II, and III were 20.1, 5.1, and 1.3 months, respectively (P<.0001); according to RPA class II-a, II-b, II-c: 9.1, 8.9, and 4.0 months, respectively (P<.0001); and according to GPA score 0-1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0: 2.5, 4.4, 9.0, and 19.1 months, respectively (P<.0001). By multivariate analysis, the favorable independent prognostic factors for survival were as follows: for gastrointestinal tumor, a high Karnofsky performance status (KPS) (P=.0003) and an absence of extracranial metastases (ECM) (P=.003); for kidney cancer, few BM (P=.002); for melanoma, few BM (P=.01), an absence of ECM (P=.002), and few ECM (P=.0002); for lung cancer, age (P=.007), a high KPS (P<.0001), an absence of ECM (P<.0001), few ECM and BM (P<.0001 and P=.0006, respectively), and control of the primary tumor (P=.004); and for breast cancer, age (P=.001), a high KPS (P=.007), control of the primary tumor (P=.05), and few ECM and BM (P=.01 and P=.0002, respectively). The triple-negative subtype was a significant unfavorable factor (P=.007). Conclusion: Prognostic factors varied by pathology. Our analysis confirms the strength of prognostic factors used to determine the GPA score, including the genetic subtype for breast cancer. © 2013 Elsevier Inc.


Anton D.,Paul Strauss Cancer Center | Anton D.,University of Strasbourg | Burckel H.,University of Strasbourg | Josset E.,University of Strasbourg | And 2 more authors.
International Journal of Molecular Sciences | Year: 2015

Cell culture is an important tool for biological research. Two-dimensional cell culture has been used for some time now, but growing cells in flat layers on plastic surfaces does not accurately model the in vivo state. As compared to the two-dimensional case, the three-dimensional (3D) cell culture allows biological cells to grow or interact with their surroundings in all three dimensions thanks to an artificial environment. Cells grown in a 3D model have proven to be more physiologically relevant and showed improvements in several studies of biological mechanisms like: cell number monitoring, viability, morphology, proliferation, differentiation, response to stimuli, migration and invasion of tumor cells into surrounding tissues, angiogenesis stimulation and immune system evasion, drug metabolism, gene expression and protein synthesis, general cell function and in vivo relevance. 3D culture models succeed thanks to technological advances, including materials science, cell biology and bioreactor design. © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Clavier J.-B.,Paul Strauss Cancer Center | Antoni D.,Paul Strauss Cancer Center | Atlani D.,Colmar Civil Hospital | Ben Abdelghani M.,Paul Strauss Cancer Center | And 4 more authors.
Diseases of the Esophagus | Year: 2014

Summary: Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42-81). Median radiation dose was 62.5Gy (38-72) with 1.8-2Gy fraction. Median follow-up was 20.8 months (2.8-92.4). Three and 5-year local recurrence-free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5-year locoregional recurrence-free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5-year disease-free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) ≥ 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5-year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI ≥ 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials. © 2012, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.


Guihard S.,Paul Strauss Cancer Center | Ramolu L.,Paul Strauss Cancer Center | Macabre C.,Paul Strauss Cancer Center | Wasylyk B.,French Institute of Health and Medical Research | And 3 more authors.
International Journal of Oncology | Year: 2012

Human papillomavirus (HPV)-related oropharyngeal cancer represents a distinct head and neck squamous cell carcinoma (HNSCC) subpopulation, with improved diseasefree and overall survival. In general, HPV-positive HNSCCs express wild-type TP53, which could explain its increased radiosensitivity. However, the molecular mechanisms underlying this higher sensitivity remain elusive. We have previously shown that HPV-related oropharyngeal carcinomas express decreased levels of the NEDD8-activating enzyme 1/amyloid β precursor protein-binding protein 1 (NAE1/APP-BP1) gene. NAE1/APP-BP1 function is required for the NEDDylation of target proteins, and has been shown to be a negative regulator of p53 transcriptional activity. In this study, we addressed the hypothesis that NAE1/APP-BP1 expression levels regulate p53 activity and cell survival upon ionizing irradiation. We used the radiosensitive and naturally HPV16-infected UPCI:SCC90 cell line and the radioresistant and HPV-negative SQ20B cell line as the control. NAE1/APP-BP1 expression levels were modulated with expression constructs and siRNAs. Radiosensitivity was evaluated with clonogenic survival assays. p53 transcriptional activity was measured with a luciferase assay. The overexpression of NAE1/APP-BP1 in UPCI:SCC90 cells resulted in the increased NEDDylation of p53, inhibition of p53 activity and increased cell resistance to ionizing radiation. Conversely, the inhibition of NAE1/APP-BP1 expression in SQ20B cells induced p53-dependent cell death after treatment with X-rays. Taken together, these results indicate that NAE1/APP-BP1 and NEDDylation are invovled in modulating p53 activity and regulating its role in the response of cells to ionizing radiation. Our findings bring new insights in the molecular mechanisms underlying the increased radiosensitivity of HPV-related oropharyngeal tumors. This is of importance, as no reliable and robust predictive biomarkers for tumor response to radiotherapy are currently available. These results also have potential clinical significance, as drugs targeting NAE1/APP-BP1 have recently emerged as a novel therapeutic modality in cancer treatment.


PubMed | University of Strasbourg and Paul Strauss Cancer Center
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2015

Cell culture is an important tool for biological research. Two-dimensional cell culture has been used for some time now, but growing cells in flat layers on plastic surfaces does not accurately model the in vivo state. As compared to the two-dimensional case, the three-dimensional (3D) cell culture allows biological cells to grow or interact with their surroundings in all three dimensions thanks to an artificial environment. Cells grown in a 3D model have proven to be more physiologically relevant and showed improvements in several studies of biological mechanisms like: cell number monitoring, viability, morphology, proliferation, differentiation, response to stimuli, migration and invasion of tumor cells into surrounding tissues, angiogenesis stimulation and immune system evasion, drug metabolism, gene expression and protein synthesis, general cell function and in vivo relevance. 3D culture models succeed thanks to technological advances, including materials science, cell biology and bioreactor design.


PubMed | Aix - Marseille University, University of Strasbourg and Paul Strauss Cancer Center
Type: Journal Article | Journal: European journal of nuclear medicine and molecular imaging | Year: 2016

To evaluate the performance of (18)F-L-dihydroxyphenylalanine ((18)F-DOPA) PET/CT in the detection of locoregional and distant medullary thyroid carcinoma (MTC) metastases and to compare imaging findings with histological data.We retrospectively evaluated 86 MTC patients with persistently high serum calcitonin levels after initial surgery who had undergone (18)F-DOPA PET/CT between January 2007 and December 2014 in two referral centres. They were followed up for at least 6months after the PET/CT assessment. The results were compared with histological data or with the findings obtained during follow-up using a complementary imaging modality.(18)F-DOPA PET/CT was positive in 65 of the 86 patients, corresponding to a patient-based sensitivity of 75.6 %. Distant metastatic disease (M1) was seen in 29 patients including 11 with previously unknown metastases revealed only by PET/CT. Among the 36 patients without distant metastatic spread, 25 had nodal involvement limited to the neck, and 10 of these 25 patients underwent reoperation. The lymph node compartment-based sensitivity of (18)F-DOPA PET/CT was 100 % in the two institutions but lesion-based sensitivity was only 24 %. Preoperative and postoperative median calcitonin levels were 405 pg/mL (range 128-1,960 pg/mL) and 259 pg/mL (range 33-1,516 pg/mL), respectively. None of the patients achieved normalization of serum calcitonin after reoperation.(18)F-DOPA PET/CT enables early diagnosis of a significant number of patients with distant metastasis. It has a limited sensitivity in the detection of residual disease but provides high performance for regional analysis. A surgical compartment-oriented approach could be the approach of choice whatever the number of nodes revealed by (18)F-DOPA PET/CT.


PubMed | Paul Strauss Cancer Center
Type: Journal Article | Journal: International journal of oncology | Year: 2013

Human papillomavirus (HPV)-related oropharyngeal cancer represents a distinct head and neck squamous cell carcinoma (HNSCC) subpopulation, with improved disease-free and overall survival. In general, HPV-positive HNSCCs express wild-type TP53, which could explain its increased radiosensitivity. However, the molecular mechanisms underlying this higher sensitivity remain elusive. We have previously shown that HPV-related oropharyngeal carcinomas express decreased levels of the NEDD8-activating enzyme 1/amyloid precursor protein-binding protein 1 (NAE1/APP-BP1) gene. NAE1/APP-BP1 function is required for the NEDDylation of target proteins, and has been shown to be a negative regulator of p53 transcriptional activity. In this study, we addressed the hypothesis that NAE1/APP-BP1 expression levels regulate p53 activity and cell survival upon ionizing irradiation. We used the radiosensitive and naturally HPV16-infected UPCI:SCC90 cell line and the radioresistant and HPV-negative SQ20B cell line as the control. NAE1/APP-BP1 expression levels were modulated with expression constructs and siRNAs. Radiosensitivity was evaluated with clonogenic survival assays. p53 transcriptional activity was measured with a luciferase assay. The overexpression of NAE1/APP-BP1 in UPCI:SCC90 cells resulted in the increased NEDDylation of p53, inhibition of p53 activity and increased cell resistance to ionizing radiation. Conversely, the inhibition of NAE1/APP-BP1 expression in SQ20B cells induced p53-dependent cell death after treatment with X-rays. Taken together, these results indicate that NAE1/APP-BP1 and NEDDylation are invovled in modulating p53 activity and regulating its role in the response of cells to ionizing radiation. Our findings bring new insights in the molecular mechanisms underlying the increased radiosensitivity of HPV-related oropharyngeal tumors. This is of importance, as no reliable and robust predictive biomarkers for tumor response to radiotherapy are currently available. These results also have potential clinical significance, as drugs targeting NAE1/APP-BP1 have recently emerged as a novel therapeutic modality in cancer treatment.


PubMed | Lorraine Institute of Oncology, Institute Claudius Regaud, Montpellier Cancer Institute, Clinique Pasteur and 9 more.
Type: Journal Article | Journal: International journal of radiation oncology, biology, physics | Year: 2016

This cost analysis aimed to prospectively assess differences in costs between TomoTherapy and volumetric modulated arc therapy (VMAT) in patients with head and neck cancer.Economic data were gathered from a multicenter study. However, randomization was not possible due to the availability of equipment. Costs were calculated using the microcosting technique from the hospitals perspective (in 2013 euros), and the time horizon was radiation therapy. Only resources that entered the hospital production process and which were likely to vary between the strategies being compared were considered. Acute adverse events observed within the time horizon were also assessed.The cost analysis was based on a total of 173 patient treatments given between 2010 and 2012 in 14 French cancer centers: 73 patients were treated with TomoTherapy, 92 with VMAT RapidArc, and 8 with VMAT SmartArc. Estimated costs of SmartArc were removed from the comparison due to the small sample size. The meanSD cost per patient of the treatment planning phase was 314 (214) for TomoTherapy and 511 (590) for RapidArc. Mean costsSD per patient of irradiation reached 3144 (565) for TomoTherapy and 1350 (299) for RapidArc. The most sensitive parameter of irradiation was the annual operating time of accelerators. Ninety-five percent confidence intervals for the mean costs of irradiation were 3016 to 3272 for TomoTherapy and 1281 to 1408 for RapidArc. The number of acute adverse events during radiation therapy was not significantly different between strategies.TomoTherapy appeared to be more expensive than RapidArc mainly due to the higher price of the accelerator, the higher costs of maintenance, and the longer duration of treatment sessions. Because strategies were not significantly different in clinical effect, RapidArc appeared to be the strategy to be recommended at this stage of knowledge.


PubMed | Paul Strauss Cancer Center
Type: Journal Article | Journal: Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus | Year: 2014

Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42-81). Median radiation dose was 62.5Gy (38-72) with 1.8-2Gy fraction. Median follow-up was 20.8 months (2.8-92.4). Three and 5-year local recurrence-free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5-year locoregional recurrence-free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5-year disease-free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5-year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials.

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