Clinique des Grangettes

Genève, Switzerland

Clinique des Grangettes

Genève, Switzerland

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Sappino A.-P.,Clinique des Grangettes | Buser R.,University of Geneva | Seguin Q.,University of Sfax | Fernet M.,Institute Curie | And 5 more authors.
Oncogenesis | Year: 2012

The p53 tumor-suppressor protein has a key role in the induction of cellular senescence, an important barrier to cancer development. However, very little is known about the physiological mediators of cellular senescence induced by p53. CEACAM1 is an immunoglobulin superfamily member whose expression is frequently lost in human tumors and exhibits tumor-suppressor features in several experimental systems, including Ceacam1 knockout mice. There is currently little understanding of the pathways and mechanisms by which CEACAM1 exerts its tumor-suppressor function. Here we report that CEACAM1 is strongly upregulated during the cellular response to DNA double-strand breaks (DSBs) starting from the lowest doses of DSB inducers used, and that upregulation is mediated by the ataxia telangiectasia mutated (ATM)/p53 pathway. Stable silencing of CEACAM1 showed that CEACAM1 is required for p53-mediated cellular senescence, but not initial cell growth arrest, in response to DNA damage. These findings identify CEACAM1 as a key component of the ATM/p53-mediated cellular response to DNA damage, and as a tumor suppressor mediating cellular senescence downstream of p53. © 2012 Macmillan Publishers Limited. All rights reserved.


Aleman B.M.P.,Netherlands Cancer Institute | Moser E.C.,Champalimaud Foundation | Nuver J.,University of Groningen | Suter T.M.,University of Bern | And 4 more authors.
European Journal of Cancer, Supplement | Year: 2014

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC).Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results.Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment. © 2014.


Perrone G.,Obstetrics and Urology | Kinkel K.,Clinique des Grangettes | Di Tola M.,University of Rome La Sapienza | Brunelli R.,Obstetrics and Urology
Radiology | Year: 2016

Purpose: To prospectively determine whether the apparent diffusion coefficient (ADC) of the cervix is associated with preterm delivery in asymptomatic patients with a sonographic cervical length of 15 mm or less and positive fetal fibronectin test results between 23 and 28 weeks of gestation. Materials and Methods: The institutional review board approved this prospective hypotheses-generating study. A total of 30 pregnant women (mean gestational age, 26 weeks) with a sonographic short cervix (?15 mm) underwent pelvic 1.5-T magnetic resonance (MR) imaging. Oblique sagittal diffusion-weighted images were obtained with b values of 0, 400, and 800 sec/mm2. ADC values at MR imaging of the subglandular and stromal cervix and the difference between both were correlated to the interval to delivery. Receiver operating characteristic curve analysis was performed to obtain sensitivity and specificity of ADC values in association with delivery within 7 days. Results: Eight (27%) of 30 patients delivered within 6 or 7 days after MR imaging (impending delivery group), and 22 (73%) of 30 patients delivered between 18 and 89 days after imaging (mean, 55 days) (late delivery group). Mean subglandular ADC and mean ADC difference were higher (P , .001) in patients with impending delivery than in those with late delivery ([2406.3 6 166.0] 3 1026 mm2/ sec vs [1708.9 6 108.1] 3 1026 mm2/sec and [657.3 6 129.9] 3 1026 mm2/sec vs [69.2 6 70.2] 3 1026 mm2/sec, respectively). Subglandular ADC inversely correlated with the interval between MR imaging and delivery (r = 20.75). Receiver operating characteristic curve analysis of subglandular ADC revealed 100% sensitivity (95% confidence interval: 63.1, 100) and 100% specificity (95% confidence interval: 84.6, 100) in association with impending delivery with a 1921 3 1026 mm2/sec threshold. Stromal ADC and sonographic cervical length showed no difference between groups (P = .072 and P = .511, respectively). Conclusion: Cervical subglandular ADC at MR imaging is associated with impending preterm birth in patients with a short sonographic cervix. © RSNA, 2016.


PubMed | Netherlands Cancer Institute, Clinique des Grangettes, University of Groningen, University of Oxford and 3 more.
Type: Journal Article | Journal: EJC supplements : EJC : official journal of EORTC, European Organization for Research and Treatment of Cancer ... [et al.] | Year: 2015

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.


Gumy-Pause F.,University of Geneva | Pardo B.,University of Geneva | Khoshbeen-Boudal M.,University of Geneva | Ansari M.,University of Geneva | And 4 more authors.
Genes Chromosomes and Cancer | Year: 2012

Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup. © 2011 Wiley Periodicals, Inc.


Lippuner K.,Universitatspoliklinik For Osteoporose | Buchard P.A.,Clinique Romande de Readaptation | De Geyter C.,University of Basel | Imthurn B.,Universitatsspital | And 6 more authors.
European Spine Journal | Year: 2012

Background/aim: Raloxifene is the first selective estrogen receptor modulator that has been approved for the treatment and prevention of osteoporosis in postmenopausal women in Europe and in the US. Although raloxifene reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer, it is approved in that indication in the US but not in the EU. The aim was to characterize the clinical profiles of postmenopausal women expected to benefit most from therapy with raloxifene based on published scientific evidence to date. Methods: Key individual patient characteristics relevant to the prescription of raloxifene in daily practice were defined by a board of Swiss experts in the fields of menopause and metabolic bone diseases and linked to published scientific evidence. Consensus was reached about translating these insights into daily practice. Results: Through estrogen agonistic effects on bone, raloxifene reduces biochemical markers of bone turnover to premenopausal levels, increases bone mineral density (BMD) at the lumbar spine, proximal femur, and total body, and reduces vertebral fracture risk in women with osteopenia or osteoporosis with and without prevalent vertebral fracture. Through estrogen antagonistic effects on breast tissue, raloxifene reduces the risk of invasive estrogen-receptor positive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Finally, raloxifene increases the incidence of hot flushes, the risk of venous thromboembolic events, and the risk of fatal stroke in postmenopausal women at increased risk for coronary heart disease. Postmenopausal women in whom the use of raloxifene is considered can be categorized in a 2 × 2 matrix reflecting their bone status (osteopenic or osteoporotic based on their BMD T-score by dual energy X-ray absorptiometry) and their breast cancer risk (low or high based on the modified Gail model). Women at high risk of breast cancer should be considered for treatment with raloxifene. Conclusion: Postmenopausal women between 50 and 70 years of age without climacteric symptoms with either osteopenia or osteoporosis should be evaluated with regard to their breast cancer risk and considered for treatment with raloxifene within the framework of its contraindications and precautions. © 2012 Springer-Verlag.


PubMed | Medical Center Utrecht, EORTC Headquarters, Institute Regional du Cancer Montpellier, Center Georges Francois Leclerc and 12 more.
Type: Journal Article | Journal: JAMA oncology | Year: 2016

Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy.The EORTC boost no boost trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up.Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III boost no boost trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years.No further treatment or 16-Gy boost, after BCS and 50-Gy WBI.Time to ipsilateral breast tumor recurrence (IBTR) as first event.The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P<.001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P=.001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P<.001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P<.001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P<.001) in high-risk patients (50 years with DCIS present).The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately.clinicaltrials.gov Identifier: NCT02295033.


Taylor S.,Hopital Ambroise Pare | van Muylem A.,Hopital Erasme | Howarth N.,Clinique des Grangettes | Gevenois P.A.,Hopital Erasme | Tack D.,EpiCURA
European Radiology | Year: 2016

Objectives: To determine variability of volume computed tomographic dose index (CTDIvol) and dose–length product (DLP) data, and propose a minimum sample size to achieve an expected precision. Methods: CTDIvol and DLP values of 19,875 consecutive CT acquisitions of abdomen (7268), thorax (3805), lumbar spine (3161), cervical spine (1515) and head (4106) were collected in two centers. Their variabilities were investigated according to sample size (10 to 1000 acquisitions) and patient body weight categories (no weight selection, 67–73 kg and 60–80 kg). The 95 % confidence interval in percentage of their median (CI95/med) value was calculated for increasing sample sizes. We deduced the sample size that set a 95 % CI lower than 10 % of the median (CI95/med ≤ 10 %). Results: Sample size ensuring CI95/med ≤ 10 %, ranged from 15 to 900 depending on the body region and the dose descriptor considered. In sample sizes recommended by regulatory authorities (i.e., from 10–20 patients), mean CTDIvol and DLP of one sample ranged from 0.50 to 2.00 times its actual value extracted from 2000 samples. Conclusions: The sampling error in CTDIvol and DLP means is high in dose surveys based on small samples of patients. Sample size should be increased at least tenfold to decrease this variability. Key Points: • Variability of dose descriptors is high regardless of the body region. • Variability of dose descriptors depends on weight selection and the region scanned. • Larger samples would reduce sampling errors of radiation dose data in surveys. • Totally or partially disabling AEC reduces dose variability and increases patient dose. • Median values of dose descriptors depend on the body weight selection. © 2016 European Society of Radiology


Oliveri A.,Free University of Colombia | Howarth N.,Clinique des Grangettes | Gevenois P.A.,Hopital Erasme | Tack D.,EpiCURA
European Radiology | Year: 2016

Purpose: To test the hypothesis that quality clinical audits improve compliance with the procedures in computed tomography (CT) scanning. Materials and methods: This retrospective study was conducted in two hospitals, based on 6950 examinations and four procedures, focusing on the acquisition length in lumbar spine CT, the default tube current applied in abdominal un-enhanced CT, the tube potential selection for portal phase abdominal CT and the use of a specific “paediatric brain CT” procedure. The first clinical audit reported compliance with these procedures. After presenting the results to the stakeholders, a second audit was conducted to measure the impact of this information on compliance and was repeated the next year. Comparisons of proportions were performed using the Chi-square Pearson test. Results: Depending on the procedure, the compliance rate ranged from 27 to 88 % during the first audit. After presentation of the audit results to the stakeholders, the compliance rate ranged from 68 to 93 % and was significantly improved for all procedures (P ranging from <0.001 to 0.031) in both hospitals and remained unchanged during the third audit (P ranging from 0.114 to 0.999). Conclusion: Quality improvement through repeated compliance audits with CT procedures durably improves this compliance. Key Points: • Compliance with CT procedures is operator-dependent and not perfect. • Compliance differs between procedures and hospitals, even within a unified department. • Compliance is improved through audits followed by communication to the stakeholders. • This improvement is sustainable over a one-year period. © 2015, European Society of Radiology.


PubMed | EpiCURA, Clinique des Grangettes, Hopital Erasme and Free University of Colombia
Type: Journal Article | Journal: European radiology | Year: 2016

To test the hypothesis that quality clinical audits improve compliance with the procedures in computed tomography (CT) scanning.This retrospective study was conducted in two hospitals, based on 6950 examinations and four procedures, focusing on the acquisition length in lumbar spine CT, the default tube current applied in abdominal un-enhanced CT, the tube potential selection for portal phase abdominal CT and the use of a specific paediatric brain CT procedure. The first clinical audit reported compliance with these procedures. After presenting the results to the stakeholders, a second audit was conducted to measure the impact of this information on compliance and was repeated the next year. Comparisons of proportions were performed using the Chi-square Pearson test.Depending on the procedure, the compliance rate ranged from 27 to 88% during the first audit. After presentation of the audit results to the stakeholders, the compliance rate ranged from 68 to 93% and was significantly improved for all procedures (P ranging from <0.001 to 0.031) in both hospitals and remained unchanged during the third audit (P ranging from 0.114 to 0.999).Quality improvement through repeated compliance audits with CT procedures durably improves this compliance. Compliance with CT procedures is operator-dependent and not perfect. Compliance differs between procedures and hospitals, even within a unified department. Compliance is improved through audits followed by communication to the stakeholders. This improvement is sustainable over a one-year period.

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