Thomas Filleron

Institut Claudius Regaud, Tolosa de Llenguadoc, Midi-Pyrénées, France

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Publications (67)230.52 Total impact

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    ABSTRACT: The use of potential surrogate endpoints for overall survival, such as disease-free-survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCT) in cancer. However, the definition of time-to-event (TTE) endpoints is rarely precise and lacks uniformity across trials. Endpoint definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE endpoints. We report guidelines for RCT in sarcomas and gastro-intestinal-stromal tumors (GIST).
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 07/2014;
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    ABSTRACT: Health-related quality of life (QoL) has prognostic value in many cancers. A recent study found that the performance of prognostic systems for metastatic colorectal cancer (mCRC) were improvable. We evaluated the independent prognostic value of QoL for overall survival (OS) and its ability to improve two prognostic systems'performance (Kohne and GERCOR models) for patients with mCRC.
    Health and Quality of Life Outcomes 05/2014; 12(1):69. · 2.27 Impact Factor
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    ABSTRACT: To describe long-term outcome after combined-modality treatment including radiation therapy in patients with localized sarcoma within irradiated field. Individual clinical data from all consecutive patients diagnosed and treated for a localized sarcoma within irradiated field between January 2000 and October 2011 at the Institut Claudius-Regaud, Toulouse, France, were retrospectively reviewed. Twenty-seven patients were eligible for this study. Ten patients were re-irradiated with a rate of unresectable, gross or microscopically positive margins disease significantly higher than the rest of the cohort (90% vs. 12%; P<0.001). After a median follow-up of 3.8years, there is a non-significant trend toward longer 4-year relapse free survival in the subgroup of patients who received adjuvant or definitive radiation therapy compared to the rest of the cohort (53% vs. 27%; P=0.09) with an acceptable toxicity profile allowing conservative management. The complete surgical resection sarcoma within irradiated field is often difficult to achieve enhancing the risk of relapse. Radiation therapy should be discussed when faced with an unresectable tumour or after suboptimal surgery as part of intensified local management with a curative intent.
    Cancer/Radiothérapie 04/2014; · 1.48 Impact Factor
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    ABSTRACT: To establish an external validation of the updated nomogram from Briganti et al, which provides estimates of the probability of specimen-confined disease from age, PSA, clinical stage, and biopsy Gleason score in preoperatively defined high risk PCa. 523 high-risk PCa patients as defined by d'Amico classification undergoing RP and bilateral lymph node dissection in two academic centres between 1990 and 2013. Specimen-confined (SC) disease was defined as pT2-pT3a node-negative PCa with negative surgical margins. The Receiver Operating Characteristic (ROC) curve was obtained to quantify the overall accuracy (Area Under the Curve, AUC) of the model to predict SC disease. Calibration curve was then constructed to illustrate the relationship between the risk-estimates obtained by the model (X-axis) and the observed proportion of SC disease (y-axis). Kaplan-Meier method was used for biochemical recurrence-free survival (BCR) assessment. Median age and PSA level were 64 years and 21 ng/ml. Definition of high risk PCa was based on PSA level only in 38.3% of cases, a biopsy Gleason score >7 in 34.5% of cases, a clinical stage >T2b in 6.9% of cases, or a combination of these 2 or 3 factors in 20.3% of cases. Positive surgical margins were observed in 43.6% with a rate of 14.8% in pT2 cancers, lymph node metastasis in 12.1% patients. pT stage was pT0:0.9%, pT2:28.9%, pT3a:37.5%, and pT3b-4:32.7%. Overall, 44.4% of PCa had (n=232) SC disease. PSA, and cT were independently predictive for SC disease. The 2-, 5-, and 8-year BCR free recurrence was significantly improved in specimen-confined disease as compared with not organ-confined disease (respectively 80.87% [73.67; 86.29] vs 37.55% [30.64; 44.44]; 63.53% [52.37; 72.74] vs 26.93% [19.97; 34.36]; 55.08 % [41.49; 66.74] vs 19.52% [12.50; 27.70]; p<0.0001). ROC curve analysis showed relevant accuracy of the model (AUC: 0.6470 (95%CI=[0.60-0.69])) although the calibration plot suggested that, for risks ranging from 0.3 and 0.5, the odds of extracapsular extension were underestimated. This external validation of the Briganti nomogram shows relevant accuracy although the relative imprecision for intermediate risks may limit its clinical relevance. Our follow-up findings confirm the large proportion of specimen-confined PCa with good oncologic outcomes in this heterogeneous subgroup of high risk PCa.
    BJU International 03/2014; · 3.05 Impact Factor
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    ABSTRACT: Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing. All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials. Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n=25) or conservative resection (n=37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI=[88.2;99.7]) and 89.5% (95% CI=[76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma. The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component.
    Cancer/Radiothérapie 03/2014; · 1.48 Impact Factor
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    ABSTRACT: Post-therapeutic surveillance is one important component of cancer care. However, there still is no evidence-based strategies to schedule patients' follow-up examinations. Our approach is based on the modeling of the probability of the onset of relapse at an early asymptotic or preclinical stage and its transition to a clinical stage. For that we consider a multistate homogeneous Markov model, which includes the natural history of relapse. The model also handles separately the different types of possible relapses. The optimal schedule is provided by the calendar visit that maximizes a utility function. The methodology has been applied to laryngeal cancer. The different follow-up strategies revealed to be more efficient than those proposed by different scientific societies.
    Statistical Methods in Medical Research 02/2014; · 2.36 Impact Factor
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    ABSTRACT: Breast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals' genomic alterations. From June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France. Comparative genomic hybridisation (CGH) array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five centres. Therapeutic targets were decided on the basis of identified genomic alterations. The primary objective was to include 30% of patients in clinical trials testing a targeted therapy and, therefore, the primary outcome was the proportion of patients to whom a targeted therapy could be offered. For the primary endpoint, the analyses were done on the overall population registered for the trial. This trial is registered with ClinicalTrials.gov, number NCT01414933. 423 patients were included, and biopsy samples were obtained from 407 (metastatic breast cancer was not found in four). CGH array and Sanger sequencing were feasible in 283 (67%) and 297 (70%) patients, respectively. A targetable genomic alteration was identified in 195 (46%) patients, most frequently in PIK3CA (74 [25%] of 297 identified genomic alterations), CCND1 (53 [19%]), and FGFR1 (36 [13%]). 117 (39%) of 297 patients with genomic tests available presented with rare genomic alterations (defined as occurring in less than 5% of the general population), including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Therapy could be personalised in 55 (13%) of 423 patients. Of the 43 patients who were assessable and received targeted therapy, four (9%) had an objective response, and nine others (21%) had stable disease for more than 16 weeks. Serious (grade 3 or higher) adverse events related to biopsy were reported in four (1%) of enrolled patients, including pneumothorax (grade 3, one patient), pain (grade 3, one patient), haematoma (grade 3, one patient), and haemorrhagic shock (grade 3, one patient). Personalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations. French National Cancer Institute, Breast Cancer Research Foundation, Odyssea, Operation Parrains Chercheurs.
    The Lancet Oncology 02/2014; · 25.12 Impact Factor
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    ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a potentially malignant dermal mesenchymal tumour with a high risk of local recurrence. DFSP presents a sprawling appearance whose complete excision requires important margins. DFSP was initially resected with a 5cm excision margins, and more recently 3cm then 2cm margins were recommended. Mohs micrographic surgery (MMS) helps reduce these margins thanks to a 3-dimensional excision around the tumour, which is analysed in its entirety. We used the modified MMS called slow-MMS and tried every time it was possible to perform direct closure. Thirty-five patients presenting a DFSP between 2004 and 2013 within the Plastic Surgery unit at Claudius Regaud Institute were included in this retrospective study. The patients were treated with slow-MMS using paraffin-embedded sections. One surgery was necessary for 72% of patients. For 17%, we had to perform a second surgery, and for 11% a third one. Our median clinical excision margins was 17mm (range 9.0:30.0). After a median follow-up of 46 months (range 35.2:60.2), we didn't observe any recurrence. Only one case required a local flap; for the others, the loss of substance was resolved with a direct closure. Slow-MMS enabled a local control of the margins without recurrence at 46 months in our series. Besides, it helps performing smaller margins than wide excision and thus preserving the tissues. In our opinion, this is the treatment of choice regarding DFSP for which tissue sparing is essential. It seems particularly appropriate near functional areas or on the face.
    Annales de chirurgie plastique et esthetique 01/2014; · 0.33 Impact Factor
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    ABSTRACT: The aim of the study was to report on the oncologic outcome of the disease spread to celiac lymph nodes (CLNs) in advanced-stage ovarian cancer patients. All patients who had CLN resection as part of their cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer were identified. Patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included. The median follow-up was 26.3 months. The median overall survival values in the group with positive CLNs and in the group with negative CLNs were 26.9 months and 40.04 months, respectively. The median progression-free survival values in the group with metastatic CLNs and in the group with negative CLNs were 8.8 months and 20.24 months, respectively (P = 0.053). Positive CLNs were associated with progression during or within 6 months after the completion of chemotherapy (P = 0.0044). Tumor burden and extensive disease distribution were significantly associated with poor progression-free survival, short-term progression, and overall survival. In multivariate analysis, only the CLN status was independently associated with short-term progression. Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of lymph node progression, and worst oncologic outcome.
    International Journal of Gynecological Cancer 01/2014; 24(1):48-53. · 1.94 Impact Factor
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    ABSTRACT: Purpose Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing. Patients and methods All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials. Results Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n = 25) or conservative resection (n = 37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI = [88.2;99.7]) and 89.5% (95% CI = [76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma. Conclusion The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component.
    Cancer/Radiothérapie 01/2014; · 1.48 Impact Factor
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    ABSTRACT: Purpose To describe long-term outcome after combined-modality treatment including radiation therapy in patients with localized sarcoma within irradiated field. Patients and methods Individual clinical data from all consecutive patients diagnosed and treated for a localized sarcoma within irradiated field between January 2000 and October 2011 at the Institut Claudius-Regaud, Toulouse, France, were retrospectively reviewed. Results Twenty-seven patients were eligible for this study. Ten patients were re-irradiated with a rate of unresectable, gross or microscopically positive margins disease significantly higher than the rest of the cohort (90% vs. 12%; P < 0.001). After a median follow-up of 3.8 years, there is a non-significant trend toward longer 4-year relapse free survival in the subgroup of patients who received adjuvant or definitive radiation therapy compared to the rest of the cohort (53% vs. 27%; P = 0.09) with an acceptable toxicity profile allowing conservative management. Conclusion The complete surgical resection sarcoma within irradiated field is often difficult to achieve enhancing the risk of relapse. Radiation therapy should be discussed when faced with an unresectable tumour or after suboptimal surgery as part of intensified local management with a curative intent.
    Cancer/Radiothérapie 01/2014; · 1.48 Impact Factor
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    ABSTRACT: Purpose Because lactate accumulation is considered a surrogate for hypoxia and tumor radiation resistance, we studied the spatial distribution of the lactate-to-N-acetyl-aspartate ratio (LNR) before radiation therapy (RT) with 3D proton magnetic resonance spectroscopic imaging (3D-1H-MRSI) and assessed its impact on local tumor control in glioblastoma (GBM). Methods and Materials Fourteen patients with newly diagnosed GBM included in a phase 2 chemoradiation therapy trial constituted our database. Magnetic resonance imaging (MRI) and MRSI data before RT were evaluated and correlated to MRI data at relapse. The optimal threshold for tumor-associated LNR was determined with receiver-operating-characteristic (ROC) curve analysis of the pre-RT LNR values and MRI characteristics of the tumor. This threshold was used to segment pre-RT normalized LNR maps. Two spatial analyses were performed: (1) a pre-RT volumetric comparison of abnormal LNR areas with regions of MRI-defined lesions and a choline (Cho)-to- N-acetyl-aspartate (NAA) ratio ≥2 (CNR2); and (2) a voxel-by-voxel spatial analysis of 4,186,185 voxels with the intention of evaluating whether pre-RT abnormal LNR areas were predictive of the site of local recurrence. Results A LNR of ≥0.4 (LNR-0.4) discriminated between tumor-associated and normal LNR values with 88.8% sensitivity and 97.6% specificity. LNR-0.4 voxels were spatially different from those of MRI-defined lesions, representing 44% of contrast enhancement, 64% of central necrosis, and 26% of fluid-attenuated inversion recovery (FLAIR) abnormality volumes before RT. They extended beyond the overlap with CNR2 for most patients (median: 20 cm3; range: 6-49 cm3). LNR-0.4 voxels were significantly predictive of local recurrence, regarded as contrast enhancement at relapse: 71% of voxels with a LNR-0.4 before RT were contrast enhanced at relapse versus 10% of voxels with a normal LNR (P<.01). Conclusions Pre-RT LNR-0.4 in GBM indicates tumor areas that are likely to relapse. Further investigations are needed to confirm lactate imaging as a tool to define additional biological target volumes for dose painting.
    International journal of radiation oncology, biology, physics 01/2014; · 4.59 Impact Factor
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    ABSTRACT: To review the clinical outcome of I-125 permanent prostate brachytherapy (PPB) for low-risk and intermediate-risk prostate cancer and to compare 2 techniques of loose-seed implantation. 574 consecutive patients underwent I-125 PPB for low-risk and intermediate-risk prostate cancer between 2000 and 2008. Two successive techniques were used: conventional implantation from 2000 to 2004 and automated implantation (Nucletron, FIRST system) from 2004 to 2008. Dosimetric and biochemical recurrence-free (bNED) survival results were reported and compared for the 2 techniques. Univariate and multivariate analysis researched independent predictors for bNED survival. 419 (73%) and 155 (27%) patients with low-risk and intermediate-risk disease, respectively, were treated (median follow-up time, 69.3 months). The 60-month bNED survival rates were 95.2% and 85.7%, respectively, for patients with low-risk and intermediate-risk disease (P=.04). In univariate analysis, patients treated with automated implantation had worse bNED survival rates than did those treated with conventional implantation (P<.0001). By day 30, patients treated with automated implantation showed lower values of dose delivered to 90% of prostate volume (D90) and volume of prostate receiving 100% of prescribed dose (V100). In multivariate analysis, implantation technique, Gleason score, and V100 on day 30 were independent predictors of recurrence-free status. Grade 3 urethritis and urinary incontinence were observed in 2.6% and 1.6% of the cohort, respectively, with no significant differences between the 2 techniques. No grade 3 proctitis was observed. Satisfactory 60-month bNED survival rates (93.1%) and acceptable toxicity (grade 3 urethritis <3%) were achieved by loose-seed implantation. Automated implantation was associated with worse dosimetric and bNED survival outcomes.
    International journal of radiation oncology, biology, physics 11/2013; 87(4):651-8. · 4.59 Impact Factor
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    ABSTRACT: To report on clinical outcome and toxicity profile after combined treatment that included radiation therapy (RT) in patients with localized sarcoma within an irradiated field. Individual clinical data from all consecutive patients diagnosed and treated for a localized SIF between January 2000 and October 2011 at the Institut Claudius Regaud, Toulouse, France, were retrospectively reviewed. Outcomes of patients with SIF who underwent adjuvant or definitive radiotherapy were compared with patients who did not receive further RT. Of the 27 patients eligible for this study: surgery alone (S), surgery followed by RT (S + RT) or definitive RT (RT) was performed in 16, 8 and 2 cases respectively. The rate of unresectable, gross or microscopically positive margin disease among the 10 re-irradiated patients was significantly higher than the non re-irradiated group (90% vs. 12% p < 0.001). After a median follow-up of 3.8 years, there was a trend toward longer survival and better local control in the subgroup of patients who received adjuvant or definitive RT compared to the rest of the cohort with an acceptable toxicity profile. The 4-year relapse free survival rates of patients treated with and without RT were 53% and 27% respectively (p = 0.09). SIF complete surgical resection is often difficult to achieve, enhancing the risk of relapse. RT should be discussed in case of unresectable tumor or after suboptimal surgery as part of intensified local management that has a curative intent.
    European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 09/2013; · 2.56 Impact Factor
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    ABSTRACT: HER2 instant-quality fluorescence in-situ hybridization (IQFISH) is a new fluorescence in-situ hybridization (FISH) assay developed with a non-toxic buffer that reduces the hybridization time to 1-2 h, enabling a turnaround time of 3 h 30 min from dewax to counting. The aim of this study was to compare assessment of HER2 status using IQFISH and assessment using standard FISH. We selected 160 breast cancer samples according to their HER2 status as determined by immunohistochemistry (IHC) in a retrospective multicentre cohort (40 cases in each scoring category, i.e. 0/1+/2+/3+). Each participating site (n = 5) constructed its tissue microarray (TMA) of 32 archival cases and sent it to the central site (site 1). HER2 IHC, HER2 FISH and HER2 IQFISH were performed blindly at site 1. IQFISH provided excellent quality signals without any background staining, thus allowing excellent reading conditions even on TMA. Statistical analysis showed almost perfect agreement between IQFISH and FISH (99.3%, κ = 0.98). The only discordant case was an equivocal one with an HER2/CEP17 ratio near the ASCO/CAP cut-off. The highly concordant data support IQFISH as a useful alternative to FISH, allowing reliable assessment of HER2 status. Use of this method could lead to reporting of HER status to the oncologist within a day.
    Histopathology 08/2013; · 2.86 Impact Factor
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    ABSTRACT: To date, chemosensitivity to neoadjuvant chemotherapy of patients with high-grade osteosarcoma is evaluated on surgical resection by evaluation of the percentage of necrotic cells. As yet, no predictive profile of response to chemotherapy has been used in clinical practice. Because we have previously shown that the integrin pathway controls genotoxic-induced cell death and hypoxia, we hypothesized that in primary biopsies, expression of proteins involved in this pathway could be associated with sensitivity to neoadjuvant chemotherapy in high-grade osteosarcoma. We studied β1, β3, and β5 integrin expression and integrin-linked kinase, focal adhesion kinase (FAK), glycogen synthase kinase 3β (GSK3β), Rho B, angiopoietin-2, β-catenin, and ezrin expression by immunohistochemistry in 36 biopsies of osteosarcomas obtained before treatment. All patients received a chemotherapy regimen in the neoadjuvant setting. An immunoreactive score was assessed, combining the percentage of positive tumor cells and staining intensity. We evaluated the correlation of the biomarkers with response to chemotherapy, metastasis-free survival, and overall survival. A combination of 3 biomarkers (β5 integrin, FAK, and GSK3β) discriminated good and poor responders to chemotherapy, with the highest area under the curve (89.9%; 95% confidence interval, 77.4-1.00) and a diagnostic accuracy of 90.3%. Moreover, high expression of ezrin was associated with an increased risk of metastasis (hazard ratio, 3.93; 95% confidence interval, 1.19-12.9; P = .024). We report a protein expression profile in high-grade osteosarcoma associating β5 integrin, FAK, and GSK3β that significantly correlates with poor response to neoadjuvant chemotherapy. This biomarker profile could help select patients for whom an alternative protocol using inhibitors of this pathway can be proposed.
    Human pathology 07/2013; · 3.03 Impact Factor
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    ABSTRACT: Although young age at diagnosis is an independent prognostic factor of poor survival; no specific recommendation are provided concerning the timing and modalities of follow-up for this population. These patients are followed similarly to older women during post-therapeutic surveillance. The objective of this study is to examine patterns of recurrence in a large series of positive lymph node breast cancer women aged 35 years or below and treated within adjuvant chemotherapy trials. Data of 200 patients (≤ 35 years) included in three UNICANCER adjuvant trials for node positive breast cancer were used. Competing risks methodology was used to identify prognostic factors associated with time to first failure according to type of event. After a median follow-up of 52.4 months, 84 pts had disease related events (17 loco-regional, five contralateral, and 62 distant metastasis). Variables associated with an increased rate of first event were the number of involved lymph nodes and the type of surgery. In univariate analysis, prognostic factors associated with high potential curative recurrence were number of positive lymph nodes and vascular invasion. Only number of positive lymph node remained significant in multivariate analysis. Concerning distant metastasis, only the number of lymph node involved was associated to an increased risk of metastasis. Using the number of positive nodes as important prognostic factors, it should be possible to identify patients at a higher risk of loco-regional relapse or contralateral breast cancer, in order to propose more individualized follow-up.
    Bulletin du cancer 07/2013; · 0.61 Impact Factor
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    ABSTRACT: Blood vessels and tumor angiogenesis are generally associated with tumor growth and poor clinical outcome of cancer patients. However, we recently discovered that some blood vessels present within the tumor microenvironment can be associated with favorable prognosis. These vessels, designated tumor high endothelial venules (HEVs), appear to facilitate tumor destruction by allowing high levels of lymphocyte infiltration into tumors. In this study, we investigated the mechanisms regulating HEV blood vessels in human breast cancer. We found that lymphotoxin β was overexpressed in tumors containing high densities of HEVs (HEV(high)) and correlated to DC-LAMP, a marker of mature DCs. DCs were the main producers of lymphotoxin β in freshly resected HEV(high) breast tumor samples, and the density of DC-LAMP(+) DCs clusters was strongly correlated with the density of tumor HEVs, T and B cell infiltration, and favorable clinical outcome in a retrospective cohort of 146 primary invasive breast cancer patients. Densities of tumor HEVs and DC-LAMP(+) DCs were strongly reduced during breast cancer progression from in situ carcinoma to invasive carcinoma, suggesting that loss of tumor HEVs is a critical step during breast cancer progression. Finally, an increase in the infiltration of regulatory T cells was observed in HEV(high) breast tumors, indicating that tumor HEVs can develop in the presence of regulatory T cells. Together, our results support a key role for DCs and DC-derived lymphotoxin in the formation of tumor HEVs. These findings are important because novel therapeutic strategies based on the modulation of tumor HEVs could have a major impact on clinical outcome of cancer patients.
    The Journal of Immunology 07/2013; · 5.52 Impact Factor
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    ABSTRACT: After a curative treatment for cancer, patients enter into a posttherapeutic surveillance phase. This phase aims to detect relapses as soon as possible to improve the outcome. Mould and others predicted with a simple formula, using a parametric mixture cure model, how long early-stage breast cancer patients should be followed after treatment. However, patients in posttherapeutic surveillance phase are at risk of different events types with different responses according to their prognostic factors and different probabilities to be cured. This paper presents an adaptation of the method proposed by Mould and others, taking into account competing risks. Our loss function estimates, when follow-up is stopped at a given time, the proportion of patients who will fail after this time and who could have been treated successfully. We use the direct approach for cumulative incidence modeling in the presence of competing risks with an improper Gompertz probability distribution as proposed by Jeong and Fine. Prognostic factors can be taken into account, leading to a proportional hazards model. In a second step, the estimates of the Gompertz model are combined with the probability for a patient to be treated successfully in case of relapse for each event type. The method is applied to 2 examples, a numeric fictive example and a real data set on soft tissue sarcoma. and CONCLUSION: The model presented is a good tool for decision making to determine the total length of posttherapeutic surveillance. It can be applied to all cancers regardless of the localizations.
    Medical Decision Making 06/2013; · 2.89 Impact Factor
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    ABSTRACT: The role of UVB-induced apoptosis in the formation of squamous-cell carcinoma (SCC) is recognized. We previously identified the small RhoB GTPase, an early response gene to cellular stress, as a critical protein controlling apoptosis of human keratinocytes after UVB exposure. Here we generate SKH1 mice invalidated for RhoB to evaluate its role in UVB-induced skin carcinogenesis in vivo. We show that rhob-/- mice have a lower risk of developing UVB-induced keratotic tumors and actinic keratosis which is associated with a higher sensitivity of UVB-exposed keratinocytes to apoptosis. We extend this observation to primary cultures of normal human keratinocytes in which RhoB was down regulated with siRNA and further show that the RhoB-mediated hypersensitivity to apoptosis depends on Bcl-2 down regulation. In rhob-/- mice, the UVB-induced tumors were preferentially undifferentiated and highly proliferative. Lastly, we show in human an almost constant loss of RhoB expression in undifferentiated SCC. These undifferentiated and RhoB-deficient tumors have elevated γH2AX and 53BP1, two markers of DNA double-strand breaks. Together, our results indicate that UVB-induced RhoB expression participates to in vivo SCC initiation by increasing keratinocyte survival. Conversely RhoB may limit tumor aggressiveness as loss of RhoB expression in tumor cells is associated with tumor progression.Journal of Investigative Dermatology accepted article preview online, 21 June 2013; doi:10.1038/jid.2013.278.
    Journal of Investigative Dermatology 06/2013; · 6.19 Impact Factor

Publication Stats

196 Citations
230.52 Total Impact Points

Institutions

  • 2010–2014
    • Institut Claudius Regaud
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2013
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
    • Centre Hospitalier Universitaire d'Amiens
      Amiens, Picardie, France
  • 2011
    • IPBS - Institut de Pharmacologie et de Biologie Structurale
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2006–2009
    • Institut du Cancer de Montpellier Val d'Aurelle
      Montpelhièr, Languedoc-Roussillon, France
    • Dokuz Eylul University
      Ismir, İzmir, Turkey