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Villejuif, France

Mazouni C.,Institute Gustave Roussy | Mazouni C.,Laboratoire Of Transfert Biologique Oncologique | Bonnier P.,Institute Beauregard | Goubar A.,IGR | And 2 more authors.
European Journal of Cancer | Year: 2010

Objective: Oestrogen receptor (ER) determination in breast cancer (BC) is a major yardstick for the prognosis and for response to hormonal therapy (HT). As several techniques have been proposed for ER quantification, the purpose of our study was to assess whether the qualitative or quantitative analysis of ER expression might influence the prognosis and response to treatment. Materials and methods: We analysed overall survival (OS) and disease-free survival (DFS) in 797 primary BC cases with ER determination by enzyme immunoassay (EIA) and immunohistochemistry (IHC). The clinical impact according to qualitative or quantitative analysis of ER expression was assessed. Response to HT was evaluated according to quantitative EIA-determined ER expression levels. Results: According to the qualitative analysis of ER expression, patients with EIA-determined and IHC-determined ER-positive tumours had significantly longer OS and DFS (p < 0.001). The analysis stratified on quartiles of ER levels showed significantly different outcomes according to EIA- and IHC-determined subgroups. In the group of patients who received adjuvant treatment, 5-year OS was significantly different between the groups, with a clear benefit for the highest EIA-determined ER quartiles (p < 0.001). Comparatively, in terms of 5-year DFS, a clear separation was noted between groups for adjuvant treatment (p < 0.001). The group with moderate ER+ values was clearly distinct from the ER-negative population. Quantitative ER expression helped to better distinguish the beneficial or detrimental effect of HT within quartiles of ER-expressing tumours. Based on the STEPP analysis which showed a trend towards an ER effect on DFS as a function of HT assignment, we confirm the benefit of HT in patients with a very high EIA-determined ER level and a detrimental impact on negative and weakly positive groups. Conclusion: Quantitative ER expression in BC helps to better discriminate heterogeneity in clinical outcome and response to HT. © 2010 Elsevier Ltd. All rights reserved.

Friboulet L.,French Institute of Health and Medical Research | Friboulet L.,Institute Of Cancerologie Gustave Roussy Igr | Friboulet L.,University Paris - Sud | Barrios-Gonzales D.,Institute Of Cancerologie Gustave Roussy Igr | And 33 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Excision repair cross-complementation group 1 (ERCC1) is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously shown the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small-cell lung cancer (NSCLC). However, little is known about the molecular characteristics of ERCC1-positive and ERCC1-negative tumors. Experimental Design: We took advantage of a cohort of 91 patients with resected NSCLC, for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1-positive and ERCC1-negative tumors of NSCLC. We carried out a global molecular analysis including assessment of ERCC1 expression levels by using both immunohistochemistry (IHC) and quantitative reverse transcriptase PCR (qRT-PCR), genomic instability, global gene and miRNA expression, and sequencing of selected key genes involved in lung carcinogenesis. Results: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1-negative tumors had a higher rate of genomic abnormalities versus ERCC1-positive tumors. ERCC1-positive tumors seemed to share a common DNA damage response (DDR) phenotype with the overexpression of seven genes linked to DDR. The miRNA expression analysis identified miR-375 as significantly underexpressed in ERCC1-positive tumors. Conclusions: Our data show inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Furthermore, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1- negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC. ©2011 AACR.

Immediately after the detection by Swift/BAT on June 15.77197 ut, the VSNET collaboration team31 started a worldwide photometric campaign of V404 Cyg. There was also an independent detection by CCD (charge coupled device) photometry on June 16.169 ut32. Time-resolved CCD photometry was carried out at 27 sites using 36 telescopes with apertures of dozens of centimetres (Extended Data Table 2). We also used the public AAVSO data33. We corrected for bias and flat-fielding in the usual manner, and performed standard aperture photometry. The observers, except for TAOS34, used standard filters (B, V, R , I ; we write R and I for R and I in the main text and figures for brevity) and measured magnitudes of V404 Cyg relative to local comparison stars whose magnitudes were measured by A. Henden (sequence 15167RN) from the AAVSO Variable Star Database35. We applied small zero-point corrections to some observers’ measurements. When filtered observations were unavailable, we used unfiltered data to construct the light curve. The exposure times were mostly 2–30 s, with some exceptional cases of 120 s in B band, giving typical time resolution of a few seconds. All of the observation times were converted to BJD. For the Swift/XRT light curves (Fig. 3 and Extended Data Fig. 2), we extracted source events from a region with a 30-pixel radius centred on V404 Cyg. To avoid pile-up effects, we further excluded an inner circular region if the maximum count rate of the XRT raw light curves, binned in 10 s intervals, exceeded 200 counts s−1. The inner radii are set to be 10 and 20 pixels at the maximum raw rate of 1,000 counts s−1 and 2,000 counts s−1, respectively, and those for intermediate count rates were determined via linear interpolation between the two points. The presented light curves were corrected for photon losses due to this exclusion by using the xrtlccorr tool. In addition, from Fig. 3a, c and d, we can see a time delay in the start of a dip in optical light, relative to that in X-rays. The delay time was ~1 min, which is similar to the reported value of 0–50 s (ref. 36). This was determined by cross-correlating the U-band and X-ray (0.3–10 keV) light curves obtained with Swift/UltraViolet and Optical Telescope (UVOT) and Swift/XRT on ut 2015 June 2136. The observations were carried out when the source showed little rapid optical flickering and no extreme flares, and thus the nature of the lag may be different from that in our observations. We also note that the apparent difference between the Swift/UVOT and the ground-based times36 is caused by the drift of the clock on board the satellite, to which we have applied the necessary corrections. In order to examine the possibility that absorption by gas in the line-of-sight causes the observed violent flux variations in the optical and X-ray bands (Fig. 3), we studied intensity-sliced X-ray spectra. A striking example is shown in Extended Data Fig. 3a. The period shown corresponds to that in Fig. 3a when both the X-ray and optical fluxes exhibited a sudden intensity drop towards the latter part of the period. We divided it into five intervals (T1 to T5; Extended Data Fig. 3a), and generated spectra through the tools xrtpipeline and xrtproducts in standard pipeline processing. We excluded the central 60-arcsecond strip from this Windowed Timing (WT) mode data, to avoid the heavy pile-up effect when the raw count rate exceeds ~150 counts s−1. We compared the vF spectra of the five intervals, where the spectra are fitted by a single power-law model multiplied by photoelectric absorption (phabs × pegpwrlw; in the standard X-ray spectral fitting package XSPEC). The absorbed X-ray flux ranges by two orders of magnitude, from 2.1 × 10−9 erg s−1 cm−2 in T5 to 3.0 × 10−7 erg s−1 cm−2 in T3. However, the best-fit column density and photon index were relatively stable over the five intervals, ~(2–6) × 10−21 cm−2 and ~1.0–1.5, respectively. Since the X-ray spectrum does not show a noticeable rise in column density when the X-ray flux sharply dropped, and since there is no stronger iron edge in the latter part of the observation, absorption cannot be the primary cause of the time variation in our data sets that cover the X-ray and optical bands simultaneously. In Extended Data Table 3 we show the list of X-ray binaries that have shown violent short-term variations either in X-rays or in optical wavelengths. IGR J17091−3624 is known as the second black hole X-ray binary whose X-ray light curves showed a variety of patterns, resembling those of GRS 1915 + 10518. The variations observed in the 2011 outburst of this object were classified as ρ (‘heartbeat’), ν (similar to class ρ but with secondary peak after the dips), α (‘rounded-bumps’), β/λ (repetitive short-term oscillations after low-quiet period) and μ (ref. 18). The Rapid Burster (RB or MXB 1730−335), a low-mass X-ray binary (LMXB) containing a neutron star (NS), was discovered by Small Astronomy Satellite (SAS-3) observations37. This object has been recently reported to show cyclic long X-ray bursts with periods of a few seconds resembling class ρ (‘heartbeat’) variations and those with periods of 100–200 s resembling class θ (“M”-shaped light curves) variations of GRS 1915 + 10524. The emission of the Rapid Burster did not reach the Eddington luminosity during these variations38. V4641 Sgr was originally discovered as a variable star39 and was long confused with a different variable star, GM Sgr40. V4641 Sgr is famous for its short and bright outburst in 1999, which reached a optical magnitude of at least 8.8 mag (refs 41, 42, 43, 44). V4641 Sgr showed short-term variations in optical wavelengths during the 2002, 2003 and 2004 outbursts14, 45, 46, 47. It was the first case in which short-term and large-amplitude variations in the optical range during an outburst were detected. V4641 Sgr is classified as a LMXB, and has a long orbital period. Its mass-accretion rate is less than the Eddington rate (except for the 1999 outburst44, 48). These properties are similar to those of V404 Cyg. However, while the short-term variations of V4641 Sgr seemed to be random, those of V404 Cyg showed repetitive patterns; this is the greatest difference between these two objects. There has been a suggestion that V4641 Sgr is a ‘microblazar’49 because the jets observed during the outburst in 1999 were proposed to have the largest bulk Lorentz factor among known galactic sources43. There are also other X-ray transients showing short-term optical variations (for example, XTE J1118+480 and GX 339−4). However, these two sources are quasi-periodic oscillations (QPOs), characterized by very short periods. The periods are much shorter than those of repetitive patterns (tens of seconds to a few hours) that we discuss in this Letter. Furthermore, the amplitudes of their variations are significantly smaller than those observed in V4641 Sgr4, 50 on timescales longer than tens of seconds. Following the method in ref. 15, we estimated the mass stored in the disk at the onset of the outburst. By integrating the X-ray light curve of Swift/BAT and assuming the spectral model C in table 1 in ref. 15, we obtained a value of 5.0 × 1025 g assuming a radiative efficiency of 10% and a distance of 2.4 ± 0.2 kpc (ref. 8). The mass during the 1989 outburst has been updated to 3.0 × 1025 g by using this updated distance. The stored mass in the 2015 outburst was approximately the same as that in the 1989 one. As discussed in ref. 15, these masses are far smaller than the mass of a fully built-up disk, estimated to be 2.0 × 1028 g, if these outbursts were starting at the outermost region. We compare the published optical light curves of the 1989 and 1938 outbursts51, 52 with our data from the 2015 outburst (Extended Data Fig. 4). We can see that these outbursts have different durations. The 1938 outburst was apparently longer than the others, and it may have had different properties from the 1989 and 2015 ones. The fading rates of the 1989 and 2015 outbursts are significantly larger than those of classical X-ray transients6, or of FRED (fast rise and exponential decline)-type outbursts, such as 0.028 mag d−1 in V518 Per = GRO J0422+32 (ref. 53) and 0.015 mag d−1 in V616 Mon = A0620−00 (ref. 54). This supports the hypothesis that the outbursts in 1989 and 2015 are different from typical outbursts of classical X-ray transients and that the stored disk mass was a factor of ~103 smaller in the 1989 and 2015 outbursts than the mass of a fully built up disk. We performed power spectral analyses on BJD 2,457,193, BJD 2,457,196 and BJD 2,457,200. We used the continuous and regularly sampled high-cadence data set obtained by LCO (Extended Data Table 1) with exposure times of 5 s (on BJD 2,457,193) and 2 s (others). The durations of these observations are 1.4, 3.1 and 2.2 h, respectively. Considering the read-out times of 1 s, the Nyquist frequencies of these observations are 0.08 and 0.17 Hz, respectively. The power spectral densities (PSDs) were calculated using powspec software in the FTOOLS Xronos package on magnitude measurements. We did not apply de-trending of the light curve since the durations of the individual observations were shorter than the timescale of the global variation of the outburst. The power spectra are well expressed by a power law (P ∝ f −Γ ) with an index Γ of 1.9 ± 0.1, 1.8 ± 0.1, and 2.3 ± 0.1 on BJD 2,457,193, 2,457,196 and 2,457,200, respectively (Extended Data Fig. 5). Interpretation of the physical origins on the basis of these variations is difficult, because a power law index of ~2 in the PSDs is often observed in natural phenomena. In this region (f < 0.01 Hz), the power originating in the optical variations of V404 Cyg is significantly higher than that of white noise estimated from the observations. We next summarize the other reports on short-term variations of V404 Cyg during the present outburst. On BJD 2,457,191, this object was observed using the Argos photometer on the 2.1m Otto Struve Telescope at McDonald Observatory with an exposure time of 2 s55. They reported that the power spectrum was dominated by steep red noise. Observations on BJD 2,457,193 and BJD 2,457,194 were also performed using the ULTRACAM attached with the 4.2m William Herschel Telescope on La Palma observatory with a high time resolution (466.8 ms)56. They reported that the variations were dominated by timescales longer than tens of seconds. Although large amplitude flares (0.3–0.4 mag) on timescales shorter than 1 s were reported57, these flares may be of different origin. For the variations with timescales longer than 100 s, our results agree with these reports55, 56. The timescale τ of heating/cooling waves in dwarf novae and X-ray transients58 is a function of the mass of the central object (M ) and radius (r) with the form , where α is the viscosity parameter59. Here, we estimate the disk radius of V404 Cyg assuming that the timescale of the final fading reflected a dwarf nova-type cooling wave. Using the Kepler data of V344 Lyr and V1504 Cyg, we measured a fading rate of 1.5 mag d−1 of the normal outbursts immediately preceding superoutbursts. During the outbursts in V344 Lyr and V1504 Cyg60, the disk radius is expected to be very close to the 3:1 resonance radius. Adopting a typical mass of a white dwarf in a cataclysmic variable (M  = 0.83M ; ref. 61), we estimated the disk radius of V404 Cyg to be 7.8 × 1010 cm for a black hole mass of 9M . This is much smaller than the radius (1.2 × 1012 cm) expected for a fully built-up disk15. Extended Data Fig. 6a shows the multi-wavelength SED on BJD 2,457,199.431 to 2,457,199.446, when the source was simultaneously observed in the X-ray, ultraviolet (UV) and optical bands. The optical fluxes in the V and I bands are taken from our photometric data averaged over the period. Note that R -band data are also available but not used here, because of the contamination by the continuum strong Hα line62, 63, 64. The X-ray spectrum is extracted from simultaneous Swift/XRT data (ObsID 00031403058) which were taken in the WT mode. The data are processed through the pipeline processing tool xrtpipeline. The events detected within 20 pixels around the source position are removed to mitigate pile-up effects. The U-band flux is obtained from the Swift/UVOT images with the same ObsID as the XRT, through the standard tool uvot2pha provided by the Swift team. A circular region centred at the source position with a radius of 5 arcsec is adopted as the source extraction region of the UVOT data. The optical, UV and X-ray data are corrected for interstellar extinction/absorption by assuming A (interstellar extinction in the V band) = 4 (ref. 65) and using the extinction curve in ref. 66 and the N (hydrogen column density) versus E(B−V) relation in ref. 67. Radio data are from the RATAN-600 observation performed in the same period68. The multi-wavelength SED can be reproduced with the diskir model69, 70, which accounts for the emission from the accretion disk, including the effects of Comptonization in the inner disk and reprocessing in the outer disk. We find that partial covering X-ray absorption (using the pcfabs model implemented in the spectral analysis software XSPEC) improves the quality of the fit significantly. The inner-disk temperature is estimated to be 0.12 ± 0.01 keV, and the electron temperature and photon index of the Comptonization component, the ratio between the luminosity of the Compton tail and disk blackbody (L /L ), and the fraction of the bolometric flux thermalized in the outer disk (f ), are 17.5 ± 0.8 keV, 1.78 ± 0.03, 1.17 ± 0.03, and , respectively (the errors in this section represent 90% confidence ranges for one parameter). The inner radius (R ) is estimated to be (1.5–5.4) × 108 cm, and the outer radius (R ) is (2.5 ± 0.3) × 1012 cm. The derived value of R is comparable to or even larger than the binary separation (~2.2 × 1012 cm). However, it could be smaller due to uncertainties in interstellar/circumbinary extinction71 and/or the contribution of jet emission. For instance, if A is 0.4 mag larger than the assumed value (4.0), R becomes (1.9 ± 0.2) × 1012 cm. The maximum achievable radius of a stable disk for a q (mass ratio) = 0.06 object (Extended Data Table 3) is around 0.62A (radius of the 2:1 resonance) to ~0.7A (tidal limit), where A is the binary separation72. Considering the uncertainties, the result of our analysis (>~ 0.77A) is compatible with this maximum radius. Our result appears to favour a large A value. For the partial covering absorber, the best-fit value of the column density is cm−2 and that of the covering fraction is 64 ± 4%. The radio SED can be approximated by a power-law with a photon index of ~1, as in other black hole binaries in the low/hard state73. This profile is likely to be generated by the optically-thick synchrotron emission from compact jets74. Because an optically-thick synchrotron spectrum often extends up to the millimetre to near-infrared bands75, 76, 77, it may contribute to the optical fluxes, in particular at longer wavelengths. The blackbody emission from the companion, a K3III-type star7 with a radius of ~3 R and a temperature of ~4,320 K, contributes to the SED negligibly. Extended Data Figure 6b plots the simultaneous SED on BJD 2,457,191.519 to 2,457,191.524, which is ~2 orders of magnitude fainter in the X-ray band than that shown in the left panel. The X-ray, UV and optical data are taken from the Swift data (ObsID 00031403038) and our photometric measurements in the same manner as described above. This SED can be reproduced with the irradiated disk model as well, with somewhat smaller photon index and inner-disk temperature (<0.07 keV), and a larger than those on BJD 2,457,199.431 to 2,457,199.446. The bolometric luminosity L of V404 Cyg is evaluated based on the hard X-rays above ~15 keV where the intrinsic spectrum is less affected by an absorption. We processed the Swift/BAT archival survey data via batsurvey in the HEAsoft package to derive count rates with individual exposures of ~300 s. Even within this short exposure, photon statistics are good during bright states (>0.05 counts s−1). Assuming a Crab-like spectrum (1 Crab ≈ 0.039 counts s−1), the BAT count rates R (counts s−1) are then converted into 15–50 keV flux (F ) and luminosity (L ) using F  = 3.6 × 10−7R (erg s−1 cm−1) and a fiducial distance of 2.4 kpc, respectively. In Fig. 4, we show L after multiplying by a conversion factor L /L  = 7 determined from SED modelling (previous section). We find that this bolometric correction factor lies within the range 2.5–10 by fitting 19 X-ray(XRT)-optical simultaneous SED in different periods between BJD 2,457,192.019 and 2,457,201.011. Since the BAT survey data are rather sparse, in order to catch shorter-term variations, we further overlaid the INTEGRAL IBIS/ISGRI monitoring in the 25–60 keV band available at ref. 78, assuming a conversion parameter of 1 Crab rate to be 172.1 counts s−1 and a bolometric correction factor of L /L  = 9.97. The luminosity was highly variable during the outburst, changing by five orders of magnitude. While V404 Cyg sometimes reaches the Eddington luminosity (L ) at the peak of multiple sporadic flares, it also repeatedly dropped below 1–10% of L (Fig. 4). At earlier phases of this outburst, the characteristic oscillation already occurred during a lower luminosity state, as discussed in the main text. No statistical methods were used to predetermine sample size.

Raynaud C.,Service de pneumologie | Greillier L.,Aix - Marseille University | Mazieres J.,Toulouse University Hospital Center | Monnet I.,Service de pneumologie | And 13 more authors.
BMC Cancer | Year: 2015

Background: Malignant pleural mesothelioma (MPM) is a rare disease with poor prognosis in spite of significant improvement in survival, due to new chemotherapy regimens. We describe here patients' profiles and management in daily practice in France. Methods: Observational retrospective study. Data were collected from medical files. All patients with histologically proven MPM diagnosed from January 2005 to December 2008 were included in the participating sites. Results: Four hundred and six patients were included in 37 sites: mean age 68.9±9.8years, male predominance (sex ratio 3.27), latency of the disease 45.7years, epithelioïd type 83%. Diagnosis was made using thoracoscopy in 80.8% of patients. Radical surgery was performed in 6.2% of cases. Chemotherapy was administered to 74.6% of patients. First line regimens consisted mainly of platinum+pemetrexed (91%) or pemetrexed alone (7%). Objective response rate was 17.2% and another 41.6% of patients experienced disease stabilization. Half of these patients underwent second line chemotherapy (platinium+pemetrexed 31.6%, pemetrexed alone 24.6%), resulting in a 6% response rate. Third-line chemotherapy (56 patients) yielded disease control in 5.4% of cases. Conclusions: The management of MPM in France is usually in accordance with guidelines. Response rates are somewhat lower than those described in clinical trials. © 2015 Raynaud et al.

Aim: This phase II study evaluated efficacy, safety and pharmacokinetics (PK) profile of combination intravenous vinorelbine (VNL) and continuous low doses oral cyclophosphamide (CPM) combination in children and young adults with a recurrent or refractory solid tumour. Methods: A total of 117 patients (median age, 12 years) within six disease strata received intravenous VNL 25 mg/m 2 on days 1, 8 and 15 of each 28-day cycle combined with continuous daily oral CPM 25 mg/m2. Tumour response was assessed every two cycles according to WHO (World Health Organisation) criteria. PK of VNL was investigated in a subset of 18 patients aged 4-15 years. Results: In rhabdomyosarcoma (RMS) (n = 50), the best overall response rate (ORR) was 36% with four complete (8%) and 14 partial responses (28%). The best ORR was 13% in Ewing's sarcoma (n = 15), 6% in non-RMS soft tissue sarcoma (n = 16) and 6% in neuroblastoma (n = 16). No response was observed in osteosarcoma (n = 10) and medulloblastoma (n = 7). The main grade 3/4 toxicity was neutropenia (38%). Other severe toxicities were limited with 3% of peripheral neuropathy and no haemorrhagic cystitis. The PK analysis revealed equivalent blood exposure to VNL between children >4 years and adult series when the VNL dose was based on the body surface area-based dosing. Concluding statement: In heavily pre-treated children, VNL combined with CPM showed an interesting response rate in RMS and an acceptable toxicity profile supporting further evaluation of these agents in phase III trials. © 2012 Elsevier Ltd. All rights reserved.

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