Expansion of CMV-mediated NKG2C+ NK cells associates with the development of specific de novo malignancies in liver-transplanted patients.

Solid cancers are a major adverse outcome of orthotopic liver transplantation (OLT). Although the use of chronic immunosuppression is known to play a role in T cell impairment, recent insights into the specificities of NK cells led us to reassess the potential modulation of this innate immune cell compartment after transplantation. Our extensive phenotypic and functional study reveals that the development of specific de novo noncutaneous tumors post-OLT is linked to unusual NK cell subsets with maturation defects and to uncommon cytokine production associated with the development of specific cancers. Remarkably, in CMV(+) patients, the development de novo head/neck or colorectal tumors is linked to an aberrant expansion of NK cells expressing NKG2C and a high level of intracellular TNF-α, which impact on their polyfunctional capacities. In contrast, NK cells from patients diagnosed with genitourinary tumors possessed a standard immature signature, including high expression of NKG2A and a robust production of IFN-γ. Taken together, our results suggest that under an immunosuppressive environment, the interplay between the modulation of NK repertoire and CMV status may greatly hamper the spectrum of immune surveillance and thus favor outgrowth and the development of specific de novo tumors after OLT.

On-chip copper-dielectric interference filters for manufacturing of ambient light and proximity CMOS sensors.

Filter technologies implemented on CMOS image sensors for spectrally selective applications often use a combination of on-chip organic resists and an external substrate with multilayer dielectric coatings. The photopic-like and near-infrared bandpass filtering functions respectively required by ambient light sensing and user proximity detection through time-of-flight can be fully integrated on chip with multilayer metal-dielectric filters. Copper, silicon nitride, and silicon oxide are the materials selected for a technological proof-of-concept on functional wafers, due to their immediate availability in front-end semiconductor fabs. Filter optical designs are optimized with respect to specific performance criteria, and the robustness of the designs regarding process errors are evaluated for industrialization purposes.

Distinct tumor protein p53 mutants in breast cancer subgroups.

Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.

Estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast tumors: early prediction of chemosensitivity with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography during neoadjuvant chemotherapy.

BACKGROUND: The objective of this prospective study was to evaluate the ability of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Sixty-four consecutive patients underwent (18)F-FDG PET/CT scanning at baseline and after the second course of neoadjuvant chemotherapy (NAC). The evolution (Δ) between the 2 scans of image parameters (maximum standardized uptake value [SUV(max)], SUV(mean), metabolic tumor volume, and total lesion glycolysis [TLG]) was measured. Correlations between early changes in PET-derived parameters and pathologic response observed in surgical specimens after the completion of 8 courses of NAC were estimated with Mann-Whitney U tests. Response prediction on the basis of clinical data, histologic type, or molecular markers also was assessed (Fisher exact test). Receiver operating characteristic (ROC) analysis was used to compare the area under the curve (AUC) of each parameter. RESULTS: The best prediction of chemosensitivity was obtained with ΔTLG (-49% ± 31% in nonresponders vs -73% ± 25% in responders; P < .0001). Among the biologic parameters, only negative progesterone receptor status (57% responders vs 31% nonresponders; P = .04) and luminal B subtype (63% responders vs 22% nonresponders; P = .02) were predictive of a pathologic response. ROC analysis resulted in an AUC of 0.81, 0.73, 0.71, and 0.63 for ΔTLG, ΔSUV(max), luminal subtype, and progesterone receptor status, respectively. CONCLUSIONS: When patients responded to NAC, the majority of ER-positive/HER2 negative tumors exhibited partial tumor shrinkage; and the PET parameters that combined volume and activity measurements, such as TLG, offered better accuracy for early prediction than the SUV(max). Negative progesterone receptor status and luminal B subtype had weaker predictive power than PET-derived parameters.

Color filters including infrared cut-off integrated on CMOS image sensor.

A color image was taken with a CMOS image sensor without any infrared cut-off filter, using red, green and blue metal/dielectric filters arranged in Bayer pattern with 1.75 µm pixel pitch. The three colors were obtained by a thickness variation of only two layers in the 7-layer stack, with a technological process including four photolithography levels. The thickness of the filter stack was only half of the traditional color resists, potentially enabling a reduction of optical crosstalk for smaller pixels. Both color errors and signal to noise ratio derived from optimized spectral responses are expected to be similar to color resists associated with infrared filter.

Importance of pre-analytical steps for transcriptome and RT-qPCR analyses in the context of the phase II randomised multicentre trial REMAGUS02 of neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: Identification of predictive markers of response to treatment is a major objective in breast cancer. A major problem in clinical sampling is the variability of RNA templates, requiring accurate management of tumour material and subsequent analyses for future translation in clinical practice. Our aim was to establish the feasibility and reliability of high throughput RNA analysis in a prospective trial. METHODS: This study was conducted on RNA from initial biopsies, in a prospective trial of neoadjuvant chemotherapy in 327 patients with inoperable breast cancer. Four independent centres included patients and samples. Human U133 GeneChips plus 2.0 arrays for transcriptome analysis and quantitative RT-qPCR of 45 target genes and 6 reference genes were analysed on total RNA. RESULTS: Thirty seven samples were excluded because i) they contained less than 30% malignant cells, or ii) they provided RNA Integrity Number (RIN) of poor quality. Among the 290 remaining cases, taking into account strict quality control criteria initially defined to ensure good quality of sampling, 78% and 82% samples were eligible for transcriptome and RT-qPCR analyses, respectively. For RT-qPCR, efficiency was corrected by using standard curves for each gene and each plate. It was greater than 90% for all genes. Clustering analysis highlighted relevant breast cancer phenotypes for both techniques (ER+, PR+, HER2+, triple negative). Interestingly, clustering on trancriptome data also demonstrated a "centre effect", probably due to the sampling or extraction methods used in on of the centres. Conversely, the calibration of RT-qPCR analysis led to the centre effect withdrawing, allowing multicentre analysis of gene transcripts with high accuracy. CONCLUSIONS: Our data showed that strict quality criteria for RNA integrity assessment and well calibrated and standardized RT-qPCR allows multicentre analysis of genes transcripts with high accuracy in the clinical context. More stringent criteria are needed for transcriptome analysis for clinical applications.

Combining molecular targeted therapies: clinical experience.

Approximately 20 molecular targeted therapies, mainly monoclonal antibodies and tyrosine kinase inhibitors, have been approved for the treatment of various cancers. They are being increasingly investigated in combination in clinical trials. We review the rationale for combining molecular targeted therapies and the results of clinical trials to date. There have been some exciting clinical results with some combinations, for example, lapatinib/trastuzumab or bevacizumab/trastuzumab in HER2-positive metastatic breast cancer, whereas other potential combinations have provided disappointment, for example, cetuximab or panitumumab in combination with bevacizumab/chemotherapy in first-line treatment of metastatic/advanced colorectal cancer. Therefore, at this point no general guidance to study such combinations can be derived.

Données épidémiologiques d'une cohorte de patients hospitalisés pour insuffisance cardiaque. Étude mono-centrique sur 3 ans. Comparaison avec les données régionales.

INTRODUCTION: Congestiveheart failure (CHF) is associated with prolonged and recurrent hospitalizations, the prognosis remains poor. The aim of this study was to collect epidemiologic data at admission and at six month follow-up in a cohort of patients with CHF admitted to a single center between 2017 and 2019 (Saint Joseph Hospital, HSJ) and to compare these data with regional data (Ile-de-France, IdF). METHODS: Local and regional data were provided by National Health Service, Regional Department of Ile de France(DRSM) using national data base. CHF in-hospital stay was defined by appropriate CIM 10 code reported on the final medical form. RESULTS: From 2017 to 2019, 1967 CHF in-hospital stays were collected, mean age of the population was 81.4 (=mean) ± 11.7 yearsIC95% [80.8; 81.9], mean length of stay was 8.6 ± 6.8 days IC95% [8.3; 8.9], in-hospital mortality was 5.3 %, 9.6% at 2nd month and 15.9% at 6th month. Readmission rate was 23.7%, time to readmission was 59.5 ± 47.5 days IC95% [57.4; 61.6]. IdF data collected 60973 CHF in-hospital stays at the same period. Compared to the IdF population, our population was older (81.4 ± 11.6 versus 80.4 ± 12.6 years, p = 0.001). Length of stay was shorter (8.6 ± 6.8 versus 11.3 ± 10.1 days p<0.001), in-hospital mortality was lower (5.3% versus 7.8% p < 0.001), 2nd month and 6th month mortality was lower (respectively 9.6% versus 14.2% and 15.9% versus 21.3%, p <0.001), home discharge rate was higher (66.9% versus 60.8%, p < 0.001) in the HSJ population. The proportion of patients included in PRADO-IC program (Programme d'aide au retour à domicile-Insuffisance Cardiaque, Returning home support program) was higher in SJ population (22.6% versus 8.8% p < 0.001). CONCLUSION: CHF admission involved elderly patients, the in-hospital and 6th month mortality is high, with early and frequent readmissions. Differences between HSJ and IdF populations may be explained by the heterogeneity of health care facilities, management facilities and organization of transition of care.

The European Medicines Agency review of ofatumumab (Arzerra®) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use.

On April 19, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union (EU) for ofatumumab (Arzerra®; Glaxo Group Ltd, Greenford, Middlesex, U.K.). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a conditional marketing authorization for ofatumumab for the treatment of chronic lymphocytic leukemia (CLL) in patients refractory to fludarabine and alemtuzumab. A conditional marketing authorization means that additional data to confirm the benefit-risk balance of ofatumumab are awaited. The active substance of Arzerra® is ofatumumab, a monoclonal antibody medicinal product (ATC code L01XC10). The recommended dose is 300 mg of atumumab for the first infusion and 2,000 mg of atumumab for all subsequent infusions. The infusion schedule is eight consecutive weekly infusions, followed 4-5 weeks later by four consecutive monthly (i.e., every 4 weeks) infusions. Ofatumumab targets CD20, a cell surface marker of B lymphocytes, which is followed by cell lysis via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The benefit of ofatumumab is the control of CLL in patients who are refractory to both fludarabine and alemtuzumab, which was indicated by a high response rate. The most common side effects are infections and infusion reactions. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients.

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial.

Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial.

PURPOSE: Circulating tumor cells in blood from metastatic breast cancer patients have been reported as a surrogate marker for tumor response and shorter survival. The aim of this study was to determine whether circulating tumor cells are present in the blood of patients with large operable or locally advanced breast cancer before neoadjuvant chemotherapy and after neoadjuvant chemotherapy before surgery. EXPERIMENTAL DESIGN: Blood samples of 7.5 mL were obtained on CellSave tubes from patients included in a phase II trial (REMAGUS 02). Circulating tumor cells were immunomagnetically separated and fluorescently stained by the CellSearch system. Blood from 20 metastatic breast cancer patients was used as a positive control. RESULTS: From October 2004 to July 2006, preneoadjuvant chemotherapy and/or postneoadjuvant chemotherapy blood samples were obtained from 118 patients. At least 1 circulating tumor cell was detected in 22 of 97 patients with preneoadjuvant chemotherapy samples (23%; 95% confidence interval, 15-31%; median, 2 cells; range, 1-17 cells). Circulating tumor cell positivity rates were 17% in 86 postneoadjuvant chemotherapy samples and 27% in all 118 patients. Persistence of circulating tumor cells at the end of neoadjuvant chemotherapy was not correlated with treatment response. After a short median follow-up of 18 months, the presence of circulating tumor cells (P=0.017), hormone receptor negativity, and large tumor size were independent prognostic factors for shorter distant metastasis-free survival. CONCLUSION: Circulating tumor cells can be detected by the CellSearch system at a low cutoff of 1 cell in 27% of patients receiving neoadjuvant chemotherapy. Circulating tumor cell detection was not correlated to the primary tumor response but is an independent prognostic factor for early relapse.

Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial.

PURPOSE: The overexpression of cyclooxygenase 2 (COX-2) gene, also known as prostaglandin-endoperoxide synthase 2 ( PTGS2), occurs in breast cancer, but whether it affects response to anticox drugs remains unclear. We investigated the relationships between PTGS2 expression, celecoxib use during neoadjuvant chemotherapy (NAC), and both event-free survival (EFS) and overall survival (OS). MATERIALS AND METHODS: We analyzed a cohort of 156 patients with human epidermal growth factor receptor 2 -negative breast cancer from the REMAGUS02 (ISRCTN Registry No. 10059974) trial with pretreatment PTGS2 expression data. Patients were treated by sequential NAC (epirubicin plus cyclophosphamide followed by docetaxel with or without celecoxib). Experimental validation was performed on breast cancer cell lines. The Cancer and Leukemia Group B (CALGB) 30801 ( ClinicalTrials.gov identifier: NCT01041781) trial that tested chemotherapy with or without celecoxib in patients with lung cancer served as an independent validation cohort. RESULTS: After 94.5 months of follow-up, EFS was significantly lower in the celecoxib group (hazard ratio [HR], 1.7; 95% CI, 1 to 2.88; P = .046). A significant interaction between PTGS2 expression and celecoxib use was detected ( Pinteraction = .01). In the PTGS2-low group (n = 100), EFS was lower in the celecoxib arm (HR, 3.01; 95% CI, 1.45 to 6.24; P = .002) than in the standard treatment arm. Celecoxib use was an independent predictor of poor EFS, distant relapse-free survival, and OS. Celecoxib in addition to docetaxel enhanced cell viability in PTGS2-low cell lines but not in PTGS2-high cell lines. In CALGB 30801, a trend toward poorer progression-free survival was observed in the patients with low urinary metabolite of prostaglandin E2 who received celecoxib (HR = 1.57; 95% CI, 0.87 to 2.84; P = .13). CONCLUSION: Celecoxib use during chemotherapy adversely affected survival in patients with breast cancer, and the effect was more marked in PTGS2-low and/or estrogen receptor-negative tumors. COX-2 inhibitors should preferably be avoided during docetaxel use in patients with breast cancer who are undergoing NAC.

The potential of anti-vascular endothelial growth factor therapy in metastatic breast cancer: clinical experience with anti-angiogenic agents, focusing on bevacizumab.

The importance of angiogenesis in tumour growth and development is well known. Overexpression of vascular endothelial growth factor (VEGF), the key mediator of angiogenesis, is associated with poor prognosis in breast cancer. As a result, several therapeutic agents that inhibit the actions of VEGF or its receptors are currently in development for use in metastatic breast cancer (MBC). This review describes the function of VEGF in normal and tumour angiogenesis, explores the rationale behind the use of anti-VEGF therapy in MBC and details the therapeutic impact of such agents on tumour vasculature. Clinical data from trials of anti-VEGF agents in MBC are discussed, with a particular focus on the efficacy and safety of bevacizumab, the anti-VEGF agent at the most advanced stage of development in this tumour type. Future potential uses of bevacizumab in breast cancer are introduced.

NF-kappa B genes have a major role in inflammatory breast cancer.

BACKGROUND: IBC (Inflammatory Breast cancer) is a rare form of breast cancer with a particular phenotype. New molecular targets are needed to improve the treatment of this rapidly fatal disease. Given the role of NF-kappaB-related genes in cell proliferation, invasiveness, angiogenesis and inflammation, we postulated that they might be deregulated in IBC. METHODS: We measured the mRNA expression levels of 60 NF-kappaB-related genes by using real-time quantitative RT-PCR in a well-defined series of 35 IBCs, by comparison with 22 stage IIB and III non inflammatory breast cancers. Twenty-four distant metastases of breast cancer served as "poor prognosis" breast tumor controls. RESULTS: Thirty-five (58%) of the 60 NF-kappaB-related genes were significantly upregulated in IBC compared with non IBC. The upregulated genes were NF-kappaB genes (NFKB1, RELA, IKBKG, NFKBIB, NFKB2, REL, CHUK), apoptosis genes (MCL1L, TNFAIP3/A20, GADD45B, FASLG, MCL1S, IER3L, TNFRSF10B/TRAILR2), immune response genes (CD40, CD48, TNFSF11/RANKL, TNFRSF11A/RANK, CCL2/MCP-1, CD40LG, IL15, GBP1), proliferation genes (CCND2, CCND3, CSF1R, CSF1, SOD2), tumor-promoting genes (CXCL12, SELE, TNC, VCAM1, ICAM1, PLAU/UPA) or angiogenesis genes (PTGS2/COX2, CXCL1/GRO1). Only two of these 35 genes (PTGS2/COX2 and CXCL1/GRO1)were also upregulated in breast cancer metastases. We identified a five-gene molecular signature that matched patient outcomes, consisting of IL8 and VEGF plus three NF-kappaB-unrelated genes that we had previously identified as prognostic markers in the same series of IBC. CONCLUSION: The NF-kappaB pathway appears to play a major role in IBC, possibly contributing to the unusual phenotype and aggressiveness of this form of breast cancer. Some upregulated NF-kappaB-related genes might serve as novel therapeutic targets in IBC.

COX2/PTGS2 Expression Is Predictive of Response to Neoadjuvant Celecoxib in HER2-negative Breast Cancer Patients.

BACKGROUND: The prognostic and predictive role of cyclo-oxygenase-2 (COX2) in breast cancer is still debated, and in particular, its role as a target of COX2 inhibitor (celecoxib) in neoadjuvant setting. MATERIALS AND METHODS: We analyzed a series of 156 breast cancer samples from patients of the COX2 inhibitor-treated arm included in the REMAGUS-02 randomized phase II trial. COX2 gene expression was assessed by reverse transcription and quantitative polymerase chain reaction using ribonucleic acid from frozen biopsies. Pathological complete response (pCR) was the surrogate end-point. RESULTS: Significantly higher rates of grade 3, and estrogen and progesterone receptor negativity were observed in tumors with the highest expression of COX2. pCR rates were significantly higher in COX2-overexpressing tumors in patients receiving celecoxib. The test for interaction between COX2 gene expression and the celecoxib effect was statistically significant (p<0.01), but was not retained in the multivariate analysis. CONCLUSION: COX2 overexpression is predictive of pCR in patients with celecoxib-treated tumors. The efficacy of celecoxib in breast cancer might be improved by quantification of COX2 gene expression.

Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen.

BACKGROUND: In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown. METHODS AND FINDINGS: In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m(2) epirubicin and 1,200 mg/m(2) cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status. CONCLUSIONS: This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin-cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features.

Rationale and delineation of a composite index of relative antitumoural efficacy (In-RATE).

Over the last decades, the development of new drugs has allowed cancer patients to experience several lines of chemotherapy, the objective of which is a long term stabilization of the tumour. The objectives of this work was to delineate a composite index of relative antitumoural efficacy (In-RATE) of a regimen over another, including response rate (RR), median time to progression (TTP) and progression rate (PR). When considering two treatments a and b, the In-RATE was defined as RRa/RRb x TTPa/TTPb x PRb/PRa. Values significantly superior or inferior to 1 reveal an advantage for treatment a or b, respectively. The applicability of the In-RATE to published randomized trials in four frequent tumour types (colorectal, non-small cell lung, advanced ovarian and metastatic breast cancers) was suggested to more precisely distinguish the effects of different drugs, and sometimes to detect a significant difference when the published data did not conclude to statistical difference.

A nationwide survey on bariatric surgery in France: two years prospective follow-up.

BACKGROUND: Most studies on bariatric surgery outcomes have been performed in clinical trials (eg. the SOS) or reflect the clinical experience and practice of specific and experienced centers. Little is known about the current practice at a nationwide level. METHODS: This is a systematic nationwide study on the 2-year outcome of all consecutive 1,236 bariatric operations performed in France. Data on mortality, weight loss, complications, and patient satisfaction were collected independently from the medical and surgical team involved in the patients' care. RESULTS: 87.3% of the patients underwent an adjustable gastric banding (ABG), 8.6% a vertical banded gastroplasty (VBG), 3.8% a Roux-en-Y gastric bypass (RYGBP) and 0.3% a biliopancreatic diversion (BPD). Loss of follow-up was 12% at year 1 and 18% at year 2. The rate of laparoscopic procedures was 98% for ABG and 73% for RYGBP. Mortality rate was 0.16% in the operative period and 0.27% during follow-up. Excess weight loss ranged from 43% (AGB) to 66% (RYGBP). Co-morbidities improved in more than 70% of patients. CONCLUSION: Outcomes of bariatric surgery in routine practice (mortality, weight loss, course of co-morbidities, and quality of life) are similar to the results published in clinical trials.