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In France, approximately 1200 cases of Legionnaires disease (LD) are reported annually, and isolates are available for approximately 20% of cases identified since 2000. All Legionella pneumophila serogroup 1 (sg1) isolates are characterized by sequence-based typing at the National Reference Centre. LD cases caused by L. pneumophila sg1 reported from 2008 through 2012 were considered for the study. Our study objective was to describe cases according to their sequence type (ST). We also constructed multivariable modified Poisson regression models to estimate the incidence rate ratio (IRR) and to identify characteristics potentially associated with ST23 clones compared to ST1 and ST47 clones. We studied 1192 patients infected by ST1 (n = 109), ST23 (n = 236), ST47 (n = 123) or other STs (n = 724). The geographic distribution of the ST23 cases across the country was significantly different compared to other ST groups. This genotype was significantly associated with the absence of corticosteroid therapy compared to ST1 (IRR = 0.56; p 0.016). Concerning exposure, the ST23 genotype was significantly less associated with hospital-acquired infections compared to ST1 (IRR = 0.32; p 0.001), but it was more associated with infections acquired in hospitals and elderly settings compared with ST47. Finally, the ST23 genotype was less frequently associated with travel than other STs. Despite the large number of cases of ST23 infection, we did not identify any characteristics specific to this ST. However, we identified independent associations between ST1 and nosocomial transmission and steroid therapy. These findings should encourage further exploration, especially in terms of environmental diffusion, strain virulence and host factors.

Background: Advanced sarcoma is a group of heterogeneous disease with poor prognosis and poor efficacy of medical treatment. They represent a promising group of tumors to assess molecular-based therapy (MBT) strategy. Patients and methods: Genomic profiles of patients with advanced sarcoma included in the ProfiLER program were established by NGS using a 69 genes panel and CGH array. A weekly molecular board reviewed genomic reports to select relevant genomic alterations and propose recommendations for MBT. Results: A genomic profile was available for 158 of 164 patients. At least 1 relevant genomic alteration was reported for 106 patients (67%), with frequent multiple alterations (68%). In total, 289 relevant genomic alterations were identified in 143 different genes; 139 homozygous deletions, 86 gene amplifications and 64 somatic mutations. The most frequently impacted genes were TP53, Rb1, CDKN2A, CDK4, MDM2, and PTEN. MBT was recommended for 47 patients and initiated for 13 patients.One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization. Conclusion: Genomic profiling for advanced sarcoma is feasible, even for bone sarcoma. A small proportion of patients are eventually treated with MBT, similar to other tumor types. We could not demonstrate this strategy to be beneficial to patients. Our data suggest that molecular profiling should not be used in routine practice but warrants further exploration in clinical trials, focusing on sarcoma with complex genomic, and adding transcriptomic analysis to the copy number and mutational analyses.

Background: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. Methods: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. Results: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1–3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. Conclusion: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti–PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC. Materials and methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle. Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months. Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing. Clinical trial registration number: NCT03000257Statement on originality of the workThe manuscript represents original work and has not been submitted for publication elsewhere nor previously published.Statement of prior presentationData from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.

A growing body of research suggests that dysbiosis of the gut microbiota induced by environmental pollutants, such as pesticides, could have a role in the development of metabolic disorders. We have examined the long-term effects of 3 doses of the Roundup(R) herbicide (made of glyphosate and formulants) on the gut microbiota in male and female Sprague-Dawley rats. A total of 141 bacteria families were identified by a 16S sequencing analysis approach. An OPLS-DA analysis revealed an increased Bacteroidetes family S24-7 and a decreased Lactobacillaceae in 8 out of the 9 females treated with 3 different doses of R (n = 3, for each dose). These effects were confirmed by repetitive sequence-based PCR fingerprinting showing a clustering of treated females. A culture-based method showed that R had a direct effect on rat gut microbiota. Cultivable species showed different sensitivities to R, including the presence of a high tolerant or resistant strain identified as Escherichia coli by 16S rRNA sequencing. The high tolerance of this E. Coli strain was explained by the absence of the EPSPS gene (coding glyphosate target enzyme) as shown by DNA amplification. Overall, these gut microbiome disturbances showed a substantial overlap with those associated with liver dysfunction in other studies. In conclusion, we revealed that an environmental concentration of R (0.1 ppb) and other two concentrations (400 ppm and 5,000 ppm) have a sex-dependent impact on rat gut microbiome composition and thus warrants further investigation. Keywords: Glyphosate, Roundup, Gut microbiome, Pesticides, Toxicity

Background: The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS)., Patients and Methods: This retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020., Results: Overall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%., Conclusions: Early phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit., Competing Interests: Disclosure J-YB declares research support and honoraria from Bayer, Roche, Deciphera, Novartis, and GSK. OM has received consultancy fees from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Eli Lilly, Ipsen, Lundbeck, Merck Sharpe & Dohme, Pfizer, Roche, Servier, and Vifor Pharma. PP reports consultancy/advisory board fees from Roche, AstraZeneca, Tesaro, Clovis, Onxeo, MSD, GSK, and Genentech; research funding from PharmaMar; and travel expenses from Roche, AstraZeneca, and GSK. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments., Patients and Methods: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted., Results: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis., Conclusion: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types., Competing Interests: Disclosure DP: research grant: MSDAVENIR; honoraria: Roche, BMS, MSD, AstraZeneca; travel: AstraZeneca. AF: grants, personal fees and nonfinancial support from ROCHE, AZ, Pfizer, MSD, BMS. JF: grants, personal fees and nonfinancial support from AZ, MSD, BMS, Merck Serono, Biogen, Rakuten, Roche, Servier. OT: Roche, AstraZeneca, Novartis, Pfizer, MSD, BMS, Sandoz. HB received travel expenses from BMS, Pfizer and honoraria from BMS and Pfizer. MP: grants, personal fees and nonfinancial support from Roche, Genentech, Eli Lilly, Pfizer, Boehringer-Ingelheim, MSD, Bristol-Myers Squibb, Novartis, Pierre Fabre, AstraZeneca, Takeda, Chugai, Amgen (adboards and symposiums). TB: advisory board and travel from Roche, Novartis, AstraZeneca, Pfizer and Seattle Genetics. PC: Roche/Genentech, AZ, Amgen, EMD/Merck Serono, Novartis (symposiums/adboard). VA: honoraria for advisory boards from Bristol-Myers Squibb. E-MN-B received travel expenses and honoraria from MSD, BMS, Pierre Favre and Novartis. FN: grants, personal fees and nonfinancial support from Novartis, Incyte Biosciences, Sun Pharma Ltd., Ylang Pharma Inc. AS received honoraria for advisory boards from Roche, Bristol-Myers Squibb; symposiums: Roche, AstraZeneca, Bristol-Myers Squibb. PS: Research grant from BMS and Roche. PM declares to have interest in NETRIS Pharma as founder and minority shareholder. IR-C: honoria from AbbVie, Agenus, Advaxis, BMS, Pharma Mar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; advisory/consultancy from AbbVie, Agenus, Advaxis, BMS, Pharma Mar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; research grant from MSD, Roche and BMS. JYB: research support and honoraria from Roche, MSD, BMS, Bayer, Novartis, GSK, AstraZeneca. The remaining authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting., Patients and Methods: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate., Results: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response., Conclusion: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The Notch pathway plays an essential role during embryonal development and tissue in adults. Notch signaling occurs through transmembrane receptors which undergo several proteolytic cleavages that lead to the release of the Notch intracytoplasmic domain (NICD), which in turn activates the transcription of target genes. Oncogenic alterations of Notch receptors were first identified in T acute lymphoblastic leukemia and subsequently in solid tumors and other hematological malignancies. The important role of Notch signaling in cancer makes it an interesting target for drug development. Several classes of compounds targeting Notch signaling are currently in clinical development. However, the complexity of Notch signaling as well as its importance in tissue homeostasis makes the clinical development of these therapies more complex than anticipated. Additional clinical and preclinical investigations are needed to adequately target Notch signaling in cancer therapy., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Legionella pneumophila serogroup 1 (Lp1) sequence type 47 is the leading cause of legionellosis in north-western Europe, but, surprisingly, it is rarely isolated from environmental samples. Comparative genomics was applied to develop a PCR assay and to better understand the evolution of this strain., Methods: Comparative analysis of 36 genomes representative of the Lp species was used to identify specific PCR targets, which were then evaluated in silico on 545 sequenced genomes and in vitro on 436 Legionella strains, 106 respiratory samples, and three environmental samples from proven ST47 sources. Phylogenetic analyses were performed to understand the evolution of ST47., Results: The gene LPO&#95;1073 was characterized as being 100% conserved in all 129 ST47 genomes analysed. A real-time PCR designed to detect LPO&#95;1073 was positive for all 110 ST47 strains tested and agreed with culture and typing results previously obtained for 106 respiratory samples. The three environmental samples were also positive. Surprisingly, 26 of the 44 ST109 strains tested among 342 non-ST47 strains scored positive for LPO&#95;1073. SNP-based phylogenetic analysis was undertaken to understand this result: the PCR-positive ST109 genomes were almost identical to ST47 genomes, with the exception of a recombined region probably acquired by ST47 from a ST62(-like) strain., Conclusion: The genomic analysis allowed the design of a highly specific PCR assay for rapid detection of ST47 strains. Furthermore, it allowed us to uncover the evolution of ST47 strains from ST109 by homologous recombination with ST62. We hypothesize that this recombination generated the leading cause of legionellosis in north-western Europe., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Since the first draft of the human genome sequence published in 2001, the cost of sequencing has dramatically decreased. The development of new technologies such as next generation sequencing led to a comprehensive characterization of a large number of tumors of various types as well as to significant advances in precision medicine. Despite the valuable information this technological revolution has allowed to produce, the vast amount of data generated resulted in the emergence of new challenges for the biomedical community, such as data storage, processing and mining. Here, we describe the contribution and challenges of Big Data in oncology., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points., Patient and Methods: This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed., Results: When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS., Conclusion: In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted., Clinicaltrialsgov Identifier: NCT01362107., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Solitary fibrous tumors of the pleura (SFTP) refer as to a heterogeneous group of mesenchymal malignancies with various anatomic and histology features. Upfront surgical resection is the standard approach, but recurrences may be aggressive and difficult to treat. The most widely accepted staging system has been proposed by De Perrot et al. Because SFTPs are rare, evidence to support a role for perioperative chemotherapy is scarce. Likewise, the predictive or prognostic relevance of the De Perrot system may be questioned., Methods: Multicenter retrospective study of patients with histologically proven SFTP with complete follow-up from surgical diagnostic to tumor recurrence and death., Results: Sixty-eight patients were included. Tumor stage was 0/I for 29 (43%) patients, II for 23 (34%) patients, III for seven (10%) patients, and IV for nine (13%) patients. Postoperative chemotherapy was given to seven patients, mostly with stage III/IV SFTP, mostly consisting of doxorubicin-based regimen. Recurrence rate and median relapse-free survival after surgery were 3%, 52%, 71%, and 80% (p < 0.001), and 107, 70, 29, 11 months (p < 0.001) for stage 0/I, II, III, and IV tumors, respectively. At time of tumor recurrence, 14 patients received exclusive chemotherapy. Highest disease control rates were observed with trabectedin, and gemcitabine-dacarbazine combination., Conclusion: Our study confirms the prognostic value of the De Perrot staging system, as well as its possible predictive value for perioperative chemotherapy decision-making, whereas the efficacy of currently available regimens to significantly reduce the risk of tumor recurrence remains questionable. Trabectedin may be of interest for recurrent tumors.

Soft tissue sarcomas (STS) are a set of very heterogeneous tumors with numerous histological categories. The development of the molecular biology allowed identifying recurring molecular anomalies in certain subgroups of sarcomas, being able to represent diagnostic, prognosis and therapeutic tools. The molecular classification of STS includes until today 5 main groups of abnormalities: sarcomas with "simple genomic profile" showing reciprocal (1) chromosomal translocations, (2) activating mutation, (3) inhibitive mutation or (4) simple amplification; (5) sarcomas with "complex genomic profile" can include several tens of molecular abnormalities. The development of new-targeted therapies is based on the identification of a target, specific of a tumors subgroup and involved in carcinogenesis mechanisms and/or tumoral growth. Then, the aim of clinical research is to establish the proof of the concept through clinical trials, demonstrating the benefit brought to the patient and ending in the marketing of the drug. This proof of the concept was clearly established for imatinib, sunitinib and regorafenib in gastrointestinal stromal tumors, for imatinib in dermatofibrosarcoma protuberans and pigmented vilo-nodular synovitis, for denosumab in giant cell tumors of the bone, ending in the authorization to use these new therapies in these indications. It is in progress and promising for anti-IGF-1R in Ewing sarcomas, for crizotinib in myofibroblastic inflammatory tumors, for mTOR inhibitor in PEComas... The role of molecular abnormalities identified in the mechanisms of tumoral progress for sarcomas and their potential therapeutic impact will be detailed., (Copyright © 2015. Published by Elsevier Masson SAS.)

In France, approximately 1200 cases of Legionnaires disease (LD) are reported annually, and isolates are available for approximately 20% of cases identified since 2000. All Legionella pneumophila serogroup 1 (sg1) isolates are characterized by sequence-based typing at the National Reference Centre. LD cases caused by L. pneumophila sg1 reported from 2008 through 2012 were considered for the study. Our study objective was to describe cases according to their sequence type (ST). We also constructed multivariable modified Poisson regression models to estimate the incidence rate ratio (IRR) and to identify characteristics potentially associated with ST23 clones compared to ST1 and ST47 clones. We studied 1192 patients infected by ST1 (n = 109), ST23 (n = 236), ST47 (n = 123) or other STs (n = 724). The geographic distribution of the ST23 cases across the country was significantly different compared to other ST groups. This genotype was significantly associated with the absence of corticosteroid therapy compared to ST1 (IRR = 0.56; p 0.016). Concerning exposure, the ST23 genotype was significantly less associated with hospital-acquired infections compared to ST1 (IRR = 0.32; p 0.001), but it was more associated with infections acquired in hospitals and elderly settings compared with ST47. Finally, the ST23 genotype was less frequently associated with travel than other STs. Despite the large number of cases of ST23 infection, we did not identify any characteristics specific to this ST. However, we identified independent associations between ST1 and nosocomial transmission and steroid therapy. These findings should encourage further exploration, especially in terms of environmental diffusion, strain virulence and host factors.

Background: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs., Methods: Patients were identified via a survey from 16 FSG centers (n = 105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation., Results: 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n = 82), a pancreaticoduodenectomy (PD, n = 23), and data were missing for 4 patients. Resections were R0 (n = 87, 79%), R1 (n = 8, 7%), R2 (n = 6). Tumor characteristics were: KIT+ (n = 104), CD34+ (n = 58). Miettinen risk was low (n = 43), and high (n = 52). Imatinib was administered preoperatively (n = 11) and post-operatively (n = 20). With a median follow-up of 36 months (2-250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups (P > 0.05). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse., Conclusions: Patients with resected duodenal GIST have a reasonably favorable prognosis. This study favors a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma., Methods: This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy., Results: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia., Conclusions: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted., Clinicaltrialsgov Identifier: NCT01267955.

Objective: The authors had for objective to describe patients with confirmed influenza A(H1N1)pdm09 admitted to an intensive care unit (ICU) in a university hospital and to identify risk factors correlated with the severity of the disease., Design: A prospective study was conducted in an university hospital during the A(H1N1)pdm09 influenza pandemic. Severe laboratory confirmed cases (admitted to an ICU) were described and compared with non-severe confirmed cases (not admitted to an ICU)., Results: Sixty-nine patients were included; 36 (52%) were 15 to 44 years of age. Sixteen (23%) cases were defined as severe, ten of these (63%) concerned patients 45 to 64 years of age. The independent factors associated with severity were: a history of heart disease, obesity, and tobacco abuse., Conclusions: This work reinforces the need to identify and protect groups at risk of severe outcomes., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to investigate the risk factors associated with CTX-M-producing Escherichia coli strains isolated from infected or colonized patients. From 191 clinical samples, a case-control study was designed. From January 2005 to December 2007, 98 hospitalized patients infected or colonized with CTX-M-producing E. coli were included in the study. They were matched 1 : 1 with controls that had a non-CTX-M-producing E. coli infection on the basis of the site of sample, the unit of hospitalization and the time at risk. The rate of CTX-M-producing E. coli among those producing extended spectrum β-lactamases was always ≥90% from 2005 to 2008. All strains were susceptible to carbapenems. However, we observed a high rate of co-resistance to ciprofloxacin (61%), sulphonamides (86%) and gentamicin (34%). Significant risk factors identified by multivariate analysis were recurrent infections (OR = 2.93), presence of artificial nutrition (OR = 3.99), and recent exposure to quinolones (OR = 4.39), third- or fourth-generation cephalosporin (OR = 3.49) and the combination of both antibiotic classes (OR = 5.50). This report highlights the dramatic increase of CTX-M-producing E. coli and the need for changes in the use of antimicrobial drugs and in infection control measures to manage this major health concern., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

Neuroendocrine small cell carcinoma of the bladder is a rare and aggressive cancer with a very pejorative behavior. Neuroendocrine small cell carcinoma of bladder is a histological entity with special characteristics, rapidly aggressive and metastatic and with a poor prognosis. Because it is rare, there is no consensus to date. Its management should be multidisciplinary, involving surgery, chemotherapy and radiotherapy. We report the case of an 84-year-old patient with neuroendocrine small cell carcinoma of the bladder, treated by neoadjuvant chemotherapy followed by a combined chemoradiotherapy. A review of the literature on this topic is also presented., (Copyright © 2011 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors.

Soft tissue sarcomas are rare tumors. They may occur in any part of the body. Early step of management are essential because they directly affect functional consequences and survival of patients. It is very important to rapidly evoke the diagnostic of soft tissue sarcoma. Multidisciplinary discussion is indispensable at different step of the management: before the diagnostic to organize radiological check up and preoperative biopsy, before resection of localized tumor to decide the surgical procedure, with anatomopathological results to discuss an adjuvant treatment, at metastatic setting to decide a systemic treatment to start or inclusion in a clinical trial.

Imatinib mesylate (Gleevec, Glivec, Novartis, Basel, Switzerland) is a small molecule inhibitor of the tyrosine kinase c-abl, c-kit and the platelet derived growth factor receptor (PDGFR). Imatinib was developed for the treatment of chronic myeloid leukaemia (CML) but was approved both in Europe and the US fro the treatment of CML and gastrointestinal stromal tumors (GIST). Given its activity against both c-kit and PDGFR kinases and its remarkable safety profile, imatinib has been 'tried' in several solid tumors; results however have often been deceiving. We review the current data regarding the activity of imatinib in solid tumors, including GIST.

The growth of breast cancers, as is the case in other solid tumors, is dependent on the development of neo-vessels. This has been clearly demonstrated in preclinical models and clinical-biological studies. Yet, the biological mechanisms involved in angiogenesis are heterogeneous; pathways activated by vascular endothelial growth factor (VEGF) seem to play a prominent role in the early stages of the disease, whereas a number of other pathways are involved in the development of progressive and metastatic tumors. This might account for the disappointing results of phase III studies of bevacizumab in breast cancer as compared with results reported in renal or colon cancers. The use of new drugs targeting other angiogenic factors and a better selection of patients eligible for treatment might improve these results. This is a review of the major biological and clinical data available on the critical role of angiogenesis in breast cancer. We will also review the different clinical studies reported to date in this area.

To study the behavior of the toxins E and A destruxin in biological media, a method was developed with direct injection on to a liquid chromatographic (LC) column. Either slightly lipophilic C1 and C4 "wide-pore" packings or the column-switching approach with a guard column were used. To confirm the results of the direct LC analysis, a "classical approach" with pretreatment prior to injection on to a C8 packed column was also developed. Further, parallel fast atom bombardment MS monitoring in the negative-ion mode was carried out on the same biological samples, to obtain complementary information on the destruxin metabolism in locusts. Thus, the behaviours of E and A destruxin were examined in vivo in different organs of locusts. For E destruxin, several detoxication processes could be observed, such as hydrolysis and conjugation with glutathione.

Multidimensional chromatographies (MDC) implying either a single column with an unique packing designed for providing several separation modes such as internal surface reversed-phase (ISRP), or C1 large pores particles, or multi-column switching technique using the previous supports as guard columns, allow fast and easy direct monitoring of pesticides into plant or animal biological media. In such a way, the comparative study of the agricultural fungicide cymoxanil in two strains of Botrytis cinerea of different sensitivities gave concordant conclusions with the previous work using radiolabelled cymoxanil and TLC. Moreover, as a comparison, a study of the metabolism of this xenobiotic was also followed in animal biological fluids likely to contain peptidases. In locust or lobster haemolymph, an unusual isomerization into a cyclic compound was thus demonstrated accompanying the classical peptidase-depending metabolism generally observed in plants. The same chromatographic approaches were tested and compared for monitoring the metabolism of the natural insecticide toxin E-destruxin in insects. A detoxication process leading to the less toxic E-diol destruxin was evidenced in the organs or haemolymph of the locust Locusta migratoria chosen as a model of non-target insects.

High-performance liquid chromatography with internal surface reversed-phase packing provides an analytical tool for studying the in vitro and in vivo metabolism of A and E destruxins in the haemolymph and various organs of male adults of Locusta migratoria. A slight amount of injected E destruxin is shown to be hydrated into E-diol destruxin in the haemolymph. The rest of the toxin is recovered unchanged in the fat-body, pericardial tissues and Malpighian tubules, and some further E-diol destruxin formation occurs in these organs. Because E-diol destruxin is only weakly toxic, this appears to be a detoxication process.

The yolk sac from normal pregnant rats contains a vitamin D-dependent calcium-binding protein (CaBP). To localize CaBP within the yolk sac, a rabbit antiserum specifically directed against purified rat CaBP, in indirect immunofluorescence and immunoperoxidase, has been used. Using yolk sac sections, positive reactions indicative of the presence of CaBP were found only in the endodermal cell layer. A method for isolation of pure endodermal cells, using EDTA treatment, was developed. On smears of isolated endodermal cells exposed to anti-CaBP antiserum, CaBP was distributed throughout the endodermal cytoplasm; no CaBP was detected in the nucleus. Our results suggest that the endodermal cells, which are functional absorptive cells of the yolk sac, may play a role in vitamin D-mediated processes.