Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Improved survival using specialized multidisciplinary board in sarcoma patients.

BACKGROUND: Sarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of a multidisciplinary tumor board (MDTB) presentation before treatment in a nationwide study over 5 years. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients in France. Patients' characteristics and follow-up are collected in a database regularly monitored and updated. The management and survival of patients presented to these MDTB before versus after initial treatment were analyzed. RESULTS: Out of the 12 528 patients aged ≥15 years, with a first diagnosis of soft tissue and visceral sarcoma obtained between 1 January 2010 and 31 December 2014, 5281 (42.2%) and 7247 (57.8%) were presented to the MDTB before and after the initiation of treatment, respectively. The former group had generally worse prognostic characteristics. Presentation to a MDTB before treatment was associated with a better compliance to clinical practice guidelines, for example, biopsy before surgery, imaging, quality of initial surgery, and less reoperations (all P < 0.001). Local relapse-free survival and relapse-free survival were significantly better in patients presented to a MDTB before initiation of treatment, both in univariate and multivariate analysis. CONCLUSION: The compliance to clinical practice guidelines and relapse-free survival of sarcoma patients are significantly better when the initial treatment is guided by a pre-therapeutic specialized MDTB.

Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice.

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.

[Plan of the day adaptive radiotherapy for bladder cancer: Dosimetric and clinical results]. / Résultats dosimétriques et cliniques d'une stratégie de radiothérapie adaptativede type "bibliothèque de plans" des cancers de la vessie localisés.

PURPOSE: To account of individual intra-pelvic anatomical variations in muscle invasive bladder cancer (MIBC) irradiation, adaptive radiotherapy (ART) using a personalized plan library may have dosimetric and clinical benefits. MATERIAL AND METHODS: The data from ten patients treated for localized MIBC according to the "plan of the day" (P0oD) individualized ART technique were collected and retrospectively analysed. Target volumes and organs at risk (OAR) were delineated at different bladder fill rates, resulting in two or three treatment plans. Daily Cone-Beam CT (CBCT) was used for the selection of PoD at each fraction. Retrospectively, we delineated rectal, intestinal and target volumes on each CBCT, to assess target volume coverage and dose sparing to healthy tissues. A comparison with the conventional radiotherapy technique was performed. The secondary objectives were toxicity and efficacy. RESULTS: The target coverage was respected with the adaptive treatment: 97.3% for the bladder Clinical Target Volume (CTV) (99.5; [60.1-100]) and 98% for the bladder+lymph nodes CTV (98.6; [85.4-100]). Concerning OAR, the volume of healthy tissue spared was 43.7% on average and the V45Gy for the small bowel was 43,4cc (35; [0-129]) (versus 57,6cc). The rectal D50 was on average 18,7Gy for the adaptive treatment (15.9; [2.4-44.1]) versus 17Gy with the conventional approach. With a median follow-up of 2.94 years (95% CI: [0.92-4.02]), we observed three grade 3 toxicities (30%). No grade 4 toxicity was observed. The 2-year overall survival and progression-free survival rates were 65.6% (95% CI: [26-87.6]) and 45.7% (95% CI: [14.3-73]), respectively. CONCLUSION: The ART technique using a PoD strategy showed a reduction of the irradiated healthy tissue volume while maintaining a similar bladder coverage, with an acceptable rate of toxicity.

Cytokine signalling via gp130 in gastric cancer.

Cytokine signalling pathways that depend on gp130 are dysregulated in several epithelial cancers including gastric cancer. It has been established that blockade of SHP2 activation of MAPK signalling results in hyperactivation of STAT3 resulting in increased cell proliferation, angiogenesis, inflammation and inhibition of both immunocyte and epithelial cell apoptosis. Additionally, key genes regulated downstream of gp130 via MAPK activation such as the stomach-specific tumor suppressor gene tff1 are suppressed, contributing to the oncogenic outcome. The main cytokine driver of gp130 signalling in the stomach is IL-11, with IL-6 having little activity in the antral stomach in which most pathology initiates. IL-11 is up-regulated in both mouse and human gastric cancer and in pre-neoplastic mucosa. A characteristic gene signature specifically associated with IL-11 drive has been observed, although the prognostic value of the signature has not yet been assessed. Infection of human or mouse stomach with Helicobacter pylori, especially that expressing the CagA cytotoxin, produces constitutive MAPK activation, but also activated STAT3 and increases IL-11 expression. The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics.

Phonological processing in post-lingual deafness and cochlear implant outcome.

Cochlear implants work well, yet the outcome is not fully accounted by the data routinely available to the clinician, and remains unpredictable. A more in-depth understanding of the neural mechanisms that determine the clinical recovery after cochlear implantation is warranted, as they may provide the background for an accurate individual prognosis. In this study in post-lingually deaf adults, we show that while clinical data offer only prognosis trends, fMRI data can prospectively distinguish good from poor implant performers. We show that those deaf cochlear implant (CI) candidates who will become good performers rely on a dorsal phonological route when performing a rhyming task on written regular words. In contrast, those who will become poor performers involve a ventral temporo-frontal route to perform the same task, and abnormally recruit the right supramarginal gyrus, a region that is contralateral to classical phonological regions. These functional patterns reveal that deafness either enhances "normal" phonological processing, or prompts a substitution of phonological processing by lexico-semantic processing. These findings thus suggest that a simple behavioral pre-operative exploration of phonological strategies during reading, to determine which route is predominantly used by CI candidates, might fruitfully inform the outcome.

Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut.

We have shown that bacterial mutation rates change during the experimental colonization of the mouse gut. A high mutation rate was initially beneficial because it allowed faster adaptation, but this benefit disappeared once adaptation was achieved. Mutator bacteria accumulated mutations that, although neutral in the mouse gut, are often deleterious in secondary environments. Consistently, the competitiveness of mutator bacteria is reduced during transmission to and re-colonization of similar hosts. The short-term advantages and long-term disadvantages of mutator bacteria could account for their frequency in nature.

Impact of bedside diagnosis of influenza in the paediatric emergency ward.

OBJECTIVES: This prospective study performed in the paediatric emergency department of the University Hospital of Saint-Etienne aimed to measure the impact of the 24/7 bedside use of the Veritor™ System (Becton Dickinson) on the reduction of supplementary investigations, hospital stay and antimicrobial use. METHODS: Influenza virus A and B antigens were detected with a rapid influenza digital immunoassay (DIA) on nasopharyngeal aspirates (NPAs) sampled from the children consulting at the paediatric emergency department between January and March 2016 for influenza-like illness. The same NPA was tested by immunofluorescence and/or molecular routine assays. Before performing the DIA, the clinician filled in a questionnaire listing the tests that he/she would have prescribed in the absence of the rapid testing. The prescription of complementary investigations, antimicrobial treatments and hospital stay were also compared to those of the 3 previous years. RESULTS: A total of 514 children with flu-like symptoms were included. The use of the DIA at bedside decreased the prescription of blood puncture by 47.9% (21.2% to 6.6%), of chest X-rays by 69.0% (33.3% to 10.3%), of lumbar puncture by 77.8% (7.0% to 1.6%), of urine culture by 79.2% (23.3% to 4.9%), of antibiotic treatments by 70.1% (16.9% to 5.1%), and of hospital stay by 25.0% (27.2% to 20.4%), resulting in a reduction of medical costs estimated to more than €69 000 in a season. CONCLUSIONS: In addition to delivering a rapid aetiological diagnosis, this strategy saves medical costs and favours an antimicrobial stewardship strategy. However, further prospective studies are needed to confirm our findings.

Cross-modal plasticity underpins language recovery after cochlear implantation.

Postlingually deaf subjects learn the meaning of sounds after cochlear implantation by forming new associations between sounds and their sources. Implants generate coarse frequency responses, preventing place-coding fine enough to discriminate sounds with similar temporal characteristics, e.g., buck/duck. This limitation imposes a dependency on visual cues, e.g., lipreading. We hypothesized that cross-modal facilitation results from engagement of the visual cortex by purely auditory tasks. In four functional neuroimaging experiments, we show recruitment of early visual cortex (V1/V2) when cochlear implant users listen to sounds with eyes closed. Activity in visual cortex evolved in a stimulus-specific manner as a function of time from implantation reflecting experience-dependent adaptations in the postimplant phase.

[Between "pragmatic" interpretation and "disturbing" understanding: Embryonic cryopreservation for IVF patients]. / Entre lecture pragmatique et vision anxiogène : vécu de la cryoconservation embryonnaire par les patients en parcours de FIV.

OBJECTIVES: The aim of this article is to question the feeling of IVF patients towards embryonic cryopreservation, in order to understand their potential reluctance to freeze embryos and their difficulties to consider the fate of their frozen embryos once their parental project completed. METHODS: Twenty-seven semi-directive interviews with homologous IVF patients were conducted. These persons were followed in two fertility centres in Marseille. RESULTS: If all the patients interviewed have accepted embryonic cryopreservation or have accepted on principle, a majority have an ambivalent attitude towards this technique. If some share the "pragmatic" vision of professionals (embryologists, technicians and gynaecologists), they are numerous to worry about a possible deterioration of embryonic quality, or again about a disrupted order of generation. Finally, it appears that patients do not anticipate the possible fate of their frozen embryos if they are uninscribed from their parental project. CONCLUSIONS: Patients are mainly ambivalent towards embryonic cryopreservation. They prioritize different rationality depending on the situations and issues they are dealing with.

[The complex phenotype of ARC syndrome: A new case]. / Le phénotype complexe du syndrome ARC : une nouvelle observation.

ARC syndrome (arthrogryposis - renal dysfunction - cholestasis) is a rare lethal multisystemic autosomal recessive disease. A newborn of consanguineous parents of Algerian descent presented cholestatic jaundice, dehydration, and Fanconi syndrome at 10 days of life. The blood smear showed a very characteristic gray appearance of platelets. A homozygous mutation was evidenced in the VPS33B gene. This gene codes for a protein involved in trafficking of intracellular vesicles. The mutation (c.604-2A>G) present in the heterozygous state in the parents affects an invariant base of the splice acceptor site and to our knowledge has not been reported yet. This child died at the age of 3 months. Prenatal diagnosis was offered to the family; another pregnancy was carried to completion and a girl was born without the disease. The combination of cholestasis and proximal tubulopathy should suggest the diagnosis in a newborn with orthopedic problems. A blood smear greatly facilitates diagnosis.

The rise and fall of mutator bacteria.

Bacteria with elevated mutation rates are frequently found among natural isolates. This is probably because of their ability to generate genetic variability, the substrate for natural selection. However, such high mutation rates can lead to the loss of vital functions. The evolution of bacterial populations may happen through alternating periods of high and low mutation rates. The cost and benefits of high mutation rates in the course of bacterial adaptive evolution are reviewed.

Aggressive fibromatosis--impact of prognostic variables on management.

OBJECTIVE: To determine the impact of prognostic variables on local control in patients with aggressive fibromatosis treated with or without radiation. MATERIALS AND METHODS: Forty-two patients presenting to the combined sarcoma clinic at Johannesburg Hospital with aggressive fibromatosis from 1990 to 2003 were analysed retrospectively. There were 14 males and 28 females. The lesions involved the head and neck in 6 cases (14%), the thorax in 6 (14%), the extremities in 19 (45%) and the abdomen in 11 (26%). Thirty-seven patients (88%) presented to the clinic for the first time, whereas 5 (12%) had recurrent disease at presentation. Fifteen patients (36%) underwent excision only, 15 (36%) had excision followed by postoperative radiation, 8 (19%) had biopsy only, and 4 (9%) had radiation only. The median dose of radiation was 60 Gy (range 9 - 70 Gy). RESULTS: One patient had local failure following excision and postoperative radiation therapy. The local control was 100% for surgery alone and 86% for surgery followed by postoperative radiation at > or = 24 months. On univariate analysis, age, sex, positive margins, primary or recurrent presentation, site of involvement and initial treatment did not affect local control significantly. Eight of 19 patients (42%) receiving radiation developed severe moist desquamation following treatment, and all these patients had doses of 60 Gy or more. CONCLUSION: Surgery with or without radiation therapy gave excellent local control. The addition of radiation therapy to surgery as well as other known prognostic parameters did not impact on local control. The morbidity of radiation treatment is considerable, as noted in this series, and adjuvant radiation therapy should therefore be considered only in situations where the risk of recurrence and the morbidity of re-excision are high.

Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease.

BACKGROUND AND PURPOSE: We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor-2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of ovalbumin (OVA)-induced chronic AAD in 6­8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL(−1)), TFF2 (0.5 mg·mL(−1)), DEX (0.5 mg·mL(−1)), RLX + TFF2 or RLX + TFF2 + DEX from days 67­74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA). KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50­90%) and also normalized the reduction of cDyn. CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti-inflammatory corticosteroids

The pregnant ovine endometrium constitutively expresses and secretes a highly stable bombesin-like peptide, which shares C-terminal sequence but differs structurally from gastrin-releasing peptide.

Previous studies have shown that a peptide closely related to gastrin releasing peptide (GRP) is expressed by the pregnant ovine endometrium throughout gestation, however its molecular form and the mode of its secretion have not been defined. We have partially purified the endometrial GRP-like peptide and characterised it chromatographically. In contrast to other tissues, the main molecular form of endometrial GRP is larger (6-8 kDa versus 1-3 kDa), and based on the increased hydrophobicity of its circulating form after reduction, contains at least one disulfide bond. Reduction and treatment with chaotropic agents showed that the protein is not a cleavage product of pro-GRP bound to a binding protein. Tryptic cleavage demonstrated that the C-terminus of the peptide is closely related to GRP18-27 suggesting that bioactivity is likely. The partially purified peptide remained intact after incubation in ovine plasma for 16 h indicating that it is extremely stable and consistent with an hormonal role during pregnancy. Quantification of peptide from monolayer cultures of ovine endometrial cells showed that the GRP-like peptide was secreted constitutively. These data show that a stable, GRP-like peptide, distinct from the known processing products of pre-pro-GRP is constitutively expressed by the gravid ovine endometrium. Since endometrial GRP has an intact bioactive C-terminus and is mitogenic for numerous tissues including the uterus, then it is likely to play an important regulatory role in ovine pregnancy.

The role of capsulin in the morphogenesis and differentiation of fetal rat gastric mucosa.

The signals that guide the morphogenesis and differentiation of rat fetal gastric mucosa remain largely unknown. We have investigated the role of capsulin in pit/gland formation and epithelial cell differentiation in cultured stomach tissue. Embryonic day 16.5 (E 16.5) stomach tissue cultured for three days in the presence of 1 microM hydrocortisone underwent dramatic transformation, from undifferentiated, stratified cells to differentiated epithelia composed of polarised columnar cells with mucous cells and pit/glands. In the presence of capsulin antisense oligonucleotides directed against capsulin mRNA, tissues do not undergo further development. Significantly, both mucous granules and pit/gland formation were inhibited compared to capsulin sense/scrambled oligonucleotide treated controls. However, in tissues treated with specific anti-rat HGF-antiserum to neutralise secreted HGF, pit/gland formation was inhibited, but the number of mucous granules remained unchanged compared to controls treated with non-specific antiserum (mouse monoclonal cytokeratin 8 antiserum). This data suggests that capsulin may have a role in the morphogenesis of pit/glands and mucin granule formation in the developing rat gastric mucosa. We discuss the possibility that this role of capsulin may be partly mediated through the actions of HGF.

Trefoil peptides are early markers of gastrointestinal maturation in the rat.

Trefoil peptides are members of a unique family of proteins found predominately throughout the gastrointestinal tract, whose proposed functions include mucus stabilization, stimulation and/or differentiation of epithelial cells during wound repair. Recent trefoil knockout studies have reported delays in epithelial cell migration or maturation pathways together with almost a complete lack of mucus. In order to fully explore the role of trefoil peptides in gastrointestinal maturation, these studies were undertaken to accurately characterize the expression of trefoil peptides in the developing rat gut. The results of RPA suggest that trefoil mRNA's are expressed as early as 15 days post coitus (dpc) in the intestine and stomach. Proteins are detected at 17 dpc by radioimmunoassay and immunohistochemical studies, which localize trefoil peptide expression to the lumenal surface of epithelial cells. At 17 dpc the gut is lined by pseudo-stratified, undifferentiated epithelial cells. Polarized, columnar cells are not detected until at least 18 dpc, with sparse mucus staining and parietal cell markers not being detected until 18 and 19 dpc respectively. This data demonstrates that trefoil peptides are early markers of epithelial cell maturation in the developing rat gut. The time course of their expression, well before the mucus cell type is specified, suggests a potential role in epithelial cell differentiation.

Shb deficiency in endothelium but not in leucocytes is responsible for impaired vascular performance during hindlimb ischaemia.

AIM: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischaemia. This study was conducted in order to assess the contribution of Shb deficiency in myeloid cells to impaired vascular function in ischaemia. METHODS: Wild type and Shb-deficient mice were subjected to peritoneal vascular endothelial growth factor A (VEGFA) followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leucocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. RESULTS: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not lipopolysaccharide (LPS) in the absence of Shb. Furthermore, the macrophage population in ischaemic muscle was unaffected by Shb deficiency after 2 days but reduced 7 days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leucocyte genotype. CONCLUSION: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.