[Neuroendocrine neoplasms : a new era to the top of multidisciplinarity !] / Néoplasies neuroendocrines : une nouvelle ère a l'apogée de la multidisciplinarité !

Neuroendocrine neoplasms are histologically defined by a common neuroendocrine cellular phenotype. These are still considered as rare tumours even though their incidence is increasing. Heterogeneity is everywhere whether in the localization of the primitive cancer, the clinical presentation, the histological classification, the prognosis, as well as in therapeutic options, which clearly justifies specialized multidisciplinary care. Heterogeneity and scarcity explain the still fragmented nature of knowledge in this domain. Thanks to an increase in incidence, a desire for standardization of classification as well as the arrival of major therapeutic advances, such as vectorized internal radiotherapy, the future of neuroendocrine neoplasia seems more than promising and exciting. In our daily clinical practice at CHU Liège, we hope to bring our stone to the building by listing as many cases as possible in national and/or international databases, by centralizing therapeutic discussions within specific multidisciplinary concertations and by participating in multicenter study protocols.

Les néoplasies neuroendocrines sont définies histologiquement par un phénotype cellulaire neuroendocrine commun. Ces néoplasies sont toujours considérées comme des tumeurs rares, bien que leur incidence soit en constante augmentation. L'hétérogénéité est omniprésente, que ce soit dans la localisation du cancer primitif, la présentation clinique, la classification histologique, le pronostic ainsi que dans les diverses options thérapeutiques, justifiant impérativement une prise en charge pluridisciplinaire spécialisée. Cette hétérogénéité et cette rareté expliquent que les connaissances soient parcellaires. Grâce à une majoration d'incidence, une volonté d'uniformisation de classification ainsi que l'arrivée d'avancées thérapeutiques majeures, telles que la radiothérapie interne vectorisée, l'avenir des néoplasies neuroendocrines semble plus que prometteur et palpitant. En pratique clinique quotidienne au CHU de Liège, nous espérons apporter notre pierre à l'édifice en recensant un maximum de cas dans des bases de données nationales et/ou internationales, en centralisant les discussions thérapeutiques au sein de concertations multidisciplinaires dédiées et en participant à des protocoles d'études cliniques multicentriques.

A combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol stabilizes hypoxia-inducible factor 1-alpha and improves hair density in female volunteers.

OBJECTIVE: The aim of this study was first to demonstrate that a combination of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol could synergize in vitro on biological pathways associated with hair growth and then to demonstrate the benefit on hair density in a clinical study. METHODS: The effects of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol directly on the hypoxic inducible factor-1α protein (HIF-1α) and related genes expression were demonstrated on keratinocytes in culture in vitro using western-blot analysis and real time quantitative polymerase chain reaction analysis. The effect of resveratrol against oxidative stress induced by hydrogen peroxide treatment was studied in hair follicle and hair matrix cells in vitro using the sensitive probe Dichloro-dihydro-fluorescein diacetate (DCFH-DA). Finally, a randomized clinical study on hair density was conducted on 79 Caucasian female subjects to assess the effect of this combination of actives. RESULTS: Pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol stabilized HIF-1a protein and increased the expression of HIF-1α target genes. Resveratrol significantly reduced the oxygen peroxide-induced oxidative stress generated in hair follicle and hair matrix cells. The clinical study showed that a topical treatment with the combination significantly increased the hair density on women from 1.5 months. CONCLUSION: In addition to the antioxidant properties of resveratrol, the association of pyridine-2, 4-dicarboxylic acid diethyl ester and resveratrol revealed a synergistic effect on the HIF-1α pathway. The results of the clinical study confirmed the importance of such a combination to increase the hair density.

L'alopécie peut affecter 50% des femmes au cours de leur vie ce qui induit une perte de leur estime de soi et une diminution de leur qualité de vie. Au-delà des solutions chirurgicales et des traitements pouvant induire des effets secondaires potentiellement dangereux, il y a un besoin d'améliorer l'efficacité des produits cosmétiques qui permettent de prévenir la chute des cheveux tout en préservant la sécurité des patients. Ainsi, nous avons sélectionné une combinaison de pyridine-2, 4-dicarboxylic acide diethyle ester et de resvératrol pour activer des voies biologiques associées à la croissance du cheveu. Nous avons d'abord montré, in vitro, que la combinaison de pyridine-2, 4-dicarboxylic acide diethyle ester et de resvératrol permet de stabiliser la protéine HIF-1α conduisant ainsi à un effet synergique sur l'expression de gènes clés de la voie HIF-1α. Nous avons aussi démontré, in vitro, que le resvératrol permet de protéger significativement les follicules pileux et les cellules de la matrice du stress oxydatif induit par traitement au peroxide d'hydrogène. En final, une étude clinique randomisée mesurant la densité capillaire a été réalisée sur 79 femmes caucasiennes. Cette étude montre qu'une application topique d'une solution contenant de 5% pyridine-2, 4-dicarboxylic acide diethyle ester et 0.25% de resvératrol augmentent significativement la densité capillaire chez les femmes après 1.5 mois. En conclusion, ces résultats démontrent l'intérêt de stimuler la voie HIF-1α tout en protégeant les cheveux et le scalp du stress oxydatif afin d'améliorer la croissance des cheveux chez les femmes.

Gangliosides in breast cancer: new perspectives.

Gangliosides are essential compounds of the plasma membrane involved in cell adhesion, proliferation, and recognition processes, as well as in the modulation of signal transduction pathways. These functions are mainly supported by the glycan moiety, and changes in the structure of gangliosides occur under pathological conditions including cancers. With progress in mass spectrometric analysis of gangliosides, the role of gangliosides in breast cancer progression was recently demonstrated. In this review, we summarize current knowledge on the biosynthesis of gangliosides and of the role of disialogangliosides in triple-negative breast cancer progression and metastasis. New perspectives in breast cancer therapy targeting gangliosides are also discussed.

Destructuring ionic liquids in ionogels: enhanced fragility for solid devices.

Confining ionic liquids (ILs) with added lithium salt within silica host networks enhances their fragility and improves their conductivity. Overall, conductivity measurements, Raman spectroscopy of the TFSI anion and NMR spectroscopy of the lithium cation show segregative interaction of lithium ions with the SiO2 host matrix. This implies at IL/SiO2 interfaces a breakdown of aggregated regions that are found systematically in bulk ILs. Such destructuration due to the interface effect determines the fragility and thus results locally at the interface in short relaxation times, low viscosity, and good ionic conductivity. The "destructuration" of ion pairs or domains makes ILs within ionogels a competitive alternative to existing solid ionic conductors in all-solid devices, such as lithium batteries and supercapacitors.

Management and control of a carbapenem-resistant Acinetobacter baumannii outbreak in an intensive care unit.

OBJECTIVE: We had for aim to describe the identification and management of a 14-clonal carbapenem-resistant Acinetobacter baumannii (CRAB) outbreak, following admission of a known CRAB-infected patient in an ICU. METHODS: We reviewed the carriers' files and outbreak management procedures. RESULTS: The index patient was admitted with strict isolation precautions. The outbreak started 2 months after his discharge. It persisted despite reinforcement of strict isolation precautions, staff and patient cohorting, and extensive environmental decontamination including 2 rounds of routine terminal cleaning and disinfection or 1 round of cleaning and disinfection followed by hydrogen peroxide treatment. A second epidemic peak, after 4 weeks without any case, led to another wide environmental sampling and decontamination rounds. The source of the CRAB outbreak was suspected to be the blood pressure cuffs Velcro. Switching to cuffs submersible in a disinfectant stopped the outbreak. CONCLUSIONS: CRAB outbreaks are difficult to manage and sources of persistent colonization can be unexpected.

Clostridium difficile colitis acquired in the intensive care unit: outcome and prognostic factors.

PURPOSE: We assessed factors associated with mortality and complicated course in the case of Clostridium difficile infection (CDI) acquired in the intensive care unit (ICU). METHOD: Retrospective cohort study conducted from 1 January 2002 through 1 January 2012. All patients who acquired CDI in our ICU were included. RESULTS: Thirty-one patients were included. Twenty patients (65 %) had mild colitis, 8 (25 %) moderate colitis, and 3 (10 %) severe colitis. Initial antibiotherapy was metronidazole (n = 30, 97 %) and vancomycin (n = 1, 3 %). Seventeen patients (55 %) experienced at least one complication: failure of initial treatment (n = 16, 52 %), shock (n = 11, 34 %), need for surgery (n = 1, 3 %) or renal replacement (n = 4, 13 %), or death (n = 8, 26 %). Risk factors of ICU mortality were history of corticosteroids prescription, prolonged ICU stay, low serum albumin level, and high Sequential Organ Failure Assessment (SOFA) score at the time of CDI diagnosis. Factors associated with a complicated course were high Simplified Acute Physiology Score (SAPS II), high SOFA score, and low serum albumin level at the time of CDI onset. CONCLUSION: Risk factors of poor outcome in patients with CDI acquired in the ICU are different from those in the general population suffering from CDI. The implementation of treatment algorithms taking into account these factors may reduce complication rates in this specific population.

Clinical spectrum and outcome of critically ill patients suffering from prosthetic joint infections.

PURPOSE: To report the clinical characteristics and prognosis of prosthetic joint infections (PJIs) in Intensive care units (ICUs). METHODS: Forty-one patients consecutively admitted to ICUs for PJIs between January 2004 and June 2011 were included in a retrospective case series. RESULTS: A majority of patients (73 %) had severe underlying disease. Acute infection affected 26 patients (63 %). Blood cultures were positive in 16 patients (39 %). Staphylococcus species were the most commonly implicated causative organisms (n = 36, 88 %). The surgical strategy was two-stage replacement in 25 cases (61 %). The surgical procedure leading to ICU admission was mainly prosthesis removal with spacer implantation (n = 13, 32 %). Initial antibiotherapy was a broad-spectrum beta-lactam antibiotic combined with a glycopeptide, linezolid, or daptomycin in 26 cases (63 %). Mortality in the ICU was 20 %. In nonsurvivors, diabetes, acute infection, and American Society of Anesthesiologists (ASA) score >3 were more frequent. The distribution of surgical strategies and procedures was not statistically different in survivors and nonsurvivors. The proportion of patients treated with antibiotherapy adjusted according to previous microbiological findings was higher in nonsurvivors (50 vs. 12 %, p = 0.02). CONCLUSIONS: In our case series of critically ill patients suffering from PJI, factors associated with a poor outcome were diabetes mellitus, ASA score >3, and acute infection. Surgical strategies and surgical procedures had no significant impact on the ICU mortality. Adjustment of initial antibiotherapy according to previous microbiological findings should be made with caution.

[Adult onset Still's disease revealed by a myocarditis]. / Myocardite révélant une maladie de Still de l'adulte.

Adult onset Still's disease is an inflammatory disorder characterized by daily spiking high fevers, arthritis and an evanescent rash. It is a rare disease of unknown aetiology and can be life-threatening. We present a case of adult onset Still's disease associated with myocarditis requiring the use of invasive ventilation, in which the patient responded well to systemic steroids.

Impact of combination therapy with aminoglycosides on the outcome of ICU-acquired bacteraemias.

Pharmacodynamic studies report on the rapid bactericidal activity of aminoglycosides, conferring them as being of theoretical interest for bacteraemia treatment. We assessed this issue in a retrospective study of patients with intensive care unit (ICU)-acquired bacteraemias. To determine the impact of aminoglycosides in antimicrobial combination on the outcome of patients with bacteraemia, we performed a monovariate analysis and a logistic regression analysis comparing patients treated with or without aminoglycosides. Forty-eight bacteraemias in 48 patients were included. Eighteen patients received aminoglycosides. Baseline characteristics as well as adaptation and adequation of antibiotherapy did not differ in patients who did or did not receive aminoglycosides. Patients who received aminoglycosides had longer time alive away from the ICU (11.3 ± 8.9 (10 [0-20]) vs. 3.2 ± 6.6 (0 [0-2] days; p = 0.002) and free from mechanical ventilation (12.5 ± 9.3 (14 [0-21] vs. 5.5 ± 9.2 (0 [0-10] days; p = 0.02) on day 28. The ICU mortality was 16% in the aminoglycoside group versus 46% (p = 0.03). In the multivariate analysis, patients treated with aminoglycosides were 6 times less likely to die than those treated without aminoglycosides (confidence interval [CI] = [1.3-28.9]; p = 0.02). Our study supports the hypothesis that combination short-term antibiotherapy with an aminoglycoside for ICU-acquired bacteraemias could increase survival.

Edelfosine protects precultured heart fragments against the invasion of malignant cells through altered sialylation.

1-O-octadecyl-2-O-methylglycero-3-phosphocholine (ET-18-OMe)-treated precultured heart fragments (PHF) are resistant to the invasion of malignant cells. Previous studies have demonstrated that this effect is due to the alterations of the N-linked glycoproteins in PHF after 48-h ET-18-OMe treatment. Moreover, the observed effect was still present seven days after ET-18-OMe was omitted. The present study reveals that approximately 13.4% of the administered ET-18-OMe was taken up by PHF and about 75% of the initial uptake was still present after ET-18-OMe was removed. In addition, we found significant changes in the sialic acid content and sialyltransferase activities in both conditions. Overall, these results clearly demonstrate that the uptake and retention of ET-18-OMe are responsible for the resistance to the invasion of malignant cells due to the altered sialylation of the cell surface glycoproteins in PHF.

ST6GalNAc I expression in MDA-MB-231 breast cancer cells greatly modifies their O-glycosylation pattern and enhances their tumourigenicity.

Sialyl-Tn is a carbohydrate antigen overexpressed in several epithelial cancers, including breast cancer, and usually associated with poor prognosis. Sialyl-Tn is synthesized by a CMP-Neu5Ac:GalNAcalpha2,6-sialyltransferase: CMP-Neu5Ac: R-GalNAcalpha1-O-Ser/Thr alpha2,6-sialyltransferase (EC 2.4.99.3) (ST6GalNAc I), which transfers a sialic acid residue in alpha2,6-linkage to the GalNAcalpha1-O-Ser/Thr structure. However, established breast cancer cell lines express neither ST6GalNAc I nor sialyl-Tn. We have previously shown that stable transfection of MDA-MB-231, a human breast cancer cell line, with ST6GalNAc I cDNA induces sialyl-Tn antigen (STn) expression. We report here the modifications of the O-glycosylation pattern of a MUC1-related recombinant protein secreted by MDA-MB-231 sialyl-Tn positive cells. We also show that sialyl-Tn expression and concomitant changes in the overall O-glycan profiles induce a decrease of adhesion and an increase of migration of MDA-MB-231. Moreover, STn positive clones exhibit an increased tumour growth in severe combined immunodeficiency (SCID) mice. These observations suggest that modification of the O-glycosylation pattern induced by ST6GalNAc I expression are sufficient to enhance the tumourigenicity of MDA-MB-231 breast cancer cells.

Normal matrix mineralization induced by strontium ranelate in MC3T3-E1 osteogenic cells.

There is growing evidence that strontium ranelate (SR; S12911-2, PROTELOS; Institut de Recherches Internationales Servier, Courbevoie, France), a compound containing 2 atoms of stable strontium (Sr), influences bone cells and bone metabolism in vitro and in vivo. We previously reported that SR increases bone mass in rats and mice by stimulating bone formation and inhibiting bone resorption. We also showed that short-term treatment with SR enhances osteoblastic cell recruitment and function in short-term rat calvaria cultures. Because Sr incorporates into the bone matrix, it was of interest to determine whether SR may affect matrix mineralization in long-term culture. To this goal, osteogenic mouse calvaria-derived MC3T3-E1 osteoblastic cells were cultured for up to 14 days in the presence of ascorbic acid and phosphate to induce matrix formation and mineralization. Matrix formation was determined by incorporation of tritiated proline during collagen synthesis. Matrix mineralization was quantified by measuring the number and surface of mineralized nodules using a digital image analyzer. In this model, 1,25(OH)2 vitamin D (1 nmol/L) used as internal control, increased alkaline phosphatase (ALP) activity, an early osteoblast marker, on days 4, 10, and 14 of culture. Treatment with SR (1 mmol/L Sr(2+)) increased ALP activity at days 4 and 14 of culture. SR also increased collagen synthesis at days 4 and 10 of culture. In contrast, 1,25(OH)2 vitamin D (1 nmol/L) inhibited collagen synthesis at 4 to 14 days of culture. Long-term treatment with SR (0.1 to 1 mmol/L Sr(2+)) dose dependently increased Sr concentration into the calcified nodules, but did not alter matrix mineralization in long-term culture, as shown by the ratio of the surface of mineralized nodules to the number of mineralized nodules on day 14 of culture. These results show that long-term treatment with SR increases collagenous matrix formation by MC3T3-E1 osteoblasts without inducing deleterious effect on matrix mineralization.

Prognostic value of tumoral sialyltransferase expression and circulating E-selectin concentrations in node-negative breast cancer patients.

AIMS AND BACKGROUND: A crucial step in the metastatic process is the interaction between the endothelial molecule E-selectin and its tumoral ligands sialyl-Lewis- and sialyl-Lewis. Sialyltranferases are involved in the biosynthesis of these ligands. The aim of this study was to assess the prognostic value of tumoral sialyltransferase expression and of circulating soluble E-selectin (sE-selectin) in node-negative breast cancer patients. METHODS: Using a multiplex RT-PCR method, we measured the expression of five sialyltransferases (ST3Gal III, ST6Gal I, ST3Gal IV, ST3Gal I and ST3Gal II) in tumors of 135 surgically treated node-negative breast cancer patients. Circulating sE-selectin concentrations were measured by an ELISA method prior to surgery. We also analyzed tumor size, histoprognostic grading and steroid hormone receptor status. RESULTS: The median follow-up was 7.5 years. Expression of estrogen receptors was associated with a good prognosis for relapse-free survival in univariate analysis. A high ST3Gal III/ST6Gal I ratio and a high sE-selectin concentration were associated with a bad prognosis for relapse-free survival and overall survival in univariate and multivariate analysis. CONCLUSION: In the present study, tumoral sialyltransferase expression and circulating sE-selectin concentrations had prognostic value in patients with node-negative breast cancer. This result provides further evidence for the important role of these agents in the metastatic process.

[Damage control laparotomy for haemorragic abdominal trauma. A retrospective multicentric study about 109 cases]. / La laparotomie écourtée dans les traumatismes abdominaux hémorragiques. Etude multicentrique rétrospective sur 109 cas.

AIM OF THE STUDY: Damage control laparotomy is a new approach to the more severe abdominal traumas. It stems from a better understanding of the physiopathology of the haemorragic shock. PATIENTS AND METHODS: A national retrospective study from 27 centers about 109 trauma patients who underwent a damage control procedure between January 1990 and December 2001, is analysed. Surgical procedures included 97 hepatic packing, 10 abdominal packing, 4 exclusive skin closure, 1 open laparotomy technique and 3 digestive stapplings. RESULTS: The mortality rate is 42%. Eleven abdominal compartment syndromes have occurred with 7 decompressive laparomy (4 deaths). CONCLUSION: This study is based on the largest series of damage control laparotomy published in France. Results in terms of mortality and morbidity are similar to those of published studies from the USA.

Involvement of glycosylation in the intracellular trafficking of glycoproteins in polarized epithelial cells.

The surface of epithelial cells is composed of apical and basolateral domains with distinct structure and function. This polarity is maintained by specific sorting mechanisms occurring in the Trans-Golgi Network. Peptidic signals are responsible for the trafficking via clathrin-coated vesicles by means of an interaction with an adaptor complex (AP). The basolateral targeting is mediated by AP-1B, which is specifically expressed in epithelial cells. In contrast, the apical targeting is proposed to occur via apical raft carriers. It is thought that apically targeted glycoproteins contain glycan signals that would be responsible for their association with rafts and for apical targeting. However, the difficulty in terms of acting specifically on a single step of glycosylation did not allow one to identify such a specific signal. The complete inhibition of the processing of N-glycans by tunicamycin often results in an intracellular accumulation of unfolded proteins in the Golgi. Similarly, inhibition of O-glycosylation can be obtained by competitive substrates which gave a complex pattern of inhibition. Therefore, it is still unknown if glycosylation acts in an indirect manner, i.e. by modifying the folding of the protein, or in a specific manner, such as an association with specific lectins.