Prise en charge du carcinome hépatocettulaire en 2010 [Management of hepatocellular carcinoma]

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide and its incidence has increased over the last years in most developed countries. The majority of HCCs occur in the context of liver cirrhosis. Therefore, patients with cirrhosis and those with hepatitis B virus infection should enter a surveillance program. Detection of a focal liver lesion by ultrasound should be followed by further investigations to confirm the diagnosis and to permit staging. A number of curative and palliative treatment options are available today. The choice of treatment will depend on the tumor stage, liver function and the presence of portal hypertension as well as the general condition of the patient. A multidisciplinary approach is mandatory to offer to each patient the best treatment.

Liver, gastrointestinal and cardiac toxicity in intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting beads: Results from the PRECISION V randomized trial : B-240

Purpose: To evaluate the toxicity focussing on hepatic, gastrointestinal and cardiac parameters following PRECISION TACE with DC Bead? versus conventional transarterial chemoembolization (cTACE) in the treatment of intermediate-stage hepatocellular carcinoma (HCC). Methods and Materials: This prospective, randomized, multicentre study was conducted under best practice trial management and authorized by local institutional review boards. Informed consent was obtained. 212 patients (185 men/27 women; mean: 67 years) were randomized to be treated with DC Beads? or cTACE. The majority of both groups presented in a more advanced stage. Safety was measured by rate of adverse events (South West Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed by means of left ventricular ejection fraction (LVEF) in MRI or echocardiography. The results of the two groups were compared using the chi-square test and Student`s t-test. Results: Mean maximum alanine transaminase increase in the DC Bead group was 50% in the cTACE group (p < 0.001) and 59% for aspartate transaminase (p < 0.001). For bilirubin, mean increase was 5.30±15.13 vs. 13.53±73.89 µmol/L. Concerning gastrointestinal disorders, 120 adverse events (AEs) occurred in 57/93 (61.3%) patients in the DC Bead group vs. 114 in 49/108 (45.4%) in cTACE. Concerning hepatobiliary disorders, serious AEs occurred in 8/93 (8.6%) vs. 11/108 (10.2%) patients. LVEF showed an increase in the DC Bead group by +2.7±10.1 percentage points and a small decrease by -1.5±7.6 in the cTACE group, p=0.018. Conclusion: PRECISION TACE is safe, even in more advanced HCC patients. Serious liver and cardiac toxicity were significantly lower in the DC Bead group.

Disponibilidade biológica do fósforo de diferentes fontes para eqüinos em crescimento

Objetivou-se neste estudo, determinar a disponibilidade biológica do P de diferentes fontes, para eqüinos em fase de crescimento. Utilizaram-se dezesseis eqüinos machos em fase de crescimento, submetidos à aplicação de quatro fontes fosfatadas -- fosfato de rocha de Tapira (TAP), fosfato de rocha de Patos de Minas (PAT), fosfato bicálcico (BIC) e farinha de osso (FOS) --, adicionadas à dieta basal em quantidades suficientes para fornecer 22 g de P/animal/dia. No 16º dia, foram-lhes injetados 30 MBq de 32P/animal, e coletaram-se amostras de sangue, fezes e urina, durante sete dias. Foram determinadas as atividades específicas no plasma, fezes e urina e calculou-se a perda endógena fecal e a absorção real de P. Os valores obtidos quanto ao P consumido, P excretado, P no plasma e P retido não apresentaram diferenças estatísticas (P>0,05). Os valores de absorção real do P do TAP, PAT, BIC e da FOS foram, respectivamente, 25,23%, 33,97%, 31,71% e 29,36%. Não houve diferenças estatísticas (P>0,05) entre as fontes estudadas. Em relação ao BIC, as rochas fosfáticas apresentaram altos valores de disponibilidade biológica.

Old age from antiquity to post modernity

Teksti suomeksi

Lipid-bloated subretinal microglial cells are at the origin of drusen appearance in CX3CR1-deficient mice.

Drusen, the white yellowish deposits that can be seen in funduscopy, are a hallmark of age-related macular degeneration. Histologically, drusen are believed to be dome-shaped or more confluent lipid accumulations between the retinal pigment epithelium and the choriocapillaries. Recent advances in mouse funduscopy have revealed the presence of drusen-like structures in chemokine knockout animals in the absence of sizeable dome-shaped material below the retinal pigment epithelium. We show that aged CX3CR1-/- mice present with drusen-like appearance in funduscopy that is associated with a progressive age-related microglial cell accumulation in the subretinal space. We demonstrate that the anatomical equivalent of the drusen-like appearance in these mice are lipid-bloated subretinal microglial cells rather than subretinal pigment epithelium deposits [Combadière C, et al: J Clin Invest 2007;117:2920-2928].

Use of NSAIDS compared to paracetamol as potential risk factors for asthma

Introduction: Use of paracetamol has been associated with an increased risk of asthma in several epidemiological studies. In contrast, it has been suggested that non-steroidal anti-inflammatory drugs (NSAIDs) might be protective (Kanabar, Clin Ther 2007), but data relating to these drugs are scarce. Methods: Prevalence of asthma and intake of analgesics in the past 2 years were assessed by questionnaire in 2008 in young adults (&#8805;;16 years) diagnosed with cancer between 1976 and 2003 (Swiss Childhood Cancer Survivor Study). In a multivariate logistic regression we analysed the association between asthma and intake of paracetamol only, NSAIDs only or their combination, adjusting for age, sex, cancer diagnosis, cancer therapy and time since diagnosis. Results: Of the 1293 participants (response rate 68%), 83 (6%) reported asthma and 845 (65%) intake of analgesics in the past 2 years. Of these, 257 (29%) took paracetamol only, 224 (25%) NSAIDs only, 312 (35%) a combination of both and 52 (6%) other analgesics. Adjusted Odds ratios for asthma were 2.2 (95% CI 1.0-4.7; p = 0.04), 1.9 (0.9-4.3; p = 0.12) and 2.9 (1.4-6.1; p <0.01) in those using paracetamol only, NSAIDs only or their combination respectively. Conclusion: These cross-sectional data in a selected population do not support a protective effect of NSAIDs against asthma, neither taken alone nor in combination with paracetamol. All analgesics were positively associated with reported asthma episodes in the past two years. This can be explained by reverse causation, with intake of analgesics being a result rather than a cause of asthma events. Randomised controlled trials in unselected populations are needed to clarify the direction of causation.

Evaluation et validation des équations de prédiction du risque de diabète dans la population lausannoise : étude CoLaus

Le diabète de type 2 est une maladie fréquente et en augmentation dans le monde entier. Malheureusement, elle est souvent diagnostiquée à un stade ou des complications sont déjà apparues. Depuis quelques années, des scores ont été développés pour identifier les sujets à risque de développer cette maladie. L'utilisation d'un tel score par le praticien pourrait amener ces patients à des mesures préventives, telles que le changement d'hygiène de vie, ou la prescription d'un traitement médicamenteux. Le but de notre étude est de comparer et de valider différents scores de risques de diabète de type 2 et de déterminer leur capacité à prédire la survenue de cette maladie dans la population de la cohorte CoLaus. Les premiers résultats, en étude transversale, ont tout d'abord montré de grandes différences quant à la population à risque d'un score à l'autre. En effet, le nombre de personnes à traiter varie considérablement selon la méthode utilisée. Ces différents scores ont donc nécessité une validation prospective. Ces résultats ont fait l'objet d'une publication (Schmid et col, Diabetes Care. 2011 Aug;34(8):1863-8). Au moyen des données du suivi à 5 ans, il est sorti qu'un score de risque utilisant des variables biologiques et cliniques, ainsi qu'un score utilisant des variables uniquement cliniques, obtenaient de très bon résultats quant à la prédiction du diabète de type 2. En effet, un des scores testés donne une valeur prédictive positive d'environ 20% à 5 ans, ce qui signifie qu'un patient « détecté » sur 5 pourrait bénéficier d'une intervention précoce. Toutefois, ces résultats concernent la population lausannoise et ne sont donc pas forcément applicables à l'ensemble de la population suisse. De plus, de plus amples études sont nécessaires évaluer l'efficacité d'un tel score dans la prévention du diabète en Suisse. Ces résultats ont fait l'objet d'une seconde publication (Schmid et col, Arch Intern Med. 2012 Jan 23;172(2):188-9). Dans un troisième volet de l'étude, l'impact de marqueurs génétiques a été évalué dans un sous- groupe de la population CoLaus. Les résultats n'ont toutefois montré qu'une très faible amélioration de la prédiction du risque en utilisant ces marqueurs. Ceci devrait nous encourager à intensifier les efforts de prévention sur le style de vie pour toute la population, plutôt qu'une approche ciblée sur les personnes génétiquement prédisposées. Ces résultats ont fait l'objet d'une troisième publication (Schmid et col, J Clin Endocrinol Metab. 2012 Apr 24. [Epub ahead of print]). La même démarche méthodologique a été utilisée pour évaluer l'importance pronostique de plusieurs marqueurs inflammatoires (interleukines 1 et 6, &#932; &#925; F-, protéine C-réactive) hépatiques (GT) ou adipocytaires (leptine et adiponectine) dans la survenue du diabète. Ces résultats sont actuellement soumis au Journal of Clinical Endocrinology and Metabolism).

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC. METHODS: Analysis of the database of the Swiss Hepatitis C Cohort Study, a multicentre study that is being carried out in eight major Swiss hospitals since the year 2000. Patients with chronic hepatitis C and HCC were regrouped and compared to the patients without HCC. RESULTS: Among the 3,390 patients of the cohort, 130 developed an HCC. Age was one of the determining factors. Cirrhosis and its complications ascites and porto-systemic encephalopathy were associated with HCC. Males presented a higher risk for HCC than females. Alcohol consumption was associated with HCC. Diabetes mellitus was an important risk factor, especially in patients with low fibrosis. Patients with Hepatitis C genotype 2 had significantly less HCC than patients with other genotypes. A low socioeconomic status (income, education, profession) was associated with HCC. CONCLUSIONS: Beside the expected characteristics (age, gender, cirrhosis, alcohol), these data stress the role of diabetes mellitus and reveal the importance of low socioeconomic status as a risk factor for HCC in Swiss patients infected with hepatitis C virus. This vulnerable population should be closely monitored.

Plataforma de resolució de problemes RCPSP utilitzant SMT

El problema d'operacions (scheduling) és un procés de presa de decisions quejuga un paper molt important en organitzacions de manufactura i serveis, jaque té una aplicació a la producció, transport i distribució, i a la comunicaciói processament d'informació, entre d'altres. Consisteix en assignar d'unamanera apropiada els recursos disponibles per al processament de tasquesde manera que es puguin optimitzar els objectius de l’organització.Com cas particular de la programació d'operacions, hi ha la programacióde projectes (Project Scheduling), que és el procés de planificar, organitzari controlar activitats i recursos per aconseguir un objectiu concret, generalmentamb limitacions de temps, recursos o costos. Dins aquest grup essituen els problemes de programació de projectes (PSP), que és un nomgenèric que es dóna a tota una classe de problemes en els quals és necessàriala programació de manera òptima el temps, el cost i els recursos dels projectes.La finalitat d'aquest projecte és crear una plataforma RCPSP que puguillegir diferents formats d'entrada (fitxers del tipus :.rcp,.sch,.sm,.data,.pat),pre-processar-los, codificar-los a través de diferents modelitzacions (TaskRD,TimeRD...) per tal de poder-los passar a instàncies SMT i poder executar-losa través de la API de Yices. L'objectiu és trobar el temps d'inici percada activitat de manera que es minimitzi la longitud del makespan senseque es violin les restriccions.Cal dissenyar una aplicació en C++, que sigui escalable i que puguiaconseguir el resultat del problema en el temps més òptim possible

Rosvoromantiikkaa ja rasisminvastaisuutta

Luettua

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C&gt;G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004.

Upward trends in mortality from hepatocellular carcinoma (HCC) were recently reported in the United States and Japan. Comprehensive analyses of most recent data for European countries are not available. Age-standardized (world standard) HCC rates per 100,000 (at all ages, at age 20-44, and age 45-59 years) were computed for 23 European countries over the period 1980-2004 using data from the World Health Organization. Joinpoint regression analysis was used to identify significant changes in trends, and annual percent change were computed. Male overall mortality from HCC increased in Austria, Germany, Switzerland, and other western countries, while it significantly decreased over recent years in countries such as France and Italy, which had large upward trends until the mid-1990s. In the early 2000s, among countries allowing distinction between HCC and other liver cancers, the highest HCC rates in men were in France (6.8/100,000), Italy (6.7), and Switzerland (5.9), whereas the lowest ones were in Norway (1.0), Ireland (0.8), and Sweden (0.7). In women, a slight increase in overall HCC mortality was observed in Spain and Switzerland, while mortality decreased in several other European countries, particularly since the mid-1990s. In the early 2000s, female HCC mortality rates were highest in Italy (1.9/100,000), Switzerland (1.8), and Spain (1.5) and lowest in Greece, Ireland, and Sweden (0.3). In most countries, trends at age 45-59 years were consistent with overall ones, whereas they were more favorable at age 20-44 years in both sexes. CONCLUSION: HCC mortality remains largely variable across Europe. Favorable trends were observed in several European countries mainly over the last decade, particularly in women and in young adults.

Hemodialysis for cefepime intoxication: A case report

Introduction: We report a case of cefepime intoxication with acute severe neurologic symptoms, which was treated by temporary hemodialysis. Patients (or Materials) and Methods: Cefepime 2 g BID for endovascular prosthesis infection was prescribed to a frail, chronically ill 88-year-old woman with a serum creatinine of 199 &#956;mol/L and an estimated creatinine clearance of 13 mL/min (Cockroft formula). Two days later, she was transferred to a neurocritical care unit because of acute aphasia, myoclonic jerks, and delirium with a Glasgow coma scale score of 12/15. The following day, in the absence of other causes, cefepime intoxication was hypothesized, and cefepime was withdrawn after a total of 7 doses = 14 g. Over the next 24 hours, two 3-hour hemodialysis (HD) sessions were performed under cefepime concentration monitoring. Results: Cefepime plasma levels were measured by liquid chromatography/ mass spectrometry. There is no validated reference range, but a study (Chapuis T et al, Critical Care, 2010) found a 50% risk of neurotoxicity with residual levels > 15 mg/L. In our patient, levels were 83.3 mg/L 10 hours after last dose, 24.1 mg/L immediately after the first HD session, 13.4 mg/L immediately before the second HD session, and 2.5 mg/L immediately after the second HD session. The patient made a full clinical recovery over the next 48 hours. The 70% to 80% fall in plasmatic levels observed during each HD session is in accordance with literature data (Schmaldienst S et al, Eur J Clin Pharmacol, 2000, and Manyor LM et al, Pharmacotherapy, 2008). According to kinetic simulation, cefepime dropped at a concentration < 15 mg/L 15 hours earlier with HD than it would have without. Conclusion: Neuropsychiatric adverse effects of beta-lactam antibiotics can be easily overlooked by clinicians. One should be especially cautious with their use in very old and frail patients in whom plasma creatinine poorly estimates renal function and cognitive impairment is highly prevalent. Temporary hemodialysis effectively clears cefepime, but its role in hastening clinical recovery may be limited.

Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction.

Context: Fibroblast growth factor (FGF) 8 is important for GnRH neuronal development with human mutations resulting in Kallmann syndrome. Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown.Objective: The objective of this study was to screen for FGF8 mutations in patients with septo-optic dysplasia (n = 374) or holoprosencephaly (HPE)/midline clefts (n = 47).Methods: FGF8 was analyzed by PCR and direct sequencing. Ethnically matched controls were then screened for mutated alleles (n = 480-686). Localization of Fgf8/FGF8 expression was analyzed by in situ hybridization in developing murine and human embryos. Finally, Fgf8 hypomorphic mice (Fgf8(loxPNeo/-)) were analyzed for the presence of forebrain and hypothalamo-pituitary defects.Results: A homozygous p.R189H mutation was identified in a female patient of consanguineous parentage with semilobar HPE, diabetes insipidus, and TSH and ACTH insufficiency. Second, a heterozygous p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves, and Moebius syndrome. FGF8 was expressed in the ventral diencephalon and anterior commissural plate but not in Rathke's pouch, strongly suggesting early onset hypothalamic and corpus callosal defects in these patients. This was consolidated by significantly reduced vasopressin and oxytocin staining neurons in the hypothalamus of Fgf8 hypomorphic mice compared with controls along with variable hypothalamo-pituitary defects and HPE.Conclusion: We implicate FGF8 in the etiology of recessive HPE and potentially septo-optic dysplasia/Moebius syndrome for the first time to our knowledge. Furthermore, FGF8 is important for the development of the ventral diencephalon, hypothalamus, and pituitary. (J Clin Endocrinol Metab 96: E1709-E1718, 2011)

Charles d'Orléans. Le Livre d'Amis : poésies à la cour de Blois (1440-1465)

Né en 1394, Charles d'Orléans, prince à la fleur de lys, est fait prisonnier à la bataille d'Azincourt (1415). C'est avant tout l'image du poète vêtu de noir, exilé pendant vingt-cinq ans en Angleterre, qui s'est imposée auprès du public. Les ballades, rondeaux, chansons et complaintes écrites après son retour en France témoignent pourtant d'une conception du lyrisme bien moins marquée au sceau de la mélancolie que ne le voudrait notre vision romantique. S'il a été malheureux en politique, Charles d'Orléans a su faire de son château de Blois un centre culturel vivant où se rencontraient amis et écrivains de passage : leurs poésies côtoient celles du prince dans le célèbre manuscrit 25458, en partie autographe, du fonds français de la Bibliothèque Nationale de France. La présente édition/traduction réunit les textes de cette « coterie », avec l'espoir de permettre au lecteur de saisir le fonctionnement spécifique de l'album personnel de Charles d'Orléans, entre 1440 et 1465. Il s'agit d'un véritable Livre d'Amis non pas dominé par un seul je, mais fondé sur le désordre de l'écriture collaborative et de voix multiples qui se répondent à travers un réseau d'images et de thèmes qui donnent au recueil son unité. L'ordre des pièces, tel qu'il se présente dans le manuscrit, a été respecté afin de rendre au mieux l'aspect social et ludique d'une poésie qui naît de la dynamique culturelle et littéraire du cercle de Blois, réuni autour d'un prince et poète qui sait jouer de l'ironie et pratique volontiers le clin d'oeil allusif, réservé à ceux qui savent en goûter la finesse.