Portal vein embolization before right hepatectomy: prospective clinical trial.

OBJECTIVE: To assess the impact of liver hypertrophy of the future liver remnant volume (FLR) induced by preoperative portal vein embolization (PVE) on the immediate postoperative complications after a standardized major liver resection. SUMMARY BACKGROUND DATA: PVE is usually indicated when FLR is estimated to be too small for major liver resection. However, few data exist regarding the exact quantification of sufficient minimal functional hepatic volume required to avoid postoperative complications in both patients with or without chronic liver disease. METHODS: All consecutive patients in whom an elective right hepatectomy was feasible and who fulfilled the inclusion and exclusion criteria between 1998 and 2000 were assigned to have alternatively either immediate surgery or surgery after PVE. Among 55 patients (25 liver metastases, 2 cholangiocarcinoma, and 28 hepatocellular carcinoma), 28 underwent right hepatectomy after PVE and 27 underwent immediate surgery. Twenty-eight patients had chronic liver disease. FLR and estimated rate of functional future liver remnant (%FFLR) volumes were assessed by computed tomography. RESULTS: The mean increase of FLR and %FFLR 4 to 8 weeks after PVE were respectively 44 +/- 19% and 16 +/- 7% for patients with normal liver and 35 +/- 28% and 9 +/- 3% for those with chronic liver disease. All patients with normal liver and 86% with chronic liver disease experienced hypertrophy after PVE. The postoperative course of patients with normal liver who underwent PVE before right hepatectomy was similar to those with immediate surgery. In contrast, PVE in patients with chronic liver disease significantly decreased the incidence of postoperative complications as well as the intensive care unit stay and total hospital stay after right hepatectomy. CONCLUSIONS: Before elective right hepatectomy, the hypertrophy of FLR induced by PVE had no beneficial effect on the postoperative course in patients with normal liver. In contrast, in patients with chronic liver disease, the hypertrophy of the FLR induced by PVE decreased significantly the rate of postoperative complications.

Prévalence de la dénutrition chez 143 adultes en bilan prétransplantation hépatique. Experience lausannoise de 1997 a 2005 [Prevalence of undernutrition in 143 patients before liver transplantation. The Lausanne experience between 1997 and 2005]

The prevalence of undernutrition was prospectively studied in 143 patients before liver transplantation between 1997 and 2005. Nutritional assessment is a particularly tricky problem in cirrhosis and mid-arm muscle circumference is considered as the best reliable anthropometric tool. In this prospective study, prevalence rate is very high (61%) and undernutrition is more frequent in alcoholic cirrhotic patients. In conclusion, these patients should benefit from an early dietician intervention before liver transplantation.

IFN stimulated gene expression in the liver is a better predictor of treatment response in chronic hepatitis c than the IL28b (IFN lambda 3) genotype

Background: Therapy of chronic hepatitis C (CHC) with pegIFNa/ribavirin achieves sustained virologic response (SVR) in ~55%. Pre-activation of the endogenous interferon system in the liver is associated non-response (NR). Recently, genome-wide association studies described associations of allelic variants near the IL28B (IFNλ3) gene with treatment response and with spontaneous clearance of the virus. We investigated if the IL28B genotype determines the constitutive expression of IFN stimulated genes (ISGs) in the liver of patients with CHC. Methods: We genotyped 93 patients with CHC for 3 IL28B single nucleotide polymorphisms (SNPs, rs12979860, rs8099917, rs12980275), extracted RNA from their liver biopsies and quantified the expression of IL28B and of 8 previously identified classifier genes which discriminate between SVR and NR (IFI44L, RSAD2, ISG15, IFI22, LAMP3, OAS3, LGALS3BP and HTATIP2). Decision tree ensembles in the form of a random forest classifier were used to calculate the relative predictive power of these different variables in a multivariate analysis. Results: The minor IL28B allele (bad risk for treatment response) was significantly associated with increased expression of ISGs, and, unexpectedly, with decreased expression of IL28B. Stratification of the patients into SVR and NR revealed that ISG expression was conditionally independent from the IL28B genotype, i.e. there was an increased expression of ISGs in NR compared to SVR irrespective of the IL28B genotype. The random forest feature score (RFFS) identified IFI27 (RFFS = 2.93), RSAD2 (1.88) and HTATIP2 (1.50) expression and the HCV genotype (1.62) as the strongest predictors of treatment response. ROC curves of the IL28B SNPs showed an AUC of 0.66 with an error rate (ERR) of 0.38. A classifier with the 3 best classifying genes showed an excellent test performance with an AUC of 0.94 and ERR of 0.15. The addition of IL28B genotype information did not improve the predictive power of the 3-gene classifier. Conclusions: IL28B genotype and hepatic ISG expression are conditionally independent predictors of treatment response in CHC. There is no direct link between altered IFNλ3 expression and pre-activation of the endogenous system in the liver. Hepatic ISG expression is by far the better predictor for treatment response than IL28B genotype.

Atrial natriuretic peptides: reproducibility of renal effects and response of liver blood flow.

To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 microgram/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 microgram/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p less than 0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.

HCV infection after liver transplantation is associated with lower levels of alloreactive CD4+CD25+CD45RO+IL-7R+high+ T cells

Aim: Expression of IL-7R discriminates alloreactive CD4 T cells (Foxp3 negative), from IL-7Rlow regulatory CD4 T cells (Foxp3 positive). Chronic hepatitis C virus infection (HCV) reduces expression of IL-7R on T cells thus promoting persistence of infection. The aim of this study was to analyze the effect of HCV infection on the expression of IL-7R of activated CD4+ T cells in liver transplant patients. Patients and methods: We analyzed PBMC from liver transplant recipients for the expression of CD4, CD25, FoxP3, IL-7R (24 HCV negative and 29 HCV-chronically infected). We compared these data with non-transplanted individuals (52 HCV-chronically infected patients and 38 healthy donors). Results: In HCV-infected liver transplant recipients, levels of CD4+CD25+CD45RO+IL-7R+ T cells were significantly reduced (10.5+/-0.9%) when compared to non-HCV-infected liver transplant recipients (17.6+/-1.4%) (P<0.001), while both groups (HCV-infected and negative transplant recipients) had significantly higher levels than healthy individuals (6.6+/-0.9%) (P<0.0001). After successful antiviral therapy (sustained antiviral response), 6 HCV-infected transplant recipients showed an increase of CD4+CD25+CD45RO+IL-7R+ T cells, reaching levels similar to that of non-HCVinfected recipients (10.73+/-2.63% prior therapy versus 21.7+/-6.3% after clearance of HCV). (P<0.05) In 4 non-responders (i.e. HCVRNA remaining present in serum), levels of CD4+CD25+CD45RO+IL-7R+ T cells remained unmodified during and after antiviral treatment (11.8+/- 3.3% versus 11.3+/-3.3% respectively). Conclusions: Overall, these data indicate that CD4+CD25+CD45RO+IL-7R+ T cells appear to be modulated by chronic HCV infection after liver transplantation. Whether lower levels of alloreactive T cells in HCV-infected liver transplant recipients are associated with a tolerogenic profile remains to be studied.

An alteration in the levels of populations of CD4+ Treg is in part responsible for altered cytokine production by cells of aged mice which follows injection with a fetal liver extract.

We have shown previously that a fetal sheep liver extract (FSLE) containing significant quantities of fetal ovine gamma globin chain (Hbgamma) and LPS injected into aged (>20 months) mice could reverse the altered polarization (increased IL-4 and IL-10 with decreased IL-2 and IFNgamma) in cytokine production seen from ConA stimulated lymphoid cells of those mice. The mechanism(s) behind this change in cytokine production were not previously investigated. We report below that aged mice show a >60% decline in numbers and suppressive function of both CD4(+)CD25(+)Foxp3(+) Treg and so-called Tr3 (CD4(+)TGFbeta(+)), and that their number/function is restored to levels seen in control (8-week-old) mice by FSLE. In addition, on a per cell basis, CD4(+)CD25(-)Treg from aged mice were >4-fold more effective in suppression of proliferation and IL-2 production from ConA-activated lymphoid cells of a pool of CD4(+)CD25(-)T cells from 8-week-old mice than similar cells from young animals, and this suppression by CD25(-)T cells was also ameliorated following FSLE treatment. Infusion of anti-TGFbeta and anti-IL-10 antibodies in vivo altered Treg development following FSLE treatment, and attenuated FSLE-induced alterations in cytokine production profiles.

Endoscopic mucosal resection in the esophagus with a new rigide device : an animal study

Résumé: Introduction : L'utilisation de méthodes endoscopiques peu invasives est en constante augmentation pour le traitement des lésions tumorales précoces de l'oesophage. Le but du traitement comprend l'éradication complète de tous les foyers de dysplasie ou de carcinome in situ, notamment dans les métaplasies intestinales de l'oesophage de Barrett, qui peuvent dégénérer en adénocarcinome. Plusieurs techniques d'ablation de la muqueuse oesophagienne (laser, argon plasma, electrocoagulation, photothérapie dynamique, résection endoscopique) ont été utilisées jusqu'à présent, mais aucune n'a vraiment donné entière satisfaction. Les techniques actuelles de résections endoscopiques par fibroscopie sont entre autres limitées par le grand nombre de séances nécessaires à l'éradication complète de la lésion et par la petite taille des fragments de muqueuse obtenus, ce qui rend l'analyse histologique difficile. Dans notre étude animale, nous avons évalué la faisabilité, l'efficacité et la sécurité d'une méthode de résection endoscopique à l'aide d'un nouvel oesophagoscope rigide. Matériel et méthode : Le résectoscope est formé d'un oesophagoscope rigide avec une fenêtre distale transparente à travers laquelle la muqueuse et une partie de la sous-muqueuse sont aspirées et ensuite réséquées avec une anse thermique. Les diverses fenêtres utilisées ont une taille comprise entre 2.2 et 4.4 cm. Le mouton a été choisi en raison de la ressemblance de son oesophage avec celui de l'humain en ce qui concerne l'épaisseur de son oesophage et sa structure histologique. Nous avons effectué 55 résections hémi-circonférentielles sur 21 animaux et 11 résections circonférentielles sur 11 autres. La Mitomycine-C, une substance qui inhibe la prolifération fibroblastique, a été utilisée dans 8 résections circonférentielles à différents intervalles de temps afin d'empêcher la survenue de sténoses oesophagiennes. Résultats : Toutes les résections hémi-circonférentielles ont permis d'obtenir des fragments compacts de tissu avec des bords nets, ce qui permet une excellente étude histologique. La surface du tissu prélevé était en corrélation avec la taille de la fenêtre du resectoscope. Nous avons ainsi pu obtenir des fragments avec des dimensions comprises entre 6 et 12 cm2. Pour les résections circonférentielles, les tissus étaient obtenus en 2 parties, en inversant de 180° la position de l'appareil. La profondeur de la résection a été optimale dans 58 cas sur 65 avec une découpe précise au niveau de la sous-muqueuse sans lésion de la couche musculaire sous- jacente. Il n'y a pas eu de complications après les résections hémi-circonférentielles. Les complications engendrées par les résections circonférentielles (sténose, perforation) n'ont plus été rencontrées après application locale de Mitomycine-C administrée à des intervalles de temps bien précis. Conclusion : Notre méthode de résection endoscopique de la muqueuse oesophagienne offre une nouvelle approche très prometteuse par rapport aux options déjà disponibles. Elle apparaît supérieure en ce qui concerne la taille de tissu prélevé, la précision et régularité de la profondeur de résection, ainsi que la facilité et sûreté du diagnostic histologique et des marges de sécurité. Les résections hémi-circonférentielles se sont révélées sûres chez le modèle animal. Cette nouvelle technique mérite de plus amples investigations pour les résections circonférentielles avant son utilisation chez l'humain. Abstract: Background and Study Aims: We undertook this retrospective study to evaluate the frequency and prognosis of endoscopic treatment of laterally spreading tumors (LSTs) in the rectum. The recurrence rate for lesions of the lower rectum was compared with that of the upper rectum. Patients and Methods: During the period from July 1989 to June 2002, a total of 1237 rectal tumors were detected. LSTs accounted for 6.9% (85/1237) of all rectal tumors. A total of 224 tumors of the lower rectum were detected among the 1237 rectal tumors. LSTs accounted for 16.1 % (36/224) of all the lower rectal tumors. From 85 LST lesions, 67 were evaluated for their prognosis after endoscopic mucosal resection (EMR). Patients whose LSTs had been resected were followed up by endoscopy at the following frequencies: once 15 (22.4%); twice (more than 1 year), 20 (29.9%); three times (more than 3 years), 21(31.3%); and four times or more (more than 5 years), 11 (16.4%). Results: A total of 67 patients with endoscopically treated LSTs were followed up by endoscopy. We observed recurrences in two lesions of the upper rectum (2/38, 5.3%) and five lesions of the lower rectum (5/29, 17.2%) (P = 0.2364); all seven lesions were resected piecemeal. LSTs whose horizontal margin reached the pectinate line frequently recurred in the lower rectum, at a rate of 80% (4/5). However, all patients were completely cured by additional endoscopic resections, the greatest number of treatments being four. Conclusion: For early detection of recurrence and successful endoscopic cure, further colonoscopic examination within a few months after the first treatment is necessary.

Ex vivo ultrasound control of resection margins during partial nephrectomy.

Purpose: Surgery remains the treatment of choice for localized renal neoplasms. While radical nephrectomy was long considered the gold standard, partial nephrectomy has equivalent oncological results for small tumors. The role of negative surgical margins continues to be debated. Intraoperative frozen section analysis is expensive and time-consuming. We assessed the feasibility of intraoperative ex vivo ultrasound of resection margins in patients undergoing partial nephrectomy and its correlation with margin status on definitive pathological evaluation.Materials and Methods: A study was done at 2 institutions from February 2008 to March 2011. Patients undergoing partial nephrectomy for T1-T2 renal tumors were included in analysis. Partial nephrectomy was done by a standardized minimal healthy tissue margin technique. After resection the specimen was kept in saline and tumor margin status was immediately determined by ex vivo ultrasound. Sequential images were obtained to evaluate the whole tumor pseudocapsule. Results were compared with margin status on definitive pathological evaluation.Results: A total of 19 men and 14 women with a mean +/- SD age of 62 +/- 11 years were included in analysis. Intraoperative ex vivo ultrasound revealed negative surgical margins in 30 cases and positive margins in 2 while it could not be done in 1. Final pathological results revealed negative margins in all except 1 case. Ultrasound sensitivity and specificity were 100% and 97%, respectively. Median ultrasound duration was 1 minute. Mean tumor and margin size was 3.6 +/- 2.2 cm and 1.5 +/- 0.7 mm, respectively.Conclusions: Intraoperative ex vivo ultrasound of resection margins in patients undergoing partial nephrectomy is feasible and efficient. Large sample studies are needed to confirm its promising accuracy to determine margin status.

Alveolar echinococcosis of the liver: Diffusion-weighted MRI findings and potential role in lesion characterisation

PURPOSE: To report the diffusion-weighted MRI findings in alveolar echinococcosis (AE) of the liver and evaluate the potential role of apparent diffusion coefficients (ADCs) in the characterisation of lesions. MATERIALS AND METHODS: We retrospectively included 22 patients with 63 AE liver lesions (≥1cm), examined with 3-T liver MRI, including a free-breathing diffusion-weighted single-shot echo-planar imaging sequence (b-values=50, 300 and 600s/mm(2)). Two radiologists jointly assessed the following lesion features: size, location, presence of cystic and/or solid components (according to Kodama's classification system), relative contrast enhancement, and calcifications (on CT). The ADCtotal, ADCmin and ADCmax were measured in each lesion and the surrounding liver parenchyma. RESULTS: Three type 1, 19 type 2, 17 type 3, three type 4 and 21 type 5 lesions were identified. The mean (±SD) ADCtotal, ADCmin and ADCmax for all lesions were 1.73±0.50, 0.76±0.38 and 2.63±0.76×10(-3)mm(2)/s, respectively. The mean ADCtotal for type 1, type 2, type 3, type 4 and type 5 lesions were 1.97±1.01, 1.76±0.53, 1.73±0.41, 1.15±0.42 and 1.76±0.44×10(-3)mm(2)/s, respectively. No significant differences were found between the five lesion types, except for type 4 (p=0.0363). There was a significant correlation between the presence of a solid component and low ADCmin (r=0.39, p=0.0016), whereas an inverse correlation was found between the relative contrast enhancement and ADCtotal (r=-0.34, p=0.0072). CONCLUSION: The ADCs of AE lesions are relatively low compared to other cystic liver lesions, which may help in the differential diagnosis. Although ADCs are of little use to distinguish between the five lesion types, their low value reflects the underlying solid component.

Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection.

Polymorphisms in IL28B were shown to affect clearance of hepatitis C virus (HCV) infection in genome-wide association (GWA) studies. Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We performed a 2-stage GWA study of liver fibrosis progression related to HCV infection. We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment. We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a filtered primary cohort of 1161 patients using 780,650 single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10(-5) from an independent replication cohort of 962 patients. We then assessed the most interesting replicated SNPs using DNA samples collected from 219 patients who participated in separate GWA studies of HCV clearance. In the combined cohort of 2342 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P(combined) = 8.9 × 10(-9) and 1.1 × 10(-9), respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. The SNP rs4374383, together with another replicated SNP, rs9380516 (P(combined) = 5.4 × 10(-7)), were linked to the functionally related genes MERTK and TULP1, which encode factors involved in phagocytosis of apoptotic cells by macrophages. Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.

Successful surgical resection in non-lesional operculo-insular epilepsy without intracranial monitoring.

Pre-operative assessment and surgical management of patients with non-lesional extratemporal epilepsy remain challenging due to a lack of precise localisation of the epileptic zone. In most cases, invasive recording with depth or subdural electrodes is required. Here, we describe the case of 6.5-year-old girl who underwent comprehensive non-invasive phase I video-EEG investigation for drug-resistant epilepsy, including electric source and nuclear imaging. Left operculo-insular epilepsy was diagnosed. Post-operatively, she developed aphasia which resolved within one year, corroborating the notion of enhanced language plasticity in children. The patient remained seizure-free for more than three years.

Liver-specific loss of lipin-1-mediated phosphatidic acid phosphatase activity does not mitigate intrahepatic TG accumulation in mice.

Lipin proteins (lipin 1, 2, and 3) regulate glycerolipid homeostasis by acting as phosphatidic acid phosphohydrolase (PAP) enzymes in the TG synthesis pathway and by regulating DNA-bound transcription factors to control gene transcription. Hepatic PAP activity could contribute to hepatic fat accumulation in response to physiological and pathophysiological stimuli. To examine the role of lipin 1 in regulating hepatic lipid metabolism, we generated mice that are deficient in lipin-1-encoded PAP activity in a liver-specific manner (Alb-Lpin1(-/-) mice). This allele of lipin 1 was still able to transcriptionally regulate the expression of its target genes encoding fatty acid oxidation enzymes, and the expression of these genes was not affected in Alb-Lpin1(-/-) mouse liver. Hepatic PAP activity was significantly reduced in mice with liver-specific lipin 1 deficiency. However, hepatocytes from Alb-Lpin1(-/-) mice had normal rates of TG synthesis, and steady-state hepatic TG levels were unaffected under fed and fasted conditions. Furthermore, Alb-Lpin1(-/-) mice were not protected from intrahepatic accumulation of diacylglyerol and TG after chronic feeding of a diet rich in fat and fructose. Collectively, these data demonstrate that marked deficits in hepatic PAP activity do not impair TG synthesis and accumulation under acute or chronic conditions of lipid overload.