Good outcome of liver transplantation in patients with pre-existing renal cell carcinoma.

The presence of a pre-existing or recent extra-hepatic solid tumor was considered for a long time as an absolute contraindication to liver transplantation, by fear of futility with an unacceptable increase in non-liver-related mortality. However, cancer-related mortality in solid malignancies is heterogeneous, and experts suggest that case-by-case multidisciplinary decisions should be made. Here, we report the cases of 3 patients with favorable oncological and liver outcome in patients with renal cell carcinoma detected during pre-transplant evaluation that nonetheless underwent liver transplantation.

[Telomeropathies: A study of 15 cases]. / Téloméropathies de recrutement hématologique : étude de 15 cas.

INTRODUCTION: Telomeres are composed of a repeated sequence of double-stranded nucleotides TTAGGG and numerous proteins including the Shelterin complex. Their main role is to maintain the stability of the genome during cell replication through a mechanism of copying the repeted sequence by the telomerase complexe. All the diseases involving a deregulation of this complex are now grouped together under the term telomeropathies. They are difficult to diagnose and manage. Our objective was to describe the clinico-biological characteristics and treatments used, in patients affected by telomeropathies previously seen by an hematologist followed at the Lille University Hospital Center. METHODS: This is a retrospective, single-center study carried out within the department of internal medicine-clinical immunology, Reference center for rare autoimmune and systemic diseases at Lille University Hospital Center between 2005 and 2020 including all patients followed for telomeropathy. RESULTS: Probands and relatives were included. Fifteen patients were studied from 10 independant families. Sixty percent had an heterozygous TERC gene mutation. Sixty seven percent had haematological diseases including macrocytosis, anemia and/or thrombocytopenia, 20 % had a fibrotic hepatic disease, 27 % had a fibrotic pulmonary disease. Lymphocyte immunophenotyping showed a double negative T lymphocyte population with γδ TCR expression in 5 (33 %) patients. Forty-seven percent of the patients had not received any treatment. Twenty-seven percent were on androgen therapy. Twenty percent had received cyclosporine and 13 % anti-lymphocyte serum in the context of initial misdiagnosis. CONCLUSION: It is important to be aware of the complexity of telomeropathies, a differential diagnosis of immune aplastic anemia, in order to optimize management and avoid inappropriate treatments. Allografting of hematopoietic stem cells is the only potentially curative treatment. Our analysis found particularities in immunophenotyping lymphocyte not previously described to our knowledge, whose physiopathological imputability remains to be demonstrated.

The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

Management of liver failure in general intensive care unit.

OBJECTIVE: To produce French guidelines on Management of Liver failure in general Intensive Care Unit (ICU). DESIGN: A consensus committee of 23 experts from the French Society of Anesthesiology and Critical Care Medicine (Société française d'anesthésie et de réanimation, SFAR) and the French Association for the Study of the Liver (Association française pour l'étude du foie, AFEF) was convened. A formal conflict-of-interest (COI) policy was developed at the start of the process and enforced throughout. The entire guideline process was conducted independently of any industrial funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide their assessment of the quality of evidence. The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasised. Some recommendations were ungraded. METHODS: Two fields were defined: acute liver failure (ALF) and cirrhotic patients in general ICU. The panel focused on three questions with respect to ALF: (1) Which etiological examinations should be performed to reduce morbidity and mortality? (2) Which specific treatments should be initiated rapidly to reduce morbidity and mortality? (3) Which symptomatic treatment should be initiated rapidly to reduce morbidity and mortality? Seven questions concerning cirrhotic patients were addressed: (1) Which criteria should be used to guide ICU admission of cirrhotic patients in order to improve their prognosis? (2) Which specific management of kidney injury should be implemented to reduce morbidity and mortality in cirrhotic ICU patients? (3) Which specific measures to manage sepsis in order to reduce morbidity and mortality in cirrhotic ICU patients? (4) In which circumstances, human serum albumin should be administered to reduce morbidity and mortality in cirrhotic ICU patients? (5) How should digestive haemorrhage be treated in order to reduce morbidity and mortality in cirrhotic ICU patients? (6) How should haemostasis be managed in order to reduce morbidity and mortality in cirrhotic ICU patients? And (7) When should advice be obtained from an expert centre in order to reduce morbidity and mortality in cirrhotic ICU patients? Population, intervention, comparison and outcome (PICO) issues were reviewed and updated as required, and evidence profiles were generated. An analysis of the literature and recommendations was then performed in accordance with the GRADE® methodology. RESULTS: The SFAR/AFEF Guidelines panel produced 18 statements on liver failure in general ICU. After two rounds of debate and various amendments, a strong agreement was reached on 100% of the recommendations: six had a high level of evidence (Grade 1 ±), seven had a low level of evidence (Grade 2 ±) and six were expert judgments. Finally, no recommendation was provided with respect to one question. CONCLUSIONS: Substantial agreement exists among experts regarding numerous strong recommendations on the optimum care of patients with liver failure in general ICU.

[Setting-up and evaluation of an educational program for the teaching of breast and pelvic examination in undergraduate medical students: the "PRESAGE" simulation center experience of the medicine university of Lille, France]. / Mise en place et évaluation d'un apprentissage par simulation des examens gynécologiques.

OBJECTIVES: To report the setting-up of a new educational program in the teaching of female pelvic and breast examinations and to investigate and compare the views and experience of undergraduate medical students and teachers on the program. PATIENTS AND METHODS: Prospective evaluation of the teaching program through completion of a satisfaction questionnaire including items related to the educational value of the session by the students and the teachers. RESULTS: The educational program included an online preparation for the session, 3 workshops on training models (breast examination, pelvic examination, cervical snear procedure) and a video clip. In total, 419 (80.6%) of 520 second study year students (and 15 [50%] of 30 teachers [13 doctors and 17 midwifes] responded to the questionnaire). The students and the teachers were either very satisfied (56.6% and 13.4%, respectively) or satisfied (43.2% and 86.6%, respectively). On average, 89.7% of students wanted more lessons of this type and all teachers felt these useful or very useful training for students. DISCUSSION AND CONCLUSION: Teaching sessions for pelvic and breast examination, which make combined use of videos and training models, are associated with a high degree of satisfaction from teachers and students in their second student's year.

Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. OBJECTIVES: To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. ANIMALS: A total of 260 dogs in CHF because of MMVD. METHODS: A prospective single-blinded study with dogs randomized to receive pimobendan (0.4-0.6 mg/kg/day) or benazepril hydrochloride (0.25-1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. RESULTS: A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30-276 days versus benazepril 59 days, IQR 11-121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water.

Tumor size of hepatocellular carcinoma in noncirrhotic liver: a controversial predictive factor for outcome after resection.

BACKGROUND: Hepatocellular carcinoma in noncirrhotic liver (NC-HCC) presents usually with large size, which is seen as a contraindication to liver transplantation (LT) or even resection. The objective of our single-center study was to identify prognostic factors following resection of large NC-HCCs and to subsequently devise a treatment strategy (including LT) in selected patients. METHODS: From 2000 to 2010, 89 patients who had hepatic resection for NC-HCC (large ≥ 8 cm in 52) were analyzed with regard to pathological findings, postoperative and long-term outcome. RESULTS: Five patients died postoperatively. After a mean follow-up of 35 ± 30 months, NC-HCC recurred in 36 patients (26/47 survivors in group 8 cm+, 10/37 in group 8 cm-; p = 0.007). Five-year overall (OS) and disease-free survival (DFS) rates were significantly worse for group 8 cm+ (43.4% vs. 89.2% and 39.3% vs. 60.7% for group 8 cm-, p < 0.05). Seven patients underwent re-hepatectomy and/or LT for isolated intrahepatic recurrence, with 5-year DFS of 57.1%. In a multivariate analysis, the factors associated with poor OS and DFS were vascular invasion and tumor size ≥ 8 cm in the overall population and vascular invasion, fibrosis and satellite nodules in group 8 cm+. Adjuvant transarterial chemotherapy was a protective factor in group 8 cm+. In 22 isolated NC-HCC cases with no vascular invasion or fibrosis, tumor size had no impact on five-year DFS (85%). CONCLUSIONS: Although patients with NC-HCC ≥ 8 cm had a poorer prognosis, the absence of vascular invasion or fibrosis was associated with excellent survival, regardless of the tumor size. In recurrent patients, aggressive treatment (including LT) can be considered.

Meta-analysis: the impact of IL28B polymorphisms on rapid and sustained virological response in HCV-2 and -3 patients.

BACKGROUND: Recent studies suggested that IL28B polymorphisms may affect rapid and sustained virological response rates in HCV patients infected with genotype 2 or 3. AIM: To assess the role of IL28B polymorphisms on the virological response in HCV-2 and -3 patients. METHODS: We performed meta-analysis of studies evaluating the impact of rs12979860 and rs8099917 polymorphisms on rapid and sustained virological response in HCV-2 or -3 patients. RESULTS: Twenty-three studies involving 3042 patients were included. The first meta-analysis evaluated the impact of rs12979860 polymorphism and included 1963 patients. When compared with rs12979860 CT/TT patients, CC patients had a higher rapid virological response rate (mean difference: 12.9%, 95% CI: 6.5-19.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 4.9%, 95% CI: 0.1-9.8%, P = 0.046). The second meta-analysis evaluated the impact of rs8099917 polymorphism and included 2246 patients. When compared with rs8099917 TG/GG patients, TT patients had a higher rapid virological response rate (mean difference: 14.8%, 95% CI: 7.2-22.4%, P < 0.001) and a higher sustained virological response rate (mean difference: 5.5%, 95% CI: 0.4-10.6%, P = 0.033). When considering only patients treated for 24 weeks, results were unchanged. No potential sources of between-study heterogeneity were identified. CONCLUSIONS: Favourable IL28B polymorphisms are associated with higher rapid and sustained virological response rates in HCV-2 and -3 patients. However, as the impact on a sustained response is very limited, it is unlikely that IL28B polymorphisms provide additional predictive value when considering other predictors of a sustained response.

Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score.

BACKGROUND: Sorafenib increases median survival and time to radiological progression in patients with advanced hepatocellular carcinoma, but its benefit for Child-Pugh B patients remains uncertain. AIM: To evaluate the safety and efficacy of sorafenib in real-life clinical practice conditions and to assess the influence of Child-Pugh class B on safety and efficacy. METHODS: All patients treated with sorafenib for advanced hepatocellular carcinoma in our institution were included prospectively. Adverse events, overall survival and time to progression were recorded. A case control study was performed to compare outcome of patients with comparable stages of hepatocellular carcinoma, but a different Child-Pugh class. RESULTS: From March 2007 to May 2009, 120 patients were included. Overall survival was 11.1 months, Child-Pugh A patients (n=100) had significantly higher median survival than Child-Pugh B patients (n=20) (13 vs. 4.5 months, P=0.0008). In multivariate analysis, Child-Pugh class B, α-fetoprotein level and total size of lesions were independent predictive factors of death. Patients with radiological progression in the first 3 months had shorter median survival (5.4 vs. 17.4 months). In a case control study, time to symptomatic progression (2.5 vs. 3.6 months), frequency of adverse events and discontinuation of sorafenib were not correlated with Child-Pugh class. CONCLUSIONS: Patients with advanced hepatocellular carcinoma treated with sorafenib had a median survival of 11 months. Sorafenib therapy must be considered with caution in Child-Pugh B patients due to their poor survival. Radiological assessment of tumour progression at an early stage may be advantageous when tailoring sorafenib therapy.

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy.

BACKGROUND: In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. AIM: To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. METHODS: Thirty-two naïve patients were treated with Peg-IFN-α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600mg per week and adapting EPO when haemoglobin (Hb) fell below 10g/dL (adaptive strategy) or starting ribavirin at 1000mg per week while increasing EPO from the start of treatment (preventive strategy). RESULTS: Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9g/dL, P=0.02) and more frequent median Hb levels below 10g/dL (58 vs. 5%, P=0.0007) despite lower median ribavirin doses (105 vs. 142mg/day, P<0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P=0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7mg/L, P=0.007) and similar concentrations thereafter. SVR was reached in 50%. CONCLUSIONS: Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.

Contrast-enhanced magnetic resonance angiography of patent ductus arteriosus in a dog.

Gadolinium-enhanced three-dimensional magnetic resonance angiography is a relatively new technique in the veterinary field. A mature dog with suspected patent ductus arteriosus underwent contrast-enhanced magnetic resonance angiography at 1.0 T with a three-dimensional fast low-angle shot (FLASH) gradient-echo technique. Qualitatively, three-dimensional images of the ductus were particularly clear with surface reconstructions, and ductus diameters were easy to assess in native images. Contrast-enhanced magnetic resonance angiography is a fast, relatively non-invasive procedure that could be particularly useful when non-surgical interventional procedures are anticipated for ductus occlusion.

A 2-log drop in viral load at 1 month is the best predictor of sustained response in HCV patients with normal ALT: a kinetic prospective study.

The most reliable predictor of a sustained virological response in patients with persistently normal ALT has not been identified. We analysed 17 patients with genotype 1 chronic HCV who underwent therapy with pegylated interferon alfa 2b and ribavirin for 48 weeks. Two patients discontinued therapy within 28 days because of side effects and the remaining 15 patients were analysed in detail. An analysis of on treatment virological response using area under the receiver operating characteristic analyses showed that a 2 log drop in HCV RNA at day 28 was the best predictor of a sustained virological response and a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a sustained virological response. Introduction of this early discontinuation rule in patients with normal ALT would allow nearly half of the patients to discontinue futile therapy at an early stage.

Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study.

BACKGROUND: Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. HYPOTHESIS: Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. ANIMALS: Two hundred and sixty client-owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. METHODS: A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4-0.6 mg/kg/d) or benazepril hydrochloride (0.25-1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. RESULTS: Eight dogs were excluded from analysis. One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL]=0.516-0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.

[Nuclear receptor PPAR and hepatology: pathophysiological and therapeutical aspects]. / Récepteurs nucléaires PPAR et hépatologie: implications physiopathologiques et thérapeutiques.

In last few years, the topic of nuclear receptor has been developed in the field of hepatology allowing envisaging therapeutic strategies for the most frequent chronic liver diseases. Peroxysome proliferator-activated receptors (PPAR) contribute to wide physiological processes within the liver such as lipid/glucid metabolisms, inflammatory response, cell differenciation and cell cycle. In vitro experiments and animal studies showed that PPARalpha discloses anti-inflammatory property and PPARgamma discloses anti-inflammatory, antifibrogenic and antiproliferative properties in the liver. Main available agonists are fibrates (PPARalpha) used for 20 years in cases of lipid metabolism abnormalities and glitazones (PPARgamma) used since 2000 for type 2 diabetes. In terms of therapy, animal studies and human trials have been conducted in steatopathies. However, clinicians have to be aware of potential specific side effects related to glitazones especially on cardiovascular system.

Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features.

BACKGROUND: Studies using consecutive liver biopsies constitute an attractive approach to gaining insight into the pathogenesis of alcoholic liver disease. AIM: To analyse histological factors at baseline, which are predictive of fibrosis progression and recurrence of alcoholic hepatitis. RESULTS: A total of 193 drinkers underwent consecutive biopsies at an interval of 4 years. At baseline, 20 had normal livers, 135 steatosis, five fibrosis and 33 alcoholic hepatitis. The fibrosis score increased from 1.07 +/- 0.07 to 1.7 +/- 0.94 (P < 0.001). In multivariate analysis, only steatosis (P = 0.04), alcoholic hepatitis (P = 0.0004) and stage of fibrosis (P < 0.0001) were independent predictive factors of the fibrosis score at the second biopsy. Cirrhosis developed more frequently in patients with steatosis (11%) and alcoholic hepatitis (39%) than in others (0%, P < 0.0001). Alcoholic hepatitis recurred more frequently in patients with alcoholic hepatitis at baseline: 58% vs. 15%, P < 0.0001. In multivariate analysis, alcoholic hepatitis at the first biopsy was the only predictive factor of its recurrence (P < 0.0001). CONCLUSIONS: In a large cohort of drinkers with consecutive biopsies, steatosis, fibrosis stage and alcoholic hepatitis at baseline were independent predictive factors of fibrosis progression. In terms of mechanisms, we propose a novel concept of multiple hits of alcoholic hepatitis occurring in the same patient.

Phaeochromocytoma treated by en bloc resection including the suprarenal caudal vena cava in a dog.

A 10-year-old, neutered male Cairn terrier was examined after experiencing intermittent vomiting of several months' duration and sudden onset of acute depression. Abdominal ultrasound examination revealed an adrenal mass invading the suprarenal part of the caudal vena cava. The vascular invasion could not be corrected so en bloc ligation/excision of the adrenal neoplasm and the suprarenal part of the vena cava was performed. Microscopic examination identified an adrenal phaeochromocytoma. The dog recovered well and had no significant vascular or renal dysfunction at follow-up 20 months after surgery. To the authors' knowledge, this is the first report of a dog surviving long term after resection of the suprarenal caudal vena cava.