Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Liver fibrosis is associated with cutaneous inflammation in the imiquimod-induced murine model of psoriasiform dermatitis.

BACKGROUND: Psoriasis exhibits several extracutaneous manifestations. Little is known about hepatic parameters specifically associated with psoriasis. OBJECTIVES: To study whether psoriasiform dermatitis is associated with liver injury. METHODS: We studied liver parameters of inflammation and fibrosis in a murine model of psoriasiform dermatitis induced by topical application of imiquimod for 9 weeks. RESULTS: Topical treatment with imiquimod induced a form of psoriasiform dermatitis reminiscent of the human disorder, characterized by thickened and scaly skin, psoriasiform epidermal hyperplasia, altered keratinocyte differentiation and cutaneous overexpression of interleukin-17A. Mice with dermatitis displayed hepatitis, as shown by elevation of plasma transaminase levels, as well as portal and periportal hepatitis, characterized by T-lymphocyte (CD3ε+ ) and polymorphonuclear cell (Gr1+ ) infiltrates. The hepatitis progressed towards liver fibrogenesis, as shown by excessive Sirius red staining, which is consistent with the expression of α-smooth muscle actin by hepatic stellate cells. CONCLUSIONS: These results indicate that liver inflammation and fibrosis are associated with experimental psoriasiform dermatitis. Our results suggest that psoriatic inflammation may be associated with specific liver injury.

Predictors of disease-free survival in colorectal cancer with microsatellite instability: An AGEO multicentre study.

BACKGROUND: A microsatellite instability (MSI) phenotype is found in about 12% of colorectal cancers (CRCs) and is associated with a low recurrence rate after curative surgery. Several studies have identified clinical and pathological factors predictive of recurrence in resected CRC, but not in the MSI subgroup. PATIENTS AND METHODS: This multicentre retrospective study included patients with stage I, II or III MSI CRCs. Disease-free survival (DFS) was calculated with the Kaplan-Meier method. Factors associated with DFS were identified in univariate and multivariate Cox analyses. RESULTS: We studied 521 patients with MSI CRC. Respectively 11%, 51% and 38% of patients were at stage I, II and III. Mean age was 68.7years and 36% of the patients received adjuvant chemotherapy. Median follow-up was 32.8months. The disease recurrence rates were 6% and 21% in stage II and III patients, respectively. The 3-year DFS rate was 77%. In univariate analysis, age, bowel obstruction, lymph node invasion, stage T4, vascular emboli, lymphatic invasion and perinervous invasion were associated with poorer DFS (P<0.05). Three relevant independent predictors of poor DFS were identified in multivariate analysis, namely bowel obstruction (HR=2.46; 95%CI 1.31-4.62, P=0.005), vascular emboli (HR=2.79; 95%CI 1.74-4.47, P<0.001) and stage T4 (HR=2.16; 95%CI 1.31-3.56, P=0.002). CONCLUSIONS: Bowel obstruction, vascular emboli and stage T4 are independently associated with MSI CRC recurrence, suggesting that screening for vascular emboli in routine clinical practice may assist with adjuvant chemotherapy decision-making.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS: Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS: A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS: These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

Management of esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma is increasing in Western countries with a tendency to exceed that of squamous-cell carcinoma. Prognosis is unfavorable with 5-year survival less than 15%, irrespective of treatment and the stage. At the time of diagnosis, more than two thirds of patients have a non-operable cancer because of extension or associated co-morbidities. Most studies have included different tumoral locations (esophagus and stomach) and different histological types (adenocarcinoma and squamous-cell carcinoma), making it difficult to interpret results. Surgery is currently the standard treatment for small tumors. Surgery should be preceded by neo-adjuvant treatment for patients with locally advanced resectable tumors, either preoperative chemotherapy or preoperative chemoradiation therapy. The therapeutic choice should be decided during multidisciplinary meetings according to patient and tumor characteristics and the expertise of the center. For patients with contraindications to surgery, exclusive chemoradiation therapy is recommended. Herein we reviewed and synthesized the different therapeutic strategies for esophageal adenocarcinoma.

The impact of the prevention programme of hepatitis C over more than a decade: the French experience.

To assess the impact of the French national hepatitis C prevention programme initiated in 1999, we analysed trends in hepatitis C virus (HCV) prevalence, testing and characteristics of HCV-infected patient at first referral from 1994 to 2006. We used four data sources: Two national population-based sero-prevalence surveys carried out in 1994 and 2004; two surveillance networks, one based on public and private laboratories throughout France and the other on hepatology reference centres, which aim to monitor, respectively, trends of anti-HCV screening and of epidemiological-clinical characteristics of HCV patients at first referral. Between 1994 and 2004, the anti-HCV prevalence for adults aged 20-59 years decreased from 1.05 (95% confidence interval 0.75-1.34) to 0.71 (0.52-0.97). During the same period, those anti-HCV positive with detectable HCV RNA decreased from 81 to 57%, whereas, the proportion of anti-HCV positive persons aware of their status evolved from 24 to 56%. Anti-HCV screening activity increased by 45% from 2000 to 2005, but decreased in 2006 (-10%), while HCV positivity among those tested decreased from 4.3 to 2.9%. The proportion of cirrhosis at first referral remains around 10% between 2001 and 2006, with many patients with excessive alcohol consumption (34.7% among males) or viral co-infections (HIV seropositivity for 5.2% patients). Our analysis indicates that the national programme had a positive impact at the population level through improved prevention, screening and management. There is still a need to identify timely those at risk for earlier interventions, to assess co-morbidities better and for a multidisciplinary approach to HCV management.

Use of a risk analysis method to improve care management for outlying inpatients in a university hospital.

OBJECTIVE: To improve the quality of care provided for inpatients outlying in inappropriate wards of a teaching hospital because of lack of vacant beds in appropriate specialty wards. METHODS: A multidisciplinary team consisting of hospital doctors, nurses and managers performed a prospective risk analysis of the process of care provided for outlying patients during their hospitalisation. The design of the study was Failure Modes, Effects and Criticality Analysis (FMECA). Failure modes were defined and classified according to their criticality, in order to identify priority actions for improvement. Criticality indices were calculated by multiplying occurrence, severity and detection scores. RESULTS: Measures for improvement indicated by the most critical failure modes were the identification of specialist doctors in appropriate specialty wards to be responsible for the care of outlying patients falling within their sphere of competence; the identification of a nurse coordinator in each department to improve communication between the emergency department, appropriate specialty wards and outlying wards; the standardisation of medical records throughout the whole hospital to ensure better traceability and access to information. CONCLUSIONS: Using FMECA, we were able to identify the most critical failure modes of the complex process of care provided for outlying patients and to suggest subsequent improvement measures. Follow-up indicators were defined to assess implementation.

Increased immunoglobulin A in alcoholic liver cirrhosis: exploring the response of B cells to Toll-like receptor 9 activation.

Alcoholic liver cirrhosis (ALC) is characterized by increased circulating levels of immunoglobulins (Igs). ALC patients undergo bacterial translocation evidenced by the presence of bacterial DNA in peripheral blood. Bacterial pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), peptidoglycan (PGN) and unmethylated cytosine-guanine dinucleotide (CpG) DNA are ligands of Toll-like receptor (TLR)-4, TLR-2 and TLR-9, respectively. Although TLR activation results generally in the secretion of proinflammatory cytokines, activation of B cells through TLR-7 or TLR-9 is involved in their maturation and Ig synthesis. The aim of the present study was to assess Ig synthesis by ALC B cells under PAMP activation in order to evaluate the possible involvement of TLR pathways in the increased Ig levels, and especially the hyper-IgA observed in ALC. CpG, in combination with interleukin (IL)-10 or IL-21, enhanced IgA, IgG and IgM synthesis by healthy donor (HD) PBMCs, but had only a weak effect on ALC PBMCs. Relative CpG-induced IgA production by purified ALC B cells was less important when compared to HD B cells, in accordance with the lower TLR-9 expression on ALC B cells compared to HD B cells, but the absolute IgA production by CpG-activated B cells was enhanced significantly for ALC when compared to HD, in agreement with their intrinsic ability to produce spontaneously more IgA than HD. LPS and PGN had no direct activity on B cells, whereas R848 also enhanced Ig synthesis, as reported recently. Taken together, these results suggest that TLR priming of B cells could account for the hyperimmunoglobulinaemia observed in ALC patients.

Epidemiological characteristics and medical follow-up of 61 patients with acute hepatitis C identified through the hepatitis C surveillance system in France.

This study aimed to describe current epidemiological and clinical characteristics, medical follow-up and outcome in the real practice of acute hepatitis C (AHC) patients. AHC cases were retrospectively identified through the French Hepatology Reference Centres Surveillance system and additional data were collected. Sixty-one patients with AHC were identified (sex ratio: M/F 1.7/1; mean age 39 years). Forty-four (72%) had documented seroconversion within a 6-month period. Main reported risk exposures were intravenous or nasal drug use (35%), invasive medical procedures (25%) and sexual contact with a HCV-positive partner (20%). Spontaneous clearance of HCV RNA was observed in seven out of 16 patients followed without therapy. This study confirms the major role of drug use in HCV transmission and highlights the role of invasive medical procedures and occupational exposure.

Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study.

This cross-sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6-month period. HCV genotyping in the 5'-non-coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer-specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non-subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

[Crohn's disease with anoperineal lesions: use of MRI]. / Maladie de Crohn révélée par des lésions anopérinéales: intérêt de l'IRM.

The authors report a case of perineal Crohn disease with three anal fissures. Because of a persistant fever without any clinical aspect of abscess they practiced MRI examination that discovered an abscess of the recto-vaginal wall. The patient was operated under general anaesthesia. This clinical case shows the interest of radiologic exams, particularly pelvic MRI for the precise lesional diagnosis of anoperineal lesions of Crohn's disease, that is still complex and difficult to treat.

Early administration of vapreotide for variceal bleeding in patients with cirrhosis.

BACKGROUND: In patients with cirrhosis, pharmacologic or endoscopic treatment may control variceal bleeding. However, the effects of early administration of a somatostatin analogue followed by endoscopic treatment are unknown. METHODS: We studied the effects of treatment with vapreotide, a somatostatin analogue, begun before endoscopic treatment in 227 patients with cirrhosis who were hospitalized for acute upper gastrointestinal bleeding. The patients were randomly assigned to receive vapreotide (a 50-microg intravenous bolus followed by an infusion at a rate of 50 microg per hour for five days) or placebo within a mean (+/-SD) of 2.3+/-1.5 hours after admission. All the patients received endoscopic treatment a mean of 2.6+/-3.3 hours after the infusion was begun. After the exclusion of 31 patients whose bleeding was not caused by portal hypertension, there were 98 patients in each group. RESULTS: At the time of endoscopy, active bleeding was evident in 28 of 91 patients in the vapreotide group (31 percent), as compared with 43 of 93 patients in the placebo group (46 percent) (P=0.03). During the five-day infusion, the primary objective--survival and control of bleeding--was achieved in 65 of 98 patients in the vapreotide group (66 percent) as compared with 49 of 98 patients in the placebo group (50 percent) (P=0.02). The patients in the vapreotide group received significantly fewer blood transfusions (2.0+/-2.2 vs. 2.8+/-2.8 units, P=0.04). Overall mortality rates at 42 days were not significantly different in the two groups. CONCLUSIONS: In patients with cirrhosis and variceal bleeding, the combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone as a method of controlling acute bleeding. However, the use of combination therapy does not affect mortality rates at 42 days.

[Liver abscess]. / Abcès du foie.

Liver abscesses are bacterial or parasitic. In a patient presenting with fever, fatigue and upper right abdominal pain, abdominal ultrasound must be performed to reveal a liver mass. Clinical history and serologies allow presumptive diagnosis. Pyogenic abscesses are mostly secondary to biliary tree infection. Pus aspiration and culture confirm the diagnosis. Gram-negative bacilli and anaerobes are the most frequent germs. Percutaneous drainage combined with antibiotics is the standard treatment. Earlier diagnosis, better techniques for bacterial culture and adapted treatment have improved prognosis. Amoebic abscesses are less frequent but their incidence is increasing in the presence of immunosuppressed state. The diagnosis is based on abdominal ultrasound and serology. Treatment is principally medical.

Prospective study on the application of the Baveno II Consensus Conference criteria in patients with cirrhosis and gastrointestinal bleeding.

BACKGROUND/AIMS: This study aimed to evaluate the Baveno II criteria defining key events in variceal bleeding. METHODS: These criteria were applied to 196 patients with cirrhosis admitted for upper gastrointestinal bleeding due to portal hypertension and enrolled in a trial. Blood pressure, heart rate, hematocrit and clinical signs of upper digestive tract hemorrhage were recorded for 5 days. The blind overall clinical judgment of hemodynamic stability was recorded separately by the Steering Committee. RESULTS: The evaluation of several hemodynamic criteria was left to the judgment of the clinician. The first time point for the control of bleeding, fixed at 6 h after admission, was impractical since 13% of the patients had not yet received specific treatment. The independent judgment did not agree in 38% of 82 cases without control of bleeding. In 15% of cases this was due to tachycardia. Calculation of several judgment criteria was not defined in the Baveno II criteria: survival without bleeding at 5 days, transfusion rate, and length of hospital stay. CONCLUSIONS: Although the Baveno II criteria have improved the definitions of key events, the criteria are hampered by limits such as false positive criteria of failure to control bleeding. We make several proposals for improvement.

[Treatment of hepatitis C virus infection in the Poitou- Charentes region]. / Prise en charge de l'infection par le virus de l'hépatite C dans la région Poitou-Charentes.

OBJECTIVES: The prognosis of hepatitis C virus infection could be improved by early treatment. However, this is only possible if most patients with hepatitis C consult a specialized institution. The aim of this study was to evaluate the modalities of care of hepatitis C virus infection in one French district. METHODS: Between November and December 1997, 89 biological laboratories from the "Poitou-Charentes" district were asked to provide results of hepatitis C virus serology tests performed during this period. A questionnaire concerning epidemiological and follow-up data was sent to the medical practitioner who prescribed the test, for all positive tests. RESULTS: Seventy eight out of 89 (88%) laboratoires agreed to participate in the study. During the study period, 6,168 subjects were tested and 196 (3.2%) were positive. This test was a diagnostic test in 69 cases (53%) and a confirmation test in 61 cases (47%). The epidemiological questionnaire was filled out in 130 cases. The main putative factors of viral contamination were: intravenous or nasal drug addiction in 69 cases (53%), blood transfusion in 39 cases (30%), and a nosocomial risk factor in 16 cases (12%). Treatment and care of virus infection was evaluated in 113 cases from the follow-up questionnaire: a liver biopsy was performed in 30 cases (27%) and interferon therapy was administered in 13 cases (12%). Liver biopsy was not performed in 83 cases (73%) due to normal transaminase levels or a contraindication to interferon therapy. The main causes of an absence of care or follow-up were: fear of complications of liver biopsy and/or side effects to interferon therapy (19%), chronic alcoholism (18%) and active drug addiction (8%). CONCLUSION: The main causes of failure to administer adequate care in hepatitis C patients were chronic alcoholism, drug addiction and fear of liver biopsy or side effects of interferon therapy. These data should be taken into account for future screening or information compaigns for the general population.

[Pancreatic necrosis infection by Candida parapsilosis associated with fungemia]. / Infection de nécrose pancréatique à Candida parapsilosis associée à une fungémie.

Pancreatic necrosis infection is the most common complication affecting mortality of severe acute pancreatitis (death rate 80%). Bacterial infections particularly with coliforms or anaerobes account for the majority of cases of infected necrosis. Fungal pancreatic infections with Candida species are rare and often nosocomial. We report herein the first case of pancreatic necrosis infection with Candida parapsilosis associated with fungemia confirmed by molecular typing.

[Antiviral treatment of hepatitis C virus infection]. / Traitements antiviraux de l'infection par le virus de l'hépatite C.

Hepatitis C virus infection is common and almost always chronic and can lead to cirrhosis and hepatocellular cancer. The primary goal of the treatment is virus eradication and the secondary is to reduce inflammation and liver cell damage. Interferon is the only effective therapy but disappearance of the virus is sustained in only 10 to 15%. The factors most closely associated with a response to treatment are absence of cirrhosis, low serum hepatitis C virus RNA level and genotype other than type 1. Recent studies have suggested that interferon treatment may reduce the subsequent risk of hepatocellular carcinoma in responders. The combination of interferon and oral ribavirin therapy increase the sustained response rate to about 40% in initial treatment and 50% for the treatment of relapse. The other therapeutic combination are less well documented. New agents such as hepatitis C virus-specific anti-protease may be available in the next future and treatment is evolving toward multiple-drug regimens.