Plasma phospholipids and fatty acid composition differ between liver biopsy-proven nonalcoholic fatty liver disease and healthy subjects.

BACKGROUND: There is growing evidence that nonalcoholic fatty liver disease (NAFLD) is associated with perturbations in liver lipid metabolism. Liver phospholipid and fatty acid composition have been shown to be altered in NAFLD. However, detailed profiles of circulating lipids in the pathogenesis of NAFLD are lacking. OBJECTIVE: Therefore, the objective of the present study was to examine circulating lipids and potential mechanisms related to hepatic gene expression between liver biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH) and healthy subjects. SUBJECTS: Plasma phospholipid and fatty acid composition were determined in 31 healthy living liver donors as healthy controls (HC), 26 patients with simple hepatic steatosis (SS) and 20 with progressive NASH. Hepatic gene expression was analyzed by Illumina microarray in a subset of 22 HC, 16 SS and 14 NASH. RESULTS: Concentrations of phosphatidylethanolamine (PE) increased relative to disease progression, HC

Adjuvant sunitinib following chemoradiotherapy and surgery for locally advanced esophageal cancer: a phase II trial.

The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m2 ) + Cisplatin (30 mg/m2 ) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4-8. Sunitinib was commenced 4-13 weeks after surgery and continued for one year. Sixty-one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12-month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3-year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2-year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2-year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer.

Degree of tumor shrinkage following neoadjuvant chemoradiotherapy: a potential predictor for complete pathological response in esophageal cancer?

Neoadjuvant chemoradiotherapy (CRT) before surgery results in a pathological complete response (pCR) rate in about 1/3 of the patients, which is correlated with survival. It was hypothesized that volumetric tumor response to CRT would correlate with outcomes. Patients who completed trimodality therapy, where planning, pre-, and post-CRT computed tomography scans were available, and pathology was reviewed by a central pathologist, were eligible for analysis. Absolute and relative tumor volume change pretreatment and post-treatment were correlated with pCR, locoregional recurrence (LRR), disease-free survival, and overall survival. Fifty-six patients were analyzed. pCR was observed in 30% of patients. Median follow up was 20.3 (range 4-89) months. The 2- and 4-year overall survival was 61.3% (95% confidence interval [CI]: 45-74) and 25.0% (95%CI: 11-41); proportion disease free was 32.1% (95% CI: 19-46) and 20.6% (9-36) at 2 and 4 years, respectively. The median relative volume reduction was 17% (95% CI: -24, -3%). Using 20% as the criteria, the proportion of patients with pCR of ≥20% versus <20% was 13/25 (52%) versus 4/31 (13%) for those who did not (odds ratio 7.3; 95% CI: 2-27). The LRR at 2 and 4 years were 29.5% (95% CI: 16-43) and 36.2% (95% CI: 23-50). The relative tumor reduction ≥20% was significantly correlated with LRR (hazard ratio 0.24; 95% CI: 0.07-0.8; p 0.02) at 2 and 4 years, respectively. Relative tumor volume reduction following CRT is correlated with pCR and LRR. Further investigations are warranted to examine the effect of volume change, alone or in conjunction with other factors as potential predictors for pathological response.

Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma.

Globally, hepatocellular carcinoma (hcc) is the third most common cause of death from cancer, after lung and stomach cancer. The incidence of hcc in Canada is increasing and is expected to continue to increase over the next decade. Given the high mortality rate associated with hcc, steps are required to mitigate the impact of the disease. To address this challenging situation, a panel of 17 hcc experts, representing gastroenterologists, hepatologists, hepatobiliary surgeons, medical oncologists, pathologists, and radiologists from across Canada, convened to provide a framework that, using an evidence-based approach, will assist clinicians in optimizing the management and treatment of hcc. The recommendations, summarized here, were developed based on a rigorous methodology in a pre-specified process that was overseen by the steering committee. Specific topics were identified by the steering committee and delegated to a group of content experts within the expert panel, who then systematically reviewed the literature on that topic and drafted the related content and recommendations. The set of recommendations for each topic were reviewed and assigned a level of evidence and grade according to the levels of evidence set out by the Centre for Evidence-based Medicine, Oxford, United Kingdom. Agreement on the level of evidence for each recommendation was achieved by consensus. Consensus was defined as agreement by a two-thirds majority of the 17 members of the expert panel. Recommendations were subject to iterative review and modification by the expert panel until consensus could be achieved.

Oxidative stress and nutritional factors in hepatitis C virus-positive liver recipients, controls, and hepatitis C virus-positive nontransplant patients.

BACKGROUND: Hepatitis C virus (HCV) is the most common indication for liver transplantation, but HCV recurrence is frequent after 1 year and is associated with increased morbidity and mortality. Oxidative stress (OxS) is involved in the pathogenesis of HCV, but little is known about its presence prior to disease recurrence. AIM: To determine if at 6 months HCV-positive liver recipients (HCV-OLT) without recurrence were oxidatively stressed. METHODS: 33 HCV-OLTs, 12 controls, and 39 HCV-positive nontransplant patients (HCV-NTs). OxS was assessed by using commercial kits to measure liver lipid peroxidation (LPO) and antioxidant potential (AOP). Plasma vitamin E, retinol (HPLC), and vitamin C (spectrophotometry) were assessed. We collected Anthropometry and 3-day food records. We performed analysis by the Kruskal-Wallis test expressing data as mean values +/- standard errors of the mean. RESULT: Waist-hip ratio was higher in both HCV-OLTs and HCV-NTs compared to the controls. HCV-OLTs showed higher hepatic LPO (mumol malondialdehyde/g tissue) versus controls (1.4 +/- 0.20 vs 0.54 +/- 0.10; P = .010) and compared to HCV-NTs (0.98 +/- 0.17; P = .030). No significant differences were found among the groups regarding hepatic AOP. However, lower plasma AOP (micromols UEA) were observed in HCV-OLTs (0.07 +/- 0.008) versus controls (0.17 +/- .040; P = .021) or HCV-NTs (0.08 +/- 0.009; P = .015) versus controls. Plasma gamma-tocopherol was higher in HCV-OLTs and HCV-NTs compared to controls (P = .001). We observed lower vitamin A intake in HCV-OLTs compared with the other two groups (P = .001). CONCLUSIONS: HCV-OLTs without disease recurrence are oxidatively stressed compared with control and HCV-NTs. Future research is needed to determine the impact of this increased oxidative stress on HCV disease recurrence.

Liver allograft pathology: approach to interpretation of needle biopsies with clinicopathological correlation.

The spectrum of diseases encountered in post-transplant liver pathology biopsies is broad. In this review, these have been divided as belonging to one of three categories: (1) new-onset/de novo post-transplant abnormalities (early and late), (2) rejection, and (3) recurrence of original disease. The clinical and pathological features of the entities making up each category, with the relevant differential diagnosis and overlaps between and within these groups, are discussed and illustrated. Recurrent or de novo neoplasms make up a fourth category not included in this review. Early new-onset conditions are mostly related to surgical complications, donor factors and ischaemia to the graft. These include reperfusion/preservation injury, lipopeliosis, small-for-size-syndrome, biliary sludge syndrome and hepatic artery thrombosis. The various forms of rejection (cellular, chronic, antibody-mediated, and late atypical rejection) are detailed. Most chronic liver diseases can and do recur in the graft. They may display features that overlap with de novo conditions (eg, primary sclerosing cholangitis versus chronic rejection). As with most cases of allograft biopsy interpretation, accurate diagnosis rests with careful correlation of histological features with clinical, imaging and laboratory findings, and often comparison with previous sequential and follow-up biopsies. Late-onset new diseases include biliary strictures, idiopathic chronic hepatitis and de novo autoimmune hepatitis, among others. This review provides a practical approach to the interpretation of these challenging biopsies. Selected difficult scenarios or conundrums are identified and discussed in the relevant sections.

Hepatic lipid peroxidation and antioxidant micronutrients in hepatitis virus C liver recipients with and without disease recurrence.

BACKGROUND: Hepatitis C virus (HCV) reinfection after liver transplantation is universal and progresses to cirrhosis in 10% to 30% of patients. Several risk factors are associated with progression. Oxidative stress may be involved because it has a role in the pathogenesis of HCV. OBJECTIVE: To determine whether HCV liver recipients with disease recurrence are more oxidatively stressed than those with no recurrence. METHODS: Measurements were performed at 12 months posttransplantation, and in a subgroup of patients at 6 months. Liver lipid peroxidation (LPO), antioxidant potential, plasma vitamin E, retinol, and vitamin C were measured. Demographic data, pretransplantation viral load, anthropometry, and 3-day food records were also obtained. Data were log-transformed; analysis was performed using the independent t test, Pearson correlation, and multivariate regression analysis. RESULTS: Recipients of HCV livers with recurrence (n = 21) had higher liver LPO (mean [SEM] micromoles of malondialdehyde per gram of liver tissue, 1.66 [0.28]) vs those with no recurrence (n = 16; 0.88 [0.13]) (P = .02). A significant relationship was found between liver LPO and HCV recurrence, and this significance continued when accounting for pretransplantation viral load and donor age. Six patients with recurrence and 11 with no recurrence also had measurements obtained at 6 months posttransplantation. Those with recurrence at 12 months had significantly higher hepatic LPO at 6 months (1.86 [0.62]) compared with those with no recurrence (0.75 [0.14]) (P = .04). CONCLUSIONS: Recipients of HCV livers with recurrence are more oxidatively stressed at 6 and 12 months compared with those with no recurrence. Accounting for viral load and donor age, oxidative stress was independently associated with recurrence. More research is needed to confirm this association.

Haematogenous infection of a resurfacing hip replacement after transurethral resection of the prostate.

A 66-year-old man presented with an infected resurfacing hip replacement in the immediate post-operative period following an uneventful transurethral resection of the prostate. Prophylactic antibiotics had been administered on induction of anaesthesia. The hip prosthesis had been inserted seven years previously and had been hitherto asymptomatic. The hip was washed out and microbiological examination identified Enterococcus faecalis as the infecting micro-organism. Despite current recommendations, clinicians undertaking invasive procedures which can lead to bacteraemia in patients with prosthetic joint replacements should be aware of the risk of haematogenous seeding in such prostheses, which although low, has potentially disastrous consequences.

A clinical decision rule for triage of children under 5 years of age with hydrocarbon (kerosene) aspiration in developing countries.

BACKGROUND: Unintended hydrocarbon ingestion is a common reason for pediatric hospitalization in the developing world. OBJECTIVE: To derive a clinical decision rule, to identify patients likely to require a higher level facility (resource-requiring cases), that can be used at primary health care facilities with limited diagnostic and therapeutic resources. METHODS: A prospective study of children 2 to 59 months old presenting to a poison treatment facility within 2 hours of oral hydrocarbon exposure. History and objective signs were recorded at admission and at 6, 12, 24 and, if present, 48 hours. Inclusion in the resource-requiring outcome group required: oxygen saturation <94%; any CNS depression; any treatment with (salbutamol); any care in the ICU; or death. RESULTS: 256 met the inclusion criteria and completed the study. Of these, 170 had a course requiring resources unavailable at most primary health care facilities, and 86 did not. The presence of wheezing, any alteration in consciousness (lethargy or any restlessness), or a rapid respiratory rate for age (RR >or= 50/min if age < 12 mo, >or= 40/min if age >or= 12 mo) at presentation identified 167 of 170 of these patients (sensitivity 0.98). Thirty-six of 86 patients classified as non-resource requiring were correctly identified (specificity 0.42). No combination of clinical symptoms provided better discrimination while preserving sensitivity. CONCLUSIONS: This study suggests a triage decision rule based on the presence of wheezing, altered consciousness, or a rapid respiratory rate within 2 hours of hydrocarbon exposure. Such a rule requires validation in other settings.

Regenerating nodules in arteriohepatic syndrome: a case report.

We report the multimodality imaging features of two cases of arteriohepatic syndrome (AS) complicated by a regenerating nodule. CT, ultrasound and MRI revealed nodular liver lesions with cirrhotic and portal hypertension changes. A large mass identified in both cases appeared hyperdense on unenhanced CT, hypointense on T(2) weighted imaging and showed normal-appearing hepatic vasculature coursing through the lesion in all contrast-enhanced imaging, highly suggestive of a regenerating nodule. Knowledge of this entity is quite important as patients with AS are also predisposed to hepatocellular carcinoma.

Fracture of the hydroxyapatite-ceramic-coated JRI-Furlong femoral component: body mass index and implications for selection of the implant.

We describe three cases of fracture of the titanium JRI-Furlong hydroxyapatite-ceramic (HAC)-coated femoral component. We have examined previous case reports of failure of this stem and conclude that fracture may occur in two places, namely at the neck-shoulder junction and at the conical-distal cylindrical junction. These breakages are the result of fatigue in a metallurgically-proven normal femoral component. All the cases of failure of the femoral component have occurred in patients with a body mass index of more than 25 in whom a small component, either size 9 or 10, had been used. In patients with a body mass index above normal size 9 components should be avoided and the femoral canal should be reamed sufficiently to accept a large femoral component to ensure that there is adequate metaphyseal fixation.

Distinguishing nonalcoholic steatohepatitis from fatty liver: serum-free fatty acids, insulin resistance, and serum lipoproteins.

OBJECTIVES: The prognosis of nonalcoholic fatty liver disease is determined by liver biopsy; steatohepatitis can be progressive whereas fatty liver is benign. Insulin resistance and increased hepatic-free fatty acids are central to the pathophysiology of this disorder. Our objective was to assess whether serum-free fatty acids, lipoproteins, and insulin resistance are increased in steatohepatitis compared with fatty liver and healthy controls, and thus may be potential noninvasive markers for liver disease severity. METHODS: Fifteen subjects with biopsy proven nonalcoholic steatohepatitis, 15 with histological fatty liver, and 15 healthy controls were enrolled. Fasting serum glucose and insulin levels, serum-free fatty acids, HDL, LDL, and cholesterol were collected from each subject. Insulin resistance was calculated using the homeostasis assessment model. RESULTS: Insulin resistance, LDL, and cholesterol-to-HDL ratio values were significantly higher in steatohepatitis, whereas HDL was significantly lower compared with both fatty liver and controls. Free fatty acids were similar in all groups. CONCLUSIONS: Along with insulin resistance, serum LDL, and cholesterol-to-HDL ratio values increase with worsening severity of liver histology, and serum HDL values decline. Free fatty acids, however, do not vary between groups.

Gene expression profiling of acute liver stress during living donor liver transplantation.

During liver transplantation, the donor graft is subjected to a number of acute stresses whose molecular basis is not well-understood. The effects of surgical stress, preservation and reperfusion injury were studied in 24 consecutive living donor liver transplant (LDLT) operations. Liver biopsies were taken early in the donor operation (OPENING), after transection of the donor liver (PRECLAMP) and following implantation of the graft (post hepatic artery, [PHA]); these were evaluated for histology, tissue glutathione content and gene expression using a 19K-human cDNA microarray. LDLT was associated with an ischemia/reperfusion injury, with accumulation of small numbers of neutrophils and decreased glutathione in the PHA biopsies. Following reperfusion, the expression of 129 genes increased and 106 genes decreased when compared to OPENING levels (> or <2-fold, p < 0.01). By real-time PCR a subset of 25 genes was verified (15 increased, 10 decreased). These genes were similarly altered in another condition of acute liver stress (the response to brain-death), but not in three chronic liver disease states (HCV, HBV and PBC). This study has identified a set of genes whose expression is altered in acute, but not chronic, liver stress, likely to play a central role in the pathogenesis of acute liver injury of liver transplantation.

Indeterminate colitis.

Indeterminate colitis (IC) originally referred to those 10-15% of cases of inflammatory bowel disease (IBD) in which there was difficulty distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) in the colectomy specimen. However, IC is increasingly used when a definitive diagnosis of UC or CD cannot be made at colonoscopy, in colonic biopsies or at colectomy. The diagnostic difficulties may explain the variably reported prevalence of IC. Clinically, most patients with IC evolve to a definite diagnosis of UC or CD on follow up. The role of ancillary tests in the distinction of UC from CD is reviewed. The low sensitivity of serological markers limits their usefulness. Other tests include upper endoscopy and magnetic resonance imaging. The definition of IC may not be a purely histological one derived from resected specimens, but rather a clinicopathological one. This review offers some personal observations and viewpoints, and proposes an approach to some of the relatively more esoteric combinations of findings.

Liver fibrosis attributed to lipid lowering medications: two cases.

We identified two cases of chronic active hepatitis with liver fibrosis induced by lipid lowering drugs of the statin and fibrate classes despite regular monitoring of transaminases. There are few reports of clinically significant hepatitis induced by these drugs and even fewer cases of fibrosis. Given the growing use of these drugs, there are implications for monitoring patients on long-term therapy for liver damage.

The pathology of epithelial pre-malignancy of the gastrointestinal tract.

This chapter deals with pre-malignant epithelial lesions of the gastrointestinal tract that have the potential to become cancers. Pre-malignant lesions are divided into two types: those characterized by dysplastic mucosa and those without dysplasia. Examples of the two types are present in the oesophagus, stomach and intestine. In the oesophagus, dysplasia of the squamous epithelium is a precursor to squamous carcinoma. There are differences in interpretation between Western and Japanese pathologists in the diagnosis of oesophageal squamous lesions. Dysplasia in Barrett's oesophagus is regarded as a precursor of adenocarcinoma. The goal of endoscopic surveillance in Barrett's mucosa is the detection of high-grade dysplasia. There are several problems with our current knowledge of high-grade dysplasia and controversies regarding its management. There are differences in the interpretation of biopsies of gastric epithelial dysplasia between Japanese and Western pathologists. In the colon, pre-malignant lesions include dysplasia seen in inflammatory bowel disease and colonic adenomas. The most significant predictor of the risk of malignancy in patients with inflammatory bowel disease is the presence of dysplasia in colonic biopsies. Because of the similarity of neoplasia throughout the gastrointestinal tract, there have been attempts to unify its classification, terminology and diagnostic criteria internationally, the most recently proposed modified classification of gastrointestinal neoplasia being the Vienna classification. Dysplasia of the columnar mucosa has a similar appearance in Barrett's oesophagus, the stomach and the colon. Criteria for its histological diagnosis and grading are reviewed, with an emphasis on areas of diagnostic difficulty such as interobserver variation, and discrepancies between Western and Japanese pathologists. Implication of the presence of dysplasia that are specific to each organ site are discussed, highlighting weaknesses and controversies in current knowledge.

Role of activated host T cells in the promotion of MALT lymphoma growth.

Gastric mucosa-associated lymphoid tissue (MALT) B cell lymphomas contain activated helper T cells. The evidence supports the presence of mechanisms of T cell dependence underlying the development of these lymphomas. It appears that the T cells, which activate B cells, may contribute to lymphoma pathogenesis. Co-stimulatory molecules necessary for effective B cell/T cell interaction are expressed in MALT lymphomas. The studies suggest that CD40 signaling, in combination with cytokines, is essential for the development and progression of MALT lymphomas. Activated T cells of low grade gastric MALT lymphoma, while delivering full help to B cells, are apparently deficient in two cytotoxic mechanisms involved in the concomitant control of B cell growth.