Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo.

BACKGROUND: Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man. METHODS: We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa. RESULTS: Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists. CONCLUSION: While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.

Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia.

BACKGROUND & AIMS: The clonality of colitis-associated neoplasia has not been fully determined. One previous report showed polyclonal origins with subsequent monoclonal outgrowth. We aimed to assess the clonality and mutation burden of individual crypts in colitis-associated neoplasias to try to identify gatekeeping founder mutations, and explore the clonality of synchronous lesions to look for field effects. METHODS: Individual crypts (range, 8-21 crypts) were microdissected from across 17 lesions from 10 patients. Individual crypt adenomatous polyposis coli (APC), p53, K-RAS, and 17p loss of heterozygosity mutation burden was established using polymerase chain reaction and sequencing analysis. Serial sections underwent immunostaining for p53, beta-catenin, and image cytometry to detect aneuploidy. RESULTS: In most lesions an oncogenic mutation could be identified in all crypts across the lesion showing monoclonality. This founder mutation was a p53 lesion in the majority of neoplasms but 4 tumors had an initiating K-RAS mutation. Some nondysplastic crypts surrounding areas of dysplasia were found to contain clonal p53 mutations and in one case 3 clonal tumors arose from a patch of nondysplastic crypts containing a K-RAS mutation. CONCLUSIONS: This study used mutation burden analysis of individual crypts across colitis-associated neoplasms to show lesion monoclonality. This study confirmed p53 mutation as initiating mutation in the majority of lesions, but also identified K-RAS activation as an alternative gatekeeping mutation. Local and segmental field cancerization was found by showing pro-oncogenic mutations in nondysplastic crypts surrounding neoplasms, although field changes are unlikely to involve the entire colon because widely separated tumors were genetically distinct.

A case of liver metastasis from an oncocytoma with a focal area of chromophobe renal cell carcinoma: a wolf in sheep's clothing.

In 2004, the World Health Organization classified the renal oncocytomas as benign neoplasms of the kidney. There are reports of subtypes of renal tumors, with similar histological morphology to oncocytoma, but with malignant potential, one of these tumors is the eosinophilic variant of chromophobe renal cell carcinoma. It is important to characterize the histological features and the subtype of tumor, as this predicts biological behavior and cancer-specific survival rate. A rare case of a liver metastasis from a focal area of eosinophilic variant of chromophobe renal cell carcinoma mixed in oncocytoma in a 69-year-old woman is reported. Although some renal tumors may contain oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma histology, caution should be exercised while diagnosing oncocytomas in needle biopsies as there may be unsampled area of chromophobe carcinoma which has a potential for metastatic spread representing a wolf in sheep's clothing.

Outcome of liver transplantation for patients infected by hepatitis C, including those infected by genotype 4.

Predictors of hepatitis C virus (HCV)-related liver disease posttransplantation are still unclear. The impact of HCV genotype on outcome of transplantation has been studied, but conclusions are not in agreement. The role of HCV genotype 4 on the result of liver transplantation requires further study. The aim of this study is to examine the outcome of liver transplantation for patients with HCV genotype-4 infection. The study group included 128 patients who underwent transplantation for HCV infection: 28 patients, genotype 1; 11 patients, genotype 2; 19 patients, genotype 3; and 32 patients, genotype 4. For 64 of 128 patients, genotype was known and an assessable histological specimen was available. Median interval from transplantation to biopsy was 1.92 years (range, 0.24 to 11.48 years). Twenty-six percent of HCV genotype-4 patients developed either severe fibrosis or cirrhosis versus 6.7% in the genotype non-4 group (P =.04). A statistically significant greater fibrosis progression rate was observed in genotype-4 than genotype non-4 patients. In univariate and multivariate analysis, rapid liver fibrosis was associated with the presence of HCV genotype-4 infection. In addition, donor and recipient age and graft warm ischemic time also were associated with rate of fibrosis progression. Five-year cumulative rates for the development of cirrhosis or severe liver fibrosis were 84% in genotype-4 and 24% in genotype non-4 patients (P =.02). Five-year survival rates for patients with genotypes 1, 2/3, and 4 were 72%, 80%, and 79%, respectively (P =.8). In conclusion, 5-year survival for patients who underwent transplantation for HCV genotype-4 infection was similar to that of genotype non-4 patients; however, more severe fibrosis and rapid fibrosis progression was observed after transplantation in patients with genotype-4 infection.