Seeding of hepatocellular carcinoma into the stomach wall following endoscopic ultrasound and fine-needle aspiration biopsy.

Delayed gastrointestinal metastasis is a rare complication of hepatocellular carcinoma (HCC). We present the case of a patient who presented with melaena and microcytic anaemia 6 years after receiving an orthotopic liver transplant for hepatitis B-induced HCC. Oesophagogastroduodenoscopy revealed a fungating gastric mass at the lesser curve and histology from biopsies confirmed metastatic recurrence of HCC in the stomach. The route of metastasis is likely due to iatrogenic seeding of tumour cells during pre-transplant endoscopic ultrasound (EUS) and fine needle aspiration (FNA) biopsy. Subsequent positron emission tomography and magnetic resonance imaging failed to reveal further metastatic disease and the patient was managed with a total gastrectomy. This is the first reported description in the literature of needle-track metastasis in the stomach due to liver EUS-FNA for HCC.

Mandard tumour regression grade, perineural invasion, circumferential resection margin and post-chemoradiation nodal status strongly predict outcome in locally advanced rectal cancer treated with preoperative chemoradiotherapy.

AIMS: The pathology of tumours after chemo/radiotherapy for locally advanced rectal cancer can be difficult to interpret. The ypTNM staging does not accurately predict outcomes. Therefore, we developed a new prognostic index for this purpose. MATERIALS AND METHODS: The Nottingham Rectal Cancer Prognostic Index (NRPI) is based on a study of 158 patients with locally advanced rectal cancer treated with preoperative chemo/radiotherapy at Nottingham University Hospital between April 2001 and December 2008. Patients were treated with radiotherapy to a dose of 50 Gy in 25 fractions over 5 weeks with/without concurrent capecitabine chemotherapy. Surgery was carried out after an interval of 6-10 weeks. Factors found to be significant on univariate analysis to predict for disease-free (DFS) and overall survival were further explored in multivariate analysis. The significant factors (Mandard tumour regression grade, perineural invasion, circumferential resection margin status and nodal status) were weighted to establish a score for the index. The median follow-up was 40 months (range 3-90 months). RESULTS: On survival analysis, four distinct prognostic groups were found: Score 0 = excellent prognosis, 1-3 = good prognosis, 4-8 = moderate prognosis, 9-14 = poor prognosis. The NRPI significantly predicted both DFS and overall survival (P < 0.0001). DFS at 5 years was 95, 63, 25 and 0% for the four groups. On multivariate analysis the NRPI was found to be the strongest predictor of DFS including nodal and circumferential resection margin status (P < 0.0001). It was a stronger predictor of overall survival than the American Joint Committee on Cancer/Dukes staging (P < 0.0001). CONCLUSIONS: The NRPI allocates patients into distinct prognostic categories. This seems to be a much stronger predictive factor than the American Joint Committee on Cancer/Dukes staging. This requires further validation, but seems to be a useful clinical index for future studies.

Helicobacter pylori downregulates expression of human ß-defensin 1 in the gastric mucosa in a type IV secretion-dependent fashion.

Helicobacter pylori establishes a chronic lifelong infection in the human gastric mucosa, which may lead to peptic ulcer disease or gastric adenocarcinoma. The human beta-defensins (hßDs) are antimicrobial peptides, hßD1 being constitutively expressed in the human stomach. We hypothesized that H. pylori may persist, in part, by downregulating gastric hßD1 expression. We measured hßD1 and hßD2 expression in vivo in relation to the presence, density and severity of H. pylori infection, investigated differential effects of H. pylori virulence factors, and studied underlying signalling mechanisms in vitro. Significantly lower hßD1 and higher hßD2 mRNA and protein concentrations were present in gastric biopsies from infected patients. Those patients with higher-level bacterial colonization and inflammation had significantly lower hßD1 expression, but there were no differences in hßD2. H. pylori infection of human gastric epithelial cell lines also downregulated hßD1. Using wild-type strains and isogenic mutants, we showed that a functional cag pathogenicity island-encoded type IV secretion system induced this downregulation. Treatment with chemical inhibitors or siRNA revealed that H. pylori usurped NF-κB signalling to modulate hßD1 expression. These data indicate that H. pylori downregulates hßD1 expression via NF-κB signalling, and suggest that this may promote bacterial survival and persistence in the gastric niche.

Neurofibroma of the bile duct: a rare cause of obstructive jaundice.

Neurofibromas of the common bile duct are extremely rare. The lack of specific clinical or radiological features makes preoperative diagnosis in the absence of histology difficult. We report the case of a female patient who presented with obstructive jaundice and evidence of a common bile duct stricture on imaging. She underwent an exploratory laparotomy, and intraoperative frozen section confirmed clear margins and a benign lesion. Excision of the extrahepatic bile duct and A Rouxen-Y hepaticojejunostomy was performed. We discuss the clinical features and management of neurofibromas of the bile duct in light of the literature.

Prognostic importance of Mandard tumour regression grade following pre-operative chemo/radiotherapy for locally advanced rectal cancer.

PURPOSE: To assess the prognostic value of the Mandard tumour regression score (TRG) following pre-operative chemo/radiotherapy in patients with locally advanced rectal cancer. METHODS AND MATERIALS: The study involved 158 patients with locally advanced rectal cancer treated with pre-operative long course chemo/radiotherapy at Nottingham University Hospital between April 2001 and December 2008. Patients were treated with radiotherapy to a dose of 50 Gy in 25 fractions over 5 weeks with or without concurrent capecitabine chemotherapy at a dose of 1650 mg/m(2)/day. Surgery was normally performed after an interval of 6-10 weeks. The response to pre-operative treatment was carefully graded by a single pathologist using the five point Mandard score. The median follow-up was 40 months (range 3-90 months). RESULTS: Of the 158 patients 14% were TRG1, 41% were TRG2, 31% were TRG3, 13% were TRG4 and 1% were TRG5. The groups were combined into TRG1, TRG2 and TRG3-5 to simplify further analysis. The Mandard score was clearly related to both disease-free (p < 0.001) and overall survival (p = 0.012). On multivariate analysis perineural invasion, nodal status, TRG and circumferential resection margin status were the most powerful predictors of disease-free survival. CONCLUSIONS: The Mandard tumour regression score is an independent prognostic factor and predicts for long-term outcome following pre-operative chemo/radiotherapy in rectal cancer.

Mucins and CD56 as markers of tumour invasion and prognosis in periampullary cancer.

BACKGROUND: This study investigated the association of mucins and cluster of differentiation (CD) 56 with vascular and perineural invasion and survival in patients with periampullary cancer. METHODS: Immunohistochemical staining was performed on formalin-fixed pancreatic tissue microarrays (cancer, chronic pancreatitis and normal pancreatic tissue) constructed from 126 pancreatic resections (cancer, 104; chronic pancreatitis, 22). Mucin (MUC) 1, MUC4 and MUC5AC expression was quantified using the immunohistochemical score (range 0-300), MUC3 expression was described as membranous or cytoplasmic, and expression of CD56, MUC2 and MUC6 as present or absent. RESULTS: In cancers, vascular invasion correlated with overexpression (immunohistochemical score of 100 or more) of MUC1 (P = 0.003) and presence of MUC6 (P = 0.024), and perineural invasion correlated with overexpression of MUC5AC (P = 0.015). Reduced survival was observed with overexpression of MUC4 (P = 0.032) and MUC5AC (P = 0.048), membranous expression of MUC3 (P = 0.048), and presence of CD56 (P = 0.041). Perineural invasion also correlated with CD56 expression (P = 0.001). Overexpression of MUC4 and MUC5AC correlated with tumour recurrence (P = 0.001 and P = 0.034 respectively). Multivariable analysis identified membranous expression of MUC3 (P = 0.023), lymphatic invasion (P = 0.015) and perineural invasion (P = 0.004) as independent predictors of poor survival. CONCLUSION: Mucins and CD56 may be markers of prognosis in patients with periampullary cancer.

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P=0.006), optimal debulking (P=0.009), and overall survival (P=0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P=0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P=0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P=0.007), vascular invasion (P=0.05), and poorly differentiated tumours (P=0.068). A trend was noticed with advanced stage (P=0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

Regression of rectal cancer with radiotherapy with or without concurrent capecitabine--optimising the timing of surgical resection.

AIMS: To determine tumour regression (volume-halving time) obtained after chemo/radiotherapy, and thereby the ideal interval between the start of treatment and surgery in order to obtain a high rate of complete response. MATERIALS AND METHODS: In total, 106 patients with cT3,4 rectal cancer who received preoperative radiotherapy alone or concurrently with capecitabine chemotherapy at Nottingham City Hospital, UK were studied. The rectal tumour volume visible on the computed tomography planning scan was compared with the residual pathological volume and the tumour volume-halving time calculated. The radiotherapy response was graded according to the Mandard system. RESULTS: Fifty-three patients had radiotherapy alone, with 53 patients having concurrent chemoradiotherapy. The median tumour volume-halving time was found to be 14 days and not influenced by the addition of chemotherapy. The Mandard score, the interval from the start of treatment to surgery and the tumour volume-halving time were statistically associated with tumour regression. The median tumour volume in our series of 54 cm(3) would require an interval of 20 weeks after the start of treatment to surgery to regress to <0.1 cm(3) (10 volume-halving times; 140 days). CONCLUSIONS: The initial tumour volume and median volume-halving time provide the best estimates for determining the optimum length of interval between the completion of preoperative chemo/radiotherapy and surgery in locally advanced rectal cancer.

Helicobacter pylori-induced peptic ulcer disease is associated with inadequate regulatory T cell responses.

BACKGROUND AND AIMS: Helicobacter pylori infection is the major cause of peptic ulceration and gastric adenocarcinoma. To address the hypothesis that the human acquired immune response to H. pylori influences pathogenesis, we characterised the gastric T helper (Th) and regulatory T cell (Treg) response of infected patients. METHODS: The human gastric CD4(+) T cell response of 28 donors who were infected with H. pylori and 44 who were not infected was analysed using flow cytometry. The T cell associated mucosal cytokine response was analysed by real-time polymerase chain reaction assay of samples from 38 infected and 22 uninfected donors. Recombinant interleukin 10 (IL10) was added to co-cultures of H. pylori and AGS cells and its suppressive effects upon inflammatory responses were measured. RESULTS: We found that the H. pylori-specific response consists of both T helper 1 and 2 subsets with high levels of IL10-secreting Tregs. People with peptic ulcer disease had a 2.4-fold reduced CD4(+)CD25(hi)IL10(+) Treg response (p = 0.05) but increased Th1 and Th2 responses (Th1: 3.2-fold, p = 0.038; Th2: 6.1-fold, p = 0.029) compared to those without ulcers. In vitro studies showed that IL10 inhibited IL8 expression and activation of nuclear factor kappa B induced by H. pylori in gastric epithelial cells, and enhanced H. pylori growth in a bacterial-cell co-culture model. CONCLUSIONS: Together our data suggest that H. pylori induces a regulatory T cell response, possibly contributing to its peaceful coexistence with the human host, and that ulcers occur when this regulatory response is inadequate.

Brunner's gland hyperplasia at the ampulla of Vater.

Brunner's gland hyperplasia (BGH) is a diagnostic challenge where in the pathophysiology and natural history remain poorly understood. This Case Report describes BGH arising at the ampulla of Vater, causing abdominal pain and vomiting in a 46-year-old man. Owing to the inconclusive nature of imaging studies and suspicious intraoperative findings, a Whipple resection was performed without any complications. Histological analysis showed that the obstructing lesion was BGH, with no evidence of malignancy. This is only the second such case of its kind at the ampulla of Vater to be reported. In addition, we present the previously unreported endoscopic ultrasound findings. The subsequent literature review focuses on the pathophysiology, clinical presentation, diagnosis and management of BGH.

Small bowel volvulus due to giant mesenteric lipoma.

We report on a 14-year-old girl with acute intestinal obstruction due to volvulus of the small bowel caused by a giant mesenteric lipoma. To the best of our knowledge, this presentation of a mesenteric lipoma is unknown in the previous paediatric literature.

Improving diagnostic yield of biliary brushings cytology for pancreatic cancer and cholangiocarcinoma.

Biliary brushings are currently the best accepted method to obtain a cytological diagnosis of pancreatic cancer or cholangiocarcinoma. The technique has good specificity but poor sensitivity. Two dedicated pathologists reviewed 137 consecutive biliary brushings from 127 patients between February 1997 and February 2000. The ultimate diagnosis was determined by review of radiology, operative diagnosis and patient outcome. The sensitivity, specificity, positive predictive value and negative predictive value of the original results and the review results were calculated and compared. Additional diagnostic categories 'suspicious' and 'atypical possibly benign' were included on review. After review, the sensitivity improved from 49.4% to 89.0% and the specificity remained 100%. The use of the additional diagnostic category 'suspicious' increased the sensitivity to 90.4%, at the expense of a fall of the specificity to 66.7%. We conclude that review by two dedicated pathologists and additional diagnostic categories can improve the diagnostic accuracy of biliary brushings.

Metastatic rectal adenocarcinoma to the liver associated with focal nodular hyperplasia.

A 45-year-old female patient underwent right hemihepatectomy for metastatic rectal adenocarcinoma. Preoperative imaging demonstrated an area of focal nodular hyperplasia (FNH) in segment VIII and metastatic carcinoma in segment VI of the liver. Gross and microscopic examination of the former lesion showed features typical of FNH with an intralesional metastatic adenocarcinoma. To the best of our knowledge, this is the first reported case of metastatic adenocarcinoma located within a lesion of FNH. The possibility of a pathogenetic association behind this occurrence is discussed.

Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C.

BACKGROUND: Hepatic fibrosis is one of the main consequences of liver disease. Both fibrosis and steatosis may be seen in some patients with chronic hepatitis C and alcoholic liver disease (ALD). AIMS: To quantitate fibrosis and steatosis by stereological and morphometric techniques in patients with chronic hepatitis C and compare the results with a control group of patients with ALD. In addition, to correlate the quantitative features of fibrosis with the Ishak modified histological score. MATERIALS AND METHODS: Needle liver biopsies from 86 patients with chronic hepatitis C and from 32 patients with alcoholic liver disease (disease controls) were analysed by stereological and morphometric analyses using the Prodit 5.2 system. Haematoxylin and eosin and Picro-Mallory stained sections were used. The area fractions (A(A)) of fibrosis, steatosis, parenchyma, and other structures (bile duct and central vein areas) were assessed by stereological method. The mean diameters of fat globules were determined by morphometric analysis. RESULTS: Significant differences were found in the A(A) of fibrosis, including fibrosis within portal tract areas, between chronic hepatitis C patients and those with ALD (mean (SD): 19.14 (10.59) v 15.97 (12.51)). Portal and periportal (zone 1) fibrosis was significantly higher (p = 0.00004) in patients with chronic hepatitis C compared with the control group (mean (SD): 9.04 (6.37) v 3.59 (3.16)). Pericentral fibrosis (zone 3) occurred in both groups but was significantly more pronounced in patients with ALD. These results correlate well with the modified Ishak scoring system. However, in patients with cirrhosis (stage 6) with chronic hepatitis C the A(A) of fibrosis varied between 20% and 74%. The diameter of fat globules was significantly lower in patients with hepatitis C (p = 0.00002) than the ALD group (mean (SD): 14.44 (3.45) v 18.4 (3.32)). Microglobules were more frequent in patients with chronic hepatitis C than in patients with ALD. In patients with chronic hepatitis C, the fat globules had a zonal distribution in comparison with pan steatosis in ALD. CONCLUSION: Quantitative, stereological techniques are simple and reliable for evaluating hepatic fibrosis and steatosis in chronic hepatitis C. They are most useful for assessing the origin, location, and the stage of fibrosis. Stereology and morphometry are recommended for the quantitation of fibrosis and steatosis, particularly for the evaluation of new treatment strategies in patients with chronic hepatitis C.