Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer.

Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130F/F and Gan) characterized by high tumor TLR2 expression. Notably, enrichment of this TLR2-regulated gene signature also positively correlated with augmented TLR2 expression in human GC tumors, and served as an indicator of poor patient survival. Furthermore, treatment of gp130F/F and cell line-derived xenograft (MKN1) GC mouse models with a humanized anti-TLR2 antibody suppressed gastric tumor growth, which was coincident with alterations to the TLR2-driven gene signature. Collectively, our study demonstrates that in the majority of GC patients, elevated TLR2 expression is associated with a growth-potentiating gene signature which predicts poor patient outcomes, thus supporting TLR2 as a promising therapeutic target in GC.

Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis.

Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) littermates. At the molecular level, suppressed tumourigenesis in gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained unaltered compared with gp130(F/F) mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis.

Liver fluke-associated and sporadic cholangiocarcinoma: an immunohistochemical study of bile duct, peribiliary gland and tumour cell phenotypes.

AIM: To compare cell phenotypes displayed by cholangiocarcinomas and adjacent bile duct lesions in patients from an area endemic in liver-fluke infestation and those with sporadic cholangiocarcinoma. METHODS: 65 fluke-associated and 47 sporadic cholangiocarcinomas and 6 normal livers were studied. Serial paraffin-wax sections were stained immunohistochemically with monoclonal antibodies characterising a Brunner or pyloric gland metaplasia cell phenotype (antigens D10 and 1F6), intestinal goblet cells (antigen 17NM), gastric foveolar apomucin (MUC5AC), a gastrointestinal epithelium cytokeratin (CK20) and the p53 protein. RESULTS: 60% of the 112 cholangiocarcinomas expressed antigen D10, 68% MUC5AC, 33% antigen 17NM and 20% CK20; 37% showed overexpression of p53. When present together in a cholangiocarcinoma, cancer cells expressing D10 were distinct from those displaying 17NM or MUC5AC. Many more fluke-associated cholangiocarcinomas than sporadic cholangiocarcinomas displayed 17NM and p53 expression. Most cases of hyperplastic and dysplastic biliary epithelium expressed D10 strongly. Pyloric gland metaplasia and peribiliary glands displayed D10 and 1F6, with peribiliary gland hyperplasia more evident in the livers with fluke-associated cholangiocarcinoma; goblet cells in intestinal metaplasia stained for 17NM. No notable association of expression between any two antigens (including p53) was found in the cancers. CONCLUSIONS: Most cases of dysplastic biliary epithelium and cholangiocarcinoma display a Brunner or pyloric gland cell phenotype and a gastric foveolar cell phenotype. The expression of D10 in hyperplastic and dysplastic epithelium and in cholangiocarcinoma is consistent with a dysplasia-carcinoma sequence. Many more fluke-associated cholangiocarcinomas than sporadic cholangiocarcinoma display an intestinal goblet cell phenotype and overexpress p53, indicating differences in the aetiopathology of the cancers in the two groups of patients.

Liver failure complicating non-alcoholic steatohepatitis following allogeneic bone marrow transplantation for Shwachman-Diamond syndrome.

Bone marrow transplantation is potentially curative therapy for the hematologic complications associated with Shwachman-Diamond syndrome (SDS). This syndrome is, however, also associated with significant pancreatic and hepatic dysfunction, which may complicate BMT. We report a case of liver failure due to non-alcoholic steatohepatitis (NASH) following BMT for SDS. This case illustrates the need for assessing liver dysfunction pre-BMT in these patients, in addition to highlighting the potential risk posed by pre-existing steatosis for the development of rapidly progressive hepatic failure following transplantation.

Local recurrence after curative anterior resection with principally blunt dissection for carcinoma of the rectum and rectosigmoid.

PURPOSE: The aim of this study was to determine the incidence of local pelvic recurrence of carcinoma of the rectum and rectosigmoid (tumors where the lower edge is 18 cm or less from the anal verge) in a consecutive series of patients operated on by a single surgeon. All patients underwent curative anterior resection and a formal anatomic dissection of the rectum where mobilization was achieved through a principally careful blunt manual technique along fascial planes, preserving an oncologic package. METHOD: During the period April 1986 to December 1997, 157 consecutive anterior resections for carcinoma of the rectum and rectosigmoid were performed by one surgeon (ALP). One hundred thirty-eight (87.9 percent) were curative, and 19 (12.1 percent) were palliative. The mean follow-up period was 46 +/- 31.6 (range, 2-140) months. Data were retrospectively collated and computer coded by an independent contracted medical research team. Follow-up data were available on all patients. RESULTS: Four (3.1 percent) of the 131 patients undergoing curative anterior resection had local recurrence. Local recurrences occurred between 16 and 38 months from the time of resection, and the cumulative risk of developing local recurrence at five years was 5.2 percent. All tumors in which pelvic recurrence occurred were high grade, and the probability of developing local recurrence at five years for this group was 13.9 percent, which is significantly higher compared with patients who had average or low-grade tumors (P = 0.01). The probability of developing local recurrence at five years for Stage I tumors was 0, Stage II was 5.9 percent, and Stage III was 8.9 percent. In addition, there was a significantly higher incidence of local recurrence in the group of patients undergoing ultralow anterior resection (between 3 and 6 cm from the anal verge) as compared with patients undergoing low or high anterior resection (P = 0.03). Local recurrence developed in 3 of 28 (10.7 percent) patients having ultralow anterior resection, 1 of 57 (1.8 percent) patients having low anterior resection (between 6 and 10 cm from the anal verge), and no patients having high anterior resection (above 10 cm from the anal verge). The clinical anastomotic leak rate for curative anterior resection was 7 of 131 patients (5.3 percent). Thirty-seven of the 131 (28.2 percent) required a proximal defunctioning stoma; 35 (41.2 percent) of these were established for low or ultralow anterior resections and 2 for high anterior resection. The overall five-year cancer-specific survival rate of the entire group of 131 patients was 81.8 percent, and the overall probability of being disease free at five years including both local and distal recurrence was 72.9 percent. Three local recurrences occurred in the 101 patients (77 percent) who did not receive any form of adjuvant therapy. One local recurrence occurred in the 18 patients (13.7 percent) who had adjuvant chemoradiation. No recurrence occurred in the 12 patients (9.2 percent) who had adjuvant chemotherapy alone. CONCLUSION: Curative anterior resection for carcinoma of the rectum and rectosigmoid with principally blunt dissection of the rectum in this study is associated with a 3.1 percent incidence and a 5.2 percent probability at five years of developing local recurrence. Evidence from this study indicates that, as with sharp pelvic dissection, a low incidence and probability of local recurrence can be achieved by a principally blunt mobilization technique through careful attention to preservation of fascial planes in the pelvis and removal of an oncologic package with selective rather than routine adjuvant or neoadjuvant chemoradiation.

Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is common in severely obese subjects and can progress to cirrhosis and liver failure. Predicting advanced or progressive disease may help in selecting patients for liver biopsy and assist the development of therapeutic options. METHODS: Liver biopsies were taken at laparoscopic obesity surgery in 105 consecutive patients. The clinical and biochemical variables were analyzed for correlation with specific histologic features. RESULTS: Twenty-six patients (25%) were found to have nonalcoholic steatohepatitis (NASH), and 11 (42%) of these had advanced fibrosis. A raised index of insulin resistance (odds ratio [OR] 9.3, 95% confidence interval [CI] 3.4-26), systemic hypertension (OR 5.2, 95% CI 2.0-13.5), and raised alanine aminotransferase (OR 8.6, 95% CI 3.1-23.5) were independent predictors of NASH. A combination of 2 or 3 of these predictors allows a sensitivity of 0.8 and specificity of 0.89 for NASH. Alcohol consumption was associated with a reduction in NASH (OR 0.35, 95% CI 0.12-1.00) and diabetes (OR 0.18, 95% CI 0.047-0.67). CONCLUSION: Insulin resistance and systemic hypertension, features of the metabolic syndrome, are independently associated with advanced forms of NAFLD. Moderate alcohol consumption seems to reduce the risk of NAFLD in the severely obese, possibly by reducing insulin resistance.

Overexpressed growth hormone (GH) synergistically promotes carcinogen-initiated liver tumour growth by promoting cellular proliferation in emerging hepatocellular neoplasms in female and male GH-transgenic mice.

BACKGROUND/AIMS: Growth hormone (GH), when overexpressed in male and female GH-transgenic mice, is known to induce liver tumours within 1 year. This study aimed to gain a clearer understanding of the interaction between GH and tumour cells in vivo. METHODS/RESULTS: The carcinogen diethylnitrosomine (DEN) was administered to neo-natal transgenic and non-transgenic mice maintained in a "hepatocarcinogenesis resistant" genetic background (C57BL/6J). Macroscopic, microscopic and liver weight/body weight ratio analyses revealed that carcinogen-induced hepatocarcinogenesis was dramatically accelerated in young GH-transgenic mice compared to non-transgenic counterparts. Image analysis of microscopic hepatocellular neoplasms showed rapidly increasing tumour burdens, and neoplastic foci size over time in young adult GH-transgenic mice. The magnitude of enhanced tumour growth was equivalent in both male and female transgenic mice, whereas much lower and sexually dimorphic tumour growth rates (males>females) were observed in non-transgenic mice treated with DEN. BrdU labelling experiments demonstrated that rapid tumour growth in carcinogen-treated GH-transgenic mice was due to the promotion of cell proliferation in emerging lesions. Tumour cell proliferation in young GH-transgenic mice was 2.6- and 4-fold higher, respectively, than that observed in similar age male and female non-transgenic mice. Interestingly, both GH-transgenic and non-transgenic mice displayed progressively slower tumour growth rates in older animals. CONCLUSION: Overall, GH synergistically promotes carcinogen-induced hepatocarcinogenesis in both sexes of GH-transgenic mice by stimulating tumour cell proliferation.

Compound heterozygosity for haemochromatosis gene mutations and hepatic iron overload in allogeneic bone marrow transplant recipients.

Iron overload has been proposed as a cause of liver dysfunction after BMT Factors which could be relevant to iron overload include the number of red cell transfusions and mutations within the haemochromatosis gene (HFE). Two point mutations, Cys282Tyr and His63Asp, have been described within HFE. Cys282Tyr homozygosity is associated with haemochromatosis; the effect of compound heterozygosity, Cys282Tyr/His63Asp, on iron status is variable. We analysed HFE status in 52 allograft patients surviving more than 6 months. Compound heterozygosity was identified in three patients (Cases 1-3). Iron status and liver function were evaluated and, in Cases 1 and 2, liver histology and iron content as well. Case 3 who received 12 units of red cells had a normal ferritin and liver function. Cases 1 and 2 received 29 and 59 units, respectively, and had high serum ferritins and transferrin saturations, abnormal liver function and significant hepatic iron overload on biopsy. Iron overload in Case 1 patient progressed in the context of GVHD and in the absence of further transfusion, suggesting that liver GVHD may increase hepatic iron accumulation. These cases demonstrate the variable phenotypic expression of HFE compound heterozygosity in BMT recipients, which may be only partly explained by transfusional iron loading. Venesection or chelation therapy should be considered in patients with coexistent hepatic GVHD and iron overload.

High, persistent hepatocellular proliferation and apoptosis precede hepatocarcinogenesis in growth hormone transgenic mice.

AIMS/BACKGROUND: Growth hormone (GH) transgenic mice are known to develop hepatocellular adenomas and carcinomas. In order to understand more about hepatocarcinogenesis in the GH-transgenic mouse model we quantitated the rates of hepatocellular proliferation and apoptosis in these mice. METHODS: Two lines of GH-transgenic mice and non-transgenic control mice were generated and sacrificed at regular intervals between one and nine months. Hepatocellular replication was measured by in vivo incorporation of bromodeoxyuridine (BrdU) and counting BrdU-positive nuclei in histological liver sections. Serial sections taken from these mouse livers were also assessed for rates of hepatocellular apoptosis using the in situ end-labelling of fragmented DNA (TUNEL) method. RESULTS: High levels of hepatocellular replication were sustained life-long in this model. Increased rates of hepatocellular proliferation preceded the onset of hepatic inflammation, a prominent feature in the liver pathology of GH-transgenic mice. In tumour tissue, cellular proliferation was up to 17-fold greater than in surrounding non-tumour tissue. Apoptosis rates were also elevated in non-tumour regions of GH-transgenic mouse livers compared to controls. Interestingly, large dysplastic hepatocytes were common in the fraction of cells undergoing apoptosis, especially in older mice with inflamed livers. The increase in the rate of hepatocellular apoptosis in GH-transgenic animals largely balanced the augmented levels of proliferation seen in these mice. In tumour tissue, however, the profound increase in the number of proliferating tumour cells outstripped the increase in apoptosis. CONCLUSION: Relatively high and enduring levels of hepatocellular replication and apoptosis precede hepatocarcinogenesis in GH-transgenic mice. Increased cellular proliferation and resistance to apoptosis were evident in tumour growth in older animals.

Gastric mucous neck cell and intestinal goblet cell phenotypes in gastric adenocarcinoma.

AIM: To investigate the phenotype of cells comprising diffuse and intestinal-type gastric cancers using monoclonal antibodies to two antigens. One antigen (designated D10) is characteristic of gastric mucous neck cells, cardiac glands, pyloric glands, and Brunner's glands. The second antigen (designated 17NM) is specific to the mucous vacuole of intestinal goblet cells. METHODS: Thirty two gastrectomy specimens with adenocarcinoma were studied. Serial paraffin sections were stained immunohistochemically for D10 and 17NM and histochemically for acid and neutral mucins. The cancers were classified histologically as of either diffuse or intestinal type according to Lauren. RESULTS: Of 15 diffuse-type gastric carcinomas, 11 showed the majority of cancer cells staining for D10 while four were typical signet ring cell cancers staining predominantly for 17NM; five tumours displayed both phenotypes with the two phenotypes segregated in different areas of the tumours. In contrast, of 16 intestinal-type cancers, six expressed 17NM, three D10, five neither antigen, and two expressed both antigens. One indeterminate-type cancer expressed both antigens. The staining of individual cells for D10 and 17NM was mutually exclusive in both diffuse and intestinal types. In contrast to the diffuse cancers, intestinal-type cancers typically expressed either antigen only in occasional small groups of cells and individual cells. CONCLUSIONS: In disease, the gastric stem cell can assume the capacity of the duodenal stem cell for divergent differentiation into either intestinal goblet cells (for example, as in intestinal metaplasia) or Brunner's gland cells (for example, as in pyloric gland/Brunner's gland metaplasia). With neoplastic transformation, this potential for divergent differentiation is maintained and gives rise to diffuse-type cancers that display either the D10 phenotype, the 17NM phenotype, or the clonal expression of both phenotypes. In the more cell cohesive (intestinal-type) tumours, differentiation for antigen expression is poorly developed and more frequently directed towards the intestinal goblet cell phenotype.

Comparison of intrahepatic lymphocytes from normal and growth hormone transgenic mice with chronic hepatitis and liver cancer.

Mice expressing an ovine growth hormone-mouse metallothionein promoter fusion gene (METoGH mice) develop chronic hepatitis which becomes progressively more severe over time, hepatocellular adenomas, and eventually carcinoma in the oldest animals. T-lymphocyte expression of activation/memory-associated markers was compared between liver and blood lymphocytes isolated from METoGH and non-transgenic mice at 7, 10 and 12 months of age. The percentage of intrahepatic lymphocytes (IHL) which were CD4+ was markedly diminished in METoGH mice at all times. CD4+ and CD8+ IHL in METoGH mice expressed Ly-6A/6D at increased density, and were CD45RBlo at later time-points. Ly-6C+ and NK1.1+ CD4+ cells, which are common in normal mouse liver, were found at decreased frequency in METoGH livers. Further analysis demonstrated that, as a proportion of total T-cell receptor (TCR) alpha beta cells, NK1.1+ TCR alpha beta int CD4+ cell numbers (NKT cells) were diminished in the livers of METoGH mice. Observations made in METoGH mice support the hypothesis that sustained liver inflammation and hepatocellular injury may be linked to liver cancer. Additionally, it is possible that the relative lack of NKT cells may create an environment permissive for the growth of liver tumours.

Colonoscopy and biopsy.

The place of colonoscopy in the management of ulcerative colitis is restricted to clinical situations where the information provided will change clinical management. The information provided will be answers to the questions?inflammatory bowel disease, o r, in the patient with known colitis: inflammatory bowel disease?type?activity extent?dysplasia. Biopsy is pivotal to the diagnosis and provides the certainty of tissue diagnosis, assessment of activity and detection of dysplasia. Sigmoidoscopy is sufficient for providing information for clinical management in most circumstances, but colonoscopy is important where clinical features are disproportionate to sigmoidoscopic findings and systemic parameters of inflammatory activity; to determine type and extent of inflammatory bowel disease and when surveillance needs to start; and for biopsy to detect dysplasia. Ileoscopy is an important aspect of colonoscopy for differential diagnosis, and is the unique definer of total colonoscopy.

The so-called bile duct adenoma is a peribiliary gland hamartoma.

The cell phenotype of so-called bile duct adenoma (BDA) was investigated immunohistochemically using monoclonal antibodies to two recently identified antigens (designated D10 and 1F6) extracted from human liver and cultured biliary epithelium. The acini and tubules of BDA consisted of serous and mucous cells that expressed D10 and 1F6. The intrahepatic peribiliary glands of normal liver, comprising intramural mucous glands and extramural tubuloalveolar seromucinous glands, similarly expressed D10 and 1F6 antigens. Antigen 1F6 was present in the cells forming the canals of Hering and normal bile ductules but not in interlobular and larger bile ducts. Proliferating bile ductules associated with large bile duct obstruction and alcoholic cirrhosis or the epithelia of the von Meyenberg complex and polycystic liver did not exhibit this combined profile of D10 and 1F6 expression and mucous cells. These findings suggest an origin of BDA from peribiliary glands rather than from bile ductules or ducts. Consistent with this view was our finding that 18 of the 30 BDA were spatially related to a large-calibre bile duct. Therefore, BDA, well known for its benign behavior is a small mass of disorganized but mature peribiliary gland acini and tubules within a variable amount of stroma and should properly be called a peribiliary gland hamartoma.

Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma.

Cancers share many similarities in growth patterns, cellular morphology, and oncofetal antigen expression with embryonic tissue. To better understand the mechanisms underlying malignant transformation and its relationship to developmental processes, we studied the expression of Cdx-2, an intestinal epithelium-specific homeodomain protein, in colorectal adenoma and carcinoma. By immunohistochemistry with a polyclonal Cdx-2 antibody we have shown that Cdx-2 expression is markedly reduced in the later stages of human colorectal carcinogenesis, namely, high grade dysplasia and invasive carcinoma. The same findings occur in 1,2-dimethylhydrazine-induced rat colorectal tumors, confirming the parallels between the rat model and the human disease. As homeodomain proteins play major roles in directing the regionalization of body parts and in organogenesis and cellular phenotypic specification, a reduction of Cdx-2 expression in the late stages of colorectal carcinogenesis may reflect a concomitant deviation of the neoplastic tissue from the normal intestinal epithelial phenotype.

Effect of changes in vascular tone on the haemodynamic characteristics of the portal vascular bed of the isolated perfused rat liver.

The effect of altered vascular tone on the haemodynamic characteristics of the intrahepatic portal vascular bed was studied in the isolated perfused rat liver preparation. The relationship between portal venous inflow (Q) and portal perfusion pressure (P) was determined in the presence of a maximally effective concentration of a vasoconstrictor agent (noradrenaline, NAmax, 3 x 10(-5)mol/L), an intermediate concentration (NAmed, 1 x 10(-6)mol/L) or a vasodilator agent (papaverine, PAP, 6 x 10(-4)mol/L). At flow rates greater than 20 mL/min, the pressure-flow relationship could be regarded as linear (P < 0.001), with mean values for the extrapolated intercept with the pressure axis (Po) of 6.8 +/- 0.9 mmHg for NAmax, 4.5 +/- 0.5 mmHg for NAmed, and 1.65 +/- 0.05 mmHg for PAP-treated preparations. Over the full flow range (0-70 mL/min), in both NA- and PAP-treated preparations, portal vascular conductance (G = Q/P) was related directly to perfusion pressure. Thus, G = C.P, where C is a constant (mean values for NAmax, NAmed, and PAP-treated preparations were 0.0090 +/- 0.0020, 0.023 +/- 0.005, and 0.26 +/- 0.02 mL/min per g per mmHg2, respectively). It is concluded that both C and Po may be useful indices of tone in the isolated perfused rat liver, and that analysis of hepatic portal haemodynamics in this manner may have considerable practical value in studies of the action of vasoactive agents.

Phenotypic identity of gastric mucous neck cells and mucous cells of cardiac, pyloric, and Brunner's glands.

AIM: To investigate the tissue specificity of a novel monoclonal antibody raised to a tissue fraction of normal human liver and which identified certain cells of gastric and duodenal mucosa. METHODS: A total of 155 samples of various tissues obtained from 100 surgical specimens were fixed in cold ethanol-paraformaldehyde, embedded in paraffin wax, and 3 microns sections were studied by immunohistochemical and lectin staining procedures. RESULTS: Immunohistochemical staining showed a major tissue specific component which was strongly expressed by mucous neck cells of the body of the stomach, glands of the cardia and pyloric antrum, and by Brunner's glands. Staining for antigen in the periductal glands of normal major biliary and pancreatic ducts was variable and relatively weaker. It was not detected elsewhere in normal intestine or in the other normal tissues tested. Barrett's mucosa of gastric cardia type, and pyloric gland metaplasia in the gall bladder and small bowel affected with Crohn's disease stained for the antigen. The tissue distribution of the antigen was identical with that of a glycoprotein, demonstrated by an induced affinity for concanavalin A following treatment of tissue sections with periodic acid. The antigen was not sensitive to sialidase. CONCLUSIONS: The tissue component identified (designated here as antigen D10) seems to be characteristic of certain differentiated epithelial cells derived from that part of foregut giving rise to stomach, duodenum, and biliary and pancreatic ducts. The antibody will be of use in investigating pathological processes involving tissue differentiation at these sites, and in the oesophagus and intestines.

Percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins.

BACKGROUND: Knowledge of the portal pressure may be of value in the assessment of patients with chronic liver disease but its measurement is problematic. AIMS: To evaluate the ease and safety of percutaneous transhepatic measurement of the pressure gradient between the portal and hepatic veins and to determine directly the need for an internal zero. METHODS: Sixty-one patients undergoing liver biopsy for suspected liver disease had pressures in branches of portal and hepatic veins measured using a flexible 22G (Chiba) needle. RESULTS: The procedure was successful in all patients, took less than ten minutes in most, and was associated with minimal discomfort. Post-procedure morbidity was similar to that of liver biopsy. Portal pressure using an external zero (either puncture site or sternal angle) was inaccurate compared with pressures obtained using the generally accepted gold standard internal zero, hepatic venous pressure, and led to incorrect classification of the presence or absence of portal hypertension in at least 10% of patients. Variations in hepatic venous pressure were not predictable on clinical grounds. The only histopathological feature predictive of portal hypertension was cirrhosis, 20 of 25 patients with and four of 36 patients without cirrhosis having portal hypertension. Of routine biochemical and haematological tests, only plasma albumin and platelet count jointly (and negatively) predicted hepatic venous pressure gradient on multiple regression analysis (R2 = 0.40). CONCLUSIONS: The use of an internal zero is essential for accurate measurement of portal pressure and this can be achieved safely using the percutaneous, transhepatic route in patients with well compensated liver disease.