Caroline Finlayson

Eicosapentaenoic acid (EPA) reduces crypt cell proliferation and increases apoptosis in normal colonic mucosa in subjects with a history of colorectal adenomas.

Background and aimsOmega-3 fatty acids in fish oil exert a protective effect on the development of colorectal cancer in animal models. Patients with colorectal adenomas have been shown to have increased crypt cell proliferation and decreased apoptosis in macroscopically normal appearing colonic mucosa. We investigated whether dietary supplementation with eicosapentaenoic acid (EPA) could alter crypt cell proliferation and apoptosis in such patients.Patients/methodsThirty subjects were randomised to either 3xa0months of highly purified EPA in free fatty acid form (2xa0g/day) or to no treatment. Colonic biopsies were taken at the initial colonoscopy and repeated 3xa0months later, and analysed for cell proliferation and apoptosis (immunohistochemistry) and mucosal fatty acid content.Results/findingsCrypt cell proliferation was significantly reduced whilst apoptosis was significantly increased after EPA supplementation. Neither crypt cell proliferation nor apoptosis were altered in the control group. EPA in the mucosa increased significantly after EPA supplementation, whereas there was no significant change in controls.ConclusionsDietary supplementation with EPA significantly increases levels of this fatty acid in colonic mucosa, associated with significantly reduced proliferation and increased mucosal apoptosis. Further studies are needed to assess the potential efficacy of EPA supplementation in preventing polyps in the chemoprevention of colorectal cancer.

A deficiency of interstitial cells of Cajal in Chagasic megacolon.

Disordered gut motor activity is a feature of patients with Chagas’ disease: colonic involvement leads to the development of megacolon and symptoms of constipation. Interstitial cells of Cajal are thought to modulate gut motility. The aim of this study was to test the hypothesis that there is an abnormality of the density of distribution of interstitial cells of Cajal in Chagasic megacolon. Interstitial cells of Cajal were identified by immunohistochemistry using an anti-c-kit antibody. Six patients with Chagasic megacolon were compared with normal controls. The density of distribution of interstitial cells of Cajal was assessed in the longitudinal and circular muscle layers, and in the intermuscular plane of the Chagasic and normal colon. Statistical analysis was performed using Fisher’s exact test. The interstitial cells of Cajal density in Chagasic megacolon was much reduced in comparison to normal colonic tissue in the longitudinal muscle layer (P50.0084), intermuscular plane (P,0.0001), and circular muscle layer (P50.0051). The lack of interstitial cells of Cajal may play a role in the pathophysiology of the disease, leading to the development of megacolon and symptoms of constipation.

Regional and transmural density of interstitial cells of Cajal in human colon and rectum

The interstitial cells of Cajal (ICC) are thought to play an important role in the control of gut motility. The regional and transmural pattern of distribution of ICC in the normal human colon and rectum was evaluated with immunohistochemistry using an anti-c- kit antibody. The transmural distribution of ICC was constant throughout the whole colon, the density of ICC was significantly greater at the myenteric plexus than at either the longitudinal or circular muscle layers, and in the rectum the transmural distribution was more even. Regionally, at the myenteric plexus, the transverse colon had a significantly greater density of ICC compared with the right colon ( P = 0.038), left colon ( P = 0.006), and rectum ( P = 0.008). The pattern of distribution of ICC identified in this study is consistent with the proposed roles of ICC as colorectal pacemakers, intermediaries of the neural control of muscle activity, and coordinators of colorectal muscle activity. The highest density of ICC was at the myenteric plexus of the transverse colon, which is the proposed region of pacemaking activity.

A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer

Background Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. Aim To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). Methods This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. Findings 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. Interpretation Artesunate has anti-proliferative properties in CRC and is generally well tolerated.

Dengue Hemorrhagic Fever with Fulminant Hepatic Failure in an Immigrant Returning to Bangladesh

An immigrant from Bangladesh living in the United Kingdom presented with a nonspecific febrile illness after visiting his homeland and subsequently developed fulminant hepatic failure accompanied by hypotension, ascites, a generalized coagulopathy, and thrombocytopenia. Serology and detection of dengue virus serotype 3 by PCR established a postmortem diagnosis of hepatic failure secondary to dengue hemorrhagic fever.

Impact of Microscopic Extranodal Tumor Deposits on the Outcome of Patients With Rectal Cancer

AbstractPURPOSE: Microscopic mesorectal soft tissue extranodal deposits discontinuous with the primary tumor are identified in many rectal adenocarcinomas. Current guidelines consider them to be involved lymph nodes. We studied the impact of these deposits on the outcome of patients with rectal cancer. nMETHODS: This was a retrospective study, in which histology slides were reviewed from 55 patients whose resection specimens for rectal cancer were staged as Dukes C or Dukes B with extranodal deposits. Twenty-nine patients had extranodal deposits (19 males), and 26 control patients had lymph node involvement only (14 males). Patient outcome was analyzed in terms of local and systemic control and survival. nRESULTS: Distant metastases were diagnosed earlier in patients with extranodal deposits (mean, 14 months) compared with controls (mean, 37 months; P = 0.001). On follow-up, 31.03 percent (9/29) from the extranodal deposit group developed liver metastases compared with 11.5 percent (3/26) of the control group (P = 0.08). Local recurrence was seen in 17.2 percent of patients from the extranodal deposit group and 3.8 percent of the control group (P = not significant). Cancer-related mortality was higher in the extranodal deposit group (16 vs. 7 patients; P = 0.09). The three-year actuarial survival was 48.27 percent in patients with extranodal deposits and 65.38 percent in those without. A significant association was noted between the number of extranodal deposits and intramural vascular invasion (P = 0.017), extramural vascular invasion (P = 0.039), perineural invasion (P = 0.039), and lymph node involvement (P = 0.008). nCONCLUSION: These data suggest that extranodal deposit is a distinct form of metastatic disease in patients with rectal cancer. The association with vascular invasion and earlier development of metastases probably infers that a significant proportion of extranodal deposits may represent blood-borne spread. These tumor foci should be considered as indicators of poor prognosis.

Distribution of the interstitial cells of Cajal in the human anorectum

The interstitial cells of Cajal are proposed to have a role in the control of gut motility. The aim of this study was to establish the distribution of interstitial cells of Cajal in the wall of the normal human anorectum. Interstitial cells of Cajal express the proto-oncogene c-kit. Interstitial cells of Cajal were identified in the colon by immunohistochemical staining, using a rabbit polyclonal anti-c-kit antibody. Anorectal tissue was obtained at surgical resection for carcinoma of the colorectum. Density of interstitial cells of Cajal was graded. Statistical analysis was performed using chi2 tests. In the longitudinal and circular muscle layers of the rectum interstitial cells of Cajal were seen in the bulk of the muscle layer. In the intermuscular plane interstitial cells of Cajal encased the myenteric plexus. Interstitial cells of Cajal were found at the inner margin of the circular muscle and in association with neural elements of the submuscular plexus. Within the internal anal sphincter interstitial cells of Cajal were infrequently scattered among the muscle fibres. The density of interstitial cells of Cajal in the internal anal sphincter was significantly lower than that observed in the circular muscle layer of the rectum (P = 0.014). In conclusion, interstitial cells of Cajal are evenly distributed in the layers of the muscularis propria of the rectum, but have a lower density in the internal anal sphincter.

Colorectal cancer in the young: trends, characteristics and outcome

BackgroundColorectal cancer (CRC) in young patients is associated with a poor outcome due to advanced stage at diagnosis and poor differentiation.AimThe aim of this study is to compare clinicopathological characteristics, overall survival (OS) and disease-free survival (DFS) of young (≤40xa0years) and older patients with CRC.MethodsA total of 2,538 patients including 59 young patients (age ≤40xa0years) with CRC were identified over 20xa0years. The clinicopathological variables of young patients were compared with a group of consecutive older patients (nu2009=u2009416) spanning both decades. Survival analysis was done using Kaplan–Meier, log-rank and Cox regression models.ResultsThe frequency in young patients increased from 1.4% to 3.0% from first to second decade (overall −2.3%, pu2009=u20090.006). There was a higher frequency of tumours with poor differentiation (43% vs. 16%, pu2009=u2009<u20090.001), T4 stage (47% vs. 30%, pu2009=u20090.005) and vascular invasion (VI; 38% vs. 29%, pu2009=u20090.13) in younger group. There was no significant difference in OS (pu2009=u20090.116) and DFS (pu2009=u20090.261) between the two groups. Node-negative young patients had a significantly better OS (pu2009=u20090.046). Young patients with VI had significantly reduced OS (pu2009=u20090.043), whereas young patients without VI had significantly better OS (pu2009=u20090.012). Multivariate analysis showed T4 status (pu2009=u20090.001) and vascular invasion (pu2009=u20090.002) as independent prognostic factors for OS and T4 status (pu2009=u20090.004) as independent factor influencing DFS.ConclusionThe frequency of CRC in young patients increased significantly. Vascular invasion is the single most important prognostic factor in young CRC. Along with vascular invasion, high proportion of T4 status in young patients increases the chances of recurrence and negates any survival advantage in young patients.

Effect of Helicobacter pylori eradication on gastric metaplasia of the duodenum.

Helicobacter pylori associated duodenal ulcers occur in patches of gastric metaplasia. The pathogenesis of gastric metaplasia is unclear, but it has been produced in experimental animals by acute injury and has been shown to be present to a greater extent of H pylori positive subjects. This study aimed to discover if gastric metaplasia regressed with eradication of H pylori or healing of duodenal ulcers, or both. Thirty two duodenal ulcer patients with H pylori infection confirmed by biopsy urease test and by antral histological examination were studied. Patients were treated with triple therapy (deNol 240 mg twice daily, amoxycillin 500 mg three times daily, and metronidazole 400 mg three times daily) for two weeks after the first endoscopy and were subsequently re-endoscoped. Three duodenal bulb biopsy specimens were obtained per patient at each endoscopy. Biopsy sections were stained with haematoxylin and eosin to determine the severity of duodenitis, and with diastase periodic acid-Schiff/alcian blue to assess the extent of gastric metaplasia. Slides were assessed by two histopathologists unaware of treatment status. H pylori was eradicated in 63% of subjects and all ulcers were healed at follow up. The median extent of gastric metaplasia at the start of treatment and 6-18 months (median 10) after treatment was compared in the two groups. Gastric metaplasia declined in eradicators from 16% to 8% (p < 0.05) while in non-eradicators there was no significant change (25% initially and at follow up). A positive relation between extent of gastric metaplasia and duodenal inflammation score was present before treatment (r(s) = 0.74, p < 0.001) and was unchanged after treatment in the non-eradicator group (r(s) = 0.89, p < 0.001). In the eradicator group, however, the inflammation score had significantly declined (p < 0.02) and the close relation with gastric metaplasia was no longer present. These results suggest that H pylori itself is at least in part responsible for producing gastric metaplasia of the duodenum.

Serum intercellular adhesion molecule-1 in alcoholic liver disease and its relationship with histological disease severity

BACKGROUNDnInfiltration of the liver by leukocytes is a histological feature of alcoholic liver disease. Intercellular adhesion molecule-1 (ICAM-1) mediates the migration of lymphocytes from the circulation to target sites of inflammation. It has been demonstrated in the liver of alcoholic liver disease subjects and as a circulating soluble form (sICAM-1). The origin of sICAM-1 and its relationship to disease severity is unknown, although it has been postulated that it may arise from activated T lymphocytes and is an inflammatory marker.nnnAIMSnThe aim of the study was to determine the relationship of sICAM-1 to clinical and histological severity of alcoholic liver disease and to serum T-cell (soluble interleukin-2 receptor (sIL-2R), beta 2-microglobulin) and monocyte (neopterin) immune activation markers.nnnMETHODSnSerum from 48 outpatients with biopsy proven alcoholic liver disease (steatosis = 9, cirrhosis = 28, hepatitis +/- cirrhosis = 11), 31 with primary biliary cirrhosis and 27 normals was assayed for sICAM-1, sIL-2R, beta 2-microglobulin, and neopterin.nnnRESULTSnsICAM-1 was significantly elevated, p = 0.0001, in alcoholic liver disease and primary biliary cirrhosis patients compared to normals. Circulating sIL-2R (p = 0.0001) and beta 2-microgloblin (p = 0.0034) were significantly elevated in alcoholic liver disease compared to controls. There was a highly significant correlation between levels of sICAM-1 and histological grade of disease, Rs = 0.80 (p = 0.0001), but no significant correlation with clinical correlates of disease severity or circulating immune activation markers.nnnCONCLUSIONSnsICAM-1 is elevated in alcoholic liver disease, is a marker of histological severity of disease and does not appear to originate from activated T lymphocytes. Measurements of sICAM-1 may be useful in assessing histological severity of alcoholic liver disease.