Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer

The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with NISS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (P = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, NISS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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.

Progressive loss of expressive language in a journalist: What news for dementia?

A 77-year-old man with 8 year progressive language deterioration in the face of grossly intact memory was followed. No acute or chronic physiological or psychological event was associated with symptom onset. CT revealed small left basal ganglia infarct. Mild atrophy, no lacunar infarcts, mild diffuse periventricular changes registered on MRI. Gait normal but slow. Speech hesitant and sparse. Affect euthymic; neurobehavioral disturbance absent. MMSE 26/30; clock incorrect, concrete. Neuropsychological testing revealed simple attention intact; complex attention, processing speed impaired. Visuospatial copying and delayed recall of copy average with some perseveration. Apraxia absent. Recall mildly impaired. Mild deficits in planning, organization apparent. Patient severely aphasic, dysarthric without paraphasias. Repetition of automatic speech, recitation moderately impaired; prosody intact. Understanding of written language, nonverbal communication abilities, intact. Frontal release signs developed over last 12 months. Repeated cognitive testing revealed mild deterioration across all domains with significant further decrease in expressive, receptive language. Neurobehavioral changes remain absent to date; he remains interested, engaged and independent in basic ADLs. Speech completely deteriorated; gait and movements appreciably slowed. Although signs of frontal/executive dysfunction present, lack of behavioral abnormalities, psychiatric disturbance, personality change argue against focal or progressive frontal impairment or dementia. Relative intactness of memory and comprehension argue against Alzheimer’s disease. Lack of findings on neuroimaging argue against CVA or tumor. It is possible that the small basal ganglia infarct has resulted in a mild lateral prefrontal syndrome. However, the absence of depression as well as the relatively circumscribed language problem suggests otherwise. The progressive, severe nature of language impairments, with relatively minor impairments in attention and memory, argues for a possible diagnosis of primary progressive aphasia.

Plasma antioxidant status, immunoglobulin G oxidation and lipid peroxidation in demented patients:Relevance to Alzheimer disease and vascular dementia

A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD, but there is a substantial lack of data regarding the simultaneous behavior of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobulin G (IgG) levels of protein carbonyls and dityrosine] in patients and controls. With the exception of β-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, AD patients showed a significantly higher IgG dityrosine content as compared to controls. AD and VaD patients showed similar plasma levels of plasma antioxidants and MDA as well as a similar IgG content of protein carbonyls and dityrosine. We conclude that, independent of its nature - vascular or degenerative - dementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development. Copyright © 2004 S. Karger AG, Basel.

P4-235 protein oxidation, lipid peroxidation and antioxidant status are similarly altered in Alzheimer disease and vascular dementia

Background: A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. A vascular component might be critical in the pathophysiology of AD. Objective(s): To evaluate the simultaneous behavior of a broad spectrum of peripheral antioxidants and biomarkers of oxidative stress in AD and vascular dementia (VaD). Methods: Sixty-three AD patients, 23 VaD patients and 55 controls were included in the study. We measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, [3-cryptoxanthin, lycopene, c~- and [3-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation [malondialdehyde (MDA)] and of protein oxidation [immunoglobniin G (Ig G) levels of protein carbonyls and dityrosine] in patients and controls. Results: AD and VaD patients showed significantly decreased plasma levels of the water-soluble vitamin C and uric acid, of the lipophilic vitamin Eand vitamin A, and of the carotenoids lutein, zeaxanthin, 13-cryptoxanthin, lycopene and (x-carotene as compared to controls; among biomarkers of oxidative stress, only the content of dityrosine in Ig G was found to be significantly higher (p < 0.01) in AD patients as compared to controls; although a trend towards higher levels of dityrosine was also observed in VaD subjects compared to controls (6.3 4- 1.7 ~M in VaD patients vs. 5.1 4- 1.6 IxM in controls; p = 0.06), it did not reach statistical significance. In a cumulative analysis of all patient samples, a significant inverse association was found between plasma lycopene and MDA levels (r = -0.53, p < 0.0001). Conclusions: Independent of its nature-vascular or degenerativedementia is associated with the depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. This might be relevant to the pathophysiology of dementing disorders, particularly in light of the recently suggested importance of the vascular component in AD development.