Is the carbohydrate sialosyl-Tn a marker for altered,non-malignant activity in squamous epithelium in the head and neck region?

Cell surface carbohydrates are involved in many cell functions such as cellular differentiation, adhesion, and invasion. A carbohydrate, sialosyl-Tn (STn), is expressed in many human carcinomas but generally not in normal epithelia. In the oral mucosa, however, STn had recently been observed on basal cell in some lesions with epithelial hyperplasia and dysplasia. The aim of this study was to carry out a systematic investigation of STn expression on epithelial basal cells in hyperplastic, ‘borderline’ malignant, and malignant head and neck lesions, to see if the expression of STn is associated specifically with hyperplastic conditions. Using the primary monoclonal antibody TKH2, normal controls did not reveal STn. STn was detected on probably post-mitotic basal cells in hyperplastic head and neck lesions and on basal cells adjacent to cancers, but not within the carcinomas. A Ki67 antibody reacted with basal cells in other locations. The most highly differentiated lesions, such as focal epithelial hyperplasia and verrucous hyperplasia, revealed a high percentage (86 per cent in both cases) of STn reactivity. The least-differentiated verrucous carcinomas (VCs) and keratoacanthomas (KAs) did not express STn, in contrast to the highly differentiated VCs and KAs. These findings indicate that STn-negative cases may have a greater malignant potential that the STn-positive cases. In conclusion, STn expressed on basal cells is possibly a marker for non-malignant conditions with altered basal cell activity and for highly differentiated verrucous carcinomas.     

Incidental prostatic carcinoma: Morphometry correlated with histological grade

Summary The histological grades of prostatic carcinoma, as defined by Gleason, were correlated with three methods of morphometry in 254 step-sectioned prostates obtained at autopsy. The variables studied were 1) the number of tumours in each prostate; 2) bilaterality and 3) tumour volume. Each characteristic yielded a statistically significant correlation with histological grade. The strongest correlations were obtained using tumour volume. These autopsy studied help to explain the inconsistent results obtained from morphometric analyses of surgical material, and lend support to the Gleason system as a means of predicting tumour behavior.Supported in part by research contracts PH 64-10, NCI-72-3213, N01-CP-53521; Grant R01-CA-33644; and the Grant-in-Aid for Cancer Research (33) from the Ministry of Health and Welfare     

TP53 mutations in prostatic cancer. Analysis of pre- and post-treatment archival formalin-fixed tumour tissue

The TP53 gene mutation pattern in prostatic cancer was examined in relation to progression and survival, using archival formalin-fixed pre-and post-treatment tumour specimens from 84 prostatic cancer patients. Thirty-four had hormone-sensitive tumours and 50 were hormone-resistant. Six of the 34 (18 per cent) therapy-responding tumours and 19 of the 50 (38 per cent) hormone-resistant tumours showed p53 protein accumulation in the post-treatment specimen. Both pre- and post-treatment specimens from these 25 patients were analysed for mutation of the conserved regions of the TP53 gene (exons 5–8), using constant denaturant gel electrophoresis (CDGE) followed by DNA sequencing. In the post-treatment samples, mutations were detected in three of the six patients with hormone-responsive tumours and in 11 of the 19 patients with hormone-resistant tumours. The three (100 per cent) patients with therapy-responsive tumours with mutations and nine of the 11 (82 per cent) patients with therapy-resistant tumours with mutations died of the disease. Thirteen of the 14 mutations in the post-treatment specimens were transitions, 11 occurring at CpG dinucleotides in which codon 273 was involved in ten. A significantly higher proportion of tumours with mutations were poorly differentiated compared with tumours without mutation (P<0·04). Our findings indicate that TP53 mutation is a late event in tumour development of the prostate gland and that codon 273 might be a ‘hotspot’ for mutation in the progression of the disease.     

Electron microscopic studies of endocrine hyperplasia in duodenal adenomas in familial adenomatous polyposis

Summary Electron microscopical studies on endocrine cell hyperplasia of duodenal adenomas from five patients with familial adenomatous polyposis were performed. All the endocrine cell types normally found in the duodenal mucosa were identified. A constant feature was proliferation of duodenal-enterochromaffin cells but an increase in the number of all other endocrine cell types apart from pyloricgastrin cells and somatostatin cells, was also observed. Certain types of intestinal endocrine cells (the intestinal enterochromaffin cell and the glicentin cell) are rare cells in the normal duodenal mucosa. The finding of these cells may indicate increased biological aggressivity.     

Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome

Recent studies have shown that mutations in a newly described RNA editing enzyme, activation-induced cytidine deaminase (AID), can cause an autosomal recessive form of hyper IgM syndrome. To determine the relative frequency of mutations in AID, we evaluated a group of 27 patients with hyper IgM syndrome who did not have defects in CD40 ligand and 23 patients with common variable immunodeficiency. Three different mutations in AID were identified in 18 patients with hyper IgM syndrome, including 14 French Canadians, 2 Lumbee Indians, and a brother and sister from Okinawa. No mutations were found in the remaining 32 patients. In the group of patients with hyper IgM syndrome, the patients with mutations in AID were older at the age of diagnosis, were more likely to have positive isohemagglutinins, and were less likely to have anemia, neutropenia, or thrombocytopenia. Lymphoid hyperplasia was seen in patients with hyper IgM syndrome and normal AID as well as the patients with hyper IgM syndrome and defects in AID.     

Stretching the limits: Stem cells in regeneration science

The focus of regenerative medicine is rebuilding damaged tissues by cell transplantation or implantation of bioartificial tissues. In either case, therapies focus on adult stem cells (ASCs) and embryonic stem cells (ESCs) as cell sources. Here we review four topics based on these two cell sources. The first compares the current performance of ASCs and ESCs as cell transplant therapies and the drawbacks of each. The second explores somatic cell nuclear transfer (SCNT) as a method to derive ESCs that will not be immunorejected. The third topic explores how SCNT and ESC research has led to the ability to derive pluripotent ESCs by the dedifferentiation of adult somatic cells. Lastly, we discuss how research on activation of intrinsic adult stem cells and on somatic cell dedifferentiation can evolve regenerative medicine from a platform consisting of cell transplantation to one that includes the chemical induction of regeneration from the body's own cells at the site of injury. Developmental Dynamics 237:3648–3671, 2008. © 2008 Wiley‐Liss, Inc.     

Urothelial carcinoma of the urinary bladder with a component of acinar/tubular type differentiation simulating prostatic adenocarcinoma

We report a case of an 83-year-old man with a high-grade carcinoma of the urinary bladder who underwent cystoprostatectomy. The invasive carcinoma showed mixed, morphologically distinct patterns consisting of conventional high-grade urothelial carcinoma, glandular differentiation resembling enteric type adenocarcinoma, and acinar/tubular type differentiation, morphologically similar to Gleason grade 3 prostatic adenocarcinoma. Immunohistochemical studies revealed the acinar/tubular component of the tumor to be negative for prostate-specific antigen and prostatic acid phosphatase, but positive for cytokeratin 7, cytokeratin 20, high molecular weight cytokeratin (34 beta E12), and thrombomodulin, consistent with origin from the bladder rather than the prostate. Although bladder carcinomas composed of mixed morphologic patterns are not uncommon, to our knowledge, the presence of acinar/tubular type features simulating prostatic adenocarcinoma in such tumors has not been described elsewhere.     

Myelolipoma: A New Adrenal Finding in Carney's Complex?

Pigmented nodular cortical hyperplasia, a rare cause of Cushing’s syndrome, is characterized by resistance to inhibition with dexamethasone and normal sized adrenal glands with multiple, small pigmented nodules. The disorder may be a component of a syndrome inherited as an autosomal dominant pattern that includes intra- and extracardiac myxomas, lentiginous lesions, blue nevi, other functional endocrine tumors, and peripheral nerve tumors (Carney’s complex). We report a patient in whom bilateral myelolipomas were found, in addition to the usual features of this complex. A 29-yr-old man was admitted to the hospital for Cushing’s syndrome of probably more than 15 yr duration. Physical examination showed diffuse facial hyperchromatic macules, 0.2–0.5 cm, predominantly around the lips and on the palmar surfaces of the fingers. Results with dexamethasone suppression nocturnal testing (1 and 8 mg) were compatible with an adrenal adenoma. The computed tomography (CT) of the sella turcica was normal. Adrenal CT showed a tumor in the left gland with a double component: one solid and another suggestive of fat, consistent with an angiomyelolipoma. Following 5 wk treatment with ketoconazole, 800 mg per day po, serum cortisol decreased to 5.9 μg/dL, morning and evening, respectively. Bilateral adrenalectomy was performed. Pathologic examination revealed pigmented nodular cortical hypersplasia and a dominant myelolipoma in the left adrenal. A microscopic myelolipoma was identified in the right adrenal. An echocardiogram showed a mass on the posterior wall of the left ventricle which was a myxoma. Study of the patient's family disclosed two sisters with facial lentigines. Echocardiograms were performed on all available first degree relatives: all were normal. Nocturnal inhibition with dexamethasone revealed that one of the patient’s sisters with lentigines also had hypercortisolism. Myelolipoma has been reported in association to Cushing syndrome in humans and experimentally after pituitary extracts in animals. The relationship between this finding and the Carney’s complex remain elusive.     

Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material

The expression and cellular localization of angiotensin II (Ang II) and AT(1) receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT(1) receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4+/-0.2%, n=5 vs. BPH: 22.7+/-1.9%, n=5, p<0.001). However, AT(1) receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4+/-2.2%, n=4 vs. BPH: 9.4+/-1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT(1) receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functions on cellular growth and smooth muscle tone in the human prostate. Furthermore, AT(1) receptor down-regulation in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. These data extend previous findings in support of the novel concept that overactivity of the renin-angiotensin system (RAS) may be involved in the pathophysiology of BPH.