Cell cycling in bladder carcinoma determined by monoclonal antibody Ki67

Current methods of predicting prognosis in transitional cell carcinoma of the bladder fail to provide consistently reliable information about future tumour behaviour. The monoclonal antibody Ki67 recognises an antigen present in actively dividing cells and Ki67 reactivity has been shown to correlate with conventional prognostic indicators in several tumours. In this study, Ki67 antibody was used to determine the proportions of cells undergoing active division in 26 transitional cell carcinomas of the bladder. The proportion of cells stained in muscle invasive tumours (12.3 +/- 5.4%) was significantly greater than in superficial tumours (4.3 +/- 1.9%) and poorly differentiated tumours showed significantly greater proportions of cells staining compared with well or moderately well differentiated tumours. These results show that Ki67 reactivity correlates with high tumour stage and poor differentiation. Ki67 staining provides an easy method of determining tumour cell turnover that might provide additional prognostic information.     

Epidermal growth factor receptor and bladder cancer: a review.

Recently, expectations have been raised that molecular biological studies of human tumours may be of value in helping to predict future clinical behaviour, in terms of therapeutic response and long-term survival. The epidermal growth factor receptor (EGFr) is a cell surface receptor for EGF and transforming growth factor-alpha which is overexpressed by a number of human tumours. This article principally reviews previous investigations of the role of the epidermal growth factor receptor in bladder cancer and examines methods of detection, the correlation between EGFr status and known prognostic indicators and the value of assessing EGFr status in predicting clinical outcome in patients with bladder cancer. Recent studies of the c-erbB-2 proto-oncogene in bladder cancer and of cell cycling using Ki-67 are included.     

Compensation for spin-lock artifacts using an off-resonance rotary echo in T1rhooff-weighted imaging.

The origin of image artifacts in an off-resonance spin-locking experiment is shown to be imperfections in the excitation flip angle. A pulse sequence for off-resonance spin locking is implemented that compensates for imperfections in the excitation flip angle through an off-resonance rotary echo. The off-resonance rotary echo alternates the frequency offset and phase of the RF transmitter during two spin-locking pulses of equal duration. The underlying theory is detailed, and MR images demonstrate the effectiveness of the technique in agarose gel phantoms and in in vivo human brain at 3T.     

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.     

A dog model of fulminant hepatic failure produced by paracetamol administration.

Oral administration of graded doses of paracetamol to dogs produced hepatic necrosis with some similarities to the clinical syndrome seen in man following a paracetamol overdose. Coma, with raised levels of arterial ammonia, was produced and the aspartate aminotransferase levels became markedly elevated in 2 animals who survived more than 24 h. However, the extent of the hepatic necrosis and the time of survival following paracetamol administration were too variable for this model to be of value for the testing of new methods of temporary liver support. When paracetamol was given by intraperitoneal injection many of the animals died of respiratory distress. Significant methaemoglobinaemia was detected, which was associated with a reduction in the arterial partial pressure of oxygen and was partly reversed by the administration of methylene blue.     

Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo.

For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.     

Alteration in urinary matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio predicts recurrence in nonmuscle-invasive bladder cancer.

PURPOSE: The purpose is to assess the prognostic significance of matrix metalloproteinase (MMP)-9 in patients with bladder cancer using a combination of ELISA (to measure MMP-9 in voided urine) and immunohistochemistry (to study MMP-9 in bladder tumors). The relationship between MMP-9 and its principal inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 (in voided urine samples) was also studied. EXPERIMENTAL DESIGN: A total of 134 patients with bladder tumors (7 cis, 76 T(a), 27 T(1), 24 T(2)-T(4); 40 G1, 43 G2, and 44 G3), 33 patients with benign urological conditions, and 36 healthy volunteers was studied. Samples from 106 patients with bladder cancer and 12 controls were stained for MMP-9. Clinical follow-up data were available on 116 patients (median: 25 months; range: 4-36 months). RESULTS: MMP-9 was present in all urine samples analyzed. There were no differences between patients with cancer and patients with benign disorders. However, patients had significantly higher urinary MMP-9 than normal volunteers (P = 0.0167). Urinary MMP-9 was associated with bladder tumors of advanced stage (P = 0.0065) and large size (P < 0.0001) but not with grade (P = 0.14), multiplicity (P = 0.31), recurrence (P = 0.55), progression (P = 0.83), or survival (P = 0.55). Low MMP-9:TIMP-1 ratios in patients with nonmuscle-invasive tumors were associated with higher recurrence rates (P = 0.0035). Sixty percent (64 of 106) of bladder tumor specimens expressed MMP-9 compared with none of 12 normal urothelial biopsies (P < 0.0001). MMP-9 staining was associated with tumor size (P = 0.014), disease progression (P = 0.005), and poor disease-specific survival (P = 0.022) but was unrelated to tumor stage (P = 0.46), grade (P = 0.26), multiplicity (P = 0.85), or recurrence rate (P = 0.62). CONCLUSIONS: High urinary MMP-9 levels are associated with large bladder tumors. A low urinary MMP-9:TIMP-1 ratio may indicate a higher risk of intraluminal nonmuscle-invasive tumor recurrence and may assist in planning follow-up surveillance protocols.     

Neural network analysis of clinicopathological and molecular markers in bladder cancer

PURPOSE: To evaluate retrospectively the ability of an artificial neural network (ANN) to predict bladder cancer recurrence within 6 months of diagnosis and stage progression in patients with Ta/T1 bladder cancer, and 12-month cancer-specific survival in patients with T2-T4 bladder cancer. MATERIALS AND METHODS: Data were analyzed using a NeuralWorks Professional II/Plus software package. The input neural data consisted of clinicopathological and molecular characteristics. Distinct patient groups were used for the prediction of stage progression and tumor recurrence in Ta/T1 bladder cancers, and 12-month cancer-specific survival for patients with T2-T4 tumors. ANN predictions were compared with those of four consultant urologists. RESULTS: The accuracy of the neural network in predicting stage progression and recurrence within 6 months for Ta/T1 tumors and 12-month cancer-specific survival for T2-T4 cancers was 80%, 75% and 82% respectively; with corresponding figures for clinicians being 74%, 79% and 65%. On restricting the validation subset to patients with T1G3 tumors in relation to stage progression, the sensitivity of the ANN analysis increased to 100% with a specificity of 78% and an overall accuracy of 82%. The performance of the ANN in predicting stage progression in T1G3 tumors was significantly higher than that of clinicians (p = 0.25 for the ANN and p = 0.008 for clinicians, McNemar test). CONCLUSIONS: Data analysis using an ANN has been shown to be a useful adjunct in predicting outcomes in patients with bladder cancer and out-performs clinicians' predictions of stage progression in the high risk group of patients with T1G3 disease.