The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells (G(0)), makes it an excellent marker for determining the so-called growth fraction of a given cell population. In the first part of this study, the term proliferation marker is discussed and examples of the applications of anti-Ki-67 protein antibodies in diagnostics of human tumors are given. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of the disease. The best-studied examples in this context are carcinomas of the prostate and the breast. For these types of tumors, the prognostic value for survival and tumor recurrence has repeatedly been proven in uni- and multivariate analysis. The preparation of new monoclonal antibodies that react with the Ki-67 equivalent protein from rodents now extends the use of the Ki-67 protein as a proliferation marker to laboratory animals that are routinely used in basic research. The second part of this review focuses on the biology of the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure, mRNA splicing, expression, and cellular localization during the cell-division cycle is summarized and discussed. Although the Ki-67 protein is well characterized on the molecular level and extensively used as a proliferation marker, the functional significance still remains unclear. There are indications, however, that Ki-67 protein expression is an absolute requirement for progression through the cell-division cycle.

The Ki‐67 protein: From the known and the unknown

Pathology and genetics of tumours of the urinary system and male genital organs

BACKGROUND AND AIMS Controversy surrounds the risk of colorectal cancer (CRC) in ulcerative colitis (UC). Many studies have investigated this risk and reported widely varying rates. METHODS A literature search using Medline with the explosion of references identified 194 studies. Of these, 116 met our inclusion criteria from which the number of patients and cancers detected could be extracted. Overall pooled estimates, with 95% confidence intervals (CI), of cancer prevalence and incidence were obtained using a random effects model on either the log odds or log incidence scale, as appropriate. RESULTS The overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2–4.2%). Of the 116 studies, 41 reported colitis duration. From these the overall incidence rate was 3/1000 person years duration (pyd), (95% CI 2/1000 to 4/1000). The overall incidence rate for any child was 6/1000 pyd (95% CI 3/1000 to 13/1000). Of the 41 studies, 19 reported results stratified into 10 year intervals of disease duration. For the first 10 years the incidence rate was 2/1000 pyd (95% CI 1/1000 to 2/1000), for the second decade the incidence rate was estimated to be 7/1000 pyd (95% CI 4/1000 to 12/1000), and in the third decade the incidence rate was 12/1000 pyd (95% CI 7/1000 to 19/1000). These incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The worldwide cancer incidence rates varied geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. Over time the cancer risk has increased since 1955 but this finding was not significant (p=0.8). CONCLUSIONS Using new meta-analysis techniques we determined the risk of CRC in UC by decade of disease and defined the risk in pancolitics and children. We found a non-significant increase in risk over time and estimated how risk varies with geography.

https://gut.bmj.com/content/gutjnl/48/4/526.full.pdf

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs. The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure. The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer.

Cancer as an evolutionary and ecological process.

The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. A survey of recent literature revealed the use of 19 different formulas for determining the size of subcutaneous tumors grown as xenografts in nude mice (2 for determining tumor area, 3 for tumor diameter, and 14 for calculating tumor volume). We compared the volumes, areas, and diameters predicted by each of the 19 formulas with the actual weights of 50 tumors ranging from 0.46 to 22.0 g established in nude mice as xenografts from human cell lines. In addition to determining how well each formula predicted relative tumor size, we analyzed how well each formula estimated actual tumor mass. The ellipsoid volume formulas (π/6 x L x W x H and 1/2 x L x W x H) were best for estimating tumor mass (r=0.93), whereas measurements of diameter correlated poorly with tumor mass (r<0.66). Although determination of tumor area correlated well with tumor mass in small tumors (r=0.89), correlations of area with tumor mass for large tumors were poor (r=0.41). We conclude that determination of the ellipsoid volume from measurements of three axes consistently yields the most accurate estimations of both relative and actual tumor mass.

Determination of subcutaneous tumor size in athymic (nude) mice

A total of 115 patients with invasive transitional cell carcinoma of the bladder underwent radical radiotherapy between 1975 and 1986 and were followed up until the end of 1990. Apart from routine clinical observations, flow cytometric DNA measurements made on fresh tumour material were available for analysis. Actuarial cancer-free survival controlling for response to treatment was analysed with the log-rank test, bivariate and multivariate analyses using Cox's stepwise regression model on probable prognostic factors. The overall actuarial 5-year cancer-free survival rate was 30%. Survival was significantly correlated with response to treatment: 59% for patients with complete regression and 5% for those with residual tumour. Prognostic factors that significantly correlated with death from cancer were advanced stage, large size, incomplete resection, ureteric obstruction, anaemia, carcinoma in situ grade 3 and occurrence of more than one aneuploid cell population. However, only 3 of these factors were of independent power in the multivariate analysis: stage, size and carcinoma in situ. Of 21 patients with a history of primary or secondary carcinoma in situ, 19 died from cancer during follow-up: 18 of the 21 patients had tumours that were aneuploid with more than one aneuploid cell population. It is concluded that curative radiotherapy can be successful only in patients with less advanced tumours assessed according to clinical stage and size, aneuploid tumours with not more than one aneuploid cell line, no carcinoma in situ, no ureteric obstruction, and in whom a complete transurethral resection of the exophytic tumour is possible.

DNA analysis in predicting survival of irradiated patients with transitional cell carcinoma of bladder.

In seven patients with longstanding ulcerative colitis, multiple mucosal biopsies taken at colonoscopy were assessed for DNA content and histological dysplasia. DNA analyses were performed using flow cytometric analyses in biopsies and microspectrophotometry in imprint slides prepared from the biopsies. Abnormal aneuploid DNA content was detected in five of the patients in eight separate locations in the colon. There was good conformity between the two methods in the detection of aneuploidy. Both methods of DNA analysis are considered to be applicable in mucosal biopsies from patients with ulcerative colitis. In two patients with significant low grade dysplasia in association with macroscopical lesions (DALMs), there was a relationship with aneuploid DNA pattern found by flow cytometric or microspectrophotometric analyses. Indefinite changes, probably dysplastic were found in three other patients and two of those also displayed aneuploidy, although only once in the same biopsy location. In five locations aneuploidy was detected without concomitant dysplasia. DNA-aneuploidy seems therefore to appear earlier than dysplasia and may be an early marker of malignant transformation of the mucosa in ulcerative colitis. Prospective trials are needed before the clinical significance of early findings of aneuploidy can be determined.

https://gut.bmj.com/content/gutjnl/30/12/1731.full.pdf

Comparative DNA analyses in longstanding ulcerative colitis with aneuploidy.

Low IL-1α Expression in Bladder Cancer Tissue and Survival

The radiation beams are formed from a single light source (1) and the beams have different wavelengths. A light source is provided with a wide spectral energy-spectrum or with different distinct wavelengths. Also conventional optical components such as a condenser lens system (2), lenses, dichroic beam dividers and optical filters are arranged so that independent radiation beams are formed. The independent radiation beams are separately modified and then are passed into each other. The light beam thus formed consists of different wavelengths. A dichroic double mirror (10) or a rejection band filter is provided, which transmits with higher efficiency, as well as reflecting the different excitation beams besides the fluorescence colours. USE/ADVANTAGE - For detecting characteristics eg of biological cell esp. for observing fluorescence characteristics of DNA, RNA etc. Simple optical system facilitates quantitative measurement of fluorescent light of different wavelengths of different colouring, with min. effects of chromatic aberrations in excitation light path.

Optical system for incident light illumination fluorescence microscopy - splits light from source into several beams for independent modification before recombination

Bernhard Tribukait

Papers

DNA analysis in predicting survival of irradiated patients with transitional cell carcinoma of bladder.

Comparative DNA analyses in longstanding ulcerative colitis with aneuploidy.

Low IL-1α Expression in Bladder Cancer Tissue and Survival

Optical system for incident light illumination fluorescence microscopy - splits light from source into several beams for independent modification before recombination

Discontinuous RNA and protein synthesis and accumulation during cell cycle of Ehrlich ascites tumour cells