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

BACKGROUND

Although the assessment of serum prostate-specific antigen (PSA) has become a powerful instrument in the diagnosis and for prognosis of prostate carcinoma, there are few quantitative studies of PSA in tissue sections. Methods: We developed a technique using double-fluorescence image microscopy for quantifying immunohistochemical reactions in tissue sections. PSA was stained by Texas Red and the cellular DNA was counterstained with 4,6-diamidino-2-phenylindole, dihydrochloride (DAPI). The fluorescence of Texas Red and DAPI was quantified separately after subtraction of background and shading correction. The amount of PSA related to the amount of DNA in identical tissue parts was studied in archival specimens from patients with hyperplasia and prostate carcinoma. Results: The amount of tissue PSA decreased with the increase in tumor grade, Gleason score, and the change from diploid to aneuploid. Conclusion: Double-fluorescence image microscopy is a valuable technique for obtaining quantitative information of cellular constituents. For standardization of immunochemical reactions in tissue sections, cellular DNA seems to be most appropriate. Cytometry (Clin. Cytometry) 50:144–152, 2002. © 2002 Wiley-Liss, Inc.

Double-fluorescence image microscopy for quantitation of prostate-specific antigen in histologic sections of the prostate

Wirkung Ionisierender Strahlung auf Grenzflächen: Zyklische Änderungen der elektrophoretischen Eigenschaften von Albumin und Quarz nach Bestrahlung mit niedriegen Dosen von Röntgenstrahlen

l.a order to investigate the significance ofp53 deletion, 42 specimens of transitional cell carcinoma were analyzed by intemphasecytogenetics with a fluorescence in situ hybridization technique and compared with dinico pathological and cytochemical parameters. In total, 27 (64%) and 16 (38%) specimensdemonstrated p53 deletion and ovemexpmession, respec. tively. ThepS3 deletion was sIgnificantlycorrelated with grade (P < 0.01), stage (P < 0.05), S-phase fraction (P < 0.05), and DNA ploidy (P < 0.01), whilep53 ovemexpmession correlated only with grade (P < 0.05). The close correlation of p53 deletion with dinicopathological parameters suggests p53 deletion to be of clinical importance to indicate the malignant poten tial of human urothelial tumors.

p53 Deletion as a Genetic Marker in Urothelial Tumor by Fluorescence

Pathologic complete response (pCR) predicts the long-term outcome of neoadjuvantly treated (NAC) breast cancer (BC) but is reached in <10% of hormone-receptor-positive patients. Biomarkers enabling adjustment or interruption of an ineffective therapy are desired. Here, we evaluated whether changes in the serum concentration of thymidine kinase 1 (sTK1) during NAC could be utilized as a biomarker. In the PROMIX trial, women with localized HER2- BC received neoadjuvant epirubicin/docetaxel in six cycles. sTK1 was measured with an ELISA in 54 patients at cycles 1–4 and in an additional 77 patients before and 48 h after treatment 1. Treatment resulted in a 2-fold increase of sTK1 before and a 3-fold increase 48 h after the cycles, except for the first cycle, where half of the patients reacted with a significant decrease and the other half with an increase of sTK1. In Kaplan–Meier estimates of ER+ patients divided by the median of the post/pre-treatment sTK1 ratio at the first treatment cycle, OS was 97.7% and 78% (p = 0.005), and DFS was 90.7% and 68% (p = 0.006), respectively. Thus, the response of sTK1 at the first cycle of chemotherapy could be used both as an early biomarker for the guidance of chemotherapy and for the study of inherent tumor chemo-sensitivity, which could predict long-term outcome prior to therapy.

/pdf/dynamics-of-serum-thymidine-kinase-1-at-the-first-cycle-of-3d0pcc7l0i.pdf

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-receptor-positive Breast Cancer

Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988–1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.

/pdf/prediction-of-overall-survival-by-thymidine-kinase-1-3jtdazjk.pdf

Bernhard Tribukait

Papers

Double-fluorescence image microscopy for quantitation of prostate-specific antigen in histologic sections of the prostate

Wirkung Ionisierender Strahlung auf Grenzflächen: Zyklische Änderungen der elektrophoretischen Eigenschaften von Albumin und Quarz nach Bestrahlung mit niedriegen Dosen von Röntgenstrahlen

p53 Deletion as a Genetic Marker in Urothelial Tumor by Fluorescence

Dynamics of Serum Thymidine Kinase 1 at the First Cycle of Neoadjuvant Chemotherapy Predicts Outcome of Disease in Estrogen-receptor-positive Breast Cancer

Prediction of Overall Survival by Thymidine Kinase 1 Combined with Prostate-Specific Antigen in Men with Prostate Cancer