Heterogeneity Of Proliferative Activity Research Articles

Analysis of NSCLC tumour heterogeneity, proliferative and 18F-FDG PET indices reveals Ki67 prognostic role in adenocarcinomas.

The role of tumour metabolic and proliferative indices in predicting non-small-cell lung cancer (NSCLC) patients' prognosis is unclear. We correlated fluorine 18 ((18) F)-fluorodeoxyglucose (FDG)-positron emission tomography (PET) value and Ki67 index to patients' survival, taking into account tumour heterogeneity, disease characteristics and genetic aberrations. A series of 383 NSCLCs was arranged into tissue microarrays and Ki67 staining was analysed by immunohistochemistry. The maximum standardized uptake (SUV(MAX) ) value detected by (18) F-FDG-PET analysis was calculated over a region of interest. Large-cell and squamous cell carcinomas had higher proliferative and metabolic activities than adenocarcinomas, and the two measures were correlated significantly. The hot-spot Ki67 value was correlated with patients' survival and the cut-off to discriminate patients in the survival risk groups was 20%. Ki67 hot-spot values were greater in anaplastic lymphoma kinase (ALK) rearranged tumours. Adenocarcinomas showed the highest intratumour heterogeneity in proliferative activity and the hot-spot Ki67 value predicted only the prognosis of patients in this group. Although tumour metabolic activity was not associated with patients' prognosis, a SUV(MAX) > 2 was related to nodal metastases, tumour size and grade. Our results highlight how tumour heterogeneity influences evaluation of prognostic biomarkers. Our data support Ki67 evaluation to estimate NSCLC patients' prognosis, particularly for adenocarcinoma.

Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index.

The effects of regional heterogeneity on the accuracy of histological grading of gliomas are well known, but little has been reported about its implications for other diagnostic modalities. This study investigated the relationships of regional heterogeneity in tumor proliferative activity, measured by Ki-67 labeling indices (LI), and histological grades for 16 regionally sampled glioma resections. There was a strong correlation between histological grades and Ki-67 LI in individual regions (p < 0.001), and both methods demonstrated comparable heterogeneity. Heterogeneity increased with tumor grade, probably as an expression of the increased genetic instability that accompanies tumor progression. Similarly, regions with comparable proliferative activity tended to cluster, paralleling clonal expansion. Thus, both histological grading and Ki-67 LI are subject to heterogeneity-induced sampling errors that limit their diagnostic accuracy, particularly in small biopsies. However, fewer grading errors occurred when using both methods together than when using either method alone, suggesting that the use of multiple techniques may reduce the adverse effects of regional heterogeneity on diagnostic accuracy. Regional heterogeneity appears to be a ubiquitous feature of gliomas: it also has been reported in karyotype, p53 oncogene mutations, and PDGF and EGFR expression. The effects of regional heterogeneity on new methods for studying gliomas need to be considered.

Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations.

The proliferative activity of 16 tumour specimens from 13 patients with neuroendocrine tumours of the gastroenteropancreatic endocrine system was studied by DNA flow cytometry and immunohistology for the nuclear Ki67 proliferation antigen. Equivalent results were obtained with both methods, which showed the proliferative activity of gastroenteropancreatic neuroendocrine tumours to be heterogeneous. In four malignant small intestinal carcinoids and one extravisceral carcinoid localised in the retroperitoneum the percentage (index) of proliferating tumour cells as measured by DNA flow cytometry ranged from 2.9 to 36.2% corresponding to low, moderate, or high proliferative activity. In four malignant pancreatic endocrine tumours and their metastases indices ranged from 8.7 to 18.3%, corresponding to low, moderate, or high proliferative activity. In four benign pancreatic endocrine tumours indices ranged from 4.3 to 7.7%, all corresponding to low proliferative activity. This heterogeneity of proliferative activity may in part explain the heterogeneous results reported of chemotherapy treatment. As chemotherapy of tumours is largely affected by favourable cell cycling kinetics, individual diagnostic investigations of the proliferative activity of these neuroendocrine tumours may be of value for identifying patients suitable for this treatment.

The prognostic value of DNA-ploidy in colorectal carcinoma: a prospective study

One hundred and fifty-seven patients with usual colorectal cancer were analysed prospectively for DNA-ploidy, DNA-index and S-phase fraction (SPF) using flow cytometry. An abnormal DNA-stemline was observed in 68% of tumours. The patients have been followed for a median of 36 months. In univariate analysis, tumour stage was the most significant prognostic factor. After excluding patients with stage D disease, DNA-aneuploidy was significantly associated with a shorter survival and a shorter disease free survival. SPF, however, did not correlate with prognosis. In multiple samples from the same tumour there was on average a 29% difference between the highest and the lowest SPF indicating considerable heterogeneity in proliferative activity within the tumours. In diploid tumours the variation was even higher. Patients with proximal tumours as well as female patients had DNA-diploid tumours more often than the others. This may indicate that there are different, so far unknown, aetiological factors leading to different types of ploidy pattern.

Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate.

Growth and functional activity within the prostate gland is known to be regulated by androgens whose effects are thought to be mediated via androgen receptors. This concept has been derived in large part through analysis of whole organ homogenates, an approach which ignores potential heterogeneity of biological activity within the gland and the importance of cell-cell interactions. In this review recent findings are summarized which demonstrate that growth of the prostatic ductal network during prepubertal periods, as well as during prostatic regeneration in androgen-treated adult castrates, is nonuniform, with ductal growth being highest at the ductal tips and much lower in proximal ducts closer to the urethra. Androgen dependency for maintenance of ductal architecture following castration follows a similar pattern in that castration results in total destruction of distal ductal architecture, while proximal ducts are maintained albeit in an atrophic state. Thus, striking differences in biological properties are found in distal versus proximal prostatic ducts. Morphogenesis, growth, and secretory cytodifferentiation within the developing prostate is elicited by androgens which act via mesenchymal-epithelial interactions. Through analysis of chimeric prostates constructed with androgen-receptor-positive wild-type mesenchyme and androgen-receptor-negative Tfm (testicular feminization) bladder epithelium, it is now evident that androgenic effects can be elicited in androgen-receptor-deficient (androgen-insensitive) Tfm prostatic epithelium, provided that the connective tissue component of the chimeric prostate is wild type. This observation has been made for both the developing and adult prostate. From this data it is evident that certain androgenic effects (ductal morphogenesis, epithelial growth, and secretory cytodifferentiation) do not require the presence of intraepithelial androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)