Extent Of Tumor Growth Research Articles

Renal cell carcinoma may adapt to and overcome anti-angiogenic intervention with thalidomide.

To report on the failure of thalidomide to inhibit tumour growth in an animal model of human renal cell carcinoma (RCC). An orthotopic xenograft model of human RCC was used in which tumour cells were implanted in the left kidney of male 'severe combined immunodeficient' mice. Thalidomide was administered by intraperitoneal injection and after 34 days the mice were killed. The extent of tumour growth was compared in treated and untreated mice. Total RNA was extracted from both tumour-affected and contralateral kidneys, and analysed by reverse transcription-polymerase chain reaction for various genes implicated in angiogenesis and metastasis in RCC. Thalidomide failed to inhibit the growth of xenograft tumours. The expression of angiogenic genes, e.g. vascular endothelial growth factor and fibroblast growth factor type 2 (FGF-2) within normal and tumour-affected kidney tissue was not reduced by thalidomide. Intratumoral transcription of beta3-integrin, a critical component of angiogenesis, was significantly increased in response to thalidomide treatment (P < 0.01). There was also a trend to increased expression of FGF-2 and tumour necrosis factor-alpha in thalidomide-treated tumours. These findings suggest that RCC is capable of adapting to the inhibitory effects of thalidomide. The current uncertainty surrounding the action of thalidomide in vivo warrants caution about its use in humans. Further studies of thalidomide should be carried out in animal models, particularly to establish its safety and effectiveness as part of a combined therapeutic strategy.

Conjugated Linoleic Acid and Disease Prevention: A Review of Current Knowledge

Conjugated linoleic acid (CLA), a derivative of a fatty acid linoleic acid (LA), has been reported to decrease tumorigenesis in animals. CLA is unique because unlike most antioxidants which are components of plant products, it is present in food from animal sources such as dairy foods and meats. CLA concentrations in dairy products typically range from 2.9 to 8.92 mg/g fat of which the 9-cis, 11-trans isomer makes up to 73% to 93% of the total CLA. Low concentrations of CLA are found in human blood and tissues. In vitro results suggest that CLA is cytotoxic to MCF-7 cells and it inhibits the proliferation of human malignant melanoma and colorectal cancer cells. In animal studies, CLA has inhibited the development of mouse epidermal tumors, mouse forestomach cancer and rat mammary cancer. Hamsters fed CLA collectively had significantly reduced levels of plasma total cholesterol, non-high-density lipoprotein cholesterol, (combined very-low and low-density lipoprotein) and triglycerides with no effect on high-density lipoprotein cholesterol, as compared to controls. Dietary CLA modulated certain aspects of the immune defense but had no obvious effect on the growth of an established, aggressive mammary tumor in mice. It is now thought that CLA itself may not have anti-oxidant capabilities but may produce substances which protect cells from the detrimental effects of peroxides.There is, however, insufficient evidence from human epidemiological data, and very few of the animal studies have shown a dose-response relationship with the quantity of CLA feed and the extent of tumor growth. Further research with tumor models is needed to test the efficacy and utility of CLA in cancer and other disease prevention and form the basis of evaluating its effect in humans by observational studies and clinical trials.

Prognostic influence of p53 expression in gastric cancer.

The presence of the nuclear phosphoprotein p53 was investigated in a series of 120 consecutive gastric carcinomas. This immunohistochemical study on formalin-fixed, paraffin-embedded material found p53 expression in 43 per cent (n = 51) of carcinomas using a monoclonal antibody (DO-1), whereas no immunoreactivity for p53 was present in tumour-associated non-neoplastic gastric mucosa or tumour stroma. There was no statistically significant correlation with known prognostic parameters such as extent of tumour growth (pT state), nodal involvement (pN state), or tumour grade. The same applied for association with patient age and sex or pathological parameters such as tumour size, localization, or growth pattern according to histological classification. Kaplan-Meier analysis revealed marginal statistically significant differences in survival times between patients with p53-positive tumours with more than 35 per cent of p53-positive tumour cells and those with less than 35 per cent of p53-positive tumour cells or p53-negative tumours (P = 0.04). However, by multivariate analysis, p53 immunoreactivity did not turn out as an independent prognostic parameter. p53 expression can easily be detected in a variety of human malignancies including gastric cancer by immunohistochemical methods, but its prognostic significance and possible role as an independent marker of poor prognosis still have to be confirmed by further studies.

PS2 protein in gastric carcinoma and normal gastric mucosa: Association with clinicopathological parameters and patient survival

The presence of pS2 protein (pS2) was studied in a total of 120 consecutive patients with gastric carcinomas. This immunohistochemical study found pS2 expression in 48 per cent (n = 58) of carcinomas. pS2 expression was also detected in normal gastric mucosa in 95 per cent (n = 102) of specimens in upper antral mucopeptic glands and deep foveolar cells of the gastric pits but not in intestinal metaplasia. There was a significant statistical correlation between pS2 expression and extent of tumour growth (pT state) and expression of pepsinogen II by the tumours. There was no statistical correlation with clinical features such as patient age or sex or other pathological parameters (tumour stage, size, grade, and localization or growth pattern according to histological classification). There were no statistically significant differences in survival times between patients with pS2-positive and pS2-negative tumours. In contrast to findings concerning breast cancer, pS2 expression in gastric carcinomas had no influence on the patient's prognosis. On the other hand, strong expression of pS2 by surface epithelium of normal gastric mucosa may indicate that pS2 might play a role in physiological cell renewal of normal gastric mucosa.

Uptake of 2-Deoxy, 2-(18F) Fluoro-D-Glucose in Bladder Cancer: Animal Localization and Initial Patient Positron Emission Tomography

An orthotopically transplanted, locally metastasizing rat bladder tumor model was developed to evaluate the extent of uptake of fluoro-deoxy-glucose (FDG) in bladder cancer. Significant uptake of FDG in localized bladder tumors in rats was shown, with an average tumor-to-blood ratio of 39 at 2 hours after intravenous FDG administration. Metastases (3 nodal and 1 peritoneal) also showed significant uptake of FDG, with an average metastasis-to-blood ratio of 21.7, and tumor involved-to-normal lymph node ratio of 5.3. Because FDG is excreted in the urine, urinary FDG potentially could prevent the use of FDG/positron emission tomography (FDG/PET) scanning for localized bladder cancer. Bladder lavage successfully reduced the retention of FDG in the normal rat bladder, with an estimated uptake ratio of tumor-to-normal bladder of 13.1 after 5ml. saline irrigation.Based on these data, we performed an FDG/PET scan of a patient with biopsy proved recurrent intravesical bladder cancer after radiation therapy. Computerized tomography (CT) of the pelvis showed abnormalities consistent with radiation scarring and extravesical tumor. Due to the scarring, the extent of tumor growth could not be determined. The patient also had pulmonary opacities seen on chest radiography. The FDG/PET scan of this patient showed significant extravesical uptake in the pelvis, confirming the abnormality noted on CT. Good images of the clinically apparent metastases in the chest also were obtained. These preliminary data indicate that FDG/PET imaging of bladder cancer is feasible and it may provide new information for the diagnosis and staging of patients with bladder cancer.

Endoluminal ultrasound of the bile ducts

Miniaturization of ultrasound probes has made possible endoluminal investigation of small duct systems. We have used a 360 degree transaxial real-time sector-scan imaging system with a field of view of 3-5 cm. It operates at ultra-high frequencies, which allows very high resolution. Ten jaundiced patients, aged 35-73 years, were investigated. Malignant bile-duct obstructive disease was present in eight and benign strictures in the remaining two. In all of them the intrahepatic bile ducts had undergone percutaneous transhepatic cannulation for diagnostic and therapeutic purposes. The resolution capacity has been sufficient to allow studies of the bile duct wall and adjacent tissues, and it has thus been possible to study the papilla of Vater, biliary-enteric anastomoses, and adjoining portions of the pancreatic and cystic ducts. Adjacent vessels have been identified. This preliminary study indicates that the character of strictures and the extent of tumour growth may be evaluated, thereby demonstrating the clinical potential of these miniature transducers. Endoluminal ultrasound evaluation of the bile ducts may also be possible intraoperatively and as a supplement to duodenoscopy.

Extent of mesorectal spread and involvement of lateral resection margin as prognostic factors after surgery for rectal cancer

The extent of tumour growth beyond the muscularis propria (mesorectal spread) was measured in specimens from 167 consecutive patients with rectal cancer. The 5-year survival was significantly greater in patients with slight mesorectal spread (4 mm or less) than in those with more extensive mesorectal spread (55% [95% confidence interval 42-66%] vs 25% [13-38%]). The prognostic value for survival of mesorectal spread was independent of the presence of lymphnode metastases. There were also significant differences in survival between patients with slight and extensive mesorectal spread among patients with Dukes' stage B tumours (66% [41-82%] vs 37% [14-60%]) and those with Dukes' stage C tumours (30% [12-52%] vs 18% [6-34%]). Thus mesorectal spread of rectal cancer is an important determinant of survival, and its accurate measurement may serve to subdivide Dukes' B and C cases. In this study tumour involvement of the lateral resection margin was not a useful predictor of local recurrence, but it did correlate with poor prognosis.

Brain Stem Gliomas: A Classification System Based on Magnetic Resonance Imaging

MR scans of 87 pediatric patients with brain stem gliomas were retrospectively reviewed to develop a new classification scheme based on MR imaging. The scheme that has been developed utilizes primarily T2-weighted images, as these most accurately show tumor extent. Tumors are characterized as to location of origin, focality, direction and extent of tumor growth, degree of brain stem enlargement, degree of exophytic growth, and presence or absence of cysts, necrosis, hemorrhage, and hydrocephalus. The use of this classification allowed identification of differences in a population of patients who were selected to be as similar as possible. This system will aid in the assessment of new protocols for treatment of brain stem tumors.

Resectability of Liver Tumours Evaluated by Computed Tomography

In a retrospective study of CT examinations of liver tumours in 37 patients intra- and extrahepatic tumour growth was estimated in order to see if resectability could be predicted. The findings were compared with the evaluation at laparatomy. Four out of 15 tumours, resectable according to CT, turned out to be unresectable and 9 out of 37 CT examinations did not reveal the total extent of tumour growth. A more reliable preoperative radiologic assessment may be obtained by improvement of current CT techniques, by computed tomographic angiography, intraoperative ultrasound or MR imaging.

Resectability of liver tumours evaluated by computed tomography

In a retrospective study of CT examinations of liver tumours in 37 patients intra- and extrahepatic tumour growth was estimated in order to see if resectability could be predicted. The findings were compared with the evaluation at laparatomy. Four out of 15 tumours, resectable according to CT, turned out to be unresectable and 9 out of 37 CT examinations did not reveal the total extent of tumour growth. A more reliable preoperative radiologic assessment may be obtained by improvement of current CT techniques, by computed tomographic angiography, intraoperative ultrasound or MR imaging.

Tumor angiogenesis activity of human choriocarcinoma cells grown in vitro

The growth of five different kinds of human Choriocarcinoma cell lines in vitro was quite alike. However, two distinct types of rapid and slow growth were observed in tumors grown in the hamster cheek pouch. The rapidly grown tumor tissues (BeWo, JEG-3, and NUC-1) involved significantly large numbers of blood vessels per microscopic field, as compared to slowly grown ones (SCH and HM). The vascular response was assayed using cell-free crude tumor angiogenesis factors (TAF) on chorioallantoic membrane (CAM) of the chick embryo. In all cell lines TAF activity correlated well with the extent of tumor growth in vivo. Gel filtration analysis showed that relatively high-molecular-weight (more than 10,000) factors could induce neovascularization in the both assays using CAM and rabbit cornea. These results suggest that a heterogeneity of TAF activity is present among human Choriocarcinoma cell lines and tumor growth in xenograft depends on the secretion of TAF by the tumor cells themselves.

Tumor angiogenic activity (TAA) production in vitro and growth in the nude mouse by human malignant melanoma

The production of angiogenic activity by eleven human melanoma lines in vitro was compared with the extent of tumor growth in the nude mouse. Angiogenic activity was assayed by measuring the vascular response of the chick chorioallantoic membrane to serum-free supernatants. Growth in the nude mouse was determined after subcutaneous injection of cells 60 days later. Angiogenic activities ranged from negative to highly positive. In five lines angiogenic activity in vitro correlated with the extent of tumor growth in the nude mouse. In contrast, two lines did not show such a correlation, e.g. they produced large tumors without any detectable angiogenic activity. Histological examination of these two tumors revealed moderate degrees of vascularization and only low degrees of necrosis. It is concluded that the extent of tumor growth in the nude mouse is partly independent of the production of angiogenic activity by the tumor cells themselves.

Serum levels of glycosyltransferases and related glycoproteins as indicators of cancer: biological and clinical implications.

Many studies have suggested that malignant transformation is associated with fundamental changes in the cell surface; similar changes have been described for normal stem cells and cells of embryonic or fetal origin. There is now evidence that the tumor cell secretes or sheds glycoproteins and glycosyltransferases into the surrounding medium and into serum. There are claims that some of these serum glycoproteins and glycosyltransferases are associated with, or specifically related to, the extent of tumor growth and may serve as a cancer marker. A cancer-associated galactosyltransferase isoenzyme (GT-II) has been described and purified. Different isoelectric forms of fucosyltransferase have also been described as indicative of malignancy. The articles to be published in CRC Critical Reviews in Clinical Laboratory Sciences will analyze the evidence for the association of these membrane factors with tumor growth. In order to better understand the possible significance of altered glycoproteins and of increased or different forms of glycosyltransferases during tumor growth, recent data on glycoprotein synthesis will be discussed including the new concepts on the control of glycoprotein synthesis through lipid intermediates. The possible mechanisms whereby malignant transformation could alter glycoprotein synthesis will be discussed with particular emphasis on the significance of these alterations to the biology of the malignant cell. Changes in surface membrane glycoproteins have long been implicated in the ability of a cell to metastasize. Secretion and/or shedding of the cell surface may also be important in the process of metastasis and in altering the host immune response. Detection and the study of these "shed" materials in patients appear to be indicating a new approach to cancer biology detection and therapy.

Colorectal cancer in patients less than 40 years of age in Denmark, 1943-1967.

A retrospective review of all the 951 patients less than 40 years of age with colorectal cancer in Denmark 1943-67 is described. The annual incidence in Denmark of colorectal cancer in this age group is 1.4/100,000. These patients do not differ from other patients with colorectal cancer with regard to sex ratio, tumor localization, extent of tumor growth, histologic type, frequency of intestinal obstruction and perforation. Of these patients 53 per cent were subjected to radical operation. The five-year crude survival rate was 32 per cent for all patients and 65 per cent in cases of radical operation. The operative mortality was 9 per cent. The extent of tumor growth according to Dukes' classification and the presence of intestinal obstruction and/or perforation were the only factors found to influence the prognosis. The survival rates correspond to rate given in the literature in respect of colorectal cancer, regardless of age. It is concluded that colorectal cancer in young patients differs in no respect from the disease in older patients.

Investigations on prostatic adenocarcinomas in rats.

Metastatic prostate adenocarcinomas, derived from aging germfree Wistar rats, have been propagated in rats and in tissue culture. A protocol has been developed and demonstrated for assay of treatments which retard or which accelerate the rate and extent of tumor growth and of metastasis in tumor-bearing rats. The pattern of spread has been retarded by cyclophosphamide, aspirin, indomethacin, and Corynebacterium parvum. The spread pattern has been accelerated by oral administrations of sodium barbiturate.

The interaction between Walker tumour cells and mucosa cells in the lamina propria of gastric mucosa in rats. The tumour behaviour in previously X-irradiated mucosa compared to normal mucosa.

One series of 12 rats was exposed to X-irradiation (1500 R) of the stomach 19 days before implantation of Walker tumour cells in the gastric mucosa, and the frequency of tumour take and the extent of tumour growth after 10 days were compared with a second series with the same tumour implantation, but without X-ray exposure. In a third series simple gastric ulcers without tumour were produced by clamping the gastric wall with a heated (80 degrees) surgical needle holder, and the animals were killed 5-7 day later. All the rats were given injections of vinblastine sulfate 3 hours and of 3H-TDR 1 hour before sacrifice. In viewfields with diameter 180 mu the vinblastine-arrested mitoses and labelled cells on the tumour side of the tumour/mucosa border were calculated as percentages of all tumour cells. In the mucosa the total number of proliferating cells was counted at various distances from the border of the tumour or ulcer. No clear differences in the frequency of tumour take and the extent of tumour growth were found between the X-irradiated and the normal rat stomachs, and it is concluded that the X-ray exposure 3 weeks prior to tumour implantation did not reduce the normal mucosal resistance to tumour growth. The percentage of arrested mitoses and labelled cells in the tumour decreased one view field away from the mucosal border, and the number of proliferating cells in the mucosa bordering on the tumours showed a gradual fall with increasing distance up to 0.8-1.0 mm from the tumour border; within these distances, however, the numbers were much higher than at corresponding distances from edges of the ulcers. The Walker tumour thus seems to stimulate cell proliferation in mucosa to a much greater extent than a simple ulcer does. The causes of this phenomenon and the possible roles of "chalones" or "anti-chalones" are discussed.