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BACKGROUND: Although successful xenotransplantation of human tumors in nude mice highly predicts prognosis, little is known regarding the biologic background of this correlation. In this study, the relationship between the macroscopic growth pattern of first-generation xenografts of human renal cell carcinomas in nude mice and prognosis was studied. METHODS: Macroscopic growth patterns of the first-generation xenografts of locally confined renal cell carcinomas were analyzed according to the best-fit Gompertz recursion formulas. RESULTS: The parameter "b" of the growth pattern, the measure of the intensity of growth deceleration as a function of tumor growth, strongly predicted prognosis after nephrectomy as a single factor; faster growth deceleration, i.e., lower b values, predicted better prognosis (mean follow-up, 5.2 years; P = 0.000008 for the disease free period and P = 0.000018 for overall survival). It is also the most significant single prognostic parameter among others (including staging and grading) according to a multivariate analysis. CONCLUSIONS: The parameter expressing the Gompertzian macroscopic growth deceleration of the first-generation xenografts of clinically locally confined renal cell carcinomas in nude mice explains the strong prognostic impact of xenotransplantation. Cancer

BACKGROUND: The prognosis of patients with locally confined renal cell carcinoma is variable. To improve the prognostic knowledge and select patients at high risk, additional prognostic parameters are needed. METHODS: The significance with respect to survival and tumor recurrence of "classic" and "new" prognostic parameters has been examined by following 41 patients with locally confined renal cell carcinoma after nephrectomy (mean follow-up, 5.2 years). The significance of histologic grade, tumor stage, Ki-67 index, proliferating cell nuclear antigen index, 3H-thymidine labeling index, tumor ploidy status, and tumor growth after xenotransplantation into nude mice (GAX range) was tested using the Kaplan-Meier plots by the log rank test or Tarone's test and also by the Cox multiple hazard regression analysis. RESULTS: Tumor stage (P < 0.0025), histologic grade (P < 0.005), Ki-67 index (P < 0.006), and GAX range (P < 0.00004) were found to be significant prognostic parameters for survival and tumor recurrence using single-factor analysis. Applying the multivariate analysis, the combination of the "new" factors, GAX range and Ki-67 index, resulted in even a higher prognostic relevance than the combination of the "classic" prognostic factors, tumor stage and histologic grade. The calculated prognostic index based on the results of the Cox analysis, which, except for stage and grade, included the Ki-67 index, was shown to be highly correlated with survival (P = 0.00002) and tumor recurrence (P = 0.0004). Its prognostic validity was studied with the receiver operating characteristics procedure and was found to be considerably superior to that of the two conventional prognosticators. CONCLUSIONS: The additional determination of the Ki-67 labeling index increases the prognostic assessment of patients with locally confined renal cell carcinoma. Cancer

The effect of biological response modifiers on macroscopic tumor growth and on tumor cell proliferation of a human renal cell carcinoma and a squamous cell carcinoma (hypopharynx) in nude mice has been studied. Tumor necrosis factor alpha (TNF-alpha) and interferon alpha (IFN-alpha) as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) were applied either alone or in combination, and TNF-alpha was also combined with etoposide (ETP). TNF-alpha and IFN-alpha alone or in combination did not substantially affect the course of tumor growth, however, they did influence the pattern of tumor growth. There was also only a marginal effect on tumor cell proliferation. However, IFN-alpha protects the animals from tumor growth associated weight loss. ETP and ETP plus TNF-alpha leads to a deceleration of tumor growth, a decrease of the labeling index and to a significant decrease of the animal weight which indicates that the first two effects may be partly due to the toxicity of the treatment. GM-CSF modifies cell proliferation in a dose-dependent manner, i.e. stimulation at low doses and tendency to inhibition at higher doses. Although there is no substantial direct antineoplastic effect of the agents studied, the results make clear that indirect effects of therapeutic agents due to therapy induced cachexia should always be regarded. It is interesting that IFN-alpha has a protective effect against cachexia. Cell Mol Biol (Noisy-le-grand)

Unfortunately the efficacy of the treatment of the metastatic or recurrent renal cell carcinoma (RCC) has not improved during the last few years. Recently effort has been put into the experimental and clinical evaluation of so-called "biological response modifiers" (BRM; cytokines and related peptides) as treatment modalities for RCC. The present results are, however, still disappointing. Since BRM, if applied alone, are largely ineffective as antineoplastic agents, more experimental studies are now necessary to test the antineoplastic value of their combinations, which seem to be more promising. In the present study, the in vivo effect of tumor necrosis factor a (TNF a) and/or interferon a (IFN a) on the macroscopic tumor growth (external caliper measurements of tumor size) and on the cell proliferation (in vivo 3H-thymidine labelling index, LI, and mitotic index, MI) of a human RCC xenograft line in nude mice has been investigated. Neither of these substances alone nor their combination was effective in changing the time course of the tumor sizes and the growth patterns of the treated tumors in a statistically significant manner as compared to the untreated controls. Also the cell kinetic parameters were only marginally affected by these treatments, whereby TNF a alone proved to be more effective than IFN a alone. However, compared to the effect of TNF alpha alone, the combination with IFN alpha leads to some amelioration of the cell kinetic perturbations and also to an appreciable shift in the growth patterns of the tumors from distinct Gompertzian (under TNF alpha alone) to near exponential (under the combination treatment; p < 0.05). As a consequence, the tumors grow more slowly under the combined treatment during the observation time, and on the other hand, their growth does not decelerate as much as under TNF alpha alone. Actually, if tumor growth continues in the same way, the extrapolation of the present data predicts smaller and greater tumors than the control tumors in the TNF alpha and in the combination treatment groups respectively. Notably, in the combination the effect of the IFN alpha seems to predominate. This is also seen in the effect of this combination on the cachexia of these tumor-bearing animals: either alone or in combination with TNF alpha, IFN alpha partially protects the animals from tumor-growth associated weight loss. Although the direct antineoplastic in vivo effect of the present cytokine combination against this human RCC xenograft line is rather limited, the potential antagonizing effect of IFN alpha on the development of cachexia should be further explored. Anticancer Res

The effect of tumor size and tumor age on the efficiency, and particularly on the lethal toxicity, of a single application of cyclophosphamide (300 micrograms/g body weight i.p.) to C57bl/6j mice bearing the adenocarcinoma EO 771 has been investigated by treating tumors of the same size but different age on the one hand and tumors of the same age but different size on the other. Treatment of animals bearing larger tumors is consistently associated with increased toxicity: 71/74 animals with tumors > 1.25 g at the time of treatment die of toxicity as opposed to only 1/33 animals with tumors < 1.25 g (relative risk of death of toxicity is 31.7 for animals with tumors > 1.25 g as compared to those bearing tumors < 1.25 g). On the contrary, the age of the tumor does not appreciably influence the toxicity of treatment. The reason for the increased toxicity of the antineoplastic chemotherapy with increasing tumor size is not clear. However, the rather abrupt manifestation of lethal toxicity as a function of tumor size coincides well with the beginning of tumor cachexia in the same animals. Possible mechanisms for this interrelationship of cachexia and potentiation of treatment toxicity are discussed. Anticancer Res

Growth curves of 26 EO 771 adenocarcinomas transplanted under identical conditions into 26 syngeneic C57bl/6 male mice of the same age but with different body weight were analyzed using the method of the recursion formula of the Gompertz function. The results of this analysis were then related to the body weight of the animals at the time of tumor implantation. Although all tumors grew according to the Gompertz mode of growth, the growth curves differed from each other. Moreover, there is a statistically significant correlation between the parameters of the individual growth curves and the corresponding animal weight at the time of tumor implantation (p less than 0.025). In animals with higher body weight the tumors grew with a higher initial growth rate and subsequently with a faster growth deceleration compared to animals with lower body weight. The physiological basis for this relationship is unknown but the question arises whether this relationship also has some meaning for human malignancies. In Vivo

The relationship between the dynamics of tumor growth and the development of cachexia in C57b1/6j mice bearing the syngeneic transplantable adenocarcinoma EO 771 has been studied. The tumors grow independently of the inoculum size according to the Gompertzian mode of growth, with a maximum growth rate at a tumor size of about 3 g. As a dynamic measure of the degree of cachexia, the cachexia index "K", i.e. the quotient of the alteration of the carcass weight of the animal divided by the alteration of the tumor weight during the same time interval, is introduced. K is superior to a simple estimation of the alteration of the carcass animal weight because it also considers local weight-reducing effects of the infiltrating tumor growth. With respect to cachexia, three phases of tumor growth can be distinguished; cachexia develops mainly during the 2nd phase, i.e. for tumor sizes between 1.0 to 3.5 g which strongly correlates with the maximum growth rate of the tumor. Anticancer Res

Growth and proliferation were studied of a transplantable mouse tumor, the adenocarcinoma EO 771 (Adca EO 771) growing in C 57 and in nude mice on the one hand, and of human tumors (renal cell and hypopharynx carcinoma) growing in nude mice on the other. There is almost no difference in tumor growth, histology and proliferation whether the Adca EO 771 grows in C 57 or in nude mice. However, there are great differences in this respect between the transplantable mouse tumor and human tumors. Growth of the Adca EO 771 and C 57 and in nude mice occurs according to the Gompertz function, whereas growth of human tumors in nude mice differs, some tumors grow exponentially and some according to the Gompertz function. The proportion of necrotic tissue strongly increases with increasing tumor size in the case of the Adca EO 771, while it is about constant in human tumors regardless of the tumor size. The tumor cell density of the Adca EO 771 increases considerably with increasing tumor size, however, it remains about constant in human tumors. Concerning tumor cell proliferation an S phase duration was found that is rather similar for the cells of the transplantable mouse tumor as well as of the human tumors suggesting that DNA synthesis might be regulated by the host organism. A quantitative study of the growth of the metastases of the Adca EO 771 exhibited an allometric correlation between the growth of the metastases and that of the primary tumor. This leads to the consequence that metastases might originate later than estimated until now assuming exponential growth of metastases. Treatment of the Adca EO 771 with cyclophosphamide results in the death of almost all tumor cells; however the tumor repopulates. The toxic effect of cyclophosphamide on the mouse organism strongly depends on the size of the tumor at the time of treatment. Acta Histochem Suppl