OBJECTIVETo develop a model to predict the outcome before surgery for non-metastatic renal cell carcinoma (RCC). PATIENTS AND METHODSThe records of 660 patients with nonmetastatic RCC, operated at three European medical institutes, were reviewed. Univariate and multivariate analyses were used to assess the clinical and pathological variables affecting disease-free survival. RESULTSThe median (range) follow-up was 42 (2-180) months; the disease recurred in 110 patients (16%). The 2-and 5-year overall survival was 87% and 54%, respectively. Five variables were significant in the univariate analysis, i.e. clinical presentation, clinical and pathological size, tumour grade and stage ( P < 0.05). The preoperative variables, e.g. clinical presentation and clinical tumour size, were retained from the multivariate model. A recurrence risk formula (RRF) was constructed from this model, as (1.28 ¥ presentation (asymptomatic = 0; symptomatic = 1) + (0.13 ¥ clinical size)). Using this equation, the 2-and 5-year disease-free survival was 96% and 93% for an RRF of £ 1.2 and 83% and 68% for an RRF of >1.2. CONCLUSIONA formula was developed which, independent of stage, can be used to predict the rate of treatment failure in patients who undergo nephrectomy for non-metastatic RCC. The RRF might be useful for more accurate subgrouping of good-prognosis patients, and for counselling patients before surgery, their personalized follow-up or adjuvant treatment once available.

Today, it is known that all human biological functions are under two fundamental regulatory systems, consisting of the endocrine system and the cytokine network. Moreover, it has been shown that the cytokines released from the activated immune cells do not influence only immune functions, but also the whole biological system, including the various metabolic activities, the cardiovascular system, and the functionless of the neuroendocrine system itself. Unfortunately, despite the well-demonstrated importance of cytokines in maintaining the status of health, from a clinical point of view the routine evaluation of the cytokine system still remains unconsidered to establish the status of health, since it is investigated only in severe conditions, such as septic shock, disseminated intravascular coagulation and respiratory distress, which have been demonstrated to be due to an abnormal endogenous production of inflammatory cytokines, namely IL-6, TNF-alpha, and IL-1 beta. This clinical deficiency was depended on several factors, particularly on the complexity of cytokine interactions themselves, but also on the decision to use artificial molecules, such as monoclonal antibodies against the various cytokines, to counteract their eventual abnormally enhanced endogenous production, rather than to investigate the mechanisms responsible for their altered production and to correct eventual alterations. The main reason of the complexity of the cytokine network is related to the fact that the interactions occurring among the different cytokines are often founded on positive feedback mechanisms, then on reciprocal stimulatory actions, while the endocrine system is substantially based on negative feedback circuits. The aim of the present review is to propose a synthetic knowledge regarding the main effects and the source of origin of each single interleukin discovered up to now, to elaborate a first preliminary fundamental physiology of the cytokine network.

The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno-inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases.

The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology.

The recent advances in the knowledge of the psychoneuroimmunological pathogenesis of human neoplasms have demonstrated the existence of feed-back mechanisms operating between interleukins and endocrine secretions, which play an important role in the regulation of the immune responses, including the anticancer immunity. In contrast, few studies only have been performed to investigate the possible relation between endocrine activities and hematopoietic growth factors. The present study was performed to analyze the acute endocrine effects of erythropoietin-alpha (EPO) on the main endocrine secretions. The study was carried out in 10 advanced solid tumor patients. EPO was injected subcutaneously at a dose of 10,000 U, and venous blood samples were collected before and 2, 4 and 6 h after EPO administration. No significant changes in mean serum levels of FSH, LH and TSH were seen in response to EPO. Cortisol and DHEAS concentrations increased after EPO injection, whereas those of PRL decreased, but none of these differences was statistically significant. Finally, mean serum levels of both growth hormone (GH) and somatomedin-C (IGF-1) significantly decreased after EPO administration. This preliminary study shows that EPO may inhibit GH secretion from the pituitary gland and IGF-1 production. Since GH would stimulate EPO release, the results of this study may suggest the existence of feedback mechanism operating between GH secretion and EPO production, with inhibitory effect of EPO on GH secretion, and stimulatory action of GH on EPO production. Therefore, this study would describe the first example of hemato-endocrine feedback mechanisms. Moreover, this study, by showing an inhibitory effect of EPO on IGF-1 secretion, would suggest a possible use of EPO in the medical oncology not only for the treatment of cancer related anemia, but also to counteract tumor growth by blocking IGF-1 production, which has been proven to be a growth factor for several tumor histotypes. Obviously, IGF-1 is not the only tumor growth factor, but it could play a fundamental role in the regulation of production and activity of several other tumor growth factors. In any case, this study describes the only acute endocrine effects of EPO. Therefore, further studies, by evaluating the endocrine effects of a chronic treatment with EPO, will be required to establish which may be its effect on IGF-1 endogenous production, and its consequence on survival time.