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.

Despite the well documented potential stimulatory activity of prolactin (PRL) on mammary tumors, hyperprolactinemia following breast surgery has proven to be able to predict a more favourable prognosis in breast cancer. This apparent controversial result is probably due to mammary stimulation that induces PRL secretion in normal conditions, therefore the failure of PRL increase after breast surgery could reflect an alteration in the neuroendocrine control of mammary tissue growth and differentiation. On this basis, a study was planned in order to investigate the effects of breast surgery on PRL secretion in Triple Negative Breast Cancer (TNBC), which represents the most malignant subtype of mammary tumors. The study included 100 breast cancer patients treated by quadrantectomy, evaluating PRL serum levels before and 7 days after surgery. The diagnosis of TNBC occurred in 16/100 investigated patients. Postsurgical hyperprolactinemia was observed in 53/84 (63%) patients with common breast cancer and in only 2/16 (13%) TNBC patients. This difference was statistically significant. The present preliminary study, demonstrates a lower frequency of surgery-induced hyperprolactinemia in TNBC compared to the other mammary tumorhistotypes and furthermore it suggests that the more aggressive behavior of TNBC could depend to some extent on a more pronounced alteration in the neuroendocrine control of mammary tissue.

The future of laboratory analyses would require the identification of clinical parameters involving the main integrative biological functions including neuroendocrine, immune and cardiovascular systems, and capable of predicting the evidence of metabolic alterations and the possible occurrence of systemic diseases.According to the clinical data available up to now, the status of health may be identified by the following five major biomarkers, consisting of normal circadian rhythm of cortisol and the pineal hormone melatonin, normal blood concentrations of fatty acid amide hydrolase (FAAH), whose increase is associated with an endocannabinoid system deficiency, normal lymphocyte-to-monocyte ratio (LMR) values, normal blood levels of TGF-beta, the main immunosuppressive anti-inflammatory endogenous molecule, and normal values of ANP-to-ET-1 ratio.Since the evidence of alterations involving these five parameters may predispose to the onset of more severe metabolic disorders or systemic disease, the clinical evaluation of these five biomarkers could constitute the routinary laboratory analyses for realizing a real Preventive Medicine.

Despite it is known since more than 50 years that the pineal hormone melatonin (MLT) may play an anticancer activity, as confirmed by several experimental and clinical studies, the clinical use of MLT in the treatment of cancer is still at the beginning. Most clinical studies have been performed with MLT dose of 20 mg/once daily in the dark period. Preliminary clinical studies with MLT in untreatable advanced cancer patients have demonstrated an inhibitory effect on tumor progression, with a prolonged 1-year survival. However, at present it is still unknown whether the antitumor action of MLT may be a dose-dependent event in human neoplasms. This preliminary study was performed to evaluate the doseefficacy ratio of MLT in the treatment of human neoplasms. The study was performed in 14 consecutive metastatic solid tumor patients, for whom no other standard antitumor therapy was available. MLT was administered at a dose of 20 mg/day orally in the evening. In the case of progressive disease, MLT dose was progressively enhanced until 100 mg/day. MLT therapy at a dose of 20 mg/day induced a disease control in 7/145 patients, consisting of partial response (PR) in one patient and a stable disease (SD) in other 6 patients. After progression, dose increase of MLT until 100 mg induced again a SD in 6/14 (43%) and 1–year survival was achieved in 8/14 (56%). The results of this preliminary study would demonstrate that the antitumor activity of MLT may increase by increasing MLT dose, and then it seems to be a dose-dependent phenomenon.

Several natural agents, including both human endogenous neuroendocrine substances, namely the pineal hormones, and plants, mainly Aloe, Myrrh and Magnolia, have been proven to exert anticancer activities, due to antiproliferative and immunomodulating properties. On this basis, a study was planned in an attempt to evaluate the therapeutic efficacy of a psychoneuroendocrinoimmun-phytotherapic (PNEIF) regimen with pineal hormones and antitumor plants in a group of untreatable metastatic solid tumor patients, for whom no treatment other than the palliative therapy was available, because of lack of response to previous chemotherapies, poor clinical status or personal refusal of chemotherapy, and with a life expectancy less than 1 year. The pineal hormone melatonin (MLT) and 5-methoxytryptamine (5-MTT) were given orally at 100 mg/day in the dark period and at 5 mg in the light period of the day, respectively, in association with Aloe and Myrrh mixture at 10 ml thrice/day, Magnolia cortex at 500 mg twice/day and Bowellia at 1000 mg/day in patients with brain metastases. A complete response (CR) and partial response (PR) were achieved in 2 and in 8 patients. Then, an objective tumor regression was obtained in 10/132 (8%) patients. A stable disease (SD) was found in 61 patients, then a disease control (DC), consisting of CR plus PR plus SD, was achieved in 71/132 (54%) patients, whereas the remaining patients had a progressive disease (PD). A survival longer than 1 year was seen in 63/132 (48%) patients, and the percent of 2 and 3-year survival obtained in patients with response or SD was significantly longer than that found in patients with PD. The treatment was well tolerated and no relevant biological toxicity occurred. This preliminary study would demonstrate that a PNEIF combination with natural anticancer agents may prolong the survival time in patients, for whom no standard therapy was available other than the only palliative therapy, and with an expected survival less than 1 year.

BACKGROUND:Cancer progression has been associated with neuroendocrine alterations involved in the control of the circadian rhythms, particularly those of cortisol. Moreover, the evidence of an altered cortisol rhythm may predict a poor prognosis in cancer patients. Finally, cancer progression has been proven to be associated with alterations in the pineal gland, which plays a fundamental role in the control of circadian biological rhythms. On this basis, a study was planned to evaluate the effects of a chronic treatment with the pineal hormone melatonin (MLT) in advanced cancer patients with altered cortisol circadian rhythm.PATIENTS AND METHODS:The study included 14 untreatable metastatic cancer patients showing alterations of cortisol rhythm. They were treated by MLT at 20 mg/day orally, in the evening, for 3 consecutive months.RESULTS:a normalization of cortisol rhythm was achieved in 4/14 (29%) patients. Moreover, stable disease (SD) was obtained in 6/14 (43%) patients under MLT therapy, whereas the other 8 patients had progressive disease (PD). Finally, the percentage of cortisol rhythm normalization achieved in patients with SD was significantly higher than that observed in patients with PD.CONCLUSION:These results show that MLT may normalize cortisol rhythm in advanced cancer patients and this effect appears to be associated with SD, thus confirming the negative prognostic significance of cortisol rhythm alterations in cancer.

BACKGROUND: The anti-oxidant and immunomodulating natural agents may enhance the efficacy of cancer chemotherapy. One of the most important agents is the pineal hormone melatonin (MLT) which may exert both anti-oxidant and antiproliferative immunostimulating anticancer effects. This study was performed to evaluate the efficacy of a bio-chemotherapeutic regimen in metastatic cancer patients, and its therapeutic activity in relation to the psychospiritual status of patients.METHODS: The study included 50 metastatic non-small cell lung cancer (NSCLC) patients and a control group of 100 patients. Chemotherapy consisted of cisplatin plus gemcitabine. MLT was given orally at 20 mg/day in the evening. Patients were subdivided into 5 psychic profiles, as follows: spiritual faith, rationale faith, anxiety, apathy, and accusation behavior.RESULTS: Tumor response rate was significantly higher in patients treated by chemotherapy plus MLT than in those treated by chemotherapy alone (21/50 vs. 24/100, p < 0.001). However, the percentage of objective tumor regressions obtained in patients with spiritual faith was significantly higher than that found in the overall other patients concomitantly treated by chemotherapy plus MLT (6/8 vs. 15/42, p < 0.01).CONCLUSIONS: In conclusion, the efficacy of chemotherapy may be enhanced by the pineal hormone MLT, by representing a new promising biochemotherapeutic combination; also despite its objective ability to enhance chemotherapy efficacy, the activity of MLT is depending at least in part on the psychospiritual status of cancer patients, and it is maximal in the presence of a real spiritual faith.

BACKGROUND:At present, it is known that cancer-related immunosuppression would mainly depend on an immunosuppressive action mediated by a subtype of CD4+ lymphocytes, the so-called regulatory T lymphocytes (T-reg), which are identified as CD4+CD25+ cells. Moreover, it has been shown that anticancer immunity is under psychoneuroendocrine regulation, mainly mediated by the pineal hormone melatonin (MLT). This study was performed to investigate the in vivo and in vitro effects of MLT on T-reg generation.MATERIALS AND METHODS:We evaluated the in vivo effects of MLT (20 mg/daily orally in the evening) in 20 patients with untreatable metastatic solid tumor and the in vitro effects of MLT incubation (at 10 and 100 pg/ml) of pure lymphocyte cultures on T-reg cell count.RESULTS:MLT induced a statistically significant decline in mean T-reg cell numbers in patients who achieved disease control, whereas no effect was seen in those who had progressed. In contrast, no in vitro effect of MLT incubation was apparent.CONCLUSION:This preliminary study would suggest that MLT may exert in vivo an inhibitory action on T-reg cell generation in cancer patients which is associated with a control of the neoplastic progression, whereas no direct effect was seen in vitro on lymphocyte differentiation. This finding would suggest that MLT may counteract T-reg cell generation in vivo by inhibiting macrophage activity which is involved in stimulating T-reg cell production.

Background: The recent advances in the analysis of tumor immunobiology suggest the possibility of biologically manipulating the efficacy and toxicity of cancer chemotherapy by endogenous or exogenous immunomodulating substances. Aloe is one of the of the most important plants exhibiting anticancer activity and its antineoplastic property is due to at least three different mechanisms, based on antiproliferative, immunostimulatory and antioxidant effects. The antiproliferative action is determined by anthracenic and antraquinonic molecules, while the immunostimulating activity is mainly due to acemannan. Patients and Methods: A study was planned to include 240 patients with metastatic solid tumor who were randomized to receive chemotherapy with or without Aloe. According to tumor histotype and clinical status, lung cancer patients were treated with cisplatin and etoposide or weekly vinorelbine, colorectal cancer patients received oxaliplatin plus 5-fluorouracil (5-FU), gastric cancer patients were treated with weekly 5-FU and pancreatic cancer patients received weekly gemcitabine. Aloe was given orally at 10 ml thrice/daily. Results: The percentage of both objective tumor regressions and disease control was significantly higher in patients concomitantly treated with Aloe than with chemotherapy alone, as well as the percent of 3-year survival patients. Conclusion: This study seems to suggest that Aloe may be successfully associated with chemotherapy to increase its efficacy in terms of both tumor regression rate and survival time.

BACKGROUND:Node involvement, negative estrogen receptor (ER) and HER2 expression are the main negative prognostic factors for breast cancer. Prolactin (PRL) is involved in the control of breast cancer growth and differentiation. Surgery-induced hyperprolactinemia seems to be a positive prognostic factor for operable breast cancer, whereas high PRL levels may predict a poor prognosis in women with metastatic breast cancer. In this study, we evaluated the relation between HER2 expression and PRL blood concentrations in women with metastatic breast cancer women and those whit operable breast cancer patients prior to before and 7 days after surgery.PATIENTS AND METHODS:The study included 50 women with breast cancer, 22 of whom had metastatic disease. HER 2 expression and serum levels of PRL were evaluated by fluorescence in situ hybridization (FISH) method and immunoradiometric assay (IRMA) method, respectively.RESULTS:HER2 expression occurred in 11/28 operable cases and in 8/22 metastatic cases. The percentage of surgery-induced hyperprolactinemia was significantly higher in HER2-negative patients than in those with its expression. Moreover, HER2-positive metastatic cases showed significantly higher mean serum PRL levels than in the negative group.CONCLUSION:These preliminary results show that metastatic cancer-related hyperprolactinemia and lack of surgery-induced hyperprolactinemia are statistically more frequent in HER2-positive patients, thus suggesting a link between PRL endogenous secretion and HER2 expression in breast cancer.

Background and aims Innate immunity cells play a crucial role in host anticancer defense: cancer patients with high levels of natural killer (NK) cells and eosinophils have a better prognosis. Recombinant interleukin-2 (rIL-2) immunotherapy stimulates innate immunity cells. This study aims to evaluate the toxicity of pre- and postoperative rIL-2 treatment and the effects on innate immunity both in peripheral blood and in cancer tissue of patients with resectable pancreatic adenocarcinoma. Materials and methods Seventeen patients received high dose rIL-2 preoperative subcutaneous administration and two low dose postoperative cycles. We evaluated NK cell and eosinophil count in blood and in pancreatic surgical specimens. Results Toxicity was moderate. In the early postoperative period, blood NK cells and eosinophils significantly increased compared to basal values ( p < 0.02). Histopathological analysis did not find significant intratumoral infiltration of NK cells nor of eosinophils. Conclusions Preoperative high dose rIL-2 administration is able to counteract surgery-induced deficiency of NK cells and eosinophils in peripheral blood in the early postoperative period, although it cannot overcome local mechanisms of immune tumor escape in cancer tissue. The amplification of innate immunity, induced by immunotherapy, may improve the control of metastatic cells spreading in the perioperative period.

BACKGROUND:The cannabinoids have been proposed in the treatment of cancer. Generally, the cannabinoids are believed to be useful only in the palliative therapy of cancer-related symptoms, namely pain, anorexia and cachexia. However, preliminary experiments would also suggest an inhibitory effect of cannabinoids on cancer growth, whereas their influence on anticancer immunity is still controversial. The present study aimed to evaluate the influence of the endogenous cannabinoid anandamide (AEA) on T-cell phenotype and function.MATERIALS AND METHODS:The in vitro effects of AEA were evaluated at different concentrations on lymphocyte proliferation, cytotoxicity and differentiation, and in particular on T-regulator generation.RESULTS:AEA did not modify lymphocyte proliferation, neither under basal conditions, nor after IL-2 stimulation. Moreover, AEA did not induce the generation of regulatory T-lymphocytes nor the production of the immunosuppressive cytokine, IL-IO.CONCLUSION:The direct antitumor activity of AEA together with the absence of negative effects on T-cell functions might provide new insights into the potential use of cannabinoid agents in cancer immunotherapy.

Several clinical investigations showed that the immune status is a prognostic variable in cancer patients, even tough the evaluation of the anticancer immunity is not generally considered in the medical oncology. Several immune parameters, including lymphocyte subsets and cytokine blood concentration, had been proposed to quantify the functional status of the anticancer immunity, but recent discoveries would suggest that the end-result of the various immune interactions is represented by a subtype of CD4 lymphocytes capable of suppressing the antitumor immune reaction, the so called T-regulatory lymphocytes (T-reg). This study was performed to detect T-reg count and percentage in solid tumor patients, in relation to tumor histotype, disease extension, lymphocyte sub-populations and cortisol circadian secretion. The study included 114 consecutive cancer patients affected by the most frequent tumor histotypes, 69 of whom showed a metastatic disease. In each patient we evaluated T-reg cells, identified as CD4 + CD25 + , in relation to T helper (CD4), T cytotoxic (CD8) and NK (CD16CD56) cells. Abnormally high values of T-reg cells were seen in 52/114 (46%) patients, and the percentage of high values of T-reg was significantly higher in metastatic patients than in non-metastatic ones. In contrast, no significant difference was seen in relation to tumor histotype. Patients with increased T-reg count had a significantly lower NK cell number. Finally no significant difference in T-reg number was seen between patients with altered or normal rithm of cortisol. The study confirmed that, irrespectively of tumor histotype the metastatic disease is associated with a progressive and increased T-reg generation, with a following suppression of anticancer immunity.

BACKGROUND Anticancer immunity is under psychoneuroendocrine regulation, mainly via the pineal gland and brain opioid system, which may stimulate and inhibit antitumor immunity respectively. Cancer-related immuno-suppression does not depend only on functional damage of immune cells, but also on alterations of systems responsible for the neuroimmunomodulation, the most frequent of wich is a decline in blood levels of the pineal hormone melatonin (MLT). PATIENTS AND METHODS A study was performed to evaluate the influence of an exogenous administration of MLT alone or MLT plus subcutaneous (SC) low-dose interleukin-2 on tumor progression and survival time in patients with untreatable metastatic solid tumors. The study included 846 patients with metastatic solid tumor (non-small cell lung cancer or gastrointestinal tract tumors) randomized to receive the best supportive care only, supportive care plus MLT (20 mg/day, orally in the evening), or MLT plus SC low-dose IL-2 (3 MIU/day for 5 days/week, for 4 consecutive weeks). RESULTS The MLT alone was able to induce a significant increase of disease stabilization and survival time with respect to supportive care alone. The association of lL-2 with MLT provided a further improvement in the percentage of tumor regressions and of 3-year survival with respect to MLT alone. CONCLUSION The administration of IL-2 and the pineal hormone MLT may induce control of neolplastic growth and a prolonged survival time in patients with metastatic solid tumors, for whom no other conventional anticancer therapy is available.

Cancer-associated immunodeficiency is seriously worsened by surgical trauma. Short-term preoperative interleukin-2 (IL-2) immunotherapy abolishes postoperative immunodeficiency and can induce immunological control of the growth of minimal residual disease. Growth factors play an important role in oncological practice in treating neutropenia (G-CSF) or associated anaemia during chemotherapy (erythropoietin). Unfortunately, lymphocytopenia is not considered a biological marker with regard to survival. On the other hand, the role of the immune response to surgical trauma has been emphasised by many surgeons, and to counteract it immune nutrition (omega 3 fatty acid, mRNA, arginine) or thymic hormone have been tried. We believe that the obvious method of counteracting postoperative lymphocytopenia is the administration of the specific growth factor for T lymphocytes, i.e. IL-2. The aim of this study was to report on our experience with IL-2 preoperative immunoactivation in colorectal cancer and the long-term outcome of patients treated in comparison with a control group operated on without immunotherapy. In order to obtain activated lymphocytosis at the time of operation administration of IL-2 (6 million I.U. twice daily subcutaneously) for 3 preoperative days is sufficient, starting 4 days before surgery. The inclusion/exclusion criteria were histologically documented colorectal cancer, elective surgery, laparotomic surgery, no second tumour, age 20-80 years, no cardiovascular, hepatic or renal failure. From June 1992 to December 2005, 67 patients were treated (Dukes B/C: 46/21) with IL-2 immunotherapy. The clinical and biological results were compared with those of a control group of 173 patients (Dukes B/C 114/59) operated on in the same period and recruited with the same criteria. Dukes stage-C patients in both groups underwent adjuvant chemotherapy plus radiotherapy for rectal cancer. Data were statistically analysed using Fisher's exact test, Student's T-test and analysis of variance, as appropriate. The overall survival curves were plotted with the Kaplan-Mayer method. After a median follow-up of 69 months (range: 12-169) the progression rate was 15/67 (22%) vs 68/173 (39%) in controls (p = 0.02). Important results were obtained in Dukes-B patients: progression rate 7/46 (15%) vs 37/114 (32,4%) in controls (p = 0.03). We can conclude that immunotherapy is well tolerated. IL-2 is capable of counteracting surgery-induced immunodeficiency. The amplification of the immune response in the post-operative period is capable of controlling minimal residual disease after radical surgery, of reducing the progression rate, and of improving the prognosis and overall survival.