Search

Today, it is known that inflammation represents the common mechanism of human systemic diseases, including cancer and autoimmunity. Obviously, the endothelial system is involved in all inflammatory processes. Then, the control of the endothelial functions could constitute a new medical strategy to treat several pathological conditions, including ischemic and thrombotic events. Moreover, in addition to the action of angiogenic and anti-angiogenic factors, the endothelial system has been proven to be physiologically under a double control, represent by the cytokine network and the neuroendocrine system. Most cytokines have appeared to exert angiogenic and inflammatory effects, which are balanced by an anti-angiogenic and an anti-inflammatory action exerted by the pineal hormone melatonin (MLT), cannabinoid agents, and the product of ACE2, the angiotensin 1-7 (Ang 1-7). Then, a neuroendocrine approach with MLT, cannabinoids and Ang 1-7 could constitute a new way in the treatment of endothelial alterations and angiogenesis.

The recent proposal of cancer immunotherapy with anti-checkpoint inhibitor monoclonal antibodies, as well as the previous immunotherapy with IL-2, would require an interpretation of cancer chemotherapy not only in terms of therapeutic strategy carried out to destroy cancer cells, but also as an approach potentially able to influence and modulate the cytokine network in an attempt to correct cancer-related cytokine alterations responsible for tumor progression itself. This statement is justified by the fact that the efficacy of cancer immunotherapy is depending at least in part on the cytokine secretions of patients. Despite the great number of cancer-related cytokine alterations, the main alterations provided by a physiopathological and prognostic significance would consisting of low blood levels of IL-2 and IL-12 in association with abnormally high concentrations of IL-1, IL-6, TNF-alpha, IL-10 and TGF-beta. The effects of chemotherapy on cytokine secretions have appeared to depend on the type of agent, as well as on its dosage and schedule of administrarion. At present, the main effects of chemotherapy provided by a potential clinical application would be represented by the stimulatory action of adriamycin on IL-2 secretion, the inhibitory effect of cisplatin on IL-6 secretion, the stimulatory effect of gemcitabine on IL-12 production, and the inhibitory action of both cyclophosphamide and gemcitabine on regulatory T cell system. Then, the future chemo-immunotherapeuticregimenswouldhavenot to be elaborated not only on the bases of empiristic criteria and on the cytotoxic effects of che various chemotherapeutic agents, but also by taking into consideration their specific activity on the secretion of those cytokines, whose anomalous production has to be corrected and neutralized.

Today, it is known that the prognosis of human neoplasms depends not only on the genetic characteristics of tumor cells, but also on the immunobiological response of patients. Moreover, despite its complexity, at present it is known that the antitumor immunity is generally suppressed by the macrophage system, and stimulated by T lymphocytes, with the only exception of regulatory T cells, which in contrast inhibit the anticancer immunity through the release of immunosuppressive cytokines, the most important of them is TGF-beta. Finally, it is known that lymphocytopenia may predict a negative prognosis in the advanced neoplasms, and a more negative significance is played by the occurrence of abnormally low values of lymphocyte-to-monocyte ratio (LMR), whose decline could depend on both lymphocyte decrease and monocyte increase. At present, the only cytokine able to enhance lymphocyte count still remains IL-2. Therefore, because of the negative prognostic significance of cancer-related lymphocytopenia, the use of IL-2 to correct cancer-related lymphocytopenia could constitute a new strategy in the immunotherapy of cancer. On these bases, a study was planned to evaluate the effects of a neuro-immunotherapeutic combination with SC very-low dose IL-2 in association with the antitumor immunostimulating pineal hormone melatonin (MLT) on lymphocyte count, and their persistence on time in a group of untreatable lymphocytopenic advanced cancer patients. The study included 14 lymphocytopenic cancer patients, who were eligible for the only palliative therapy. IL-2 was SC injected at 1.8 MIU/day for 5 days/week for 2 consecutive weeks, in association with MLT at 100 mg/day orally during the dark period of the day. A normalization of lymphocyte count was achieved in 9/14 (64%) patients within the two weeks of therapy. Both lymphocyte and LMR mean values significantly increased on therapy with respect to the pre-treatment values. On the other hand, monocyte mean values diminished on therapy, without, however, significant differences. The median duration of lymphocyte count normalization was 160 days (range 39-240 days). These preliminary results would suggest a new possible clinical use of IL-2 immunotherapy to counteract advanced cancer-related lymphocytopenia, because of its well documented negative effects on the survival, in an attempt to control tumor growth by activating the natural antitumor immunobiological response, which is fundamentally an IL-2-dependent phenomenon, and which is altered in the advanced human neoplasms. Keywords: Cancer immunotherapy, Interleukin-2, Lymphocytopenia, Immunosuppression, Melatonin, Pineal gland

Despite the well-known importance of lymphocytes in tumor cell destruction and the evidence that lymphocytopenia is associated with a poor prognosis and lower survival in almost all tumor histotypes, lymphocyte count is not generally taken into consideration by the oncologists and no specific protocol has been proposed to treat cancer-related lymphocytopenia because of its negative impact on the clinical course of the neoplastic disease. Obviously, the most effective agents to stimulate the proliferation of lymphocytes would have to be their major growth factor, consisting of IL-2, whose in vivo biological activity may be further amplified by an association with some neuro-immunomodulating agents, such as the pineal hormone melatonin (MLT). This study was performed to evaluate the effects of subcutaneous (SC) low-dose IL-2 plus high-dose MLT in a group of metastatic cancer patients with persistent lymphocytopenia, who failed to respond to the standard anticancer therapies. The study included 14 patients who received MLT orally at 100 mg/day in the evening every day without interruption plus IL-2 SC at 1.8 MIU/day for five days a week for two consecutive weeks, corresponding to one complete cycle. A second cycle was repeated after a rest period of two weeks. A normalization of lymphocyte count was achieved in 9/14 (64%) patients, 4 of them (29%) just after the first week of therapy. Because of the association between cancer-related lymphocytopenia and lower survival and the fundament role of lymphocyte in mediating cancer cell destruction, the correction of advanced cancer-related lymphocytopenia by a short-term SC low-dose IL-2 therapy could improve the clinical course of cancer patients, including those suitable for the only palliative treatment.

The recent advances in the clinical application of the complementary medicine to cancer therapy have shown that some plants may potentially exert an antitumor activity due to the action of specific antitumor molecules, rather than a simple palliative effects. Then, the aim of the complementary medicine would have to be not only the improvement of the quality of life, but also the increase in the survival time. Alone and Myrrh represent some of the potential antitumor plants. On these bases, a randomized study was planned with Aloe arborescens solution alone or with Aloe arborescens plus Myrrh solution (60 to 40%) in patients with metastatic solid tumours, which did not respond to the conventional anticancer therapies. Both agents were orally given at 10 ml twice/day. The study included 60 consecutive patients suffering from different solid tumour histotypes. Both therapies induced a disease control (DC) and the percentage of DC obtained in patients concomitant treated with Aloe plus Myrrh was significantly higher than that achieved in patients treated with Aloe alone. These preliminary results justify further clinical studies with potential antitumor plants to achieve a control of the neoplastic growth rather than a simple improvement in the clinical status of patients.

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.

Fil: Lissoni, Paolo. Instituto de Medicina Biológica; Italia Fil: Brivio, Fernando. Instituto de Medicina Biológica; Italia Fil: Fumagalli, Luca. Surgical Division; Italia Fil: Rovelli, Franco. Instituto de Medicina Biológica; Italia Fil: Colciago, Massimo. Instituto Nacional de Descanso y Atención al Adulto Mayor; Italia Fil: Messina, Giusy. Instituto de Medicina Biológica; Italia Fil: Monzon, Alejandra. Instituto de Medicina Biológica; Italia Fil: Pelizzoni, Francesco. Instituto de Medicina Biológica; Italia Fil: Lissoni, Arianna. Instituto de Medicina Biológica; Italia Fil: Porro, Giorgio. Instituto de Medicina Biológica; Italia Fil: Di Fede, Giuseppe. Instituto de Medicina Biológica; Italia Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas; Argentina Abstract: Recent advances in the area of the psycho-neuroendocrine-immunology have demonstrated that the inflammatory and immune reactions depend not only on immune factors, but also, they are under an intricate neuroendocrine regulation. In turn, the activity of the nervous and endocrine systems is affected by immune-inflammatory signals. Although most hormones and neuromodulators can potentially influence the immune function, main immunomodulatory properties seem to be exerted by opioid and cannabinoid systems. Brain opioid and cannabinoid systems are endocrinologically connected to the adrenal, and to the pineal gland, respectively. In addition, the neurohypophysis is also important for the neuroimmunomodulation through the release of vasopressin and oxytocin. Experimental evidence supports the conclusion that two fundamental functional circuits occur, including a brain opioid system-vasopressin-adrenal axis, characterized by a prevalent immunosuppressive activity, and a brain cannabinoid-oxytocin-pineal axis, which exerts an immunostimulatory role. The latter is relevant mainly for anticancer immunity. The opioid-adrenal functional axis is active in stress and depressive conditions, while the cannabinoid-pineal axis has been proven to be involved in pleasure perception and spiritual expansion of mind. The findings could explain the predisposition to severe systemic diseases played by stress and depression, and on the other hand the protective action of pleasure and spirituality in the onset of important pathologies. The clinical and therapeutic applications of these concepts may constitute a landmark for future Medicine.

Metastatic cancer and autoimmune diseases are commonly considered to be the expression and the consequence of two opposite...

It is known that lung injury due to COVID-19 responsible for the respiratory distress would mainly depend on host inflammatory response, depending on the excessive production of inflammatory cytokines, such as IL-6, and TNF-alpha, rather than direct virus-induced tissue damage, as well as for other forms of respiratory distress. Moreover, it is known that the inflammatory cytokines may induce profound changes in the behavior of the hematic cells, namely neutrophils, monocytes, and lymphocytes, with a following enhanced tissue infiltration by their inflammatory cells. According to the data available up to now, IL-6 and TNF-alpha would be the main cytokines involved in determining COVID-19-induced lung injury, as well as in other coronavirus infections, and most in general in all conditions of respiratory distress. Since it is known that the functionlessness of the whole immune system is namely depending on the interactions between lymphocyte and macrophage system, a preliminary study was planned to analyze the lymphocyte-to-monocyte ratio (LMR) in COVID-19 infective disease. The study included 17 consecutive patients, who underwent ventilator therapy for COVID-19-induced respiratory distress, and 100 healthy subjects, as a control group. Lymphocytopenia and monocytosis occurred in 14/17 (82%) and in 8/17(47%), respectively. Then, abnormally low values of LMR was found in 12/17 (71%) patients, and LMR men values observed in patients were significantly lower than in control (P

Several clinical studies have shown that blood pressure (BP) declines during the night in the healthy subjects, and that BP circadian rhythm tends to disappear with age. The mechanisms responsible for BP circadian rhythm and its aging-dependent loss need to be further understood. At present, it is already known that the two main hormones provided by hypotensive activity, consisting of the cardiac hormone atrial natriuretic peptide (ANP) and the pineal indole hormone melatonin (MLT), are mainly produced during the night, whereas hypertensive hormones, such as cortisol, are mainly produced during the early period of light phase. Then, the circadian variations of BP would be the consequence of changes in the neuroendocrine system. On this basis, a preliminary study was performed to establish which relation may exist among BP, ANP and MLT rhythms in the healthy subjects. The study included 20 65-year younger, and 20 65-year older healthy subjects. In 65-year younger subjects, both systolic and diastolic BP mean values significantly decreased during the night, whereas no significant difference occurred in the 65-older ones, because of BP values decreased in the night only in 13/20 (65) subjects. In addition, within the 65-year older group, both ANP and MLT night mean values were significantly higher in subjects with BP rhythm than in those, who had no BP daily variations. These preliminary results would suggest that age-dependent loss in the circadian rhythm of BP may be caused by the concomitant loss in the circadian secretion of at least two major hypotensive hormones, such as ANP and MLT.

Despite its apparent failure in cancer therapy, IL-2 still remains fundamental in the activation of antitumor immunity. Areas covered: The aim of this review is the reinterpretation of the role of IL-2 in anticancer immunity, according to knowledge gained of the cytokine network, by highlighting its importance in inducing T helper-1 (TH1) cell proliferation, natural killer (NK) actHivation and IL-12 secretion. However, its main negative effect is the stimulation of regulatory T cells (Tregs), which in contrast suppresses anticancer immunity. Expert commentary: Cardiovascular toxicity, which was the main clinical problem at the beginning of IL-2 therapy at high intravenous doses, has almost been completely solved by subcutaneous low-dose IL-2 injection. In order to enhance the anticancer efficacy of IL-2, several strategies have been explored, including chemotherapy and interferon, but up until now no regimen has appeared to be clearly better than IL-2 alone. However, considering the role of immune checkpoints (PD-1 and CTLA-4) in Tregs stimulation, the most effective immunotherapy in the future could be concomitant IL-2 administration, to enhance lymphocyte count, and checkpoint inhibitors, such as anti-PD1 or anti-CTLA-4 monoclonal antibodies, or IL-12, which is also able to counteract IL-2-induced Treg cell generation. Therefore, the time for IL-2 immunotherapy in cancer treatment has finally arrived.

BACKGROUND In cancer patients, the accumulation of Tregs is associated with tumor progression and the suppression of anti-tumor immune response. Metronomic cyclophosphamide (mCTX) induces a profound and selective reduction of circulating Tregs, whereas no data are available regarding a possible effect on immune system. In the present analysis, we report preliminary data of Treg frequencies and function during a period of treatment of 2 months and correlations with anti-tumour T-cell response, in a group of HR+/HER2ve ABC pts. PATIENTS AND METHODS Following approval by the Ethical Committee, a sample of 3 ml of peripheral blood was drawn from 12 ABC pts for which mVRL 40- 50 mg thrice a week (N=10), ± mCAPE 1500 mg/day (N=2), was indicated. Median age was 66,5 years (45-86); 2/ 12 received the mCHT as 1st-line therapy, 10/12 as 2nd-line or further. Blood samples were collected at baseline (T0) and after 14 (T1), 28 (T2), 42 (T3) and 56 days (T4) of treatment. Total lymphocytes (TL) and lymphocyte subgroups were determined according to NaacK et Al guide lines. The Treg subpopulations have been identified by monoclonal antibodies CD45 V500, CD3 V450, CD4 PerCP-Cy5.5, CD25 PE, CCR4 PE-Cy7, CD 27 Alexa 647, CD45RO APC-H7, CD28 FITC, (BD Biosciences, San Jose, CA) and analyzed with BD FACS CantoTM II (Becton Dickinson, San Jose, CA), technic Lyse/Wash and software FACSDivaTM. RESULTS Data for the purpose of this analysis are available for 10 out of 12 enrolled pts. mVRL ± mCAPE induced a significant reduction of circulating Treg in 6/10 pts (60%) – Group A - at day 14. Median percentages of Treg among CD4+ cells were 9.4% ±1.5% SE at baseline vs 6.8% ± 4.5% SE and 7.6% ± 1.2% SE after 14 and 28 days of treatment in Group A. In patients without Treg depletion – Group B – median percentages of Treg were 8.4% ± 0.9% SE, 9.6% ± 1.3%SE and 8.2% ± 1.5%SE as measured at the same time points. The depletion of Treg is associated with a slight expansion of CD8+ cells in Group A at all times of evaluation. No increase in CD8+ population has been observed in Group B. Median percentages of Treg and CD8+ cells in the two Groups are reported in Tables 1 & 2. Frequency of CD4+CD25+ (Treg) among total CD4+ T cells in Group A (pts with Treg depletion) and Group B (pts w/o Treg depletion)Time of evaluationMean Treg % +/- SE% - Group AMean Treg % +/- SE% - Group BT0 (baseline)9.4% +/- 1.5%8.4% +/- 0.9%T1 (+14 days)6.8% +/- 4.5%9.6% +/- 1.3%T2 (+28 days)7.6% +/- 1.2%8.2% +/- 1.5% Frequency of CD8+ cells among total lymphocites in Group A (pts with Treg depletion) and Group B (pts w/o Treg depletion) Mean CD8+ (%) +/- SE% - Group AMean CD8+ +/- SE% - Group BT0 (baseline)20.6% +/- 1.9%30.6% +/- 3.8%T1 (+14 days)21.6% +/- 1.9%30.6% +/- 4.3%T2 (+28 days)225.5 +/- 1.9%30.8% +/- 4.7% CONCLUSION Our results suggest that mVRL induces different immunomodulation effects in an unselected population of ABC pts. Treg depletion seems to increase the adaptive immune response. Data obtained from a longer follow up will be presented. These findings are hypothesis-generating for future evaluation of mVRL as a priming agent to increase response to anti PDL-1 agents. Citation Format: Cazzaniga ME, Baroni S, Riva F, Vigorè L, Malandrin S, Cicchiello F, Pelizzoni D, Lissoni P, Manfrida I, Brando B, Bidoli P. Immunomodulation effects of metronomic oral Vinorelbine (mVRL), with or without capecitabine (CAPE), on Treg levels in advanced breast cancer (ABC) patients (pts). Preliminary results of the VICTOR-5 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-05.

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 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.

Until few years ago, the in vivo immune responses were considered to be identical to the reactions occurring in vivo, but the recent discoveries in the Psychoneuroendocrinoimmunology (PNEI) area have demonstrated that the immune system is under a psychoneuroendocrine regulation, which represents the biochemical mediation of the influence of emotions and consciousness states on the immune system, by allowing the possibility to modulate the immune functions by acting on their neuroendocrine control rather than directly on the immune cells. The immune responses are inhibited by the opioid system, mainly by acting on mu-opioid receptors, whereas they are stimulated by the pineal-cannabinergic system functional axis. The metastatic cancer is characterized by low blood concentrations of IL-2 and IL-12, in association with abnormally high levels of TGF-beta, IL-10 and IL-6, with a following decline in TH-1 lymphocytes and an increase in T regulatory (T reg) cell count. The autoimmune diseases are characterized also by enhanced levels of proinflammatory cytokines, namely IL-17, in association with low values of TGF-beta and IL-10 as the consequence of a decline in T reg cell count. Cancer progression is associated with a progressive decline in the endocrine function of the pineal gland, which may release at least three molecules provided by antitumor activity: melatonin, 5-methoxytryptamine and pinealine. The inhibitory effects of opioids on the anticancer immunity may be abrogated by the administration of the long-acting mu-opioid antagonist naltrexone. The deficiency of pineal indole hormones, which play a fundamental anticancer activity, as well that of the main antitumor cytokines, including IL-2 and IL-12, may be simply corrected by their exogenous administration. Finally, IL-17-induced immunoinflammatory response occurring in the autoimmune diseases may be counteracted by cannabinoid agonists, which may inhibit IL-17 secretion. The pineal hormones also may contribute to inhibit the chronic inflammatory response.

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.

Aging and advanced cancer are characterized by similar neuroendocrine and immune deficiencies; the most important of them consist of diminished nocturnal production of the pineal hormone melatonin (MLT) and decreased production of IL-2. At present, however, it is known that the pineal gland may produce indole hormones other than MLT. The most investigated of them is represented by 5-methoxy-tryptamine (5-MTT), which may exert antitumor, anticachectic, and immunomodulating effects under experimental conditions, in addition to those effects produced by MLT itself. In an attempt to obtain some preliminary data in human subjects about the potential therapeutic properties of 5-MTT, three different studies of 5-MTT have been carried out in advanced solid tumor patients. The first study of MLT plus 5-MTT included 14 thrombocytopenic cancer patients who did not respond to MLT alone. In the second study we have compared the clinical efficacy of MLT plus 5-MTT in a group of 25 untreatable metastatic cancer patients to the results obtained in a control group of 25 cancer patients receiving MLT alone. Finally, the third study of MLT plus 5-MTT included 14 untreatable metastatic cancer patients who did not respond to MLT alone. In all of these studies, MLT and 5-MTT were given orally at the level of 20 mg/day in the evening and at 5 mg/day during the period of maximum light. A normalization of platelet number was achieved by MLT plus 5-MTT in 5 of 14 (36%) thrombocytopenic cancer patients who did not respond to MLT alone. The percentage of disease control obtained by MLT plus 5-MTT in untreatable metastatic cancer patients was significantly higher than that achieved by MLT alone (15/25 [60%] vs. 8/25 [32%], P < 0.05). Finally, the association of 5-MTT with MLT induced disease stabilization in 4 of 14 (29%) untreatable metastatic cancer patients who did not respond to MLT alone.

Thanks to the discoveries of psychoneuroendocrinoimmunology, we now know that every psychological state is mediated by a specific neurochemical condition and every neurochemical change in turn influences psychological status. We can now identify three different levels of neurochemical mediation of the psychological states: neurotransmission, neuromodulation, and the psychoneuromodulation. Neurotransmission is composed of five main neural pathways, noradrenaline, acetylcholine, dopamine, serotonin, and histamine; neuromodulation; and the psychoneuromodulation. We have performed several clinical studies in an attempt to correlate the psychological status of cancer patients with the immune alterations characteristic of the clinical history of neoplastic disease. We have studied the immunologic status by evaluating cytokine blood levels and the lymphocyte subpopulation; the psychological status was assessed by the Rorschach's test; and spiritual status was evaluated by a previously published test to explore spiritual faith. These preliminary psychological studies seem to suggest that a pre-treatment analysis of psychological and spiritual status may predict the efficacy of both chemotherapy and immunotherapy in advanced cancer patients.

Recent advances in the knowledge of the mechanisms responsible for antitumor immunity have stimulated the elaboration of new cancer immunotherapeutic strategies. Moreover, more recent discoveries have demonstrated that immune responses are under a physiological modulatory control played by several neuroendocrine pathways, which explain the differences between the in vivo and in vitro immune responses. While until a few years ago the evaluation of the immune status of cancer patients was substantially established on the basis of clinical empirical criteria, recent discoveries of the antitumor cytokine network have allowed the biochemical bases of anticancer immunity to be defined, leading to new anticancer immunotherapeutic strategies, on the basis of patient neuroendocrine and neuroimmune status, in an attempt to correct the great number of cancer-related alterations on the basis of knowledge of the physiopathology of anticancer immunity. The rationale for cancer neuroimmunotherapy consists of the possibility to enhance the efficacy of the various immunotherapeutic strategies by a concomitant administration of antitumor cytokines (namely IL-2), in addition to neuroendocrine endogenous molecules (namely the pineal indole hormones), able to stimulate the anticancer immunoresponse by amplifying the anticancer reaction and/or by counteracting the generation of immunosuppressive events.

Riassunto Introduzione Neuroanatomia, neurochimica e neurofisiologia dell’orientamento sessuale restano a oggi ancora un enigma. Il problema attuale e quello di dedurre dai numerosi e a volte contraddittori dati sperimentali una teoria sistemica dello stato psicosessuale della persona. Discussione Una delle aree encefaliche maggiormente coinvolte nella regolazione dell’orientamento sessuale sarebbe rappresentata dal nucleo interstiziale ipotalamico-anteriore, mentre dal punto di vista neurochimico l’orientamento sessuale sarebbe dovuto principalmente al rapporto fra attivita enzimatica aromatasica (responsabile della trasformazione del testosterone in estradiolo) e 5-alfa-reduttasica (responsabile dell’attivazione del testosterone in diidrotestosterone). La differenziazione psicocerebrale in senso maschile sarebbe indotta dall’ormone femminile estradiolo, mentre quella in senso femminile dall’ormone maschile attivato. Nell’omosessualita si avrebbe una situazione opposta, vale a dire nel maschio una maggiore concentrazione ipotalamica di 5-alfa-reduttasi rispetto a quella dell’aromatasi e nella femmina una maggiore concentrazione di aromatasi rispetto a quella di 5-alfa-reduttasi. L’orientamento sessuale dell’omosessuale maschio potrebbe pertanto essere riorientato in senso eterosessuale dagli inibitori della 5-alfa-reduttasi (quali la finasteride), mentre quello dell’omosessuale femmina dagli inibitori dell’aromatasi (quali l’anastrozolo).

Lymphocyte number still remains one of the most important immune parameters predicting the prognosis of advanced cancer patients. IL-2 and IL-12 are the main antitumor cytokines in humans, and their effect is modulated by the neuroendocrine system, mainly by the pineal gland through the circadian release of melatonin (MLT) and perhaps that of other indole hormones, such as 5-methoxytryptamine (5-MTT), and 5-methoxytryptophol (5-MTP). MLT has been proven to exert important antitumor immunomodulating effects, whereas the possible immunomodulatory properties of the other pineal indoles are still controversial. In an attempt to better define the pineal neuroendocrine regulation of the anticancer cytokine network, we have evaluated in metastatic solid-tumor patients the effects on lymphocyte number induced by different neuroimmune regimens, consisting of MLT alone (20 mg/day orally in the evening), subcutaneous (s.c.) low-dose IL-2 alone (3 MIU/day in the evening for 6 days/week), s.c. low-dose IL-12 alone (0.5 mcg/kg once/week in the morning), IL-12 plus MLT, IL-2 plus MLT, and IL-2 plus MLT plus 5-MTT (10 mg/day orally in the afternoon) plus 5-MTP (5 mg/day orally at noon). The results showed the following evidence: (1) MLT alone is unable to induce lymphocytosis; (2) MLT significantly enhances IL-2-induced lymphocytosis; (3) IL-12 alone determines lymphocytopenia, which can be reversed by MLT; (4) IL-2 plus IL-12 induces a very pronounced lymphocytosis, which can be further amplified by MLT; (5) a total pineal endocrine replacement therapy with MLT, 5-MTT, and 5-MTP further increases IL-2-induced lymphocytosis with respect to MLT plus IL-2 alone. Therefore, this study confirms that IL-2- and IL-12-dependent anticancer immunity is under a pineal modulation.

Numerous experimental data have documented the oncostatic properties of melatonin. In addition to its potential direct antitumor activity, melatonin has proved to modulate the effects of cancer chemotherapy, by enhancing its therapeutic efficacy and reducing its toxicity. The increase in chemotherapeutic efficacy by melatonin may depend on two main mechanisms, namely prevention of chemotherapy-induced lymphocyte damage and its antioxidant effect, which has been proved to amplify cytotoxic actions of the chemotherapeutic agents against cancer cells. However, the clinical results available at present with melatonin and chemotherapy in the treatment of human neoplasms are generally limited to the evaluation of 1-year survival in patients with very advanced disease. Thus, the present study was performed to assess the 5-year survival results in metastatic non-small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin (20 mg/day orally in the evening). The study included 100 consecutive patients who were randomized to receive chemotherapy alone or chemotherapy and melatonin. Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin. This suggests a new biochemotherapeutic strategy in the treatment of human neoplasms.

Abnormally high blood levels of vascular endothelial growth factor (VEGF) appear to be associated with a poor prognosis in advanced cancer, probably as a consequence of its angiogenic and immunosuppressive effects. The prognostic significance of changes in VEGF secretion during cancer chemotherapy is still unknown. This study aimed to investigate the relation between VEGF variations and therapeutic results during chemotherapy in advanced malignancies. The study included 90 metastatic cancer patients, 59 with non-small cell lung cancer and 31 with colorectal carcinoma. Chemotherapy consisted of cisplatin plus etoposide for NSCLC and camptothecin for colorectal cancer. Abnormally high (>2 SD with respect to values in healthy controls) pretreatment VEGF levels were found in 38/90 (42%) patients. The percentage of non-progressive disease in response to chemotherapy was significantly higher in patients with normal levels of VEGF prior to therapy than in those with elevated pretreatment values of VEGF (10/32 vs 4/27; p