The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results.

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.

Relationship between psychoncology and psychoneuroendocrinoimmunology (PNEI): enhanced T-regulatory lymphocyte activity in cancer patients with self-punishement, evaluated by Rorschach test.

BACKGROUND: Psychological studies have documented the presence of a self-punishment profile in cancer patients. Recent immuno-oncological studies have shown that within the group of CD4(+) cells, which play a fundamental role in the generation of anticancer immunity, there is a subtype of cells that in contrast mediates the suppression of the anticancer immunity, the so-called T-regulatory cells (T-reg), which may be identified as CD4(+)CD25(+) cells. PATIENTS AND METHODS: On this basis, we performed a psychoncological study to evaluate CD4(+)CD25(+) cell numbers in relation to the response to Rorschach's test in a group of 30 cancer patients suffering from the most frequent tumor histotypes. RESULTS: Normal values obtained in our laboratory (95% confidence limits) of T-reg lymphocytes and CD4(+)/CD4(+)CD25(+) were <240/mm(3) and >4mm(3), respectively. The psychological profile of self-punishment was found in 18/30 patients (60%). The percentage of patients with abnormally high CD4(+)CD25(+) values observed in the group with self-punishment was significantly higher than that found in patients without self punishment (11/18 vs. 3/12 (25%), p<0.05). In the same way, the percentage of patients with abnormally low CD4(+)/CD4(+)CD25(+) ratios was significantly higher in the group with self-punishment (16/18 vs. 4/12, p<0.01). The mean numbers of T-reg lymphocytes observed in the group with self-punishment was significantly higher than that found in patients who had no self-punishment (314+/-39 vs. 173+/-27, p<0.05). In addition, the mean CD4(+)/ CD4(+)CD25(+) ratio was significantly lower in patients with self-punishment than in the other group (2.6+/-0.2 vs. 5.2+/-0.8, p<0.025). On the contrary, no significant difference was seen in the mean number of CD4(+) lymphocytes. CONCLUSION: The study suggests that self-punishment may inhibit the generation of an effective anticancer immune response by stimulating the activation and proliferation of T-reg lymphocytes, which in turn stimulate tumor dissemination by suppressing anticancer immunity. The abnormally high number of T-reg lymphocytes in patients with self-punishment would suggest a specific immune alteration, as suggested by the evidence of a normal profile for other immune parameters, such as total CD4(+) lymphocytes.

Oxytocin both increases proliferative response of peripheral blood lymphomonocytes to phytohemagglutinin and reverses immunosuppressive estrogen activity.

BACKGROUND: It has been shown that the neurohypophyseal peptide oxytocin is present in the human thymus and in vitro it can mimic interleukin (IL)-2 action in the induction of interferon-gamma production. In the present study, we tested the capacity of oxytocin to modulate the response of peripheral blood mononuclear cells (PBMCs) to phytohemagglutinin (PHA) and its ability to change the membrane expression of IL-2 receptor CD25 and the CD95 activation marker. Furthermore, whether oxytocin was able to reverse the inhibition of PBMC blastic response and CD25 expression induced by estradiol benzoate (E(2)B) was studied. PATIENTS AND METHODS: Fifteen healthy women were studied with a mean age of 33.8 years, no previous pregnancies, all in the early follicular phase of the cycle with normal values of circulating estrogens. RESULTS: The addition of oxytocin (1x10(-10) M, 1x10(-11) M, 1x10(-12) M) significantly increased the PBMC blastic response to PHA as well as the expression of both CD25 and CD95. These results were due to interaction of oxytocin with its specific receptor since the addition of an oxytocin antagonist completely reversed the oxytocin activity. In contrast, E(2)B induced a marked decrease of PHA-stimulated PBMC cell cycle progression and CD25 expression: the inhibitory effect of E(2)B was significantly counteracted by low concentrations of oxytocin. CONCLUSION: The present results support the hypothesis that neuropeptides may act as a link in the network between the immune and the neuroendocrine systems.

Synchronization of cortisol circadian rhythm by the pineal hormone melatonin in untreatable metastatic solid tumor patients and its possible prognostic significance on tumor progression.

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.

HER2 expression in breast cancer: correlation with endocrine function and psychological status in operable and metastatic breast cancer.

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.

A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus Aloe arborescens in patients with metastatic cancer.

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.

The endocannabinoid anandamide neither impairs in vitro T-cell function nor induces regulatory T-cell generation.

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.

Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors.

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.

How to Monitor the Neuroimmune Biological Response in Patients Affected by Immune Alteration-Related 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.

Therapy implications of the role of interleukin-2 in cancer.

INTRODUCTION: 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.

Pre-operative immunoprophylaxis with interleukin-2 may improve prognosis in radical surgery for colorectal cancer stage B-C.

Cancer-associated immunodeficiency is seriously worsened by surgical trauma. Short-term pre-operative interleukin-2 (IL-2) administration abolished post-operative immunodeficiency. The effects of a pre-operative IL-2 immunotherapy on the prognosis of colorectal cancer patients (Dukes' stages B and C), undergoing radical surgery, are reported. The study included, after post-operative stratification, 86 consecutive patients with colorectal cancer Dukes' stage B (57) and C (29), undergoing radical laparotomic surgery, randomised to be treated pre-operatively, with or without a short-term course of subcutaneous (s.c.) IL-2 immunotherapy. Human recombinant IL-2 was given s.c. at 6x10(6) I.U. twice daily pre-operatively for 3 consecutive days. Surgery was performed 36 hours after the last IL-2 injection. Dukes' C patients of both groups received standard adjuvant chemotherapy consisting of 5-FU plus folates and radiotherapy for rectal cancer patients. After a median follow-up of 54 months (range 18-86), the progression rate was significantly lower in patients pre-treated with IL-2 than in controls: 9/42 (21.4%) IL-2 group vs. 19/44 (43.1%) controls, (p <0.03). The positive effect of immunotherapy was detected both in the Dukes' B group, with 5/29 (17%) progression in the IL-2 group vs. 9/28 (32%) in controls, and Dukes' C patients with 4/13 (30%) vs. 10/16 (62%). This study shows that a 3-day pre-operative course of IL-2 immunotherapy may improve prognosis in patients with colorectal cancer at Dukes' stages B and C, as previously demonstrated in patients with more advanced disease. Therefore, the early activation of the antineoplastic immune system in the first post-operative days following a presurgical activation with IL-2 may counteract the growth of minimal residual disease and prevent late disease progression.

Effects of IL-2 preoperative immunotherapy on surgery-induced changes in angiogenic regulation and its prevention of VEGF increase and IL-12 decline.

BACKGROUND/AIMS: IL-2 preoperative immunotherapy has been proven to abrogate surgery-induced immunosuppression in cancer patients. In contrast, at present there are no data about the possible influence of IL-2 on angiogenesis-related molecular changes determined by the surgical operation. At present, it is known that VEGF (vascular endothelial growth factor) is the main endogenous angiogenic factor, whereas the antitumor cytokine IL-12 has appeared to play an anti-angiogenetic role. On this basis, a study was planned to evaluate the influence of IL-2 presurgical immunotherapy on the perioperative changes in VEGF and IL-12 secretions. METHODOLOGY: The study was performed on 30 colorectal cancer patients undergoing radical surgery, who were randomly chosen to be treated with or without preoperative immunotherapy of IL-2 (12 million IU/day subcutaneously for 3 consecutive days prior to surgery). Serum levels of VEGF and IL-12 were measured by ELISA for blood samples collected before surgery, and at days 3, 7 and 10 of the postoperative period. RESULTS: VEGF mean concentrations progressively and significantly increased during the postoperative period in patients treated with surgery alone. Mean values of VEGF were enhanced also in patients pretreated with IL-2, but VEGF increase observed in the IL-2 group was delayed, more transient and significantly lower with respect to that found in controls. IL-12 mean concentrations significantly decreased during the postoperative period only in the control patients, whereas in the IL-2-treated patients IL-12 postoperative mean values were not significantly lower than those found before surgery. CONCLUSIONS: This preliminary study would suggest that IL-2 preoperative immunotherapy may abrogate surgery decline in IL-12 levels and reduce, although not completely prevent, VEGF increase during the postoperative period in surgically treated cancer patients. These results would suggest that IL-2 presurgical immunotherapy may counteract surgery-induced stimulation of the angiogenesis, by either opposing the decline in blood levels of the anti-angiogenetic cytokine IL-12, or reducing the increase in those of the angiogenic factor VEGF.

The pineal gland as a central regulator of cytokine network.

Even though cytokines may fundamentally act as local factors, the recent advances in the knowledge of neuroimmunomodulation (NIM) would suggest the existence of a central regulation of their secretion and activity. Several neuroactive substances have appeared to influence cytokine secretion, and on the other hand cytokines may modulate the neuroendocrine functions. However, at present only for the pineal gland, whose fundamental NIM role is well known, it is possible to recognize reciprocal influences between cytokine action and pineal endocrine activity, suggesting the existence of feedback mechanisms responsible for a central regulation of cytokine network. Melatonin (MLT), which is the most investigated pineal immunomodulating hormone, may stimulate IL-2 release by T helper-1 (TH-1) lymphocytes and that of IL-12 by dendritic cells (DC), whereas both IL-2 and IL-12 would inhibit MLT release. The physiological significance of IL-2-IL-12-MLT interactions would be the maintenance of an effective TH-1-dependent cellular immunity, including the anticancer immune response. A third possible pineal-cytokine feedback mechanism involves tumor necrosis factor-alpha (TNF-alpha) secretion, with a stimulatory effect of TNF-alpha on MLT release and an inhibitory one of MLT on TNF-alpha production. This finding would explain the anti-cachectic property of MLT itself. A further knowledge of pineal-cytokine interactions, as well as of other endocrine-immune circuits, will allow a better definition of the physiopathology of human chronic immunoinflammatory diseases, whose clinical course has appeared to be influenced by psychoemotional factors.

Efficacy of bromocriptine in the treatment of metastatic breast cancer- and prostate cancer-related hyperprolactinemia.

OBJECTIVE: Hyperprolactinemia is a frequent evidence occurring in both metastatic breast cancer and prostate cancer, and it has been proven to be associated with poor prognosis and reduced efficacy of the anticancer therapies. Therefore, the pharmacological control of cancer-related hyperprolactinemia could improve the prognosis of advanced breast and prostate carcinomas. Unfortunately, at present it is still controversial which may be the treatment of cancer-related hyperprolactinemia, which could depend at least in part on a direct autocrine production by cancer cells themselves. The present study was performed to evaluate the acute effects of the long-acting dopaminergic agonist bromocriptine on cancer-related hyperprolactinemia. METHODS: The study included 10 women affected by metastatic breast cancer and 10 men with metastatic prostate cancer, showing persistent hyperprolactinemia. Venous blood samples were collected before bromocriptine, and 2, 4, 10 and 24 hours after bromocriptine administration (2.5 mg orally) serum levels of PRL were measured with the double antibody RIA method. RESULTS: Bromocriptine induced a normalization of PRL levels in both groups of patients with breast and prostate cancers. Moreover, mean levels of PRL persisted significantly lower than those found before therapy during the whole 24-hour circadian period. DISCUSSION: This preliminary study shows that low-dose bromocriptine is sufficient to acutely normalize PRL secretion in both metastatic breast cancer and prostate carcinoma patients, irrespectively of the mechanisms involved in inducing cancer-related hyperprolactinemia. Therefore, low-dose bromocriptine could be recommended in association with the classical antitumor therapies in the treatment of metastatic breast cancer and prostate carcinoma patients showing cancer-related hyperprolactinemia, in an attempt to improve the efficacy of anticancer therapies themselves.

Evidence of pineal endocrine hypofunction in autistic children.

OBJECTIVE: The pineal hormone melatonin (MLT) has been proven to play a fundamental physiological regulatory role on both biological and psychic functions and alterations of the light/dark circadian rhythm of MLT have been described in several chronic immunoinflammatory diseases and in psychic disorders. Aim of the present biological explanatory study was the evaluation of MLT circadian rhythm in autistic children, in order to preliminary assess the pineal endocrine function in the autistic syndrome. METHODS: The study included 14 children suffering from classical infantile autism, who were investigated for the whole 24-hour circadian rhythm by collecting venous blood samples at 4-hour intervals. Serum levels of MLT were measured by the RIA method. The control group consisted of 20 age-matched healthy children. RESULTS: No autistic patient showed a normal MLT circadian rhythm. Moreover, autistic children showed significantly lower mean concentrations of MLT, mainly during the dark phase of the day, with respect to the values observed in the controls. CONCLUSION: The results of this preliminary study suggest the existence of a pineal endocrine hypofunction in autistic children, whose pathophysiological significance needs to be thoroughly investigated in successive clinical studies.

Oncostatic activity of pineal neuroendocrine treatment with the pineal indoles melatonin and 5-methoxytryptamine in untreatable metastatic cancer patients progressing on melatonin alone.

OBJECTIVE: The recent advances in psycho-neuro-endocrino-immunology have demonstrated the existence of several endogenous neuroendocrine substances, capable of affecting both tumor growth and host anticancer immune defenses. The pineal gland would represent one of the most important organs releasing antiproliferative and immunostimulating substances, the most known of them is melatonin (MLT). However, MLT would not be the only pineal indole provided by antitumor activity. Other pineal indoles, namely 5-methoxytryptamine (5-MTT), would play antitumor effects, by either inhibiting cancer cell proliferation or stimulating the anticancer immunity. Preliminary data have shown that MLT may deserve antitumor activity in the treatment of human neoplasms, whereas at present there are no clear data about 5-MTT. In an attempt to obtain some preliminary data about the anticancer properties of 5-MTT in humans, we have evaluated the efficacy of MLT plus 5-MTT in untreatable advanced cancer patients progressing on MLT alone. METHODS: The study included 73 untreatable advanced solid tumor patients, who had progressed after two months of MLT therapy alone. According to tumor histotype, patients were randomized to receive MLT alone (20 mg/day orally in the evening) or MLT plus 5-MTT (1 mg at noon orally), every day for at least two months. The clinical response was evaluated according to WHO criteria. RESULTS: A partial response (PR) occurred in two patients treated with MLT + 5-MTT and in none of the patients receiving MLT alone. A stable disease (SD) was achieved in only 2/37 patients on MLT therapy alone, and in 8/36 patients receiving MLT plus 5-MTT. Therefore, the percent of non-progressing patients (SD + PR) obtained with MLT plus 5-MTT was significantly higher than that obtained with MLT alone. Moreover, the relief of asthenia and depressant symptoms was significantly higher in patients concomitantly treated with 5-MTT. DISCUSSION: This preliminary study would suggest that the concomitant administration of the less known pineal indole 5-MTT, also provided by antiproliferative and immunomodulating effects, may further amplify the oncostatic activity of the pineal hormone MLT in the palliative and curative therapy of advanced untreatable human solid neoplasms.

Neuroimmunotherapy of untreatable metastatic solid tumors with subcutaneous low-dose interleukin-2, melatonin and naltrexone: modulation of interleukin-2-induced antitumor immunity by blocking the opioid system.

OBJECTIVES: The preliminary applications of the psychoneuroimmunological knowledges to the treatment of human diseases have confirmed the possibility to amplify IL-2-dependent anticancer immunity by the pineal hormone melatonin (MLT) or by opioid antagonist, such as naltrexone (NTX), which act by activating TH1 lymphocytes or suppressing TH2 lymphocytes, respectively. At present, however, there are no data about the immunobiological effects of a concomitant administration of both MLT and NTX on IL-2-induced anticancer immunity. This preliminary study was carried out to evaluate whether the association of NTX may further enhance the lymphocytosis induced by the neuroimmunotherapy with IL-2 plus MLT. MATERIALS & METHODS: The study included 14 consecutive untreatable metastatic solid tumor patients. According to a cross-over randomized study, the patients were treated during two consecutive immunotherapeutic cycles at 21-day intervals with IL-2 plus MLT alone or with IL-2 plus MLT plus NTX. IL-2 was injected subcutaneously at 3 MIU/day for 6 days/week for 4 weeks, MLT was given orally at 20 mg /day in the evening every day, and NTX was given orally at 100 mg in the morning every next day. For the immune evaluation, venous blood samples were drawn before the onset of treatment and at weekly intervals. RESULTS: Lymphocyte mean number significantly increased after both IL-2 plus MLT and IL-2 plus MLT plus NTX. However, the concomitant administration of NTX induced a significantly higher increase in lymphocyte mean number with respect to that achieved with IL-2 plus MLT alone. In contrast, the increase in eosinophil mean number was significantly higher on IL-2 plus MLT alone. CONCLUSIONS: This preliminary study shows that the association of NTX further amplifies the lymphocytosis obtained by IL-2 plus MLT. Since the lymphocytosis represents the most important favourable prognostic variable predicting the anticancer efficacy of IL-2 immunotherapy, it is probable that a cancer neuroimmunotherapy with IL-2 plus both MLT and NTX to activate TH1 and suppress TH2 cells respectively, may deserve more promising results in the treatment of human neoplasms according to the psychoneuroimnunological knowledge.

A new neuroimmunotherapeutic strategy of subcutaneous low-dose interleukin-2 plus the long-acting opioid antagonist naltrexone in metastatic cancer patients progressing on interleukin-2 alone.

OBJECTIVES: Recent advances in knowledge of Psychoneuroimmunology have shown that several neuroactive substances, including neurohormones and neuropeptides, may exert immunomodulatory effects. However, despite the great variety of potential neuroimmune interactions, at present we may recognize two major neuroendocrine systems exerting a physiological neuroimmunomodulatory function, consisting of the pineal gland and the brain opioid system, provided by immunostimulatory and immunosuppressive effects, respectively. Recent in human studies have demonstrated the possibility to amplify the biological activity of IL-2, the major anticancer cytokine, by pineal indoles. MATERIALS & METHODS: The present study was carried out to draw some preliminary in human results on the possible immunomodulatory effects of the inhibition of the brain opioid activity by a long-acting opioid antagonist, naltrexone (NTX). The study was performed in 10 metastatic renal cell cancer patients, who had progressed on a previous immunotherapeutic cycle with IL-2 alone. Patients were treated with the same doses of IL-2 (6 million lU/day subcutaneously for 6 days/week for 4 weeks) plus an oral administration of NTX at a dose of 100 mg every 2 days. RESULTS: The clinical response consisted of a partial response in 1 and a stable disease in 5 patients, whereas the other 4 patients progressed. Therefore, the percent of non-progressive disease was 6/10 (60%). Moreover, mean lymphocyte increase achieved during IL-2 plus NTX was significantly higher (P<0.05) than that obtained during the previous treatment with IL-2 alone. CONCLUSIONS: This study shows that a blockade of the brain opioid system, which plays a physiological immunosuppressive role, may improve the anticancer effects of IL-2 in humans.

Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study.

OBJECTIVES: It is known since many years that the pineal gland plays an anticancer role, and melatonin (MLT), the most investigated pineal hormone, has been proven to exert antitumor activity. However, MLT would not be the only hormone responsible for the antitumor action of the pineal gland. In fact, recent advances in the pineal investigations have shown that pineal indoles other than MLT may also exert anticancer activity, namely the three main indoles, consisting of 5-methoxytriptamine (5-MTT), 5-methoxytryptophol (5-MTP) and 5-methoxy-indole acetic acid (5-MIA). Cancer progression has appeared to be associated with a concomitant decline in the pineal endocrine function. Therefore, the replacement of a complete pineal function in the advanced cancer patients would require the exogenous administration of the overall four pineal indoles. Several clinical studies have shown that MLT alone at pharmacological doses may induce a control of the neoplastic progression in about 30% of untreatable metastatic solid tumor patients. The present study was performed in an attempt to evaluate the therapeutic of a total pineal endocrine substitution therapy with its four indole hormones in cancer patients, for whom no other conventional therapy was available. METHODS: The study included 14 metastatic solid tumor patients, who had failed to respond to the conventional anticancer therapies. The pineal indoles were given orally according to a schedule elaborated in an attempt to reproduce their physiological circadian secretion during the daily photoperiod. MLT was given at 20 mg/day during the night, whereas the other indoles were given at 1 mg/day, by administering 5-MIA in the morning, 5-MTP at noon and 5-MTT in the afternoon. RESULTS: A disease-control was achieved in 9/14 (64%) patients, consisting of partial response (PR) in one patient and stable disease (SD) in the other 8 patients. The median time of disease-control (PR + SD) was 6 months (range: 4-10). CONCLUSIONS: This preliminary study shows that a total pineal endocrine replacement therapy by an exogenous administration of the overall four pineal indoles may induce a disease-control in about 60% of untreatable metastatic solid tumor patients. Then, these results would be clearly superior with respect to those described with MLT alone, by confirming in humans that MLT is not the only hormone responsible for the anticancer property of the pineal gland. Since Cartesius was the first author who suggested the fundamental role of the pineal in the connection between consciousness and biological life, this therapy could be defined as a Cartesian therapy.

Psychooncology and cancer progression-related alterations of pleasure-associated neurochemical system: Abnormal neuroendocrine response to apomorphine in advanced cancer patients.

OBJECTIVES: The clinical approach of the Psychooncology is generally limited to the investigation of the only psychological status of cancer patients, without taking into consideration the well demonstrated cancer progression-related psychoneuroendocrine alterations, namely consisting of a progressive decline in the pineal endocrine function and an anomalous activity of brain opioid system. The endocrine response to apomorphine, a dopaminergic agent, has been proven to reflect the dopaminergic sensitivity, which would be involved at least in part in pleasure-related neurochemical mechanisms. The present study was performed to analyze the endocrine response to apomorphine in metastatic cancer patients, as a preliminary approach to the investigation of pleasure-related neuroendocrine mechanisms in human neoplasms. MATERIALS & METHODS: The study included 10 metastatic cancer male patients and 6 male volunteers as a control group. Apomorphine was given orally at 0.01 mg/kg body weight in the morning, and venous blood samples were collected before, and at 20, 60 and 120 minutes after apomorphine administration. The endocrine analysis consisted of the measurement of serum levels of GH, PRL and cortisol. RESULTS: All cancer patients presented alterations involving one or more endocrine responses to apomorphine. GH and cortisol mean levels after apomorphine were significantly higher in controls than in cancer patients, whereas no substantial difference occurred in those of PRL. CONCLUSIONS: This preliminary study, by showing an altered endocrine response to apomorphine in metastatic cancer patients, would suggest that cancer progression may be associated with an altered dopaminergic sensitivity. Because of the involvement of the dopaminergic system in pleasure-related neurochemical mechanisms, this finding would demonstrated that the decline in the perception of pleasure with cancer progression may depend not only on psychological factors, but also, at least in part, on psychochemical alterations occurring during the clinical course of the neoplastic disease.