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Patients with advanced cancer are known to have dysfunctions of the immune system. Dendritic cells (DCs) are potent antigen-presenting cells that play a crucial role in antitumor immune response. At least two peripheral blood DC subsets have been described: myeloid-derived CD11c+CD123- DCs (DC1) and lymphoid-derived CD11c-CD123+ DCs (DC2). Upon interaction with T cells, DC2 seemed to support the generation of a Th2 response, while DC1 predominantly prime a Th1 response. Our study was aimed at investigating the number of circulating DCs, and their subsets and functions in 32 patients with advanced breast cancer that achieved an objective response after a standard-dose sequential chemotherapy (CT), compared to 40 healthy controls. Circulating DC subsets and intracellular cytokine production in CD4+ and CD8+ subsets were analyzed using a tri-color flow cytometry assay. DC subsets were identified in peripheral blood, calculating their percentage gated as lin- HLA-DR+ and using BDCA-1, BDCA-2 and BDCA-3 specific markers, as DC1 and DC2 according to expression of CD11c and CD123, respectively. Intracellular cytokines were evaluated in CD4+(Th1 and Th2) and CD8+ (Tc1 and Tc2) T lymphocytes. The mean percentage of BDCA-1+BDCA-2+BDCA-3 was similar to that of DC1+DC2 (p=ns). The mean percentage of DCs and DC1/DC2 ratio were slightly decreased before CT in cancer patients compared with healthy controls (p=ns). After CT, the percent-age of DC1 further decreased (p=0.02). The production of IFN-gamma (Th1 and Tc1) significantly decreased (p<0.03) while that of IL-4 (Th2 and Tc2) increased (p=0.04), thus confirming a shift toward a Th2 CD4 and Tc2 CD8 phenotype and the predominance of type 2 DCs. Our results could help clarify the mechanisms of the immune response or immune status of patients with advanced breast cancer that undergo cytotoxic CT and contribute to improve the selection of potential candidates for active immunotherapy trials.

The evaluation of the biological status of cancer patients should not be limited only to investigation of immune reactivity, but should also include analysis of the endocrine condition, namely concerning those hormones which have appeared to be tumor growth factors, such as prolactin (PRL) for breast and prostate carcinomas. This statement is justified by the fact that the evidence of abnormally high serum concentrations of PRL has been proven to be associated with poor prognosis in breast and prostate cancer patients. Moreover, since hyperprolactinemia negatively influences the efficacy of anticancer therapies in breast cancer, it could be fundamental to achieve a normalization of PRL levels by long-acting dopaminergic agents, such as cabergoline. On this basis, a study was planned to evaluate the effect of cabergoline on PRL levels in hyperprolactinemic metastatic breast cancer subjects. The study included 20 hyperprolactinemic metastatic breast cancer subjects, who were randomized to receive no therapy or cabergoline at 0.5 mg/week orally for 4 consecutive weeks. Cabergoline therapy induced a normalization in all patients, whereas no spontaneous normalization of PRL levels occured in the control group. These results show that a weekly oral administration of the long-acting dopaminergic agent cabergoline is a well tolerated and effective treatment of metastatic breast cancer-related hyperprolactinemia. The possible prognostic impact of PRL normalization needs to be established by successive studies.

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.

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 < 0.05). Moreover, the percentage of VEGF level normalization during chemotherapy was significantly higher in patients with objective tumor response or stable disease than in progressing patients (10/18 vs 0/20; p < 0.001). Finally, among patients with tumor response or disease stabilization, the one-year survival rate was significantly higher in patients with chemotherapy-induced normalization of VEGF than in those with persistently high VEGF blood levels (9/10 vs 3/8; p < 0.05). These results suggest that changes in VEGF levels during chemotherapy may represent a useful biomarker to predict the effect of chemotherapy in terms of tumor response and survival in patients with metastatic solid neoplasms.

Objective: It has been demonstrated that the hematopoiesis is under a neuroendocrine control, namely mediated by the pineal gland. The pineal indole melatonin (MLT) has appeared to exert thrombopoietic and lymphopoietic activity, whereas it has no relevant effect on red cell differentiation. The present study was performed to evaluate the influence of another pineal indole, the 5-methoxytryptamine (5-MTT) on red cell line and hemoglobin production., Materials & Methods: The study was carried out in metastatic lung cancer patients who underwent a chemotherapeutic combination containing cisplatin, which is known to induce anemia. The study included 20 patients treated with cisplatin plus etoposide, who were randomized to receive chemotherapy alone or chemotherapy plus 5-MTT (1 mg/day orally at noon every day)., Results: Hemoglobin mean blood concentrations significantly decreased in both groups of patients. However, the decrease in hemoglobin levels observed in patients treated with chemotherapy alone was significantly higher with respect to that observed in patients concomitantly treated with 5-MTT. Moreover, the percent of patients who had no progressive disease on treatment was significantly higher in the group treated with chemotherapy plus 5-MTT., Conclusions: Even though the low number of patients does not allow us to draw define conclusions, these preliminary results would show that the concomitant administration of 5-MTT may reduce cisplatin-induced anemia in cancer patients, by suggesting a hematopoietic activity of 5-MTT on red cell line differentiation and hemoglobin production. Moreover, the study would suggest that 5-MTT, as well as previously demonstrated for MLT, may also enhance the cytotoxic activity of cancer chemotherapy.

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.

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.

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.

Immunochemotherapeutic combinations containing IL-2 theoretically represent the most effective therapies for metastatic melanoma, particularly in association with cisplatin (CDDP); however, both IL-2 and CDDP have been generally utilized at high doses, with the consequence of considerable toxicity. According to psychoneuroimmunological knowledge, the antitumor activity of IL-2 has been proven to be enhanced by the immunomodulating pineal neurohormone melatonin (MLT), which has also been shown to increase the cytotoxicity of cancer chemotherapy and reduce its toxicity. On this basis, a study was planned with low-dose IL-2 and CDDP in association with MLT as a second-line therapy for metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. The study included 13 evaluable patients. CDDP was injected i.v. at 30 mg/m2/day for 3 days every 21 days. IL-2 was administered s.c. at 3 million IU/day from days 4 to 9 and from days 11 to 16 of the cycle. Finally, MLT was given orally at 20 mg/day in the evening, every day without interruption. One patient obtained a complete response (CR), while partial response (PR) was achieved in 3 other patients. Therefore, the objective tumor response-rate (CR + PR) was 4 out of 13 (31%). A stable disease occurred in 5 patients, whereas the remaining 4 patients had a progressive disease. The treatment was extremely well-tolerated in all patients and, in particular, no CDDP-related neurotoxicity was observed. The results of this preliminary study would suggest that low-dose CDDP and IL-2 in association with the pineal hormone MLT (P.I.M. schedule), given as a second line therapy, is an effective and well-tolerated treatment for metastatic melanoma, with a clinical efficacy at least comparable to that obtained with a first-line therapy of dacarbazine plus interferon-alpha.

Prolactin (PRL) constitutes a growth factor for breast cancer cell proliferation and abnormally elevated blood concentrations of PRL are associated with poor prognosis and reduced efficacy of antitumor therapies in metastatic breast carcinoma. It has already been demonstrated that low-dose bromocriptine, an antiprolactinemic long-acting dopaminergic drug, normalizes PRL blood concentrations in metastatic breast cancer patients with abnormally elevated PRL levels. In addition, previous clinical studies have already demonstrated a lower efficacy of chemotherapy with taxotere in metastatic breast cancer, with persistent hyperprolactinemia. We planned a controlled clinical study to evaluate the influence of a concomitant administration of the antiprolactinemic drug bromocriptine on the efficacy of chemotherapy with taxotere, in metastatic breast cancer patients progressing after chemotherapeutic combinations containing anthracyclines. The study included 30 randomized consecutive patients treated with taxotere alone or taxotere plus bromocriptine. Taxotere was given I.V. at 100 mg/m2 every 21 days for 3 cycles. Bromocriptine was given orally at 2.5 mg/day every day until the end of the chemotherapeutic treatment. Bromocriptine therapy induced a significant decline in PRL mean blood concentrations compared to patients treated by chemotherapy alone. No complete response was obtained. A partial response (PR) occurred in 5 out of 14 (36%) patients treated with taxotere plus bromocriptine and in only 2 out of 16 (13%) patients treated with taxotere alone. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with taxotere alone and in 7 out of 14 patients concomitantly treated with bromocriptine. Therefore, the percent of non-progressive disease (PR + SD) achieved in patients treated with taxotere plus bromocriptine was significantly higher with respect to that found in patients treated with taxotere alone (12 out of 14 vs 7 out of 16, p < 0.025). This preliminary clinical study would suggest that the inhibition of PRL secretion by antiprolactinemic drugs such as bromocriptine may enhance the efficacy of chemotherapy for metastatic breast cancer.

After more than ten years of clinical investigations, IL-2 immunotherapy appears to constitute the most effective treatment metastatic renal cell carcinoma (RCC),at least in terms of survival time. Moreover, it has been shown that comparable results may be achieved with different schedules of treatment, including intravenous high-dose or subcutaneous (SC) low-dose IL-2. Finally, it has been demonstrated that the association with interferon-alpha does not increase the efficacy of IL-2. Therefore, SC low-dose IL-2 alone may be considered as an adequate therapy for metastatic RCC. In fact, our previous studies with SC low-dose IL-2 alone have shown a 5-year survival time similar to that described with higher and more toxic doses of IL-2. This study was performed to analyze the 10-year survival results with SC low-dose IL-2 in metastatic RCC The study included 44 consecutive metastatic RCC patients, with a minimum follow-up of 120 months. One comlete immunotherapeutic cycle consisted of IL-2 at 3 million IU twice/day SC, 5 days/week for 6 consecutive weeks. In non-progressing patients, a second cycle was planned after a 21-day rest period. Complete response (CR) was achieved in only 2 out of 44 (4%) patients, while partial response (PR) was obtained in 8 out of /44 (18%) patients. Therefore, the response rate (CR + PR) was 10 out of 44 (22%), with a median response duration of 12 months. Stable disease (SD) occurred in 21 out of 44 (48%) patients,whereas the remaining 13 out of 44 (30%) patients had a progressive disease (PD). A 10-year survival was achieved in 2 out of 44 (5%) and the percent of survival at 10 years was significantly higher in patients with response or SD than in those with PD. This study confirms at 10 years the results previously referred to by other authors and by ourselves, in showing that the efficacy of IL-2 immunotherapy in terms of control of cancer growth is associated with a clear prolongation of the overall survival time in metastatic RCC.

Objectives: The secretion of prolactin (PRL), which is a growth factor for prostate cancer cell proliferation, has been proven to present profound alterations in advanced prostate cancer patients, consisting of abnormally elevated baseline levels and paradoxical response to L-dopa. Moreover, the efficacy of standard therapies for prostate cancer may be mediated at least in part by changes in PRL secretion. The present study was carried out to analyze the effects of the new antiandrogen agent bicalutamide on basal levels of PRL and on its response to L-dopa in metastatic prostate cancer patients., Material & Methods: The study included 10 metastatic prostate cancer patients. They were treated with bicalutamide at a dose of 50 mg/day orally. They were investigated with L-dopa test before therapy and after one month of treatment. L-dopa was given orally at 500 mg, by collecting blood samples before and at 60, 120 and 180 minutes after L-dopa administration. Serum levels of PRL were measured by the RIA method., Results: Abnormally basal levels of PRL were seen in 4/10 (40%) patients. Mean PRL basal levels decreased after bicalutamide therapy, without, however, significant differences. Before therapy, a paradoxical increase in PRL levels after L-dopa occurred in 4 patients, 3 of them showed basal concentrations of PRL within the normal range. Moreover, bicalutamide therapy significantly reduced PRL increase in response to L-dopa., Conclusions: This study would suggest that the measurement of the only basal levels is not sufficient to define as normal the secretion of PRL in advanced prostate cancer, because of the possible existence of altered response to the dynamic tests for PRL secretion. Moreover, the study shows that the antitumor therapy with the new anti-androgen bicalutamide may reduce PRL secretion and improve its paradoxical secretion in response to L.-Dopa. Further studies will be required to better define the possible prognostic impact of changes in PRL secretion on the efficacy of treatments for metastatic prostate cancer.

With the advances in the knowledge of neuroimmunomodulation, a new era of investigations about the chemical basis of the state of mind has been initiated. Both emotions and states of spiritual consciousness may influence immune functions and cancer growth. Stress, anxiety and depressive states are associated with immunosuppression and enhanced frequency of tumors. On the other hand, the states of sexual pleasure and spiritual joy enhance the immune efficacy, by counteracting tumor onset and dissemination. The biochemistry of pleasure and immunostimulation is mainly mediated by pineal indoles and cannabinergic substances, whereas that of stress, anxiety and depression is associated with enhanced production of adrenal steroids, opioids and catecholamines. The sexual repression would allow a progressive immunosuppression through a profound damage in the biochemistry of pleasure. Therefore, a better definition of psychospiritual status-associated neuroimmunochemistry could allow us to improve the immune dysfunction by acting on the same neuroendocrine secretions which are involved in mediating the psychic influence on the immunity, including that against cancer.

Elevated VEGF blood concentrations have been proven to be associated with poor prognosis in human neoplasms. This finding is generally explained as a consequence of the potential angiogenic properties of VEGF itself. However, preliminary experimental studies suggest that VEGF, in addition to its angiogenic activity, may also play an immunosuppressant role by inhibiting dendritic cell (DC) maturation. The present study was performed to analyze blood levels of VEGF in cancer patients in relation to those of another potentially angiogenic tumor growth factor, endothelin-1 (ET-1), and to the absolute number of circulating immature and mature DC, and serum levels of the best known antitumor cytokine, IL-12. The study was performed in 100 healthy controls and in 80 solid tumor patients (colorectal cancer: 24; gastric cancer: 17; cancer of pancreas: 4; lung cancer: 13; breast cancer: 11; renal cell cancer: 6; gynecologic tumors: 5), 48 of whom showed distant organ metastases. In each patient, we have evaluated serum concentrations of VEGF-165, total VEGF, ET-1, IL-12 and the circulating number of immature (CD123+) and mature (CD11c+) DC. Mean serum levels of VEGF-165 were significantly higher in metastatic patients than in controls or in non-metastatic patients, whereas the total amounts of VEGF were not significantly higher. Moreover, it has been observed that patients with abnormally elevated blood concentrations of VEGF-165 showed significantly lower mean values of immature DC, mature DC and IL-12 and significantly higher mean levels of ET-1 than those with normal concentrations. This study, by confirming that advanced neoplastic disease may be associated with increased endogenous secretion of VEGF, seems to suggest that the association between high blood levels of VEGF and poor prognosis in cancer does not depend only on VEGF-induced stimulation of the neovascularization, but also on VEGF-related immunosuppression.

In addition to its efficacy in the treatment of chemotherapy-induced neutropenia, recent evidence would suggest that GM-CSF may have immunomodulatory effects on anticancer immunity. In particular, GM-CSF has been proven to promote dendritic cell maturation, with following potential stimulation of the anticancer cytokine, IL-12. Unfortunately, at present there are only few and controversial results on GM-CSF effects on IL-12 secretion in cancer patients. This preliminary study was performed to evaluate IL-12 response to an acute injection of GM-CSF in human neoplasms. The study included 20 advanced cancer patients, who received GM-CSF for chemotherapy-induced neutropenia. GM-CSF was injected at 3 micrograms/kg at 8.00 A.M., and venous blood samples were drawn before GM-CSF, and at 4, 8, 12 and 24 hours after its injection. Serum levels of IL-12 were measured by an enzyme immunoassay. High basal levels of IL-12 were seen in 8/20 patients. In patients with abnormally high pretreatment levels of IL-12, no significant change occurred in IL-12 mean serum concentration after GM-CSF administration. In contrast, patients with normal baseline levels of IL-12 showed a significant increase in IL-12 mean concentrations in response to GM-CSF, with a peak after 12 hours. This preliminary study seems to show that GM-CSF may acutely stimulate IL-12 secretion in cancer patients. Further studies are required to evaluate the effects of chronic GM-CSF administration, and the impact of GM-CSF-induced secretion of IL-12 on the efficacy of the immunotherapies of cancer with cytokines, such as IL-2. In any case, this study would justify further research in the emerging oncological applications of GM-CSF as an immunomodulatory agent on host anticancer defenses.

Objectives: Recent studies have suggested the involvement of the pineal gland and its main hormone melatonin (MLT) in the pathogenesis of psychiatric disturbances, namely the depressive syndrome. In contrast, the behavior of MLT secretion in schizophrenia is still controversial., Material & Methods: The present study was carried out to analyze light/dark rhythm of MLT secretion in relation to that of cortisol and prolactin (PRL) in schizophrenic patients. The study included 13 schizophrenic patients, 8 of whom were untreated, while the other 5 patients were on neuroleptic therapy. Serum levels of MLT, PRL and cortisol were measured by RIA on venous blood samples collected at 8 A.M., 12 A.M., 8 P.M. and 1 A.M. The control group consisted of 20 age-matched healthy subjects., Results: A physiological nocturnal increase in MLT levels occurred in 6/13 patients, whereas the other 7 patients showed an abnormally low MLT peak during the night. Moreover, both light and night mean levels of MLT were significantly lower in patients than in controls. In addition, mean nocturnal levels of MLT were significantly lower in chronic patients than in those evaluated at the onset of disease. Cortisol rhythm was normal in 11/13 patients, whereas PRL levels were abnormally high in 10/13 patients., Conclusions: This preliminary study would suggest that schizophrenia may be associated with a diminished secretion of MLT from the pineal gland, and pineal deficiency would be more evident in the chronic disease. Finally, pineal alterations have appeared to be associated with an altered secretion of PRL and cortisol, by suggesting that the schizophrenic disease may be characterized by marked neuroendocrine disturbances, whose physio-pathological and prognostic significance needs to be established by successive clinical investigations.

Objective: Several cytokines, particularly IL-2 and interferons, are thought to be effective in the palliative therapy of neoplastic effusions. We report on the activity and toxicity of intracavitary administration of low-dose IL-2 in a case series of 100 cancer patients with neoplastic effusions., Methods: One hundred patients with advanced solid tumors and neoplastic effusions underwent IL-2 intracavitary injection as first-line treatment. The most common sites of fluid accumulation were pleura (n = 68), peritoneum (n = 21) and pericardium (n = 11). Breast cancer, lung cancer and mesothelioma were the most frequent neoplasms in our series. One cycle consisted of intracavitary IL-2 at 6,000,000 IU on days 1 and 7., Results: According to Paladine's criteria, an objective clinical response was achieved in 72% (complete response in 27% and partial response in 45%), with a median duration of 5 months (range: 1-11 months). The peritoneum was the least responsive site for neoplastic effusion reduction. IL-2 intracavitary injection was well tolerated in all patients; the only toxicity observed was fever >38 degrees C in 6% of the patients., Conclusion: This study shows that intracavitary injection of IL-2 represents a feasible, well-tolerated and effective therapy of neoplastic fluid accumulation. Further studies are needed in order to compare the effectiveness of intracavitary IL-2 with other standard treatments., (Copyright 2001 S. Karger AG, Basel.)

Objectives: The anticancer activity of the indole melatonin has been explained to be due to its immunomodulatory, anti-prolferative and anti-oxidant effects, whereas at present no data are available about its possible influence on the angiogenesis, which has been shown to be one of the main biological mechanisms responsible for tumor dissemination. Vascular endothelial growth factor (VEGF) is the most active angiogenic factor, and the evidence of abnormally high blood levels or VEGF has been proven to be associated with poor prognosis in cancer patients. To investigate the influence of melatonin on angiogenesis, in this preliminary study we have evaluated the effects of melatonin therapy on VEGF blood levels in advanced cancer patients., Material & Methods: The study included 20 metastatic patients, who progressed on previous conventional antitumor therapies and for whom no other effective treatment was available. Melatonin was given orally at 20 mg/day in the evening for at least 2 months. Serum levels of VEGF were measured by an enzyme immunoassay on venous blood samples collected at 15-day intervals., Results: The clinical response consisted of minor response (MR) in 2, stable disease (SD) in 6 and progressive disease (PD) in the remaining 12 patients. VEGF mean levels decreased on therapy, without, however, statistical differences with respect to the pre-treatment values. In contrast, by evaluating changes in VEGF levels in relation to the clinical response, non-progressing patients (MR + SD) showed a significant decline in VEGF mean concentrations, whereas no effect was achieved in progressing patients., Conclusions: This study, by showing that melatonin-induced control or the neoplastic growth is associated with a decline in VEGF secretion, would suggest that the pineal hormone may control tumor growth at least in part by acting as a natural anti-angiogenic molecule, with a following opposition or angiogenesis-dependent cancer proliferation.

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.

The recent availability of adequate methods for cytokine measurement could contribute to better understanding the immunophysiopathology of neoplastic disease. Unfortunately, very little data is available about cytokine secretion in cancer patients. At present, IL-2, IL-12 and IL-15 represent the major antitumor cytokines in humans. Preliminary clinical studies have shown a progressive decline in IL-2 levels with cancer progression, whereas IL-12 seems to increase in the advanced disease. IL-18 is the latest cytokine discovered by potential anticancer and anti-angiogenetic activity, and it has effects similar to those of IL-12. This preliminary study was carried out to analyze IL-18 secretion in early or advanced cancer patients. The study included 40 cancer patients (lung cancer, 21; gastrointestinal tumors, 19), 17 of whom had metastatic disease, and 50 healthy controls. Serum levels of IL-18 were measured by ELISA. No significant difference in IL-18 mean levels was seen between controls and non-metastatic patients. In contrast, metastatic patients showed significantly higher IL-18 mean values with respect to both healthy controls and non-metastatic patients. This preliminary study seems to suggest that metastatic disease may be characterized by enhanced IL-18 secretion the biological and prognostic significance to be established by successive clinical investigation.

Cancer-related deficiency in circulating dendritic cells (DC), whose important anticancer role is well established, has been proven to be associated with lymphocytopenia. This study was performed to evaluate which lymphocyte subset is most markedly related to the failure of the DC system. The study included 30 patients with gastrointestinal tract cancer, 10 of whom had distant organ metastases. Immature and mature DCs were measured by FACS and monoclonal antibodies against CD123 and CD11c antigens, respectively. Low levels of immature and mature DCs were observed in 63% and 43% of patients, respectively. Patients with low levels of circulating mature DCs had significantly lower values of T lymphocytes, T helper lymphocytes and NK cells than those with normal mature DC levels. In contrast, no significant difference was seen between patients with normal or abnormally low values of immature DCs. Conversely, patients with a decreased number of T lymphocytes, T helper lymphocytes and NK cells showed significantly lower values of circulating mature DCs than those with lymphocyte subsets within the normal range, whereas no difference was seen in immature DC amounts. This study suggests that only mature DC deficiency may be associated with important lymphocyte subset alterations in cancer patients, whereas deficiency in immature DCs does not seem to be related to other immune cell disorders.

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.

Melatonin (MLT) has been proven to counteract chemotherapy toxicity, by acting as an anti-oxidant agent, and to promote apoptosis of cancer cells, so enhancing chemotherapy cytotoxicity. The aim of this study was to evaluate the effects of concomitant MLT administration on toxicity and efficacy of several chemotherapeutic combinations in advanced cancer patients with poor clinical status. The study included 250 metastatic solid tumour patients (lung cancer, 104; breast cancer, 77; gastrointestinal tract neoplasms, 42; head and neck cancers, 27), who were randomized to receive MLT (20 mg/day orally every day) plus chemotherapy, or chemotherapy alone. Chemotherapy consisted of cisplatin (CDDP) plus etoposide or gemcitabine alone for lung cancer, doxorubicin alone, mitoxantrone alone or paclitaxel alone for breast cancer, 5-FU plus folinic acid for gastro-intestinal tumours and 5-FU plus CDDP for head and neck cancers. The 1-year survival rate and the objective tumour regression rate were significantly higher in patients concomitantly treated with MLT than in those who received chemotherapy (CT) alone (tumour response rate: 42/124 CT + MLT versus 19/126 CT only, P < 0.001; 1-year survival: 63/124 CT + MLT versus 29/126 CT only, P < 0.001). Moreover, the concomitant administration of MLT significantly reduced the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia. This study indicates that the pineal hormone MLT may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients of poor clinical status.

Aims and Background: Prolactin (PRL) may be a growth factor for breast cancer. Abnormally high levels of PRL have been proven to be associated with a poor prognosis in metastatic breast cancer. However, most studies have been limited to the evaluation of basal levels of PRL rather than its response to the classical endocrine dynamic tests. This study was performed to analyse the dynamic secretion of PRL under stimulatory and inhibitory tests in metastatic breast cancer., Methods: The study included 10 untreated metastatic breast cancer women, who were evaluated after the classical stimulatory and inhibitory tests for PRL secretion with the antidopaminergic agent Metoclopramide (10 mg iv as a bolus) and with L-dopa, respectively. Serum levels of PRL were measured by RIA before and at subsequent intervals after drug administration. PRL levels were considered to be elevated when they were higher than 25 ng/ml., Results: Abnormally high basal levels of PRL were seen in 6/10 patients. L-dopa was unable to inhibit PRL secretion, whose mean concentrations paradoxically significantly increased in response to L-dopa, with values comparable to those observed after the classical stimulatory test with metoclopramide., Conclusions: This study confirm the existence of hyperprolactinemia associated with metastatic breast cancer. In addition, by showing a paradoxical rise of PRL in response to L-dopa, which inhibits PRL secretion in physiological conditions, this study would suggest that breast cancer-related hyperprolactinemia may depend at least in part on endogenous disease-related neuroendocrine alterations.

IL-12, which play a fundamental antitumor role, would be also involved in the physiological regulation of neuroendocrine and immune interactions. At present, however, there are no data about the endocrine effects of IL-12. This preliminary study was performed to investigate the acute endocrine effects of IL-12 in metastatic renal cell cancer patients. Each IL-12 injection consisted of 0.5 micrograms/kg/bw subcutaneously in the morning. The study has evaluated the effects of 6 different injection cycles. Serum samples were collected before, and 4, 8 and 12 hours from IL-12 injection. In each sample, we have measured by the RIA method serum levels of GH, PRL, TSH, FSH, LH, T3, T4, cortisol, testoterone, estradiol and the pineal hormone melatonin. No significant change occurred in TSH, FSH, LH, T3, T4, testoterone and melatonin mean serum levels in response to IL-12 administration. In contrast, cortisol, PRL and estradiol significantly increased after Il-12 injection. GH also increased in response to IL-12, without however, significant differences with respect to the baseline values. This preliminary study shows that the acute subcutaneous injection of IL-12 may influence the endocrine secretions in humans. In particular, IL-12 would stimulate the secretions of cortisol, PRL and estradiol. Therefore, this study would further confirm that IL-12 may act as biological response modifier in humans, not only on the immune system, but also on the neuroendocrine functions.