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Aims and Background: The antitumor activity of IL-2 is mediated by an increase in lymphocyte number. Moreover, our previous studies have shown that therapy for 1 week/month with low-dose subcutaneous IL-2 is sufficient to maintain high levels of lymphocytes in cancer patient who have had tumor regression or stable disease (SD) in response to IL-2 immunotherapeutic cycles. This study was performed to establish whether tumor progression in cancer patients chronically treated with IL-2 may be associated with lymphocyte number decline., Methods: The study included 53 metastatic renal cell cancer patients, who were treated with 2 induction cycles of IL-2 subcutaneous immunotherapy (6 million IU/day for 5 days/week for 6 weeks, corresponding to one cycle). Tumor regression occurred in 15/53 patients, 20 patients had a SD, and the remaining 18 cases progressed. Non progressed patients (n = 35) underwent a maintenance therapy consisting of one week of therapy every month. After a median follow-up of 18 months, 26/35 patients with response or SD had progressed. The immune investigation consisted of lymphocyte, T lymphocyte, NK cell number determination and sCD25 level detection., Results: The mean number of lymphocytes, T lymphocytes and NK cells observed on IL-2 maintenance therapy was significantly higher than that seen before beginning the immunotherapy. Moreover, mean number of lymphocytes and mean levels of sCD25 observed at the time of tumor progression were respectively lower and higher than those seen on maintenance therapy in the same patients, without, however, significant differences., Conclusion: Despite the importance of lymphocytes in mediating the antitumor activity of IL-2, this study shows that tumor progression in cancer patients chronically treated with low-dose IL-2 after response or SD during IL-2 induction cycles is not associated with a significant decline in lymphocyte, T lymphocyte or NK cell numbers. Further studies, carried out to analyze the functional status of immune cells at the time of tumor progression, will be necessary to define the role of immunity in cancer patients progressing under IL-2 chronic therapy.

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effect and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

Previous experimental studies have suggested the possibility to modulate the biological activity and toxicity of cytokines by immunomodulating neurohormones. In particular, the pineal hormone melatonin (MLT) has been proven to amplify the immune effects of IL-2 and to reduce its toxicity. On this basis, we decided to investigate the effect of MLT on biological activity and toxicity of another important antitumor cytokine, TNF. The study was performed in 14 metastatic solid tumor patients, for whom no effective standard antitumor therapy was available. Informed consent was previously obtained from each patient. Patients were randomized to be treated with TNF or TNF plus MLT. Recombinant human TNF was given at a daily dose of 0.75 mg intravenously for 5 consecutive days. MLT was given orally at a daily dose of 40 mg, starting 7 days before TNF. Lymphocyte mean number observed at the end of TNF infusion was significantly higher in patients treated with TNF plus MLT than in those receiving TNF alone. On the contrary, no significant difference occurred in hemoglobin, platelet and neutrophil mean values. Asthenia and hypotension were significantly less frequent in patients treated with TNF plus MLT, whereas no difference occurred in the frequency of fever and chills. Even though limited to a small number of patients, this preliminary study would suggest the possibility to modulate TNF toxicity and biological activity by a concomitant treatment with the pineal hormone MLT.

Aims and Background: Prolactin (PRL) may be a tumor growth factor, mainly for breast cancer. The antidopaminergic drugs commonly used in the treatment of chemotherapy-induced vomiting stimulate PRL release, and this finding could represent a potentially negative biologic event for cancer patients. This study was performed to analyze PRL response to the serotonin-type 3 receptor antagonist ondansetron, a new active drug in the treatment of vomiting due to chemotherapy, in cancer patients., Methods: The study included 8 premenopausal breast cancer patients undergoing adjuvant chemotherapy. Ondansetron was given intravenously at a dose of 8 mg, and venous blood samples were drawn at 0, 20, 60 and 120 min. The result were compared to those seen in 10 breast cancer patients treated with metoclopramide (10 mg. i.v.)., Results: PRL mean levels significantly increased in response to metoclopramide. In contrast, no significant changes in PRL mean values occurred after ondansetron injection., Conclusions: The study showed that ondansetron, whose efficacy in the treatment of chemotherapy-induced vomiting is well known, does not stimulate the tumor growth factor PRL in cancer patients, in contrast the the action of the most commonly used antidopaminergic drugs.

Aims and Background: In addition to estrogens, prolactin (PRL) and IGF-I have also appeared to stimulate breast cancer growth. The present study was performed to evaluate IGF-I blood levels in operable breast cancer in relation to PRL values and the main prognostic variables., Methods: The study included 40 patients, clinical stage T1-3NO-2MO. Venous blood samples were collected before and 7 days after surgery. PRL and IGF-I were measured by radioimmunoassay. The control group consisted of 50 healthy women., Results: Mean serum levels of IGF-I were significantly higher in patients than in controls, without any apparent relation to the main prognostic variables, including estrogen receptor and node status. Surgery-induced hyperprolactinemia occurred in 22/40 patients. IGF-I mean concentrations observed in the postoperative period in patients with surgery-induced hyperprolactinemia were significantly lower than those seen in patients showing no postoperative PRL rise., Conclusions: The study showed that operable breast cancer may be associated with abnormally high levels of tumor growth factor IGF-I, and that surgery was followed by an IGF-I decline only in patients who showed surgery-induced hyperprolactinemia. Our previous studies have shown that postoperative hyperprolactinemia is a favorable prognostic factors for operable breast cancer. The present study, by showing that a postoperative PRL rise is associated with a fall in IGF-I, would suggest that surgery-induced hyperprolactinemia may determine a lower tumor relapse rate by determining a diminished secretion of breast tumor growth factor IGF-I.

Experimental studies have shown that IL-2 may antagonize chemotherapy-induced lymphocytopenia. On this basis, we have evaluated the influence of low-dose IL-2 on lymphocyte and NK cell numbers in cancer patients treated with the anthracycline drug, epirubicin. The study included 7 metastatic breast cancer women treated with epirubicin at a dose of 25 mg/m2 i.v. weekly. IL-2 was given subcutaneously at 3 million IU/day for 6 days/week. Venous blood samples were drawn at weekly intervals, and the results were compared to those seen in 14 patients treated with epirubicin alone. Lymphocyte mean number observed on treatment was higher in patients concomitantly treated with IL-2 than in those receiving epirubicin alone, without, however, significant differences. In addition, NK cell mean number was significantly higher in patients receiving IL-2 than in those treated with epirubicin alone. These preliminary results would suggest that IL-2 may antagonize lymphocyte and NK cell declines during cancer chemotherapy with anthacyclines. Further studies will be required to confirm these results and to establish their possible influence on chemotherapy-induced tumor regressions.

It is known that IL-2 cancer immunotherapy is associated with hypotension. The present study was performed to evaluate the influence of low-dose IL-2 subcutaneous therapy on blood pressure in cancer patients with idiopathic hypertension requiring hypotensive therapy. The study included 12 patients, who received IL-2 at 6 million IU/day for at least 4 weeks. Mean values of both systolic and diastolic pressure significantly decreased under IL-2 therapy, and the hypotensive agents were interrupted within 2 weeks in 10/12 patients. Moreover, 6 of them still showed normal blood pressure values without hypotensive therapy after a median follow-up of 6 months. This preliminary study would suggest that low-dose IL-2 subcutaneous therapy may normalize blood pressure values in cancer patients with idiopathic hypertension.

Experimental studies have showed that hepatocellular carcinoma (HCC) cells are susceptible to cytolysis of interleukin (IL)-2-activated lymphocytes. Moreover, our previous studies demonstrated that the pineal neurohormone melatonin (MLT) may enhance IL-2 efficacy. On this basis, a study was started with low-dose IL-2 (3 million U/day subcutaneously for 6 days/week for 4 weeks) plus MLT (50 mg/day orally every day given in the evening) as a first-line therapy of unresectable HCC. The study included 14 patients. Objective tumour regressions were obtained in 5/14 (36%) patients (one complete response, four partial responses), with a median duration of 7+ months. 6 patients had stable disease, while the other 3 progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapy with low-dose IL-2 plus MLT is a new well-tolerated and effective therapy of advanced HCC.

The intravenous immunotherapy with interleukin 2 (IL-2) represents one of the most active therapies of metastatic renal cell carcinoma (RCC). Recently, it has been demonstrated that IL-2 given subcutaneously in association with interferon alpha (IFN) may determine a response rate in RCC comparable to that obtained with an intravenous route of administration, but with a lower toxicity. Moreover, our previous data have suggested that IFN is not essential for IL-2 efficacy. On the basis of these data, we have designed a protocol of immunotherapy with IL-2 alone given subcutaneously in the treatment of metastatic RCC. The study included 48 consecutive evaluable patients. IL-2 was given at a daily dose of 6 million IU for 5 days/week for 6 consecutive weeks, corresponding to one IL-2 cycle. The overall response rate was 14/48 (29%; CR:1; PR:13). Response rate was significantly higher in nephrectomized than in nonnephrectomized patients, and in patients with a good compared to those with a low performance status. Patients with an interval between the diagnosis of primary renal tumor and of its metastases longer than 1 year did better than those with a lower interval, as did patients with a single metastasis compared to those with multiple metastases, while no significant difference was seen in relation to sex, age and previous IFN therapy. As far as dominant metastasis sites are concerned, patients with liver metastases showed a response rate significantly lower than that seen in patients with metastases in sites other than liver. Toxicity was low in all patients. This study shows that the subcutaneous immunotherapy with IL-2 alone is a well tolerated and effective therapy of metastatic RCC. The evidence of a low PS, disseminated tumor and liver metastases represents the most important negative prognostic factor for the response to therapy.

High levels of the macrophage activation marker neopterin have been described in metastatic cancer patients. Since macrophages may either counteract or stimulate tumor development, it is important to establish which macrophage activity is mainly related to neopterin release. The present study was carried out to evaluate neopterin levels in metastatic solid tumor patients in respect with the antitumor macrophage cytokine TNF and with soluble IL-2 receptor (SIL-2R), whose secretion is stimulated by macrophages and it is associated with the immunosuppressive status of cancer patients. The study included 35 patients with metastatic solid neoplasms. Serum levels of neopterin, TNF and SIL-2R were measured in blood samples collected during the morning. Abnormally high concentrations of neopterin were seen in 18/35 (51%) patients. Patients with high levels of neopterin showed significantly higher concentrations of SIL-2R than those with normal neopterin values, whereas no difference was found in TNF levels. This study would suggest that the increased secretion of neopterin may reflect macrophage-mediated immunosuppression in metastatic solid neoplasms, rather than to be associated with the antitumor activity of macrophages.

Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.

Aims and Background: Patients with disseminated gastric cancer are generally in very bad clinical conditions, which make them not eligible for potentially active polychemotherapies. This justifies the development of less toxic therapies such as the use of biological response modifiers. Unfortunately, IL-2, one of the most promising cytokines, does not seem to be effective in gastric cancer. Our previous studies have shown that the pineal hormone melatonin (MLT) may amplify IL-2 activity, which becomes biologically effective also at very low doses. Based on these considerations, a pilot study was performed with low-dose subcutaneous IL-2 in combination with MLT in metastatic gastric cancer patients with low performance status., Methods: The study included 14 patients with metastatic gastric cancer who received IL-2 at a dose of 3 million IU/day at 8.00 p.m. subcutaneously for 6 days/week for 4 weeks. MLT was given orally at a dose of 50 mg/day at 8.00 p.m. every day starting 7 days before IL-2. In patients in whom the disease did not progress, a second cycle was given after a rest period of 21 days., Results: A tumor regression was obtained in 3/14 (21%) patients, complete response in 1 and partial in 2, with a median duration of 13 + months. The disease stabilized in 6/14 (43%) patients and progressed in the remaining 5 (36%). Survival was significantly longer in patients with response or stable disease than in those with progression. Toxicity was low in all cases., Conclusions: These preliminary results show that the combination on of low-dose subcutaneous IL-2 and the pineal hormone MLT may represent a new well tolerated biotherapy, capable of inducing objective tumor regression also in patients with metastatic gastric cancer and low performance status.

Aims and Background: IL-2 given subcutaneously in combination with interferon-alpha 2b (IFN) appears to induce a response rate comparable to that obtained with IL-2 intravenous injection in patients with metastatic renal cell carcinoma (RCC) but with lower toxicity. The role of IFN when combined with IL-2 has however still to be defined. The present study was performed to draw some preliminary conclusions about the effect of IFN in combination with IL-2 in metastatic RCC., Methods: The study included 30 consecutive patients with metastatic RCC who were randomized to treatment with IL-2 subcutaneous therapy (3 million IU twice/daily for 5 days/week for 6 weeks) or with IL-2 plus IFN (5 million U/m2 subcutaneously thrice weekly). In patients without progressive disease, a second cycle was repeated after a 28-day rest period., Results: No significant difference in partial response rate was found between patients treated with IL-2 alone and those given IL-2 plus IFN (5/15 vs 4/15). Similarly, no difference was seen in the percentage of stable disease (7/15 vs 7/15). Toxicity was higher in patients who received IL-2 plus IFN. Lymphocyte and eosinophil mean increase was higher in patients treated with IL-2 alone than in those treated with IL-2 plus IFN, without however any significant difference., Conclusions: The present results, which require confirmation in a larger series, indicate that combination with IFN does not increase the efficacy of IL-2 subcutaneous immunotherapy in metastatic RCC but only the toxicity of treatment.

The mechanisms responsible for the immunostimulatory role of the pineal hormone melatonin (MLT) are still obscure. To investigate the influence of MLT on interleukin-2 (IL-2)-induced immune effects in cancer, we compared the results obtained in 14 cancer patients treated with IL-2 (6 x 10(6) IU/day s.c. for 5 days/week for 4 weeks) plus MLT (10 mg/day orally) with those seen in 14 patients treated with IL-2 alone and with those obtained from 14 other patients treated with MLT only. All patients were affected by metastatic solid neoplasms. The increase in the mean number of lymphocytes, T lymphocytes, natural killer cells, CD25-positive cells and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. On the contrary, the increase in mean serum levels of the macrophage marker neopterin was significantly higher in patients treated with IL-2 alone than in those treated with IL-2 plus MLT. Finally, MLT alone has no significant effect on immune cell mean number and on neopterin secretion. These results would suggest that the immunostimulatory action of MLT requires the concomitant presence of IL-2 and that two of the main target cells for MLT activity in humans are represented by T helper lymphocytes of type 2, which are involved in IL-2-induced eosinophilia by the release of IL-5, and macrophages, which may inhibit IL-2-dependent immune functions.

The inappropriate endogenous secretion of tumour necrosis factor (TNF) could play a role in the pathogenesis of acute respiratory distress syndrome (ARDS), one of the most frequent causes of death in cancer patients. Because of its capacity to inhibit TNF secretion in vitro, pentoxifylline (PTX) could be extremely useful in ARDS therapy. In this study 30 advanced cancer patients with ARDS were randomized to receive either the conventional care or conventional care plus PTX (100 mg i.v. twice a day for 7 days followed by an oral administration of 400 mg three times a day) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome. Serum levels of TNF were measured before and after 7 days of therapy. The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls (12/15 versus 3/15; P < 0.001). The mean survival time was significantly higher in the PTX-treated group than in the controls. A clinical and/or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group (P < 0.01). TNF mean levels significantly decrease in the PTX-treated group. These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS. Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects.

Aims and Background: Beta-interferon (beta-IFN) has been proven to influence some IL-2-induced immune effects. On the basis of these experimental data, we evaluated the immunobiologic effects of an association between very low-dose IL-2 and beta-IFN in advanced cancer patients., Methods: The study was performed in 15 metastatic colon cancer patients, who progressed in response to a first-line chemotherapy with 5-FU plus folates. IL-2 was given subcutaneously at a daily dose of 3 million IU in the evening for 6 days/week for 4 weeks. beta-IFN was injected subcutaneously at a dose of 3 million U/day for 7 days before the first IL-2 injection, then thrice/week until the end of IL-2 administration. In nonprogressed patients, a second cycle was given after a 14-day rest period., Results: No objective tumor regression was seen. Stable disease was obtained only in 2/15 patients; the other 13 progressed. Toxicity was low in all cases. Natural killer cell and T-activated lymphocyte mean number significantly increased during the immunotherapy. Lymphocyte and eosinophil mean number also increased, without, however, significant differences. IL-2-induced suppressive events, consisting of an increase in T-suppressor cell number, and soluble IL-2 receptor levels were not blocked by beta-IFN., Conclusions: The study showed that the concomitant administration of beta-IFN may determine an improvement in the immune performance in metastatic cancer patients treated with very low-dose IL-2, even though this biologic improvement does not seem to be associated to a control of tumor development. Further studies in patients with less advanced disease are needed to better define the impact of the immune improvement induced by low-dose IL-2 plus beta-IFN on the clinical course of the neoplastic disease.

The antitumor efficacy of IL-2 is limited to renal cancer and melanoma. Several cytokines have been associated with IL-2 in an attempt to improve its activity, without, however, any clear benefit. Recent experimental and clinical studies have suggested the possibility to manipulate the host biological response by immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On the bases of these considerations, we have designed a neuroimmunotherapeutic protocol with low-dose IL-2 subcutaneous therapy (3 million IU/day for 6 days/week for 4 weeks) plus MLT (40 mg/day orally, starting 7 days before IL-2) in advanced solid neoplasms other than renal cancer and melanoma, which are generally resistant to IL-2 alone. The study included 82 patients, 72 of whom showed distant organ metastases. Tumor histotypes were, as follows: non-small cell lung cancer: 19; hepatocarcinoma: 16; colon cancer: 15; gastric cancer: 11; cancer of pancreas: 11; breast cancer: 6; miscellaneous: 4. Objective tumor regression were achieved in 17/82 (21%) patients, consisting of CR in 4 (liver: 2; pancreas: 1; stomach: 1) and PR in 13 (lung: 4; liver: 4; stomach: 2; pancreas: 1; breast: 1; colon: 1). The median duration of response was 8+ months. A stabilization of disease was obtained in 30 patients, while the other 35 patients progressed. The lack of progression was associated with a significantly higher increase in lymphocyte and eosinophil mean number and with a significantly lower increase in neopterin mean levels. The treatment was well tolerated in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aims and Background: It is known that interleukin-2 (IL-2) activated cytotoxic lymphocytes require a cell-cell contact to exert their anticancer action. Therefore, the pronounced fibrosis that generally characterizes the neoplastic mass could counteract the action of cytotoxic lymphocytes. Some preliminary studies have shown that progesterone and its analogs may inhibit fibroblast proliferation. On the basis of such evidence, we have designed a clinical study with or without the progestational agent medroxyprogesterone acetate (MPA) in metastatic renal cancer patients in maintenance therapy with IL-2 following response or stable disease (SD) after two cycles of IL-2 subcutaneous immunotherapy, in an attempt to evaluate the influence of MPA on free-from progression (FPP) period., Methods: The study included 30 consecutive patients who were randomized to receive IL-2 alone (3 million IU twice/day for 5 days/month subcutaneously) or IL-2 plus low-dose MPA (500 mg orally one day/week) without interruption until disease progression., Results: A FPP period longer than 1 year was obtained in 8/14 patients treated with IL-2 plus MPA and in only 3/16 patients treated with IL-2 alone. The difference was statistically significant. On the contrary, no significant difference was seen in the mean number of lymphocytes and eosinophils, which was evaluated monthly. Finally, no hyperglycemic or thromboembolic complications occurred in patients concomitantly treated with MPA., Conclusions: This preliminary study would suggest that the concomitant administration of low-dose MPA may prolong the FFP period in metastatic renal cancer patients under maintenance therapy with IL-2. A longer follow-up will be required to evaluate the influence of MPA on overall survival.

SIL-2R levels mainly depend on a T lymphocyte production. The mechanisms responsible for the elevated blood concentrations of SIL-2R in advanced solid tumors are still unknown. To investigate the role played by the monocyte-macrophage system on SIL-2R release, we have evaluated serum levels of SIL-2R in 10 head and neck cancer patients during GM-CSF subcutaneous administration (3 mcg/kg/day for 11 consecutive days). Serum levels of TNF and neopterin, both produced by macrophages, were also measured. SIL-2R mean concentration significantly enhanced in response to GM-CSF, and their rise positively correlated to that in TNF and neopterin values, while lymphocyte mean number did not increase during the study. The present results represent the first in vivo demonstration that SIL-2R release is related to macrophage activation, rather than to depend only on lymphocyte proliferation.

Aims and Background: Malignant gliomas remain untreatable as the different therapeutic combinations are generally only palliative. Recent experimental evidence suggests that endogenous opioid peptides are involved in brain tumor growth. The aim of the present study was to evaluate the effect on survival of concomitant administration of the long-acting opioid antagonist naltrexone (NTX) in patients with malignant astrocytomas treated with radiotherapy (RT)., Methods: 21 patients with high grade malignant gliomas were randomized to receive RT alone or RT plus NTX. The dose of RT was 60 Gy. NTX was given orally at a dose of 100 mg every other day without interruption until disease progression., Results: The objective tumor regression rate in patients treated with RT plus NTX was higher than that of those treated with RT alone but not significantly so. On the contrary, the percentage of survivals at 1 year was significantly higher in patients treated with RT plus NTX than in those treated with RT alone (5/10 vs 1/11, P < 0.05). NTX therapy was substantially well tolerated in most patients., Conclusions: The finding of longer survival in brain tumor patients treated with RT plus NTX than in those who received RT alone suggests in vivo involvement of endogenous opioid peptides in regulating the growth of malignant astrocytomas.

Aims and Background: Cardiac toxicity has been observed during IL-2 cancer immunotherapy. Because of its trophic action on the myocardial tissue, the use of L-carnitine has been evaluated during IL-2 therapy in advanced cancer patients with clinically important cardiac diseases., Methods: The study included 30 cancer patients, who were randomized to treatment with IL-2 alone or IL-2 plus L-carnitine (1000 mg/day orally). IL-2 was injected subcutaneously at a daily dose of 6 million IU for 5 days/week for 4-6 weeks., Results: The percentage of cardiac complications was significantly lower in patients concomitantly treated with L-carnitine than those receiving IL-2 alone (0/15 vs 4/15; P < 0.05), whereas no difference was seen in mean creatine phosphokinase levels on study., Conclusions: The results would suggest that L-carnitine may be used successfully to prevent cardiac complications during IL-2 immunotherapy in cancer patients with clinically relevant cardiac disorders. Since cardiac metabolism depends mainly on fatty acid oxidation, the stimulatory role of L-carnitine on fatty acid oxidation could explain at least in part its ability to prevent heart disturbances in response to IL-2 administration.

The advanced tumours of the digestive tract are generally less responsive to conventional chemotherapies. Moreover, preliminary results with IL-2 immunotherapy also seem to show a low efficacy. On the basis of our previous studies suggesting s synergistic action between IL-2 and some neurohormones, such as the pineal indole MLT, a clinical trial was performed to investigate the clinical efficacy and tolerability of an immunotherapy with IL-2 plus MLT in patients with advanced neoplasms of the digestive tract. The study included 35 patients (colorectal cancer: 14; gastric cancer: 8; hepatocarcinoma: 6; pancreas adenocarcinoma: 7). Distant organ metastases were present in 31/35 patients. MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In nonprogressed patients, a second cycle was given after a 21-day rest period. A complete response was achieved in two patients (gastric cancer: 1; hepatocarcinoma: 1). Six other patients obtained a partial response: (gastric cancer: 2; hepatocarcinoma: 2; colon cancer: 1; pancreas cancer: 1). Therefore, the overall response rate was 8/35 (23%). Stable disease was obtained in 11/35 (31%) patients, whereas the remaining 16 patients (46%) progressed. The response rate was significantly higher in untreated patients than in those previously treated with chemotherapy. Toxicity was low in all patients, who received the treatment as a home therapy. This study shows that the immunotherapy with low-dose IL-2 plus the pineal hormone MLT is a new well tolerated and effective therapy of advanced tumours of the digestive tract, mainly in gastric cancer and hepatocarcinoma.

The intravenous injection of interleukin-2 (IL-2) has appeared to induce tumor regression in metastatic renal cell carcinoma (RCC). IL-2 given subcutaneously has also appeared to be effective when it is administered in association with interferon-alpha (INF), but with a lower toxicity in comparison to the intravenous route of administration. The present study was carried out to evaluate the efficacy of a subcutaneous immunotherapy with IL-2 alone in metastatic RCC. The study included 30 consecutive patients affected by metastatic RCC, 14 of whom had been pretreated with INF plus vinblastine, while the other 16 patients received IL-2 as a first line therapy of their metastatic disease. IL-2 was given subcutaneously at a dose of 3 million IU twice/day for 5 days/week for 6 consecutive weeks, corresponding to one cycle of immunotherapy. No complete response was obtained. A partial response (PR) was achieved in 10/30 (33%) patients (median duration: 7 months, range 5-25), without any significant difference between patients pretreated with IFN and nonpretreated patients (4/14 vs 6/16). Response rate was significantly higher in nephrectomized patients than in those who did not undergo nephrectomy (10/25 vs 0/5; P < 0.01). Moreover, response rate was significantly higher in patients with performance status (PS) greater than 40% than in those with PS lower than 40% (10/23 vs 0/7; P < 0.01). A stable disease (SD) was obtained in 12/30 (40%) patients (median duration 5 months, range 3-13), while the remaining 8/30 (27%) progressed. The increase in lymphocyte and eosinophil mean number was significantly higher in patients with PR or SD than in the progressed ones.(ABSTRACT TRUNCATED AT 250 WORDS)

TNF, in addition to its antitumor activity, would play an important role in the pathogenesis of cancer-related severe complications, including ARDS and DIC. Therefore, the modulation of TNF secretion could be important in the supportive care of advanced cancer patients. At present, PTX is the only drug which has been proven to be able to inhibit in vitro the release of TNF. The present study was performed to evaluate the effect of PTX on TNF blood concentrations in disseminated cancer patients with abnormally high TNF values. The study included 14 cancer patients, with initial or conclamate signs of ARDS (n = 8) or DIC (n = 6). PTX was given intravenously at a dose of 300 mg/day for 7 days. Mean serum levels of TNF significantly decreased in response to PTX therapy, and they returned to normal range in 5/14 patients. These preliminary data would suggest that PTX may be considered as a biological response modifier, capable of inhibiting TNF secretion in humans, with a following potential use in the treatment of cancer-related severe complications.

Aims: Epirubicin is an analogue of doxorubicin with a similar activity but less toxicity. The aim of this study was to evaluate the efficacy and the tolerability of a weekly schedule of epirubicin., Methods: Fifty-three patients with metastatic breast cancer, pretreated and/or with a low performance status, were treated with 25 mg/m2/week of the drug., Results: Of the 49 evaluable patients, 3 achieved a complete response (6.1%) and 21 a partial response (42.8%) with a median duration of 6.3 months. Median survival was significantly higher in responders than in nonresponders: 15.2 vs 6.0 months (P < 0.005). Furthermore, a marked improvement in performance status was observed (ECOG scale). No cardiologic toxicity was observed, and gastrointestinal toxicity was low., Conclusions: Epirubicin administered weekly represent a valid alternative to conventional treatments.

On the basis of the demonstrated existence of immunoneuroendocrine interactions and on the previously observed synergistic action between the pineal hormone melatonin (MLT) and interleukin-2 (IL-2), we have designed a neuroimmunotherapeutic combination consisting of low-dose IL-2 and MLT in the treatment of advanced solid neoplasms. The study included 24 patients with advanced solid tumours (non-small cell lung cancer 9; colorectal cancer 7; gastric cancer 3; breast cancer 2; cancer of pancreas 1; hepatocarcinoma 1; unknown primary tumour 1), 21 of whom showed distant organ metastases. Not all patients responded to previous chemotherapies, or had tumours for which no standard therapy was available. Moreover, not all patients were able to tolerate IL-2 immunotherapy at the conventional doses. IL-2 was given subcutaneously at a dose of 3 x 10(6) U/day at 8:00 p.m. for 6 days/week for 4 weeks. MLT was given orally at a dose of 50 mg at 8:00 p.m. every day, starting 7 days before IL-2 injection. In non-progressed patients, a second cycle was given after a 21-day rest period. A partial response was seen in 3/24 patients (lung 2; stomach 1; duration: 11, 4, 4 months, respectively). Moreover, a minimal response (duration: 8+ months) was seen in 1 lung cancer patient. Stable disease was obtained in 14/24 patients (median duration: 6+ months), while the remaining 6 patients progressed. An improvement in performance status was seen in 7/24 patients. No important toxicity was observed. Mean eosinophil and lymphocyte levels significantly increased during the immunotherapy, and their rise was significantly higher in patients with response or stable disease than in those with progressive disease. These preliminary results show that neuroimmunotherapy with low-dose IL-2 and the pineal hormone MLT is a biologically active and well tolerated strategy, capable of determining an apparent control of tumour growth in patients with advanced solid neoplasms, for whom no standard effective therapy is available.

Eosinophilia, which occurs during IL-2 immunotherapy, has appeared to be due to an enhanced secretion of IL-5 and to be associated with a clinical response. Since our previous experimental studies showed that the pineal hormone MLT potentiates IL-2 efficacy, a study was started to evaluate the influence of a concomitant MLT administration on IL-2-induced eosinophilia. The study included 30 advanced solid tumor patients, 16 of whom received IL-2 alone (6 million IU/day) and the other 14 IL-2 plus MLT (10 mg/day orally at 8.00 P.M.). Eosinophil mean number was significantly enhanced during both treatments, but its increase in patients receiving IL-2 plus MLT was significantly higher than that seen in patients treated with IL-2 alone. These results show that MLT may enhance IL-2-induced eosinophilia, by suggesting that T helper lymphocyte- type 2, which is the source of IL-5, may be the target cell for MLT action.

It is known that the anemias of chronic diseases, which often occur in neoplastic and in systemic inflammatory disorders, are characterized by high levels of ferritin associated with generally low iron concentrations, by suggesting an iron transfer defect due to unknown factors. Since both chronic inflammatory diseases and advanced neoplasms are characterized by alterations in the endogenous production of cytokines, a possible involvement of interleukins in chronic disease-related anomalies of iron metabolism cannot at present be excluded. The present study was carried out to investigate the effect of low-dose IL-2 subcutaneous immunotherapy (3 million IU/day for 6 days/week for 4 weeks) on ferritin, transferring and iron serum levels in cancer patients. Six patients with metastatic gastrointestinal carcinomas were evaluated. Ferritin mean levels significantly decreased during IL-2 treatment, and this finding was associated with a significant increase in transferrin values. Iron mean levels increased in response to IL-2, without, however, significant differences in respect to the pretreatment concentrations. These preliminary data, by showing changes in ferritin, transferrin and iron in cancer patients during the immunotherapy with IL-2, would suggest the existence of a cytokine regulation of iron transfer from tissues to blood, perhaps by modulating the macrophage function.

The concomitant generation of macrophage-mediated suppressive events, as documented by the increase in neopterin and soluble interleukin-2 (IL-2) receptor (SIL-2R), and the enhanced production of cortisol, would represent the most investigated phenomena responsible for the reduced anticancer efficacy of IL-2 immunotherapy in humans. Based on our preliminary experimental studies suggesting a modulatory role of IL-3 on immune and endocrine effects induced by IL-2, a study was performed to evaluate the influence of IL-3 on biological effects of IL-2 cancer immunotherapy. We have evaluated 12 immunotherapeutic courses with IL-3 plus IL-2, which were performed in 6 patients with metastatic non-small cell lung cancer. The results were compared to those seen in 22 courses with IL-2 alone, carried out in 12 patients with metastatic non-small cell lung cancer. IL-3 was given intravenously at a daily dose of 1 microgram/kg/b.w. at 6 p.m. for 14 consecutive days, starting 7 days before IL-2. IL-2 was given subcutaneously at a dose of 3 million IU twice/daily for 5 days/week for 3 weeks. The increase in serum levels of the specific macrophage marker neopterin, induced by IL-2, was completely blocked by IL-3. The IL-2-induced SIL-2R rise was significantly lower during IL-3 plus IL-2 than under IL-2 alone. The increase in cortisol levels in response to IL-2 was neutralised by IL-3. The increase in lymphocyte, T lymphocyte, natural killer (NK) cell, activated T lymphocyte and eosinophil mean number was significantly higher during IL-3 plus IL-2 than during IL-2 alone. Episodes of fever, asthenia, anorexia, vomiting, anaemia and thrombocytopenia were significantly more frequent in patients receiving IL-2 alone than in those treated with IL-3 and IL-2. This preliminary study would suggest that IL-3 may improve the tolerability of IL-2 immunotherapy and enhance the biological antitumour properties of IL-2 by neutralising cortisol increase and macrophage-mediated suppressive events, with a following potential amplification of Il-2 anticancer efficacy.

Objective: A phase 2 study to evaluate the effects of a short preoperative course of interleukin-2 (IL-2) on the postoperative course of patients with cancer., Design: Open study., Setting: San Gerardo Hospital, Monza, Italy., Subjects: 16 Consecutive patients with locally advanced colorectal cancer, with or without metastases., Intervention: IL-2 in a dose of 9 x 10(6) IU/m2 twice daily for three days; patients were operated on within 36 hours of the cessation of IL-2 treatment., Main Outcome Measures: Morbidity, mortality, and changes in numbers of lymphocytes, T lymphocytes, natural killer (NK) cells, and CD25 (cluster of determination) positive cells., Results: There was no morbidity or mortality--in particular, there were no infections even in the patients who were at highest risk. The mean numbers of lymphocytes, T lymphocytes, NK cells, and CD25 positive cells increased significantly during the postoperative period. All patients showed evidence of infiltration of lymphocytes or eosinophils (or both) into the tumour tissue., Conclusions: The results suggest that a three day course of IL-2 preoperatively is well tolerated, stimulates would repair, neutralizes the lymphocytopenia induced by major operation, and induces immune cells to infiltrate the tumour. Randomised studies are needed to confirm these results.

On the basis of our previous preliminary data which showed that the pineal hormone melatonin (MLT) may potentiate IL-2 activity and reduce the dose of IL-2 required to determine an effective host antitumor response, we performed a clinical study with low-dose IL-2 given once/day subcutaneously (3 million IU/day for 6 days/week for 4 weeks) in association with MLT (50 mg/day orally at 8.00 p.m. every day) as a second-line therapy in metastatic colorectal cancer patients pretreated with 5-fluorouracil. Evaluable patients were 13/14, and most of them showed disseminated liver metastases. No objective tumor regression was seen. A stabilization of disease was achieved in 4/13 patients (median duration 5+ months), and the other 9 patients progressed. Mean number of lymphocytes and eosinophils significantly increased during the treatment. Moreover, the mean increase in lymphocyte number was significantly higher in patients with stable disease than in those with progressive disease, whereas there was no difference as regards eosinophils. Serum levels of neopterin and tumor necrosis factor (TNF) significantly increased during therapy, and TNF increase was correlated to the side effects rather than to the control of cancer development. This study shows that neuroimmunotherapy with low-dose interleukin-2 and MLT, even though capable of determining an evident expansion of immune cells involved in host antitumor response, does not seem to be effective in terms of tumor regression in metastatic colon cancer patients pretreated with 5-fluorouracil.

It has been observed that neopterin, a specific marker of macrophage activation, increases during cancer immunotherapy with IL-2, and this effect is mediated by interferons produced by IL-2-stimulated lymphocytes. Moreover, our previous studies have shown that neopterin rise during IL-2 immunotherapy is associated with an enhanced release of soluble IL-2 receptor (SIL-2R), which may suppress IL-2-dependent immune functions. This finding would suggest that neopterin increase may be related to the generation of suppressive events, which occur during IL-2 immunotherapy. On the basis of the documented modulatory effect of IL-3 on macrophage functions, we have evaluated the influence of IL-3 on neopterin secretion during IL-2 immunotherapy. The study was performed in advanced lung cancer patients. We have investigated 9 immunotherapeutic courses consisting of IL-2 (6M IU/day s.c. for 5 days/week for 3 weeks) plus IL-3 (1 microgram/(kg x day) i.v. for 14 days, starting 7 days before IL-2). The results were compared to those found during 18 courses with IL-2 alone. Mean neopterin levels increased significantly during IL-2 alone, but not in response to IL-3 plus IL-2. SIL-2R rise was significantly higher during IL-2 than during IL-3 plus IL-2. Mean numbers of NK cells and activated lymphocytes increased significantly in both groups of patients, but were significantly lower at the end of the treatment in patients receiving IL-2 alone than in those treated with IL-3 plus IL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

The simultaneous occurrence of breast cancer and pregnancy is rare. Little data are available about cytostatic treatment in patients with breast cancer during pregnancy. We report on a 31-year-old woman with a 28-week pregnancy and a T3 N+ Mx breast cancer treated with weekly doxorubicin chemotherapy. This was a well tolerated treatment without toxicity or complications for the mother. A partial response of the tumor was observed after 4 treatment courses. A normal baby was delivered. Doxorubicin and its metabolites were not detected in amniotic fluid collected through amniocentesis. Macroscopic and pathologic examinations of the placenta were normal. Although larger experiences are needed, weekly doxorubicin seems to yield satisfactory results without additional risks of fetal distress or malformations when given in women during the second and third trimester of pregnancy.

Recent experiments have shown that a great variety of neurohormones can interact with IL-2 in the modulation of host antitumor immune response. On the basis of these data, a study was started to evaluate the effect of the pineal hormone melatonin (MLT) on IL-2-induced immune changes in cancer. The study included 30 advanced cancer patients. They were randomized to be treated with IL-2 at a dose of 3 million IU subcutaneously twice/daily (8.00 a.m. and 8.00 p.m.) for 6 days/week for 4 weeks, with IL-2 once/daily in the evening, with IL-2 once/daily plus MLT at 10 or at 50 mg/day. MLT was given orally at 8.00 p.m. Both IL-2 given twice daily and IL-2 given once daily and IL-2 given once daily in association with MTL induced a significant increase in mean number of lymphocytes, T lymphocytes, NK cells, CD25-positive cells and eosinophils, whereas the single administration of IL-2 alone was unable to determine a significant rise in the mean number of immune cells. Soluble IL-2 receptor and neopterin increase was significantly higher during IL-2 given twice/daily than during IL-2 plus MLT, while no difference was seen in TNF rise. This study would suggest that a single daily injection of low-dose IL-2 is able to efficiently activate the lymphocyte proliferation in cancer patients when it is given in association with the pineal hormone MLT.

It is known that several cytokines can exert hormonal effects. At present, no data are available about the possible influence of IL-3 on the endocrine system. In order to investigate the endocrine effects of IL-3 in humans, we have evaluated serum levels of cortisol, beta-endorphin, GH, PRL, FSH, LH, TSH and melatonin in response to intravenous injection of IL-3 at a dose of 1 mcg/kg b.w. at 6.00 p.m. The study was performed in 5 non-small cell lung cancer patients. GH increased significantly in response to IL-3. PRL showed a progressive decrease after IL-3 injection, but its variations were not statistically significant. All other hormones, including cortisol, were not affected by IL-3. This preliminary study shows that IL-3 may exert endocrine effects in humans, which would seem at variance with previously reported results on most other cytokines.

The stimulatory effect of IL-2 on cortisol rise represents an undesirable biological event during IL-2 cancer immunotherapy. At present, no cytokine has been proven to be able to counteract IL-2-induced cortisol increase. This study was carried out to evaluate the influence of IL-3 on IL-2 stimulation of cortisol secretion. Five lung cancer patients were investigated after IL-2 (3 x 10(6) IU s.c.), after IL-3 (1 mcg/kg b.w. i.v.) and after IL-3 plus IL-2, by administering IL-3 two hours before IL-2 injection. IL-2 significantly stimulated cortisol secretion. IL-3 alone had no effect on cortisol levels. The pretreatment with IL-3 completely neutralizes IL-2-induced cortisol release. These preliminary results would suggest that IL-3 may be associated with IL-2 during cancer immunotherapy to modulate the effect of IL-2 on the endocrine system.

Several interleukins and interferons have been proven to induce endocrine effects. On the contrary, only few data are available about the possible hormonal activity of hemopoietic growth factors. This study was carried out to evaluate the endocrine influence of GM-CSF in humans. The study included nine head and neck cancer patients, evaluated in basal conditions and after an acute subcutaneous injection of GM-CSF at a dose of 3 mcg/kg b.w., by determining serum levels of cortisol, growth hormone (GH), prolactin (PRL) and melatonin. Both cortisol and GH significantly increased in response to GM-CSF, while PRL, and melatonin were not influenced. This preliminary study shows that hemopoietic growth factors, as well as interleukins, may also play endocrine effects in humans.

TNF, a cytokine produced by macrophages, is able either to exert an antitumor activity, or to determine severe clinical complications, such as cachexia and septic shock. Increased blood levels of TNF have been described in cancer patients. The present study was performed to better define TNF secretion in patients with solid tumors. The study included 48 cancer patients (lung cancer: 22; colon cancer: 11; breast cancer: 10; renal cancer: 5), and among them 27 showed distant organ metastases. TNF serum levels were measured by IRMA method. The control group comprised 40 healthy subjects. TNF levels were also evaluated in relation to those of SIL-2R, whose increase seems to be associated with an unfavorable prognosis in cancer. High levels of TNF were seen in 27/48 (56%) patients. Mean levels of TNF were significantly higher in cancer patients than in controls. Moreover, within the cancer group, TNF mean values were significantly higher in metastatic patients than in those without metastases; the highest levels were observed in patients with visceral lesions as dominant metastasis sites. Finally, patients with high TNF concentrations showed significantly higher mean levels of SIL-2R than those with normal values. This study shows that the neoplastic metastatic disease is associated with an exaggerated TNF secretion.

The metastatic non-small cell lung cancer (NSCLC) still remains an untreatable disease, and the role played by chemotherapy has yet to be defined. The new immunotherapeutic strategies, such as interferon and IL-2, seem to be also less effective, since they generally determine only a stabilisation of disease. On the basis of previous experimental results suggesting a synergistic action between IL-2 and the pineal neurohormone melatonin (MLT), a study was started to evaluate the clinical efficacy and toxicity of a neuroimmunotherapeutic combination consisting of IL-2 plus MLT as a first line therapy in metastatic NSCLC. The study included 20 patients (adenocarcinoma: 10; epidermoid cell carcinoma: 7; large cell carcinoma: 3). MLT was given orally at a dose of 10 mg day-1 at 8.00 pm every day, starting 7 days before the onset of IL-2 administration. IL-2 was given subcutaneously at a dose of 3 x 10(6) IU m-2 every 12 h for 5 days/week for 4 weeks, corresponding to one cycle of immunotherapy. In responder patients or in those with stable disease, a second cycle was given after a rest-period of 21 days. A partial response was achieved in 4/20 (20%) patients. Ten other patients had a stable disease (50%), whereas the last six patients progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapeutic therapy with IL-2 and the pineal hormone MLT may represent a new effective and well tolerated treatment in metastatic NSCLC, with results comparable to those obtained with chemotherapy, but with an apparent lower biological toxicity.

Cytokines have recently appeared to be effective in the palliative therapy of neoplastic effusions. The present study was carried out to evaluate the efficacy and the tolerability of an intracavitary injection of IL-2 in patients with neoplastic effusion due to solid tumors. The study included 14 patients with cytologically positive effusion (pleura, 11; peritoneum, 2; pericardium, 1). Tumor histotypes were: mesothelioma, 5; non-small cell lung cancer, 3; breast cancer, 2; ovarian cancer, 2; cervix carcinoma, 1; unknown primary tumor, 1. The efficacy was evaluated according to the criteria of Paladine et al. (Cancer 38: 1903, 1976). An objective response was achieved in 10/14 (71%) patients (4 CR, 6 PR), with a median duration of 4 months (range, 2-8). No important toxicity was seen. This preliminary study showed that low dose IL-2 given intracavitarily is an effective and well-tolerated therapy in patients with neoplastic effusions.

It is known that major surgery may determine immunosuppression. This side effect might have a prognostic significance particularly in cancer patients, in whom the decrease in host defenses during the postoperative period could promote the proliferation of possible micrometastases. Since antitumor immune response is an IL-2-dependent phenomenon, a study was started to evaluate the effects of a preoperative injection of IL-2 on surgery-induced immune changes in cancer patients. The study included 12 colon cancer patients, treated subcutaneously with IL-2 at a dose of 9 x 10(6) IU/m2 twice daily for 3 consecutive days before surgery. Patients underwent surgery within 36 h from IL-2 interruption. The results were compared to those found in a control group of 18 colon cancer patients. Mean number of lymphocytes, T lymphocytes and NK cells significantly decreased after surgery in control patients; on the contrary, no postoperative decrease in immune cells was seen in IL-2 group. No anesthesiologic or surgical complication was seen in patients pretreated with IL-2 before surgery. This preliminary study would suggest that a preoperative therapy with IL-2 is an effective and well tolerated medical approach to neutralize surgery-induced immunosuppression in cancer patients.

At present, there is no effective medical therapy in metastatic nonsmall cell (NSC) lung cancer patients who progressed under a first-line chemotherapy containing cisplatin. Since recent data have demonstrated the antineoplastic properties and the lack of toxicity of the pineal hormone melatonin (MLT), a randomized study was designed to evaluate the influence of an MLT treatment (10 mg/day orally at 7.00 p.m.) on the survival time at 1 year from the progression under chemotherapy in respect to supportive care alone in a group of metastatic NSC lung cancer patients, who did not respond to a first-line chemotherapy containing cisplatin. The study includes 63 consecutive metastatic NSC lung cancer patients, who were randomized to receive MLT (n = 31) or supportive care alone (n = 32). The percentage of both stabilizations of disease and survival at 1 year was significantly higher in patients treated with MLT than in those treated only with supportive care. No drug-related toxicity was seen in patients treated with MLT, who, on the contrary, showed a significant improvement in performance status. This randomized study shows that the pineal hormone MLT may be successfully administered to prolong the survival time in metastatic NSC lung cancer patients who progressed under a first-line chemotherapy with cisplatin, for whom no other effective therapy is available up to now.

IL-2, in addition to its immunomodulating and antitumour properties, induces important systemic actions, including cardiovascular, neuroendocrine and metabolic effects. The present study was carried out to evaluate IL-2 effects on cholesterol metabolism. The study included 14 advanced cancer patients (renal carcinoma: ten; colon carcinoma: four), who received IL-2 subcutaneously at a dose of 1.8 x 10(6) IU ml-2 twice daily for 5 days/week for 6 weeks. Venous blood samples were collected 7 days before, on days 0, 3, 7, 14, 21, 42 of IL-2 therapy, and on days 14 and 28 of the rest-period. IL-2 induced a rapid and evident decrease in cholesterol levels, with a normalisation of its concentrations within 7 days in 10/10 hypercholesterolemic patients. The lowest mean levels of cholesterol were reached within the first 2 weeks; after that they still slowly increased. LDL-/HDL-cholesterol ratio was significantly reduced by IL-2 therapy. Cholesterol fall was associated with a marked increase in conjugated biliary acid levels. Finally, triglyceride values increased during IL-2 therapy, but not in a significant manner. These results, by showing that IL-2 exerts an evident and very rapid cholesterol-lowering activity, would represent a further demonstration of the physiological importance of cytokines in the control of cholesterol metabolism.

The concomitant induction of immunosuppressive events, at least in part mediated by macrophages, would represent one of the mechanisms responsible for the lower activity of IL-2 in vivo than in vitro. Since macrophages have recently appeared to be under neuroendocrine control, the present study was carried out to evaluate the effect of the pineal neurohormone MLT on IL-2-induced macrophage activation during cancer immunotherapy, by determining serum levels of neopterin, which is a specific marker of macrophage activity. The study included 21 advanced cancer patients (lung cancer: 12; renal cancer: 9), 10 of whom received IL-2 subcutaneous therapy alone (1.8 x 10(6) IU/m2 twice daily), or IL-2 plus MLT (10 mg/day orally at 8.00 P.M.). Neopterin levels increased in all patients during IL-2 immunotherapy, but neopterin mean peak was significantly higher in patients treated with IL-2 alone than in those who received IL-2 plus MLT. This preliminary study would suggest the possible use of neurohormones to modulate host antitumor immune response during cancer immunotherapy with IL-2.

Intravenous interleukin-2 (IL-2) administration has been shown to influence several hormonal secretions. The present study was carried out to investigate the endocrine effects of subcutaneous therapy with IL-2. Six patients with advanced renal cancer were studied. They were treated subcutaneously with IL-2 according to the schedule proposed by Atzpodien et al. Venous blood samples were collected at O-time and 1, 8 and 12 hours after the first IL-2 pulse of 9 X 10(6) IU/m2 at 8.00 a.m.; on a separate occasion, samples were collected during a saline infusion only. In each blood sample, serum levels of cortisol, beta-endorphin, GH, PRL, FSH, LH, TSH and the pineal hormone melatonin were measured by RIA. Both cortisol and beta-endorphin significantly increased after IL-2 injection. GH rose but not to a significant extent. PRL, FSH, LH and TSH did not change after IL-2. Finally, melatonin levels markedly decreased after IL-2 injection in the only 2 patients with elevated concentrations of this hormone before the start of immunotherapy. These results suggest that the endocrine effects of subcutaneous IL-2 therapy are similar to those previously described with intravenous administration.

Mitoxantrone (DHAD), an anthracenedione with antineoplastic properties similar to doxorubicin, was tested for therapeutic efficacy and for immunomodulating action on lymphocyte subsets in 16 metastatic breast cancer patients, 12 of whom had been previously treated with chemotherapy. DHAD was given intravenously at a dose of 14 mg/m2 every 21 days. To evaluate total T lymphocytes (CD3), T helper (CD4), and T suppressor/cytotoxic cells (CD8) and the CD4/CD8 ratio, venous blood samples were drawn before and after the first DHAD cycle. Moreover, in 8/16 patients, B lymphocytes (CD20), T suppressor cells (CD8+/CD57+), T cytotoxic cells (CD8+/CD57-), NK (CD16) and IL-2 receptor-expressing cells (CD25) were also measured at the same time. An objective tumor response was achieved in 5/16 (31%) patients and the response rate was significantly higher in patients pretreated with hormone therapy alone than in those pretreated with chemotherapy. No relation was found between clinical response and changes in the CD4/CD8 ratio. Neither the mean number nor the percentage of CD3, CDA and CD8 cells observed after DHAD were significantly different with respect to those seen before. In contrast, the mean number of T suppressor cells, B lymphocytes and CD25-positive cells was significantly lower after than before DHAD administration, whereas no difference was seen in NK cells. These results confirm in humans the immunomodulating properties of DHAD previously described in experimental conditions. However, the DHAD-induced changes in lymphocyte subsets do not seem to be related to the clinical response in breast cancer.

Recent observations have demonstrated that somatomedins, mainly insulin-like growth factor-I (IGF-I), are growth factors for non-small cell lung cancer (NSCLC). On the basis of this evidence, a study was started to evaluate serum levels of IGF-I in a group of untreated NSCLC patients. The study included 46 patients, 25 of whom had an operable tumor, while the other 21 showed distant organ metastases. IGF-I and GH serum levels were measured by RIA in each patient; moreover, in operable patients, hormonal detections were made either before, or 7 days after surgery. The control group comprised 38 age-matched healthy subjects. Mean serum levels of IGF-I were significantly higher in cancer patients with respect to controls, while no difference was seen in mean GH values. Moreover, patients with metastases showed significantly higher levels of IGF-I than the patients without. Within the operable group, patients with lung adenocarcinoma had higher levels of IGF-I than those with epidermoid cell carcinoma, but this difference was not significant. Finally, no significant difference in IGF-I mean values was seen before and after surgical removal of tumors. This preliminary study shows that NSCLC patients may present abnormally high levels of IGF-I. Because of the stimulating role of IGF-I on NSCLC growth, this evidence could play a role in the clinical course of neoplastic lung disease.

Surgically induced immunosuppression may play a role in cancer, because of the possible existence of micrometastases at the time of surgical removal of tumors. Antitumor immune reactions are mediated by interleukin-2 (IL-2). IL-2 acts on a specific IL-2 cell surface receptor; moreover, a soluble form of IL-2 receptor (sIL-2R) can be released in the blood. This study was carried out to evaluate the effect of surgery on sIL-2R serum levels in patients with operable solid tumors. A total of 48 patients with cancer and 11 controls who underwent major surgery for non-neoplastic disease were evaluated before and 7 days after surgery. Serum mean levels of sIL-2R were significantly higher after than before surgery in both the cancer and control groups. No correlation was seen between surgery-induced changes in sIL-2R and in T lymphocyte subsets. Because of its capacity of binding to IL-2, the increased blood concentrations of sIL-2R could reduce the IL-2 availability and negatively affect antitumor immune reactions.