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Biomedical subjects

F Brivio

Publications and source records attributed to F Brivio.

86 records · Page 5Linked to original sources
PubMedDate not supplied

Neuroimmunotherapy of human cancer with interleukin-2 and the neurohormone melatonin: its efficacy in preventing hypotension.

The pineal hormone melatonin (MLT) has been shown to influence many biological functions, including immune response, cancer growth and brain neurotransmitter contents. On the basis of its biological properties, a study was started to evaluate the influence of MLT on IL-2 immunotherapy toxicity. The study was carried out in metastatic renal cancer patients. Thirty-three 5-day courses of IL-2 at a daily dose of 3 x 10(6) Cetus U/m2 were randomized to consist of IL-2 alone or IL-2 plus MLT (10 mg/day orally at 8.00 p.m.). The frequency of episodes of severe hypotension was significantly greater during IL-2 alone than during IL-2 + MLT. Moreover, the depressive symptomatology occurred more frequently during IL-2 alone. No other toxicity, including capillary leak syndrome, vomiting and fever, were significantly influenced by the concomitant treatment with MLT. These preliminary results would suggest that the pineal hormone MLT may be successfully associated with IL-2 in the immunotherapy of human tumors.

Circadian Rhythm↗
PubMedDate not supplied

Role of the pineal gland in the control of macrophage functions and its possible implication in cancer: a study of interactions between tumor necrosis factor-alpha and the pineal hormone melatonin.

Recent studies have shown the existence of reciprocal links between cytokine activity and immunomodulating neurohormones or neuropeptides. In particular, the pineal hormone melatonin (MLT) appears to influence IL-2 activity in cancer. The present study was performed to evaluate which interaction exists between MLT and another important cytokine, tumor necrosis factor-alpha (TNF), which is responsible for both antitumor cytolytic activity and cancer-related cachexia. In a first study, we analyzed MLT circadian rhythm under TNF administration (0.75 mg/day i.v. for 5 days) in 10 metastatic solid tumor patients. In a second study, we evaluated TNF serum levels in 10 metastatic solid tumor patients under therapy with MLT alone (20 mg/day orally in the evening for at least 1 month). In a third study, we have measured concomitantly daily serum levels of MLT and TNF in 30 patients with metastatic solid neoplasms. Nocturnal mean serum concentrations significantly increased in response to TNF injection. MLT therapy induced a significant decline in TNF mean values. Finally, patients with abnormally high MLT diurnal levels showed significantly lower TNF mean concentrations with respect to those with normal levels of the pineal hormone. This study, by showing the stimulatory effect of TNF on MLT secretion and the inhibitory action of MLT on TNF release, would suggest the existence of feed-back mechanisms operating between the pineal gland and TNF released from macrophages in human neoplasms.

Adult↗
PubMedDate not supplied

A study of interactions among markers of macrophage functions in metastatic solid tumors: neopterin levels in relation to those of tumor necrosis factor-alpha and of soluble interleukin-2 receptors.

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.

Adult↗
PubMedDate not supplied

Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin.

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)

Adult↗
PubMedDate not supplied

Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.

Surgery-induced immunosuppression could influence tumor/host interactions in surgically treated cancer patients. Previous studies have shown that high-dose IL-2 preoperative therapy may neutralize surgery-induced lymphocytopenia. Moreover, experimental studies have demonstrated that the immunomodulating neurohormone melatonin (MLT) may amplify IL-2 activity and reduce its dose required to activate the immune system. On this basis, we have compared the immune effects of presurgical therapy with high-dose IL-2 with respect to those obtained with preoperative neuroimmunotherapy consisting of low-dose IL-2 plus MLT. The study included 30 patients with gastrointestinal tract tumors, who were randomized to undergo surgery alone, or surgery plus a preoperative biotherapy with high-dose IL-2 (18 million IU/day subcutaneously for 3 days) or low-dose IL-2 (6 million IU/day subcutaneously for 5 days) plus MLT (40 mg/day orally). Patients underwent surgery within 36 hours from IL-2 interruption. Both IL-2 plus MLT were able to prevent surgery-induced lymphocytopenia. However, mean number of lymphocytes, T lymphocytes and T helper lymphocytes observed on day 1 of postoperative period was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. Moreover, toxicity was less in patients treated with IL-2 and MLT. This biological study shows that both immunotherapy with high-dose IL-2 or neuroimmunotherapy with low-dose IL-2 plus MLT preoperatively are tolerated biotherapies, capable of neutralizing surgery-induced lymphocytopenia in cancer patients. Moreover, the study would suggest that the neuroimmunotherapy may induce a more rapid effect on postoperative immune changes with respect to IL-2 alone.

Adult↗
PubMedDate not supplied

Relation between macrophage and T helper-2 lymphocyte functions in human neoplasms: neopterin, interleukin-10 and interleukin-6 blood levels in early or advanced solid tumors.

At present, it is known that there are two main mechanisms responsible for cancer-related immunosuppression, mediated by macrophages and by TH2 lymphocytes. The relation existing between macrophage- and TH2-mediated immunosuppression still remains to be understood. The present study was performed in an attempt to establish which is the correlation existing in cancer patients between IL-10 and neopterin levels, which reflect TH2- and macrophage-mediated suppressive events, respectively. The study included 40 solid tumor patients and 60 healthy subjects as controls. Serum concentrations of neopterin and IL-10 were measured by the RIA method and by an immuno-enzymetric assay, respectively. Because of its possible production both by TH2 and macrophages, serum levels of IL-6 were also determined. Neopterin, IL-10 IL-6 mean concentrations were significantly higher in cancer patients than in controls. Mean values of both neopterin and IL-6 were significantly higher in metastatic patients than in those with locally limited disease. IL-10 mean levels were also significantly higher in patients with metastatic disease. IL-6 levels were significantly correlated with those of neopterin, whereas no correlation was found between neopterin and IL-10 values. This preliminary study would suggest that macrophage- and TH2-mediated immunosuppression may occur independently in solid tumors, and that it becomes more evident with disease progression.

Adult↗
PubMedDate not supplied

Neuroimmunotherapy with low-dose subcutaneous interleukin-2 plus melatonin in AIDS patients with CD4 cell number below 200/mm3: a biological phase-II study.

A phase-II pilot clinical study was performed to evaluate the effects of low-dose subcutaneous IL-2 with the pineal hormone melatonin (MLT) in AIDS patients with CD4 counts below 200/mm3. The study included 11 patients. IL-2 was given subcutaneously at 3 million IU/ day in the evening for 6 days/week for 3 weeks. MLT was given orally at 40 mg/day in the evening every day, starting 7 days prior to IL-2. The treatment was substantially well tolerated, and in particular no cardiovascular or pulmonary complication occurred. An increase in CD4 cell number greater than 30% occurred in 4/11 (36%) patients, and CD4 cell mean values observed during the study were significantly higher with respect to those found before. In addition, the treatment induced a significant increase in mean number of lymphocytes, eosinophils, T lymphocytes, NK cells, CD25- and DR-positive lymphocytes. Finally, CD4/CD8 mean ratio significantly increased during the study. This preliminary clinical study suggests that the combined neuroimmunotherapy with low-dose subcutaneous IL-2 and MLT may improve the immune status also in AIDS patients with CD4 cell counts below 200/mm3, who generally do not respond to IL-2 alone.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Treatment of cancer-related thrombocytopenia by low-dose subcutaneous interleukin-2 plus the pineal hormone melatonin: a biological phase II study.

Despite the platelet production in response to IL-2, cancer immunotherapy with IL-2 tends to induce thrombocytopenia, which probably depends on an enhanced peripheral destruction. On the basis of our previous studies, this effect may be neutralized by a concomitant administration of the pineal hormone melatonin (MLT). This study was performed to investigate the influence of an immunotherapeutic combination with low-dose IL-2 and MLT on platelet number in advanced cancer patients showing persistent thrombocytopenia. The study included 14 advanced solid tumor patients, affected by thrombocytopenia due to different causes (portal hypertension: 9; previous chemotherapies: 3; DIC: 2). IL-2 was injected at 3 million IU/day subcutaneously for 6 days/week for 4 weeks, in association with MLT (40 mg/day orally). A normalization of platelet number occurred in 10/14 (71%) patients, and platelet mean number significantly increased on treatment. No important therapy-related toxicity was observed. This preliminary study would suggest that the concomitant administration of MLT is able not only to neutralize IL-2-induced thrombocytopenia, but also to increase platelet number in thrombocytopenic cancer patients.

Adult↗
PubMedDate not supplied

Interleukin-2, melatonin and interleukin-12 as a possible neuroimmune combination in the biotherapy of cancer.

Suppressive events induced by macrophages and TH2 lymphocytes would represent the most important factors responsible for the in vivo reduced efficacy of IL-2 cancer immunotherapy. Previous studies have shown that IL-3 or the pineal hormone MLT may abrogate macrophage-related suppressive events during IL-2 immunotherapy, while TH2-mediated immunosuppression is not neutralized by MLT or IL-3. On the basis of previous experimental data suggesting the inhibitory effect of IL-12 on TH2 activation, this preliminary study has been performed in an attempt to evaluate the influence of IL-12 on TH2 stimulation induced by IL-2 alone or IL-2 plus MLT, by evaluating the release of IL-10, which represents the main suppressive factor produced by TH2 lymphocytes. Pure lymphocyte cultures were incubated for 4 days with IL-2 (100 Cetus U/ml), MLT (100 pg/ml), IL-12 (1 ng/ml), IL-2 plus MLT, IL-2 plus IL-12 or IL-2 plus MLT and IL-12. Mean medium concentrations of IL-10 were measured by Elisa. IL-2 alone significantly stimulated IL-10 secretion with respect to the control medium alone, while no difference was observed with MLT alone or IL-12. IL-2-induced stimulation of IL-10 secretion was not abrogated by a concomitant MLT incubation. On the contrary, IL-12 significantly diminished IL-10 release in response to IL-2, and this inhibitory effect was more pronounced when IL-2 was added in association with both IL-12 and MLT. This preliminary study would suggest that the two most important immunosuppressive events occurring during IL-2 therapy, which are mediated by macrophages and TH2-lymphocytes, may be abrogated by a concomitant administration of MLT and IL-12, respectively. Therefore, the association of IL-12 could further amplify IL-2 efficacy with respect to IL-2 alone or IL-2 plus MLT.

Humans↗
PubMedDate not supplied

Clinical significance of erythrosedimentation rate in cancer in relation to cytokine production: correlation with high IL-6 and low IL-2 blood concentrations.

Despite its well documented unfavourable prognostic significance in several human diseases, including cancer, the cytokinic mechanisms responsible for an increased erythrosedimentation rate (ESR) still remain to be better analyzed and defined. The recent possibility to measure cytokine concentrations in the blood of patients has allowed us to explore the possible relation between ESR values and endogenous cytokine secretions. This preliminary study was performed to evaluate the relationship between ESR values and serum levels of IL-2 and IL-6, which represent the most important cytokines responsible for the activation and the suppression, respectively, of host anticancer immune reaction. The study included 33 consecutive solid tumor patients, 22 of whom showed distant organ metastases. Abnormally high values of ESR were present in 21 patients, including 18/22 metastatic patients and 3/11 nonmetastatic patients. Patients with elevated values of ESR showed significantly higher mean levels of IL-6 and significantly lower mean concentrations of IL-2 with respect to those found in patients with normal ESR values. These results would show that cancer-related increase in ESR values is associated with low levels of IL-2 and high levels of IL-6. Since IL-2 plays an essential role in the anticancer immunity and IL-6 may suppress the antitumor immune defenses, the evidence of low levels of IL-2 and high values of IL-6 in cancer patients with increased ESR values would explain the unfavourable prognostic significance of high ESR values in human neoplasms.

Adult↗
PubMedDate not supplied

Melatonin as a new possible anti-inflammatory agent.

Several experiments have suggested that the pineal hormone melatonin (MLT) may regulate cancer growth by exerting both oncostatic and immunomodulating effects. In particular, MLT would stimulate the anticancer immunity induced by interleukin-2 (IL-2). Recent studies seem to suggest that the activation of the inflammatory response may counteract the anticancer efficacy of IL-2 immunotherapy because of the immunosuppressive action of inflammatory-related cytokines, mainly IL-6. At present, it is still unknown whether MLT may influence host immune antitumor defences by modulating the inflammatory response. To analyze this hypothesis, we have evaluated the effects of a chronic administration of MLT on some of the commonly used markers of inflammation, including erythrosedimentation rate (ESR), IL-6, neopterin and SIL-2R, in patients with evidence of activation of the inflammatory response due to advanced solid neoplasms or auto-immune diseases. The study included 14 patients (solid tumors: 9; autoimmune diseases: 5). MLT was given orally at 20 mg/day during the dark phase of the day for 7 consecutive days. Mean serum levels of IL-6, neopterin and SIL-2R significantly decreased in both groups of patients. ESR values also decreased on therapy, without, however, significant differences. This preliminary study shows that the pineal hormone MLT may inhibit the acute inflammatory reaction. Therefore, because of the immunosuppressive section of inflammation-related cytokines, this study could suggest that MLT may contribute to the generation of the immune reaction against cancer at least in part by removing the immunosuppression related to the activation of the inflammatory response.

Adjuvants, Immunologic↗
PubMedDate not supplied

Physiopathology of IL-12 in human solid neoplasms: blood levels of IL-12 in early or advanced cancer patients, and their variations with surgery and immunotherapy.

Experimental studies have shown that IL-12 plays an important role in the activation of the anticancer immune defenses. Unfortunately, at present the behavior of IL-12 secretion in human neoplasms remain to be established. In an attempt to draw some preliminary data about IL-12 secretion in human cancer, in the present study we have evaluated serum levels of IL-12 in a group of non-metastatic and metastatic solid tumor patients in relation to the survival time, and their changes in surgically treated cancer patients and in metastatic patients undergoing immunotherapy with IL-2. Mean serum levels of IL-12 were significantly higher metastatic patients (n = 40) than in those with locally limited solid neoplasm (n = 16). Moreover, within the metastatic group, the percent of 1-year survival was significantly higher in patients with abnormally elevated blood concentrations of IL-12 than in those with normal values. In the group of 10 patients surgically treated for gastrointestinal tract tumors, the surgical operation induced a significant decline in IL-12 mean serum levels. Finally, in a group of 23 metastatic renal cell cancer patients treated with IL-12 immunotherapy (6 million IU/day S.C. for 6 days/week for 4 weeks), the treatment was associated with a significant and progressive increase in IL-12 mean values. Moreover, serum mean levels of IL-12 observed in therapy in patients with response or stable disease were significantly higher than those found in progressing patients. This preliminary study seems to suggest that the evidence of high levels of IL-12 may have a favourable prognostic significance in solid tumor patients, either in baseline conditions or in response to IL-2 cancer immunotherapy.

Adult↗