[Variations in interleukin-2 and interleukin-6 due to surgical trauma in cancer patients]. / Variazioni di interleuchina-2 e interleuchina-6 da trauma chirurgico in pazienti oncologici.

Inflammatory response after surgical trauma, which is necessary for infection control and tissue repairing, can actually produce some cytokines suppressive of the antitumoral immunity response. In this study the authors evaluate pre- and post-operative IL-2 (antitumor response activator) and IL-6 (lymphocytic response inhibitor and tumor growth factor) levels in 26 cancer patients undergoing resective surgery. Analysis of the results showed a significative IL-6 increase and a tendency to IL-2 decrease in the post-operative period. It is thus confirmed, even on the basis of the cytokines, the meaningful immunosuppressive effect of the surgical trauma on neoplastic growth control.

Circadian secretions of IL-2, IL-12, IL-6 and IL-10 in relation to the light/dark rhythm of the pineal hormone melatonin in healthy humans.

It has been demonstrated that cytokine activities are under neuroendocrine control, recently mainly exerted by the pineal gland through the circadian secretion of its main hormone melatonin (MLT). It is mainly released during the night, but at present it is still unclear which relation exists between MLT and the circadian secretion of cytokines. This study was performed to evaluate the circadian secretion of IL-2, IL-6, IL-10 and IL-12 in relation to that of MLT. The study included 10 healthy volunteers whose venous blood samples were collected at 8 a.m., noon, 4 p.m., 8 p.m., 1 a.m. and 4 a.m. The mean levels of MLT were significantly higher during the night than during the light phase of the day. Similarly, IL-2 mean levels significantly increased during the night. IL-6 mean values were higher during the light period of the day without, however, any significant differences with respect to the nocturnal mean levels. Finally, no substantial circadian variation was seen in IL-10 and IL-12 mean concentrations. These results show that IL-2 secretion increases during the night, concomitantly to that of the pineal hormone MLT, whereas there is no evidence of a circadian secretion for the other cytokines. Since the pineal gland has been proven to stimulate IL-2 endogenous production, the nocturnal increase in IL-2 blood concentrations could depend at least in part on the promoting action of MLT, whose release increases during the dark period of the day.

[Hernioplasty using a Lichtenstein polypropylene mesh]. / Ernioplastica con rete in polipropilene sec. Lichtenstein. Risultati a distanza.

"Tension free" technique with prosthetic mesh for inguinal hernia repair was introduced since 1988 in Authors' Institution. In a review of 98 hernioplasties performed, only one relapse was observed (around 1%), while prosthetic infection cases were never observed. The disorder most frequently complained by the patients is a pain in the pubic area, persisting even months after the operation. Therefore this technique seems to be reliable, safe, and easy. While waiting for a long-term follow up to confirm these results, the Authors however suggest to limit the indications for this technique avoiding the use of prosthetic material in young patients since Shouldice's hernioplasty assures a low percentage of relapse for them.

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.

Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma.

Several experimental studies have shown that melatonin has an oncostatic action, either by stimulating host antitumor immune defenses or by directly inhibiting the growth of some cancer histotypes, including melanoma. Our previous clinical studies demonstrated that melatonin may induce stabilization of the disease in untreatable metastatic solid tumor patients, and these results have been confirmed by others, at least in patients with metastatic melanoma. On the contrary, at present there are no data related to the possible efficacy of melatonin as an adjuvant endocrine therapy. This study was performed to investigate the impact of melatonin therapy on the disease-free survival (DFS) in melanoma patients surgically treated for regional node recurrence. The study included 30 node-relapsed melanoma patients, who were randomized to receive no treatment or adjuvant therapy of melatonin (20 mg/day orally in the evening) every day until disease progression. After a median follow up of 31 months, the percent of DFS was significantly higher in melatonin-treated individuals than in controls. The DFS curve was also significantly longer in melatonin group than in controls. No melatonin-related toxicity was observed. This preliminary study suggests that an adjuvant endocrine therapy with melatonin may be effective in preventing disease progression in node-relapsed melanoma patients.

Pre-operative interleukin-2 immunotherapy induces eosinophilic infiltration in colorectal neoplastic stroma.

Interleukin-2 (IL-2) may induce peripheral eosinophilia and this phenomenon is related with response to IL-2 immunotherapy in patients with metastatic renal cell carcinoma. In previous experiences is reported that preoperative course with IL-2 may reverse the surgery-induced immunosuppression. This study's objective is to evaluate the histological changes of inflammatory infiltration in tumour stroma, in patients pretreated with IL-2 immunotherapy. 7 patients admitted to our surgical department with resectable recurrent colorectal cancer were treated with pre-operative course of IL-2; the tissue samples were analyzed for eosinophilic and inflammatory infiltration and compared with the samples obtained in the primary operation, performed without immunotherapy. In all patients were observed an increase of eosinophilic infiltration in tumour tissue. The mean increase were 200%, with high statistical significance (p < 0.0001). IL-2 pre-operative immunotherapy is able to change the interaction between host and tumour, by modifying the histological inflammatory infiltration in colorectal cancer tissue.

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.

Preoperative neuroimmunotherapy with subcutaneons low-dose interleukin-2 and melatonin in patients with gastrointestinal tumors - its efficacy in preventing surgery-induced lymphocytopenia.

Our previous studies have shown that a preoperative injection of high dose IL-2 is able to abrogate surgery-induced immunosuppression in colorectal cancer patients. Moreover, our previous clinical investigations have indicated the possibility of amplifying IL-2 activity by a concomitant administration of the pineal immunomodulating hormone melatonin (MLT). On this basis, a biological study was performed to investigate the immune effects of a preoperative biotherapy consisting of low-dose IL-2 plus MLT in patients with gastrointestinal tumors. The study included 20 consecutive patients with gastrointestinal tract tumors, who underwent radical or palliative surgery. Patients were randomized to receive no preoperative treatment or a presurgical neuroimmunotherapeutic regimen consisting of low dose of IL-2 and MLT. IL-2 was injected subcutaneously at 3 million IU twice/day for 5 days in combination with MLT at 40 mg/day in the evening. Patients underwent surgery within 36 h from the last IL-2 injection. The mean number of lymphocytes, T lymphocytes and NK cells significantly decreased during the postoperative period in control patients, whereas it increased in patients pre-treated by immunotherapy. CD25-positive mean cell number increased in both groups of patients; however, postoperative mean number of CD25 expressing cells was significantly higher in patients pretreated with IL-2 and MLT than in controls. No immunotherapy-related toxicity occurred. This preliminary study would suggest that a neuroimmunotherapeutic regimen with low-dose IL-2 and MLT given preoperatively is a well tolerated therapy, which is able to prevent surgery-induced lymphocytopenia in cancer patients. This perioperative manipulation of host anticancer defenses could have a prognostic role in the clinical course of the neoplastic disease.

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.