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It is known that the pineal gland has some antitumor activity. Melatonin, its most important hormone, has been shown to inhibit tumor growth in vivo and in vitro. Moreover, some investigations have demonstrated an altered melatonin secretion in cancer patients. Despite these interesting data, clinical trials have never been carried out to evaluate the effects of melatonin on human neoplasms. The aim of this study was to draw some preliminary conclusions on melatonin therapy in advanced human neoplasms. Nineteen patients suffering from advanced solid tumors, which did not respond to standard therapies, entered the study. Performance status (PS) was 20 or less in 9 cases, and more than 20 in the other 10. Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period with lower doses in patients who had a remission, a stabilization of disease or an improvement in PS. Among patients with a PS higher than 20, a partial response was achieved in one case with cancer of the pancreas; moreover, 5 of 10 had stable disease, but the other 4 cases had a progression; an evident improvement of PS was obtained in 6 of the 10 cases. In contrast, among patients with a very poor PS, 7 of 9 died within the first 2 months of therapy. This preliminary study would suggest that melatonin may be of some value in treating cancer patients in whom standard antitumor therapies have failed, particularly in improving their PS and quality of life.

Both prolactin (PRL) and melatonin (MLT) (the most important pineal hormone) have been shown to play a role in regulating breast cancer growth. The present study was carried out to investigate the relationship between PRL and MLT secretions in human breast cancer. Twenty-four women with breast cancer, at clinical stage T1-2 N0-2 M0, were evaluated before and after radical mastectomy. As controls, 14 women who underwent surgery for reasons other than neoplastic disease were included in the study. PRL and MLT serum levels were measured by RIA before and 15 days after surgery. There were no significant differences in mean PRL serum levels between patients and controls; mean MLT serum values were significantly higher in patients than in controls. In no control subject was PRL affected by surgery. In contrast, 13/24 breast cancer women showed high PRL levels after mastectomy; the PRL rise induced by surgery was significantly higher in patients without axillary node involvement. MLT was not affected by mastectomy in 13 patients, whereas it was enhanced in 5 women and decreased in the last 6 cases. No significant correlation was seen between PRL and MLT changes induced by mastectomy. The present study shows that radical mastectomy influences PRL and MLT secretions, however, its clinical significance remains to be established.

Measurements of cell cycle kinetics have been found to correlate with the clinical course of patients with breast cancer. However, the thymidine labeling index and more rapid methods like flow cytometry remain complicated and costly. We assessed cell proliferation of 67 breast carcinomas by an immunoperoxidase procedure using a monoclonal antibody, Ki-67, which reacts with a nuclear antigen in proliferating cells. The percentage of Ki-67 positive cells ranged from 2% to 70 %. Tumors with high mitotic rate, high nuclear grade, high histologic grade, and negative estrogen receptors had statistically higher Ki-67 labeling rates. We found no significant differences between the Ki-67 labeling rate and other clinical (age at diagnosis, menopausal status) or pathologic (necrosis, fibrosis, vascular invasion, lymphatic invasion, cellular reaction, tumor size, lymph node metastases) features assessed. These results parallel previously reported data, and confirm that this immunohistochemical staining of breast carcinoma by Ki-67 monoclonal antibody can be considered a rapid and convenient method for assessing cell cycle kinetics. However, further studies, evaluating the correlation between Ki-67 labeling rate and prognosis are needed to better define the real usefulness of this analysis in clinical practice.

It is known that prolonged therapy with cytotoxic drugs may affect the endocrine system. The present study was carried out to establish whether administration of chemotherapeutic drugs acutely influences hypophyseal and pineal activities. Nineteen patients affected by solid tumors were included in the study, 5 of whom were treated with CMF, 4 with FEC, 4 with CEV, and 6 with CDDP. Cytotoxic drugs were intravenously administered. Venous blood samples were collected at zero time and at 30, 60, 120 and 180 min after drug administration. On a separate occasion, venous blood samples were drawn during a saline infusion only. In each sample FSH, LH, GH, PRL, TSH, Cortisol, melatonin and β-endorphin were determined by the RIA method. The only significant changes observed in this study were a rise in PRL and a decrease in β-endorphin after CDDP administration. Melatonin was enhanced after CDDP and CMF, and Cortisol decreased after CMF and FEC, but their variations were not statistically significant with respect to those seen during saline infusion.

Both activated normal and transformed lymphocytes produce not only cell-associated but also cell-free IL-2R. Evidence of high serum concentrations of IL-2R appears to serve as a tumor marker in patients with lymphomas On the contrary, the role of soluble IL-2R in solid neoplasms has still to be defined. This investigation was carried out to analyze soluble IL-2R production in human solid tumors. The study included 35 patients with solid tumors (12 without and 23 with metastases), 58 healthy subjects and 6 lymphoma patients. Among cancer patients, lung and breast carcinoma were the two most frequent neoplasms. In each subject or patient, serum levels of IL-2R were measured by using an enzyme immunoassay. Moreover, in 14/23 patients with metastatic solid tumors, lymphocyte subpopulations were also evaluated. Serum levels of IL-2R were significantly higher in the cancer patients than in the normal subjects. The patients with metastatic solid tumors showed significantly higher mean levels than those without metastases, and similar to those observed in the lymphoma patients. Finally, there was no correlation between serum levels of IL-2R and the T4/T8 ratio, which was reduced in 5/14 cancer patients. Further studies will be needed to establish if elevated concentrations of IL-2R in the serum can contribute to the immunoincompetence of patients with disseminated solid neoplasms.

Clinical studies have demonstrated an altered pineal function in cancer patients. Owing to the documented antineoplastic activity of the pineal gland, these anomalies could have a prognostic significance. This study was carried out to monitor changes in blood levels of melatonin, the most important pineal hormone, in relation to the clinical response to chemotherapy in human neoplasms. The study included 42 cancer patients of both sexes (breast cancer, 10; lung cancer, 13; colon cancer, 11; soft tissue sarcoma, 4; testicular cancer, 1; Hodgkin's disease, 1; peritoneal mesothelioma, 2). Melatonin serum levels were measured by radioimmunoassay before and 28 days after each cycle of chemotherapy. The results showed that, irrespectively of the type of tumor and chemotherapeutic regimen, 12/16 patients (75%) whose melatonin markedly enhanced after chemotherapy had an objective regression. In contrast, 2/26 patients only (8%) whose melatonin did not enhance after chemotherapy had a clinical response. The percentage of objective responses was statistically significantly higher in patients with a chemotherapy-induced melatonin increase than in those with no melatonin increase (p < 0.001). This study seems to demonstrate that melatonin determination can be used as a predictor of the objective response to chemotherapy in cancer patients. Moreover, it suggests that the antineoplastic effect of cytotoxic drugs may require participation of the pineal gland.

Endogenous opioid peptides have been seen to play a role in regulating immunity and tumor growth. This study was carried out to investigate opioid activity in human cancer. We evaluated by radioimmunoassay β-endorphin plasma levels on blood samples collected at 9.00 a.m. from 121 cancer patients and 42 healthy subjects. In 22 cancer patients and in 12 controls, β-endorphin circadian rhythm was also investigated. Finally, in 14 cancer patients and in 10 controls GH, PRL, FSH, LH and Cortisol serum levels were measured after the administration of a metenkephalin analogue, FK 33–824 (0.3 mg i.v.). No significant differences were seen in β-endorphin mean levels between cancer patients and normal subjects. Moreover, no differences were found between patients with or without metastases, nor between those with or without chronic pain. β-Endorphin circadian rhythm appeared to be altered in 16/22 cancer patients, and anomalous hormonal responses to FK 33–824 were seen in 13/14 patients. This study shows an altered opioid activity in human neoplasms, whose clinical significance remains to be determined.

Buserelin represents one of the main LHRH analogues. It appears to be effective in untreated metastatic breast cancer, whereas its activity in pretreated advanced patients remains to be established. To evaluate endocrine and clinical effects of buserelin in pretreated advanced mammary carcinoma, 14 postmenopausal women with metastatic breast cancer, which had been previously treated with hormones and/or chemotherapy, entered the study. Buserelin was subcutaneously injected at a daily dose of 1.5 mg for 7 days, then intranasally at a daily dose of 1.2 mg until progression. Before and after the 7 days of subcutaneous administration of the LHRH analogue, FSH, LH, estradiol, testosterone basal serum levels, and PRL response to TRH were examined. After the 7 days of buserelin subcutaneous injection, a significant decrease in FSH, LH and estradiol values was observed, whereas testosterone was not affected. PRL response to TRH did not change after buserelin subcutaneous treatment in 8 patients, it decreased in one and was completely abolished in the last 5 cases. All patients whose PRL response to TRH did not decrease had a progression within the first month of therapy, whereas only 1 of 6 patients whose PRL response to TRH was reduced or abolished following buserelin administration showed a progression. Among the other 5 cases, 2 minor responses and 3 stable diseases were achieved. These preliminary results suggest that buserelin has only a limited effectiveness in metastatic breast cancer patients who have been previously treated with hormones and/or chemotherapy, and that its activity in the control of tumor growth is associated with a reduction in PRL secretion.

While prolactin (PRL) has been shown to stimulate the development of mammary carcinoma in several animal species, its role in human breast cancer remains to be established. To further investigate PRL secretion in human breast cancer, its basal levels and response to thyrotropin-releasing hormone (TRH) were evaluated in 16 patients (6 with no metastases and 10 with metastatic locations). The control group consisted of 19 healthy women. High PRL basal concentrations were seen in 2 patients only; no significant differences were found between the other patients and the normal subjects. The PRL increase induced by TRH administration was significantly higher in patients than in controls. Finally a change in the hormonal secretion was found after chemotherapy in 3 of the 5 patients in whom PRL response to TRH was evaluated either before or 10-12 days after a cycle of intravenous CMF adjuvant chemotherapy. These results demonstrate the existence of an exaggerated response of PRL to TRH in patients with breast cancer, even in the presence of normal basal levels. Moreover, they would seem to suggest a possible influence of CMF on PRL response to TRH stimulation.

To investigate the function of the hypothalamic-hypophyseal-gonadal axis in testicular germ cell tumors, we evaluated gonadotropin responses to gonadotropin-releasing hormone (GnRH) in 12 untreated patients with testicular cancer (5 seminomas and 7 non-seminomas). GnRH was given i.v. at a dose of 100 μg as a bolus, and venous blood samples were collected at 0, 20, 60, and 120 min. As controls, 14 healthy males were studied. Basal levels of testosterone, estradiol and prolactin were also detected in each patient. Hormonal serum concentrations were measured by the radioimmunoassay. Mean basal testosterone, estradiol and prolactin levels were not significantly different from those of controls. Patients had a lower FSH and LH peak after GnRH than controls, without, however, any significant difference. As regards histology, nonseminoma patients lacked an FSH response to GnRH and had statistically lower mean peak levels than controls. Moreover, non-seminoma patients had statistically lower mean peak values of LH after GnRH than controls. These data show that patients with testicular germ cell tumor, and more particularly those with non-seminomas, have an altered function of the hypothalamic-hypophyseal-gonadal axis, which is already present prior to therapy. Further studies, particularly in stage I patients treated only with orchiectomy, should be performed to confirm and better define the Physiopathologic significance of the altered hypothalamic-hypophyseal-gonadal axis in testicular cancer and to clarify the alteration of fertility, which is frequently present before treatment.

This is the eighteenth case of testicular tumor in a father and son reported in the literature. The father had a seminoma and the son an embryonal carcinoma. The trend favoring more malignant tumors occurring at younger ages in the sons is confirmed by this report.

The mechanisms responsible for cancer cachexia have not yet been clarified. To further investigate the role played by the hypothalamic-pituitary-thyroid axis in cancer cachexia, we evaluated serum levels of T3, FT3, T4, FT4, TSH and TBG in a group of 26 cancer patients, 14 of whom showed cachexia, whereas the other 12 had a body weight within the normal range despite their advanced diseases. As controls, 58 healthy subjects and 11 patients with benign weight loss were included in the study. Low levels of both T3 and FT3 were observed in all patients with benign weight loss and in 9/12 advanced cancer patients who had no cancer cachexia. On the contrary, only 4/14 cachectic cancer patients presented decreased values of T3 and FT3. Moreover, the mean serum levels of T3 and FT3 in cachectic oncologic patients were significantly higher than those seen both in non-cachectic cancer patients and in patients with benign weight loss. Since T3 is the biologically active thyroid hormone, the lack of a decrease in its production might play a role in the pathogenesis of cancer cachexia.