Retinal detachment and convexity intracranial meningioma: an uncommon association.

CASE REPORT: A 70-years-old woman presented with a one week history of progressive loss of vision in the right eye (RE) diagnosed as retinal detachment from 7 to 1 o' clock with retinal break at the 10.30 o' clock associated. Gadolinium enhanced magnetic resonance imaging (MRI) scan of the brain and orbits with fat suppression showed a convexity meningioma. Scleral buckling with a segmental sponge, subretinal fluid drainage and cryopexy were performed with detachment repair. CONCLUSION: In our patient with retinal detachment and convexity meningioma without significant neurological symptoms, performing ocular surgery and close follow up care seemed to be the optimal treatment option.

Relation between lymphocyte subpopulations and pineal function in patients with early or metastatic cancer.

It has been demonstrated that melatonin and other pineal hormones play a role in the neuroendocrine control of immunity. Anomalies of both pineal and immune functions have been reported in cancer. Pineal and lymphocyte functions, however, have never been simultaneously evaluated in oncologic patients. This preliminary study was carried out in order to analyze the melatonin-lymphocyte relationship in human neoplasms. In a first investigation, we evaluated melatonin serum levels and lymphocyte subpopulations on venous blood samples collected during the morning from 46 healthy controls and from 27 cancer patients, 13 of whom had metastases, while the other 14 were without metastases. Moreover, melatonin levels were high in 10 oncological patients and within the normal range in the other 17 cases. B lymphocyte (B), total T lymphocyte (T3), T helper/inducer (T4) and T suppressor/cytotoxic (T8) mean percentages and T4/T8 mean ratios did not significantly differ, either between patients with high and normal melatonin levels, or between metastatic and nonmetastatic cancer patients. In a second study, we evaluated the effects of a prolonged treatment with melatonin (20 mg/daily intramuscularly at 3:00 p.m. for 2 months) on 8 patients with advanced cancer, in whom conventional antitumor therapies had failed. Mean percentages of B, T3, T4, T8 lymphocytes and T4/T8 mean ratios were not significantly different before or after melatonin treatment. In only one patient did the T4/T8 ratio decrease after therapy; in this case only, a stabilization of the disease was obtained, while in all 7 other patients the neoplastic disease progressed also during melatonin treatment, even if an evident improvement of the performance status was seen as it was in most cases. These results seem to exclude that melatonin may influence lymphocyte functions in cancer. Longitudinal studies and further data, however, will be needed to clarify this question.

Serum levels of melatonin in cancer patients and their relation to body sizes.

Melatonin secretion is often enhanced in patients with cancer. In the light of a reported correlation between melatonin levels and body size, we investigated blood levels of this pineal hormone in a group of 72 patients affected by cancer, 30 of whom had body weight within the normal range, 30 were obese and the last 12 cases had body weight below the normal range, in order to establish whether in fact melatonin blood concentrations were related to body size. Melatonin levels were high in 19/72 patients (26%). The mean levels of the pineal hormone were similar in patients with normal, low and high body weight. Finally, there was no significant correlation between melatonin values and body weight, height or surface. Melatonin secretion thus does not appear to be influenced by body size in cancer patients.

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.

Melatonin circadian rhythm in anorexia nervosa and obesity.

The mean 24-hour secretion and circadian rhythm of melatonin were studied in 12 female subjects with anorexia nervosa (AN), 13 massively obese (OB) women, and 9 normal weight healthy volunteers to investigate the relationship between type of feeding behavior and hormonal secretory pattern. Blood samples for melatonin were drawn every 4 hours from 0400 h to 2400 h and every 2 hours from 2400 h to 0400 h. Mean 24-hour melatonin secretion was significantly higher in AN than in OB patients and controls. Melatonin circadian rhythms were disrupted in 8 of the 12 AN patients and in 9 of the 13 OB subjects, with phase-advanced nocturnal rises, abnormal diurnal peaks, or no nocturnal rises. The population mean cosinor analysis validated the existence of a significant circadian rhythm of the hormone in AN but not in OB subjects. No significant correlation between mean 24-hour secretion or type of circadian alterations and degree of weight deficit or excess was observed. The circadian alterations of melatonin in AN and OB may be linked to impaired secretory tonus of noradrenalin in the central nervous system, possibly unrelated to feeding patterns.

Correlation between changes in prolactin and melatonin serum levels after radical mastectomy.

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.

Clinical study of melatonin in untreatable advanced cancer patients.

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.

Alteration of opioid peptide circadian rhythm in cancer patients.

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 beta-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, beta-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 beta-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. beta-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.

Acute effects of various chemotherapeutic combinations on hypophyseal and pineal hormone secretions in cancer patients.

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 beta-endorphin were determined by the RIA method. The only significant changes observed in this study were a rise in PRL and a decrease in beta-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.

Action of morphine on melatonin release in the rat.

Some data from the literature raised the possibility of an interaction between the opioidergic system and pineal secretion. The present study was undertaken in order to investigate the acute influence exerted by opioids upon plasma melatonin levels in the albino rat. Different doses of morphine hydrochloride were injected (1, 1.5, 2, 3 mg/kg) intraperitoneally into anaesthetized adult male rats bearing a cannula previously inserted into the carotid. Blood samples were collected subsequently at 30-min intervals, within a period of 90 min following drug administration. Plasma melatonin contents were determined by a radioimmunoassay (RIA) method. Acute administration resulted in a dose-dependent increase in plasma melatonin concentration when compared to the respective controls. This effect is blocked by pretreatment with Naloxone. The present result seem to support the hypothesis that the opioidergic system, in certain circumstances, might contribute to the activation of melatonin secretion.

Effects of cephacetrile on reproduction cycle.

The research of possible effects of cephacetrile (Celospor) on the reproductive function was carried out on two animal species, rats and rabbits. The animals were divided into experimental groups, each treated subcutaneously with different amounts of cephacetrile (50, 100 and 500 mg/kg/die), control group receiving physiological solution. Effects of the preparation on fertility and post-natal growth in rats were analyzed, and trials were performed to test perinatal toxicity and teratogenesis in rabbits. From the observation of the experimental data collected it can be assumed that cephacetrile, administered subcutaneously in the given doses--1, 2 and 10 times, respectively, higher than the maximum therapeutic dose advisable--does not alter fertility, gestation and post-natal development of term foetuses of rats and fertility and gestation of rabbits.

Comparison of the rat pinealocyte ultrastructure with melatonin concentrations during daytime and at night.

The aim of this study was to investigate the ultrastructure of rat pinealocyte during daytime (1600 h) and at night (0100 h) and to compare these observations with serum melatonin levels in the same animals. In addition, pineal melatonin concentrations were determined in other animals. Both serum and pineal melatonin concentrations were significantly higher at night than during daytime (34 and 21 times, respectively). Sizes of pinealocytes, their nuclei, and nucleoli, as well as cross-sectional areas of mitochondria and granular endoplasmic reticulum were also higher at night than during daytime, whereas areas of lysosomes, Golgi apparatus, and vacuoles containing flocculent material did not differ at the time points studied. In contrast, the number of dense-core vesicles was higher during daytime. The results of the present study show that morphological patterns of higher metabolic activity of the rat pinealocyte at night when compared to those during daytime correlate with melatonin concentrations.

Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies.

The pineal hormone melatonin (MLT) is able to exert an oncostatic action. Its possible use in the treatment of human tumors, however, has not yet been investigated. The present study was carried out to evaluate the effects of MLT in patients with metastatic solid tumors resistant to conventional therapies. The study included 54 patients, most of them were affected by lung cancer or colorectal carcinoma. MLT was given intramuscularly at a daily dose of 20 mg at 3.00 p.m. for 2 months; this induction phase was followed by a maintenance period at a dose of 10 mg orally in responder patients or in those with an improvement in performance status (PS). The clinical response was as follows: 1 partial response (cancer of pancreas), 2 minor responses (colon cancer and hepatocarcinoma) and 21 with stable disease. The remaining 30 patients rapidly progressed within the first 2 months of therapy. An evident improvement in PS was achieved in 18 of 54 (33%) cases. These results, by showing an apparent control of the neoplastic growth and an improvement in the quality of life in a reasonable number of cancer patients for whom no other standard therapy is available, would justify further clinical trials to better define the impact of MLT therapy on the survival and quality of life of untreatable advanced cancer patients.

The pineal gland-opioid system relation: melatonin-naloxone interactions in regulating GH and LH releases in man.

Several observations have demonstrated that the opioid system can modulate melatonin secretion from the pineal gland and that the effects of opioids may require a pineal participation. In contrast, the role played by the pineal gland in regulating the synthesis and secretion of endorphins and enkephalins in still obscure. To establish whether the neuroendocrine activity of melatonin are mediated by endogenous opioids and to demonstrate a possible action exerted by the pineal gland on opioid peptides, GH and LH serum mean levels were evaluated by RIA in 12 healthy subjects of both sexes after melatonin injection alone (0.4 mg/kg bw im at 09:00 h) and on a separate occasion after a simultaneous administration of melatonin and naloxone (1.2 mg iv as a bolus, followed by an iv infusion of 1.6 mg/h for 3h). On an other occasion, the study was performed during saline or naloxone infusion alone. In each test, venous blood samples were collected at -20, 0, 30, 60, 90, 120 and 180 min. A significant rise of GH was observed after melatonin injection alone. The simultaneous infusion of naloxone blocked melatonin-induced GH rise. Melatonin did not affected LH serum levels, while it was able to reduce LH increase induced by naloxone. These preliminary results suggest that some neuroendocrine effects of melatonin might be mediated by a modulation on the opioid tone.

Melatonin and pituitary-gonadal function in disorders of eating behavior.

In order to study the possible relationships between melatonin secretion and pituitary-gonadal function, the circadian rhythm of plasma melatonin, the basal levels of estradiol-17beta and testosterone and the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) response to luteinizing hormone-releasing hormone (LH-RH) stimulation were evaluated in normally cycling healthy women and in two groups of women with menstrual dysfunctions related to eating disorders (19 patients with anorexia nervosa and 16 with primary obesity). The circadian rhythm of plasma melatonin reached statistical significance in anorectic patients but not in obese patients. The mean 24 h melatonin level was significantly higher in anorectic than in obese patients and in control subjects. However, both groups of patients shared some abnormalities of melatonin circadian pattern, such as increased ratio between day and night melatonin levels, abnormal secretory peaks during the light hours and great interindividual variability for timing, amplitude, and duration of melatonin nocturnal peak. A selective impairment of LH secretion was observed in both anorectic and obese patients. By considering together the two groups of patients and controls, a linear inverse correlation between the circadian mesor of plasma melatonin and the basal and LH-RH stimulated LH levels was found. The persistence of a certain melatonin secretion during the light hours in both anorectic and obese patients could play an inhibitory role on the pituitary gonadal function in these subjects.

Preliminary studies on melatonin in the treatment of myelodysplastic syndromes following cancer chemotherapy.

Experimental studies have suggested that the pineal hormone melatonin, in addition to its documented antineoplastic action, plays a role in the physiological regulation of blood cell proliferation. Based on these data, we evaluated the clinical effects of melatonin therapy in patients with myelodysplastic syndrome (MDS) secondary to cancer chemotherapy for primary neoplasms. The study was carried out on six patients, and melatonin was given orally at a dose of 20 mg/daily, following a schedule prepared to reproduce the circadian rhythm of the pineal hormone. A transient improvement in platelet and neutrophil count was achieved in two of five patients with thrombocytopenia and in two of four patients with neutropenia before therapy, respectively, while no effect was seen on hemoglobin concentration. Mean survival time was 12.5 months, and a long survival, greater than 30 months, was achieved in two of six patients. These preliminary results seem to suggest that melatonin may have a role in the treatment of MDS induced by previous cancer chemotherapy.

Plasma melatonin levels in psoriasis.

Melatonin is synthesized and secreted by the pineal gland. A daily rhythm of melatonin secretion, with high plasma values during the dark period, has been found in all vertebrates studied so far. In psoriatics, several hormones, including GH and prolactin, have altered chronobiology, and some studies in humans suggest that melatonin affects the levels of GH and prolactin. We investigated circadian melatonin rhythm in 13 male psoriatics and 13 healthy males with an RIA specific for measuring the hormone in plasma. Samples were taken at 6 a.m., 8 a.m., 12.00, 4 p.m., 8 p.m. and 2 a.m. Differences in (mean +/- SD) plasma melatonin levels were analysed by Student's t-test. Our results show that psoriatic patients had lost the nocturnal peak and usual circadian rhythm of melatonin secretion. Levels of melatonin were significantly lower than in controls at 2 a.m., and higher at 6 and 8 a.m. and at 12 noon. Further investigations of this disorder of melatonin secretion in psoriasis are needed to understand its significance.

The clinical significance of melatonin serum determination in oncological patients and its correlations with GH and PRL blood levels.

In order to investigate the pineal function and its relation with the hypophysis in human neoplasms, melatonin and GH serum levels were determined in 63 patients, 42 affected by solid tumours and 21 by lymphoma or leukaemia. In women with breast cancer PRL was also measured. Melatonin, GH and PRL were evaluated in 52 healthy subjects acting as controls. The oncological patients showed significantly higher mean melatonin serum levels than the control subjects. Mean melatonin values were lower in patients with solid tumours who had metastases, than in cases without metastases. Chemotherapy caused an evident decrease in melatonin levels. Surgery was followed by a fall in melatonin in patients without metastases. Mean GH serum levels observed in oncological patients were similar to those in control subjects and were not influenced by therapy. PRL levels were within the normal range in women suffering from breast cancer.

A clinical study on the relationship between the pineal gland and the opioid system.

Recent reports point to a link between the pineal gland and the opioid system. In order to investigate this relationship, two separate studies were performed on humans. Beta-endorphin plasma levels were determined after melatonin administration (0.2 mg/kg b.w. i.m. at 2 p.m.). Melatonin serum values were evaluated after administration of FK 33-824, a met-enkephalin analogue (0.3 mg i.v. infusion at 9 a.m.). A significant decrease of beta-endorphin plasma levels was observed 120 minutes after melatonin injection. Melatonin release was stimulated by FK 33-824, with a peak at 30 minutes. The present results provide evidence of the inhibitory effect of melatonin on beta-endorphin secretion and the stimulatory action of the opioid peptides on the pineal gland. However, further studies will be required to clarify the relationship between the opioid system and the pineal gland.

Effect of an acute injection of melatonin on the basal secretion of hypophyseal hormones in prepubertal and pubertal healthy subjects.

It is well known that the pineal gland can modulate the secretion of pituitary hormones. Melatonin, the main hormone produced by the pineal gland, acts at the hypothalamic site, whereas hypophyseal sensitivity to melatonin seems to change with age. To investigate the influence of pubertal development on the role of the pineal gland in the regulation of the secretion of pituitary hormones, FSH, LH, Prl, TSH and GH responses to melatonin were evaluated in a group of 9 prepubertal and 10 pubertal healthy subjects of both sexes. Melatonin was given im at a dose of 0.2 mg/kg body weight at 3 p.m. Venous blood samples were drawn -20, 0, 20, 40, 60, 90, 120, 180 and 240 min, after melatonin injection. According to the same experimental protocol, venous blood samples were collected during a saline infusion on a separate occasion. FSH, LH, Prl, TSH and GH plasma levels were measured with RIA. In pubertal subjects, a significant rise in the mean Prl levels was seen 90 min after melatonin as compared with those during saline infusion. The Prl melatonin response area was significantly lower in prepubertal treated subjects and significantly higher in pubertal ones compared with the respective controls. The mean GH values showed a significant decrease 120 min after melatonin only in prepubertal subjects; no significant variations were seen in 8 of 10 pubertal subjects, whereas in the last 2 a marked increase was observed.(ABSTRACT TRUNCATED AT 250 WORDS)