Is there a role for melatonin in the treatment of neoplastic cachexia?

It is known that neoplastic cachexia shows metabolic characteristics different from other common causes of malnutrition, and that it is mainly due to an abnormal secretion of TNF, whose levels are often high in patients with advanced neoplasia. Previous clinical studies have suggested that the pineal hormone melatonin (MLT), which plays an essential role in the neuroendocrine regulation of biological systems, may improve the clinical status of advanced cancer patients and inhibit TNF secretion. To investigate the relationship between MLT, TNF and cancer-related weight loss, 100 untreatable metastatic solid tumour patients entered this study to receive either supportive care alone, or supportive care plus MLT (20 mg/day orally in the evening). Patients were observed for 3 months, and were considered evaluable when they were observed for at least 2 months. There were 86 evaluable patients, the other 14 patients having died from rapid progression of disease. The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01). Mean serum levels of TNF progressively increased in the supportive care group, but to levels that were not significantly different from pretreatment values. In contrast, TNF mean concentrations significantly decreased (P < 0.05) in patients concomitantly treated by MLT. These results suggest that the pineal hormone MLT may be effective in the treatment of the neoplastic cachexia by decreasing TNF blood concentrations.

A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast-cancer patients.

Recent experiments suggest the possibility of modulating the efficacy of cancer endocrine therapy by the pineal hormone melatonin (MLT). In particular, it has been demonstrated that MLT may stimulate estrogen receptor (ER) expression and enhance tamoxifen (TMX) effects other than the antiestrogenic action. Therefore, MLT could amplify the efficacy of TMX also in patients with negative ER. On this basis, a randomized study was performed with TMX versus TMX plus MLT in ER-negative metastatic breast cancer patients, who were unable to tolerate further chemotherapy, because of age, low performance status and/or heavy chemotherapeutic pretreatment. The study included 40 ER-negative post-menopausal, metastatic breast cancer patients, who were randomized to receive TMX alone (20 mg/day orally) or TMX plus MLT (20 mg/day orally in the evening). No complete response was seen. Partial response rate was significantly higher in patients treated with TMX and MLT than in those, who received TMX alone (7/19 vs 2/21, p<0.05). Moreover, the percent of survival at 1 year was significantly higher in patients treated with TMX plus MLT than in those treated with TMX alone (12/19 vs 5/21, p<0.01). No MLT-related toxicity was observed; on the contrary, most patients receiving MLT experienced a relief of anxiety and of depression. This preliminary study suggests that the association of the pineal hormone MLT may make TMX effective also in ER-negative metastatic breast cancer patients.

Central injection of morphine stimulates plasma corticosterone and interleukin (IL)-6 and IL-6 R mRNAs in the pituitary and adrenals in adjuvant-induced arthritis.

Adjuvant-induced arthritis (AA) in the rat is a T-cell mediated, chronic inflammatory stress in which circulating interleukin (IL)-6 levels are elevated. In addition, there are profound neuroendocrine changes associated with the development of hind-paw inflammation which have major implications for the ability of the rat to respond the to stress. Central injection of morphine is also able to increase circulating IL-6 concentration in control animals. In the present study we have determined the effects of a single injection of morphine into the lateral ventricle of control and AA animals on plasma corticosterone levels, on changes in plasma corticosterone and on IL-6 and IL-6 receptor mRNAs in the pituitary and adrenal gland. IL-6 and IL-6 receptor mRNAs were increased in the anterior pituitary of AA rats given moprhine compared with saline-treated AA rats. In the adrenal cortex, IL-6 mRNA was unaltered and IL-6 receptor mRNA was significantly decreased under these same conditions. AA rats were unable to mount corticosterone response to acute stress but were able to respond to acute stimulation with e.g. LPS. In the present study we found a sustained increase in plasma corticosterone in control animals which was still significantly elevated 2 hours following morphine injection, with a further significant increase in AA rats. These data suggest that alternative systems distinct from those activated in response to acute stress are activated by morphine in the AA animals. The similarity with the sustained increase in corticosterone following LPS injection suggest that either similar pathways are involved, or that central opiates may be involved in mediating HPA axis response to stress.

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.

Preliminary study on modulation of the biological effects of tumor necrosis factor-alpha in advanced cancer patients by the pineal hormone melatonin.

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.

Decrease of erythropoietin level by human recombinant tumour necrosis factor alpha (hrec TNFalpha) in patients with advanced cancer.

UNLABELLED: Anaemia is a frequent complication of chronic inflammation, infectious diseases and cancer. Inappropriate erythropoietin production is regarded as one of the main causative factors responsible for the occurrence of anaemia. The pathogenesis of TNFalpha induced-anaemia has not been fully clarified yet and its influence on hematopoiesis has been suggested. We performed a clinical study to access the influence of hrec TNFalpha administration on plasma EPO concentration and the degree of anaemia in patients with advanced solid tumours for whom no other kind of therapy but palliative treatment was available. All these patients exposed mild anaemia (HT 36.1 +/- 1.0%). Plasma EPO was estimated at 8 a.m. before and after 5 days of TNFalpha therapy with a dose of 75 pg/day iv (cycle I). Two weeks later plasma EPO was estimated again before and after 5 days of TNFalpha administration of a double dose (150 microg/day) (cycle II). The control group comprised 8 non-cancer patients (5M/3F, age 48.5 +/- 6yr) with the same degree of anaemia (HT 36 +/- 1.1%) due to haemorrhage. In the control group the plasma EPO level was significantly higher (54.2 +/- 8 mU/ml) than in cancer patients before cycle I (17.1 +/- 2.5 mU/ml) and II (14.6 +/- 3.8 mU/ml) respectively.TNF administration was followed by a significant decline of plasma EPO both after the first (17.1 +/- 2.5 vs 9.0 +/- 1.5 mU/ml) and second cycle (14.6 +/- 3.8 vs 8.4 +/- 2.0 mU/ml) of TNF treatment. CONCLUSIONS: Patients with solid cancer and mild anaemia are characterised by inappropriate low plasma EPO concentration. Therapy with TNFalpha exerts a suppressive effect on EPO secretion in these patients.

Genetic disregulation of gene coding tumor necrosis factor alpha receptors (TNF alpha Rs) in follicular thyroid cancer--preliminary report.

UNLABELLED: TNF alpha receptors participate in programmed cell death. TNF R2 efficiently assists TNF R7 effects by ligand passing. Structure of TNF alpha receptors influences TNF activity in vivo and the structure of TNF R2 gene may suggest post-transcription modification based on alternative splicing. The aim of the study was to analyse the expression of gene coding TNF alpha receptors R2 and R7 by estimation of mRNA expression of differentiated thyroid carcinomas in comparison to surrounding tissue free from neoplastic infiltration and search for differently spliced TNF alpha R2/R7 isophorms. The study included seven patients with histopathologically confirmed follicular thyroid cancer. Tissue samples removed from tumor region were obtained from the follicular thyroid cancer patients undergoing surgical treatment. The samples were divided into two parts. The first one was routinely examined histopathologically, the second was used for RNA extraction and the number of TNF and its receptors mRNA copies were subsequently quantified. RESULTS: 1) The presence of TNF alpha expression was observed in all examined samples, in contrast to TNF R1 expression; 2) The high level of TNF alpha expression was noted both for typical and sought TNF R2/R7 isoforms and 3) A considerable number of samples displayed higher levels of TNF R2 isoforms than TNF R2/R7 mRNA expression. Genetic disregulation observed in neoplastic disease usually concerns dysfunction of cytokines receptor genes.

On the holistic approach in cancer biology: tumor necrosis factor, colon cancer cells, chaos theory and complexity.

TNFalpha plays a role in the pathogenesis of septic shock, inflammatory diseases, autoimmune diseases, graft rejection reaction, acute, and chronic respiratory inefficiency among others. Its activity depends on the type of target cells and different regulating factors, but the effect of biological activity is conditioned by specific receptors such as p55 (type I, TNF R55) and p75 (type II, TNF R75). The aim of the study was to answer the following questions: 1) Is it possible to apply elements of non-linear dynamics to assess the level of expression of TNF, TNFRI, TNFRII genes in tumor cells, pathologically unchanged tissue and metastatically changed lymph nodes? 2) Is theoretically anticipated variability of cytokine and its receptors in colorectal carcinoma cells and the immediate vicinity justified in the developed mathematical model? The research material--specimens taken from tumor, unchanged tissue and metastatic lymph nodes--were histopathologically and molecularly analysed. Results of the molecular research were used to develop a mathematical model using the basic studies on the theory of chaos and biological system modelling.

Central single and chronic administration of morphine stimulates corticosterone and interleukin (IL)-6 in adjuvant-induced arthritis.

Adjuvant-induced arthritis (AA) in the rat is a chronic inflammatory stress in which circulating corticosterone and interleukin (IL)-6 levels are elevated. In addition, there are profound neuroendocrine changes associated with the development of hind-paw inflammation which have major implications for the ability of the rat to respond to stress. Central injection of morphine is able to increase plasma corticosterone and circulating IL-6 concentration in control animals. In present study we have determined the effects of a single and repeated injection of morphine into the lateral ventricle of control and AA animals on plasma corticosterone, circulating IL-6 levels and course of hind-paw inflammation in AA rats. In the present study we found a sustained increase in plasma corticosterone both after single and repeated injection of morphine in control and AA rats and an increase of the level of circulating IL-6 in AA rats after repeated injection of morphine. These data suggest that alternative systems distinct from Athose activated in response to acute stress are activated by morphine in the AA animals. The similarity with the sustained increase in corticosterone following LPS injection suggest that central opiates may be involved in mediating HPA axis and cytokines response to inflammatory stress.

Decline of met-enkephalins concentration after interleukin-2 subcutaneous administration due to renal carcinoma.

The authors have described the connections between nervous and immune systems. Endogenous opioids are one of the factors linking both systems. Endogenous and exogenous opioids can modify the function of interferons, humoral factors, antibody production and lymphocytes' activation. Concurrently, some cytokines can modify the endogenous opioid system. The aim of this study was to asses whether the subcutaneous administration of IL-2 influences the Met-Enkephalins concentration in serum after IL-2 single administration due to renal cancer. The Met-Enk level was estimated with RIA method. The IL-2 single administration results in a significant decrease of Met-Enk in serum.

The estimation of endogenous tumor necrosis factor alpha and cortisol levels in serum in advanced neoplasm.

The immune reaction mediators--cytokines may play an important role in central nervous system function and influence the neuroendocrine system. The aim of the study was to assess the hypothesis of a possible correlation between endogenous TNF-alpha and glucocorticoids secretion in advanced neoplasm. Thirty patients (17 males and 13 females) with advanced neoplasm were enrolled in the study. The levels of TNF-alpha were measured with ELISA type test and cortisol levels were estimated by RIA method. The blood samples were collected 6 times during 24-hours for TNF and 6 times a day for cortisol. Twenty healthy volunteers were studied in parallel. Both TNF-alpha and cortisol levels revealed the presence of circadian rhythm in examined patients. The levels of TNF-alpha were very high and achieved the peak value about midnight (acrophase-01.40). Cortisol peak was found typically at 08.08. The fluctuations of examined molecules showed regular patterns. TNF-alpha levels markedly decreased together with the increase of cortisol and rose when cortisol concentration in serum was low. Although the correlation was not confirmed by Spearman correlation rank the shapes displayed by both curves may suggest the presence of neuroendocrine feed-back loop between corticosteroids and TNF-alpha in advanced cancer.

Possible biological indicators of the response to recombinant tumour necrosis factor alpha in patients with advanced neoplasms.

Tumour Necrosis Factor alpha (TNF alpha) immunotherapy, in addition to that of Interleukin-2 immunotherapy, represents one of the most promising biotherapies for human neoplasms. In order to identify immunological parameters of prognostic value we studied changes in immune response during first cycle of treatment with hree TNF alpha. The study included 21 locally advanced or metastatic solid tumor patients (M/F:12/9 median age: 57 years, range 38-65) for whom no other standard therapy was available. TNF alpha was administered before midday by a 20-minute intravenous infusion at a dose of 75 microg/day for 5 consecutive days corresponding to one cycle. In the absence of progression two further cycles of TNF alpha were given at 14 day intervals during which the dose was increased by 50 microg/day i.e. 2nd cycle- 100 microg/day, 3rd cycle- 150 microg/day. Of 21 patients evaluated for both clinical and immunological responses, 4 had complete response and 4 patients had partial response. The present study suggests that TNF alpha biotherapy is not associated with an increase in the number of circulating lymphocytes. Regarding lymphocyte subtype, a slight increase has been observed as far as T lymphocyte subsets are concerned. The CD4/CD8 ratio in cancer patients treated with hree TNF alpha showed significantly lower values than before treatment. On the basis of in vitro experiments an increase in NK cell activation in tissue culture, in addition to an increase of LAK cells, was observed.

Transient increase of plasma interleukin-6 after infusion of recombinant tumor necrosis factor alpha in advanced cancer patients.

Tumor Necrosis Factor alpha administered in the therapy of advanced cancer influences certain hormones and cytokines secretion. In turn, these also modulate the biological activity of Tumor Necrosis Factor alpha. It has been shown in several studies that the cytokine Interleukin -6 (IL)-6 is produced in response to various hormones and other cytokines eg. Tumor Necrosis Factor (TNF alpha). In our study we focused on the Interleukin-6 (IL-6) secretion in response to TNF alpha administration in 12 patients undergoing TNF alpha biotherapy due to advanced neoplastic disease. Plasma IL-6 was estimated prior and at various time points (2, 3, 5 a,d 12 hours) after TNF alpha intravenous infusion. IL-6 level was estimated with ELISA method. In conclusion, we suggest the stimulating influence of hrec TNF alpha administered as therapy for advanced cancer on IL-6 secretion.

Genetic testing for breast cancer susceptibility: Polish women's attitudes.

The aim of our study was to assess Polish women's attitudes and possible acceptance of genetic tests for breast cancer susceptibility. The research was carried out in 1995-1996 and enrolled 200 women of different age, education and professional status who were asked to answer the questions included in a questionnaire. We estimate the percentage of women presenting different attitudes towards breast cancer genetic testing: 77% of women accepted genetic tests for breast cancer (BRCA) and 48% of women accepted informing their close relatives of the genetic tests results.

Circadian fluctuations of melatonin, tumor necrosis factor-alpha and its soluble receptors in the circulation of patients with advanced gastrointestinal cancer.

The objective of the study was to investigate the dynamic changes of melatonin (MLT), tumor necrosis factor alpha (TNFalpha), soluble TNFalpha receptors ( type I and type II) in serum of advanced cancer patients during 24 hours. The examined group consisted of 42 patients suffering from advanced gastrointestinal neoplasms (colorectal, gastric and pancreatic cancer). Blood samples were collected 6 times a day (8 a.m., 2 p.m., 6 p.m., 10 p.m., 2 a.m., and again 8 a.m.) as well as in healthy controls. Serum levels of TNFalpha and both its receptors were measured using ELISA type and the radioimmunoassay method was used to assess MLT levels. The circadian rhythm of MLT was altered because MLT reached its peak level at 8.50 a.m. with 5 hours delay in respect to average peak time in healthy humans. The presence of circadian rhythm of TNFalpha was proved (acrophase-1.40 a.m.), and no diurnal rhythm of soluble TNF receptors was observed. The concentration of soluble type I (p-55) receptor was distinctly lower than soluble type II (p-75). The peak of soluble type I receptor value appeared at 10.00 p.m. while the type II receptor reached its minimum level at the same time. Although there was no statistical correlation between the receptor concentrations, the shapes of both curves remained inversely proportional. The present results may suggest the presence of complex self-regulation mechanisms between the neuroendocrine system and the cytokine network in advanced gastrointestinal cancer patients.

Genetic disregulation of gene coding tumor necrosis factor alpha receptors (TNFalpha Rs) in colorectal cancer cells.

The expression of TNF ligand by malignant cells might be a mechanism for tumour immune escape. Genetic disregulation of gene coding TNF receptors was observed in neoplastic disease by an increased number of receptors on tumour cells and ligand-receptor activity. It might cause tumour proliferation and metastatic potential. Structure of TNF receptors influences TNF activity in vivo and structure of TNF R2 gene may suggest post-transcription modification based on alternative splicing. The aim of the study was to analyse the expression of gene coding TNF receptors R2 and R2/R7 (without exon 7) by estimation of mRNA expression of colorectal cancer cells in comparison with surrounding tissue free from neoplastic infiltration and searched for differently spliced TNFalphaR2/R7 isoforms. The study included fifty four patients with histopathologically confirmed adenocarcinoma (Stage III according to the AJC TNM Classification). Tissue samples removed from the tumour region were obtained from colorectal cancer patients undergoing surgical treatment. The samples were divided into two parts. The first one--was routinely examined histopathologically, the second one--was used for RNA extraction and the number of TNF and its receptors mRNA copies were subsequently quantified. The TNF and TNFRII genes expression were estimated based on the number of mRNA copies on 1 microg total RNA. The presence of TNFR2 and TNFR2/R7 isoforms in tumour, normal and metastatic cells was observed. The highest number of mRNA TNF copies and over expressed TNF genes were investigated and significantly noticed in metastatic cells (lymph nodes). The decreased number of TNFR2/R7 mRNA copies in metastatic lymph nodes secondarily influenced the decreased TNF soluble receptors' concentration. In conclusion, the genetic disregulation observed in neoplastic disease usually concerns dysfunction of cytokines receptor genes.

[Depression as a risk factor for cancer--is it still a hypothesis or a proven fact?]. / Depresja czynnikiem zagrozenia choroba nowotworowa--ciagle hipoteza czy juz udowodniony fakt.

The connection between depression and cancer has been described several times. These observations have been made on major depression and on other kinds of depression as well. It is possible that similar genetic defect may play an important role in the development of cancer and major depression. Disturbances in function of endocrine and immunological systems, which have been observed in depression, can be the risk factor for cancer. Large epidemiological research showed that in persons with depression increased risk of cancer diseases, but not every research confirm it. Large disagreement of research results don't permit of sure answer, but the hypothesis is still possible and require incessant research. Development of research methods, particularly a new domain called molecular epidemiology give hope for more precise future answer.

[A case of recurrent untreated non-hodgkin's lymphoma localized in the nasopharynx and maxillary sinuses after a 10-year remission]. / Przypadek nawrotu nie leczonego chloniaka nieziarniczego po 10-letniej remisji, zlokalizowanego w nosogardzieli i zatokach szczekowych.

We present the case of non-Hodgkin lymphoma (lymphoma malignum lymphocyticum) localised in nasal cavity and paranasal sinus (maxillary sinus). The patient suffered from weakness, fever and rhinorrhoea. We applied the chemotherapy (grade IV degrees) in COP, achieving partial remission. We also place emphasis on 10-year period of idiopathic neoplasm remission since the establishment of diagnosis.

[Cardiotoxic effect of the herec-TNF alpha preparation given intravenously to patients with advanced neoplasms]. / Dzialanie kardiotoksyczne preparatu herec-TNF alfa podawanego dozylnie pacjentom z zaawansowana choroba nowotworowa.

The group of 17 patients with advanced neoplastic disease has been treated with combined therapy with herec TNF alpha in association with IFN alpha and 5-Fu, the cardiotoxic effect of herec TNF alpha administration has been observed. The 30 minutes intravenous infusion of herec TNF alpha caused statistically significant increase of heart rate (in comparison to the previous value). There was also observed the decreasing of blood pressure value (about approximately 20-30 mmHg), spontaneously disappeared after the infusion ending. Rarely, the heart rhythm disturbances i.e.: ventricle extrasystoles in II, III, IV in Lown score have been observed. In 2 cases there was additional pharmacological treatment. In the rest of the patients the early cardiotoxic effects have not been associated with haemodynamic disturbances.