Results of chemoradiotherapy for stage I esophageal cancer in medically inoperable patients compared with results in operable patients.

The purpose of the present study was to evaluate long-term results of chemoradiotherapy for clinical T1b-2N0M0 esophageal cancer and to compare outcomes for operable and inoperable patients. Patients with stage I esophageal cancer (Union for International Cancer Control [UICC] 2009), excluding patients with cT1a esophageal cancer, were studied. All patients had histologically proven squamous cell carcinoma. Operable patients received cisplatin and 5-fluorouracil with concurrent radiotherapy of 60 Gy including a 2-week break. Inoperable patients received nedaplatin and 5-fluorouracil with concurrent radiotherapy of 60-70 Gy without a pause. End-points were overall survival rate (OS), cause-specific survival rate (CSS), progression-free survival rate (PFS), and locoregional control rate (LC). Thirty-seven operable patients and 30 medically inoperable patients were enrolled. There was a significant difference in only age between the operable group and inoperable group (P = 0.04). The median observation period was 67.9 months. In all patients, 5-year OS, CSS, PFS, and LC were 77.9%, 91.5%, 66.9%, and 80.8%, respectively. Comparison of the operable group and inoperable group showed that there was a significant difference in OS (5-year, 85.5% vs. 68.7%, P = 0.04), but there was no difference in CSS, PFS, or LC. Grade 3 or more late toxicity according to Common Terminology Criteria for Adverse Events v 3.0 was found in seven patients. Even in medically inoperable patients with stage I esophageal cancer, LC of more than 80% can be achieved with chemoradiotherapy. However, OS in medically inoperable patients is significantly worse than that in operable patients.

Hepato-vagal pathway associated with nicotine's anorectic effect in the rat.

Nicotine reduces appetite and body weight. Because the hepato-portal area senses different types of nutrients that transmit signals via vagal afferent nerves to the hypothalamus to modify food intake and feeding pattern, we investigated the effect of nicotine on a hepato-vagal-hypothalamic pathway. Low doses of nicotine (< 10 ng) injected into portal vein (i.p.v.) decreased, while high doses of nicotine increased (> or = 10 ng) electrophysiological activity of hepatic vagal afferents. Stimulatory effect of high dose of nicotine on vagal hepatic afferents was blocked by a prior i.p.v. injection of curare (30 microg) or hexamethonium (1 mg). Furthermore, activities of gastric vagal and adrenal sympathetic efferents were suppressed by low-dose, but stimulated by high-dose i.p.v. nicotine. These reflex effects did not occur in hepatic vagotomized rats. Results of experiments demonstrate that in addition to nicotine's anorectic effect being mediated via a direct central action, nicotine also acts peripherally via hepatic vagal afferents from sensors of nicotine in the hepato-portal region.

Nicotine alters the usual reciprocity between meal size and meal number in female rat.

Tobacco smoking reduces appetite and body weight (BW). Cessation of smoking leads to hyperphagia and weight gain. Daily food intake (FI) is a function of meal number (MN) and meal size (MZ), i.e., FI=MNxMZ. Under normal conditions, the female Fischer rat has a periodic reciprocal fluctuation between MZ and MN corresponding to phase of estrous cycle. Wide fluctuations between MZ and MN compensate each other to keep FI constant. Nicotine (5 mg/kg BW/day) was infused via osmotic minipump for 7 days. Controls received saline. FI, MZ, and MN were measured by an Automated Computerized Rat Eater Meter. Nicotine significantly decreased BW and FI via a decrease in MZ without compensatory increase of MN. Nicotine cessation led to hyperphagia, normalizing BW loss via an increase in MZ, which exceeded a compensatory decrease in MN. Nicotine significantly prolonged the estrous cycle by an extension of proestrous phase. Nicotine significantly lengthened the intermeal interval (IMI), delaying the start of the next meal and simultaneously decreasing subsequent MZ. Stopping nicotine led to normalization of IMI and MZ. Data show that nicotine alters the usual reciprocal regulation between MZ and MN and leads to a prolongation of the estrous cycle.

Intra-supraoptic nucleus sulpiride improves anorexia in tumor-bearing rats.

Previous studies suggest that the dopaminergic system in the supraoptic nucleus (SON) is involved not only in the water balance control but also in the food intake regulation. Since we reported that an injection of the D2 receptor antagonist, sulpiride, into specific hypothalamic nuclei (e.g. the LHA, or the VMN) increases food intake in anorectic tumor-bearing rats, as well as in normal rats, we hypothesized that an injection of sulpiride into the SON would also improve cancer anorexia. Sulpiride injection (4 microg/0.5 microl) into bilateral SON of anorectic tumor-bearing male rats significantly improved food intake via increases in both meal size and meal number. These data suggest that pharmacological manipulation of the hypothalamic dopaminergic system is feasible in amelioration of cancer anorexia.

Role of hypothalamic monoamines in nicotine-induced anorexia in menopausal rats.

BACKGROUND: Nicotine reduces body weight by reducing appetite. Estradiol modulates food intake. Menopause or ovariectomy (Ovx) increases food intake and body weight. Nicotine and estradiol individually influence hypothalamic dopamine (DA) and serotonin (5-HT), whose interaction influences food intake and body weight. We investigated whether lower weight gain in menopausal smokers is mediated via changes in hypothalamic DA/5-HT. METHODS: Ovx or sham-operated female rats had 2 microdialysis guide cannulas simultaneously implanted in ipsilateral ventromedial nucleus of hypothalamus (VMN) and contralateral lateral hypothalamic area (LHA). Rats were divided into 4 groups and received a continuous subcutaneous infusion of nicotine or saline Ovx and sham. DA and 5-HT in LHA and VMN were measured by in vivo microdialysis. RESULTS: Nicotine infusion decreased food intake and body weight in Ovx and sham groups. Increase in LHA-DA and VMN-5-HT in sham group occurred with nicotine, whereas an increase in VMN-DA in Ovx groups with and without nicotine and VMN-5-HT in Ovx group with nicotine was observed. CONCLUSIONS: In the presence of estradiol (ovary intact sham-operated rats), nicotine lowers food intake and body weight via increased LHA-DA and VMN-5-HT. In menopause (Ovx rats), nicotine lowers food intake and body weight only via increased VMN-DA and 5-HT. Data show that lower weight gain is mediated via changes in hypothalamic monoamines, primarily via ventromedial hypothalamus.

Synchronized release of dopamine and serotonin in the medial and lateral hypothalamus of rats.

A positive linear correlation between dopamine and serotonin release was found in the ventromedial hypothalamus and in the lateral hypothalamic area in fasting rats and in fed rats during intermeal intervals. Dopamine release in the ventromedial hypothalamus positively correlated with dopamine and serotonin release in the lateral hypothalamic area, which occurred only during intermeal intervals and was non-significant during the meal consumption periods or during fasting. Meal size correlated significantly only with a decrease in serotonin release in the lateral hypothalamic area. The study was designed to evaluate the relationship between dopamine and serotonin release in these hypothalamic areas and their dependence on feeding status. Microdialysis was performed simultaneously via two probes, one in the ventromedial hypothalamus and the other in the contralateral lateral hypothalamic area, of freely moving male lean Zucker rats over 24h with preserved light and dark phase, either with ad libitum access to food and water, or when no food was available. Dopamine and serotonin concentrations were measured by high-performance liquid chromatography with electrochemical detection in 20-min dialysis samples. Time-series analysis was applied to determine linear correlations between monoamines and in relation to food intake. Data showed that release of dopamine and serotonin is synchronized within the ventromedial hypothalamus and lateral hypothalamic area, particularly in the dark phase and when no food was ingested. However, synchronized release of monoamines between these nuclei occurred only during intermeal intervals: the periods of satiety. These findings suggest a tight relationship between dopaminergic and serotonergic systems of the lateral hypothalamic area and ventromedial hypothalamus, which is influenced by the feeding state and which may be involved in maintaining the balance within and between the centers of the parasympathetic and sympathetic nervous systems. The data also illustate that food intake is coupled unequivocally to the release of dopamine and serotonin in the hypothalamus, suggesting it as a mechanism of activation of postsynaptic neurons associated with new metabolic status.

From food to nutritional support to specific nutraceuticals: a journey across time in the treatment of disease.

Hospitalized patients who are unable to eat or cannot eat enough to meet their metabolic needs are given parenteral or enteral nutritional support. This form of therapy is now also given to patients at home. Nutritional support is a recent development, prior to which the value of food was recognized for its medicinal benefits as nutraceuticals. The value of such "alternative" therapy is now being rediscovered by many patients who enhance their dietary intake with these traditional remedies. In Western culture, conventional medicine until recently has largely rejected the use of such "alternative" therapeutic intervention. Based on an increasing database, though, insight has been gained concerning the scientific validity of many previously termed established nutraceuticals. We focus here on the effects of honey, green tea, ginseng, and vitamin supplementation on the immune system. Honey has proven antimicrobial activity. Green tea enhances humoral and cell-mediated immunity while decreasing the risk of certain cancers and the risk of cardiovascular disease. Ginseng enhances production of macrophages, B and T cells, natural killer cells, and colony-forming activity of bone marrow. Vitamin supplementation is associated with increased antibody titer response to both hepatitis B and tetanus vaccines as a result of macrophage and T cell stimulation. Because of these findings, nutraceuticals are becoming more widely accepted as an adjunct to conventional therapies for enhancing general well-being.

VMN dopaminergic graft and feeding pattern in obese Zucker rats.

OBJECTIVE: To study the role of dopamine in the ventromedial hypothalamus (VMN) in the regulation of meal size and meal number during obesity. METHODS: Embryonic mesencephalic cells rich in dopaminergic neurons from lean rats were grafted into the VMN of obese Zucker rats. Since food intake is the product of meal size and number, these variables were measured using a rat 'eater meter'. Dopamine and serotonin concentrations in the VMN were assayed in grafted and control rats via in vivo microdialysis and HPLC two months after transplantation. RESULTS: Food intake increased in grafted rats due to an increase of both meal size and meal number 2 weeks after implantation and to an increase of meal size with insufficient compensatory decrease of meal number 2 months after transplantation. Grafted rats showed higher absolute dopamine and lower serotonin concentrations in the VMN. CONCLUSION: It would appear that an increase of dopamine and a decrease of serotonin in the VMN of grafted obese rats may correlate with increase in meal number and meal size, respectively. Since obese Zucker rats usually display an enlarged meal size, we deduce from the data that chronically elevated VMN dopamine and low serotonin are involved in producing the large meal size observed during obesity.

VMN hypothalamic dopamine and serotonin in anorectic septic rats.

During sepsis, catabolism of proteins and associated changes in plasma amino acids occur. Tryptophan and tyrosine, and their derivatives serotonin (5-HT) and dopamine (DA), influence hypothalamic feeding-related areas and are associated with the onset of anorexia. We hypothesized that anorexia of sepsis is associated with changes in serotonin and dopamine in the ventromedial nucleus (VMN) of the hypothalamus. The aim of this study was to test our hypothesis by measuring intra-VMN changes of these two neurotransmitters at the onset of anorexia during sepsis. Fischer 344 male rats had an intracerebral guide cannula stereotaxically implanted into the VMN. Ten days later, in awake, overnight-food-deprived rats, a microdialysis probe was inserted through the in situ VMN cannula. Two hours thereafter, serial baseline serotonin and dopamine concentrations were measured. Then cecal ligation and puncture to induce sepsis or a control laparotomy was performed under isoflurane anesthesia. VMN microdialysis samples were serially collected every 30 min for 8 h after the surgical procedure to determine 5-HT and DA changes in response to sepsis. During the hypermetabolic response to sepsis, a strong association occurred between anorexia and a significant reduction of VMN dopamine concentration (P < 0.05; constant rate of dopamine decrease in the Study group of 0.99 pg per 2 h); no changes occurred in 5-HT in association with anorexia of sepsis. Six hours after operation, a single meal was offered for 20 min to assess the response of neurotransmitters to food ingestion. Food intake was minimal in anorectic septic rats (mean size of the after food-deprived meal in the Septic group was 0.03+/-0.01 g, that of the Control group was 1.27+/-0.14 g; P = 0.0001), while Control rats demonstrated anticipated changes in neurotransmitters in response to eating. We conclude that the onset of anorexia in septic rats is associated with a reduction in VMN dopamine.

Infusion of nicotine into the LHA enhances dopamine and 5-HT release and suppresses food intake.

Nicotine administration induces hypophagia. Because of the involvement of hypothalamic neurotransmitters in food intake control, we hypothesized that increased activity of the lateral hypothalamic dopamine (LHA-DA) and/or serotonin (LHA-5-HT) may be responsible for nicotine-induced hypophagia. Either 4 mM nicotine or vehicle was administered via reverse microdialysis technique into the LHA of overnight food-deprived rats for 60 min; then food was provided for 40 min. The LHA-DA, 5-HT and their intermediate metabolites, DOPAC and 5-HIAA, were continuously measured during 20-min intervals before, during, and after nicotine administration. Continuous nicotine administration for 60 min increased LHA-DA and DOPAC concentrations during the first 40 min, and induced a long-lasting increase in LHA-5-HT release, until 120 min after the start nicotine administration, even when nicotine administration was stopped. The food intake during the 40-min refeeding period was significantly lower when rats received nicotine. Eating induced a significant and short-lasting increase in the LHA-DA and a long-lasting increase in the LHA-5-HT. These findings indicate that nicotine enhances dopaminergic and serotonergic activity in the LHA, and that the enhanced LHA-5-HT activity may contribute to nicotine-induced hypophagia.

Nicotine's effect on hypothalamic neurotransmitters and appetite regulation.

BACKGROUND: Tobacco smoking reduces appetite and body weight. Cessation of smoking leads to hyperphagia and weight gain. Food intake is a function of meal number (MN) and meal size (MZ) (i.e., Food intake = MN x MZ). The effect of nicotine on these feeding components and their relationships to dopamine and serotonin in the lateral hypothalamic area (LHA) were determined. METHODS: In Fischer-344 rats the effect of 7 days of systemic nicotine infusion on the feeding patterns was measured by rat eater meter and changes in serotonin (5HT) and dopamine (DA) in the LHA were measured by in vivo microdialysis. RESULTS: Nicotine infusion caused hypophagia through a significant decrease in MN with a smaller decrease in MZ, resulting in a body weight reduction. 5HT and DA concomitantly increased in LHA. Stopping nicotine resulted in hyperphagia by a significant increase in MZ. Body weight normalized. 5HT and DA in LHA decreased after nicotine was stopped. CONCLUSION: Nicotine's hypophagic effect was associated with increased 5HT and DA in LHA, whereas hyperphagia after nicotine cessation was accompanied by decreased concentrations of the neurotransmitters. These findings suggest that nicotine affects appetite regulation, in part by modulation of LHA-DA and 5HT.

Feeding pattern in obese Zucker rats after dopaminergic and serotonergic LHA grafts.

To study the role of the lateral hypothalamic area (LHA) dopamine and serotonin in the regulation of feeding pattern during obesity, embryonic dopaminergic and serotonergic neurons from mesencephalon and rombencephalon of lean rats were grafted into the LHA of adult obese Zucker rats. Compared to the pregrafting period, a smaller increase in meal size occurred in both serotonin-grafted (9%) and dopamine-grafted (31%) rats vs control rats (51%). There was also a smaller decrease in meal number in both serotonin-grafted (3%) and dopamine-grafted (13%) rats vs control rats (28%). Although the changes in feeding pattern resulted in a decrease in total food intake in serotonin-grafted rats (5%) vs control rats, no differences in body weight gain were observed in grafted vs control rats for the duration of the study. Since adult obese Zucker rats are known to have an increased meal size and decreased meal number relative to lean rats, the data indicate the involvement of LHA dopamine and serotonin in the regulation of feeding pattern during obesity.

[Esophageal bypass operation of a patient with esophageal stenosis and esophago-bronchial fistula due to lung cancer].

Esophageal bypass operation was carried out for a patient with lung cancer who was not able to take oral feeding, due to esophageal stenosis and esophago-bronchial fistula. Stomach was used as a esophageal substitute, through antethoracal route. Abdominal esophago-jejunostomy was performed for drainage of esophago-bronchial fistula. Oral intake of foods was started from 11th postoperative day without major complication. And then, she was permitted to discharge only with a jejunostomal feeding tube. Recently the quality of life is emphasized, even in cases in which curativity of cancer cannot be expected. Surgery in such cases entails many risks and then, special care must be taken to determine the indication and procedure of this operation. In the case herein reported, such attention to detail resulted in survival for over one year.