Immunotherapy for head and neck cancer

Overall survival for patients with squamous cell carcinoma of the head and neck (SCCHN) has not improved appreciably over the past few decades. Novel therapeutic approaches, such as immunotherapy, are under clinical investigation since the standard treatments are toxic and have not successfully controlled this disease with sufficiently high success rates. Cancer immunotherapy describes various techniques to expand and activate the immune system to control tumor growth in vivo, and clinical evaluation has so far demonstrated low toxicity. Immunotherapy appears to have the most applicability in settings of minimal residual disease and to reduce distant metastases after other therapeutic interventions, and its potential clinical value is now receiving intensive evaluation. Emerging forms of SCCHN immunotherapy involve both the use of monoclonal antibodies (mAb) that target growth factor receptors where immune activation appears to contribute to tumor cell lysis, as well as various forms of active vaccination strategies which activate and direct the patient’s cellular immunity against the tumor. This article reviews immunotherapeutic strategies currently in clinical trials or under development for patients with SCCHN.     

Evidence for vagal involvement in the eating elicited by adrenergic stimulation of the paraventricular nucleus

We examined the role of the vagus nerves in mediating the eating and preprandial drinking seen after injection of norepinephrine (NE) into the region of the paraventricular hypothalamic nucleus of satiated rats. Complete subdiaphragmatic vagotomy (confirmed by gastric secretion tests) abolished the NE-elicited eating response, whether the diet used was lab chow, milk, or a milk-chow mixture, and attenuated, by 38%, the NE-elicited drinking response. These effects occurred independently of changes in body weight or daily food intake imposed by vagal surgery. The vagotomized rats retained the capacity to rapidly increase eating in response to food deprivation or insulin injection challenges, indicating that the effect of vagotomy on NE-induced eating was not due to some non-specific impairment. Efferent vagal blockade of intact rats with systemic injections of atropine methyl nitrate (0.4 mg/kg) prior to central NE infusions yielded similar results. Finally-selective section of the coeliac branch of the vagus produced a 49% reduction of NE, elicited eating, as compared with a 29% reduction in water intake, while selective section of the gastric plus hepatic vagal branches, leaving only the coeliac branch intact, did not significantly affect either ingestive response. Both of these selectively vagotomized groups displayed an unimpaired capacity to increase food intake in response to systemic insulin injections. These results suggest participation of efferent vagal mechanisms in the adrenergic feeding, and, to a lesser extent, drinking phenomena and are consistent with a particular role for some function under coeliac vagal control (perhaps insulin secretion) in modulating the effects of NE on feeding behavior.     

Glucose injection reduces neuropeptide Y and agouti-related protein expression in the arcuate nucleus: a possible physiological role in eating behavior

Evidence suggests that neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus (ARC) are modulated by glucoregulatory hormones and involved in maintaining normal eating patterns and glucose homeostasis in states of energy deficiency. This study investigated whether these peptides respond to glucose itself under conditions, e.g., before the nocturnal feeding cycle, when carbohydrate stores are low. After removal of food 3 h before dark onset, Sprague-Dawley rats were given a single, intraperitoneal (i.p.) injection of saline or 10% glucose (0.13 g/kg) and were sacrificed at different intervals, from 3.5 to 90 min later, for measurements of circulating hormones and metabolites or of NPY and AgRP mRNA in the ARC. With no change in insulin, leptin, or triglycerides, glucose injection produced a 1.8-mM rise in circulating glucose during the first 15 min, followed by a 30-60% reduction in NPY and AgRP mRNA at 30 and 60 min post-injection. A similar effect was observed with intraventricular administration of 5% glucose. At 90 min, however, this suppressive effect of i.p. glucose relative to saline was lost and actually reversed into a 50% increase in NPY and AgRP, possibly attributed to a decline in circulating glucose followed by a 50% rise in corticosterone at 60 min. These biphasic shifts over a 90-min period may reflect mechanisms underlying natural eating patterns at the onset of the nocturnal cycle, when spontaneous meals are approximately 90 min apart and rich in carbohydrate, glucose levels are low, and corticosterone and ARC peptides naturally peak.     

Impact of hypothalamic d-norfenfluramine and peripheral d-fenfluramine injection on macronutrient intake in the rat

Previous research with hypothalamic injection of serotonin (5-HT) has suggested that this monoamine may act within the medial hypothalamus to suppress carbohydrate intake in a selective, phasic and circadian-related fashion. To explore further the action of 5-HT in the brain, the present studies tested the serotonergic stimulants, d-norfenfluramine (DNF) and d-fenfluramine (DF), in freely feeding, brain-cannulated animals maintained on pure macronutrient diets (protein, carbohydrate and fat) and tested at different times of the diurnal cycle. The results show that administration of DNF into the paraventricular nucleus (PVN) potently influences appetite for a specific nutrient at a particular time of the light-dark cycle. Specifically, DNF injection at the onset of the nocturnal (active) period selectively and dose-dependently suppresses carbohydrate consumption, while leaving protein and fat intake unchanged. This drug, however, has no effect, even at high doses, on macronutrient intake in the middle and late h of the dark phase, strongly implicating a function for hypothalamic 5-HT in the control of carbohydrate ingestion at the beginning of the nocturnal cycle. The possibility that peripherally injected DF may act, in part, through this endogenous serotonergic system is supported by the additional finding that, at low doses of 0.06-0.5 mg/kg, DF preferentially modulates carbohydrate ingestion exclusively at the onset of the nocturnal period. However, at doses above 0.5 mg/kg, this compound produces a potent and general suppression of feeding of all macronutrients. In animals with brain cannulas aimed at different hypothalamic nuclei, the feeding-suppressive effect of DNF is found to be site specific; it is localized to the medial hypothalamic nuclei, including the ventromedial, suprachiasmatic and dorsomedial nuclei as well as the PVN. Serotonin in these nuclei may function to produce satiety specific for carbohydrate and, through the suprachiasmatic nucleus, control energy intake in a circadian-related manner.     

Hypophysectomy disturbs the noradrenergic feeding system of the paraventricular nucleus

Injection of norepinephrine (NE) into the hypothalamic paraventricular nucleus (PVN) of satiated rats is known to stimulate eating behavior. In addition, drinking behavior is potentiated just prior to the onset of eating, followed by a strong inhibition of water intake. To understand the relationship between these PVN noradrenergic phenomena and endocrine processes associated with the PVN, chronically hypophysectomized animals were tested for their behavioral responsiveness to PVN NE injection. Pituitary ablation was found to abolish the NE-elicited eating response and the NE drinking suppressive effect. However, hypophysectomy had no impact on the NE-elicited preprandial drinking response, nor did it affect drinking produced by carbachol, angiotensin, and histamine, or the feeding and drinking responses induced by insulin. These results demonstrate that hypophysectomy disturbs PVN noradrenergic mechanisms in a behaviorally and pharmacologically specific specific manner.