[Diagnostics and therapy for neuroendocrine neoplasia of an unknown primary - a plea for open exploration]. / Diagnostik und Therapie bei neuroendokrinen Neoplasien mit unklarem Primarius - ein Plädoyer für die offene Exploration.

BACKGROUND: Neuroendocrine neoplasia (NEN) are a rare and heterogenous tumour entity. The subgroup with unknown primary tumour (N-CUP) seems to have a worse prognosis as resection of the primary is necessary for cure. The diagnostics and therapeutic algorithms for N-CUP in a German single centre are presented. PATIENTS/METHODS: Analysis of the surgical databank showed 35 cases of N-CUP in 261 cases with NEN from gastroenteropancreatic and lung origin over 2 decades (03/1990-03/2011). Three groups were built: K1 - primary detection after operative exploration (n = 10), K2 - unknown primary after operative exploration (n = 10) and K3 - no operative exploration for various reasons (n = 13). RESULTS: Initially 13.4 % (35/261) of patients presented as N-CUP, after intensified diagnostics 12.7 % (33/261) and after operative exploration 8.8 % (23/261) remained with unknown primary tumour. The sex ratio was 1 : 1, the median age is significantly higher in N-CUP [63.8 years (y) vs. 55.9 y, p = 0.004), the 5-year-survival is lower (58 vs. 72 %, n. s.). compared to NEN with known primary. Operative exploration was performed in 60.6 % (20/33), 30 % (6/20) of them were found to have inoperable situations, in 20 % (4/20) single site metastases were removed completely and in 50 % (10/20) a primary tumour was detected (8 × midgut, 2 × pancreas) intraoperatively. In these cases 70 % (7/10) got complete tumour resection (R0) and in 30 % (3/10) primary tumour resection with debulking of liver metastasis was done. In K3 (39.4 %, 13/33) most patients [69.2 % (9/13)] were treated with chemotherapy. The median age in K1 was significantly lower than in K3 (54.9 y vs. 68.3 y, p = 0.028), male dominance was seen in K3 (3,3 : 1, n. s.). The average Ki-67 index was 4.3, 23.8 and 53 % in K1, K2 and K3 (p < 0.0001 for K1 and K3 and p = 0.035 for K2 and K3), respectively. The death rate was 20, 30 and 76.9 % in K1, K2 and K3, respectively. CONCLUSION: Primary tumours of the midgut and pancreas are often found in the subset of well differentiated neuroendocrine CUP syndrome after open surgical exploration. A high rate of complete tumour resection and cure can be achieved in these cases. After common diagnostic tools (CT, MRI and somatostatin receptor scintigraphy), immunhistochemistry can give important hints (CDX-2 for midgut, TTF-1 for lung and thyroid) for a primary lesion. Also in single site metastasis without primary tumour detection a good clinical outcome is seen after complete resection.

[Ectopic hormone secretion by neuroendocrine tumors]. / Ektope Hormonsekretion bei neuroendokrinen Tumoren.

Ectopic hormone production is a rare complication in neuroendocrine tumors. Tumors producing corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are most commonly observed, leading to the classical symptoms of Cushing's syndrome. Additionally, a very low percentage of neuroendocrine tumors can produce growth hormone-releasing hormone (GHRH) leading to classical features of acromegaly. Moreover, ectopic antidiuretic hormone (ADH) secretion has been described in neuroendocrine tumors presenting as hyponatremia due to the syndrome of inappropriate ADH secretion. Other ectopic hormone secretions, such as paraneoplastic gonadotropin release are rarely observed. Ectopic hormone secretion is not usually associated with a detectable pituitary mass and diagnosis is based on the measurement of circulating peptides. This is frequently assisted by imaging techniques, such as somatostatin receptor scintigraphy. Therapeutically a curative approach is the primary goal but in advanced tumors palliative treatment aims to control symptoms with the help of specific antihormonal compounds, such as somatostatin analogues.

Blocking AMPA receptor signalling by caroverine infusion does not affect counter-regulation of hypoglycaemia in healthy men.

AIMS/HYPOTHESIS: Glutamatergic pathways are assumed to play a critical role in the hormonal stress response to hypoglycaemia. In rats, glutamate signalling at the amino-3-hydroxy-5-methyl-4-isoxazol propionate (AMPA) receptor contributes to hormone release induced by behavioural stressors. We hypothesised that blocking the AMPA receptor by caroverine in healthy men would impair their perception of neuroglycopenia and thereby diminish hormonal counter-regulation as well as symptoms of hypoglycaemia, as a model of stress. METHODS: In a balanced double-blind study, two hypoglycaemic clamp sessions (mean blood glucose 2.4 mmol/l for 50 min) were performed in ten healthy men during intravenous administration of 80 mg caroverine or placebo. We assessed concentrations of counter-regulatory hormones as well as subjective symptoms related to hypoglycaemia. RESULTS: AMPA receptor antagonisation by caroverine did not influence the perception of neuroglycopenic and autonomic hypoglycaemia-associated symptoms (p > 0.39 for all). Notwithstanding, caroverine did increase basal and counter-regulatory glucagon secretion (p < 0.002) and slightly enhanced counter-regulatory growth hormone concentrations (p = 0.07). Counter-regulatory release of ACTH, cortisol, adrenaline (epinephrine) and noradrenaline (norepinephrine) did not differ between conditions (p > 0.11 for all). CONCLUSIONS/INTERPRETATION: Antagonising AMPA receptor signalling by caroverine infusion failed to diminish and even slightly amplified counter-regulatory hormone release during hypoglycaemia in healthy men. The discrepancy with previous findings in rats may be due to different dosages or administration routes and calls for further investigations on the role of AMPA receptor signalling in hypoglycaemia counter-regulation in humans.

A hypertensive emergency with acute visual impairment due to excessive liquorice consumption.

Hypokalaemic hypertension is the classical presentation of primary hyperaldosteronism but may also result from other mineralocorticoid activity, such as liquorice ingestion. Onset of hypertension as well as serum renin and aldosterone levels are central for the diagnosis. Liquorice ingestion has been reported to induce hypertension, hypokalaemia and metabolic alkalosis due to inhibition of the enzyme 11-ß-hydroxy steroiddehydrogenase 2. Here, we report the case of a hypertensive emergency with acute visual impairment due to hypertensive retinopathy in clear conjunction with a considerable consumption of liquorice.

The selfish brain: competition for energy resources.

The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier, has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term 'allocation' refers to the allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary-adrenal (LHPA) system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a 'glutamate command' signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress, traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine system. Disorders in the 'energy on demand' process or the LHPA-system can influence the allocation of energy and in so doing alter the body mass of the organism. In summary, the presented model includes a newly discovered 'principle of balance' of how pairs of high and low-affinity receptors can originate setpoints in biological systems. In this 'Selfish Brain Theory', the neocortex and limbic system play a central role in the pathogenesis of diseases such as anorexia nervosa and obesity.

Maturity-onset diabetes of the young and hepatic adenomatosis - characterisation of a new mutation.

Hepatocyte nuclear factor 1 alpha (HNF1A) mutations cause maturity-onset diabetes of the young (MODY) type 3. Further extending the phenotypic spectrum, HNF1A mutations are associated with hepatic adenomatosis. A 20-year old lean, female patient with newly diagnosed diabetes mellitus was negative for diabetes-associated autoantibodies and had no relevant family history. Hepatic adenomatosis was diagnosed. Her HNF1A gene was examined and identified alterations further analysed.Sequencing of her HNF1A gene revealed a previously uncharacterised Q495X nonsense mutation, along with the known A98V polymorphism, both in the heterozygous state. The patient's father was also a carrier of both the mutation and the polymorphism. An oral glucose tolerance test (OGTT) revealed impaired glucose tolerance, whereas imaging of his liver was unremarkable. Wild type HNF1A and HNF1A carrying the Q495X mutation were co-transfected in reporter gene assays. The mutation causes a dominant-negative HNF1A protein variant which blocks HNF1A wild-type-mediated gene expression.The novel Q495X mutation is the likely cause of our patient's diabetes and hepatic adenomatosis. It may also cause her father's impaired glucose tolerance. More generally speaking, if non-autoimmune diabetes is suspected, examination of the liver may provide important diagnostic clues. Furthermore, patients with hepatic adenomatosis without known diabetes should be screened by OGTT. Relatives of patients with HNF1A mutations should also be screened by OGTT to detect potential early-stage diabetes.

The principle of homeostasis in the hypothalamus-pituitary-adrenal system: new insight from positive feedback.

Feedback control, both negative and positive, is a fundamental feature of biological systems. Some of these systems strive to achieve a state of equilibrium or "homeostasis". The major endocrine systems are regulated by negative feedback, a process believed to maintain hormonal levels within a relatively narrow range. Positive feedback is often thought to have a destabilizing effect. Here, we present a "principle of homeostasis," which makes use of both positive and negative feedback loops. To test the hypothesis that this homeostatic concept is valid for the regulation of cortisol, we assessed experimental data in humans with different conditions (gender, obesity, endocrine disorders, medication) and analyzed these data by a novel computational approach. We showed that all obtained data sets were in agreement with the presented concept of homeostasis in the hypothalamus-pituitary-adrenal axis. According to this concept, a homeostatic system can stabilize itself with the help of a positive feedback loop. The brain mineralocorticoid and glucocorticoid receptors-with their known characteristics-fulfill the key functions in the homeostatic concept: binding cortisol with high and low affinities, acting in opposing manners, and mediating feedback effects on cortisol. This study supports the interaction between positive and negative feedback loops in the hypothalamus-pituitary-adrenal system and in this way sheds new light on the function of dual receptor regulation. Current knowledge suggests that this principle of homeostasis could also apply to other biological systems.

High plasma VEGF relates to low carbohydrate intake in patients with type 2 diabetes.

OBJECTIVE: Vascular endothelial growth factor (VEGF) has been suggested to enhance glucose transport across the blood-brain barrier, thereby increasing brain glucose supply. Increased brain glucose concentration is known to suppress food intake and to decrease body mass via action on hypothalamic regulation centers. Based on the crucial role of VEGF on brain glucose supply, we hypothesized that higher VEGF concentrations are associated with lower food intake and body mass in humans. METHODS: Intending to investigate subjects with high variance of blood glucose, we examined patients with type 2 diabetes mellitus. Our hypothesis was tested in a population-based cohort of 190 subjects with type 2 diabetes. Plasma VEGF levels in conjunction with other parameters known to modulate food intake were measured and subsequently correlated with food intake patterns at a breakfast buffet as well as with body mass. RESULTS: We found that subjects with higher concentrations of plasma VEGF had 17% less carbohydrate intake (P=0.003) and 4.8% lower body mass (P=0.017) than those with lower VEGF concentrations. Intake of protein and fat did not correlate with VEGF concentrations. These associations of plasma VEGF were confirmed in multiple linear regression analyses controlling for several parameters interacting with food intake. CONCLUSION: We conclude that high plasma VEGF concentrations are associated with less carbohydrate intake and lower body mass in type 2 diabetes. The role VEGF plays in facilitating glucose access to the brain represents a new aspect of food intake regulation and energy homeostasis, with relevance for diseases with body mass disturbances.

Antecedent hypoglycaemia attenuates vascular endothelial growth factor response to subsequent hypoglycaemia in healthy men.

AIM: The plasma concentration of vascular endothelial growth factor (VEGF) has recently been shown to increase sharply in response to hypoglycaemia and, thus, has been proposed as having a role in hypoglycaemia counter-regulation. Many counter-regulatory hormones show a reduced response after antecedent hypoglycaemia. We therefore investigated whether this decrease in responsiveness with repetitive hypoglycaemia also pertains to VEGF. METHODS: Three hypoglycaemic clamp experiments were performed on two consecutive days in 15 healthy men. VEGF response was assessed during the first and last hypoglycaemic period. RESULTS: As expected, plasma VEGF concentrations rose markedly during the clamps (P < 0.001). The increase was distinctly blunted during the third (+13 +/- 8 pg/ml) as compared with the first (+54 +/- 18 pg/ml) hypoglycaemic clamp (P = 0.046). CONCLUSION: This data confirms that circulating VEGF concentrations increase acutely during hypoglycaemia. Like the counter-regulatory hormones, the hypoglycaemia-induced rise in VEGF is attenuated after antecedent hypoglycaemia. The origin of increased systemic VEGF concentration during hypoglycaemia and its physiological role remains to be defined.