Prostate carcinoma with neuroendocrine differentiation: case report and literature review

Neuroendocrine differentiation in prostatic carcinomas generally confers a more aggressive clinical behavior and less favorable prognosis than usual prostatic carcinomas. In this manuscript, we report a case of a 58-year-old man with prostatic carcinoma who died 1 year after initial diagnosis. Autopsy showed a disseminated prostatic carcinoma with neuroendocrine differentiation. There were metastasis to the spleen, an organ infrequently involved by disseminated epithelial neoplasms. Neuroendocrine differentiation was demonstrated by immunohistochemical studies in the biopsy and autopsy material.

Primary neuroendocrine breast carcinoma: a case report and literature review

The authors present a case of a neuroendocrine carcinoma in an asymptomatic 75-year-old woman, detected in routine breast screening. The lesion was visible at mammography as a well circumscribed, medium density nodule, with no associated microcalcifications, and at ultrasonography as a hypoechoic nodule, with irregular shape and ill-defined margins. Magnetic resonance imaging revealed findings consistent with malignancy.

Resection of liver metastasis from neuroendocrine tumors: evaluation of results and prognostic factors

OBJECTIVES: to determine the prognostic factors that may impact on morbidity and mortality and survival of patients undergoing surgical treatment of liver metastases from neuroendocrine tumors. METHODS: We studied 22 patients undergoing liver resection for metastases from neuroendocrine tumors between 1997 and 2007. Epidemiological and clinical data were correlated with morbidity and mortality and overall and disease-free survivals. RESULTS: twelve patients were male and ten female, with a mean age of 48.5 years. Bilobar disease was present in 17 patients (77.3%). In ten patients (45.5%) the primary tumor originated in the pancreas, terminal ileum in eight, duodenum in two, rectum in one and jejunum in one. Complete surgical resection (R0) was achieved in 59.1% of patients. Eight patients (36.3%) developed complications in the immediate postoperative period, one of them dying from septicemia. All patients undergoing re-hepatectomy and/or two-stage hepatectomy had complications in the postoperative period. The overall survival at one and five years was 77.3% and 44.2%. The disease-free survival at five years was 13.6%. The primary pancreatic neuroendocrine tumor (p = 0.006) was associated with reduced overall survival. Patients with number of metastatic nodules < 10 (p = 0.03) and asymptomatic at diagnosis (p = 0.015) had higher disease-free survival. CONCLUSION: liver metastases originating from pancreatic neuroendocrine tumors proved to be a negative prognostic factor. Symptomatic patients with multiple metastatic nodules showed a significant reduction in disease-free survival.

Neuroendocrine regulation of salt and water metabolism

Neurons which release atrial natriuretic peptide (ANPergic neurons) have their cell bodies in the paraventricular nucleus and in a region extending rostrally and ventrally to the anteroventral third ventricular (AV3V) region with axons which project to the median eminence and neural lobe of the pituitary gland. These neurons act to inhibit water and salt intake by blocking the action of angiotensin II. They also act, after their release into hypophyseal portal vessels, to inhibit stress-induced ACTH release, to augment prolactin release, and to inhibit the release of LHRH and growth hormone-releasing hormone. Stimulation of neurons in the AV3V region causes natriuresis and an increase in circulating ANP, whereas lesions in the AV3V region and caudally in the median eminence or neural lobe decrease resting ANP release and the response to blood volume expansion. The ANP neurons play a crucial role in blood volume expansion-induced release of ANP and natriuresis since this response can be blocked by intraventricular (3V) injection of antisera directed against the peptide. Blood volume expansion activates baroreceptor input via the carotid, aortic and renal baroreceptors, which provides stimulation of noradrenergic neurons in the locus coeruleus and possibly also serotonergic neurons in the raphe nuclei. These project to the hypothalamus to activate cholinergic neurons which then stimulate the ANPergic neurons. The ANP neurons stimulate the oxytocinergic neurons in the paraventricular and supraoptic nuclei to release oxytocin from the neural lobe which circulates to the atria to stimulate the release of ANP. ANP causes a rapid reduction in effective circulating blood volume by releasing cyclic GMP which dilates peripheral vessels and also acts within the heart to slow its rate and atrial force of contraction. The released ANP circulates to the kidney where it acts through cyclic GMP to produce natriuresis and a return to normal blood volume

Neuroendocrine control of body fluid homeostasis

Angiotensin II and atrial natriuretic peptide (ANP) play important and opposite roles in the control of water and salt intake, with angiotensin II promoting the intake of both and ANP inhibiting the intake of both. Following blood volume expansion, baroreceptor input to the brainstem induces the release of ANP within the hypothalamus that releases oxytocin (OT) that acts on its receptors in the heart to cause the release of ANP. ANP activates guanylyl cyclase that converts guanosine triphosphate into cyclic guanosine monophosphate (cGMP). cGMP activates protein kinase G that reduces heart rate and force of contraction, decreasing cardiac output. ANP acts similarly to induce vasodilation. The intrinsic OT system in the heart and vascular system augments the effects of circulating OT to cause a rapid reduction in effective circulating blood volume. Furthermore, natriuresis is rapidly induced by the action of ANP on its tubular guanylyl cyclase receptors, resulting in the production of cGMP that closes Na+ channels. The OT released by volume expansion also acts on its tubular receptors to activate nitric oxide synthase. The nitric oxide released activates guanylyl cyclase leading to the production of cGMP that also closes Na+ channels, thereby augmenting the natriuretic effect of ANP. The natriuresis induced by cGMP finally causes blood volume to return to normal. At the same time, the ANP released acts centrally to decrease water and salt intake.

Necrolytic migratory erythema associated with glucagonoma syndrome: a case report

Necrolytic migratory erythema is a rare skin condition that consists of migrating areas of erythema with blisters that heal with hyperpigmentation. It usually occurs in patients with an alpha islet cell tumor of the pancreas-or glucagonoma-and when associated with glucose intolerance, anemia, hyperglucagonemia, and weight loss defines the glucagonoma syndrome. We describe a 52-year-old female patient with necrolytic migratory erythema associated with glucagonoma syndrome who had metastatic disease at presentation and passed away one week after her admission. The autopsy showed a tumor in the body of the pancreas, which was diagnosed as a neuroendocrine tumor and confirmed by immunohistochemistry. The diagnosis of necrolytic migratory erythema is a matter of great importance, since it might be an auxiliary tool for the early detection of glucagonoma.

The pineal neurohormone melatonin and its physiologic opiatergic immunoregulatory role

The pineal gland functions as a neuroendocrine transducer that coordinate the organism response to changing environmental stimuli such as light and temperature. The main and best known pineal neurohormone is melatonin that is synthesized and released in a circadian fashion with a peak during the night darkness hours. We have recently reported that melatonin exerts important immuno regulatory functions. Here we describe the astonishing property of exogenous melatonin which is able to counteract completely the depressive effect of anxiety-restraint stress and/or of corticosterone on thymus weight, andibody production and antiviral responses. This effect seems to be mediated by antigen-activated T cells via an opiatergic mechanism.

Tumor carcinóide de estômago tipo 1

Gastric carcinoid occurs in less than 1% of gastric neoplasias and around 2% of carcinoids tumors. They are classified into three forms: type 1, associated with atrophic gastritis, type 2, associated with multiple endocrine neoplasia 1 and Zollinger Ellison syndrome, and type 3, a sporadic tumor. This study report a case of gastric carcinoid type 1, which manifested with chronic anemia, dyspeptic symptoms and hypergastrinemia. A 44 years old female patient, presented multiple lesions with diameter between 3 and 20 mm, with lynphonodal metastases. A total gastrectomy was performed associated with lymphnodes ressection and Y Roux reconstruction.

Probable effect of photoperiod on seasonal variation in the nuclear volume of the adrenal cortex of viscacha (Lagostomus maximus maximus)

The neuroendocrine system regulates several organic functions such as reproduction, metabolism and adaptation to the environment. This system shows seasonal changes linked to the environment. The experimental model used in the present study was Lagostomus maximus maximus (viscacha). The reproduction of males of this species is photoperiod dependent. Twenty-four adult male viscachas were captured in their habitat at different times during one year. The adrenal glands were processed for light microscopy. Serial cuts were stained with hematoxylin-eosin for the morphometric study, and 100 nuclei of each zone of the adrenal cortex were counted per animal. Data were analyzed statistically by ANOVA and the Tukey test. The cells of the glomerulosa zone are arranged in a tube-shaped structure. The fasciculata zone has large cells with central nuclei and clearly visible nucleoli and with a vacuolar cytoplasm. In the reticularis zone there are two of types of cells, one with a nucleus of fine chromatin and a clearly visible nucleolus and the other with nuclear pycnosis. Morphometric analysis showed maximum nuclear volumes during the February-March period with values of 133 ± 7.3 µm3 for the glomerulosa, 286.4 ± 14.72 µm3 for the fasciculata, and 126.3 ± 9.49 µm3 for the reticularis. Minimum nuclear volumes were observed in August with values of 88.24 ± 9.9 µm3 for the glomerulosa, 163.7 ± 7.78 µm3 for the fasciculata and 64.58 ± 4.53 µm3 for the reticularis. The short winter photoperiod to which viscacha is subjected could inhibit the adrenal cortex through a melatonin increase which reduces the nuclear volume as well as the cellular activity.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.

Use of neuron-specific enolase for assessing the severity and outcome of neurological disorders in patients

Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. NSE levels in cerebrospinal fluid (CSF) are assumed to be useful to estimate neuronal injury and clinical outcome of patients with serious clinical manifestations such as those observed in stroke, head injury, anoxic encephalopathy, encephalitis, brain metastasis, and status epilepticus. We compared levels of NSE in serum (sNSE) and in CSF (cNSE) among four groups: patients with meningitis (N = 11), patients with encephalic injuries associated with impairment of consciousness (ENC, N = 7), patients with neurocysticercosis (N = 25), and normal subjects (N = 8). Albumin was determined in serum and CSF samples, and the albumin quotient was used to estimate blood-brain barrier permeability. The Glasgow Coma Scale score was calculated at the time of lumbar puncture and the Glasgow Outcome Scale (GOS) score was calculated at the time of patient discharge or death. The ENC group had significantly higher cNSE (P = 0.01) and albumin quotient (P = 0.005), but not sNSE (P = 0.14), levels than the other groups (Kruskal-Wallis test). Patients with lower GOS scores had higher cNSE levels (P = 0.035) than patients with favorable outcomes. Our findings indicate that sNSE is not sensitive enough to detect neuronal damage, but cNSE seems to be reliable for assessing patients with considerable neurological insult and cases with adverse outcome. However, one should be cautious about estimating the severity of neurological status as well as outcome based exclusively on cNSE in a single patient.

p53 immunostaining is correlated with reduced survival and is not correlated with gene mutations in resected pulmonary large cell carcinomas

Malignancy of pulmonary large cell carcinomas (LCC) increases from classic LCC through LCC with neuroendocrine morphology (LCCNM) to large cell neuroendocrine carcinomas (LCNEC). However, the histological classification has sometimes proved to be difficult. Because the malignancy of LCC is highly dependent on proteins with functions in the cell cycle, DNA repair, and apoptosis, p53 has been targeted as a potentially useful biological marker. p53 mutations in lung cancers have been shown to result in expression and protein expression also occurs in the absence of mutations. To validate the importance of both p53 protein expression (by immunostaining) and p53 gene mutations in lung LCC (by PCR-single strand conformational polymorphism analysis of exons 5, 6, 7, and 8) and to study their relationships with clinical factors and sub-classification we investigated the correlation of p53 abnormalities in 15 patients with LCC (5 classic LCC, 5 LCNEC, and 5 LCCNM) who had undergone resection with curative intent. Of these patients, 5/15 expressed p53 and none had mutant p53 sequences. There was a negative survival correlation with positive p53 immunostaining (P = 0.05). After adjustment for stage, age, gender, chemotherapy, radiotherapy, and histological subtypes by multivariate analysis, p53 expression had an independent impact on survival. The present study indicates that p53 assessment may provide an objective marker for the prognosis of LCC irrespective of morphological variants and suggests that p53 expression is important for outcome prediction in patients with the early stages of LCC. The results reported here should be considered to be initial results because tumors from only 15 patients were studied: 5 each from LCC, LCNEC and LCCNM. This was due to the rarity of these specific diseases.

Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice

Sleep disturbances have far-reaching effects on the neuroendocrine and immune systems and may be linked to disease manifestation. Sleep deprivation can accelerate the onset of lupus in NZB/NZWF1 mice, an animal model of severe systemic lupus erythematosus. High prolactin (PRL) concentrations are involved in the pathogenesis of systemic lupus erythematosus in human beings, as well as in NZB/NZWF1 mice. We hypothesized that PRL could be involved in the earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. We also investigated its binding to dopaminergic receptors, since PRL secretion is mainly controlled by dopamine. Female NZB/NZWF1 mice aged 9 weeks were deprived of sleep using the multiple platform method. Blood samples were taken for the determination of PRL concentrations and quantitative receptor autoradiography was used to map binding of the tritiated dopaminergic receptor ligands [³H]-SCH23390, [³H]-raclopride and [³H]-WIN35,428 to D1 and D2 dopaminergic receptors and dopamine transporter sites throughout the brain, respectively. Sleep deprivation induced a significant decrease in plasma PRL secretion (2.58 ± 0.95 ng/mL) compared with the control group (25.25 ± 9.18 ng/mL). The binding to D1 and D2 binding sites was not significantly affected by sleep deprivation; however, dopamine transporter binding was significantly increased in subdivisions of the caudate-putamen - posterior (16.52 ± 0.5 vs 14.44 ± 0.6), dorsolateral (18.84 ± 0.7 vs 15.97 ± 0.7) and ventrolateral (24.99 ± 0.5 vs 22.54 ± 0.7 µCi/g), in the sleep-deprived mice when compared to the control group. These results suggest that PRL is not the main mechanism involved in the earlier onset of the disease observed in sleep-deprived NZB/NZWF1 mice and the reduction of PRL concentrations after sleep deprivation may be mediated by modifications in the dopamine transporter sites of the caudate-putamen.

Cardiovascular and autonomic modulation by the central nervous system after aerobic exercise training

The autonomic nervous system plays a key role in maintaining homeostasis under normal and pathological conditions. The sympathetic tone, particularly for the cardiovascular system, is generated by sympathetic discharges originating in specific areas of the brainstem. Aerobic exercise training promotes several cardiovascular adjustments that are influenced by the central areas involved in the output of the autonomic nervous system. In this review, we emphasize the studies that investigate aerobic exercise training protocols to identify the cardiovascular adaptations that may be the result of central nervous system plasticity due to chronic exercise. The focus of our study is on some groups of neurons involved in sympathetic regulation. They include the nucleus tractus solitarii, caudal ventrolateral medulla and the rostral ventrolateral medulla that maintain and regulate the cardiac and vascular autonomic tonus. We also discuss studies that demonstrate the involvement of supramedullary areas in exercise training modulation, with emphasis on the paraventricular nucleus of the hypothalamus, an important area of integration for autonomic and neuroendocrine responses. The results of these studies suggest that the beneficial effects of physical activity may be due, at least in part, to reductions in sympathetic nervous system activity. Conversely, with the recent association of physical inactivity with chronic disease, these data may also suggest that increases in sympathetic nervous system activity contribute to the increased incidence of cardiovascular diseases associated with a sedentary lifestyle.

Pain-related diseases and sleep disorders

Pain and sleep share mutual relations under the influence of cognitive and neuroendocrine changes. Sleep is an important homeostatic feature and, when impaired, contributes to the development or worsening of pain-related diseases. The aim of the present review is to provide a panoramic view for the generalist physician on sleep disorders that occur in pain-related diseases within the field of Internal Medicine, such as rheumatic diseases, acute coronary syndrome, digestive diseases, cancer, and headache.