[Gastroenteropancreatic neuroendocrine neoplasms. Role of biopsies]. / Neuroendokrine Neoplasien der Bauchspeicheldrüse und des Gastrointestinaltrakts. Was leistet die Biopsie?

Neuroendocrine neoplasms of the pancreas and the gastrointestinal tract are heterogeneous regarding etiology (e.g. sporadic or hereditary), histomorphology, hormone expression, hormone-related functional activity and especially the malignant potential. In neuroendocrine neoplasms the biopsy-based diagnosis plays an important role for the clinical management of patients. The diagnosis most importantly relies on the differentiation (e.g. organoid versus diffuse growth patterns) and the grading of tumors. The latter is based on the proliferation activity as determined by Ki-67 immunostaining and mitotic count and results in the current tumor classification into neuroendocrine tumors G1, neuroendocrine tumors G2 or neuroendocrine carcinomas G3. Occasionally, tumors may show mixed differentiation containing a non-neuroendocrine cancer component. The neuroendocrine markers synaptophysin and chromogranin A are recommended for the immunohistochemical confirmation of the diagnosis. Furthermore, biopsy material can be used to investigate the expression of therapy-related markers, such as somatostatin receptor-2A. Moreover, if needed, the expression of transcription factors and hormones can be determined to obtain information on the possible site of origin of metastatic neuroendocrine neoplasms or to determine the syndrome-inducing hormone in functionally active neuroendocrine neoplasms. Finally, using the stomach as an example, biopsies may also be successfully used to investigate neuroendocrine precursor lesions which may harbor prognostic significance.

Otros tumores neuroendocrinos pancreáticos: glucagonomas, VIPomas, somatostatinomas, no funcionantes y tumores con secreción ectópica / Other pancreatic neuroendocrine tumors: glucagonomas, vipomas, somatostatinomas, nonfunctioning tumors and ectopic hormonesecreting tumors

Los tumores neuroendocrinos pancreáticos son poco frecuentes y representan entre el 1 y el 2% de los tumores pancreáticos. Habitualmente se presentan de forma aislada, pero pueden hacerlo asociados a otros tumores dentro del síndrome de neoplasia endocrina múltiple tipo 1 (MEN1) o el síndrome de Von Hippel-Lindau. Los tumores neuroendocrinos no funcionantes suponen aproximadamente el 30-40% de los tumores neuroendocrinos pancreáticos, se presentan con síntomas derivados de la compresión o invasión de estructuras cercanas y su diagnóstico se basa en la determinación de marcadores tumorales no específicos, como la cromogranina A. Los tumores endocrinos funcionantes distintos de gastrinoma e insulinoma (glucagonomas, VIPomas, somatostatinomas) son extremadamente raros y suelen acompañarse de un síndrome clínico muy característico. Su diagnóstico se basa en la determinación de los péptidos específicos segregados por cada tumor. En ocasiones, los tumores neuroendocrinos pancreáticos pueden liberar hormonas peptídicas características de otras glándulas endocrinas, no presentes en el tejido pancreático en condiciones normales (secreción hormonal ectópica). Estos tumores generalmente son de gran tamaño y fáciles de localizar, pero en ocasiones son necesarias técnicas muy específicas para su localización (ecografía endoscópica, gammagrafía con octreótida, angiografía). El diagnóstico suele realizarse de forma tardía, y es frecuente la presencia de metástasis. A pesar de la existencia de enfermedad diseminada un subgrupo de pacientes presentan una supervivencia prolongada. De los múltiples tratamientos disponibles (quimioembolización, radiofrecuencia, quimioterapia, análogos de somatostatina, interferón α) ninguno, salvo la resección completa del tumor, puede curar la enfermedad (AU)

Endocrine tumors of the pancreas are infrequent, representing between 1 and 2% of pancreatic tumors. These tumors are usually solitary, but may occur in association with other tumors within multiple endocrine neoplasia type 1 (MEN-1) syndrome or Von Hippel-Lindau syndrome. Nonfunctioning endocrine tumors represent approximately 30 to 40% of endocrine tumors of the pancreas, manifesting as compression symptoms or invasion of surrounding structures. Diagnosis of these tumors is based on determination of general tumoral markers such as chromogranin A. Functioning endocrine tumors other than gastrinoma and insulinoma (glucagonomas, vipomas, somatostatinomas) are extremely infrequent and are usually accompanied by a characteristic clinical syndrome. The diagnosis of these tumors is based on determination of specific peptides segregated for each tumor. Pancreatic endocrine tumors can sometimes release peptide hormones characteristic of other endocrine glands, which are not present in pancreatic tissue under normal conditions (ectopic hormone secretion). These tumors are usually large and easy to localize. However, highly specific techniques are sometimes required for their localization (endoscopic ultrasonography, octreotide scintigraphy, angiography). Diagnosis is usually made late and metastases are common. Despite the presence of disseminated disease, a subgroup of patients show prolonged survival. Of the multiple treatments available (chemoembolization, radiofrequency, chemotherapy, somatostatin analogs, interferon-alpha), the only curative therapy is complete tumoral resection (AU)

Serum resistin levels of obese and lean children and adolescents: biochemical analysis and clinical relevance.

OBJECTIVE: It was hypothesized that resistin links obesity with diabetes, but this has not been studied in children and adolescents to date. PATIENTS: We determined serum resistin levels of 135 obese (body mass index, 32.0 +/- 6.2 kg/m2; age, 12.6 +/- 3.4 yr) and 201 lean children (body mass index, 18.7 +/- 2.4 kg/m2; age, 12.5 +/- 2.5 yr) by a newly developed and extensively evaluated in-house immunoassay. These results were controlled for their association with markers of puberty, obesity, and insulin sensitivity. RESULTS: The analytical evaluation of our assay revealed different resistin isoforms with major peaks of higher than 660 and 55 kDa in the size exclusion chromatography. Using this assay system we found no difference in the resistin levels of obese compared with lean subjects (P = 0.48). However, resistin was significantly higher in girls than in boys (6.74 +/- 2.42 vs. 5.79 +/- 2.45; P < 0.001). Interestingly, in both obese and lean children, resistin correlated with age (P < 0.01), Tanner stage, and testosterone and estradiol levels (P < 0.05). In contrast, no significant correlation was found with parameters of insulin resistance such as homeostasis model assessment, insulin sensitivity index, or insulin, proinsulin, and glucose concentrations in obese subjects. CONCLUSIONS: Resistin appears to be not the main link between obesity and insulin resistance in children and adolescents but because of its association with Tanner stage, it may be related to the maturation of children during pubertal development. Additionally, we have demonstrated the presence of different molecular isoforms of resistin in human blood, and this may raise problems in comparing data from diverse assay systems.

Stimulated resistin expression in white adipose of rats with bile duct ligation-induced liver cirrhosis: relationship to cirrhotic hyperinsulinemia and increased tumor necrosis factor-alpha.

Resistin, an adipose-derived polypeptide hormone, is proposed as a candidate of insulin resistance, although its roles in inhibiting adipogenesis and in inflammation have also been suggested. Liver cirrhosis is characterized by elevated circulating proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), hyperinsulinemia and insulin resistance. The study aimed to examine resistin expression and its association with insulin and TNF-alpha in a cirrhotic rat model using bile duct ligation (BDL). The BDL-induced cirrhotic rats showed significantly lower fat mass, insulin sensitivity and elevated plasma insulin and TNF-alpha compared to sham animals. In addition, epididymal TNF-alpha and resistin mRNA and protein levels were higher in cirrhotic rats. In normal control rats, in vivo insulin infusion and ex vivo administration of TNF-alpha to cultured fat pads increased resistin gene expression significantly. These results implied that hyperinsulinemia and increased TNF-alpha levels might upregulate adipose resistin gene in BDL-induced liver cirrhosis. Further study is necessary to document the role of resistin in metabolic abnormalities of liver cirrhosis.

Changes in adipocyte hormones leptin, resistin, and adiponectin in thyroid dysfunction.

Thyroid hormones as well as the recently discovered secretory products of adipose tissue adiponectin and resistin take part in energy metabolism. To study the changes in the adipocyte hormones with changes in the thyroid functional status, we measured adiponectin, resistin, and leptin in 69 subjects with Graves' disease before and 32 patients at follow up after treatment for hyperthyroidism at hypothyroid state. Concentrations of serum adiponectin and resistin were higher in hyperthyroid state than in hypothyroid state (adiponectin: 5.73 +/- 1.1 vs. 3.0 +/- 0.5 ng/ml, P = 0.03) (resistin: 6.378 +/- 0.6 vs. 5.81 +/- 0.57 ng/ml, P < 0.0001). Resistin levels correlate positively with free t4(r = 0.37, P < 0.01), free t3 levels(r = 0.33, P < 0.01) and negatively with TSH(r = -0.22, P < 0.05). Adiponectin levels correlate with free t4(r = 0.33, P < 0.01) and free t3 (r = 0.44, P < 0.01). Though the adiponectin levels did not correlate with leptin or resistin levels, strong positive correlation of both resistin and adiponectin with thyroid hormones is noted. Serum levels of leptin did not change with change in the thyroid functional status (leptin: 53.38 +/- 2.47 vs. 55.10 +/- 2.58 NS). Leptin levels did not correlate with resistin and adiponectin. We conclude that thyroid function has effect on adipocyte hormones adiponectin and resistin but not leptin.

Resistin promotes 3T3-L1 preadipocyte differentiation.

OBJECTIVE: To investigate the relationship between resistin (a potential link between obesity and type 2 diabetes) and preadipocyte differentiation. DESIGN: A rat resistin expression vector was transfected into 3T3-L1 preadipocytes and differentiation was compared between normal 3T3-L1 cells, rat resistin-transfected cells and non-transfected cells grown in conditioned medium taken from resistin-expressing cultures. METHODS: The rat resistin gene was inserted into the pDual GC and pEFGP-N2 expression vectors for examination of the effects of resistin overexpression in 3T3-L1 cells before and after differentiation was stimulated with 3-isobutyl-1-methyxanthine (MIX), insulin and dexamethasone (DEX). Smaller conserved fragments were inserted into short interference RNA (siRNA) expression vectors, for examination of the effect of targeted resistin inhibition on differentiation of resistin-overexpressing 3T3-L1 cells. RESULTS: Prior to stimulation, the resistin-transfected 3T3-L1 cells contained many more small lipid droplets than did non-transfected 3T3-L1 cells. Following stimulation, differentiation in the resistin-transfected 3T3-L1 cells was dramatically promoted, especially in the early stages. Stimulation of differentiation was also observed in non-transfected 3T3-L1 cells grown in resistin protein-containing conditioned medium. The expression of adipocyte differentiation-associated markers such as CCAAT enhancer binding protein (C/EBPalpha), retinoid X receptor (RXRalpha) and lipoprotein lipase (LPL) was upregulated in resistin-overexpressing cells, whereas expression of preadipocyte factor-1 (Pref-1), an inhibitor of preadipocyte differentiation, was downregulated. In addition, expression of two of the three tested siRNAs inhibited the adipoconversion process, providing further evidence that resistin promotes the differentiation of preadipocytes to adipocytes. CONCLUSION: Resistin can promote preadipocyte differentiation. Based on this, we propose that resistin may be an important candidate mediator of obesity-induced insulin resistance.

[Ectopic hormone-producing tumors--research and clinics].

Recent progress in endocrinology, cytokine research, and oncology has provided new information for further understanding of ectopic hormone-producing tumors. The mechanisms responsible for this morbidity need further investigations to clarify the neuroendocrine nature of tumor cells. Meanwhile, a common hormonal substance produced by a specific tumor could serve as a specific tumor marker for the tumor, as is the case of ProGRP for small cell lung cancer. The development of drugs for ectopic hormonal syndrome might be a good lesson of the molecular targeting for hormone signaling pathways. It is reasonable to postulate that the clinical entities covered by the term 'ectopic humoral syndrome' will be increasing.

Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis.

Resistin is an adipose-derived hormone that has been proposed as a link among obesity, insulin resistance, and diabetes. In agreement with a role of resistin in insulin resistance, the administration of recombinant resistin led to glucose intolerance in mice and impaired insulin action in rat liver. However, the regulation of resistin expression by physiological conditions, hormones, or agents known to modulate insulin sensitivity does not always support the association between resistin and obesity-induced insulin resistance. In the present study we investigated the effects of leptin administration on adipose resistin expression in insulin-resistant and obese ob/ob mice. We show that the expression of resistin mRNA and protein in adipose tissue is lower in ob/ob than in wild-type control mice, in agreement with the reduced adipocyte resistin mRNA level reported in several models of obesity. Leptin administration in ob/ob mice resulted in improvement of insulin sensitivity concomitant with a decrease in resistin gene expression. The lack of effect of leptin on resistin in db/db mice indicated that the leptin inhibitory action on resistin expression requires the long leptin receptor isoform. In addition, we demonstrated that the effect of leptin on resistin expression was centrally mediated. High-fat feeding in C57BL/6J wild-type mice, which is known to induce the development of obesity and insulin resistance, produced an increase in resistin expression. Interestingly, in both ob/ob and high fat-fed mice we obtained a striking positive correlation between glycemia and resistin gene expression. In conclusion, our results demonstrate that leptin decreases resistin expression and suggest that resistin may influence glucose homeostasis.

Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein.

BACKGROUND & AIMS: Goblet cells are highly polarized exocrine cells found throughout the small and large intestine that have a characteristic morphology due to the accumulation of apical secretory granules. These granules contain proteins that play important physiologic roles in cellular protection, barrier function, and proliferation. A limited number of intestinal goblet cell-specific proteins have been identified. In this study, we investigate the expression and regulation of RELMbeta, a novel colon-specific gene. METHODS: The regulation of RELMbeta messenger RNA expression was determined in LS174T, Caco-2, and HT-29 cell lines in response to stimulation with interleukin 13 and lipopolysaccharide. Quantitative reverse-transcription polymerase chain reaction, immunoblots, and immunohistochemistry were used to examine the expression of RELMbeta in BALB/c and C.B17.SCID mice housed in conventional, germ-free, and gnotobiotic environments. RESULTS: Messenger RNA for RELMbeta is restricted to the undifferentiated, proliferating colonic epithelium. Immunohistochemistry shows that this protein is expressed in goblet cells located primarily in the distal half of the colon and cecum with lower levels detectable in the proximal colon. High levels of RELMbeta can be detected in the stool of mice and humans, where it exists as a homodimer under nonreducing conditions. Interestingly, the secretion of RELMbeta is dramatically reduced in germ-free mice. Furthermore, introduction of germ-free mice into a conventional environment results in enhanced expression and robust secretion of RELMbeta within 48 hours. CONCLUSIONS: These studies define a new goblet cell-specific protein and provide the first evidence that colon-specific gene expression can be regulated by colonization with normal enteric bacteria.

Antagonism of ghrelin receptor reduces food intake and body weight gain in mice.

BACKGROUND AND AIMS: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects of the gastric peptide ghrelin and GHS-R antagonists on energy balance and glycaemic control in mice. MATERIALS AND METHODS: Body weight, fat mass, glucose, insulin, and gene expression of leptin, adiponectin, and resistin in white adipose tissue (WAT) were measured after repeated administrations of ghrelin under a high fat diet. Gastric ghrelin gene expression was assessed by northern blot analysis. Energy intake and gastric emptying were measured after administration of GHS-R antagonists. Repeated administration of GHS-R antagonist was continued for six days in ob/ob obese mice. RESULTS: Ghrelin induced remarkable adiposity and worsened glycaemic control under a high fat diet. Pair feeding inhibited this effect. Ghrelin elevated leptin mRNA expression and reduced resistin mRNA expression. Gastric ghrelin mRNA expression during fasting was increased by a high fat diet. GHS-R antagonists decreased energy intake in lean mice, in mice with diet induced obesity, and in ob/ob obese mice; it also reduced the rate of gastric emptying. Repeated administration of GHS-R antagonist decreased body weight gain and improved glycaemic control in ob/ob obese mice. CONCLUSIONS: Ghrelin appears to be closely related to excess weight gain, adiposity, and insulin resistance, particularly under a high fat diet and in the dynamic stage. Gastric peptide ghrelin and GHS-R may be promising therapeutic targets not only for anorexia-cachexia but also for obesity and type 2 diabetes, which are becoming increasingly prevalent worldwide.

Resistin is expressed in the human placenta.

The mechanism for decreased insulin sensitivity in pregnant women is not fully clarified. Resistin, a novel peptide hormone, is specifically expressed in the adipose tissue and decreases insulin sensitivity in rodents. In the present study, we demonstrate resistin gene expression in the human placental tissue, mainly in trophoblastic cells. The resistin gene expression in term placental tissue was more prominent than was seen in the first trimester chorionic tissue. In contrast resistin gene expression in adipose tissue was rather weak and remained unchanged by pregnancy. Thus, resistin is a newly isolated placental hormone in humans which may modulate insulin sensitivity during pregnancy.

[Pre- and intraoperative localization of neuroendocrine tumors]. / Untersuchungen zur prä- und intraoperativen Lokalisation von neuroendokrinen Tumoren.

Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors of colorectal cancer have shown improved assessment of tumor spread and changes in surgical management based on added information gained by radioimmunoguided surgery. Following the injection of 180 MBq [111In-DTPA-D-Phe1]-pentetreotide and/or 500 MBq 99mTc-dimercaptosuccinic acid (both for dual-radionuclide scintigraphy) preoperative somatostatin receptor imaging [11 patients with GEP tumors] and dual-radionuclide scintigraphy. (8 patients with relapsing medullary thyroid carcinomas) was performed. One patient with a metastasizing pheochromocytoma underwent 123]-MIBg scintigraphy. Results were combined with the information obtained from conventional imaging modalities. Intraoperative radiodetection was performed 24 hours after administration of [111In-DTPA-D-Phe1]-pentetreotide or 4 hours following the injection of 99mTc(V)DMSA using a hand-held gamma probe (Tec Probe 2000. Stratec, FRG). Intraoperative gamma counting localized 39 somatostatin receptor positive lesions of GEP tumors whereas preoperative receptor imaging visualized 81%, surgical palpation 41% and radiological imaging modalities localized only 31%. In 8 patients with recurrent medullary thyroid carcinoma the surgeon was successful in localizing and removing 18 tumor lesions by the help of the gamma probe. Dual-radionuclide scintigraphy revealed 77% (Octreoscan 5/18; 99mTc-V-DMSA 9/18), surgical palpation 55% and conventional imaging methods (CT, sonography) only 38% of all lesions detected intraoperatively by the hand-held gamma probe. In summary, this preliminary data show that intraoperative hand-held gamma probe detection of microscopic and occult endocrine tumors is feasible and more sensitive than external scintigraphy and conventional imaging.

[Peptide hormone].

Clinical studies have confirmed the efficacy of peptide hormone as a routine tumor marker in the diagnosis, monitoring, and assessment of the prognosis of patients with endocrine tumors. However, in a large number of cancer patients, including those with ectopic hormone-producing tumors, the peptide hormone has limited clinical use as a routine tumor marker because of its poor specificity for tumor tissue and its low concentration in the patient sera. A new analysis product, ProGRP, is a specific and reliable serum tumor marker for small cell lung carcinoma (SCLC). It is useful not only in the evaluation of prognosis but also in the detection of SCLC at an early stage. On the other hand, recently, the RET proto-oncogene has been identified as a gene responsible for multiple endocrine neoplasia (MEN) syndromes: MEN 2A and MEN 2B. In the future, serum peptide hormone markers and molecular genetic markers may be useful in the diagnosis of endocrine tumors.

A rare case of ectopic antidiuretic hormone-producing pancreatic adenocarcinoma: new diagnostic approach.

We describe a 73-year old man with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to an ectopic ADH-producing pancreatic adenocarcinoma. His laboratory findings showed marked hyponatremia, and the water load test showed uncontrolled ADH secretion. The imaging studies revealed pancreatic body cancer. Histological examination revealed an adenocarcinoma of the pancreas, which was positive for ADH immuno-staining. The ADH in the tumor extract was 53.3 pg/g wet weight. In attempt to diagnose ADH-production from the tumor, the ADH in his pancreatic juice was measured and found to be 2.1 pg/ml. We conclude that it is valid to measure the ADH in pancreatic juice to diagnose ectopic ADH production by tumors.

Predictive testing of radiosensitivity in non-small cell carcinoma of the lung.

The paper reviews the prognostic factors which influence the radiosensitivity of non-small cell lung cancer. The clonogenic cell numbers, hypoxic fraction, tumour cell kinetics and inherent radiosensitivity are considered. In the future the measurement of these factors may play an important role in decision making as to the best management for patients with non-small cell lung cancer.

Small cell undifferentiated carcinoma of the pancreas. Report of a patient with tumor marker studies.

BACKGROUND: Small cell undifferentiated carcinoma of the pancreas is a rare type of pancreatic neoplasm. METHODS: The authors report the clinical and pathologic aspects of a patient with this malignant lesion and an extensive serologic and immunohistochemical survey of potential ectopically produced hormones or tumor markers. RESULTS: Neuron-specific enolase (NSE) emerged as a tumor marker. CONCLUSIONS: NSE could be valuable in the diagnosis and management of other patients with this rare disease.

[Ectopic hormone producing cells in non-small cell lung carcinoma (non-SCLC) and heterogeneity of lung cancer].

68 cases of non-SCLG were investigated by immunohisto-chemical technique to detect ectopic hormone producing cells and to study the heterogeneity of non-SCLC. Histologic heterogeneity was observed in 11 of 68 non-SCLC and 24 (35.3%) cases displayed hormone immunoreactivity. Ten cases were positive for NSE. More than one type of hormone producing cells could be detected in 11 tumors. Both neutral and acid mucoproteins in variable quantities were observed in 17 tumors that contained the hormone or NSE producing cells. The results indicate that there is functional heterogeneity in non-SCLC, and all types of lung carcinoma may have a common cellular origin.

Proliferation in pituitary adenomas: measurement by MAb KI 67.

The monoclonal antibody MAb KI 67 reacts with a nuclear antigen throughout the entire cell cycle and allows easy evaluation of proliferating tumour cells on routinely prepared smear and frozen sections. 120 pituitary adenomas were investigated by use of the monoclonal antibody KI 67 in a two-step avidin-biotin-peroxidase complex (ABC) technique. The KI 67 labelling index (LI) ranged in all adenomas from 0.2 to 4.6%. In 90 cases of transphenoidally operated adenomas the dura of the sella floor was investigated histologically. Adenomas with histologically proven dural infiltration showed a statistically significant higher KI 67 LI (p less than 0.001) compared to non-invasive adenomas.