Deletions of RDINK4/ARF enhancer in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors.

OBJECTIVE: The presence of an enhancer element, RD (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of p15, p14ARF, and p16 genes. However, knowledge about RD alterations and its potential contributions to cancer progression remains limited. In this study, we aimed to evaluate the incidence of RD alterations in pancreatic tumors. METHODS: DNAs from 14 gastrinomas and 6 nonfunctioning pancreatic neuroendocrine tumors were subjected to quantitative real-time polymerase chain reaction-based assays to determine deletions in p15, p14ARF, and p16 (both exons 1 and 2). RESULTS: RD was frequently deleted in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors with an incidence of 30% (6/20 samples). In comparison, the incidences of deletions of p15 (exon 1), p14ARF (exon 1ß), and p16 (exon 1α) are 10% (2/20 samples), 10% (2/20 samples), and 45% (9/20 samples), respectively. Whereas some RD deletion events arose from deletions of the entire INK4-ARF locus, RD deletions in some specimens seemed to be independent of genetic alterations in any of the p15, p14ARF, and p16 genes. CONCLUSIONS: Our results strongly support that the deletion of RD may represent a novel mechanism to simultaneously downregulate p15, p14ARF, and p16, thus contributing to the development of human pancreatic cancers.

Primary lymph node gastrinoma: a rare cause of abdominal pain in childhood.

Gastrinoma is a hormone-secreting tumor associated with the Zollinger-Ellison syndrome. It is quite rare among children. The discovery of gastrinomas in unusual locations such as lymph nodes, bones, ovaries, and the liver poses a diagnostic dilemma as to whether the tumor is primary or metastatic. Here, we present a case of a primary gastrinoma within a lymph node.

Gastrin: an acid-releasing, proliferative and immunomodulatory peptide?

Gastrin release is affected by gastric inflammatory conditions. Antral G cells respond to inflammatory mediators by increasing gastrin secretion. Accumulating experimental evidence suggests that gastrin exerts immunomodulatory and proinflammatory effects. Gastrin could be a contributing factor to these pathologies, which may constitute a new justification for pharmacological blockade of gastrin action.

Gastrinoma: sporadic and familial disease.

The physiologic sequelae of a gastrinoma can be well controlled with medical therapy. The role of surgery has shifted from managing acid hyper-secretion and ulcer complications to preventing metastatic disease and managing symptomatic metastases. With improved methods of imaging for the detection of occult gastrinomas, the prospective evaluation of the role for surgery in altering the natural history of these tumors is now possible.

Current advances in the diagnosis and treatment of pancreatic endocrine tumors.

PURPOSE OF REVIEW: A comprehensive literature review of more than 200 original manuscripts published in the last 18 months was conducted to summarize landmark studies performed on the molecular biology, diagnosis, imaging, and treatment of endocrine tumors of the pancreas. RECENT FINDINGS: Recent achievements occurred on many fronts. Identification of a novel insulin splice variant with increased translation efficiency moved forward the understanding of the molecular biology of insulinomas. Results of a 29-year prospective study from the National Institutes of Health clarified the epidemiology of multiple endocrine neoplasia-1 syndrome. Chromogranin A was identified as a promising marker for pancreatic endocrine tumors. New imaging, including F-dopa positron emission tomography and laparoscopic ultrasound, and the effective combination of existing modalities localized and staged tumors with greater accuracy. Nonoperative treatment strategies show promise; discovery of the antiangiogenic properties of octreotide and the overexpression of tyrosine kinase receptors such as c-kit, epidermal growth factor receptor, and platelet-derived growth factor receptor on malignant endocrine pancreatic tumors may lead to promising pharmacologic treatment. SUMMARY: There have been exciting recent advancements in research surrounding endocrine pancreas that hopefully will pave the way for potential improvement in clinical outcomes for patients with these tumors.

Sindrome de Zollinger-Ellison: uma revisao / Zollinger-Ellison syndrome: review article

Apesar de sua raridade, a Sindrome de Zollinger-Ellison (SZE) foi alvo de intensos estudos, os quais contribuiram para a construcao da moderna endocrinologia gastrointestinal. Tradicionalmente, as estrategias diagnosticas e terapeuticas voltaram-se apenas ao controle da hipersecrecao gastrica, obtido geralmente atraves da gastrectomia total. Entretanto, com o desenvolvimento de drogas eficazes na inibicao da secrecao gastrica, as atencoes tem se voltado as possibilidades de resseccao cirurgica e cura do processo neoplasico. A localizacao do tumor (atraves de estudos bioquimicos, radiologicos e endoscopicos) e uma etapa essencial para o...

Early effects of standard and pylorus-preserving pancreatectomy on myoelectric activity and gastric emptying.

BACKGROUND/AIMS: The main concern about pylorus preserving pancreatectomy (PPP) is delayed gastric emptying (GE). Both cancer and surgical procedures cause damage to the enteric nervous system and induce profound changes in gastric motility and emptying. The aim was to evaluate the effects of primary disease and type of surgical procedure used (standard pancreatoduodenectomy, SP vs. PPP) on myoelectric activity (MA), and solid and liquid GE in pancreatectomy patients. METHODOLOGY: Twenty-eight subjects were included, 18 after Whipple (group A) and 10 after a Traverso (group B) procedure. MA was captured by cutaneous electrodes (Synectics) and simultaneously LGE tested with ultrasonography. On separate days, the SGE of a radiolabelled meal was measured. MA and GE studies were done before and within three months after surgery. RESULTS: Before surgery LGE/SGE were delayed in 5/8 patients in group A and 2/2 in group B. Gastric dysrhythmia was observed in 6 patients in group A and 1 in group B. After PPP, the nasogastric tube was removed within 8.4+/-4.9 days and after SP within 4.6+/-4.1 days. GE studies showed accelerated LGE/SLG in 16/12 and delayed in 6/5 patients, respectively, in group A and B. Dysrhythmia was observed in 16 patients in group A and in 4 in group B. There was a strong relationship between SGE delay and dysrhythmia in patients after PPP. CONCLUSIONS: We conclude that papilla of Vater neoplasia damages mechanisms responsible for gastric emptying to a lesser extent than pancreatic cancer. In patients after PPP, post-operative MA disturbances are partially responsible for delayed GE.

The effect of Zollinger-Ellison syndrome and neuropeptide-secreting tumors on the stomach.

Zollinger-Ellison syndrome (ZES) is caused by a tumor that secretes gastrin and is the most common of the malignant islet cell tumors. ZES leads to hypergastrinemia, which, in turn, causes an overproduction of gastric acid and results in complications of peptic ulcer disease. Of all the islet cell tumors, gastrinoma tumors have undergone the most extensive study, providing a model of tumor management. Increased awareness and improved biochemical and radiologic techniques mean that these disorders are being recognized in more patients. Advances in the management of gastric acid secretion and new localization methods have significantly reduced the morbidity and mortality associated with ZES. The use of intravenous proton pump inhibitors such as pantoprazole will make surgical and perioperative management more favorable for patients. Radiologic and nuclear medicine studies permit the detection of the majority of islet cell tumors and improve the ability for surgical resection. With the recent cloning of the gene for multiple endocrine neoplasia type I (MEN-I) and the recognition of tumor markers associated with the development of islet cell tumors, early detection of these tumors may someday be possible.

Endocrine diffuse system. Histological and functional aspects interrelated with tumoral pathology.

It was first believed that all these endocrine cells are deriving from the neural crests; in time were discovered more than 40 different types of such cells with different origins and only 6 or 7 are deriving from the neural crests. Serotonin-secreting cells show yellow fluorescence, while those secreting cathecolamines show a green fluorescence, with formaldehyde. The most usual method for the stain of the cells of the endocrine diffuse system is the silver salts impregnation. In the electron microscopy the cells show dense granules, which are modified in appearance in the malignancies developed from such cells. Most of the hormones secreted in the intestine were found also to be hormones secreted in the central nervous system. The border between benign proliferation and malignant tumors arising from these endocrine cells is not well defined. DNES--diffuse neuroendocrine system.

A 7-year-old child with primary tumour localisation in the distal duodenum--new imaging procedures for an improved diagnosis.

UNLABELLED: Duodenal gastrinomas in childhood are extremely rare and often missed at first medical consultation. We report on a 7-year-old child with sporadic gastrinoma of primary localisation in the distal duodenum. Small metastases in the liver and regional nodes were detected pre-operatively by somatostatin receptor scintigraphy (SRS) but not by other conventional imaging procedures. Diagnostic procedures include pre-operative SRS, endoscopic ultrasound and intra-operative endoscopic transillumination. CONCLUSION: Gastrinomas are rare abdominal tumours in childhood. Pre-operative tumour-specific diagnosis is possible by 111indium pentreotide SRS.

Mechanisms of bombesin on growth of gastrinoma (PT) in vivo.

The growth of the human gastrinoma model (PT) in athymic nude mice is stimulated by bombesin (BBS), an amphibian peptide homologous to both human gastrin-releasing peptide (GRP) and neuromedin B (NMB). The mechanism is not known, and a potent and specific GRP-R antagonist BIM26226, which has low affinity for NMB-R, was used in vivo in athymic nude mice bearing gastrinoma subcutaneously. Both the BBS and BIM26226 stimulated the growth of PT, and the growth stimulation was even greater when given together. RT-PCR study of gastrinoma revealed the presence of both GRP-R and NMB-R mRNA, but much more abundant NMB-R mRNA. We conclude that BBS-stimulated growth of gastrinoma involves both GRP-R and NMB-R, and our findings suggest that GRP-R mediates negative and NMB-R produces positive growth effects on gastrinoma.

Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior.

The goal of this study was to provide information of prognostic value for gastric endocrine tumors. A total of 205 gastric endocrine tumors have been studied: 193 well differentiated tumors [2 gastrin cell tumors, 191 enterochromaffin-like (ECL) cell tumors] and 12 poorly differentiated carcinomas. Subtyping of ECL cell tumors (carcinoids) resulted in 152 associated with chronic atrophic gastritis (CAG) (type 1); 12 associated with hypertrophic gastropathy (HG) due to Zollinger-Ellison syndrome with multiple endocrine neoplasia type I (type 2), and 27 with no specific association (type 3, sporadic). Type 1 cases occurred most often in female (108 of 152), elderly (mean 63 years) patients, with no tumor-related death at an overall mean follow-up of 53 months. The 12 type 2 cases were equally distributed between the sexes (six of each), with a mean age of 45 years; there was one tumor-related death (49 months after diagnosis) and an overall mean survival of 84 months. Type 3 cases were mostly in men (20 of 27), with a mean age of 55 years; there were seven tumor-related deaths at a mean follow-up of 28 months. Poorly differentiated neuroendocrine carcinomas were observed in elderly patients (mean 63 years, range 41-76 years) of both sexes, with nine tumor-related deaths and a mean survival of 7 months. It was concluded that correct clinicopathologic subtyping may predict the clinical behavior of gastric endocrine tumors.

Caracterización hormonal de los adenomas hipofisarios no funcionantes / Hormonal characterization of the non fuctioning pituitary adenomas

Se estudiaron 98 pacientes con adenomas no funcionantes, 34 hombres y 64 mujeres, realizando un estudio hormonal en suero para conocer su perfil endocrino. Con tal objeto, se efectuaron determinaciones de hormona folículo estimulante y hormona luteinizante (FSH, LH), prolactina (PRL), estadiol (E2), testosterona (T), cortisol, hormona del crecimiento (GH), hormona adrenocorticotrópica (ACTH), hormona estimulante del tiroides (TSH) y gastrina (Ga) por radioinmunoanálisis. Los resultados mostraron marcado hipergonadotropismo en el 47//de los pacientes, con niveles séricos de FSH y LH muy elevados y un incremento inesperado de la concentración de Ga (Grupo I). En contraste, el resto de los pacientes tuvo concentraciones normales o bajas de gonadotrofinas y Ga (Grupo II). El grupo I mostró una relación inversa entre los niveles de gonadotropinas y esteroides gonadales (E2 o T) con cifras significativamente menores que los valores normales y los encontrados en el Grupo II (<0,00l) en el cual la relación fue lineal positiva. Tambien se observó una relación directa entre la concentración de FSH conTSH (r=0,75) y Ga (r=0,80), probablemente por los neurotransmisores que determinan la secreción de estas hormonas. La TSH al igual que las hormonas tiroideas, tuvo cifras más elevadas en el Grupo I, mientras que los valores de PRL fueron más bajos (P<0,0001). La concentración de GH y ACTH fuer normal en ambos,no obstante,el 33 por ciento de los pacientes del Grupo II presentó hipocortisolismo e hipotiroidismo. La edad promedio de los pacientes analizada por décadas, no fue estadísticmente diferente entre los grupos y no explica las diferencias encontradas, aunque en el Grupo I predominaron las mujeres. En éstas, la elevación de FSH podría estar condicionada por la deficiencia gonadal, acorde a la edad de las pacientes (49,8 9,6 años), sin embargo, algunos valores fueron extraordinariamente elevados y existe la posibilidad de que la hipófisis en condiciones patológicas, como es la forma adenomatosa,pueda producir en forma autónoma,moléculas de LH y FSH alteradas y carentes de actividad biológica, o bien, subunidad O libre, como se ha demostrado en algunos gonadotropomas. Por otra parte, algunos de los casos con TSH elevada podrían considerarse verdaderos TS-Homas, que no suprimen su secreción a pesar de la elevada concentración de hormonas tiroideas. Así, podría decirse que dentro de los no funcionantes, están enmarcados algunos de estos adenomas. Se concluye que, desde el punto de vista hormonal, los adenomas del Grupo II son los verdaderos no funcionantes

Caracterización hormonal de los adenomas hipofisarios no funcionantes / Hormonal characterization of the non fuctioning pituitary adenomas

Se estudiaron 98 pacientes con adenomas no funcionantes, 34 hombres y 64 mujeres, realizando un estudio hormonal en suero para conocer su perfil endocrino. Con tal objeto, se efectuaron determinaciones de hormona folículo estimulante y hormona luteinizante (FSH, LH), prolactina (PRL), estadiol (E2), testosterona (T), cortisol, hormona del crecimiento (GH), hormona adrenocorticotrópica (ACTH), hormona estimulante del tiroides (TSH) y gastrina (Ga) por radioinmunoanálisis. Los resultados mostraron marcado hipergonadotropismo en el 47//de los pacientes, con niveles séricos de FSH y LH muy elevados y un incremento inesperado de la concentración de Ga (Grupo I). En contraste, el resto de los pacientes tuvo concentraciones normales o bajas de gonadotrofinas y Ga (Grupo II). El grupo I mostró una relación inversa entre los niveles de gonadotropinas y esteroides gonadales (E2 o T) con cifras significativamente menores que los valores normales y los encontrados en el Grupo II (<0,00l) en el cual la relación fue lineal positiva. Tambien se observó una relación directa entre la concentración de FSH conTSH (r=0,75) y Ga (r=0,80), probablemente por los neurotransmisores que determinan la secreción de estas hormonas. La TSH al igual que las hormonas tiroideas, tuvo cifras más elevadas en el Grupo I, mientras que los valores de PRL fueron más bajos (P<0,0001). La concentración de GH y ACTH fuer normal en ambos,no obstante,el 33 por ciento de los pacientes del Grupo II presentó hipocortisolismo e hipotiroidismo. La edad promedio de los pacientes analizada por décadas, no fue estadísticmente diferente entre los grupos y no explica las diferencias encontradas, aunque en el Grupo I predominaron las mujeres. En éstas, la elevación de FSH podría estar condicionada por la deficiencia gonadal, acorde a la edad de las pacientes (49,8 Ð 9,6 años), sin embargo, algunos valores fueron extraordinariamente elevados y existe la posibilidad de que la hipófisis en condiciones patológicas, como es la forma adenomatosa,pueda producir en forma autónoma,moléculas de LH y FSH alteradas y carentes de actividad biológica, o bien, subunidad Ó libre, como se ha demostrado en algunos gonadotropomas. Por otra parte, algunos de los casos con TSH elevada podrían considerarse verdaderos TS-Homas, que no suprimen su secreción a pesar de la elevada concentración de hormonas tiroideas. Así, podría decirse que dentro de los no funcionantes, están enmarcados algunos de estos adenomas. Se concluye que, desde el punto de vista hormonal, los adenomas del Grupo II son los verdaderos no funcionantes

Zollinger-Ellison syndrome. A new look at regression of gastrinomas.

Of 44 patients with the Zollinger-Ellison syndrome treated at our institution, nine appeared to have undergone "regression" of their gastrinomas. Six of the nine patients had sporadic gastrinomas and became permanently eugastrinemic following excision of nodal metastases and total gastrectomy (n = 4), antrectomy (n = 1), or pancreatoduodenectomy (n = 1) (mean survival, 13 years). The other three patients had Zollinger-Ellison syndrome as part of the multiple endocrine adenopathy type 1 syndrome and became temporarily eugastrinemic after total gastrectomy (mean survival, 11 years). Occult submucosal duodenal-wall microgastrinomas (mean size, 3.0 mm) were found to have been serendipitously excised in four patients. Long-term follow-up of these nine patients, as well as of six other patients described in the literature, demonstrates that excision of occult duodenal-wall gastrinomas provides a plausible explanation for the phenomenon of apparent regression of primary gastrinomas and the eugastrinemia that may follow total gastrectomy.