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In cases of carcinoid crisis, the surgical or nonsurgical manipulation should be temporarily interrupted, blood volume should be substituted under the guidance of hemodynamic parameters and additional doses of i. For postoperative pain, epidural analgesia is preferred [ 58 , 59 ]. Almost all the symptoms that patients with Zollinger-Ellison syndrome ZES present are due to the effects of the gastric acid hypersecretion which is characteristic of this disease mean basal acid output is 6—7 fold higher than normal.

In gastrinoma patients, gastric acid hypersecretion should, therefore, always be treated first. In the past, surgery total gastrectomy was the only effective means of controlling the effects of acid hypersecretion. Both proton pump inhibitors PPIs and high dose histamine H2-receptor antagonists are effective, but PPIs are the drugs of choice because of their greater potency, longer duration of action and ease of administration [ 60 ].

Octreotide and lanreotide in dosages comparable to those used for carcinoid syndrome can also control acid hypersecretion in patients with gastrinomas and have a favorable outcome for prognosis and survival of patients [ 61 , 62 ]. The combination of PPI and somatostatin congeners offers an advantageous additive effect on gastric acid suppression.

Caution has to be taken in somatostatin analogue therapy in these patients, since hypoglycemia may worsen due to a more profound suppression of counterregulatory hormones, such as glucagon and growth hormone, than tumor-produced insulin. A subsequent test dose of short-acting octreotide can then be administered and blood glucose levels monitored over a period of 3—4 h. When these levels increase, the patient might benefit from one of the longer acting somatostatin congeners. Diazoxide is effective in controlling hypoglycemia, acting to reduce insulin secretion by opening ATP-sensitive potassium KATP channels in insulinoma cells and has an extrapancreatic hyperglycemic effect of increasing gluconeogenesis.

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Daily dosages of 50— mg are generally used. Side effects are edema, renal impairment, and hirsutism.

Neuroendocrine cell

Thiazide diuretics enhance the effects of diazoxide by further antagonizing insulin release and counteracting edema from sodium retention. Verapamil, glucocorticoids and phenytoin, drugs which might all reduce insulin secretion, have also been used with variable success [ 68 , 69 ].

Recent studies have demonstrated that abnormalities in the mammalian target of rapamycin mTOR pathway may be critical to the development of neuroendocrine tumors. Aberrant signaling upstream of mTOR in cancer cells then causes increased production of angiogenic growth factors and cell growth or proliferation, in addition to growth factor signaling. Hyperglycemia and impaired glucose tolerance have, therefore, been reported as important side effects of the mTOR inhibitor everolimus [ 70 ]. In metastatic insulinomas mTOR inhibitors can reduce hypoglycemic episodes by reduction of the tumor mass, by reduction of the insulin secreting capacity, or by increasing insulin resistance [ 71 , 72 ].

In the RADIANT-4 study everolimus was used for the treatment of advanced nonfunctional neuroendocrine tumors of the lung or gastrointestinal tract.

Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumor activity with acceptable tolerability across a broad range of neuroendocrine tumors, including those arising from the pancreas, lung, and gastrointestinal tract [ 73 , 74 ].

Other therapies directed at reducing tumor mass and, thereby, reducing insulin hypersecretion in patients with metastatic, malignant insulinomas are streptozotocin-based chemotherapy schedules and peptide receptor radiotherapy [ 77 — 79 ]. In patients with glucagonomas, hyperglycemia can be controlled using insulin or oral blood glucose lowering drugs [ 80 , 81 ]. In both benign and malignant glucagonoma, octreotide and lanreotide are effective in controlling necrolytic migratory erythema, but less effective in the management of weight loss and diabetes mellitus, and ineffective in reducing the incidence of venous thrombosis, all common presenting conditions in glucagonoma.

Aspirin therapy or low-dose heparin has been used for the prevention of thromboembolic disease. Topical or oral zinc therapy has been used to ameliorate necrotic migratory erythema [ 82 ]. Hypoaminoacidemia and mineral deficiencies should also be corrected. Glucocorticoids can also potentially improve diarrhea, presumably by inhibition of VIP release and by enhancing sodium absorption in the intestinal tract.

Further control of diarrhea can be acquired using loperamide and opiates [ 83 ]. Higher i. Acromegaly in patients with ectopic growth hormone-releasing hormone GHRH production can be controlled by somatostatin congeners, cabergoline, growth hormone receptor blockers, or by combinations of these agents [ 88 — 90 ].

Humoral hypercalcemia of malignancy in patients with paraneoplastic parathyroid hormone related peptide PTHrp production can be controlled by somatostatin congeners and bisphosphonates, but not by cinacalcet [ 91 , 92 ].

Neuroendocrine Parvocellular Neurons - Watts - - Major Reference Works - Wiley Online Library

As detailed above, new classes of sst subtype-selective analogues have been developed. As every sst has distinct biological functions, these new congeners may prove valuable, both in the treatment of tumors that are sensitive to the currently available octapeptide analogues, and also in tumors that express sst subtypes other than sst2 and sst5. Pasireotide S0M is a so-called universal somatostatin analogue with high affinity for sst1, sst2, sst3, and sst5 receptor subtypes [ 93 ]. New drugs which interact and cross talk with multiple receptor families are being developed. These sst subtype homo- or heterodimers may have properties which are distinct from the usual responses of individual receptors in terms of internalization, agonist-induced desensitization, and functional activity.

BIMA, an example of such a compound, targets sst2 and dopamine D2 receptors [ 94 ]. More sst antagonists are currently in pre-clinical development [ 95 ]. Gastrinomas preferentially express BB2, while ileal carcinoids often express BB1 [ 96 ]. Ongoing studies examine the expression of neurotensin receptors such as receptor subtype NRT1 , substance P such as receptor subtype NK1 , neuropeptide Y and other peptides in endocrine tumors of the gastrointestinal tract and pancreas. High levels of glucagon-like peptide-1 GLP-1 receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization using exendindiethylenetriaminepentaacetic acid DTPA conjugates [ 97 — 99 ].

LX, a drug which was designed to reduce diarrhea in patients with metastatic carcinoid tumors, is currently undergoing clinical trials. National Center for Biotechnology Information , U. Journal List Arch Med Sci v. Arch Med Sci. Published online Jun 1. Author information Article notes Copyright and License information Disclaimer. Corresponding author. E-mail: lp. Received Aug 16; Accepted Apr 7. This article has been cited by other articles in PMC. Keywords: neuroendocrine tumors, hormonal syndrome. Introduction Neuroendocrine tumors of the gastrointestinal tract and pancreas may produce one of several peptide hormones.

Somatostatin analogues Somatostatin is a small cyclic peptide hormone, which is present in the human body in the molecular forms SRIF consisting of 14 amino acids and SRIF consisting of 28 amino acids [ 6 ]. Table I Somatostatin congener binding affinities to sst subtypes. Open in a separate window.

Carcinoid syndrome Carcinoids of the small intestine previously designated as midgut carcinoids are the most likely to cause carcinoid syndrome. Medical therapy of carcinoid syndrome Treatment of carcinoid syndrome with somatostatin analogues The use of somatostatin analogues to block the release of vasoactive peptides and amines is the mainstay for the control of the symptoms of carcinoid syndrome.

Other therapies for carcinoid syndrome In patients with carcinoid syndrome, biotherapy with somatostatin congeners and interferon are the treatments of choice. Peptide receptor radionuclide therapy PRRT of gastroenteropancreatic tumors An individualized approach towards PRRT with somatostatin analogues has proven to be an effective anti-tumor effects, progression-free survival and survival and safe treatment for sst-positive, unresectable neuroendocrine tumors. Pre- and peri-intervention strategies Patients with midgut carcinoids are pre-treated with short- or long-acting somatostatin analogues to prevent an anesthesia-induced carcinoid crisis during surgery for tumor manipulation, chemoembolization or endoscopic procedures, or other interventions such as teeth extraction [ 56 , 57 ].

Medical therapy of gastrinoma Almost all the symptoms that patients with Zollinger-Ellison syndrome ZES present are due to the effects of the gastric acid hypersecretion which is characteristic of this disease mean basal acid output is 6—7 fold higher than normal. Medical therapy of glucagonoma In patients with glucagonomas, hyperglycemia can be controlled using insulin or oral blood glucose lowering drugs [ 80 , 81 ].

Conflict of interest The authors declare no conflict of interest. References 1.

Mechanisms of Hormone Action

The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev. Gastroenteropancreatic neuroendocrine tumours. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum.


Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Reisine T, Bell GI. Molecular biology of somatostatin receptors. N Engl J Med.

Reubi JC. Virchows Arch. Value of immunohistochemistry for somatostatin receptor subtype sst2a in cancer tissues: lessons from the comparison of antisst2a antibodies with somatostatin receptor autoradiography. Am J Surg Pathol. Expression of somatostatin receptor types in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis.

Somatostatin receptor sstl-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med.