Robert T. Jensen

Gastroenteropancreatic neuroendocrine tumours

Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay.

The regional distribution of cholecystokinin (CCK) in the rat brain was determined utilizing a radioimmunoassay which detects both gastrin and CCK. CCK concentration is highest in the caudate nucleus (10-14 ng CCK 8 equivalents/mg protein), followed by the cerebral cortex. Within the cerebral cortex, CCK is highest in the cingulate, pyriform, and entorhinal areas. There are substantial CCK concentrations in all other brain regions except pons, medulla and cerebellum. CCK is widely distributed in the hypothalamus, where it is highest in the median eminence and ventromedial nucleus. Considerable CCK-like immunoreactivity is also present in the posterior lobe of the pituitary gland, but is not detectable in anterior and intermediate lobes. Though the antisera used in this study cross-react with gastrin the dominant CCK-like material found in rat brain co-elutes with sulfated CCK 8 and separates from gastrin on Sephadex G-25 and HPLC chromatography.

Gastrointestinal Neuroendocrine Tumors : Pancreatic Endocrine Tumors

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patients health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.

Determinants of metastatic rate and survival in patients with zollinger-ellison syndrome: A prospective long-term study

BACKGROUND/AIMS It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES). METHODS Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively. RESULTS Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases. CONCLUSIONS Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.

Somatostatin Receptor Scintigraphy: Its Sensitivity Compared with That of Other Imaging Methods in Detecting Primary and Metastatic Gastrinomas: A Prospective Study

Studies have shown that many tumors, such as gastroenteropancreatic tumors (pancreatic endocrine tumors, carcinoid tumors), various lymphomas, and central nervous system tumors (meningiomas, astrocytomas), have a high density of somatostatin receptors and can be imaged in vivo by using somatostatin receptor scintigraphy with either [123I-Tyr3]octreotide or [111In-DTPA-DPhe1]octreotide [1-6]. Recently, [111In-DTPA-DPhe1]octreotide was approved for use in the United States for the imaging of primary and metastatic neuroendocrine tumors [6]. Many conventional imaging methods, including ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), selective arteriography, and selective intra-arterial secretin stimulation with venous sampling, already exist for the localization of gastroenteropancreatic tumors [7-10]. Although numerous studies have shown somatostatin receptor scintigraphy to be sensitive for the detection of neuroendocrine tumors, information on its sensitivity compared with that of other imaging techniques is limited; thus, it is difficult for the practitioner to define the potential role of somatostatin receptor scintigraphy in the evaluation of a patient with a gastroenteropancreatic syndrome. This is important because somatostatin receptor scintigraphy and the other imaging studies are expensive [1] and because accurate localization of the primary tumor is particularly important for the management of neuroendocrine tumors, which are often small and difficult to find [11-13]. Furthermore, accurate assessment of the extent of the tumor is essential for making decisions about resectability, tumoricidal therapy, disease progression, and liver transplantation [8, 14, 15]. Because neuroendocrine tumors are uncommon [8], many studies do not provide the data needed to define the role of somatostatin receptor scintigraphy in the management of these tumors. Several studies have compared the sensitivity of somatostatin receptor scintigraphy with that of ultrasonography or CT by assessing tumor detection on a lesion-by-lesion basis. However, few studies have compared somatostatin receptor scintigraphy with the most sensitive conventional imaging studies, particularly selective arteriography and MRI using STIR (short-time inversion-inversion recovery sequences) [8, 16, 17]. Thus, it is difficult to know the sensitivity and the role of somatostatin receptor scintigraphy in relation to these methods. Furthermore, only one study [18] has evaluated the possibility of conventional imaging combined with somatostatin receptor scintigraphy; therefore, it remains unclear whether additional localization studies are helpful when somatostatin receptor scintigraphy results are negative. Finally, most studies have not assessed the sensitivity of somatostatin receptor scintigraphy relative to other methods in different clinical situations. Patients with gastroenteropancreatic tumors are assessed for location of the primary tumor (to assist in possible tumor resection [7, 11-13]), for metastasis to the liver (for possible resectability [8, 14, 19, 20]), for the need for tumoricidal therapy [21], and for distant metastases (for possible specific tumoricidal therapies, such as local radiation to bone metastases [22]). Different localization methods are better for certain clinical situations [8, 9, 17], and somatostatin receptor scintigraphy needs to be compared with other methods in each of these clinical circumstances. Sixty percent to 90% of patients with the Zollinger-Ellison syndrome have malignant tumors, and their tumors thus resemble all pancreatic endocrine tumors with the exception of insulinomas [8, 23, 24]. The Zollinger-Ellison syndrome occurs more frequently than other malignant pancreatic endocrine tumors. Therefore, several groups, including ours, have a sufficient number of patients with this syndrome to be able to systematically address questions about localization in different clinical situations [8, 25, 26]. Gastrinomas resemble other, less common pancreatic endocrine tumors in that they are composed of amine precursor uptake and decarboxylation (APUD) cells and have similar growth patterns, locations, imaging properties, metastatic rates, immunohistochemistry, and rates of occurrence of somatostatin receptors [24, 27]. Gastrinomas are therefore an excellent model from which to obtain information that is also pertinent to the less common pancreatic endocrine tumors [25]. We prospectively compared the ability of somatostatin receptor scintigraphy with that of other conventional localization methodsultrasonography, CT, MRI, bone scanning, and selective angiographyin the localization of primary and metastatic gastrinoma in patients with the Zollinger-Ellison syndrome. Methods We prospectively studied 80 consecutive patients with the Zollinger-Ellison syndrome who were admitted to the National Institutes of Health (NIH) between June 1994 and May 1995. Our study is part of a prospective study of patients with the Zollinger-Ellison syndrome that has been ongoing at the NIH since 1974, as approved by the clinical research committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Thirty-one of the patients had no previous gastrinoma resection, and 49 had had noncurative resections of gastrinomas 0.25 years to 13 years before the study. The Zollinger-Ellison syndrome was diagnosed as described elsewhere [28]. Serum gastrin levels were determined by Bioscience Laboratories (New York, New York). The diagnostic criteria for the presence of multiple endocrine neoplasia type I in a patient with the Zollinger-Ellison syndrome have been described elsewhere [29]. Basal acid output and maximal acid output were determined for each patient by using methods described previously [30]. Doses of oral antisecretory drug were determined by establishing the dose required to reduce gastric acid output to less than 10 mEq per hour before the next dose of medication and to less than 5 mEq per hour for patients who had had gastric acid-reducing surgery or who had advanced esophageal disease [31]. Specific Protocol The localization and the extent of gastrinomas were evaluated in all patients as described elsewhere [17, 32] by using upper gastrointestinal endoscopy, CT, MRI, transabdominal ultrasonography [33], and bone scanning. With MRI, T1-weighted spin-echo sequences and STIR sequences were obtained with a repetition time of 400 to 600 ms and an echo time of 10 ms as described [16]. We did CT as described [16, 17] at 10-mm thickness with an oral contrast agent (diatrizoate sodium, Winthrop-Breon, Rensselaer, New York) with and without the rapid (2 mL/s) intravenous injection of the contrast agent iopamidol 300 (Winthrop-Breon). If surgical exploration was being considered or the extent of disease remained unclear, selective abdominal angiography was done with injection of the splenic, superior mesenteric, gastroduodenal, and hepatic arteries as described elsewhere [17, 34]. One radiologist evaluated the results of all conventional imaging studies. For somatostatin receptor scintigraphy studies, patients were hydrated before and after the intravenous injection of [111In-DTPA-DPhe1]octreotide and were given a laxative on the night of administration to avoid artifacts from radioactive accumulation in the intestines. Each patient received 6 mCi of [111In-DTPA-DPhe1]octreotide intravenously as recommended by the manufacturer for single-photon emission computed tomographic (SPECT) imaging (Mallinckrodt Diagnostic Imaging Service Radiopharmacy, Beltsville, Maryland). Images were obtained 4 and 24 hours after injection using a TRIONIX (Twinburg, Ohio) or ADAC (Milipitas, California) dual-headed camera with 20% windows at 173 and 247 keV. At 4 hours, a 30-minute whole-body scan was obtained; 10-minute planer spot views of the abdomen and other regions were obtained as needed. At 35 minutes and at 24 hours, SPECT images of the abdomen were obtained. Forty-second, 128 128 matrix SPECT images were acquired at 4-degree intervals over 360 degrees. The images were reconstructed with the manufacturers software using a standard filter back projection algorithm. A Hamming filter was used. Images were displayed as orthogonal (transverse, coronal, sagittal) sections and as reprojected views. Results of somatostatin receptor scintigraphy were obtained while the investigator was blinded to the results of the conventional imaging studies. Surgical exploration was done in all new patients and all patients who had a positive extrahepatic gastrinoma localized, had no liver metastases, had multiple endocrine neoplasia type I or a recent exploration (< 2 years), and had had exploratory laparotomy for possible gastrinoma resection (n = 15). All patients with possible liver metastases had percutaneous CT- or ultrasonography-guided biopsies (n = 24). Statistical Analysis The Fisher exact test was used to compare independent percentages, and the McNemar test was used to compare sensitivities in the same patients. Two-tailed P values and 95% CIs from the StatXact statistical package (Version 3.0, Cytel Software Corp., Cambridge, Massachusetts) are reported. P values less than 0.05 were considered statistically significant. Results The clinical and laboratory characteristics of the 80 study patients are shown in Table 1. These patients resemble patients in other large series [8, 35] with regard to sex, age, multiple endocrine neoplasia type I, basal acid output, maximal acid output, fasting serum gastrin concentration, and disease duration. Table 1. Clinical and Laboratory Characteristics of Patients with the Zollinger-Ellison Syndrome* Somatostatin receptor scintigraphy detected tumors either inside or outside of the liver in 56 of the 80 patients (70%); conventional imaging studies were significantly less sensitive (P < 0.001) (Figure 1). Angiography, CT, and MRI each detected tumors in 38% to 45% of patients; ultrasonograph

NANETS treatment guidelines: Well-differentiated neuroendocrine tumors of the stomach and pancreas

Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major subtypes of gastrointestinal NETs. Historically, there has been little consensus on the classification and management of patients with these tumor subtypes. We provide an overview of well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the treatment of patients with these malignancies.

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB1), the gastrin-releasing peptide (GRP) receptor (BB2), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB3). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB3 has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions.

Cdna Cloning, Characterization, and Brain Region Specific Expression of a Neuromedin-b Preferring Bombesin Receptor

Recent binding studies in the central nervous system and other tissues provide evidence that the mammalian bombesin-like peptides, gastrin-releasing peptide (GRP) and neuromedin-B (NMB), exert their numerous physiological effects through at least two different receptors. We describe the structure and expression of a cloned NMB-preferring bombesin receptor (NMB-R) with properties distinct from a GRP-preferring bombesin receptor (GRP-R) reported previously. In particular, the NMB-R shows higher affinity binding to NMB than to GRP in BALB 3T3 fibroblasts expressing the cloned NMB-R. The distinct regional distribution of NMB-R and GRP-R mRNA in the brain suggests that both bombesin receptor subtypes play independent roles in mediating many of the dramatic effects of bombesin-like peptides in the central nervous system.

ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes.

Pancreatic endocrine tumors (p-NETs) include both pancreatic neuroendocrine tumors (p-NETs) associated with a functional syndrome (functional p-NETs) or those associated with no distinct clinical syndrome (non-functional p-NETs) [1,2,3,4]. Non-functional p-NETs frequently secrete pancreatic polypeptide, chromogranin A, neuron-specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides, but they do not usually produce specific symptoms and thus are considered clinically to be non-functional tumors [2,3,5,6,7]. Only the functional p-NETs will be considered in this section. The two most common functional p-NETs (gastrinomas, insulinomas) are considered separately, whereas the other well-described and possible rare functional p-NETs are considered together as a group called rare functional p-NETs (RFTs) (table ​(table1)1) [1,2,3,4]. Table 1 Functional pancreatic endocrine tumor (PET) syndromes Gastrinomas are neuroendocrine neoplasms, usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES). ZES is characterized by gastric acid hypersecretion resulting in severe peptic disease (peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD)) [8,9,10]. In this section, ZES due to both duodenal and pancreatic gastrinomas will be covered together because clinically they are similar [8,10]. Specific points related to gastrinomas associated with the genetic syndrome of Multiple Endocrine Neoplasia type 1 (MEN1) (25% of cases) will also be mentioned [11,12]. Insulinomas are neuroendocrine neoplasms located in the pancreas that secrete insulin, which causes a distinct syndrome characterized by symptoms due to hypoglycemia [2,13,14,15]. The symptoms are typically associated with fasting and the majority of patients have symptoms secondary to hypoglycemic central nervous system (CNS) effects (headaches, confusion, visual disturbances, etc.) or due to catecholamine excess secondary to hypoglycemia (sweating, tremor, palpitations, etc.) [2,3,13,14,15]. RFTs can occur in the pancreas or in other locations (VIPomas, somatostatinomas, GRHomas, ACTHomas, p-NETs causing carcinoid syndrome or hypercalcemia (PTHrp-omas)) (table ​(table1)1) [1,2,3,4,5,7]. Each of the established RFT syndromes is associated with a distinct clinical syndrome reflecting the actions of the ectopically secreted hormone. Other RFTs are listed as causing a possible specific syndrome either because there are too few cases or there is disagreement about whether the described features are actually a distinct syndrome (table ​(table1)1) [1,2,3,4,5,7].

Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel‐Lindau disease (VHL), neurofibromatosis 1 (NF‐1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF‐1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed. Cancer 2008;113(7 suppl):1807–43. Published 2008 American Cancer Society.