Prevention and management of carcinoid crises in patients with high-risk neuroendocrine tumours undergoing peptide receptor radionuclide therapy (PRRT): Literature review and case series from two Australian tertiary medical institutions.

Peptide receptor radionuclide therapy (PRRT) is an important therapeutic option for somatostatin receptor (SSTR) positive metastatic and/or inoperable neuroendocrine tumours (NETs). However, in patients with poorly controlled carcinoid syndrome, it may lead to an acute flare of carcinoid symptoms or even carcinoid crisis. We report seven patients who received PRRT with (177Lu-DOTA0, Tyr3) octreotate (177Lu-octreotate-LuTate) across two Australian tertiary medical institutions who developed acute flare of carcinoid symptoms/carcinoid crisis during/after PRRT. Cases were identified as high-risk due to previous history of carcinoid crises, high tumour burden and markedly elevated tumour markers. We propose a protocol to prevent and manage severe carcinoid symptoms in high-risk patients treated with PRRT.

Gastrin: from pathophysiology to cancer prevention and treatment.

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Gastric type I carcinoid: a pilot study with human G17DT immunogen vaccination.

CONTEXT: Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence. OBJECTIVE: To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid. SETTING: Padua teaching Hospital, outpatient clinic. DESIGN AND PATIENTS: Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36 months. MAIN OUTCOME MEASURES: Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters. RESULTS: Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases. CONCLUSIONS: Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.

Prospective study of dietary fiber, whole grain foods, and small intestinal cancer.

BACKGROUND & AIMS: Although a number of epidemiologic studies have found dietary fiber and whole grains to be inversely associated with colorectal cancer incidence, studies of dietary and other risk factors for small intestinal cancer have been sparse and all of a case-control design. We conducted a prospective cohort study to determine the relationship between intake of dietary fiber/whole grains and the incidence of small intestinal cancer. METHODS: We analyzed dietary data collected in 1995 and 1996 from 293,703 men and 198,618 women in the National Institutes of Health-AARP Diet and Health Study. We used multivariate Cox proportional hazards models to estimate relative risk (RR) and 2-sided 95% confidence intervals (CIs) for quintiles of dietary fiber and whole grain intake. RESULTS: Through 2003, 165 individuals developed small intestinal cancers. Dietary fiber/whole grain intake was generally associated with a lower risk of small intestinal cancer. The multivariate RRs (95% CIs; 5th vs 1st intake quintile) were 0.79 (0.43-1.44; P trend, .41) for total dietary fiber, 0.51 (0.29-0.89; P trend, .01) for fiber from grains, and 0.59 (0.33-1.05; P trend, .06) for whole grain foods. CONCLUSIONS: Intake of fiber from grains and whole-grain foods was inversely associated with small intestinal cancer incidence; the RR values were consistent with those from the same dietary factors for large bowel cancer in this cohort. In conjunction with the anatomic and physiologic commonalities of the large and small bowel, as well as the mutually increased risks for second cancer for both organs, grain fiber and whole grain foods seem to protect against lower gastrointestinal cancers.

Development of carcinoid tumors of the glandular stomach and effects of eradication in Helicobacter pylori-infected Mongolian gerbils.

The relation between Helicobacter pylori (Hp) eradication and prevention of stomach carcinoid development has hitherto remained unclear. We therefore examined this problem using an Hp-infected and Hp-eradicated Mongolian gerbil (MG) model. Enterochromaffin-like (ECL) lesions (hyperplasia/dysplasia and carcinoid) were histopathologically evaluated in the glandular stomachs of Hp-infected and Hp-eradicated MGs. In addition, serum gastrin levels were analyzed. Hp infection induced significant increase in the development of ECL lesions in the glandular stomach, as well as serum gastrin levels as compared with non-infected MGs, while Hp eradication was associated with significant alleviation. The development of ECL lesions in the glandular stomach strongly correlated with titers of anti-Hp antibodies and serum gastrin levels in MGs. In conclusion, Hp infection induces carcinoid development, and Hp eradication prevents its occurrence in the glandular MG stomach, this being strongly linked with reduction in serum gastrin levels.

Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils.

Helicobacter pylori (Hp) infection and gastric carcinogenesis are known to have a close relationship, but the effect of eradication of Hp on Hp-related gastric carcinogenesis has not been fully studied experimentally. To evaluate the effect of eradication in gastric carcinogenesis, an experimental model with eradication in the early, middle or late period was studied using Hp-infected and N-methyl-N-nitrosourea (MNU)-treated Mongolian gerbils. The animals were divided into seven groups: group A (MNU + Hp + eradication at 15 w), group B (MNU + Hp + eradication at 35 w), group C (MNU + Hp + eradication at 55 w), group D (MNU + Hp), group E (MNU), group F (Hp) and group G (control). The tumor incidences at week 75 in the early (group A), middle (group B) and late (group C) eradicated groups were 6.7%, 27.3% and 38.2%, respectively. The incidence of 56.3% in the non-eradicated group was the highest (group D). Incidences in group E, group F and group G were 6.3%, 0.0% and 0.0%, respectively. The tumor incidences were related to the period of inflammatory status induced by Hp infection. Hp infection strongly enhanced gastric carcinogenesis initiated with a chemical carcinogen, and following eradication at an early period this enhancing effect was effectively reduced. Eradication at an early stage of inflammation might be effective in preventing Hp-related gastric carcinogenesis.

The gastritis connection: prevention and early detection of gastric neoplasms.

Most gastric polyps, adenocarcinomas, carcinoids, and B cell lymphomas arise on a gastric mucosa damaged by long-standing chronic gastritis. The most common form of chronic gastritis is caused by infection with Helicobacter pylori. All patients with H. pylori infection develop lymphoid aggregates with germinal centers that interact intimally with the gastric mucosa (mucosa-associated lymphoid tissue [MALT]); these follicles are the condition sine qua non for the development of primary B cell mantle lymphomas, also known as MALT lymphomas. As the infection progresses, atrophy of the gastric mucosa develops in a subset of patients, which is replaced by an intestinal-type epithelium (intestinal metaplasia). On this background, dysplasia and adenocarcinomas of the intestinal type may develop. When atrophy is sufficiently severe to impair acid production, the gastrin-producing cells of the antrum increase their secretion of gastrin and stimulate endocrine cells in the corpus, which may eventually proliferate, become dysplastic, and give raise to carcinoids. This development is more frequent in advanced cases of autoimmune gastritis associated with pernicious anemia. On this background, there is also extensive epithelial hyperplasia and the formation of hyperplastic or inflammatory polyps, a small percentage of which may become dysplastic and progress to adenocarcinoma. Chronic exposure of the corpus mucosa to pancreaticoduodenal secretions ("bile reflux") causes reactive mucosal changes that may predispose to neoplasia. Thus, the progression of inflammation to atrophy to metaplasia, and in some cases chronic chemical injury, may give rise, at different times and under the influence of other, unknown stimuli, to most types of gastric tumors. Other types of gastritis, including lymphocytic and granulomatous gastritis, are rare and have not been associated with gastric neoplasia. Awareness of these associations, appropriate treatment policies, and implementation of endoscopic surveillance programs would dramatically reduce the incidence of most types of gastric neoplasms and would allow the detection of many tumors at a stage when endoscopic resection or conservative treatment would still be possible.

Malignant thymic carcinoid is not prevented by transcervical thymectomy in multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant tumour syndrome. It is characterized by primary hyperparathyroidism, pituitary neoplasia and foregut lineage neuroendocrine neoplasia. Malignant thymic carcinoid tumours are an uncommon but important manifestation of MEN 1. Transcervical thymectomy is often advocated as prophylaxis against thymic carcinoids, although there is a paucity of evidence to support the efficacy of this procedure. This is the first report of a malignant thymic carcinoid occurring in an MEN 1 patient following prior parathyroidectomy and transcervical thymectomy. It is concluded that transcervical thymectomy does not reliably provide prophylaxis against thymic carcinoid.

Uptake of 14C- and 11C-labeled glutamate, glutamine and aspartate in vitro and in vivo.

To explore their potential use as in vivo tracers, the uptake of the amino acids glutamine, glutamate and aspartate, labeled with 11C or 14C, was evaluated in tumor cell aggregates, in vivo in rats and a few pilot studies with positron emission tomography (PET) in patients. The uptake in aggregates increased linearly with time, and was competitively inhibited by the same amino acids. The uptake of 14C-glutamate in carcinoid cells (BON) was inhibited by cystine but not by aspartate, contrary to the result in neuroblastoma (LAN). 6-Diazo-oxy-L-norleucine (a glutamine analogue) and Substance P had different effect on the uptake of glutamate in different cells. The metabolic fate of 14C-glutamate was evaluated with protein separation and with HPLC. The in vivo distribution in rats showed the highest uptake of 11C-glutamine and 11C-glutamate in pancreas and kidney, and of 11C-aspartate in the lung. In the human studies with PET, pancreas had the highest uptake followed by kidney with 11C-glutamate, and followed by spleen with 11C-aspartate. A primary pancreas tumour and metastases in liver were difficult to identify except in one case.

Antitumor effect of a neutralizing antibody to vascular endothelial growth factor on liver metastasis of endocrine neoplasm.

Distant metastasis of gastrointestinal endocrine neoplasm is resistant to currently available treatments. Because hematogenic metastasis is dominant, anti-angiogenic drugs are expected to be a novel therapy for this neoplasm. In the present study, the therapeutic effect of vascular endothelial growth factor neutralizing antibody (VEGFAb) on liver metastasis of an endocrine neoplasm was investigated experimentally. Cecal transplantation into nude mice of small pieces of EN-1, a xenotransplanted human intestinal endocrine neoplasm, resulted in liver metastasis. A treated group (n = 19) received 100 micrograms/mouse of VEGFAb intraperitoneally on alternate days from day 10 after tumor transplantation, and the control group (n = 19) received saline. Five of the 19 control mice died of tumor progression, of which 2 could not be evaluated. The cecal tumor weighed 6316 +/- 2333 mg (n = 17) in the control group and 1209 +/- 837 mg (n = 19) in the treated group (P < 0.01) 6 weeks after transplantation. Liver metastasis developed in 16 of 17 control mice and in 2 of 19 treated mice (P < 0.01). The VEGF level of the whole cecal tumor in the control group was significantly higher than that in the treated group (305.1 +/- 174.1 vs. 54.7 +/- 41.2 mg; P < 0.001). VEGFAb did not cause any body weight loss (28.52 +/- 1.63 in the control vs. 28.44 +/- 1.71 g in the treated group). These results indicate that VEGFAb may be a novel therapeutic agent for endocrine neoplasm with distant metastasis.

[Screening of multiple endocrine neoplasias type 1. Reflexions of the Study Group on Multiple Endocrine Neoplasias type 1]. / Dépistage des néoplasies endocriniennes multiples de type 1 (NEM 1). Réflexion du Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1 (GENEM 1).

The "Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1 (GENEM 1)" is a French group involved in a comprehensive multicentre study of Multiple Endocrine Neoplasia type 1 syndrome (NEM 1). The objectives of this group are to define diagnostic and therapeutic protocols and to carry out genetic research on NEM1. The first aim of physicians is to recognize the syndrome and to determine the appropriate screening especially into two circumstances: 1 degree In case of isolated and sporadic glandular disease -i-e-parathyroid glands, endocrine pancreas, antehypophysis, adrenal glands and neuroendocrine tumors? 2 degrees In case of very high probability of NEM 1 syndrome? This paper answers these two questions, based on the analysis of the first 150 cases collected by the GENEM 1.

Screening and prevention of colorectal cancer in Haining County.

From September 15, 1977, to April 15, 1978, 450, 477 persons over the age of 7 years were screened for schistosomiasis; a subgroup of 198,950 over 30 years were screened for colorectal cancer. Seventy-five malignant colorectal tumors were discovered in the latter group, a positive rate of 37.69 per 100,000 (seven were colonic cancers, 14 rectal cancers, 20 polyps with cancerous change, and 34 carcinoids). Of this group, 2701 had various types of polyps and 5242 had definitive diagnostic schistosomiasis. History, physical examination, and an occult blood test are simple, useful methods for detecting late colorectal cancer but are of no value in preventive screening of early cases. While digital rectal examination is an important, effective method of diagnosing rectal cancer, the positive rate is one tenth that of rectoscopy. It cannot be used for mass screening because the examining finger cannot tolerate such constant use and is too short to discover higher tumors. The sequence of colorectal cancerous change found in our center was from normal intestinal epithelium to tumorigenic polyps or colorectal ulcer, to polyps with anaplastic change, to polyps with local cancerous change, to adenocarcinoma. Cancer was seen more frequently in villous and adenomatous polyps; these are called precancerous stages of colorectal cancer. No relationship between schistosomiasis and colorectal cancer was found.