Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors.

Background and study aim: As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. Patients and methods: We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. Results: A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 - 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 - 175 months). Two patients presented a tumor recurrence during the follow-up period. Conclusions: Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk.

Endoscopic treatment of severe duodenal polyposis as an alternative to surgery for patients with familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) and severe (stage IV) duodenal polyposis are candidates for pancreaticoduodenectomy, which has high morbidity. Little information is available about the feasibility of therapeutic endoscopy for these patients. OBJECTIVE: To evaluate the long-term efficiency and risks of endoscopic therapy. DESIGN: Retrospective study. SETTING: A 2-referral center long-term cohort study. PATIENTS: Thirty-five FAP patients (15 men, mean age 48 years) presenting with stage IV duodenal polyposis were included. Patients had a mean Spigelman classification score of 9.8 points (range 9-12 points) at their first examination. INTERVENTIONS: Patients underwent a surveillance endoscopy, including lateral and axial viewing with chromoendoscopy while under sedation, along with 7 ± 4.8 therapeutic endoscopic sessions during a follow-up period of 9 ± 4.5 years (range 1-19 years) after their first endoscopy. MAIN OUTCOME MEASUREMENTS: Treatment modalities, adverse events, and efficiency (evolution of the Spigelman score) were reviewed. RESULTS: A total of 245 therapeutic endoscopies were performed and 15 adverse events (6%) occurred. During the follow-up period, Spigelman scores decreased in 95% of patients by 6 ± 2.2 points (P = .002). Modeling analysis showed that the mean Spigelman score decreased by 60% after 150 months. LIMITATIONS: Retrospective study and the duration of the follow-up, even though this is the longest follow-up reported in medical literature. CONCLUSION: Endoscopic treatment of severe duodenal polyposis in patients with FAP produces few adverse events and allows efficient downstaging of the polyposis. Long-term follow-up data did not reveal a high risk of invasive duodenal cancer in these patients.

Contrast-enhanced ultrasound after devascularisation of neuroendocrine liver metastases: functional and morphological evaluation.

OBJECTIVE: To evaluate morphological and perfusion changes in liver metastases of neuroendocrine tumours by contrast-enhanced ultrasound (CEUS) after transarterial embolisation with bead block (TAE) or trans-arterial chemoembolisation with doxorubicin-eluting beads (DEB-TACE). METHODS: In this retrospective study, seven patients underwent TAE, and ten underwent DEB-TACE using beads of the same size. At 1 day before embolisation, 2 days, 1 month and 3 months after the procedure, a destruction-replenishment study using CEUS was performed with a microbubble-enhancing contrast material on a reference tumour. Relative blood flow (rBF) and relative blood volume (rBV) were obtained from the ratio of values obtained in the tumour and in adjacent liver parenchyma. Morphological parameters such as the tumour's major diameter and the viable tumour's major diameter were also measured. A parameter combining functional and morphological data, the tumour vitality index (TVI), was studied. The Wilcoxon rank-sum test and Fisher's test were used to compare treatment groups. RESULTS: At 3 months rBF, rBV and TVI were significantly lower (P = 0.005, P = 0.04 and P = 0.03) for the group with doxorubicin. No difference in morphological parameters was found throughout the follow-up. CONCLUSIONS: One parameter, TVI, could evaluate the morphological and functional response to treatments.

MEN1 missense mutations impair sensitization to apoptosis induced by wild-type menin in endocrine pancreatic tumor cells.

BACKGROUND & AIMS: Missense mutations account for 30% of mutations identified in patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome. They raise several issues: the distinction between pathogenic mutations and polymorphisms is sometimes difficult and the functional effects of missense mutations are unclear. We aimed to evaluate the functional consequences of missense MEN1 mutations in an appropriate endocrine cellular context. METHODS: From the INS-1 insulinoma cell line, we established clones conditionally over expressing wild-type (WT) menin or its A160T, H317Y, and A541T variants. We compared the consequences of WT or variant menin over expression on apoptotic response after gamma-irradiation and analyzed the interactions of these proteins with p53. RESULTS: WT menin over expression sensitized INS-r3 cells to apoptosis through amplification of caspase-3 activation, increased p53 acetylation, and accelerated p21 activation; moreover, over expressed WT menin could be recovered in p53-containing complexes. For all 3 missense mutations tested, the functional effects observed with WT were impaired significantly and only low amounts of variant menin proteins were recovered in p53-containing complexes. CONCLUSIONS: Taking advantage of a new endocrine cellular model, we show a loss of function for 2 missense disease-related menin mutants and for a controversial variant as well. Furthermore, our results suggest the existence of functional interactions between p53 and menin for the control of apoptosis, which may cast new light on the mechanisms of endocrine tumorigenesis.

Well-differentiated endocrine carcinoma of the renal pelvis: report of a case with sustained objective response to octreotide.

Endocrine tumors of the upper urogenital tract are extremely rare. We report the case of a patient with a primary well-differentiated endocrine carcinoma of the renal pelvis metastatic to the liver, in whom an objective response was obtained under octreotide treatment. A 36-year-old woman without symptoms was admitted for exploration of a solid nodule in the right kidney. A right nephrectomy was performed. The histological examination of the surgical specimen diagnosed a primary well-differentiated endocrine tumor of the renal pelvis. Tumor cells strongly expressed synaptophysin and were focally positive for chromogranin A; they displayed faint reactivity for PSAP. Three months later, multiple liver metastases, proved by biopsy, were diagnosed. After two lines of chemotherapy, octreotide treatment was initiated because of persistent high activity at scintigraphic examination. A marked decrease in tumor volume and in chromogranin A serum levels was obtained. Two years later, there was no further progression. The patient was treated with octreotide. Our report points out the unusual immunophenotypic features which may be encountered in well-differentiated endocrine carcinoma of the upper urogenital tract and the potential interest in somatostatin analogues in the treatment of metastatic cases.

In vitro and in vivo studies with [(18)F]fluorocholine on digestive tumoral cell lines and in an animal model of metastasized endocrine tumor.

PURPOSE: The aim of this study was to investigate (a) in vitro the relationship between [(18)F]fluorocholine ([(18)F]FCH) uptake and cell growth in endocrine cell lines and (b) in vivo the uptake of [(18)F]FCH by tumoral sites in an animal model of metastasized endocrine tumor. METHODS: In vitro studies were conducted on three endocrine and two nonendocrine digestive tumoral cell lines. The proliferative ratio was estimated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The uptake of [(18)F]FCH and that of [(18)F]fluorodeoxyglucose ([(18)F]FDG) were measured before and after cytotoxic therapy. [(18)F]FCH biodistribution was studied in nude mice and in an endocrine xenografted mice model. RESULTS: The [(18)F]FCH uptake in tumoral cell lines was related to their proliferative capacities as measured by the MTT assay in basal conditions. After cytotoxic therapy, the IC(50) values calculated with the [(18)F]FCH incorporation test were very close to those determined with the MTT assay. Biodistribution studies showed that [(18)F]FCH was predominantly concentrated in the liver and kidney of nude mice. In the STC-1 xenografted animal model, the uptake of [(18)F]FCH in the primary tumor was only 1.1%. On autoradiography and micro-positron emission tomography, there was no uptake of [(18)F]FCH in liver metastases but there was a significant uptake of [(18)F]FDG. CONCLUSIONS: In vitro studies suggested that the incorporation of [(18)F]FCH in endocrine tumor cell lines was related to their growth capacities; however, in vivo studies conducted in an endocrine xenografted animal model showed an uptake of [(18)F]FCH in hepatic metastases lower than that in normal liver cells. An influence of the microenvironment or a competition phenomenon for [(18)F]FCH uptake between normal liver and endocrine tumor cells cannot be excluded.

Differential involvement of destrin and cofilin-1 in the control of invasive properties of Isreco1 human colon cancer cells.

Actin depolymerizing factor (ADF)/cofilin family proteins are key regulators of actin filament turnover and cytoskeleton reorganization. The role of cofilin-1 in cell motility has been demonstrated in several cell types but remained poorly documented in the case of colon cancer. In addition, the putative function of destrin (also known as ADF) had not been explored in this context despite the fact that it is expressed in all colon cancer cell lines examined. We were therefore prompted to evaluate the respective contributions of these proteins to the invasive properties of the human colon cancer Isreco1 cell line, which expresses a comparatively high destrin/cofilin ratio. Reduction of cofilin-1 or destrin expression in Isreco1 cells using RNA interference led to an increase of the number of multinucleated cells and altered polarized lamellipodium protrusion and distribution of paxillin-containing adhesions. Both cofilin-1 and destrin silencing enhanced cell adhesion to extracellular matrix components. However, only destrin appeared to be required for cell migration on collagen I and for cell invasion through Matrigel in response to the proinvasive neuroendocrine peptide bombesin. This differential functional involvement was supported by a destrin-dependent, cofilin-independent phosphorylation of p130Crk-associated substrate (p130Cas) upon cell adhesion to collagen I or Matrigel. Taken together, our results suggest that destrin is a significant regulator of various processes important for invasive phenotype of human colon cancer Isreco1 cells whereas cofilin-1 may be involved in only a subset of them.

p53 dependent and independent sensitivity to oxaliplatin of colon cancer cells.

Oxaliplatin is an efficient chemotherapeutic agent used for the treatment of metastatic human colon cancer, but cancer cells are frequently resistant. The aim of this study was to analyse the underlying mechanisms in a panel of 10 human colorectal cancer cell lines submitted to a short (2h) oxaliplatin treatment period, accordingly to the usual therapeutic procedure in humans. Sensitivity to oxaliplatin was a characteristic of p53 wild-type colon cancer cells. In contrast, all p53-mutated cell lines had a high IC50 to oxaliplatin, with the exception of the V9P cell line. Exposure to oxaliplatin resulted in G0/G1 arrest in p53 wild-type cell lines, and in S phase in p53-mutated cell lines. In our treatment conditions, no DNA accumulation in sub G0/G1 phase, no caspase-3 activation nor PARP cleavage were detected after oxaliplatin treatment, except for the V9P cell line. The major role of the p53-p21 pathway in oxaliplatin sensitivity was confirmed in the p53 wild-type HCT116 cell line, using siRNA duplex, and knockdown of the TAp73 protein also enhanced resistance to oxaliplatin in this cell line. Surprisingly, siRNA duplex invalidation revealed a residual effect of the mutant p53 protein in p53-mutated cell lines. Persistent sensitivity to oxaliplatin of the p53-mutated V9P cell line was associated with oxalipatin-induced apoptosis but TAp73 was not the responsible alternative pathway.

HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors.

Hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) protein, a member of the reg family, is constitutively expressed by some specialized epithelial cell subsets in the digestive tract and the pancreas. We performed a detailed analysis of the expression of HIP/PAP protein in normal digestive endocrine cells according to their localization, lineage, and differentiation stage, and in digestive endocrine tumors according to their site of origin and hormonal profile. In both adult and fetal normal tissues, HIP/PAP expression was detected only in endocrine cells of the small intestine, ascending colon, and pancreas. Two different expression patterns were identified: (a) a strong cytoplasmic labeling observed in the endocrine cells of the digestive mucosa and the outer rim of Langerhans islets specialized in the synthesis of glucagon and glucagon-like peptides; (b) a weak cytoplasmic immunoreactivity observed in the other pancreatic endocrine cell populations. HIP/PAP expression was detected in 36 of the 184 cases of digestive endocrine tumors examined; 32 of these cases (89%) were pancreatic. The 2 patterns observed in the normal state were retained: (a) a strong labeling was observed in 5% to 100% of tumor cells in 26 tumors, all expressing glucagon or glucagon-like peptides; (b) a weak labeling was present in 10 tumors, presenting various hormonal profiles. In conclusion, a strong expression of HIP/PAP is characteristic of glucagon-producing normal and neoplastic enteropancreatic endocrine cells. Our results lend further support to the concept that members of the reg family play regulatory roles in various endocrine cell populations and that their expression in endocrine cells is lineage-specific.

Follow-up and management of patients exposed to a flawed automated endoscope washer-disinfector in a digestive diseases unit.

The possible transmission of pathogens to 236 persons exposed to an endoscope processed in a flawed automated endoscope washer-disinfector in a gastrointestinal endoscopy unit was investigated. During 6 months, 197 patients (83.5%) were followed up, and no cases of acute human immunodeficiency virus, hepatitis C virus, or hepatitis B virus infection were observed. This event created the conditions for improvements in safety procedures.

[Multiple gastro-intestinal stromal tumors (GIST) in a patient with type I neurofibromatosis revealed by chronic bleeding: pre-operative radiological diagnosis]. / Tumeurs stromales gastro-intestinales (GIST) multiples chez un malade atteint d'une maladie de Recklinghausen. Diagnostic radiologique pré-opératoire devant un tableau de fuite sanguine digestive.

Recent studies have pointed out a high incidence of GIST, usually multiple and of small intestinal location, in patients with type I neurofibromatosis. We here report an additional case, revealed by chronic gastro-intestinal bleeding and diagnosed at pre-operative imaging studies. A 56-year-old patient, with known type I neurofibromatosis, was referred to our department for the exploration of chronic gastro-intestinal bleeding during anti-aggregant therapy. Endoscopical examination was negative. Enteroscanner showed the presence of four tumor lesions, 3 in the jejunum and 1 in the ileum. Segmental surgical resections were performed. At histological examination, 2 of among the 3 jejunal lesions were diagnosed as typical GIST, of low risk of malignancy, CD117+, CD34+, whereas the last jejunal and ileal lesions were identified as fibroid tumors. Mutations of c-kit gene and of the gene coding for PDGF-Ralpha were not detected. Post-operative recovery was uneventful; no recurrent bleeding was observed. Our case report underlines the potential role of enteroscanner in the management of patients with type I neurofibromatosis with possible digestive complications. It also emphasizes the importance of an accurate diagnosis of the digestive tumors associated with type I neurofibromatosis: GISTs are frequent in this setting and must not be misdiagnosed as neurofibromas.

Bombesin stimulates invasion and migration of Isreco1 colon carcinoma cells in a Rho-dependent manner.

The membrane receptor for the neuropeptide bombesin/gastrin-releasing peptide (GRP) is expressed by a large fraction of human colorectal carcinoma cells. We reported previously a stimulation of cell adhesion and lamellipodia formation by the neuropeptide bombesin in the human, bombesin/GRP receptor-expressing, Isreco1 colorectal cancer cell line (J. C. Saurin et al., Cancer Res., 59: 962-967, 1999). Using invasion and motility assays, we demonstrate in this report that bombesin can both enhance the invasive capacity of Isreco1 cells in a dose-dependent manner (maximal effect at 1 nM) and stimulate the closure of wounds performed on confluent Isreco1 cells. These effects were reversed fully by the specific bombesin/GRP receptor antagonist D-Phe(6)-Bn(6-13)OMe used at 1 micro M. MMP-9 and urokinase-type plasminogen activator were expressed by Isreco1 cells, and bombesin did not significantly alter their level of secretion. Interestingly, exoenzyme C3 (10 micro g/ml) decreased cell invasiveness induced by bombesin by 70% and completely inhibited the migration of Isreco1 cells. Similarly, the Rho-kinase inhibitor Y-27632 dose-dependently reduced the effect of bombesin on cell invasion. Moreover, pull-down assays for GTP-bound RhoA demonstrated that bombesin was able to activate the small G-protein in Isreco1 cells. These results show that the neuropeptide bombesin is able to modulate invasiveness of Isreco1 colorectal carcinoma cells in vitro through a Rho-dependent pathway, leading to an increase in cell locomotion without a significant effect on tumor-cell associated proteolytic activity. These findings indicate that bombesin/GRP receptor expression may contribute to the cellular events that are critical for invasion/migration of colorectal carcinoma cells.

Surveillance of duodenal adenomas in familial adenomatous polyposis reveals high cumulative risk of advanced disease.

PURPOSE: The development of high-grade dysplasia (HGD) on duodenal or jejunal adenomas and of late-stage (stage IV) duodenal polyposis are major clinical events for familial adenomatous polyposis (FAP) patients. Our aim was to determine their respective frequency, risk factors, and cumulative risk. PATIENTS AND METHODS: A prospective, optimized, endoscopic surveillance protocol was applied to 58 FAP patients in a university hospital. The number, size, and histology of duodenojejunal polyps were assessed, and the Spigelman's score was calculated at each endoscopy. Cox regression and linear regression analysis were used to determine risk factors for HGD development and the cumulative risk of stage IV duodenal polyposis, respectively. RESULTS: During a median (+/- standard deviation) follow-up of 47.9 +/- 15.6 months, 35 patients with at least two consecutive examinations had 107 duodenojejunal examinations. The Spigelman's score increased in 21 patients (60.0%), and HGD developed in 12 patients (34.2%). High initial Spigelman's score (> 7 points), but not age or APC mutation site, was a risk factor for HGD development. Estimated cumulative risk of developing stage IV duodenal polyposis was of 42.9% at age 60 (95% CI, 35.7% to 50.0%) and 50.0% at age 70 (95% CI, 42.9% to 57.1%). CONCLUSION: This prospective series shows a higher duodenal polyposis progression rate and cumulative risk of late-stage (stage IV) duodenal polyposis in FAP patients compared with previous series. These results suggest that current modalities for surveillance and management of these patients need revision.

Functional characterization of a promoter region in the human MEN1 tumor suppressor gene.

Our previous studies on the human MEN1 (multiple endocrine neoplasia type 1) gene revealed heterogeneity of MEN1 2.8 kb transcripts related to variation in their 5' UTR only. Six distinct exons 1 (e1A-e1F) were isolated that suggested the existence of multiple but not already identified transcriptional start sites (TSS) and of a complex transcriptional control. Identification of a minimal promoter region and its adjacent regulatory regions appears an inescapable step to the understanding of MEN1 gene transcriptional regulation in normal and pathological situations. For this purpose, we subcloned the approximately 2000 bp region situated directly upstream of the exon 2 in front of a luciferase reporter gene, and we analyzed functional consequences of 5' and 3' serial deletions, comparatively in a series of endocrine versus non-endocrine cell lines. Primer extension and RPA experiments demonstrate that in HEK293 cells transcription initiated simultaneously at several points in endogenous MEN1 promoter as well as in transfected promoter fragments in reporter plasmids, mainly in Inr elements that are efficiently employed to synthetize previously described exons e1A-e1D. Functional consequences of TSS deletion are directly related to cellular context. The minimal promoter region is localized between -135 and -36. Five large adjacent cis-regulatory regions (UR1-UR5) exist upstream of this minimal promoter region, whose activity depend not only on the cellular context but also on the presence of a downstream sequence DR1. Five small cis-regulatory elements (C1-C5) are localized between -325 and -107. Overexpression of exogenous menin, the MEN1 gene's product, in mouse embryonic fibroblasts from Men1(-/-) knock-out mice dose-dependently decreases MEN1 promoter activity, through sequences surrounding the minimal promoter. Our data highlight the existence of a complex transcriptional regulation of the MEN1 gene, whose activity is clearly modulated depending not only on the cellular context but also on menin intracellular levels. They are the molecular bases required for a future understanding of a potential specific transcription control in endocrine cells.

The DHE cell line as a model for studying rat gastro-intestinal mucin expression: effects of dexamethasone.

The expression of mucin genes was evaluated in rat intestinal cell lines in order to establish an in vitro model for investigating the regulation of intestinal mucin expression in this species. Two rat intestinal cancer cell lines (DHE, LGA) and three nontumoral rat intestinal cell lines (IEC6, IEC17, IEC18) were screened. The mRNA expression of rMuc1, rMuc2, rMuc3, rMuc4, and rMuc5AC mucin genes was studied by semiquantitative RT-PCR, real-time RT-PCR and Northern-blot analysis. Results were correlated with immunohistochemical expression of rat gastric and intestinal mucin proteins, and secretion of glycoconjugates was examined by enzyme-linked lectin assay. We showed that mRNA of rMucl and rMuc2 were constitutively expressed in all IEC cell populations but periodic acid Schiff staining of these cells did not reveal the presence of glycoproteins. DHE cells expressed rMuc1-5AC mRNA and LGA expressed the same mucins but the level of rMuc4 was much lower. Mucin mRNA expression also differed in relation with the length of cultivation. Immunocytochemical studies revealed the presence of gastric and intestinal mucins in the two tumoral cell lines. Functional experiments showed that bethanechol, A23187 and PMA stimulated release of glycoconjugates in DHE but not in LGA cells. Treatment of DHE cells with dexamethasone (10(-7) mol/l) enhanced rMuc2 mRNA but decreased rMuc1 and rMuc5AC mRNA. Real-time RT-PCR showed that the expression of rMuc1 and rMuc5AC genes was reduced by more than tenfold after 24 h. The increased expression of rMuc2 gene was confirmed by Northern blot analysis. In conclusion, DHE cells provide a valuable cellular model for research on rat mucin secretion and expression.

Inflammation of the colonic wall induced by formalin as a model of acute visceral pain.

Acute inflammation of the sigmoid wall was induced by perendoscopic injection of formalin (50 microliters, 5%) under brief anesthesia in rats. The procedure was followed by behavioral patterns that significantly differed from those in animals injected with isotonic saline instead of formalin. Analysis of the formalin-induced behaviors allowed for the calculation of a pain score that evolved in a biphasic manner along the 3 h of test. The score was dose-dependently reduced by morphine (0.5-4 mg/kg), and the analgesic effect of the largest morphine dose was abolished by naloxone (2.4 mg/kg). These results suggest that formalin into the sigmoid colon is a new model of visceral pain, presumably through direct irritation at injection site and/or localized acute inflammation of the intestinal wall.

The role of luminal gastrin in the regulation of pancreatic juice secretion in preruminant calves.

The effect of luminal gastrin on the secretion of pancreatic juice was studied in seven conscious preruminant calves employing luminal infusions of gastrin and cholecystokinin (CCK)-9 and pharmacological CCK1 and CCK2 receptor blocks with antagonists. The study was performed in the preprandial and prandial states. Pharmacological blocking of the CCK2 receptor, like that of the CCK1 receptor, resulted in reduction of pancreatic postprandial secretion and increased the duration of the prandial pattern of duodenal electrical activity. Exogenous luminal gastrin, like luminal CCK-9, enhanced the secretion of pancreatic juice proteins, though the overall effect of gastrin was weaker than that of CCK-9. The effect was inhibited by infusion of CCK2 but also by CCK1 receptor antagonist. In conclusion, duodenal luminal gastrin can stimulate exocrine pancreatic secretion by a mechanism that depends on CCK2 receptors in calves. Involvement of the CCK1 receptor in this mechanism needs further investigation. Prandial pancreatic secretory and duodenal motility cycles can be regulated by endogenous gastrin release.

Bovine pancreatic secretion in the first week of life: potential involvement of intestinal CCK receptors.

The aim of this study was to evaluate pancreatic juice secretion of calves in the first postnatal days, and determine a potential involvement of cholecystokinin (CCK) and intestinal CCK receptor in its regulation. Nine neonatal Friesian calves (five controls and four treated intraduodenally with FK480, a CCK-A receptor antagonist) were surgically fitted with a pancreatic duct catheter and a duodenal cannula before the first colostrum feeding. Collections of pancreatic juice and duodenal luminal pressure recordings were started early after recovery from anaesthesia and continued for 6 days. From day 2 or 3 of life, periodic fluctuations in pancreatic secretions were observed in concert with duodenal myoelectric motor complex (MMC) and variations in plasma pancreatic polypeptide (PP) concentrations. Intraduodenal administration of FK480 reduced pancreatic juice secretion while intravenous infusion of CCK had no effect. Immunocytochemistry indicated an association of mucosal CCK-A and -B receptors with neural components of the small intestine. In conclusion, periodic activity of the exocrine pancreas exists in neonatal calves soon after birth and local neural intestinal CCK-A receptors could be partly responsible for the modulation of neonatal calf pancreatic secretion.