Duodenal Volume Research Articles

Hypofractionated intensity-modulated radiotherapy in locally advanced unresectable pancreatic cancer: A pilot study

PurposeTo test feasibility and safety of hypofractionated intensity modulated radiotherapy (H-IMRT) in pancreatic adenocarcinoma (PAC) treatment. MethodsPatients with unresectable nonmetastatic PAC were prospectively enrolled on a pilot study. Patients received H-IMRT to gross tumor volume to a total dose of 52 Gy (4 Gy/fraction). Toxicity rates, duodenal dosimetric parameters, and clinical outcomes were evaluated. ResultsTen patients received H-IMRT regimen. Objective tumor response was recorded in all patients but one. Gastrointestinal toxicity was the most common acute side effect and its severity moderately correlated with duodenal maximum dose (ρ = 0.46) and percentage of duodenal volume exposed to 5 Gy (ρ = 0.46). The 1-year overall and disease-free survival were 83.3% and 68.6%, respectively. ConclusionH-IMRT seems to guarantee a high local control rate without severe toxicity. Its use in unresectable nonmetastatic PAC needs to be further investigated.

Characterizing Interfraction Variation of Separation Between Pancreas and Duodenum during Radiation Therapy of Pancreatic Cancer for Online Adaptive Replanning

The duodenum is often the dose-limiting organ for radiation therapy (RT) of pancreatic cancer, and its separation from the pancreas can vary between daily fractions. Understanding this inter-fractional variation can help in delivering optimal RT that maximizes the dose to the target and/or minimizes the dose to the duodenum by taking advantage of fractions where there is greater separation and using online adaptive re-planning. The aim of this study is to quantitatively characterize inter-fractional variation of the relative motion between the pancreatic head and the duodenum during pancreatic cancer RT. Daily CTs acquired using an in-room CT during routine image-guided RT for 33 patients with pancreas head tumors were analyzed. All patients were treated with chemo-RT of 50.4 Gy in 28 daily fractions. The pancreatic head and duodenum were delineated on the selected daily CTs chosen at regular intervals over the course of treatment for each patient, with a total of 177 daily CTs for all patients studied. The contours were generated by populating the planning contours from the planning CTs to the daily CTs using an auto-segmentation tool with careful editing and independent checking. Spatial separation between the pancreatic head and duodenum was quantified using a modified Hausdorff distance (HD), defined as the maximum distance of a set to the furthest point in the other set. Overlap between the pancreatic head and duodenum was quantified by uniformly expanding the pancreatic head contour by 20 mm and measuring the volume overlap (VO) between the pancreatic-head shell and the duodenum relative to the duodenal volume. The dosimetric benefits of these separations and overlaps were explored. The inter-fraction variation in the maximum separation between duodenum and pancreatic head for any patient, as measured by HD, was found to be 1.9±0.6 cm. The average HD variation for all patients was 0.9±0.3 cm. The largest HD was 2.4 cm for all the fractions. The minimum VO for any patient was found to be 11.4±4.7%. The average VO for all patients was 25.2±6.4%. The distribution of HD and VO values is presented in the table. For a fraction with HD = 1.7 cm and VO =37%, online re-planning resulted in a reduction in the duodenal volume receiving 50 Gy from 63% to 19%. Such a reduction would allow substantial dose escalation to the target for the fraction with online adaptive RT. Significant relative movement between the pancreatic head and the duodenum occurs during pancreatic cancer RT and this movement varies from fraction to fraction. In 40% of fractions where HD ≥ 1.0 cm, online adaptive RT may be used to safely escalate the dose to the target by taking advantage of the large separation or small overlap.Abstract SU_18_2178; Table 1Hausdorff Distance (HD)Volume Overlap (VO)HD ≥ 1.0 cmHD ≥ 1.5 cmHD ≥ 2.0 cmVO ≤ 15%VO ≤ 25%25% < VO ≤ 50%50% < VO ≤ 75%% of Total Fractions43.515.82.318.657.138.44.5 Open table in a new tab

A Novel Absorbable Radiopaque Hydrogel Spacer to Separate the Head of the Pancreas and Duodenum in Radiation Therapy for Pancreatic Cancer

We assessed the feasibility and theoretical dosimetric advantages of an injectable hydrogel to increase the space between the head of the pancreas (HOP) and duodenum in a human cadaveric model. Using 3 human cadaveric specimens, an absorbable radiopaque hydrogel was injected between the HOP and duodenum by way of open laparotomy in 1 case and endoscopic ultrasound (EUS) guidance in 2 cases. The cadavers were subsequently imaged using computed tomography and dissected for histologic confirmation of hydrogel placement. The duodenal dose reduction and planning target volume (PTV) coverage were characterized using pre- and postspacer injection stereotactic body radiation therapy (SBRT) plans for the 2 cadavers with EUS-guided placement, the delivery method that appeared the most clinically desirable. Modeling studies were performed using 60 SBRT plans consisting of 10 previously treated patients with unresectable pancreatic cancer, each with 6 different HOP-duodenum separation distances. The duodenal volume receiving 15Gy (V15), 20Gy (V20), and 33Gy (V33) was assessed for each iteration. In the 3 cadaveric studies, an average of 0.9cm, 1.1cm, and 0.9cm HOP-duodenum separation was achieved. In the 2 EUS cases, the V20 decreased from 3.86cm3 to 0.36cm3 and 3.75cm3 to 1.08cm3 (treatment constraint <3cm3), and the V15 decreased from 7.07cm3 to 2.02cm3 and 9.12cm3 to 3.91cm3 (treatment constraint <9cm3). The PTV coverage improved or was comparable between the pre- and postinjection studies. Modeling studies demonstrated that a separation of 8mm was sufficient to consistently reduce the V15, V20, and V33 to acceptable clinical constraints. Currently, dose escalation has been limited owing to radiosensitive structures adjacent to the pancreas. We demonstrated the feasibility of hydrogel separation of the HOP and duodenum. Future studies will evaluate the safety and efficacy of this technique with the potential for more effective dose escalation using SBRT or intensity-modulated radiation therapy to improve the outcomes in patients with unresectable pancreatic cancer.

Feasibility and reproducibility of substituting oral contrast with water for duodenal volume delineation in patients undergoing pancreatic stereotactic body radiotherapy.

This is the first known report evaluating the feasibility of substituting oral contrast with water in efforts to delineate the duodenum for pancreatic stereotactic body radiotherapy (SBRT). From January 2015 to August 2016, 13 patients were simulated after ingestion of 8 ounces of water approximately 15-20 min prior to their simulation scan. We examined the feasibility of contouring the duodenum thereafter, and measured the duodenal volume as well as its variation. Comparison was made to 40 patients treated from January 2009 to February 2012 on a prospective trial who used oral contrast. Group comparisons were performed by the Mann-Whitney U test. The duodenum was identified in all 13 patients who used water instead of oral contrast without subjective difficulty. In this group, the median duodenal volume was 72.86 cm3 (range, 44.61-130.90 cm3). In the oral contrast group, median duodenal volume was 86.21 cm3 (range, 50.11-157.89 cm3) There were no significant differences between groups (P=0.115). The approach was reproducible, as all patients were able to drink the same amount of water 15-20 min prior to each SBRT fraction to keep duodenal volumes subjectively similar to volumes on the simulation CT scan. This novel approach is effective and reproducible in delineating the duodenum for treatment planning and daily setup.

Gated carbon-ion scanning treatment for pancreatic tumour with field specific target volume and organs at risk

ObjectiveTo assess the feasibility of treatment planning for pancreatic tumours subject to respiratory motion using field-specific target volumes (FTV) and field-specific organs at risk (FOAR) using four-dimensional computed tomography (4DCT). MethodsFourteen pancreatic cancer patients underwent 4DCT. Radiation oncologists contoured the gross tumour volume (GTV), clinical target volume (CTV), spinal cord, duodenum, kidneys, and stomach. The gating duty cycle was set to 30 % around exhalation. FTV and FOAR were calculated using the 4DCT dataset. Planning target volumes (PTV) and planning organs at risk volumes (PRV) were defined as equal to FTV and FOAR, respectively. A dose of 55.2Gy relative biological effectiveness (RBE) was planned to target the PTV from four beam angles. A single field uniform dose (SFUD) plan was selected. The dose distribution, including intrafractional motion changes, was generated. ResultsThe mean volume of target receiving 95 % of the planned doses was 96.4±4.1 % to the GTV and 94.7±0.9 % to the CTV. The highest dose to 2cc of duodenal volume was 27.5Gy (RBE). The volume of the stomach receiving ⩾30Gy (RBE) was <7.0cc in all patients. All metrics for OARs satisfied dose constraints. ConclusionDose to the CTV was covered sufficiently by the 4DCT-generated FTV, and dose to OARs was reduced by 4DCT-generated FOAR. This methodology may prevent adverse reactions while preserving local tumour control.

SU‐D‐BRA‐06: Duodenal Interfraction Motion with Abdominal Compression

Purpose:To quantify the effect of abdominal compression on duodenal motion during pancreatic radiotherapy.Methods:Seven patients treated for pancreatic cancer were selected for analysis. Four patients were treated with abdominal compression and three without. The duodenum was contoured by the same physician on each CBCT (five CBCTs for patients with compression, four for non‐compression patients). CBCTs were rigidly registered using a soft tissue match and contours were copied to the delivered plans which were all radical (BED &gt; 50 Gy). The distance between the duodenum on the planning CT and each CBCT was quantified by calculating the root mean square (RMS) distance. The DVHs of each abdominal compression patient was converted to an EQD2 DVH (alpha/beta = 10) using an in‐house tool and volumes receiving at least 25, 35, 45, and 50 Gy were recorded.Results:The maximum variation in duodenal volumes on the CBCTs for the four abdominal compression patients were 19.1 cm3 (32.8%), 19.1 cm3 (20.6%), 19.9 cm3 (14.3%), and 12.9 cm3 (27.3%) compared to 15.2 cm3 (17.6%), 34.7 cm3 (83.4%), and 56 cm3 (60.2%) for non‐compression patients. The average RMS distance between the duodenum on the planning CT and each CBCT for all abdominal compression patients was 0.3 cm compared to 0.7 cm for non‐compressed patients. The largest (and average) difference between the planning CT and CBCTs in volume of duodenum receiving more than 25, 35, 45 and 50 Gy for abdominal compression patients was 11% (5%), 9% (3%), 9% (2%), and 6% (1%).Conclusion:Abdominal compression reduces variation in volume and absolute position of the duodenum throughout treatment. This is seen as an improvement but does not eliminate the need to consider dosimetric effects of motion. Abdominal compression is particularly useful in SBRT when only a few fractions are delivered.Alon Witztum is supported by an MRC/Gray Institute DPhil Studentship. Daniel Holyoake is supported by a CRUK/Nuffield Clinical Research Fellowship. Sam Warren and Mike Partridge are supported by CRUK grant C5255/A15935. Maria Hawkins received an MRC Fellowship MC_PC_12001/2.

Acute Gastrointestinal Toxicity After Robotic Stereotactic Ablative Radiotherapy for Treatment of Metastatic Gynecological Malignancies

The aim of this study was to assess acute and subacacute gastrointestinal toxicity after fractionated stereotactic ablative radiotherapy (SABR) in women having recurrent gynecological cancers in the upper abdomen. In total, 34 women underwent upper abdominal SABR (24 Gy/three divided 8 Gy consecutive daily doses) using a robotic Cyberknife® (Accuray, CA, USA) platform. Volumes of the duodenum receiving 10% increments of the prescription dose were associated to post-therapy gastrointestinal toxicities using binary logistic regression analyses. Median clinical follow-up was 10 months. In total, 14 (41%) of the 34 women manifested grade 2 or higher post-therapy gastrointestinal adverse events. The duodenal volume, receiving 80% of a 24-Gy dose, was significantly associated with gastrointestinal toxicity (p = 0.03). However, in a multivariate analysis, only patient age at SABR adjusted the odds of experiencing gastrointestinal toxicity (p = 0.02). The duodenal volume receiving 80% of 24 Gy dose may be associated with gastrointestinal toxicity from upper abdominal SABR.

EP-1246: Effect of duodenal overlap volume with PTV (Duo OLV) in locally advanced pancreatic cancer radiotherapy planning

EP-1246: Effect of duodenal overlap volume with PTV (Duo OLV) in locally advanced pancreatic cancer radiotherapy planning

SU‐E‐T‐44: Model Prediction of Radiation Induced Duodenal Toxicity for a Dose Escalation in Radiation Therapy of Pancreatic Cancer Using Published Reports

Purpose: Safe dose escalation for RT of pancreatic cancer is limited by the surrounding organs at risk, particularly the duodenum, which is adjacent to the pancreas. The purpose of this work is to estimate the radiation induced duodenal toxicity using dose‐volume response data extracted from the literature for a proposed dose escalation of 72 Gy in 28 fractions via IMRT simultaneously integrated boost.Methods: Two patients treated for pancreatic cancer at our institution were randomly selected to retrospectively alter their treatment plan to simulate the testing dose escalation of 50.4 and 72 Gy in 28 fractions to the pancreatic head and the GTV, respectively. The report by Murphy et al. on SBRT of Grade 2 or higher duodenal toxicity was used to estimate NTCP using testing protocol DVHs. The Modified LQ model by Guerrero and Li was used to calculate the iso‐effective dose in the testing protocol producing the same effect as doses in the SBRT regime. Additional analysis of NTCP variation considered alpha‐beta ratios of 3 to 5 Gy for small bowel/duodenum late effects. Results: The testing protocol iso‐effective dose, D, associated with 25 Gy in a single fraction had a median value of 61.2 Gy and ranged from 56.3 to 68.0 Gy. The first patient had a high estimated risk of toxicity (0.45) due to the duodenal volume being greater than 0.21 cubic centimeters. A lower risk of toxicity was estimated for the second patient due to the duodenal volume being less than 0.21 cubic centimeters. Conclusion: Estimates of duodenal toxicity can be made despite the limited number of toxicity data available. A conservative dose‐volume constraint would limit 0.21 cubic centimeters of the duodenal volume to no more than 56 Gy. The estimates of duodenal toxicity exhibit a dependence on the value of alpha‐beta ratio of the duodenum.

The Duodenal Aspirate Volume Does Not Correlate With the PEAK Bicarbonate Concentration During Secretin Stimulated Endoscopic Pancreas Function Testing. A Note of Caution for Secretin MRCP?

Background. Abnormal exocrine function precedes most imaging changes of CP so stimulated pancreas function tests (PFT) are used as a surrogate for early diagnosis as histology is rarely obtained. Endoscopic PFT (ePFT) have shown promise as a less technically challenging PFT but may last one hour and require special equipment. Peak pancreas exocrine output takes at least 30 minutes to occur after secretagogue stimulation so we tested if a shorter endoscopic aspiration could differentiate patients with and without chronic pancreatitis. Methods. Synthetic secretin 0.2 μg/kg (ChiRhoClin,Inc.,Burtonsville,MD) was administered IV, and sedation started 30 minutes afterwards. After gastric fluid aspiration the endoscope was advanced to the major papilla and four continuous duodenal aspirations were done at 5 minute intervals, starting 35 minutes after secretin administration, collected in a sealed polyp trap on ice, and delivered to the laboratory. The first four samples were analyzed by an autoanalyzer (Corning 965, USA) calibrated to a bicarbonate of 80 mEq/L and compared to pH back titration. Variance between the methods was ±0.02 mEq/L so subsequent measurements were done with the auto-analyzer only. Peak bicarbonate concentration (PBC) >80 mEq/L during any collection is normal. ERCP and EUS were compared to ePFT and all three to a final diagnosis of CP which was established by considering history, imaging, histology and ePFT. Results. Twenty seven ePFT have been performed (16 females). Indications were suspected CP (17), abdominal pain (7), steatorrhea (2), idiopathic recurrent acute pancreatitis (1). Nine patients (pts) received a final diagnosis of CP and 18 no CP. 15 pts had ERCP (two had one, 9 pts had 2, 2 pts had 3 and 2 pts had 5). Seven pts had a normal pancreatogram. Cambridge class was I in one pt, II in 4 pts, III in 2 pts and IV in one pt. Two pts with Cambridge II and one with Cambridge III had normal PBC. 23 pts had EUS (21 had one, one pt had two, and one pt had 3). Ten pts had > 4 criteria for CP, and 6/10 pts had an abnormal ePFT. 13 pts had a normal EUS, and 11/13 had normal PBC (one pt had PBC 78.9 mEq/L). PBC was 80 mEq/ L in 17/18 pts without CP. The sensitivity and specificity of ePFT compared to ERCP and EUS and of all three compared to a final diagnosis of CP are in the tables. Conclusion. The ePFT was as good as EUS and ERCP in predicting CP. ePFT and EUS were non-statistically superior to ERCP in ruling out CP. The final diagnosis of CP was enhanced by combining numerous tests, but this proposed shorter ePFT requires less expertise, involves routine upper endoscopy, and may be more practical for regular use. More data is needed to determine how well it predicts early chronic pancreatitis, and if results decrease the ordering of other tests when CP is suspected. Comparison of ePFT to ERCP and EUS

Duodenal complications in radiotherapy for bile duct cancer: A dose–volume histogram analysis

Purpose To establish a method of quantitative assessment of the duodenal exposure dose to avoid duodenal morbidity after radiotherapy for bile duct cancer. Methods and Materials After external beam radiotherapy (ERTx) and intraluminal high-dose-rate brachytherapy (BRTx), 4 of 10 patients developed Grade 3 or 4 ulcers at the posterior wall of the duodenal bulb (PWDB) (compromised group); the remainder exhibited no duodenal complications (spared group) for 14 (range, 7–59) months after radiotherapy. The radiation exposure to the duodenal volume at risk ( V duod) in ERTx and BRTx was individually analyzed using dose–volume histograms in terms of the mean doses (the average dose of V duod[ D ave] and the median dose of V duod [ D median]), dose covering 1% or 5% of V duod (dose covering 1% of the V duod [ D 1] and dose covering 5% of the V duod [ D 5], respectively), and the V duod receiving 100% or 150% of the prescribed radiation dose ( V 100 and V 150, respectively) in ERTx ( D ave, D median, D 5) and BRTx ( D ave, D 1, D 5, V 100, V 150). D ave and D 5 were converted to biologically effective doses (BEDs), and each corresponding values of ERTx and BRTx were summed presenting as BED ave_sum and BED 5_sum. Results The PWDB was consistently involved in 100% of the prescription dose area in ERTx. The compromised group had smaller exposure doses without significant difference (SD). In BRTx, the PWDB was exposed to higher doses. The compromised group had larger dose exposures without SD and larger volume exposures ( V 100, V 150) with SD in BRTx. The BED ave_sum and BED 5_sum showed no difference between the groups. Conclusions Measuring the duodenal volume exposed to determine doses that exceed the prescription in BRTx may be useful for predicting intractable complications in the combined radiotherapy.

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife. Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.

Relationship between intraduodenal 5-hydroxytryptamine release and interdigestive contractions in dogs.

5-hydroxytryptamine (5-HT) is released into the intestinal lumen during the fasting state. However, the relationship between the intraduodenal 5-HT and the interdigestive cyclic motor activity in conscious dogs is unclear. To correlate intraduodenal 5-HT concentrations with the interdigestive gastroduodenal migrating motor complex (MMC). 6 dogs were implanted with 2 force transducers for recording gastroduodenal contractions and 2 catheters for measuring duodenal volume by a non-absorbable marker perfusion technique. Intraduodenal 5-HT concentrations were determined by high performance liquid chromatography at 5-min intervals. During fasting, gastroduodenal motor activity cycled as the MMC; luminal 5-HT concentrations and total outputs varied cyclically in temporal association with the MMC. Mean 5-HT concentrations peaked during phase II (P<0.05 vs. phase I and III), and 5-HT outputs during phases II or III were greater than during phase I (P<0.05). Exogenous motilin (0.3 microg/kg-hr, IV) stimulated 5-HT release into the duodenal lumen with peak values (P<0.05) during motilin-induced phase II and III. Gastroduodenal motor activity was not altered, however, during exogenous intraduodenal administration of 5-HT (300 ng/mL-min). 5-HT is released cyclically into the duodenal lumen in close temporal association with the MMC, but its physiologic significance in regulation of gastroduodenal motility is unknown.

Gastric acid suppression and treatment of severe exocrine pancreatic insufficiency

Adding either H2-receptor antagonists (cimetidine or ranitidine) or proton pump inhibitors to an adequate amount of lipolytic activity improves fat malabsorption in most cases and abolishes steatorrhoea in up to 40% of children and adults with cystic fibrosis and in adults with chronic pancreatitis. Acid suppression improves fat absorption because the resultant increase in pH within the upper gastrointestinal tract improves the survival of lipolytic activity, reduces duodenal volume flow and prevents the precipitation of bile acids. These effects increase the concentration of intraduodenal lipolytic activity and promote the aggregation of bile acids and the micellar solubilization of lipid. The amount of lipase that should be recommended is controversial, but we interpret our studies as indicating that at least 90000 United States Pharmacopeia (USP) units should be ingested with meals. This amount of lipolytic activity taken with an agent that suppresses gastric acid secretion improves fat absorption in most patients and may even abolish steatorrhoea.

Negative Feedback Control of Exocrine Pancreatic Secretion: Role of Cholecystokinin and Cholinergic Pathway

Mediation of postprandial pancreatic enzyme secretion has been ascribed mainly to cholecystokinin and to vagovagal reflexes. Recent studies suggest that these pathways are subject to feedback regulation. Diversion of pancreatic juice from the duodenum stimulates cholecystokinin release and pancreatic enzyme secretion, and intraduodenal administration of trypsin or chymotrypsin inhibits cholecystokinin release and pancreatic secretion. The increased plasma cholecystokinin levels following diversion of pancreatic juice seems to be mediated by "cholecystokinin-releasing factor", a trypsin-sensitive substance secreted by the proximal small intestine. This factor may mediate pancreatic enzyme secretion in response to protein intake. Dietary protein in the intestine competes for the trypsin that would otherwise inactivate the factor. The resulting increase of this factor in the intestinal lumen releases cholecystokinin and stimulates pancreatic enzyme secretion. Enteropancreatic reflex can also be activated by distension or administration of hyperosmolar solutions in the duodenum eliciting pancreatic enzyme secretion without raising plasma cholecystokinin levels. This effect is inhibited by atropine, suggesting that it is cholinergically mediated. Pancreatic response to duodenal volume or osmolality is not suppressed by trypsin, indicating that the reflex is not affected by intraluminal proteases. Our studies also show that secretion of pancreatic polypeptide is under cholinergic control, and this peptide acts by interfering with cholinergic transmission, making it an ideal candidate to modulate pancreatic secretion stimulated by the vagal cholinergic pathway. Similar observations are made with somatostatin and calcitonin-gene related peptide which also acts preferentially to inhibit pancreatic secretion by the vagal cholinergic pathway.

Effects of cholecystokinin-receptor blockade on pancreatic and biliary function in healthy volunteers

This study used the specific cholecystokinin (CCK)-receptor antagonist loxiglumide to evaluate whether endogenous CCK, which is released after a meal, regulates pancreatic and biliary functions. Eight healthy volunteers were studied twice on separate days. The subjects received a continuous intraduodenal infusion of a 750-kcal liquid test meal for 2 hours either with or without IV infusion of 5 mg · kg−1 · h−1 of loxiglumide. Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK. Loxiglumide markedly decreased the meal-stimulated outputs of amylase, trypsin, and chymotrypsin by 55%–70% of control values but only slightly decreased duodenal volume (25% inhibition of mean integrated secretion). Loxiglumide abolished gallbladder emptying induced by infusion of nutrients and even increased gallbladder volumes when compared with prior fasting values. Correspondingly, loxiglumide almost abolished the output of bilirubin after infusion of nutrients. However, loxiglumide failed to alter the increase in circulating concentrations of glucose, insulin, and C peptide after infusion of nutrients. The present results show that CCK is one of several factors that regulate pancreatic protein secretion after absorption of nutrients. However, CCK is probably not involved in regulation of pancreatic secretion of fluid. In contrast, gallbladder function is mainly regulated by CCK, both in terms of its emptying after intestinal absorption of nutrients and in terms of maintenance of its fasting volume. Cholecystokinin does not play a major physiological role as an insulinotropic factor.

Comparative effect of distal and proximal intestinal resection and bypass on the rat exocrine pancreas

We studied the effects of small-bowel resection and bypass on pancreatic function in rats subjected to a 50% distal resection (DR), a 50% proximal resection (PR), a 50% jejunal bypass (BP) or an intestinal transection (SH) (controls). Duodenal contents were collected after cannulation (under basal conditions). Afterwards, an in vivo duodenal perfusion was made using a glucose/saline solution and perfusate was collected for 1 h. Following this, a cholecystokinin (CCK) solution was injected into the jugular vein (1 U/kg body wt.) and perfusion continued for another 1 h. Basal duodenal volume only increased in rats with a PR, and no significant changes occurred in protein content. In basal conditions, no decreases in amylase, lipase, trypsin, or chymotrypsin activities after DR, PR or BP were detected. When animals were subjected to a perfusion and CCK stimulation, no significant changes occurred in animals with BP; the volume was maintained in rats with PR and DR but a decrease in protein and enzymatic contents was found. We concluded that, in basal conditions, the lack (resections) or exclusion (BP) of 50% of the small bowel does not negatively affect the digestive function. When however, a sustained activity is required, the extirpation of intestinal surface provokes a fall in enzymatic activities and is not modified if only the intestinal transit is suppressed, as occurs in the cases of BP.

Comparison of Loxiglumide, a Cholecystokinin Receptor Antagonist, and Atropine on Hormonal and Meal-Stimulated Pancreatic Secretion in Man

The effects of loxiglumide, a potent cholecystokinin (CCK)-receptor antagonist, and atropine, a muscarinic receptor blocker, on exocrine pancreatic secretion stimulated by hormones (secretin plus CCK) and a Lundh test meal were studied in healthy young volunteers. Loxiglumide infused intravenously in gradually increasing doses (2-16 mumol/kg-h) caused a dose-dependent inhibition of pancreatic enzyme secretion induced by intravenous infusion of a constant dose of secretin (82 pmol/kg-h) plus CCK-8 (85 pmol/kg-h) but had relatively smaller influence on duodenal volume flow and bicarbonate output. Atropine (20 nmol/kg) also caused a significant reduction in pancreatic enzyme secretion but failed to affect the volume flow or bicarbonate secretion induced by secretin plus CCK, possibly owing to the high doses of secretin and CCK used in these tests. Both loxiglumide and atropine inhibited the pancreatic enzyme response to a Lundh meal, but atropine was more effective in the early phase and loxiglumide in the late phase of the postprandial secretion. Neither loxiglumide nor atropine affected the plasma gastrin and CCK levels, but both antagonists reduced plasma pancreatic polypeptide responses to the Lundh meal. We conclude that 1) loxiglumide results in a relatively stronger suppression of the pancreatic enzyme than aqueous-alkaline secretion induced by secretin plus CCK, whereas atropine inhibits only enzyme secretion; and 2) both loxiglumide and atropine suppress the pancreatic enzyme responses to the meal stimulation without affecting the postprandial plasma gastrin and CCK responses.

Duodenal volume and osmoreceptors in the stimulation of human pancreatic secretion

It is generally accepted that the intestinal phase of pancreatic secretion is initiated by the stimulation of chemoreceptors sensitive to fat and protein degradation products and hydrogen ions. The effect of the volume and osmolality of food emptied by the stomach into the duodenum has received less attention. We investigated the effects of these factors on the stimulation of pancreatic secretion by studying 8 healthy male volunteers (ages 23–69 yr), in random order on 3 separate days. On day 1, an amino acid mixture (l-phenylalanine, l-tryptophan) was infused intraduodenally at increasing rates, 0.2, 0.8, and 3.2 ml · min−1. On day 2, normal saline was infused into the intestine at the same increasing rates. On day 3, mannitol solutions of increasing osmolality 370, 520, and 700 mosmol · kg−1 were infused into the duodenum at 0.2 ml · min−1. Duodenal contents were continuously aspirated via a double-lumen tube and PEG 4000 was used as a recovery marker. All studies were repeated 90 min later during i.v. infusion of atropine (20 μg · kg−1 · h−1). Increasing volumes of amino acids significantly increase amylase and bicarbonate output (p < 0.05) in a stepwise fashion. Increasing volumes of saline also caused a similar stepwise increase in amylase and bicarbonate output. Furthermore, increasing osmolality caused an increase in enzyme output up to 520 mosmol · kg−1 and no increase was seen thereafter. The responses seen with volume and osmolality were ~40% of that obtained with the amino acids. All responses were significantly reduced (p < 0.05) during atropine infusion. We conclude that the human duodenum contains receptors for volume and osmolality that stimulate both pancreatic enzyme and bicarbonate secretion. Both mechanisms are atropine sensitive, suggesting they are mainly neurally mediated.

Effect of secretin on pancreatic duct pressure, resistance to pancreatic flow, and duodenal motor activity in the dog.

To determine the effect of graded doses of intravenously administered secretin on the relationships among pancreatic duct and duodenal pressures and duodenal motor activity, three dogs were surgically provided with three indwelling duodenal catheters and a permanent pancreaticodochocutaneous catheter. The proximal duodenal catheter was located within the first portion of the duodenum and was used to infuse a nonabsorbable marker. The middle catheter was positioned 5 cm distally so that its open tip was at the level of the pancreatic duct orifice, was water filled and utilized to measure duodenal pressures. Samples of duodenal contents were recovered from the third catheter which was 10 cm distal to the pancreatic ductal orifice. Dogs were studied for 8 hr. Saline was given intravenously for 1 hr at the beginning and end of the study and for 2 hr between two 2-hr periods of secretin administration. Secretin was administered at doses of 0.75, 1.5, 3.0 units/kg/hr. Only two doses of secretin, given in random order, were tested each day. Secretin significantly (P<0.05) reduced pancreatic duct pressure, duodenal pressure, and frequency of duodenal phase-III motor activity and increased duodenal volume flow. All of the responses were dose-related. The highest amounts of constantly infused secretin decreased pressures and increased duodenal volume flow compared with the lowest amount (P<0.05),. Moreover, calculations of resistance to pancreatic flow, the diameter of the pancreatic ductal opening, and the area of the opening indicated that secretin dilated the opening of the pancreatic duct and decreased the resistance of the flow of pancreatic juice into the duodenum as the dose of secretin was increased. Thus, it appears that a pancreatic ductal sphincter mechanism responsive to secretin is present in the dog.