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Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of T cells to the gastrointestinal (GI) endothelium by blocking the α4ß7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.

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Twelve healthy subjects were exposed to a 4-day period of hard physical exercise, calorie supply deficiency, and severe sleep deprivation. The basal acid output (BAO), the sham-feeding-induced acid output (MAOsh), and the pentagastrin-stimulated acid output (MAOpg) were measured immediately after this stress period and in a control experiment performed several weeks later. The stress induced a threefold increase in the median BAO and an increase (p less than 0.05) in the MAOsh, which, however, was not significantly elevated when basal-subtracted. MAOpg was unchanged. In contrast to acid, pepsin output was not influenced by stress. The human pancreatic polypeptide (hPP) level in serum increased twofold after the stress. The integrated hPP response induced by modified sham feeding was higher (p = 0.02) after the stress than in the control experiment. The results show that physical stress has separate influence on the gastric secretion of acid and pepsin.

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The double-pouch dog with one vagally innervated Amdrup pouch (AP) taken from the lesser curvature side of the stomach and one denervated Heidenhain pouch (HP) from the corporo-fundic part permitted comparison of gastric secretion from innervated and denervated mucosa at the same time in the same animal. Food stimulation with a mixture of liver, heart, and bonemeal showed significantly higher response from AP than from HP for all doses, and the difference between the pouches in total acid output was constant for all doses, indicating that the relative contribution of vagal innervation is diminished when the size of the protein meal is increased. The difference between innervated and denervated mucosa is achieved by an immediate high response from the AP. After 150 min the responses to the larger meals were identical in the two pouches. Acid output during stimulation with pentagastrin reached 64.4% of maximal response to histamine in the AP and 36.2% in the HP, the innervated mucosa giving a statistically significant higher response for all doses. Absence of innervation gave an HP response similar to non-competitive inhibition with significantly lower calculated maximal response and a CD50 not different from the CD50 for the AP. Twenty-four hour secretion studies during optimal physiological conditions with the dog fed two daily meals of standard composition showed sparse secretion from denervated mucosa, whereas a great part of the capacity of innervated mucosa is utilized during daily conditions.

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The present studies were performed on a double-pouch dog with one vagally innervated Amdrup pouch (AP) and one denervated Heidenhain pouch (HP), allowing comparison of pepsin secretion from innervated and denervated mucosa at the same time in the same animal. 'Non-active' secretion of pepsin was determined by instillation in the pouches of 0.1 M and 0.005 M HCl, 0.15 M NaCl, and 0.03 M phosphate buffer, and well-known stimulators of gastric secretion such as histamine, pentagastrin, bethanechol, and 2-deoxy-D-glucose (2-DG) were tested as pepsigogues. Cholinergic stimulation by 2-DG and bethanechol (Urecholine) was clearly the most potent stimulus of pepsin secretion. 2-DG elicited secretion only from innervated mucosa, whereas the responses to bethanechol were similar in the two pouches. Histamine and pentagastrin were weak stimulators, but both provoked active and sustained secretion of pepsin when given in small doses. Higher doses of histamine strongly inhibited pepsin output. The effects of histamine were independent of vagal innervation. By contrast, the active stimulation by pentagastrin only took place in innervated mucosa. The highest outputs were seen in the lowest doses, but also very high doses of pentagastrin elicited active pepsin secretion in the AP. Medium doses of pentagastrin brought the secretion down the the 'non-active' level. The chief cells in the denervated mucosa were quite insensible to pentagastrin, and the pepsin output in the HP equalled the non-active' response at all dose levels.

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Eighty patients with untreated dermatitis herpetiformis (DH) were studied. The final diagnosis was made after completion of immunofluorescence (IF) studies of the skin, iodine provocation tests and gastrointestinal investigations. IgA deposits in the skin and the HLA-DRw3 B-cell alloantigen can be demonstrated in nearly all cases of DH. Positive iodine provocation test and gastrointestinal abnormalities are present in about 78% of the cases. For diagnostic purposes tissue typing and intestinal biopsy is of value in addition to IF studies of the skin.

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The fasting serum concentration and the first-hour serum gastric response to a protein-rich meal were related to the antral G-cell population in 14 patients with peptic ulcer. They were divided into a uremic (n=5) and non-uremic group (n=9). Fasting serum gastrin correlated significantly with the total antral G-cell mass only in the non-uremic patients who showed a relatively narrow transitional body-antrum zone. Conversely, the integrated serum gastric response was inversely related to the size of this zone in both groups of patients. A presumptive endocrine G-cell mass was estimated by subtracting the G cells in the transitional zone from the total antral G-cell population. Total gastrin output correlated positively with this estimated mass in the non-uremic group and in the material as a whole. Also, the integrated gastrin response was positively correlated with the presumptive endocrine G-cell mass in the whole material. It was concluded that G cells in the transitional body-antrum zone, where also parietal cells are present, do not release gastrin into the circulation during meal stimulation like G cells in the remaining part of the pyloric antrum. On the basis of these results and our previous morphological observations (19), we propose that the G cells in the transitional zone are involved in a paracrine interrelationship with the surrounding parietal cells rather than contributing to the circulating pool of gastrin.

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Gastric acid secretion was determined by a pentagastrin test and serum gastrin concentration was determined by radioimmunoassay before and eight times during the first three hours after a test meal in six male azotemic patients and in nine male controls. The mean basal gastric acid secretion was higher, but not significantly so, in the patients than in the controls. The stimulated gastric acid secretion was equal in the two groups. The mean serum gastric concentration was found to be higher in the patient group than in the controls both in the fasting state and after the test meal. The interpretation of the results and the possible relevance of the results in deciding what prophylactic gastro-duodenal operation patients with high ulcer risk should be subjected to prior to kidney transplantation, is discussed.

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A test meal was given to 9 male controls and 9 male patients with duodenal ulcer. The serum gastrin concentrations were determined by radioimmunoassay, and gastric secretion of acid was determined before and after stimulation with 6 mug pentagastrin per kg body weight given subcutaneously. The pattern of gastrin response was found to be biphasic, with an early maximum of the first peak in the patients versus a monophasic response with a maximum in the second hour in the controls. Fasting serum gastrin levels were positively correlated to the basal acid outputs (BAO) in the patients but not in the controls. The mean quotient BAO/Fasting serum gastrin concentration was highest in the patient group, but the quotient of "maximal" acid output (MAO)-BAO/"integrated gastrin response" was equal in the two groups.

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Gastric acid secretion before and after stimulation with pentagastrin and serum gastrin response to a test meal were recorded in 9 male controls and in 7 male patients from whom more than 50 cm of the terminal ileum had been resected because of Crohn's disease. The mean gastric acid secretion before and after stimulation was not found to be significantly different in the two groups. The mean fasting serum gastrin concentration and the serum gastrin response in absolute values were not different in the two groups. The MAO-BAO/'integrated gastrin response' was higher (p less than 0.05), and the gastrin response in relation to fasting level was lower in the patients than in the controls (p less than 0.05). The results indicate that an increased parietal cell sensitivity to gastrin is present after ileal resection. The negative acid feed back mechanism, however, seems to be at work. Under physiological conditions, therefore, the increased sensitivity may not result in acid hypersecretion.

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In 37 patients with hypertension and/or renal disease, blood from a peripheral and a renal vein was drawn during renal vein catheterization. The serum gastrin concentrations were determined and found by paired comparison to be statistically significantly (p less than 0.05) higher in the peripheral than in the renal vein. A test meal was given to 9 male controls and 7 male azotemic patients, and the serum gastrin concentration response determined. The mean fasting serum gastrin values were 173 +/- 22 pg/ml in the group of patients versus 42 +/- 5.5 pg/ml in the controls. The serum gastrin response was significantly higher and of longer duration in the azotemic patients than in the controls. The pentagastrin-stimulated gastric acid secretion was, however, equal in the two groups.

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