August 1992
SELECTED SUMMARIES
recently described an additional low-molecular-weight substance elaborated by activated neutrophils that is an unusual chloride secretagogue in that it is only active if presented apically and does not appear to use known signal-transduction pathways for secretion (J Clin Invest 1991;87:1474-1477). Some of the neutrophil products listed as secretagogues may have indirect effects on the epithelium. Much of the activity of hydrogen peroxide, for example, appears to be caused by stimulation of subepithelial fibroblasts with consequent prostaglandin generation. Further, many of the secretory effects of neutrophil activators in intact tissue can be attenuated by blockade of the enteric nervous system with agents such as tetrodotoxin. Thus, Tamai et al. took the approach of studying the direct effects of monochloramine on T, cells in the current study to eliminate the possible contribution of these indirect mechanisms. They were able to show that monochloramine is a chloride secretagogue that is likely to exert its effects in intact tissue, at least in part, by interacting directly with the epithelial cells themselves. They also showed that these effects are unlikely to be caused by cytotoxicity. Importantly, the concentrations of monochloramine required to stimulate secretion are well below those having a damaging effect on the cells and are also predicted to be readily achieved in the setting of intestinal inflammation. An additional strength of the model used in these studies is its potential for the elucidation of mechanistic information. Monochloramine appeared to stimulate secretion via one of the welldescribed messengers for chloride secretion, [Ca”],, although its ability to increase [Caz+li was not apparently attributable to turnover of membrane phosphatidylinositol to yield IP,. In any event, the discovery that a neutrophil product has secretory effects mediated through the calcium-dependent pathway may have significant implications for the amplification of neutrophil-related secretion. Chloride secretagogues acting through various signaling pathways often show synergistic interactions; that is, the observed effects of combinations of such stimuli are significantly more than additive. Because other neutrophil-derived activators of chloride secretion appear to stimulate cyclic nucleotide-dependent pathways (either directly or via the release of prostaglandins that increase CAMP concentrations in the epithelium), the fact that monochloramine, at physiologically relevant concentrations, elevates [Ca’+& may have substantial relevance to the setting of inflammation, in which many mediators and cytokines are being produced simultaneously. Additionally, this observation implies that monochloramine might enhance the responsiveness of the epithelium to the neuropeptide vasoactive intestinal polypeptide, an additional secretagogue known to act through CAMP. These studies should be considered in the wider context of the current major interest in immune-related intestinal secretion. Experiments of the type described in this article may suggest new possibilities for treatment of intractable inflammatory diarrhea. However, there is still considerable work to be done to define the actual cytokine and mediator milieu existing at various stages of the inflammatory process and the relative contributions of various mediators to the observed pathophysiological function. It is to be expected that further work in this area might allow the identification of key factors responsible for this pathophysiology, thereby allowing us to target their effects, formation, or interactions with other substances as points for therapeutic intervention. K. E. BARRETT,
Reply.
PH.D.
We thank Dr. Barrett for her excellent review of our findings, but we would like to add to her comments regarding the calcium-mediated effects of monochloramine on intestinal secretion. We believe that monochloramine-stimulated increases in cytosolic calcium concentrations result from a generic, possibly ubiquitous effect on membrane calcium permeability. This may occur
711
through lipid peroxidation, which could cause a nonspecific increase in membrane calcium permeability because of fluidity or other changes (Free Radic Biol Med 1990;9:507-514), or through oxidation of thiol groups that appear to affect the activity of a number of calcium-transport proteins (FEBS Lett 1983;163:136139; Am J Physiol 1988;254:C330-C337; Am J Physiol 1989;256: H369-H374; Arch Biochem Biophys 1983;255:164-177). Thus, increased cytosolic calcium concentrations stimulated by these agents would arise from both increased plasma membrane permeability, permitting influx of extracellular calcium, and efflux from endogenous calcium organelle pools. If this is indeed the mechanism of monochloramine-stimulated increases in cytosolic calcium concentrations, it is likely that reactive oxygen metabolites increase cell calcium of nonepithelial intestinal cells in a similar manner. This may account for the observed dependence of the neural component stimulation by monochloramine in rat distal colon (J Pharmacol Exp 1990;257:884-894). In inflammation, monochloramine and other reactive oxygen metabolites could activate and amplify the response given the calcium dependence of other pathways such as the arachidonic acid cascade, activation of protein kinase C, and other calcium-binding protein-dependent events. The synergy of these mediators may be pivotal in the pathogenesis of intestinal immune and inflammatory reactions. EUGENE B.
CHANG, M.D.
MARK W. MUSCH,
PH.1).
LOCALIZATION OF ISLET CELL TUMORS BY ENDOSCOPIC ULTRASONOGRAPHY Glover JR, Shorvon PJ, Lees WR [Department of Medical Imaging, Middlesex Hospital, London, England). Endoscopic ultrasound for localization of islet cell tumors. Gut 1992;33:108-110. The aims of this study were to evaluate endoscopic ultrasonography (EUS) in localizing clinically suspected pancreatic endocrine tumors and to compare it with conventional computed tomography (CT) and transabdominal ultrasound (US). Twenty-one patients with biochemical and clinical evidence of pancreatic islet cell tumors were referred for EUS imaging of the pancreas, mostly because of the failure of other techniques to identify a lesion. It was suspected that 16 patients had insulinomas, 2 had gastrinomas, and 1 each had glucagonoma, vipoma, and multiple endocrine adenopathy type I (MEA). Eleven patients were male and 10 were female, with a mean age of 49 years. All patients had previously been evaluated with at least CT and transabdominal US. In addition, 6 patients had undergone selective angiography and 2 portal venous sampling. EUS was performed using the Olympus GF-UM2 ultrasound scope, which features a 7.5-MHz rotating transducer attached to the end of a side-viewing endoscope. The instrument was passed under direct vision to the descending duodenum and withdrawn slowly, permitting ultrasonographic imaging of the entire pancreas through the duodenal and gastric walls. All patients were examined using conscious sedation, and all were discharged on the day of the procedure unless their underlying clinical state required admission or continued hospitalization. The procedure averaged 10-30 minutes in duration and was well tolerated by all.
712
SELECTED SUMMARIES
Of the 16 patients with suspected insulinomas, positive histology was obtained at operation in 14. The tumors were distributed evenly in the head, body, and tail of the pancreas. Fifteen insulinomas were found in these 14 patients; 12 were correctly identified and localized by EUS. The 3 lesions missed consisted of a 40 X 15-mm lesion in the head of the pancreas and 2 lesions in the splenic hilum. Of the remaining 5 patients, there were 2 true negatives, one in a patient with a suspected gastrinoma and one in a patient with symptoms of recurrent vipoma. One patient had a 20-mm glucagonoma identified by EUS but three additional 5-mm lesions found at surgery that were missed by EUS. The patient with MEA was shown by EUS to have a diffusely abnormal pancreas with multiple small tumors. There was one technical failure caused by duodenal scarring that prevented passage of the endoscope beyond the pylorus in a patient with the Zollinger-Ellison syndrome. In comparison, CT identified three insulinomas and one glucagonoma in the same patients. Transabdominal US detected only two islet cell tumors and showed diffuse pancreatic abnormality in the patient with MEA. Overall, the sensitivity of EUS in identifying and localizing endocrine tumors of the pancreas was 75%, compared with 25% and 18% for CT and transabdominal US, respectively. The authors conclude that EUS is an important addition to the battery of diagnostic tests used to identify and localize islet cell tumors. Comment. Endocrine tumors of the pancreas are most often characterized according to the hormones they produce and the resulting clinical syndromes. These tumors, in order of decreasing clinical frequency, include insulinomas, gastrinomas, vipomas, glucagonomas, and somatostatinomas. Diagnosis is based on the presence of symptoms and the documentation of inappropriately high levels of the secretory product responsible for the clinical manifestations. Therapeutic management often depends on the exact localization of the primary tumor and the presence or absence of metastases. Only 10% of insulinomas but 60% of gastrinomas are considered multiple or metastatic. The pattern of metastatic spread is usually limited to local invasion of peripancreatic and portal lymph nodes, but metastasis to the liver is common in gastrinomas. Many islet cell tumors are small (
SELECTED SUMMARIES
recently described an additional low-molecular-weight substance elaborated by activated neutrophils that is an unusual chloride secretagogue in that it is only active if presented apically and does not appear to use known signal-transduction pathways for secretion (J Clin Invest 1991;87:1474-1477). Some of the neutrophil products listed as secretagogues may have indirect effects on the epithelium. Much of the activity of hydrogen peroxide, for example, appears to be caused by stimulation of subepithelial fibroblasts with consequent prostaglandin generation. Further, many of the secretory effects of neutrophil activators in intact tissue can be attenuated by blockade of the enteric nervous system with agents such as tetrodotoxin. Thus, Tamai et al. took the approach of studying the direct effects of monochloramine on T, cells in the current study to eliminate the possible contribution of these indirect mechanisms. They were able to show that monochloramine is a chloride secretagogue that is likely to exert its effects in intact tissue, at least in part, by interacting directly with the epithelial cells themselves. They also showed that these effects are unlikely to be caused by cytotoxicity. Importantly, the concentrations of monochloramine required to stimulate secretion are well below those having a damaging effect on the cells and are also predicted to be readily achieved in the setting of intestinal inflammation. An additional strength of the model used in these studies is its potential for the elucidation of mechanistic information. Monochloramine appeared to stimulate secretion via one of the welldescribed messengers for chloride secretion, [Ca”],, although its ability to increase [Caz+li was not apparently attributable to turnover of membrane phosphatidylinositol to yield IP,. In any event, the discovery that a neutrophil product has secretory effects mediated through the calcium-dependent pathway may have significant implications for the amplification of neutrophil-related secretion. Chloride secretagogues acting through various signaling pathways often show synergistic interactions; that is, the observed effects of combinations of such stimuli are significantly more than additive. Because other neutrophil-derived activators of chloride secretion appear to stimulate cyclic nucleotide-dependent pathways (either directly or via the release of prostaglandins that increase CAMP concentrations in the epithelium), the fact that monochloramine, at physiologically relevant concentrations, elevates [Ca’+& may have substantial relevance to the setting of inflammation, in which many mediators and cytokines are being produced simultaneously. Additionally, this observation implies that monochloramine might enhance the responsiveness of the epithelium to the neuropeptide vasoactive intestinal polypeptide, an additional secretagogue known to act through CAMP. These studies should be considered in the wider context of the current major interest in immune-related intestinal secretion. Experiments of the type described in this article may suggest new possibilities for treatment of intractable inflammatory diarrhea. However, there is still considerable work to be done to define the actual cytokine and mediator milieu existing at various stages of the inflammatory process and the relative contributions of various mediators to the observed pathophysiological function. It is to be expected that further work in this area might allow the identification of key factors responsible for this pathophysiology, thereby allowing us to target their effects, formation, or interactions with other substances as points for therapeutic intervention. K. E. BARRETT,
Reply.
PH.D.
We thank Dr. Barrett for her excellent review of our findings, but we would like to add to her comments regarding the calcium-mediated effects of monochloramine on intestinal secretion. We believe that monochloramine-stimulated increases in cytosolic calcium concentrations result from a generic, possibly ubiquitous effect on membrane calcium permeability. This may occur
711
through lipid peroxidation, which could cause a nonspecific increase in membrane calcium permeability because of fluidity or other changes (Free Radic Biol Med 1990;9:507-514), or through oxidation of thiol groups that appear to affect the activity of a number of calcium-transport proteins (FEBS Lett 1983;163:136139; Am J Physiol 1988;254:C330-C337; Am J Physiol 1989;256: H369-H374; Arch Biochem Biophys 1983;255:164-177). Thus, increased cytosolic calcium concentrations stimulated by these agents would arise from both increased plasma membrane permeability, permitting influx of extracellular calcium, and efflux from endogenous calcium organelle pools. If this is indeed the mechanism of monochloramine-stimulated increases in cytosolic calcium concentrations, it is likely that reactive oxygen metabolites increase cell calcium of nonepithelial intestinal cells in a similar manner. This may account for the observed dependence of the neural component stimulation by monochloramine in rat distal colon (J Pharmacol Exp 1990;257:884-894). In inflammation, monochloramine and other reactive oxygen metabolites could activate and amplify the response given the calcium dependence of other pathways such as the arachidonic acid cascade, activation of protein kinase C, and other calcium-binding protein-dependent events. The synergy of these mediators may be pivotal in the pathogenesis of intestinal immune and inflammatory reactions. EUGENE B.
CHANG, M.D.
MARK W. MUSCH,
PH.1).
LOCALIZATION OF ISLET CELL TUMORS BY ENDOSCOPIC ULTRASONOGRAPHY Glover JR, Shorvon PJ, Lees WR [Department of Medical Imaging, Middlesex Hospital, London, England). Endoscopic ultrasound for localization of islet cell tumors. Gut 1992;33:108-110. The aims of this study were to evaluate endoscopic ultrasonography (EUS) in localizing clinically suspected pancreatic endocrine tumors and to compare it with conventional computed tomography (CT) and transabdominal ultrasound (US). Twenty-one patients with biochemical and clinical evidence of pancreatic islet cell tumors were referred for EUS imaging of the pancreas, mostly because of the failure of other techniques to identify a lesion. It was suspected that 16 patients had insulinomas, 2 had gastrinomas, and 1 each had glucagonoma, vipoma, and multiple endocrine adenopathy type I (MEA). Eleven patients were male and 10 were female, with a mean age of 49 years. All patients had previously been evaluated with at least CT and transabdominal US. In addition, 6 patients had undergone selective angiography and 2 portal venous sampling. EUS was performed using the Olympus GF-UM2 ultrasound scope, which features a 7.5-MHz rotating transducer attached to the end of a side-viewing endoscope. The instrument was passed under direct vision to the descending duodenum and withdrawn slowly, permitting ultrasonographic imaging of the entire pancreas through the duodenal and gastric walls. All patients were examined using conscious sedation, and all were discharged on the day of the procedure unless their underlying clinical state required admission or continued hospitalization. The procedure averaged 10-30 minutes in duration and was well tolerated by all.
712
SELECTED SUMMARIES
Of the 16 patients with suspected insulinomas, positive histology was obtained at operation in 14. The tumors were distributed evenly in the head, body, and tail of the pancreas. Fifteen insulinomas were found in these 14 patients; 12 were correctly identified and localized by EUS. The 3 lesions missed consisted of a 40 X 15-mm lesion in the head of the pancreas and 2 lesions in the splenic hilum. Of the remaining 5 patients, there were 2 true negatives, one in a patient with a suspected gastrinoma and one in a patient with symptoms of recurrent vipoma. One patient had a 20-mm glucagonoma identified by EUS but three additional 5-mm lesions found at surgery that were missed by EUS. The patient with MEA was shown by EUS to have a diffusely abnormal pancreas with multiple small tumors. There was one technical failure caused by duodenal scarring that prevented passage of the endoscope beyond the pylorus in a patient with the Zollinger-Ellison syndrome. In comparison, CT identified three insulinomas and one glucagonoma in the same patients. Transabdominal US detected only two islet cell tumors and showed diffuse pancreatic abnormality in the patient with MEA. Overall, the sensitivity of EUS in identifying and localizing endocrine tumors of the pancreas was 75%, compared with 25% and 18% for CT and transabdominal US, respectively. The authors conclude that EUS is an important addition to the battery of diagnostic tests used to identify and localize islet cell tumors. Comment. Endocrine tumors of the pancreas are most often characterized according to the hormones they produce and the resulting clinical syndromes. These tumors, in order of decreasing clinical frequency, include insulinomas, gastrinomas, vipomas, glucagonomas, and somatostatinomas. Diagnosis is based on the presence of symptoms and the documentation of inappropriately high levels of the secretory product responsible for the clinical manifestations. Therapeutic management often depends on the exact localization of the primary tumor and the presence or absence of metastases. Only 10% of insulinomas but 60% of gastrinomas are considered multiple or metastatic. The pattern of metastatic spread is usually limited to local invasion of peripancreatic and portal lymph nodes, but metastasis to the liver is common in gastrinomas. Many islet cell tumors are small (
