1092 CORRESPONDENCE
PAF-Acether
in Necrotizing
GASTROENTEROLOGY Vol.
Enterocolitis
Dear Sir: We agree with the comments of Professor Weinberg’ concerning the inhibitory effect of steroids on tumor necrosis factor (TNF) transcription to explain the prevention of necrotizing enterocolitis in the rat as described by Israel et al.* However, an important hypothesis has been omitted: the role of PAF-acether (PAF, first described as platelet-activating factor). Elevated levels of PAF and TNF are reported in cerebrospinal fluid of children with bacterial meningitis3 and in plasma of human neonates with necrotizing enterocolitis.4 It is shown that the bowel necrosis induced by TNF in rat is mediated by PAF.’ Furthermore, PAF infusion produces in the rat ischemic bowel necrosis,’ and PAF plays a key role in mediating hypoxia-induced intestinal necrosis.‘/ Steroids inhibit phospholipase A, activity, which is the first step in PAF biosynthesis.’ Prevention of necrotizing enterocolitis in rat with prenatal cortisone could be attributed to this mechanism. Thus, to allow definitive conclusions on the involvement of PAF, it is important to investigate the effect of prenatal administration of PAF antagonists to prevent necrotizing enterocolitis. YVES DENIZOT
C. J. F. INSERM 88-03 Faculte’ de MWecine 2 rue du Docteur Marcland 87025 Limoges, France NATHALIE
NATHAN
Dt!partement d’Anesth6ie Ho^pitaI Dupuytren 2 rue Alexis Carrel 87045 Limoges, France 1. Weinberg AG. Tumor necrosis
2.
3.
4.
5.
6.
7.
8.
factor a in the pathophysiology of necrotizing enterocolitis (letter). Gastroenterology 1991; 101:594. Israel EJ, Schiffrin EJ, Carter EA, Freiberg E, Walker WA. Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterology 1990;99:1333-1338. Arditi M, Manogue KR, Caplan M, Yogev R. Cerebrospinal fluid cachectin/tumor necrosis factor-x and platelet-activating factor concentrations and severity of bacterial meningitis in children. J Infect Dis 1990;162:139-147. Caplan MS, Sun XM, Hsueh W, Hageman JR. Role of plateletactivating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990;116:960-964. Sun XM, Hsueh W. Bowel necrosis induced by tumor necrosis factor in rats is mediated by platelet-activating factor. J Clin Invest 1988;81:1328-1331. Hsueh W, Gonzalez-Crussi F, Arroyave JL. Sequential release of leukotrienes and norepinephrine after platelet-activating factor. A mechanistic study of platelet-activating factor-induced bowel necrosis. Gastroenterology 1988;94:1412-1418. Caplan MS, Sun XM, Hsueh W. Hypoxia causes ischemic bowel necrosis: the role of platelet-activating factor. Gastroenterology 1990;99:979-986. Eliakim R, Karmeli F, Razin E, Rachmilewitz D. Role of platelet-activating factor in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine and prednisolone. Gastroenterology 1988;95:1167-1172.
Reply. We appreciate the comments of Drs. Denizot and Nathan regarding the effects of corticosteroids on the NEC rat model. Just as NEC is a disease that appears to be multifactorial in its pathogenesis, the salutory effect of cortisone acetate in this model is most likely the result of numerous interactive mechanisms. Certainly, corticosteroids’ inhibition of phospholipase A,, a proximal
102, No. 3
step in the inflammatory cascade, may have mediated some of the beneficial effects of the cortisone treatment by decreasing the levels of PAF as well as other inflammatory mediators, In our paper’ we chose to investigate cortisone’s effects on one of the three major factors implicated in the multifactorial pathogenesis of NEC, bacterial colonization, and proliferation. The findings of decreased bacterial colonization in the neonatal rats treated with the NEC protocol whose mothers had been treated with cortisone prenatally may at first seem like a final result of cortisone’s beneficial effects on the NEC model. However, we have also shown that corticosteroids have a primary role in altering bacterial colonization in the neonatal rat,’ even in those not treated with the NEC protocol. We therefore suggest that this is an important component of steroids’ beneficial effects although other factors may very well be involved. ESTHER
JACOBOWITZ
ISRAEL
Division ofPediatric Gastroenterology and Nutrition Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts
Intraductal Mucin-Hypersecreting Neoplasms of the Pancreas Dear Sir: We read with great interest the clinicopathologic study of Rickaert et al. dealing with intraductal mucin-hypersecreting neoplasms of the pancreas.’ Preoperatively, the authors’ diagnosis relied mainly on ERCP, an indirect procedure that does not allow histological verification of the lesion. In 1990, we reported on pancreoscopic diagnosis of intraductal cystadenoma of the pancreas.’ Up until now, we observed five patients whose histories and ERCP pathologies were similar to those of the patients studied by Rickaert et al., and in whom we had the chance to perform endoscopic retrograde pancreoscopy again. Using a 3.2-mm prototype (Olympus Optical, Hamburg, Germany), we were able to easily insert the endoscope into the always enlarged pancreatic duct without prior endoscopic papillotomy. All patients had similar macroscopical duct pathology, a villous-like pattern of the ductal mucosa and the lumen filled with amorphous mucoid material, which could be washed out in all patients by rinsing with normal saline solution via the endoscopic channel. The endoscopic picture in our opinion is so characteristic that a clear endoscopic diagnosis can be made. Histologically, all patients revealed the pattern described by Rickaert et al.’ All our patients had pancreatic duct dilation of the head and part of the body of the pancreas with the lesion strictly defined to the pancreatic duct. Although all patients were operated on, in the final histopathologic series two still had a cystadenocarcinoma. Therefore we are not sure whether intraductal mucin-hypersecreting neoplasms (IMHN) can be so clearly distinguished from mutinous cystic neoplasms as in the authors’ report. In our patients, we did not see either a cystic abdominal mass or fistulas between the bile duct or the duodenum. Four of our patients were female and one was male. Two of five already presented with cystadenocarcinoma. In particular, small lesions like the one described in our first case’ cannot be biopsied by ultrasound-guided needle biopsy. In larger tumors, malignant cells may be detected by this technique: the pathologist, however, can diagnose a mutinous cystadenoma only if sufficient material has been obtained.3 In conclusion, we are convinced that with the aid of pancreatoscopy and biopsy, an exact preoperative diagnosis can be made. If histology reveals IMHN or mutinous cystadenoma, a surgical intervention is mandatory because, at least in mutinous cystadenoma, the malignant potential is high. Whether it may be clearly differentiated from the IMHN, in our opinion remains open.
PAF-Acether
in Necrotizing
GASTROENTEROLOGY Vol.
Enterocolitis
Dear Sir: We agree with the comments of Professor Weinberg’ concerning the inhibitory effect of steroids on tumor necrosis factor (TNF) transcription to explain the prevention of necrotizing enterocolitis in the rat as described by Israel et al.* However, an important hypothesis has been omitted: the role of PAF-acether (PAF, first described as platelet-activating factor). Elevated levels of PAF and TNF are reported in cerebrospinal fluid of children with bacterial meningitis3 and in plasma of human neonates with necrotizing enterocolitis.4 It is shown that the bowel necrosis induced by TNF in rat is mediated by PAF.’ Furthermore, PAF infusion produces in the rat ischemic bowel necrosis,’ and PAF plays a key role in mediating hypoxia-induced intestinal necrosis.‘/ Steroids inhibit phospholipase A, activity, which is the first step in PAF biosynthesis.’ Prevention of necrotizing enterocolitis in rat with prenatal cortisone could be attributed to this mechanism. Thus, to allow definitive conclusions on the involvement of PAF, it is important to investigate the effect of prenatal administration of PAF antagonists to prevent necrotizing enterocolitis. YVES DENIZOT
C. J. F. INSERM 88-03 Faculte’ de MWecine 2 rue du Docteur Marcland 87025 Limoges, France NATHALIE
NATHAN
Dt!partement d’Anesth6ie Ho^pitaI Dupuytren 2 rue Alexis Carrel 87045 Limoges, France 1. Weinberg AG. Tumor necrosis
2.
3.
4.
5.
6.
7.
8.
factor a in the pathophysiology of necrotizing enterocolitis (letter). Gastroenterology 1991; 101:594. Israel EJ, Schiffrin EJ, Carter EA, Freiberg E, Walker WA. Prevention of necrotizing enterocolitis in the rat with prenatal cortisone. Gastroenterology 1990;99:1333-1338. Arditi M, Manogue KR, Caplan M, Yogev R. Cerebrospinal fluid cachectin/tumor necrosis factor-x and platelet-activating factor concentrations and severity of bacterial meningitis in children. J Infect Dis 1990;162:139-147. Caplan MS, Sun XM, Hsueh W, Hageman JR. Role of plateletactivating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis. J Pediatr 1990;116:960-964. Sun XM, Hsueh W. Bowel necrosis induced by tumor necrosis factor in rats is mediated by platelet-activating factor. J Clin Invest 1988;81:1328-1331. Hsueh W, Gonzalez-Crussi F, Arroyave JL. Sequential release of leukotrienes and norepinephrine after platelet-activating factor. A mechanistic study of platelet-activating factor-induced bowel necrosis. Gastroenterology 1988;94:1412-1418. Caplan MS, Sun XM, Hsueh W. Hypoxia causes ischemic bowel necrosis: the role of platelet-activating factor. Gastroenterology 1990;99:979-986. Eliakim R, Karmeli F, Razin E, Rachmilewitz D. Role of platelet-activating factor in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine and prednisolone. Gastroenterology 1988;95:1167-1172.
Reply. We appreciate the comments of Drs. Denizot and Nathan regarding the effects of corticosteroids on the NEC rat model. Just as NEC is a disease that appears to be multifactorial in its pathogenesis, the salutory effect of cortisone acetate in this model is most likely the result of numerous interactive mechanisms. Certainly, corticosteroids’ inhibition of phospholipase A,, a proximal
102, No. 3
step in the inflammatory cascade, may have mediated some of the beneficial effects of the cortisone treatment by decreasing the levels of PAF as well as other inflammatory mediators, In our paper’ we chose to investigate cortisone’s effects on one of the three major factors implicated in the multifactorial pathogenesis of NEC, bacterial colonization, and proliferation. The findings of decreased bacterial colonization in the neonatal rats treated with the NEC protocol whose mothers had been treated with cortisone prenatally may at first seem like a final result of cortisone’s beneficial effects on the NEC model. However, we have also shown that corticosteroids have a primary role in altering bacterial colonization in the neonatal rat,’ even in those not treated with the NEC protocol. We therefore suggest that this is an important component of steroids’ beneficial effects although other factors may very well be involved. ESTHER
JACOBOWITZ
ISRAEL
Division ofPediatric Gastroenterology and Nutrition Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts
Intraductal Mucin-Hypersecreting Neoplasms of the Pancreas Dear Sir: We read with great interest the clinicopathologic study of Rickaert et al. dealing with intraductal mucin-hypersecreting neoplasms of the pancreas.’ Preoperatively, the authors’ diagnosis relied mainly on ERCP, an indirect procedure that does not allow histological verification of the lesion. In 1990, we reported on pancreoscopic diagnosis of intraductal cystadenoma of the pancreas.’ Up until now, we observed five patients whose histories and ERCP pathologies were similar to those of the patients studied by Rickaert et al., and in whom we had the chance to perform endoscopic retrograde pancreoscopy again. Using a 3.2-mm prototype (Olympus Optical, Hamburg, Germany), we were able to easily insert the endoscope into the always enlarged pancreatic duct without prior endoscopic papillotomy. All patients had similar macroscopical duct pathology, a villous-like pattern of the ductal mucosa and the lumen filled with amorphous mucoid material, which could be washed out in all patients by rinsing with normal saline solution via the endoscopic channel. The endoscopic picture in our opinion is so characteristic that a clear endoscopic diagnosis can be made. Histologically, all patients revealed the pattern described by Rickaert et al.’ All our patients had pancreatic duct dilation of the head and part of the body of the pancreas with the lesion strictly defined to the pancreatic duct. Although all patients were operated on, in the final histopathologic series two still had a cystadenocarcinoma. Therefore we are not sure whether intraductal mucin-hypersecreting neoplasms (IMHN) can be so clearly distinguished from mutinous cystic neoplasms as in the authors’ report. In our patients, we did not see either a cystic abdominal mass or fistulas between the bile duct or the duodenum. Four of our patients were female and one was male. Two of five already presented with cystadenocarcinoma. In particular, small lesions like the one described in our first case’ cannot be biopsied by ultrasound-guided needle biopsy. In larger tumors, malignant cells may be detected by this technique: the pathologist, however, can diagnose a mutinous cystadenoma only if sufficient material has been obtained.3 In conclusion, we are convinced that with the aid of pancreatoscopy and biopsy, an exact preoperative diagnosis can be made. If histology reveals IMHN or mutinous cystadenoma, a surgical intervention is mandatory because, at least in mutinous cystadenoma, the malignant potential is high. Whether it may be clearly differentiated from the IMHN, in our opinion remains open.
