446
Letters to the Editor
symptoms, a number of novel prokinetics were developed such as cisapride and several other 5-HT4 receptor agonists (2–4). Assuming that stronger stimulation of gastric contractility would lead to superior control of symptoms, several motilin receptor agonists and later also ghrelin receptor agonists were developed, with disappointing clinical outcomes (2–4,6,7). Our aim was to review the hypothesis that the magnitude of improvement of gastric emptying rate is a predictor of the magnitude of symptom relief in gastroparesis, and our meta-regression analysis failed to confirm this hypothesis (5). This has important implications not only for clinical practice, by questioning the rationale for (repeated) gastric emptying testing, but also for drug development. Drugs that enhance gastric emptying in animal models will not necessarily convey symptomatic benefits to gastroparesis patients and, more importantly, measuring the effect on gastric emptying rate is less likely to identify the optimal dose range to be used in symptom-driven clinical trials. Our systematic review confirmed overall improvement of symptoms with prokinetic drugs without correlation to changes in gastric emptying rate suggests that the symptom-ameliorating effects are attributable to other aspects of these drugs’ actions (8). Indeed, as pointed by Dr Sanger and others, gastroprokinetics are a heterogenous class of agents with different receptor affinities and selectivities and different effects on multiple aspects of gastric sensorimotor function (2–4,6,8,9). Hence, other modes of action underlying the therapeutic benefit of “prokinetics” such as enhancement of gastric accommodation (5-HT4 agonists), changes in gastric sensitivity, or suppression of nausea and vomiting (D2 antagonists) deserve further studies (2–4). Indeed, drugs in the so-called class of prokinetics have variable effects on these aspects of gastric function (2–8). Such studies may lead to a better understanding of the therapeutic efficacy of “prokinetics”, identification of better predictors of their symptomatic efficacy than gastric emptying rate and, perhaps, reclassification into a more appropriately named new class. We are currently pursuing the hypothesis that effects on gastric accommodation have The American Journal of GASTROENTEROLOGY
a major role in the magnitude of symptomatic benefit with motility-modifying agents, and recent pharmacological and technical advances provide a potential for better applicability and understanding of these factors in the near future (10–13). CONFLICT OF INTEREST
The author declares no conflict of interest. REFERENCES 1. Gale Encyclopedia of Medicine Copyright 2008 The Gale Group Inc. http://medical-dictionary. thefreedictionary.com. 2. Saad RJ, Chey WD. Review article: current and emerging therapies for functional dyspepsia. Aliment Pharmacol Ther 2006;24:475–92. 3. Karamanolis G, Tack J. Promotility medications--now and in the future. Dig Dis 2006;24:297–307. 4. Tack J. Prokinetics and fundic relaxants in upper functional GI disorders. Curr Opin Pharmacol 2008;8:690–6. 5. Parkman HP, Camilleri M, Farrugia G et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–33. 6. Tack J, Peeters T. What comes after macrolides and other motilin stimulants? Gut 2001;49:317–8. 7. Avau B, Carbone F, Tack J et al. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013;25:720–32. 8. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 9. Sanger G. The relation between symptom improvement and gastric emptying in the treatment of gastroparesis: remember the pharmacology. Am J Gastroenterol 2014; 109:444–5 (this issue). 10. Bisschops R, Tack J. Dysaccommodation of the stomach: therapeutic nirvana? Neurogastroenterol Motil 2007;19:85–93. 11. Tack J, Janssen P, Masaoka T et al. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012;10:1239–45. 12. Kusunoki H, Haruma K, Manabe N et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil 2012;24:540–5, e250-1. 13. Janssen P, Verschueren S, Ly HG et al. Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation. Neurogastroenterol Motil 2011;23:316–22, e153-4. 1 University Leuven—Gastroenterology, Leuven, Belgium. Correspondence: Jan Tack, MD, PhD, University Leuven—Gastroenterology, Herestraat 49, Leuven 3000, Belgium. E-mail: [email protected]
Is Intraductal Papillary Mucinous Neoplasm of the Pancreas Just a Precursor or Identical With Pancreatic Ductal Adenocarcinoma? Kazumichi Kawakubo, MD, PhD1, Hiroshi Kawakami, MD, PhD1, Masaki Kuwatani, MD, PhD1 and Naoya Sakamoto, MD, PhD1 doi:10.1038/ajg.2013.468
To the Editor: We read with great interest the article by Capurso et al. (1), a multicenter case–control study about risk factors associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. They concluded that a previous history of diabetes, chronic pancreatitis, and family history of pancreatic ductal adenocarcinoma (PDAC) are risk factors for IPMN, and overlaps with those of PDAC. IPMN and PDAC were reported to be significantly associated with each other. PDAC developed both synchronously and metachronously with IPMN (2,3). It is a matter of course that the risk factors of IPMN and PDAC overlapped with each other. Really important thing to be clarified is that the patients who have such kind of risk factor will develop only IPMN, or both IPMN and PDAC. As previously reported, the comorbidity score was significantly associated with mortality other than pancreatic cancer in patients with IPMN, so those patients will die of disease other than PDAC (4). The prognosis of IPMN was better than that of PDAC, so it would be very helpful for those patients to know the risk of PDAC rather than that of IPMN. In the study by Capuro et al. (1), the main issue is the prevalence of the risk factors of IPMN. The prevalence is important information, but the incidence of IPMN in patients who have such kind of risk factor is not clarified. Therefore, the prospective study will be necessary to evaluate the incidence, not the prevalence, of IPMN and PDAC. VOLUME 109 | MARCH 2014 www.amjgastro.com
Letters to the Editor
This study also showed important fact that family history of cancer was not associated with the IPMN except for pancreatic cancer. This constituted indirect evidence that IPMN was not associated with extrapancreatic malignancy, but pancreatic cancer (5). The controversy about the relationship between IPMN and extrapancreatic cancer will be settled from this study. CONFLICT OF INTEREST
The authors declare no conflict of interest. REFERENCES 1. Capurso G, Boccia S, Salvia R et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108:1003–9. 2. Tada M, Kawabe T, Arizumi M et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol 2006;4:1265–70. 3. Ingkakul T, Sadakari Y, Ienaga J et al. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 2010;251:70–5. 4. Kawakubo K, Tada M, Isayama H et al. Risk for mortality from causes other than pancreatic cancer in patients with intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013;42:687–91. 5. Kawakubo K, Tada M, Isayama H et al. Incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms of the pancreas. Gut 2011;60: 1249–53. 1
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Correspondence: Kazumichi Kawakubo, MD, PhD, Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita15 Nishi7, Kita-ku, Sapporo 0808638, Japan. E-mail: [email protected]
Response to Kawakubo et al. Gabriele Capurso, MD, PhD1, Stefania Boccia, MSc, DSc, PhD2 and Alberto Larghi, MD, PhD3 doi:10.1038/ajg.2013.472
To the Editor: We thank Kawakubo (1) and colleagues for their letter discussing a number of interesting issues regarding our © 2014 by the American College of Gastroenterology
recent publication on risk factors for the occurrence of IPMN (2). A first point raised is whether patients with certain specific risk factors will develop only IPMN, or both IPMN and pancreatic ductal adenocarcinoma (PDAC). Kawakubo et al. suggest that knowing the incidence of IPMN and not their prevalence in subjects with certain risk factors would be more interesting and may be able to better define which ones are associated with IPMN and/or with PDAC. The case-control design of our study did not allow us to give an answer to this important question that might be solved by a prospective cohort study. Such study, however, will require a long time to be completed. In addition, considering that most IPMNs are now diagnosed incidentally without any symptoms, it might be difficult to assess their real incidence, and the relation with putative risk factors in a cohort of subjects not actively screened for the presence of IPMN. A second important point regards the association between IPMNs and extrapancreatic malignancies. This aspect was beyond the aims of our paper. However, we have recently published another study investigating the prevalence of secondary neoplasms in the same IPMN population (3). The results of this study do indeed suggest that there is an increased prevalence of extra-pancreatic malignancies in patients with IPMN, especially colorectal adenocarcinoma, but also renal cell and thyroid cancers. Interestingly, in this second study it was found that first-degree family history of gastric cancer was a significant risk factor for extra-pancreatic malignancies, and there was a strong association (P = 0.051) for first-degree family history of colorectal carcinoma also. Future studies investigating the rate of neoplastic and pre-neoplastic colorectal lesions in patients with IPMN as compared with controls might prove useful to confirm this association. CONFLICT OF INTEREST
The authors declare no conflict of interest. REFERENCES 1. Kawakubo K, Kawakami H, Kuwatani M et al. Is intraductal papillary mucinous neoplasm of the pancreas just a precursor or identical
with pancreatic ductal adenocarcinoma? Am J Gastroenterol 2014;109:446–7 (this issue). 2. Capurso G, Boccia S, Salvia R et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108:1003–9. 3. Larghi A, Panic N, Capurso G et al. Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Oncol 2013;24:1907–11. 1
Digestive and Liver Disease Unit, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy; 2Department of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; 3Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore, Rome, Italy. Correspondence: Gabriele Capurso, MD, PhD, Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza, University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. E-mail: [email protected]
ERCP and Fluoroscopy Time Amer A. Alkhatib, MD1, Ala Abdel Jalil, MD2 and M.E. Harrison, MD3 doi:10.1038/ajg.2013.470
To the Editor: We read with interest the study of Romagnuolo and Cotton (1). The study reported different factors that predict prolonged fluoroscopy time (FT) during endoscopic retrograde cholangiopancreatography (ERCP) (1). In our multicenter study (n = 414, ERCP procedure performed by six endoscopists in three American centers) that was partially published as an abstract and presented as poster in ACG meeting 2013, the strongest predictive factor of prolonged FT utilization during ERCP procedure was the anatomical location of the pathology being treated (intrahepatic vs. pancreatic vs. extrahepatic) with mean FT 4.96 min for extrahepatic cases, 6.75 min for pancreatic cases, and 12.9 min for intrahepatic cases (P < 0.05) (2). It would be interesting if the authors can extract the relationship between FT and anatomical location of the pathology from the ERCP Quality Network. The American Journal of GASTROENTEROLOGY
447
Letters to the Editor
symptoms, a number of novel prokinetics were developed such as cisapride and several other 5-HT4 receptor agonists (2–4). Assuming that stronger stimulation of gastric contractility would lead to superior control of symptoms, several motilin receptor agonists and later also ghrelin receptor agonists were developed, with disappointing clinical outcomes (2–4,6,7). Our aim was to review the hypothesis that the magnitude of improvement of gastric emptying rate is a predictor of the magnitude of symptom relief in gastroparesis, and our meta-regression analysis failed to confirm this hypothesis (5). This has important implications not only for clinical practice, by questioning the rationale for (repeated) gastric emptying testing, but also for drug development. Drugs that enhance gastric emptying in animal models will not necessarily convey symptomatic benefits to gastroparesis patients and, more importantly, measuring the effect on gastric emptying rate is less likely to identify the optimal dose range to be used in symptom-driven clinical trials. Our systematic review confirmed overall improvement of symptoms with prokinetic drugs without correlation to changes in gastric emptying rate suggests that the symptom-ameliorating effects are attributable to other aspects of these drugs’ actions (8). Indeed, as pointed by Dr Sanger and others, gastroprokinetics are a heterogenous class of agents with different receptor affinities and selectivities and different effects on multiple aspects of gastric sensorimotor function (2–4,6,8,9). Hence, other modes of action underlying the therapeutic benefit of “prokinetics” such as enhancement of gastric accommodation (5-HT4 agonists), changes in gastric sensitivity, or suppression of nausea and vomiting (D2 antagonists) deserve further studies (2–4). Indeed, drugs in the so-called class of prokinetics have variable effects on these aspects of gastric function (2–8). Such studies may lead to a better understanding of the therapeutic efficacy of “prokinetics”, identification of better predictors of their symptomatic efficacy than gastric emptying rate and, perhaps, reclassification into a more appropriately named new class. We are currently pursuing the hypothesis that effects on gastric accommodation have The American Journal of GASTROENTEROLOGY
a major role in the magnitude of symptomatic benefit with motility-modifying agents, and recent pharmacological and technical advances provide a potential for better applicability and understanding of these factors in the near future (10–13). CONFLICT OF INTEREST
The author declares no conflict of interest. REFERENCES 1. Gale Encyclopedia of Medicine Copyright 2008 The Gale Group Inc. http://medical-dictionary. thefreedictionary.com. 2. Saad RJ, Chey WD. Review article: current and emerging therapies for functional dyspepsia. Aliment Pharmacol Ther 2006;24:475–92. 3. Karamanolis G, Tack J. Promotility medications--now and in the future. Dig Dis 2006;24:297–307. 4. Tack J. Prokinetics and fundic relaxants in upper functional GI disorders. Curr Opin Pharmacol 2008;8:690–6. 5. Parkman HP, Camilleri M, Farrugia G et al. Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–33. 6. Tack J, Peeters T. What comes after macrolides and other motilin stimulants? Gut 2001;49:317–8. 7. Avau B, Carbone F, Tack J et al. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013;25:720–32. 8. Janssen P, Harris MS, Jones M et al. The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–91. 9. Sanger G. The relation between symptom improvement and gastric emptying in the treatment of gastroparesis: remember the pharmacology. Am J Gastroenterol 2014; 109:444–5 (this issue). 10. Bisschops R, Tack J. Dysaccommodation of the stomach: therapeutic nirvana? Neurogastroenterol Motil 2007;19:85–93. 11. Tack J, Janssen P, Masaoka T et al. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012;10:1239–45. 12. Kusunoki H, Haruma K, Manabe N et al. Therapeutic efficacy of acotiamide in patients with functional dyspepsia based on enhanced postprandial gastric accommodation and emptying: randomized controlled study evaluation by real-time ultrasonography. Neurogastroenterol Motil 2012;24:540–5, e250-1. 13. Janssen P, Verschueren S, Ly HG et al. Intragastric pressure during food intake: a physiological and minimally invasive method to assess gastric accommodation. Neurogastroenterol Motil 2011;23:316–22, e153-4. 1 University Leuven—Gastroenterology, Leuven, Belgium. Correspondence: Jan Tack, MD, PhD, University Leuven—Gastroenterology, Herestraat 49, Leuven 3000, Belgium. E-mail: [email protected]
Is Intraductal Papillary Mucinous Neoplasm of the Pancreas Just a Precursor or Identical With Pancreatic Ductal Adenocarcinoma? Kazumichi Kawakubo, MD, PhD1, Hiroshi Kawakami, MD, PhD1, Masaki Kuwatani, MD, PhD1 and Naoya Sakamoto, MD, PhD1 doi:10.1038/ajg.2013.468
To the Editor: We read with great interest the article by Capurso et al. (1), a multicenter case–control study about risk factors associated with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. They concluded that a previous history of diabetes, chronic pancreatitis, and family history of pancreatic ductal adenocarcinoma (PDAC) are risk factors for IPMN, and overlaps with those of PDAC. IPMN and PDAC were reported to be significantly associated with each other. PDAC developed both synchronously and metachronously with IPMN (2,3). It is a matter of course that the risk factors of IPMN and PDAC overlapped with each other. Really important thing to be clarified is that the patients who have such kind of risk factor will develop only IPMN, or both IPMN and PDAC. As previously reported, the comorbidity score was significantly associated with mortality other than pancreatic cancer in patients with IPMN, so those patients will die of disease other than PDAC (4). The prognosis of IPMN was better than that of PDAC, so it would be very helpful for those patients to know the risk of PDAC rather than that of IPMN. In the study by Capuro et al. (1), the main issue is the prevalence of the risk factors of IPMN. The prevalence is important information, but the incidence of IPMN in patients who have such kind of risk factor is not clarified. Therefore, the prospective study will be necessary to evaluate the incidence, not the prevalence, of IPMN and PDAC. VOLUME 109 | MARCH 2014 www.amjgastro.com
Letters to the Editor
This study also showed important fact that family history of cancer was not associated with the IPMN except for pancreatic cancer. This constituted indirect evidence that IPMN was not associated with extrapancreatic malignancy, but pancreatic cancer (5). The controversy about the relationship between IPMN and extrapancreatic cancer will be settled from this study. CONFLICT OF INTEREST
The authors declare no conflict of interest. REFERENCES 1. Capurso G, Boccia S, Salvia R et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108:1003–9. 2. Tada M, Kawabe T, Arizumi M et al. Pancreatic cancer in patients with pancreatic cystic lesions: a prospective study in 197 patients. Clin Gastroenterol Hepatol 2006;4:1265–70. 3. Ingkakul T, Sadakari Y, Ienaga J et al. Predictors of the presence of concomitant invasive ductal carcinoma in intraductal papillary mucinous neoplasm of the pancreas. Ann Surg 2010;251:70–5. 4. Kawakubo K, Tada M, Isayama H et al. Risk for mortality from causes other than pancreatic cancer in patients with intraductal papillary mucinous neoplasm of the pancreas. Pancreas 2013;42:687–91. 5. Kawakubo K, Tada M, Isayama H et al. Incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms of the pancreas. Gut 2011;60: 1249–53. 1
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Correspondence: Kazumichi Kawakubo, MD, PhD, Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Kita15 Nishi7, Kita-ku, Sapporo 0808638, Japan. E-mail: [email protected]
Response to Kawakubo et al. Gabriele Capurso, MD, PhD1, Stefania Boccia, MSc, DSc, PhD2 and Alberto Larghi, MD, PhD3 doi:10.1038/ajg.2013.472
To the Editor: We thank Kawakubo (1) and colleagues for their letter discussing a number of interesting issues regarding our © 2014 by the American College of Gastroenterology
recent publication on risk factors for the occurrence of IPMN (2). A first point raised is whether patients with certain specific risk factors will develop only IPMN, or both IPMN and pancreatic ductal adenocarcinoma (PDAC). Kawakubo et al. suggest that knowing the incidence of IPMN and not their prevalence in subjects with certain risk factors would be more interesting and may be able to better define which ones are associated with IPMN and/or with PDAC. The case-control design of our study did not allow us to give an answer to this important question that might be solved by a prospective cohort study. Such study, however, will require a long time to be completed. In addition, considering that most IPMNs are now diagnosed incidentally without any symptoms, it might be difficult to assess their real incidence, and the relation with putative risk factors in a cohort of subjects not actively screened for the presence of IPMN. A second important point regards the association between IPMNs and extrapancreatic malignancies. This aspect was beyond the aims of our paper. However, we have recently published another study investigating the prevalence of secondary neoplasms in the same IPMN population (3). The results of this study do indeed suggest that there is an increased prevalence of extra-pancreatic malignancies in patients with IPMN, especially colorectal adenocarcinoma, but also renal cell and thyroid cancers. Interestingly, in this second study it was found that first-degree family history of gastric cancer was a significant risk factor for extra-pancreatic malignancies, and there was a strong association (P = 0.051) for first-degree family history of colorectal carcinoma also. Future studies investigating the rate of neoplastic and pre-neoplastic colorectal lesions in patients with IPMN as compared with controls might prove useful to confirm this association. CONFLICT OF INTEREST
The authors declare no conflict of interest. REFERENCES 1. Kawakubo K, Kawakami H, Kuwatani M et al. Is intraductal papillary mucinous neoplasm of the pancreas just a precursor or identical
with pancreatic ductal adenocarcinoma? Am J Gastroenterol 2014;109:446–7 (this issue). 2. Capurso G, Boccia S, Salvia R et al. Risk factors for intraductal papillary mucinous neoplasm (IPMN) of the pancreas: a multicentre case-control study. Am J Gastroenterol 2013;108:1003–9. 3. Larghi A, Panic N, Capurso G et al. Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Ann Oncol 2013;24:1907–11. 1
Digestive and Liver Disease Unit, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy; 2Department of Public Health, Università Cattolica del Sacro Cuore, Rome, Italy; 3Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore, Rome, Italy. Correspondence: Gabriele Capurso, MD, PhD, Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza, University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. E-mail: [email protected]
ERCP and Fluoroscopy Time Amer A. Alkhatib, MD1, Ala Abdel Jalil, MD2 and M.E. Harrison, MD3 doi:10.1038/ajg.2013.470
To the Editor: We read with interest the study of Romagnuolo and Cotton (1). The study reported different factors that predict prolonged fluoroscopy time (FT) during endoscopic retrograde cholangiopancreatography (ERCP) (1). In our multicenter study (n = 414, ERCP procedure performed by six endoscopists in three American centers) that was partially published as an abstract and presented as poster in ACG meeting 2013, the strongest predictive factor of prolonged FT utilization during ERCP procedure was the anatomical location of the pathology being treated (intrahepatic vs. pancreatic vs. extrahepatic) with mean FT 4.96 min for extrahepatic cases, 6.75 min for pancreatic cases, and 12.9 min for intrahepatic cases (P < 0.05) (2). It would be interesting if the authors can extract the relationship between FT and anatomical location of the pathology from the ERCP Quality Network. The American Journal of GASTROENTEROLOGY
447
