Journal of Gastroenterology

, Volume 44, Issue 9, pp 964–975 | Cite as

Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms

  • Tsuyoshi Hayashi
  • Hirotoshi Ishiwatari
  • Hideyuki Ihara
  • Yutaka Kawano
  • Koichi Takada
  • Koji Miyanishi
  • Masayoshi Kobune
  • Rishu Takimoto
  • Tomoko Sonoda
  • Tetsuji Takayama
  • Junji Kato
  • Yoshiro Niitsu
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Backgound

When considering surgery for branch duct-intraductal papillary mucinous neoplasms (BD-IPMNs) with suspected malignancy, it should be recognized that these lesions are frequently multifocal and are usually found in elderly patients with potential comorbidities that could affect the outcome of surgery. Clinical trials of chemoprevention have been conducted for a wide variety of malignancies.

Methods

Twenty-two BD-IPMN patients participated in the trial at our institution from June 2004 to January 2007. Ten of the 22 patients who rejected surgical therapy although their lesions or clinical symptoms met the criteria for surgical resection of the International Association of Pancreatology guidelines were assigned to the treatment group. Sulindac (150 mg twice daily) and omeprazole (20 mg once daily) were administered to these patients for 18 months. The remaining 12 patients comprised the control group. Branch duct diameter and mural nodule heights were monitored by either magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) and by endoscopic ultrasonography (EUS).

Results

Both branch duct diameter and mural nodule height of BD-IPMNs in the treatment group were significantly reduced, while those in the control group were unchanged. Immunohistochemical staining for cyclooxygenase-1 and -2 was negative in hyperplasia, adenoma and carcinoma portions of resected pancreatic specimens but was clearly positive for glutathione-S-transferase π (GST-π), suggesting that GST-π is a putative target molecule for sulindac.

Conclusions

Although a larger scale randomized controlled study is needed in future, the present results suggest the promise of chemoprevention of carcinoma derived from BD-IPMNs by sulindac.

Keywords

Intraductal papillary-mucinous neoplasm Chemoprevention Non-steroidal anti-inflammatory drugs Glutathione-S-transferase π 

Abbreviations

IAP

International Association of Pancreatology

BD-IPMNs

Branch duct intraductal papillary-mucinous neoplasm

MD-IPMN

Main duct intraductal papillary-mucinous neoplasm

ERP

Endoscopic retrograde pancreatography

CT

Computed tomography

MRCP

Magnetic resonance cholangiopancreatography

EUS

Endoscopic ultrasonography

NSAIDs

Non-steroidal anti-inflammatory drugs

COX-1

Cyclooxygenase-1

COX-2

Cyclooxygenase-2

GST-π

Glutathione-S-transferase π

References

  1. 1.
    Nakagohri T, Kenmochi T, Kainuma O, Tokoro Y, Asano T. Intraductal papillary mucinous tumors of the pancreas. Am J Surg. 1999;178:344–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Terris B, Ponsot P, Paye F, Hammel P, Sauvanet A, Molas G, et al. Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol. 2000;24:1372–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Kobari M, Egawa S, Shibuya K, Shimamura H, Sunamura M, Takeda K, et al. Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg. 1999;134:1131–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Doi R, Fujimoto K, Wada M, Imamura M. Surgical management of intraductal papillary mucinous tumor of the pancreas. Surgery. 2002;132:80–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Matsumoto T, Aramaki M, Yada K, Hirano S, Himeno Y, Shibata K, et al. Optimal management of the branch duct type intraductal papillary mucinous neoplasms of the pancreas. J Clin Gastroenterol. 2003;36:261–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, et al. International Association of Pancreatology International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006;6:17–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Sandler RS, Halabi S, Baron JA, Budinger S, Paskett E, Keresztes R, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Arber N, Eagle CJ, Spicak J, Racz I, Dite P, Hajer J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885–95.PubMedCrossRefGoogle Scholar
  10. 10.
    Akhmedkhanov A, Toniolo P, Zeleniuch-Jacquotte A, Koenig KL, Shore RE. Aspirin and lung cancer in women. Br J Cancer. 2002;87:49–53.PubMedCrossRefGoogle Scholar
  11. 11.
    Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 1999;59:4356–62.PubMedGoogle Scholar
  12. 12.
    Yip-Schneider MT, Sweeney CJ, Jung SH, Crowell PL, Marshall MS. Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells. J Pharmacol Exp Ther. 2001;298:976–85.PubMedGoogle Scholar
  13. 13.
    Crowell PL, Schmidt CM, Yip-Schneider MT, Savage JJ, Hertzler DA 2nd, Cummings WO. Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia. Neoplasia (New York). 2006;8:437–45.Google Scholar
  14. 14.
    Takayama T, Katsuki S, Takahashi Y, Ohi M, Nojiri S, Sakamaki S, et al. Aberrant crypt foci of the colon as precursors of adenoma and cancer. N Engl J Med. 1998;339:1277–84.PubMedCrossRefGoogle Scholar
  15. 15.
    Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328:1313–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Soldini D, Gugger M, Burckhardt E, Kappeler A, Laissue JA, Mazzucchelli L. Progressive genomic alterations in intraductal papillary mucinous tumours of the pancreas and morphologically similar lesions of the pancreatic ducts. J Pathol. 2003;199:453–61.PubMedCrossRefGoogle Scholar
  17. 17.
    Kloppel G, Longnecker DS, Capella C. Histological typing of tumours of the exocrine pancreas. World Health Organization international histological classification of tumours. Berlin: Springer-Verlag; 1996.Google Scholar
  18. 18.
    Hruban RH, Pitman MB, Klimstra DS. Atlas of tumor pathology. Tumors of the pancreas, 4th series, fascicle 6. Washington: Armed Forces Institute of Pathology; 2007.Google Scholar
  19. 19.
    Gong W, Wang L, Yao JC, Ajani JA, Wei D, Aldape KD, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res. 2005;11:1386–93.PubMedCrossRefGoogle Scholar
  20. 20.
    Tanno S, Nakano Y, Nishikawa T, Nakamura K, Sasajima J, Minoguchi M, et al. Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results. Gut. 2008;57:339–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Salvia R, Crippa S, Falconi M, Bassi C, Guarise A, Scarpa A, et al. Branch-duct intraductal papillary mucinous neoplasms of the pancreas: to operate or not to operate? Gut. 2007;56:1086–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Uehara H, Nakaizumi A, Ishikawa O, Iishi H, Tatsumi K, Takakura R, et al. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut. 2008;57:1561–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Nobuoka A, Takayama T, Miyanishi K, Sato T, Takanashi K, Hayashi T, et al. Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid. Gastroenterology. 2004;127:428–43.PubMedCrossRefGoogle Scholar
  24. 24.
    Niijima M, Yamaguchi T, Ishihara T, Hara T, Kato K, Kondo F, et al. Immunohistochemical analysis and in situ hybridization of cyclooxygenase-2 expression in intraductal papillary-mucinous tumors of the pancreas. Cancer. 2002;94:1565–73.PubMedCrossRefGoogle Scholar
  25. 25.
    Nakajima T, Takayama T, Miyanishi K, Nobuoka A, Hayashi T, Abe T, et al. Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester. J Pharmacol Exp Ther. 2003;306:861–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Tsuyoshi Hayashi
    • 1
  • Hirotoshi Ishiwatari
    • 1
  • Hideyuki Ihara
    • 1
  • Yutaka Kawano
    • 1
  • Koichi Takada
    • 1
  • Koji Miyanishi
    • 1
  • Masayoshi Kobune
    • 1
  • Rishu Takimoto
    • 1
  • Tomoko Sonoda
    • 2
  • Tetsuji Takayama
    • 3
  • Junji Kato
    • 1
  • Yoshiro Niitsu
    • 4
  1. 1.Fourth Department of Internal MedicineSapporo Medical University School of MedicineSapporoJapan
  2. 2.Department of Public HealthSapporo Medical University School of MedicineSapporoJapan
  3. 3.Department of Gastroenterology and Oncology, Institute of Health BiosciencesThe University of Tokushima Graduate SchoolSapporoJapan
  4. 4.Department of Molecular Target ExplorationSapporo Medical University School of MedicineHokkaidoJapan

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