Supportive Care in Cancer

, Volume 21, Issue 7, pp 2075–2083 | Cite as

Emerging evidence on the pathobiology of mucositis

  • Noor Al-Dasooqi
  • Stephen T. Sonis
  • Joanne M. Bowen
  • Emma Bateman
  • Nicole Blijlevens
  • Rachel J. Gibson
  • Richard M. Logan
  • Raj G. Nair
  • Andrea M. Stringer
  • Roger Yazbeck
  • Sharon Elad
  • Rajesh V. Lalla
  • For The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO)
Review Article

Abstract

Background

Considerable progress has been made in our understanding of the biological basis for cancer therapy-induced mucosal barrier injury (mucositis). The last formal review of the subject by MASCC/ISOO was published in 2007; consequently, an update is timely.

Methods

Panel members reviewed the biomedical literature on mucositis pathobiology published between January 2005 and December 2011.

Results

Recent research has provided data on the contribution of tissue structure changes, inflammation and microbiome changes to the development of mucositis. Additional research has focused on targeted therapy-induced toxicity, toxicity clustering and the investigation of genetic polymorphisms in toxicity prediction. This review paper summarizes the recent evidence on these aspects of mucositis pathobiology.

Conclusion

The ultimate goal of mucositis researchers is to identify the most appropriate targets for therapeutic interventions and to be able to predict toxicity risk and personalize interventions to genetically suitable patients. Continuing research efforts are needed to further our understanding of mucositis pathobiology and the pharmacogenomics of toxicity.

Keywords

Mucosal injury Cancer therapy Targeted drugs Toxicity Alimentary tract Pharmacogenetics 

Notes

Conflict of interest

This project was carried out as part of the MASCC/ISOO Mucositis Guidelines Update, which was supported by BioAlliance Pharma and Helsinn Healthcare, NA. No industry representatives participated in the development of this manuscript in any way.

References

  1. 1.
    Elting L et al (2003) The burdens of cancer therapy: clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98:1531–1539PubMedCrossRefGoogle Scholar
  2. 2.
    Sonis S et al (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025PubMedCrossRefGoogle Scholar
  3. 3.
    Capp A et al (2009) Is there more than one proctitis syndrome? A revisitation using data from the TROG 96.01 trial. Radiother Oncol 90:400–407PubMedCrossRefGoogle Scholar
  4. 4.
    Keefe D et al (2007) Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109:820–831PubMedCrossRefGoogle Scholar
  5. 5.
    Aprile G et al (2008) Application of distance matrices to define associations between acute toxicities in colorectal cancer patients receiving chemotherapy. Cancer 112:284–292PubMedCrossRefGoogle Scholar
  6. 6.
    Murphy B (2007) Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy. J Support Oncol 5:13–21PubMedGoogle Scholar
  7. 7.
    Sonis S (2004) The pathobiology of mucositis. Nat Rev Cancer 4:277–284PubMedCrossRefGoogle Scholar
  8. 8.
    Sonis S et al (2002) The gene expression sequence of radiated mucosa in an animal mucositis model. Cell Prolif 35:s92–s102CrossRefGoogle Scholar
  9. 9.
    Sonis S et al (1990) An animal model for mucositis induced by cancer chemotherapy. Oral Surg, Oral Med, Oral Pathol 69:437–443CrossRefGoogle Scholar
  10. 10.
    Paris F et al (2001) Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293:293–297PubMedCrossRefGoogle Scholar
  11. 11.
    Logan R et al (2009) Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Cancer Chemother Pharmacol 63:239–251PubMedCrossRefGoogle Scholar
  12. 12.
    Sonis S et al (2000) Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters. Oral Oncol 36:373–381PubMedCrossRefGoogle Scholar
  13. 13.
    Yeoh A et al (2005) Nuclear factor κB (NFκB) and cyclooxygenase-2 (COX-2) expression in the irradiated colorectum is associated with subsequent histopathological changes. Int J Radiat Oncol Biol Phys 63:1295–1303PubMedCrossRefGoogle Scholar
  14. 14.
    Manzano M et al (2007) Intestinal toxicity induced by 5-fluorouracil in pigs: a new preclinical model. Chemotherapy 53:344–355PubMedCrossRefGoogle Scholar
  15. 15.
    Stringer A et al (2009) Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol 90:489–499PubMedCrossRefGoogle Scholar
  16. 16.
    Stringer A et al (2009) Chemotherapy-induced changes to microflora: evidence and implications of change. Curr Drug Metab 10:79–83PubMedCrossRefGoogle Scholar
  17. 17.
    Stringer A et al (2007) Chemotherapy-induced diarrhea is associated with changes in the luminal environment in the DA rat. Exp Biol Med 232:96–106Google Scholar
  18. 18.
    Al-Dasooqi N et al (2011) Irinotecan-induced alterations in intestinal cell kinetics and extracellular matrix component expression in the dark agouti rat. Int J Exp Pathol 92:357–365PubMedCrossRefGoogle Scholar
  19. 19.
    Al-Dasooqi N et al (2010) Matrix metalloproteinases are possible mediators for the development of alimentary tract mucositis in the DA rat. Exp Biol Med 235:1244–1256CrossRefGoogle Scholar
  20. 20.
    Anthony L et al (2007) New thoughts on the pathobiology of regimen-related mucosal injury. Support Care Cancer 14:516–518CrossRefGoogle Scholar
  21. 21.
    Hannum Y (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89:1845–1853Google Scholar
  22. 22.
    Kerr J, Winterford C, Harmon B (1994) Apoptosis: its significant in cancer and cancer therapy. Cancer 73:2013–2026PubMedCrossRefGoogle Scholar
  23. 23.
    Gibson R et al (2005) Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat. Clin Exp Med 4:188–195PubMedCrossRefGoogle Scholar
  24. 24.
    Bowen J et al (2005) Cytotoxic chemotherapy up-regulates pro-apoptotic Bax and Bak in the small intestine of rats and humans. Pathology 37:56–62PubMedCrossRefGoogle Scholar
  25. 25.
    Keefe D (2000) Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 47:632–637PubMedCrossRefGoogle Scholar
  26. 26.
    Sonis S et al (1992) Effect of epidermal gorwth factor on ulcerative mucositis in hamsters that receive chemotherapy. Oral Surg, Oral Med, Oral Pathol 74:749–755CrossRefGoogle Scholar
  27. 27.
    Gibson R et al (2007) Establishment of a single-dose irinotecan model of gastrointestinal mucositis. Chemotherapy 53:360–369PubMedCrossRefGoogle Scholar
  28. 28.
    Gibson R et al (2006) Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy. Asia Pac J Clin Oncol 2:39–49CrossRefGoogle Scholar
  29. 29.
    Li C et al (2011) The correlation between the severity of radiotherapy-induced glossitis and endothelial cell injury in local tissues in a rat model. Med Oral Pathol Oral Cir Bucal 16:e711–e715CrossRefGoogle Scholar
  30. 30.
    Carneiro-Filho B et al (2004) Intestinal barrier function and secretion in methotrexate-induced rat intestinal mucositis. Dig Dis Sci 49:65–72PubMedCrossRefGoogle Scholar
  31. 31.
    Chen P et al (2011) Role of AMP-18 in oral mucositis. Oral Oncol 47:831–839PubMedCrossRefGoogle Scholar
  32. 32.
    Huang T et al (2009) Minocycline attenuates 5-fluorouracil-induced small intestinal mucositis in mouse model. Biochem Biophys Res Commun 389:634–639PubMedCrossRefGoogle Scholar
  33. 33.
    Meredith J, Fazeli B, Schwartz M (1993) The extracellular matrix as a cell survival factor. Mol Biol Cell 4:953–961PubMedGoogle Scholar
  34. 34.
    Afshar S, Phelan K, O'Donnell C, Bragdon C, Castro D, Sonis S (2002) A new in vivo model for the study of mucosal disease. International Association for Dental Research Meeting Abstract 16220Google Scholar
  35. 35.
    Phelan S, Afshar S, O'Donnell C, Bragdon C, Castro D, Shklar G, Sonis S (2002) A mucosal graft model to evaluate radiation induced injury. International Association for Dental Research Meeting Abstract 0221Google Scholar
  36. 36.
    Beutheu Youmba S et al (2012) Methotrexate modulates tight junctions through NFkB, MEK, and JNK pathways. J Pediatric Gastroenterol Nutr 54:463–470CrossRefGoogle Scholar
  37. 37.
    Hamada K et al (2010) Zonula Occluden-1 alterations and enhances intestinal permeability in methotrexate-treated rats. Cancer Chemother Pharmacol 66:1031–1038PubMedCrossRefGoogle Scholar
  38. 38.
    Al-Sadi R et al (2010) IL-1beta-induced increase in intestinal epithelial tight junction permeability is mediated by MEKK-1 activation of canonical NF-kappaB pathway. Am J Pathol 177:2310–2322PubMedCrossRefGoogle Scholar
  39. 39.
    Al-Sadi R et al (2008) Mechanism of IL-1beta-induced increase in intestinal epithelial tight junction permeability. J Immunol 180:5653–5661PubMedGoogle Scholar
  40. 40.
    Ma T et al (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286:G367–G376PubMedCrossRefGoogle Scholar
  41. 41.
    Han X, Fink M, Delude R (2003) Proinflammatory cytokines cause NO*-dependent and -independent changes in expression and localization of tight junction proteins in intestinal epithelial cells. Shock 19:229–237PubMedCrossRefGoogle Scholar
  42. 42.
    Melichar B et al (2005) Intestinal permeability in the assessment of intestinal toxicity of cytotoxic agents. Chemotherapy 51:336–338PubMedCrossRefGoogle Scholar
  43. 43.
    Logan R et al (2008) Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol 62:33–41PubMedCrossRefGoogle Scholar
  44. 44.
    Sonis S (2002) The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Crit Rev Oral BiolMed 13:380–389CrossRefGoogle Scholar
  45. 45.
    Sonis S (2004) A biological approach to mucositis. J Support Oncol 2:21–32PubMedGoogle Scholar
  46. 46.
    Sonis S et al (2004) The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. Oral Oncol 40:170–176PubMedCrossRefGoogle Scholar
  47. 47.
    Logan R et al (2007) Nuclear factor-kB (NFkB) and cyclooxygenase-2 expression in the oral mucosa following cancer chemotherapy. Oral Oncol 43:395–401PubMedCrossRefGoogle Scholar
  48. 48.
    Haagen J et al (2009) Effect of selective inhibitors of inflammation on oral mucositis: preclinical studies. Radiother Oncol 92:472–476PubMedCrossRefGoogle Scholar
  49. 49.
    Ong Z et al (2010) Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis. Radiat Oncol 16:22CrossRefGoogle Scholar
  50. 50.
    Logan R et al (2007) The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev 33:448–460PubMedCrossRefGoogle Scholar
  51. 51.
    Logan R et al (2008) Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther 7:1139–1145PubMedCrossRefGoogle Scholar
  52. 52.
    Lima V et al (2005) Effects of tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci 113:210–217PubMedCrossRefGoogle Scholar
  53. 53.
    Melo M et al (2008) Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide. Cancer Chemother Pharmacol 61:775–784PubMedCrossRefGoogle Scholar
  54. 54.
    Fiochhi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205CrossRefGoogle Scholar
  55. 55.
    de Koning B et al (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949PubMedCrossRefGoogle Scholar
  56. 56.
    Bultzingslowen I et al (2006) Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis. Support Care Cancer 14:519–527CrossRefGoogle Scholar
  57. 57.
    Gibson R et al (2002) Effect of interleukin-11 on ameliorating intestinal damage after methotrexate treatment of breast cancer in rats. Dig Dis Sci 47:2751–2757PubMedCrossRefGoogle Scholar
  58. 58.
    Antin J et al (2002) A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation. Bone Marrow Transplant 29:373–377PubMedCrossRefGoogle Scholar
  59. 59.
    Zhao J et al (2004) Oral RDP58 allows CPT-11 dose intensification for enhanced tumor response by decreasing gastrointestinal toxicity. Clin Cancer Res 10:2851–2859PubMedCrossRefGoogle Scholar
  60. 60.
    Frei E et al (1965) The nature and control of infections in patients with acute leukemia. Cancer Res 25:1511–1515PubMedGoogle Scholar
  61. 61.
    Dreizen S, Bodey G, Brown L (1974) Opportunistic gram-negative bacillary infections in leukemia. Oral manifestations during myelosuppression. Post Med 55:133–139Google Scholar
  62. 62.
    Stringer A et al (2008) Faecal microflora and β-glucuronidase expression are altered in an irinotecan-induced diarrhoea model in rats. Cancer Biol Ther 7:1919–1925PubMedCrossRefGoogle Scholar
  63. 63.
    Stringer A et al (2009) Gastrointestinal microflora and mucins play a role in the development of 5-fluorouracil-induced gastrointestinal mucositis in rats. Exp Biol Med 234:430–441CrossRefGoogle Scholar
  64. 64.
    Shao Z et al (2011) Effects of intensity-modulated radiotherapy on human oral microflora. J Radiat Res 52:834–839PubMedCrossRefGoogle Scholar
  65. 65.
    Napenas J et al (2010) Molecular methodology to assess the impact of cancer chemotherapy on the oral bacterial flora: a pilot study. Oral Surg, Oral Med, Oral Pathol, Oral Radiol Endodentics 109:554–560CrossRefGoogle Scholar
  66. 66.
    van Vliet M et al. (2010) The role of intestinal microbiota in the development and severity of chemotherapy-induced mucositis. PLoS Pathog 6(5): e1000879Google Scholar
  67. 67.
    Martin M, van Saene H (1992) The role of oral microorganisms in cancer therapy. Curr Opin Dent 2:81–84PubMedGoogle Scholar
  68. 68.
    Bochud P et al (1994) Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors. Clin Infect Dis 18:25–31PubMedCrossRefGoogle Scholar
  69. 69.
    Ruescher T et al (1998) The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Cancer 82:2275–2281PubMedCrossRefGoogle Scholar
  70. 70.
    Soga Y et al (2011) Bacterial substitution of coagulase-negative staphylococci for streptococci on the oral mucosa after hematopoietic cell transplantation. Support Care Cancer 19:995–1000PubMedCrossRefGoogle Scholar
  71. 71.
    van der Velden W, Donnelly J, Blijlevens N (2012) Lymphocyte subsets, granulocyte-colony-stimulating factor responsiveness and post-stem cell transplantation infections: mucositis is the underestimated confounder? Cytotherapy 14:381–383PubMedCrossRefGoogle Scholar
  72. 72.
    Sonis S (2009) Mucositis: the impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol 45:1015–1020PubMedCrossRefGoogle Scholar
  73. 73.
    Barasch A et al (2006) Antimicrobials, mucosal coating agents, anesthetics, analgesics, and nutritional supplements for alimentary tract mucositis. Support Care Cancer 14:528–532PubMedCrossRefGoogle Scholar
  74. 74.
    Blijlevens N, Donnelly J, DePauw B (2000) Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 25:1269–1278PubMedCrossRefGoogle Scholar
  75. 75.
    Prisciandaro L et al (2011) Probiotic factors partially improve parameters of 5-fluorouracil-induced intestinal mucositis in rats. Cancer Biol Ther 11:671–677PubMedCrossRefGoogle Scholar
  76. 76.
    Gibson R et al. (2013) Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care Cancer 21(1):313-26Google Scholar
  77. 77.
    Blijlevens N, Donnelly J (2011) Mucosal barrier injury and infections. In: Safdar A (ed) Principles and practice of cancer infectious diseases, current clinical oncology. Springer Science, New YorkGoogle Scholar
  78. 78.
    Wisplinghoff H et al (2003) Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 36:1103–1110PubMedCrossRefGoogle Scholar
  79. 79.
    Keefe D, Bateman E (2011) Tumor control versus adverse events with targeted anticancer therapies. Nat Rev Clin Oncol 9:98–109PubMedCrossRefGoogle Scholar
  80. 80.
    Sonis S et al (2010) Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 116:210–215PubMedGoogle Scholar
  81. 81.
    Toi M et al (2009) Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer 101(10):1676–1682PubMedCrossRefGoogle Scholar
  82. 82.
    Sawaki M et al (2004) Efficacy and safety of trastuzumab as a single agent in heavily pretreated patients with HER-2/neu-overexpressing metastatic breast cancer. Tumori 90(1):40–43PubMedGoogle Scholar
  83. 83.
    Keefe D, Gibson R (2007) Mucosal injury from targeted anticancer therapy. Support Care Cancer 15:483–490PubMedCrossRefGoogle Scholar
  84. 84.
    Burris H (2004) Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9:10–15PubMedCrossRefGoogle Scholar
  85. 85.
    Geyer CE et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743PubMedCrossRefGoogle Scholar
  86. 86.
    Al-Dasooqi N et al (2008) Trastuzumab induces gastrointestinal side effects in HER2-overexpressing breast cancer patients. Investig New Drugs 27:173–178CrossRefGoogle Scholar
  87. 87.
    Fountzilas G et al (2001) Weekly paclitaxel as first-line chemotherapy and trastuzumab in patients with advanced breast cancer. A Hellenic Cooperative Oncology Group phase II study. Ann Oncol 12:1545–1551PubMedCrossRefGoogle Scholar
  88. 88.
    Bartsch R et al (2007) Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol 25:3853–3858PubMedCrossRefGoogle Scholar
  89. 89.
    Ruiz M et al (2008) Phase-II study of weekly schedule of trastuzumab, paclitaxel, and carboplatin followed by a week off every 28 days for HER2+ metastatic breast cancer. Cancer Chemother Pharmacol 62:1085–1090PubMedCrossRefGoogle Scholar
  90. 90.
    Bowen J et al (2012) Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhoea. Cancer Biol Ther 13(13):1269-75Google Scholar
  91. 91.
    Peterson D, Keefe D, Sonis S (2012) New frontiers in mucositis. ASCO Educational Book. American Society of Clinical Oncology, Alexandria, pp. 545–61Google Scholar
  92. 92.
    Keefe D (1998) The effect of cytotoxic chemotherapy on the mucosa of the small intestine. Department of Medicine University of Adelaide, AdelaideGoogle Scholar
  93. 93.
    Pico J, Avila-Garavito A, Naccache P (1998) Mucositis: its occurence, consequences and treatment in the oncology setting. The Oncologist volume 3:p446–451Google Scholar
  94. 94.
    Sloan J et al (2002) Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 20:1491–1498PubMedCrossRefGoogle Scholar
  95. 95.
    Pratesi N et al (2011) Association between single nucleotide polymorphisms in XRCC1 and RAD51 genes and clinical radiosensitivity in head and neck cancer. Radiother Oncol 99:356–362PubMedCrossRefGoogle Scholar
  96. 96.
    West C, Dunning A, Rosenstein (2012) Genome-wide association studies and prediction of normal tissue toxicity. Sem Radiat Oncol 22:91–99CrossRefGoogle Scholar
  97. 97.
    Thomas F et al (2011) Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer. Br J Cancer 105:1654–1662PubMedCrossRefGoogle Scholar
  98. 98.
    Werbrouck J et al (2009) Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 73:1187–1195PubMedCrossRefGoogle Scholar
  99. 99.
    Schwab M et al (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26:2131–2138PubMedCrossRefGoogle Scholar
  100. 100.
    Cho H et al (2010) Glutathione-S-transferase genotypes influence the risk of chemotherapy-related toxicities and prognosis in Korean patients with diffuse large B-cell lymphoma. Cancer CGenet Cytogenet 198:40–46CrossRefGoogle Scholar
  101. 101.
    Hahn T et al (2010) A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant 16:801–808PubMedCrossRefGoogle Scholar
  102. 102.
    Alterovitz G et al (2011) Personalized medicine for mucositis: bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis. Oral Oncol 47:951–955PubMedCrossRefGoogle Scholar
  103. 103.
    Roseth A (2003) Determination of faecal calprotectin, a novel marker of organic gastrointestinal disorders. Dig Liver Dis 35:607–609PubMedCrossRefGoogle Scholar
  104. 104.
    Lutgens L et al. (2005) Monitoring myeloablative therapy-induced small bowel toxicity by serum citrulline concentration: a comparison with sugar permeability tests. Cancer 103(1):191–9Google Scholar
  105. 105.
    Xanthinaki A et al (2008) Apoptosis and inflammation markers in oral mucositis in head and neck cancer patients receiving radiotherapy: preliminary report. Support Care Cancer 16:1025–1033PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Noor Al-Dasooqi
    • 1
  • Stephen T. Sonis
    • 2
  • Joanne M. Bowen
    • 3
  • Emma Bateman
    • 1
  • Nicole Blijlevens
    • 4
  • Rachel J. Gibson
    • 5
  • Richard M. Logan
    • 6
  • Raj G. Nair
    • 7
  • Andrea M. Stringer
    • 8
  • Roger Yazbeck
    • 8
  • Sharon Elad
    • 9
  • Rajesh V. Lalla
    • 10
  • For The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO)
  1. 1.Discipline of MedicineUniversity of AdelaideAdelaideUSA
  2. 2.Brigham and Women’s HospitalDana-Farber Cancer InstituteBostonUSA
  3. 3.Discipline of PhysiologyUniversity of AdelaideAdelaideUSA
  4. 4.Department of HaematologyUniversity Medical Center NijmegenNijmegenThe Netherlands
  5. 5.Discipline of Anatomy and PathologyUniversity of AdelaideAdelaideUSA
  6. 6.School of DentistryUniversity of AdelaideAdelaideUSA
  7. 7.Discipline of Oral MedicineGriffith University and Department of Haematology and Oncology, Queensland HealthGold CoastAustralia
  8. 8.School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  9. 9.Division of Oral Medicine, Eastman Institute for Oral HealthUniversity of Rochester Medical CenterRochesterUSA
  10. 10.Section of Oral Medicine and Neag Comprehensive Cancer CenterUniversity of Connecticut Health CenterFarmingtonUSA

Personalised recommendations