1. Oral Oncol. 2009 Dec;45(12):1015-20. Epub 2009 Oct 13. Mucositis: The impact, biology and therapeutic opportunities of oral mucositis. Sonis ST. Harvard-Farber Cancer Center, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. ssonis@partners.org The history of mucositis is as old as radiation- and chemotherapy. Despite being regularly reported and documented as one of the worst side effects of cancer therapy, relatively little was appreciated about the complexities of mucositis' pathogenesis until relatively recently. More frustrating for patients and clinicians, no effective treatment existed. Fortunately, the situation is changing; ongoing research is leading to a comprehensive understanding of the biology of mucositis, which has resulted in the development of novel interventions. While the FDA's approval of palifermin in 2004 was limited to only a small percentage of the at-risk population, the fact that the first registered anti-OM agent derived its efficacy from its pleotropic activities was conceptually demonstrative of the therapeutic potential of drugs that selectively interfere with mucositis' pathogenesis. A number of eclectic molecules, all designed to interfere with pathways that lead to injury are in pre-clinical and clinical development. PMID: 19828360 [PubMed - in process] 2. Oral Oncol. 2009 Sep;45(9):840; author reply 841-2. Epub 2009 Feb 27. RE: Wang W, et al. The therapeutic effect of fractionated radiation on DMBA-induced hamster buccal pouch squamous cell carcinomas. Oral Oncol 2008;44:1160-66. Sonis ST. Comment on: Oral Oncol. 2008 Dec;44(12):1160-6. PMID: 19250856 [PubMed - in process] 3. Todays FDA. 2009 Aug;21(8):37, 39-45. Oral health in cancer therapy. Rankin KV, Epstein J, Hubber MA, Peterson DE, Plemons JM, Redding SS, Sanfillippo NJ, Schubert MM, Sonis ST. Republished from: Tex Dent J. 2009 May;126(5):389-97, 406-19, 422-37. PMID: 19728463 [PubMed] 4. Tex Dent J. 2009 May;126(5):389-97, 406-19, 422-37. Oral health in cancer therapy. Rankin KV, Epstein J, Huber MA, Peterson DE, Plemons JM, Redding SS, Sanfillippo NJ, Schubert MM, Sonis ST. Department of Public Health Sciences Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX, USA. Republished in: Todays FDA. 2009 Aug;21(8):37, 39-45. PMID: 19492587 [PubMed - indexed for MEDLINE] 5. Support Care Cancer. 2009 Apr 29. [Epub ahead of print] Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Lalla RV, Pilbeam CC, Walsh SJ, Sonis ST, Keefe DM, Peterson DE. Section of Oral Medicine, Department of Oral Health and Diagnostic Sciences, Head & Neck/Oral Oncology Program, Neag Comprehensive Cancer Center, University of Connecticut Health Center, MC 1605, Room L6062, 263, Farmington Avenue, Farmington, CT, 06030, USA, Lalla@uchc.edu. GOALS: Oral mucositis can be a significant and dose-limiting complication of high-dose cancer therapy. Mucositis is a particularly severe problem in patients receiving myeloablative chemotherapy prior to bone marrow or hematopoetic stem cell transplant (HSCT). The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory prostaglandins, including prostaglandin E2 (PGE2) and prostacyclin (PGI2). The objective of this small (n = 3) pilot study was to examine the role of the COX pathway in causing mucosal injury and pain in chemotherapy-induced oral mucositis. MATERIALS AND METHODS: We collected blood, saliva, and oral mucosal biopsy specimens from three autologous HSCT patients at the following time-points before and after administration of conditioning chemotherapy: Day -10, +10, +28, and +100, where day 0 is day of transplant. RNA extracted from full-thickness tissue samples was measured by RT-PCR for the following: COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), IL-1beta, and TNF-alpha. Blood and saliva samples were measured by ELISA for PGE2 and PGI2, which are markers of COX activity. Severity of oral mucositis was determined using the Oral Mucositis Index. Severity of pain due to oral mucositis was measured using a Visual Analog Scale. Relationships between the different variables were examined using Spearman rank correlation coefficients. MAIN RESULTS: Mean mucositis and pain scores increased significantly after administration of chemotherapy and then gradually declined. The correlation between changes in mucositis and pain scores was strong and statistically significant. The following additional correlations were statistically significant: between tissue COX-1 and pain; between tissue mPGES and pain; between salivary PGE1 and pain; between salivary PGI2 and pain. Other relationships were not statistically significant. CONCLUSIONS: Our finding of significant associations of pain scores with tissue COX-1 and mPGES, as well as salivary prostaglandins, is suggestive of a role for the cyclooxygenase pathway in mucositis, possibly via upregulation of pro-inflammatory prostaglandins. However, our small sample size may have contributed to the lack of significant associations between COX-2 and other inflammatory mediators with mucosal injury and pain. Thus, additional studies with larger numbers of subjects are warranted to confirm the involvement of the cyclooxygenase pathway in chemotherapy-induced mucositis. PMID: 19404685 [PubMed - as supplied by publisher] 6. Oral Oncol. 2009 Feb;45(2):164-72. Epub 2008 Aug 19. Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients. Sonis ST, Watkins BA, Lyng GD, Lerman MA, Anderson KC. Division of Oral Medicine, Dana-Farber/Harvard Cancer Center, Boston, MA, United States. ssonis@partners.org Comment in: Oral Oncol. 2009 Jun;45(6):e38; author reply e39. Osteonecrosis of the jaw is associated with aminobisphosphonate use in patients treated with intravenous doses for the prevention of bony metastases. A more complete understanding of the natural history of bisphosphonate-related osteonecrosis of the jaws (BRONJ), factors associated with risk, and its pathobiology has been limited by the availability of human material and the absence of clinical predictability. We now describe an animal model, developed in female Sprague-Dawley rats, in which we replicate many of the clinical, radiographic, and histologic features described in humans. Animals treated with a sequence of zoledronic acid (ZA) and dexamethosone (DX) over a one to three week period developed BRONJ-like changes following extraction of mandibular or maxillary molars. Whereas the extraction sites of control animals underwent predictable healing with rapid epithelialization, animals treated with ZA/DX demonstrated clinical and histological evidence of ulceration overlying areas of necrotic bone. In contrast to images from control animals, radiographs from animals treated with ZA/DX demonstrated poor definition of the alveolar ridge with mixed radiodensity. Modest increases in the extent of the inflammatory infiltrate were seen fourteen days after extraction in ZA-only treated animals compared to control or ZA/DX-treated rats. However, by post-extraction day 28, no differences were observed. Tissue vascularity was most pronounced in ZA-only treated animals compared to ZA/DX or control specimens. Apoptosis of epithelial cells was not observed in any experimental groups, and no evidence of Actinomyces was observed as determined by Periodic Acid Schiff (PAS) staining. The administration of ZA/DX preceding dental extractions in rats therefore results in the development of bony and soft tissue changes that are similar to those noted humans who develop BRONJ, and may provide a useful model for study of its pathogenesis, as well as strategies for its prevention and treatment. PMID: 18715819 [PubMed - indexed for MEDLINE] 7. Cancer Chemother Pharmacol. 2009 Jan;63(2):239-51. Epub 2008 Mar 20. Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered? Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Discipline of Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia. richard.logan@adelaide.edu.au PURPOSE: Alimentary tract (AT) mucositis is a serious problem complicating cancer treatment, however, its pathobiology remains incompletely understood. Nuclear factor-kappaB (NF-kappaB) and pro-inflammatory cytokines are considered to have important roles in its development. This has been previously demonstrated in different sites of the AT following administration of irinotecan in an animal model using the Dark Agouti rat. The aim of the present study was to determine whether the changes that occur in the AT are affected by the type of mucotoxic drug. METHODS: Female DA rats were given a single dose of either methotrexate (1.5 mg/kg intramuscularly) or 5-fluorouracil (150 mg/kg intraperitoneally). Rats were killed at 30, 60, 90 min, 2, 6, 12, 24, 48 and 72 h. Control rats received no treatment. Samples of oral mucosa, jejunum and colon were collected. Haematoxylin and eosin stained sections were examined with respect to histological evidence of damage and standard immunohistochemical techniques were used to demonstrate tissue expression of NF-kappaB, TNF, IL-1beta and IL-6. RESULTS: Both MTX and 5-FU administration caused histological evidence of tissue damage in the AT as well as changes in tissue expression of NF-kappaB and specific pro-inflammatory cytokines. This study, however, demonstrated that there were differences in the timing of histological changes as well as the timing and intensity of pro-inflammatory cytokine tissue expression caused by the different drugs. CONCLUSIONS: The results from this study suggest that there are differences in the mucositis pathobiology caused by different drugs. This may have important ramifications for the management of mucositis particularly with respect to the development of treatment regimens for mucositis. Further investigations are required to determine the exact pathways that lead to damage caused by the different drugs. PMID: 18351341 [PubMed - indexed for MEDLINE] 8. Cancer. 2008 Nov 15;113(10):2704-13. Patient-reported measurements of oral mucositis in head and neck cancer patients treated with radiotherapy with or without chemotherapy: demonstration of increased frequency, severity, resistance to palliation, and impact on quality of life. Elting LS, Keefe DM, Sonis ST, Garden AS, Spijkervet FK, Barasch A, Tishler RB, Canty TP, Kudrimoti MK, Vera-Llonch M; Burden of Illness Head and Neck Writing Committee. Collaborators: Barasch A, Brennan M, Calais G, Canty T, Elting LS, Epstein J, Feyer P, Garden A, Grunberg SM, Keefe DM, Kudrimoti M, Molassiotis A, Oster G, Raber-Durlacher JE, Schultz C, Sonis ST, Spijkervet F, Tishler R, Trotti A, Vera-Llonch M. Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. lelting@mdanderson.org BACKGROUND: The risk, severity, and patient-reported outcomes of radiation-induced mucositis among head and neck cancer patients were prospectively estimated. METHODS: A validated, patient-reported questionnaire (OMDQ), the FACT quality of life (QOL), and the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scales were used to measure mucositis (reported as mouth and throat soreness), daily functioning, and use of analgesics. Patients were studied before radiotherapy (RT), daily during RT, and for 4 weeks after RT. RESULTS: Contrary to previous reports, the risk of mucositis was virtually identical in the 126 patients with oral cavity or oropharynx tumors (99% overall; 85% grade 3-4) compared with 65 patients with tumors of the larynx or hypopharynx (98% overall; 77% grade 3-4). The mean QOL score decreased significantly during RT, from 85.1 at baseline to 69.0 at Week 6, corresponding with the peak of mucositis severity. The mean functional status score decreased by 33% from 18.3 at baseline to 12.3 at Week 6. The impact of mucositis on QOL was proportional to its severity, although even a score of 1 or 2 (mild or moderate) was associated with a significant reduction in QOL (from 93.6 at baseline to 74.7 at Week 6). Despite increases in analgesic use from 34% at baseline to 80% at Week 6, mean mucositis scores exceeded 2.5 at Week 6. CONCLUSIONS: Mucositis occurs among virtually all patients who are undergoing radiation treatment of head and neck cancers. The detrimental effects on QOL and functional status are significant, and opioid analgesia provides inadequate relief. Preventive rather than symptom palliation measures are needed. PMID: 18973181 [PubMed - indexed for MEDLINE] 9. Expert Opin Emerg Drugs. 2008 Sep;13(3):511-22. Emerging drugs for chemotherapy-induced mucositis. Keefe DM, Sonis ST, Bowen JM. Royal Adelaide Hospital, RAH Cancer Centre, North Terrace, Adelaide, SA 5000, Australia. dorothy.keefe@health.sa.gov.au BACKGROUND: Chemotherapy-induced mucositis is an increasingly recognized problem in cancer management, preventing full doses of treatment being given, compromising cure rates and reducing quality of life. Symptoms include mouth pain and ulceration, esophagitis, abdominal pain, bloating, and diarrhea. It is associated with increased infections and occasional mortality, and its palliation is very expensive. The pathobiology of mucositis is complex, and agents that target mechanisms to prevent mucositis or accelerate healing are in high demand. OBJECTIVES: To review existing and potential treatments for chemotherapy-induced mucositis in the context of current knowledge of pathobiology. METHODS: We searched for mucositis of any region of the gastrointestinal tract using Medline, the Pharmaprojects database and listed patents. RESULTS/CONCLUSIONS: There are many agents in varying stages of development for chemotherapy-induced mucositis. The field is complicated by the question of whether treatments should be developed as drugs or as medical foods, and whether the burden of proof of efficacy and safety should be different. PMID: 18764726 [PubMed - indexed for MEDLINE] 10. Cancer Biol Ther. 2008 Jul;7(7):1139-45. Epub 2008 Apr 29. Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Logan RM, Stringer AM, Bowen JM, Gibson RJ, Sonis ST, Keefe DM. Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, South Australia, Australia. richard.logan@adelaide.edu.au INTRODUCTION: Alimentary tract (AT) mucositis is a serious complication of cancer treatment. Determining changes that occur in the AT can be difficult as invasive procedures are usually contraindicated in these patients. Changes in tissue levels of the transcription factor NFkappaB and pro-inflammatory cytokines have been demonstrated. The aims of this study were to determine whether changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 following administration of different drugs predicted histological evidence of tissue damage. RESULTS: Changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 were observed following administration of each drug. These changes differed according to the drug administered. In most instances, peaks in serum levels occurred following initial histological changes, Although following MTX administration, serum IL-1beta peaked before histological changes and following 5-FU administration, serum NFkappaB, TNF, IL-1beta and IL-6 all peaked before histological evidence of tissue damage. MATERIALS AND METHODS: Female DA rats (n = 243) were given a single dose of irinotecan (200 mg/kg intraperitoneally), methotrexate (1.5 mg/kg intramuscularly) or 5-fluorouracil (150 mg/kg intraperitoneally) and killed 30, 60, 90 minutes, 2, 6, 12, 24, 48 or 72 hours later. Control rats received no treatment. Blood samples were taken via cardiac puncture and centrifuged at 5000 rpm to collect serum. Serum levels of NFkappaB, and pro-inflammatory cytokines were measured by ELISA. CONCLUSIONS: Although changes in serum levels of NFkappaB, TNF, IL-1beta and IL-6 preceded histological changes in tissues, it was concluded that measurement of these factors was not useful in predicting mucosal damage because of the critical time constraints between detectable serun changes and the histological damage. This study highlighted the systemic effects of the drugs. Further studies are required to determine the possible relationships between different toxicities and determine how, once these links are known, patient management can be improved. PMID: 18535404 [PubMed - indexed for MEDLINE] 11. Clin Cancer Res. 2008 Jul 1;14(13):4292-7. Efficacy of superoxide dismutase mimetic M40403 in attenuating radiation-induced oral mucositis in hamsters. Murphy CK, Fey EG, Watkins BA, Wong V, Rothstein D, Sonis ST. ActivBiotics, Inc., Lexington, Massachusetts, USA. chriskmurphy@hotmail.com PURPOSE: M40403 is a small-molecule superoxide dismutase mimetic that has shown efficacy in animal model disease states in which superoxide anions are thought to play a key role. Radiation treatment and chemotherapy for cancer generate free oxygen radicals that are hypothesized to trigger unwanted side effects in healthy tissue. For some patients undergoing these antineoplastic treatments, one of the most prevalent side effects is oral mucositis, which is a painful, often dose-limiting condition. Preclinical and clinical studies of this condition have shown the positive effect of treatment with compounds that decrease free oxygen radicals. This study investigated the efficacy M40403 in a clinically relevant hamster model of acute, radiation-induced oral mucositis. Methods: Oral mucositis was induced in hamsters by irradiation of the cheek pouch. The ability of i.p. administered M40403 to decrease the duration and severity of oral mucositis was assessed after treatment at different doses and dosing schedules. Oral mucositis was scored using the WHO grading scale. RESULTS: Compared with placebo-treated animals, those irradiated on day 0 and treated twice daily with 30 mg/kg M40403 had significantly less severe and shorter duration mucositis over a range of treatment schedules, including from days -1 to 3, day 0 to 3, and day 0 alone. Similar efficacy was achieved at doses of 10 and 3 mg/kg twice daily on days -1 to 3. CONCLUSIONS: These results implicate free oxygen radicals in the onset of oral mucositis and also provide the basis for further development of M40403 in the prevention of this condition in at-risk cancer patients. PMID: 18594012 [PubMed - indexed for MEDLINE] 12. Cancer Chemother Pharmacol. 2008 Jun;62(1):33-41. Epub 2007 Aug 17. Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Logan RM, Gibson RJ, Bowen JM, Stringer AM, Sonis ST, Keefe DM. Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, SA 5005, Australia. richard.logan@adelaide.edu.au PURPOSE: The pathobiology of alimentary tract (AT) mucositis is complex and there is limited information about the events which lead to the mucosal damage that occurs during cancer treatment. Various transcription factors and proinflammatory cytokines are thought to play important roles in pathogenesis of mucositis. The aim of this study was to determine the expression of nuclear factor-kappaB (NF-kappaB), tumor necrosis factor (TNF) and interleukins-1beta (IL-1beta) and -6 (IL-6) in the AT following the administration of the chemotherapeutic agent irinotecan. METHODS: Eighty-one female dark Agouti rats were assigned to either control or experimental groups according to a specific time point. Following administration of irinotecan, rats were monitored for the development of diarrhoea. The rats were killed at times ranging from 30 min to 72 h after administration of irinotecan. Oral mucosa, jejunum and colon were collected and standard immunohistochemical techniques were used to identify NF-kappaB, TNF, IL-1beta and IL-6 within the tissues. Sections were also stained with haematoxylin and eosin for histological examination. RESULTS: Irinotecan caused mild to moderate diarrhoea in a proportion of the rats that received the drug. Altered histological features of all tissues from rats administered irinotecan were observed which included epithelial atrophy in the oral mucosa, reduction of villus height and crypt length in the jejunum and a reduction in crypt length in the colon. Tissue staining for NF-kappaB, TNF and IL-1beta and IL-6 peaked at between 2 and 12 h in the tissues examined. CONCLUSIONS: This is the first study to demonstrate histological and immunohistochemical evidence of changes occurring concurrently in different sites of the AT following chemotherapy. The results of the study provide further evidence for the role of NF-kappaB and associated pro-inflammatory cytokines in the pathobiology of AT mucositis. The presence of these factors in tissues from different sites of the AT also suggests that there may be a common pathway along the entire AT causing mucositis following irinotecan administration. PMID: 17703303 [PubMed - indexed for MEDLINE] 13. Int J Radiat Biol. 2008 May;84(5):401-12. Velafermin (rhFGF-20) reduces the severity and duration of hamster cheek pouch mucositis induced by fractionated radiation. Ara G, Watkins BA, Zhong H, Hawthorne TR, Karkaria CE, Sonis ST, Larochelle WJ. CuraGen Corporation, Branford, Connecticut, USA. PURPOSE: Velafermin (recombinant human fibroblast growth factor-20, rhFGF-20) has been shown to reduce the severity and duration of mucositis in preclinical acute (single dose) radiation and chemotherapy/radiation models of oral mucositis. Our present study assessed the impact of velafermin on the severity and duration of oral mucositis that occurred as a consequence of fractionated radiation. EXPERIMENTAL DESIGN: Male Golden Syrian hamsters were exposed to eight doses of radiation (7.5 Gy/dose) to the cheek pouch on days 0, 1, 2, 3, 6, 7, 8 and 9 that resulted in severe mucositis. Velafermin (4 mg/kg intraperitoneally) was administered on days 3 and 9; days 2, 3, 8 and 9; days 3, 4, 9 and 10; or days 4, 5, 10 and 11. RESULTS: Although all velafermin-treated groups showed some reduction in the degree of mucositis relative to the vehicle control, the most significant reduction (p < 0.001) was observed in the groups treated on days 3 and 9 or on days 4, 5, 10 and 11. Further histological analysis of resected buccal mucosa revealed improvements in epithelial tissue degradation, connective tissue degradation and inflammation severity after velafermin treatment. Most notably, velafermin treatment reduced inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) production possibly through nuclear factor-kappaB (NF-kappaB) mediation. The detection of increased NF-E2-related factor-2 (NRF-2) expression in the early onset stage of mucositis in the buccal mucosa suggested additional protective benefits from reactive oxygen species (ROS) generated as a consequence of fractionated radiation treatment. CONCLUSION: Thus, velafermin provided therapeutic benefit in a hamster model of oral mucositis induced by fractionated radiation therapy. PMID: 18464069 [PubMed - indexed for MEDLINE] 14. Dent Clin North Am. 2008 Jan;52(1):61-77, viii. Management of oral mucositis in patients who have cancer. Lalla RV, Sonis ST, Peterson DE. Division of Oral Medicine, Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center MC 1605, 263 Farmington Avenue, Farmington, CT 06030, USA. lalla@nso2.uchc.edu Oral mucositis is a clinically important and sometimes dose-limiting complication of cancer therapy. Mucositis lesions can be painful, affect nutrition and quality of life, and have a significant economic impact. The pathogenesis of oral mucositis is multifactorial and complex. This review discusses the morbidity, economic impact, pathogenesis and clinical course of mucositis. Current clinical management of oral mucositis is largely focused on palliative measures such as pain management, nutritional support and maintenance of good oral hygiene. However, several promising therapeutic agents are in various stages of clinical development for the management of oral mucositis. These agents are discussed in the context of recently updated evidence-based clinical management guidelines. PMCID: PMC2266835 PMID: 18154865 [PubMed - indexed for MEDLINE] 15. J Clin Periodontol. 2007 Nov;34(11):917-30. Epub 2007 Sep 17. Clinical characteristics and microbiota of progressing slight chronic periodontitis in adults. Tanner AC, Kent R Jr, Kanasi E, Lu SC, Paster BJ, Sonis ST, Murray LA, Van Dyke TE. Department of Molecular Genetics, Clinical Research Center, The Forsyth Institute, Boston, MA 02115, USA. annetanner@forsyth.org AIM: This study sought clinical and microbial risk indicators for progressing slight periodontitis. MATERIAL AND METHODS: One hundred and seventeen periodontally healthy or slight periodontitis adults (20-40 years) were monitored clinically at 6-month intervals followed by supragingival cleaning. Inter-proximal sites with >1.5 mm increase in clinical attachment over 18 months were considered disease active. Subgingival plaque was analysed by 78 16S rDNA and 38 whole-genomic DNA probes and by PCR to Porphyromonas gingivalis and Tannerella forsythia. Characteristics were compared between active and inactive subjects. RESULTS: Twenty-two subjects showed disease activity principally at molars. Mean baseline gingival and plaque indices, bleeding on probing, probing depth and clinical attachment level (CAL) were higher in active subjects. DNA probes detected species and not-yet-cultivated phylotypes from chronic periodontitis, although few species were associated with active subjects. By PCR P. gingivalis (p=0.007) and T. forsythia (p=0.075) were detected more frequently during monitoring in active subjects. Stepwise logistic analysis associated baseline levels of gingival index, clinical attachment and bleeding with subsequent clinical attachment loss. CONCLUSIONS: Gingivitis and CAL were significantly associated with progressing slight periodontitis in 20--40-year-old adults. Species associated with moderate and advanced chronic periodontitis were detected in slight periodontitis. PMID: 17877747 [PubMed - indexed for MEDLINE] 16. J Support Oncol. 2007 Oct;5(9 Suppl 4):3-11. Pathobiology of oral mucositis: novel insights and opportunities. Sonis ST. Department of Oral Medicine, Harvard Medical School Boston, Massachusetts, USA. ssonis@partners.org Oral mucositis is a common and debilitatingly painful side effect of many forms of chemotherapy and radiation therapy. The erythematous, atrophic, and ulcerative lesions that develop are a consequence of epithelial damage and death mediated through a complex series of molecular and cellular events. The consequences of mucositis are far-reaching and include chemotherapy dose reductions, breaks in radiation treatment, cessation of cancer therapy, reliance on parenteral nutrition, administration of narcotics, hospitalization, and morbidity. In this review, the underlying molecular and cellular pathobiology of oral mucositis is characterized in five phases: initiation, the primary damage response, signaling and amplification, ulceration, and healing. The roles of reactive oxygen species, transduction and transcription pathways, signaling and functional mediators, and bacteria on the development and resolution of mucositis are described as a dynamic process in which epithelial stem cells are the targets. Insights into the mechanisms of oral mucositis are generating new approaches for effective, targeted treatment. PMID: 18046993 [PubMed - indexed for MEDLINE] 17. Cancer Treat Rev. 2007 Aug;33(5):448-60. Epub 2007 May 15. The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Logan RM, Stringer AM, Bowen JM, Yeoh AS, Gibson RJ, Sonis ST, Keefe DM. Oral Pathology, School of Dentistry, Faculty of Health Sciences, The University of Adelaide, North Terrace, Adelaide SA 5005, Australia. richard.logan@adelaide.edu.au Alimentary tract (AT) mucositis can be a major problem for patients undergoing cancer treatment. It has significant clinical and economic consequences and is a major factor that can compromise the provision of optimal treatment for patients. The pathobiology of AT mucositis is complex and the exact mechanisms that underlie its development still need to be fully elucidated. Current opinion considers that there is a prominent interplay between all of the compartments of the mucosa involving, at a molecular level, the activation of transcription factors, particularly nuclear factor-kappaB, and the subsequent upregulation of pro-inflammatory cytokines and inflammatory mediators. The purpose of this review is to examine the literature relating to what is currently known about the pathobiology of AT mucositis, particularly with respect to the involvement of pro-inflammatory cytokines, as well as currently used animal models and the role of specific cytotoxic chemotherapy agents in the development of AT mucositis. PMID: 17507164 [PubMed - indexed for MEDLINE] 18. Oral Oncol. 2007 Apr;43(4):395-401. Epub 2006 Sep 18. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Logan RM, Gibson RJ, Sonis ST, Keefe DM. Oral Pathology, School of Dentistry, The University of Adelaide, Adelaide, North Terrace, SA 5005, Australia. richard.logan@adelaide.edu.au Oral mucositis is a serious and debilitating side effect of cancer treatment. Greater understanding of the pathobiology of mucositis has recently led to the advent of targeted treatments for specific patient populations; however the treatment for mucositis remains palliative for most patients. Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase 2 (COX-2) are thought to play important roles in the development of mucositis. In this study, 20 patients undergoing cytotoxic chemotherapy had oral mucosal biopsies taken prior to and following administration of cytotoxic chemotherapy. The samples were stained for NF-kappaB and COX-2 using routine immunohistochemistry. The results from this preliminary study demonstrated statistically significant increased oral mucosal staining for NF-kappaB and COX-2 following cytotoxic chemotherapy and provide further support for the role of NF-kappaB and COX-2 in the pathogenesis of mucositis. PMID: 16979925 [PubMed - indexed for MEDLINE] 19. Cancer. 2007 Mar 1;109(5):820-31. Updated clinical practice guidelines for the prevention and treatment of mucositis. Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, Australia. dorothy.keefe@health.sa.gov.au Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condition has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the biomedical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high-dose melphalan. Recommendations against specific practices were introduced: Systemic glutamine was not recommended for the prevention of gastrointestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation-induced oral mucositis. Furthermore, new guidelines suggested that granulocyte-macrophage-colony stimulating factor mouthwashes not be used for oral mucositis prevention in the transplantation population. Advances in mucositis treatment and research have been complemented by an increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved educational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820-31. (c) 2007 American Cancer Society. PMID: 17236223 [PubMed - indexed for MEDLINE] 20. Nat Clin Pract Oncol. 2006 May;3(5):244-5. Can oral glutamine prevent mucositis in children undergoing hematopoietic stem-cell transplantation? Sonis ST. Brigham and Women's Hospital, Division of Oral Medicine at the Dana Farber Cancer Institute, Boston, MA 02115, USA. ssonis@partners.org PMID: 16683001 [PubMed] 21. J Dent Res. 2006 Apr;85(4):318-23. Subgingival and tongue microbiota during early periodontitis. Tanner AC, Paster BJ, Lu SC, Kanasi E, Kent R Jr, Van Dyke T, Sonis ST. Department of Molecular Genetics, The Forsyth Institute, Boston, MA 02115, USA. annetanner@forsyth.org Periodontal infections have a microbial etiology. Association of species with early disease would be useful in determining which microbes initiate periodontitis. We hypothesized that the microbiota of subgingival and tongue samples would differ between early periodontitis and health. A cross-sectional evaluation of 141 healthy and early periodontitis adults was performed with the use of oligonucleotide probes and PCR. Most species differed in associations with sample sites; most subgingival species were associated with subgingival samples. Few species were detected more frequently in early periodontitis by DNA probes. Porphyromonas gingivalis and Tannerella forsythia (Tannerella forsythensis) were associated with early periodontitis by direct PCR. In conclusion, the microbiota of tongue samples was less sensitive than that of subgingival samples in detecting periodontal species, and there was overlap in species detected in health and early periodontitis. Detection of periodontal pathogens in early periodontitis suggests an etiology similar to that of more advanced disease. PMCID: PMC1797065 PMID: 16567551 [PubMed - indexed for MEDLINE] 22. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005 Sep;100(3):321-9. Effects of ceramide inhibition on experimental radiation-induced oral mucositis. Hwang D, Popat R, Bragdon C, O'Donnell KE, Sonis ST. Department of Periodontology, School of Dental Medicine, University of Michigan, Ann Arbor, Michigan, USA. OBJECTIVE: Oral mucositis (OM) is a common toxicity of ionizing radiation (IR), which is used as treatment for head and neck cancer. Ceramide-mediated apoptosis may contribute to the pathogenesis of mucositis. In response to IR or other cellular stresses, ceramide production occurs either by the hydrolytic action of sphingomyelinase (SMase) or de novo via ceramide synthase. STUDY DESIGN: Male golden Syrian hamsters (10 per group) exposed to a single dose of 40 Gy ionizing radiation (day 0) were treated with subcutaneous 0.2 mL injections of either neutral SMase, acidic SMase, or ceramide synthase inhibitor (5 mmol/L glutathione, 5 micromol/L desipramine, or 1 micromol/L fumonisin B1, respectively) from day -1 to day 16. A control group was treated with saline. Two blinded examiners assessed clinical OM development from day 6 to day 26. Two animals per group were killed on days 3, 10, and 16 for immunohistochemical detection of ceramide expression in both the epithelium and in the connective tissue. RESULTS: The group exposed to fumonisin B1 exhibited a statistically significant reduction in mean daily weight gain, mean mucositis score, duration of mucositis, and expression of ceramide in the epithelium on day 3 as well as in the connective tissue on days 10 and 16 relative to control. Immunohistologic analysis also revealed significant differences in ceramide expression on days 3 and 16 for animals treated with glutathione in both the epithelial and connective tissue when compared to the control. CONCLUSIONS: These results suggest that IR triggers early de novo ceramide production and that inhibition of this process attenuates OM on a clinical level. PMID: 16122660 [PubMed - indexed for MEDLINE] 23. Eur J Cancer. 2005 Aug;41(12):1735-8. Assessment of oral mucositis in clinical trials: impact of training on evaluators in a multi-centre trial. Stokman MA, Sonis ST, Dijkstra PU, Burgerhof JG, Spijkervet FK. Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. m.a.stokman@kchir.umcg.nl In the assessment of mucositis, the inter-evaluator variability needs to be minimised and would likely to be best accomplished by training. The aim of this study was to evaluate the effect of training on concordance of evaluators in scoring oral mucositis. The evaluators were informed about the pathobiology and clinical appearance of mucositis and were trained in scoring mucositis according the Oral Mucositis Assessment Scale (OMAS). The effect of the training was evaluated by a pre- and post-training test. Each test consisted of 15 slides depicting oral mucositis. The pre- and post-training scores were compared to the reference standard. During 8 months at 6 meetings, 65 evaluators were trained. The mean percentage correctly scored slides according the OMAS increased significantly between the pre- and post-training test (P<0.001). Training evaluators in scoring oral mucositis has a significant improvement on the outcome of mucositis assessment. PMID: 16039109 [PubMed - indexed for MEDLINE] 24. J Periodontol. 2005 Apr;76(4):573-81. Clinical and other risk indicators for early periodontitis in adults. Tanner AC, Kent R Jr, Van Dyke T, Sonis ST, Murray LA. Department of Molecular Genetics, The Forsyth Institute, Boston, MA 02115, USA. annetanner@forsyth.org BACKGROUND: Periodontal diseases affect over half the adults in the U.S., disproportionately affecting minority populations. Periodontitis can be treated in early stages, but it is not clear what features indicate, or could be risk factors for, early stages of periodontal attachment loss. This study aimed to evaluate associations between clinical and other risk indicators of early periodontitis. METHODS: A cross-sectional evaluation of 225 healthy and early periodontitis adults aged 20 to 40 years was performed. Clinical measurements, demographic information, and smoking histories were recorded. Analyses evaluated demographic and clinical associations with health and early periodontitis disease categories and periodontal attachment loss. Patterns of attachment loss at interproximal and buccal/lingual sites were evaluated. RESULTS: Subject age, plaque, and measures of gingivitis exhibited associations with attachment loss and probing depth. More periodontal attachment loss was detected in African-American and Hispanic subjects compared to Asian and Caucasian subjects. Smoking history was associated with attachment loss. At interproximal sites, lower molars most frequently had attachment loss, whereas at buccal/lingual sites, higher proportions of lower bicuspid teeth demonstrated attachment loss compared with other sites. CONCLUSIONS: In this study of subjects with minimal attachment loss, gingival inflammation was associated with early periodontitis. Lower molar interproximal sites were frequently associated with interproximal attachment loss, whereas lower bicuspid teeth were at risk for gingival recession on buccal surfaces. PMCID: PMC1224718 PMID: 15857098 [PubMed - indexed for MEDLINE] 25. Nat Clin Pract Oncol. 2005 Mar;2(3):134-5. Is oral mucositis an inevitable consequence of intensive therapy for hematologic cancers? Sonis ST. Brigham and Women's Hospital, Boston, MA 02115, USA. ssonis@partners.org PMID: 16264905 [PubMed - indexed for MEDLINE] 26. J Oral Implantol. 2005;31(2):68-76. Dimensional stability of the alveolar ridge after implantation of a bioabsorbable bone graft substitute: a radiographic and histomorphometric study in rats. Hile DD, Sonis ST, Doherty SA, Tian X, Zhang Q, Jee WS, Trantolo DJ. Cambridge Scientific Inc, 180 Fawcett Street Street, Cambridge, MA 02138, USA. hiledd@yahoo.com This study evaluated reconstruction of the alveolar ridge after molar extraction in rats with bioabsorbable bone repair scaffolds. The material was prepared from the unsaturated polyester poly(propylene glycol-co-fumaric acid) (PPF), which may be cured in situ to form a porous scaffold. The intention is to use this material either as a stand-alone bone graft substitute or as an extender to autograft harvested from mandibular reconstruction sites. The bioactivity of the graft substitute was investigated in a rat residual ridge resorption model. PPF bone repair material was injected into the defect site, where it cross-linked in situ in the presence of a hydroxyapatite (HA) filler and effervescent agents. The PPF-based material develops porosity during an in situ cure by generating carbon dioxide during the effervescent reaction of citric acid and sodium bicarbonate. The incorporation of HA promotes osteoconduction within the bone repair scaffold. In this study, bioactivity of the porous scaffold was evaluated as a function of HA particle size (micrometer-sized vs nanometer-sized particles). The maxillary or mandibular molars on the right side were extracted from 96 adult Sprague-Dawley rats. A 2-mm round bur was used to create a uniform trench defect measuring 2 mm in diameter, 2 mm in depth, and 4 mm in length at each extraction site. The defect site was (1) treated with PPF bone repair material containing nanometer-sized HA, (2) treated with PPF material containing micrometer-sized HA, (3) treated with demineralized freeze-dried bone allograft, or (4) left untreated. Rats were sacrificed at 2, 4, 7, and 12 weeks postoperative. Resorption of the residual alveolar ridge was assessed by radiographic outcomes. Bone ingrowth through the defect site was measured by histomorphometric outcomes. Mandibular and maxillary ridge heights increased for all treatments used in this study. There were no clinical indications that addition of either of the PPF bone repair materials retarded hard- or soft-tissue healing of the extraction sites. Although not statistically significant, the mandibular defects treated with PPF containing nanometer-sized HA healed at a faster rate as determined by ridge height and new bone formation measurements when compared with the other treatments. These findings suggest the feasibility of using PPF bone graft substitutes for oral-maxillofacial applications. PMID: 15871525 [PubMed - indexed for MEDLINE] 27. Support Cancer Ther. 2005 Jan 1;2(2):122-7. Single-Dose Prevention or Short-Term Treatment with Fibroblast Growth Factor-20 (CG53135-05)Reduces the Severity and Duration of Oral Mucositis. Alvarez E, Gerlach VL, Gerwien RW, Fey EG, Watkins BA, Hahne WF, Sonis ST. CuraGen Corporation, Branford, CT. Oral mucositis (OM) is a treatment-limiting condition associated with myelosupressive chemotherapy and radiation therapy. The objective of this study was to evaluate the activity of recombinant human fibroblast growth factor-20 (FGF-20 or CG53135-05) in the prevention and treatment of OM in experimental animals. Oral mucositis was induced in hamsters with 5-fluorouracil (5-FU; 60 mg/kg) on days -4 and -2, followed by targeted irradiation with 30 Gy on day 0. Oral mucositis was scored every other day using severity scores of 0-5. To test for prevention of OM, animals received varying doses of FGF-20 on day 1 or days 1 and 2 after irradiation before the development of symptoms. To test the effects of FGF-20 on established mucositis, animals were allowed to develop early OM (score of 2) before treatment initiation. Animals then received FGF-20 by intraperitoneal (i.p.) administration (12 mg/kg) for 1, 2, 3, or 4 consecutive days. When prevention of OM was tested, administration of FGF-20 (12 mg/kg i.p.) on day 1 or days 1 and 2 resulted in significant reduction in duration of severe OM to 26% (P < 0.003) or 29.4% (P <0.018) of cumulative days, respectively, compared with untreated control animals, which spent 40.2% of cumulative days with OM scores >/= 3. When the effects of FGF-20 on established mucositis were tested, treatment of animals with FGF-20 for 2, 3, or 4 consecutive days resulted in significant reduction of severe OM to 27.4%, 29.2%, or 18.5% of days, respectively, compared with vehicle-treated control animals, which spent 41.1% of cumulative days with OM scores >/=3 (P < 0.05). These findings support the utility of FGF-20 as a single-dose agent in the prevention of OM. In addition, the positive effects of FGF-20 on established mucositis may permit treatment of patients with OM who may not benefit from prophylactic agents. PMID: 18628199 [PubMed - in process] 28. J Support Oncol. 2004 Nov-Dec;2(6 Suppl 3):3-8. Oral mucositis in cancer therapy. Sonis ST. Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA. ssonis@partners.org Oral mucositis induced by radiation therapy and chemotherapy is a frequently occurring toxicity in patients with cancer. Severe mucositis has a major impact on patient daily functioning,well-being, and quality of life. It can also compromise a patient's ability to tolerate planned therapy, resulting in missed doses or dose reductions. Mucositis negatively affects other health outcomes as well, increasing the risk of opportunistic infections and mortality due to sepsis. It also imposes a significant economic burden, since extended hospitalization and greater analgesic use can substantially increase treatment costs. A five-phase model of the pathobiology of mucositis has been proposed that facilitates our understanding of mucositis pathogenesis and the complex interactions that occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. Continued research is needed to optimize when these treatments should be administered during the course of cancer therapy to maximize therapeutic benefit. PMID: 15605918 [PubMed - indexed for MEDLINE] 29. DNA Cell Biol. 2004 Aug;23(8):490-5. Caspase-11 is not necessary for chemotherapy-induced intestinal mucositis. Kang SJ, Popat R, Bragdon C, Odonnell K, Phelan S, Yuan J, Sonis ST. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. Mucositis is a common, dose-limiting toxicity associated with drug and radiation therapy for cancer. The ulcerative lesions of mucositis serve as systemic portals of entry for the micro-organisms that inhabit the mucosa of the gastrointestinal tract and the oral cavity, often leading to systemic infection. The pathogenesis of mucositis is complex, and consists of varying, sequential interactions between pro-inflammatory cytokines, transcription factors, and pro-apoptotic pathways of the mucosal epithelium and the cells and tissues within the submucosa. A possible mechanism for mucositis injury is the activation of caspases, a family of cysteine proteases. Caspase-11, one of 14 members of this enzymatic family, was studied to determine its role in the development of intestinal mucositis after exposure to melphalan in caspase-11 wild-type (+/+) and knockout (-/-) mice. Immunoblots demonstrated the activation of caspase-11 in duodenal and jejunal samples 24 and 48 h after melphalan administration. No significant differences in the level of intestinal cell death or macrophage infiltration, as measured by TUNEL staining and immunohistochemistry, were present between wildtype (+/+) and knockout (-/-) mice. These findings suggest that while caspase-11 activation occurs in response to melphalan, it does not have a primary role in the pathogenesis of intestinal mucositis. PMID: 15307951 [PubMed - indexed for MEDLINE] 30. Cancer. 2004 May 1;100(9 Suppl):2026-46. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Department of Palliative Care and Rehabilitation Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA. BACKGROUND: Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation, 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary track mucositis increases mortality and morbidity and contributes to rising health care costs. Consequently, the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an expert panel to evaluate the literature and to create evidence-based guidelines for preventing, evaluating, and treating mucositis. METHODS: Thirty-six panelists reviewed literature published between January 1966 and May 2002. An initial meeting in January 2002 produced a preliminary draft of guidelines that was reviewed at a second meeting the same year. Thereafter, a writing committee produced a report on mucositis pathogenesis, epidemiology, and scoring (also included in this issue), as well as clinical practice guidelines. RESULTS: Panelists created recommendations from higher levels of evidence and suggestions when evidence was of a lower level and there was a consensus regarding the interpretation of the evidence by the panel. Panelists identified gaps in evidence that made it impossible to recommend or not recommend use of specific agents. CONCLUSIONS: Oral/GI mucositis is a common side effect of many anticancer therapies. Evidence-based clinical practice guidelines are presented as a benchmark for clinicians to use for routine care of appropriate patients and as a springboard to challenge clinical investigators to conduct high-quality trials geared toward areas in which data are either lacking or conflicting. Copyright 2004 American Cancer Society. PMID: 15108223 [PubMed - indexed for MEDLINE] 31. Cancer. 2004 May 1;100(9 Suppl):1995-2025. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Division of Oral Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115, USA. ssonis@partners.org BACKGROUND: A frequent complication of anticancer treatment, oral and gastrointestinal (GI) mucositis, threatens the effectiveness of therapy because it leads to dose reductions, increases healthcare costs, and impairs patients' quality of life. The Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology assembled an international multidisciplinary panel of experts to create clinical practice guidelines for the prevention, evaluation, and treatment of mucositis. METHODS: The panelists examined medical literature published from January 1966 through May 2002, presented their findings at two separate conferences, and then created a writing committee that produced two articles: the current study and another that codifies the clinical implications of the panel's findings in practice guidelines. RESULTS: New evidence supports the view that oral mucositis is a complex process involving all the tissues and cellular elements of the mucosa. Other findings suggest that some aspects of mucositis risk may be determined genetically. GI proapoptotic and antiapoptotic gene levels change along the GI tract, perhaps explaining differences in the frequency with which mucositis occurs at different sites. Studies of mucositis incidence in clinical trials by quality and using meta-analysis techniques produced estimates of incidence that are presented herein for what to our knowledge may be a broader range of cancers than ever presented before. CONCLUSIONS: Understanding the pathobiology of mucositis, its incidence, and scoring are essential for progress in research and care directed at this common side-effect of anticancer therapies. Copyright 2004 American Cancer Society. PMID: 15108222 [PubMed - indexed for MEDLINE] 32. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004 May;97(5):584-91. Deciphering gene expression profiles generated from DNA microarrays and their applications in oral medicine. Kuo WP, Whipple ME, Epstein JB, Jenssen TK, Santos GS, Ohno-Machado L, Sonis ST. Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Cambridge, MA 02115, USA. wkuo@genetics.med.harvard.edu Genome-wide monitoring of gene expression profiles using DNA microarrays provides a unique approach to exploring the biological processes underlying oral diseases and disorders by providing a comprehensive survey of a cell's or tissue's transcriptional mapping. This revolutionary technology allows for the simultaneous assessment of the transcription levels of tens of thousands of genes, and of their relative expression between normal and diseased cells. As microarray data analysis evolves, there is a widespread hope that microarrays will significantly impact our ability to explore the genetic changes associated with disease etiology and development, ultimately leading to the discovery of new biomarkers for disease diagnosis and prognosis prediction as well as new therapeutic tools. The goal of this manuscript is to review 2 of the most commonly used microarray technologies, provide an overview of data analyses involved in a typical microarray experiment, and comment upon the application of microarrays to oral medicine. PMID: 15153870 [PubMed - indexed for MEDLINE] 33. Nat Rev Cancer. 2004 Apr;4(4):277-84. The pathobiology of mucositis. Sonis ST. Division of Oral Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. ssonis@partners.org PMID: 15057287 [PubMed - indexed for MEDLINE] 34. Oral Oncol. 2004 Feb;40(2):170-6. The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. Sonis ST, O'Donnell KE, Popat R, Bragdon C, Phelan S, Cocks D, Epstein JB. Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts, USA. ssonis@partners.org Although cycloooxygenase-2 (COX-2) is upregulated by factors associated with oral mucositis, its role in the pathogenesis of mucositis has not been studied. We investigated the kinetics of mucosal COX-2 expression following radiation exposure, and assessed its relationship to the development of oral mucositis in an established animal model using immunohistochemical endpoints. While little or no COX-2 expression was observed in unirradiated mucosa or in tissue taken 2 days after radiation, COX-2 expression was dramatic on days 10 and 16, especially in submucosal fibroblasts and endothelium. The kinetics of COX-2 expression paralleled mucositis severity. A burst of angiogenic activity was seen on day 21 following peak COX-2 expression. The kinetics of COX-2 expression relative to mucositis progression suggests that COX-2 is not a primary driver of radiation injury, but instead plays an amplifying role. PMID: 14693241 [PubMed - indexed for MEDLINE] 35. Semin Oncol Nurs. 2004 Feb;20(1):11-5. Pathobiology of mucositis. Sonis ST. Harvard School of Dental Medicine, Boston, MA, USA. OBJECTIVE: To describe the pathogenesis of mucositis, summarize the techniques used to study the condition, and describe the current five-phase model that defines mucositis pathogenesis. DATA SOURCE: Published research articles, ongoing laboratory and clinical studies, and clinical experience. CONCLUSION: Defining the biological mechanisms associated with mucosal injury is critical for effective intervention. Research performed over the past few years has shown that the pathobiology of mucositis is complex, and involves all of the cells and tissues of the mucosa. IMPLICATIONS FOR NURSING PRACTICE: An understanding of this evolving pathobiologic model of mucositis will enable nurses to more effectively assess and manage mucositis. PMID: 15038512 [PubMed - indexed for MEDLINE] 36. J Support Oncol. 2004 Jan-Feb;2(1):21-32; discussion 35-6. A biological approach to mucositis. Sonis ST. Division of Oral Medicine at Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts, USA. ssonis@partners.org Oral mucositis is a common toxicity associated with both antineoplastic head and neck radiation and chemotherapy. In addition to exacting a terrible symptomatic toll, mucositis is associated with a number of adverse health and economic outcomes. Furthermore, its presence may compromise the use of optimum agents, doses, or dosing schedules. The current lack of an approved, effective mucositis treatment has sparked interest in the development of interventions that are based on the biological mechanisms that lead to mucosal injury. While our understanding of the molecular and cellular pathways leading to mucositis is still evolving, it is now clear that the condition represents the culmination of a dynamic sequence of events that involve all cells and tissues in the mucosa. Five phases characterize the pathophysiologic progression that results in mucositis: initiation, upregulation and message generation, signaling and amplification, ulceration, and healing. Each phase offers a potential target for therapeutic intervention. PMID: 15330370 [PubMed - indexed for MEDLINE] 37. Clin Cancer Res. 2003 Aug 15;9(9):3454-61. Preclinical characterization of CG53135 (FGF-20) in radiation and concomitant chemotherapy/radiation-induced oral mucositis. Alvarez E, Fey EG, Valax P, Yim Z, Peterson JD, Mesri M, Jeffers M, Dindinger M, Twomlow N, Ghatpande A, LaRochelle WJ, Sonis ST, Lichenstein HS. CuraGen Corp, Branford, Connecticut 06405, USA. ealvarez@curagen.com PURPOSE: The purpose of this study was to evaluate the activity of CG53135 (FGF-20), a protein with in vitro mitogenic activity on epithelial and mesenchymal cells, in two in vivo models of oral mucositis (OM). EXPERIMENTAL DESIGN: Radiation or concomitant chemotherapy/radiation-induced OM was elicited in hamsters. Activity of CG53135 was assessed at different doses and regimens in the models. Bromodeoxyuridine (BrdUrd) incorporation and pharmacokinetic studies were also performed to correlate in vivo activity of CG53135 with exposure. RESULTS: In the hamster radiation model, administration of CG53135 (600 or 1200 micro g/day, i.p.) on days 3-15 resulted in a statistically significant (P < 0.001) reduction in days spent with severe mucositis. CG53135 administered at 12 mg/kg, i.p. (days 1-2 or 1-8) in the concomitant chemotherapy/radiation model resulted in a statistically significant (P < 0.001) reduction in severe mucositis. Maximal BrdUrd incorporation was observed in cheek pouch and jejunal tissues at 8 h, and peak plasma levels of CG53135 were reached 1 h after administration. CONCLUSIONS: CG53135 demonstrates potent, regimen-dependent activity in hamster models of OM. The activity was regimen dependent. BrdUrd incorporation studies confirmed that CG53135 had proliferative activity in vivo with a favorable pharmacokinetic profile. Based in part on work described herein, CG53135 has received approval from the United States Food and Drug Administration to be evaluated in a Phase I clinical trial of cancer patients at risk for developing OM. PMID: 12960137 [PubMed - indexed for MEDLINE] 38. Cancer. 2003 Jul 15;98(2):406-12. Evaluation of pain associated with oral mucositis during the acute period after administration of high-dose chemotherapy. Cella D, Pulliam J, Fuchs H, Miller C, Hurd D, Wingard JR, Sonis ST, Martin PJ, Giles F. Institute for Health Services Research and Policy Studies, Evanston Northwestern Healthcare and Northwestern University, Evanston, Illinois 60201, USA. d-cella@northwestern.edu BACKGROUND: No single oral mucositis (OM) assessment scale is universally accepted; the most commonly used scales are deficient because they combine subjective and objective measures and do not capture the patient's perspective. Because pain is the hallmark symptom of OM, the authors sought to determine whether a simple measure of patient-reported pain was correlated with objective, physician-assessed measures of OM. The findings of the current study may provide a clinical context for understanding the relation between objective indicators and patients' perceptions of OM. METHODS: Three hundred twenty-three patients receiving stomatotoxic chemotherapy and randomized to receive either iseganan or placebo for treatment of OM underwent periodic objective and subjective evaluations of OM. Objective measures included clinician scoring of stomatitis and dysphagia using the National Cancer Institute Common Toxicity Criteria scales. A subjective measure was obtained by having patients complete a questionnaire (with questions based on an 11-point numeric scale) regarding oral pain. RESULTS: More than 90% of scheduled oral assessments were obtained. Mouth pain scores were closely related to stomatitis and dysphagia; peak mouth pain coincided with peak stomatitis and dysphagia. Analgesic use increased by 0.7 days for each unit rise on the pain scale. Patients receiving iseganan had a significantly lower level of peak mouth pain than did patients receiving placebo (P=0.041). CONCLUSIONS: A separate measurement of patient-reported pain was useful for capturing the patient's perspective on OM and was correlated with the physician's objective assessment. These findings support the use of a simple, patient-reported rating of mouth pain as a clinically relevant and responsive endpoint in clinical trials. This rating system also may provide a straightforward method of following OM in clinical practice. Copyright 2003 American Cancer Society. PMID: 12872363 [PubMed - indexed for MEDLINE] 39. Lancet Infect Dis. 2003 Jul;3(7):405-12. Antimicrobial therapy to prevent or treat oral mucositis. Donnelly JP, Bellm LA, Epstein JB, Sonis ST, Symonds RP. Supportive Care Studies, Department of Haematology, University Medical Centre, St Radboud, Nijmegen, Netherlands. p.donnelly@usa.net Erratum in: Lancet Infect Dis. 2003 Sep;3(9):598. Oral mucositis represents a significant source of morbidity after chemotherapy and radiation therapy. Since infection may have an important role in the pathophysiology of oral mucositis, several antimicrobial agents have been investigated for their efficacy in preventing and treating this disease. We sought to establish the weight of evidence for antimicrobial treatment and identified 31 prospectively designed clinical trials of which 13 reported some benefit and 15 did not. No clear pattern was identified regarding patient type, cancer treatment, or type of antimicrobial agent used, and inconsistent assessment of oral mucositis made comparison of outcomes difficult. Newer drugs, such as the topical antimicrobial peptide iseganan HCl initially showed promise in reducing mucositis and the related oral pain but the results of a phase 3 trial were disappointing and the line of enquiry was abandoned altogether. Hence, there is a need to better understand the role of the microflora in the cause of oral mucositis if an antimicrobial agent for prevention and treatment of this disease is to be developed. PMID: 12837345 [PubMed - indexed for MEDLINE] 40. Leuk Lymphoma. 2003 Jul;44(7):1165-72. A phase III, randomized, double-blind, placebo-controlled, multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (PROMPT-CT trial). Giles FJ, Miller CB, Hurd DD, Wingard JR, Fleming TR, Sonis ST, Bradford WZ, Pulliam JG, Anaissie EJ, Beveridge RA, Brunvand MM, Martin PJ; PROMPT-CT Trial Investigators. Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. frankgiles@aol.com Microfloral invasion and colonization of oral cavity mucosal tissues contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of Protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days. One hundred sixty three and 160 patients, respectively, were randomized to receive iseganan or placebo. One hundred and two patients (32%) were affected by a drug dispensing error, caused by a flawed computerized allocation system. Among all 323 patients, analyzed according to randomization assignment, 43% and 33% of iseganan and placebo patients, respectively, did not develop UOM (P = 0.067). On an 11-point scale, iseganan patients experienced less mouth pain (3.0 and 3.8 (P = 0.041), throat pain (3.8 and 4.6 (P = 0.048)), and difficulty swallowing (3.9 and 4.7 (P = 0.074)), compared to placebo patients. On the 5-point NCI CTC scale, iseganan patients experienced lower stomatitis scores (1.6 and 2.0 (P = 0.0131). Iseganan was well tolerated; no systemic absorption was detected. Iseganan is safe and may be effective in reducing UOM and its clinical sequelae. PMID: 12916869 [PubMed - indexed for MEDLINE] 41. J Am Dent Assoc. 2003 Apr;134(4):456-62. Microarrays and clinical dentistry. Kuo WP, Whipple ME, Jenssen TK, Todd R, Epstein JB, Ohno-Machado L, Sonis ST, Park PJ. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Mass. 02115, USA. winston_kuo@hms.harvard.edu Comment in: J Am Dent Assoc. 2003 Aug;134(8):1046; author reply 1046, 1048. BACKGROUND: The Human Genome Project, or HGP, has inspired a great deal of exciting biology recently by enabling the development of new technologies that will be essential for understanding the different types of abnormalities in diseases related to the oral cavity. LITERATURE REVIEWED: The authors review current literature pertaining to the advanced microarray technologies arising from the HGP and how they can contribute to dentistry. This technology has become a standard tool for monitoring activities of genes at both academic and pharmaceutical research institutions. RESULTS: With the availability of the DNA sequences for the entire human genome, attention now is focused on understanding various diseases at the genome level. Deciphering the molecular behavior of genetically encoded proteins is crucial to obtaining a more comprehensive picture of disease processes. Important progress has been made using microarrays, which have been shown to be effective in identifying gene expression patterns and variations that correlate with cellular development, physiology and function. Arrays can be used to classify tissue samples accurately based on molecular profiles and to select candidate genes related to a number of cancers, including oral cancer. This type of oral genetic approach will aid in the understanding of disease progression, thus improving diagnosis and treatment for patients. CLINICAL IMPLICATIONS: Microarrays hold much promise for the analysis of diseases in the oral cavity. As the technology evolves, dentists may see these tools as screening tests for better managing patients' dental care. PMID: 12733779 [PubMed - indexed for MEDLINE] 42. Int J Oral Maxillofac Implants. 2003 Mar-Apr;18(2):182-8. Evaluation of a porous, biodegradable biopolymer scaffold for mandibular reconstruction. Trantolo DJ, Sonis ST, Thompson BM, Wise DL, Lewandrowski KU, Hile DD. Cambridge Scientific, Cambridge, Massachusetts 02138-1112, USA. PURPOSE: Bioresorbable bone graft substitutes could eliminate disadvantages associated with the use of autografts, allografts, and other synthetic materials. The authors investigated the osteoinductive capacity of a bioresorbable bone graft substitute made from the unsaturated polyester poly(propylene glycol-co-fumaric acid) (PPF) for mandibular reconstruction in a rat model. The eventual intention is to use this material either as a stand-alone bone graft substitute or as an extender to autograft harvested from mandibular reconstruction sites. MATERIALS AND METHODS: The PPF bone graft was crosslinked in the presence of a hydroxyapatite filler and effervescent foaming agents to develop porosity in situ by generating carbon dioxide during the effervescent reaction of citric acid and sodium bicarbonate. The latter reagents are responsible for foam formation and expansion, resulting in a polymeric scaffold with pore sizes in the range of 100 to 500 microm. Twenty adult Sprague-Dawley rats had 3-mm-diameter cortical defects decorticated on the outer aspect of their left mandibular ramus using a Hall drill. Animals were divided into 2 groups of 10 animals each. Animals in group A were treated with implantation of the PPF-based bone graft substitute. Implants were applied buccally to defects on the left side. In group B animals with similar defects, the drill holes were left to heal unaided. The amount of new bone formation and the presence of an inflammatory infiltrate were evaluated at 7 weeks postoperatively. RESULTS: Histologic analysis of the healing process revealed enhanced in vivo new bone formation with the PPF bone graft substitute. These findings were corroborated by the histomorphometric analysis of new bone formation. DISCUSSION: Results of this study demonstrated biocompatibility of the porous PPF-based scaffold in a mandibular defect. CONCLUSIONS: These findings may have applicability to the further development of bone graft substitutes for oral/maxillofacial applications. PMID: 12705295 [PubMed - indexed for MEDLINE] 43. Oral Oncol. 2002 Oct;38(7):650-6. Gene expression profiling by DNA microarrays and its application to dental research. Kuo WP, Whipple ME, Sonis ST, Ohno-Machado L, Jenssen TK. Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. wpkuo@mit.edu DNA microarray technology has been used for genome-wide gene expression studies that incorporate molecular genetics and computer science skills on massive levels. The technology permits the simultaneous analysis of tens of thousands of genes for the purposes of gene discovery, disease diagnosis. improved drug development, and therapeutics tailored to specific disease processes. OBJECTIVE: In this review, the two most common microarray technologies and their potential application to dental research will be discussed. The authors review current articles pertaining to the technologies and analysis of mRNA expression using DNA micro-arrays and its application to dental research. Since many genes contribute to normal functioning, research efforts are moving from the search for a disease specific gene to the understanding of the biochemical and molecular functioning of a variety of genes and how complicated networks of interaction can lead to a disease state, such as oral cancer. With the incorporation of DNA micro-array based research, we can look forward to more accurate diagnosis and surgical treatment/drug-delivery therapy based on an individual patient's genetic profile. PMID: 12353490 [PubMed - indexed for MEDLINE] 44. Cell Prolif. 2002 Aug;35 Suppl 1:93-102. The gene expression sequence of radiated mucosa in an animal mucositis model. Sonis ST, Scherer J, Phelan S, Lucey CA, Barron JE, O'Donnell KE, Brennan RJ, Pan H, Busse P, Haley JD. Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women's Hospital and the Department of Otal Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, USA. ssonis@partners.org Oral mucositis is a common, dose-limiting, acute toxicity of radiation therapy administered for the treatment of cancers of the head and neck. Accumulating data would suggest that the pathogenesis of mucositis is complex and involves the sequential interaction of all cell types of the oral mucosa, as well as a number of cytokines and elements of the oral environment. While a number of studies have reported on gene expression of particular cell types in response to radiation, the overall response of irradiated mucosa has only been evaluated in a limited way. The present study was undertaken to evaluate the expression of a target group of genes using RNA quantification assays and, more broadly, to assess patterns of mucosal gene expression using DNA microarray hybridization. Our results demonstrate the sequential upregulation of a series of genes that, when taken collectively, suggest an intricate functional interaction. PMID: 12139712 [PubMed - indexed for MEDLINE] 45. Oncology (Williston Park). 2002 May;16(5):680-6; discussion 686, 691-2, 695. Oral complications of cancer therapy. Sonis ST, Fey EG. Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ssonis@partners.org The mouth is a frequent site of complications arising from drug or radiation cancer therapy, with mucositis, xerostomia, osteoradionecrosis, and local infections being the most common. From the stand-point of dose limitation, treatment breaks, quality of life, and health economic outcomes, mucositis is the most significant acute oral toxicity. Xerostomia, a chronic side effect of radiation, involves the salivary gland tissue, and results in changes in taste, tissue resilience, and an increased risk of caries and periodontal disease. While the incidence of osteoradionecrosis seems to be decreasing, the chronicity and symptoms of this festering bony condition are especially difficult for patients. Local oral infections resulting from the overgrowth of opportunistic organisms or the activation of latent viruses are so common as to warrant a prophylactic approach in many cases. A surge of investigational interest has been directed at understanding the mechanisms of these stomatotoxicities and at developing treatment strategies to combat them. PMID: 12108892 [PubMed - indexed for MEDLINE] 46. Crit Rev Oral Biol Med. 2002;13(5):380-9. The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Sonis ST. Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, MA 02115, USA. Ssonis@partners.org Oral mucosal barrier injury (mucositis) is a frequent, painful, serious, dose-limiting toxicity associated with many anti-neoplastic drugs and radiation to the head and neck. Results of recent studies suggest that mucositis is the result of a complex series of interactive biological events that take place in the submucosa and epithelium. The nuclear transcription factor NF-kappaB has been implicated in the control of a broad range of biological responses, the activation of a large number of specific cellular genes, and the determination of the fate of cells exposed to ionizing radiation and anti-neoplastic drugs. Of particular importance to mucositis is the fact that NF-kappaB regulates key elements in the apparent sequence that leads to normal tissue toxicity. Not the least of these is the effect that NF-kappaB activation has on apoptosis. In particular, a paradox exists between the potential pro-apoptotic effect NF-kappaB exerts on normal cells, and the anti-apoptotic and cytoprotective effect it causes in tumor cells. This paper provides a review of the structure and function of NF-kappaB and speculates how its apparent enigmatic effect on normal and tumor cells may occur. PMID: 12393757 [PubMed - indexed for MEDLINE] 47. J Immunother. 2001 Jul-Aug;24(4):384-8. Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors. Foncuberta MC, Cagnoni PJ, Brandts CH, Mandanas R, Fields K, Derigs HG, Reed E, Sonis ST, Fay J, LeVeque F, Pouillart P, Schrezenmeier H, Emmons R, Thiel E; Investigators in TGF-beta3/OM Study Protocols 203/205. Instituto Alexander Fleming, Buenos Aires, Argentina. Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM. PMID: 11565840 [PubMed - indexed for MEDLINE] 48. J Clin Oncol. 2001 Apr 15;19(8):2201-5. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, Hayden V, Eilers J, Epstein JB, LeVeque FG, Miller C, Peterson DE, Schubert MM, Spijkervet FK, Horowitz M. Brigham and Women's Hospital and Harvard School of Dental Medicine, Boston, MA, USA. PURPOSE: To explore the relationship between oral mucositis and selected clinical and economic outcomes in blood and marrow transplant patients. PATIENTS AND METHODS: Subjects consisted of 92 transplant patients from eight centers who participated in a multinational pilot study of a new oral mucositis scoring system (Oral Mucositis Assessment Scale [OMAS]). In the pilot study, patients were evaluated for erythema and ulceration/pseudomembrane formation beginning on the first day of conditioning and continuing for 28 days. We examined the relationship between patients' peak OMAS scores and days with fever (body temperature > 38.0 degrees C), the occurrence of significant infection, days of total parenteral nutrition (TPN), and days of injectable narcotic therapy (all over 28 days), days in hospital (over 60 days), total hospital charges for the index admission, and vital status at 100 days. RESULTS: Patients' peak OMAS scores spanned the full range of possible values (0 to 5) and were significantly (P <.05) correlated with all of the outcomes of interest except days with fever (P =.21). In analyses controlling for type of graft (autologous v allogeneic) and study center, a 1-point increase in peak OMAS score was associated with (1) 1.0 additional day with fever (P <.01), (2) a 2.1-fold increase in risk of significant infection (P <.01), (3) 2.7 additional days of TPN (P <.0001), (4) 2.6 additional days of injectable narcotic therapy (P <.0001), (5) 2.6 additional days in hospital (P <.01), (6) $25,405 in additional hospital charges (P <.0001), and (7) a 3.9-fold increase in 100-day mortality risk (P <.01). Mean hospital charges were $42,749 higher among patients with evidence of ulceration compared with those without (P =.06). CONCLUSION: Oral mucositis is associated with significantly worse clinical and economic outcomes in blood and marrow transplantation. PMID: 11304772 [PubMed - indexed for MEDLINE] 49. J Natl Cancer Inst Monogr. 2001;(29):3-5. Future research directions. Peterson DE, Sonis ST. School of Dental Medicine, Department of Oral Diagnosis, University of Connecticut Health Center, Farmington 06030-1605, USA. Peterson@NSO.UCHC.EDU PMID: 11694557 [PubMed - indexed for MEDLINE] 50. J Natl Cancer Inst Monogr. 2001;(29):1-2. Prevention of mucositis in cancer patients. Sonis ST, Peterson DE, McGuire DB, Williams DA. PMID: 11694556 [PubMed - indexed for MEDLINE] 51. Cancer. 2000 Dec 1;89(11):2258-65. The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy. Epstein JB, Gorsky M, Guglietta A, Le N, Sonis ST. Department of Dentistry, Vancouver Hospital and Health Sciences Center, British Columbia, Canada. jepstein@bccancer.bc.ca BACKGROUND: Epidermal growth factor (EGF) is present in biologic fluids, including saliva, and plays a role in maintenance of the epithelial barrier and in healing of damaged mucosa. The purpose of this study was to assess the relation between salivary EGF and the severity of oral mucositis in patients with carcinoma of the head and neck during radiation therapy. METHODS: Whole resting saliva (WRS) and whole stimulated saliva (WSS) were collected prior to radiation and each week during radiation treatment for 11 men and 7 women. Oral mucositis was evaluated using the National Cancer Institute (NCI) scale of 0-4 and the Oral Mucositis Assessment Scale (OMAS), which evaluates the extent of erythema (scale of 0-2) and ulcerations (scale of 0-3) in nine oral sites. The overall OMAS score of 0-45 reflected the mucosal condition. EGF was assayed in the saliva specimens. RESULTS: The total mean radiation dose delivered to the head and neck was 5667 centigrays (cGy) in a mean of 24 fractions. Ulcerative oral mucositis occurred in 94% of patients. The mean OMAS score ranged from 2.83 in the first week of treatment to 14.77 in the fifth week. The mean WRS and WSS volumes decreased significantly from pretreatment to the first week of radiation treatment and then remained stable. A similar pattern was seen for the mean total output of EGF. A significant and negative correlation was found between higher levels of EGF in stimulated saliva and low OMAS score, reflecting less severe erythema and ulceration. A general trend showing that less tissue damage was associated with a higher EGF level in resting saliva also was illustrated. EGF levels were correlated with the OMAS score; however, no correlation was found when assessing the NCI score, which combines tissue damage with function and symptoms in a single score. CONCLUSIONS: Radiation-induced mucositis appeared to be modified by saliva volume, total EGF, and concentration of EGF in the oral environment. Saliva volume and total EGF output decreased significantly in the first weeks of treatment and remained reduced throughout radiation therapy. The findings suggest that higher levels of EGF in saliva, particularly in stimulated saliva, prior to and during radiation treatment may be associated with less severe mucosal damage due to radiation therapy. It is also postulated that human EGF may affect the development and healing of radiation-damaged mucosa. PMID: 11147596 [PubMed - indexed for MEDLINE] 52. Oral Oncol. 2000 Jul;36(4):373-81. Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters. Sonis ST, Peterson RL, Edwards LJ, Lucey CA, Wang L, Mason L, Login G, Ymamkawa M, Moses G, Bouchard P, Hayes LL, Bedrosian C, Dorner AJ. Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. Oral ulcerative mucositis is a common toxicity associated with drug and radiation therapy for cancer. It impacts on quality of life and economic outcomes, as well as morbidity and mortality. Mucositis is often associated with dose limitations for chemotherapy or is a cause for dose interruption for radiation. The complexity of mucositis as a biological process has only been recently appreciated. It has been suggested that the condition represents a sequential interaction of oral mucosal cells and tissues, pro-inflammatory cytokines and local factors such as saliva and the oral microbiota. The recognition that the pathophysiology of mucositis is a multifactorial process was partially suggested by the observation that interleukin-11 (IL-11), a pleotropic cytokine, favorably altered the course of chemotherapy-induced mucositis in an animal model. In the current study, we evaluated a series of biologic and morphologic outcomes to determine their roles and sequence in the development of experimental radiation-induced mucositis and to evaluate the effects of IL-11 in attenuating them. Our results suggest that IL-11 favorably modulates acute radiation-induced mucositis by attenuating pro-inflammatory cytokine expression. Data are also presented which help define the pathobiological sequence of mucositis. PMID: 10899677 [PubMed - indexed for MEDLINE] 53. Cancer. 1999 May 15;85(10):2103-13. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett WH Jr, Mulagha MT, Peterson DE, Rose AH, Schubert MM, Spijkervet FK, Wittes JP. Division of Dentistry, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. BACKGROUND: An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications. METHODS: A panel of experts, convened to design an objective, simple, and reproducible assessment tool to evaluate mucositis with specific application to multicenter clinical trials, developed a scale that measured objective and subjective indicators of mucositis. Nine centers participated in the study's validation. Paired investigators at each center evaluated patients receiving chemotherapy or head and neck radiation. Objective measures of mucositis evaluated ulceration/pseudomembrane formation and erythema. Subjective outcomes of mouth pain, ability to swallow, and function were measured. Analgesia use for mouth sensitivity was recorded. RESULTS: One hundred eight chemotherapy and 56 radiation therapy patients were evaluated. Seventy-eight percent of chemotherapy patients and 64% of radiation therapy patients had clinically significant mucositis. Cumulative daily mucositis scores demonstrated a high correlation among observers. Using area under the curve analysis, it was found that for chemotherapy patients, the highest correlations (correlation coefficient > 0.92) occurred for the scores that selected the three highest daily values over the course of mucositis assessment. High interobserver correlations were noted for patients receiving radiation therapy. Objective mucositis scores demonstrated strong correlation with symptoms. CONCLUSIONS: The scoring system evaluated was easily used, showed high interobserver reproducibility, was responsive over time, and measured those elements deemed to be associated with mucositis. The use of concomitant symptomatic measurements appeared to be unnecessary. PMID: 10326686 [PubMed - indexed for MEDLINE] 54. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999 May;87(5):544-51. Effect of local application of the antimicrobial peptide IB-367 on the incidence and severity of oral mucositis in hamsters. Loury D, Embree JR, Steinberg DA, Sonis ST, Fiddes JC. IntraBiotics Pharmaceuticals, Inc., Mountain View, Calif 94043-1833, USA. OBJECTIVE: The purpose of this animal study was to determine whether IB-367, an antimicrobial peptide, is able to ameliorate oral mucositis by reducing microflora densities on the mucosal surfaces of the mouth. STUDY DESIGN: Oral mucositis was induced in hamsters by intraperitoneal injection of 5-fluorouracil followed by superficial abrasion of the buccal mucosa. A test formulation was applied topically to the buccal mucosa 5 or 6 times per day starting 6 to 8 hours before abrasion. RESULTS: Mucositis scores were significantly lower (P < .05) in hamsters given formulations containing 0.5 or 2.0 mg/mL of IB-367 than in placebo-treated controls. Treatment with IB-367 produced a more than 100-fold reduction in oral microflora densities. In a second experiment, treatment of hamsters with a formulation containing IB-367 at 0.12, 0.5 or 2.0 mg/mL resulted in a dose-dependent reduction in mucositis severity. CONCLUSION: The results indicate that reduction of local microflora densities through use of IB-367 may improve clinical outcomes in patients at risk for the development of oral mucositis. PMID: 10348510 [PubMed - indexed for MEDLINE] 55. Curr Opin Oncol. 1998 Aug;10 Suppl 1:S23-7. New frontiers in the management of chemotherapy-induced mucositis. Spijkervet FK, Sonis ST. Department of Oral & Maxillofacial Surgery, University Hospital Groningen, The Netherlands. About one-third of patients undergoing chemotherapy treatment suffer oral mucositis, an inflammatory-like change of the oral mucosa. Severe pseudomembranous/ulcerative mucositis can lead to secondary infection of lesions, sepsis and even cessation of treatment. Patients receiving curative head-neck irradiation are most susceptible and children undergoing chemotherapy are three times more likely to be affected. Mucositis is a costly side-effect of cancer therapy due to the extra time patients spend in hospital and currently there is no consistently effective treatment. Experimental studies with TGF-beta 3, a potent negative regulator of epithelial and haematopoietic stem cell growth, have shown that it is possible to temporarily arrest oral mucosal basal cell proliferation, and could therefore offer a new effective and safe form of preventative intervention for patients about to undergo aggressive regimens of cancer therapy. PMID: 9801855 [PubMed - indexed for MEDLINE] 56. Cancer. 1998 Jun 1;82(11):2275-81. The impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies. Ruescher TJ, Sodeifi A, Scrivani SJ, Kaban LB, Sonis ST. Harvard School of Dental Medicine, Boston, Massachusetts, USA. BACKGROUND: Antibacterial prophylaxis with quinolone antibiotics has resulted in an increase in streptococcal infections among bone marrow transplantation (BMT) recipients with myelosuppression. Oral ulceration (mucositis), which frequently occurs as a consequence of chemotherapy, has been implicated as a significant portal of entry for streptococci. The objectives of this study were to confirm the correlation between mucositis and streptococcal bacteremia, determine the risk associated with this correlation, and evaluate the impact of mucositis and streptococcal bacteremia on hospital course and costs associated with autologous BMT. METHODS. This was a retrospective, case-control study in which the charts of autologous BMT recipients treated for hematologic malignancies between 1990 and 1996 were reviewed. Twenty-four patients were identified who met the criteria of autologous BMT; their blood cultures confirmed (x2) alpha-hemolytic streptococcal sepsis. A control group of 45 without positive cultures was matched by gender, age, diagnosis, and treatment to the study group. RESULTS. The results confirm that ulcerative mucositis is a significant risk factor for alpha-hemolytic streptococcal bacteremia among autologous BMT patients. Of the 24 patients with bacteremia, 15 of 24 (62%) had ulcerative mucositis, compared with 16 of 45 (36%) of patients in the control population (P < 0.05). Patients with ulcerative mucositis were found to be three times as likely to develop alpha-hemolytic streptococcal bacteremia as those without ulcerative mucositis (odds ratio=3.02). Both independently and as a cofactor associated with bacteremia, mucositis adversely affected the length of hospital stay (LOS). Of all the patients studied, those with oral ulcerations had a LOS of 34 days, compared with 29 days for patients without oral ulcerations (P < 0.05). Of patients in the study group, those with oral ulcerations stayed in the hospital 6 days longer than patients without oral ulcerations (40 days vs. 34 days, P < 0.05). CONCLUSIONS: Oral ulcerative mucositis is a significant, common, and important risk factor for alpha-hemolytic streptococcal bacteremia in BMT recipients with myelosuppression; it results in longer hospital stay and increased costs. PMID: 9610710 [PubMed - indexed for MEDLINE] 57. Oral Oncol. 1998 Jan;34(1):39-43. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Sonis ST. Division of Oral Medicine, Oral and Maxillofacial Surgery and Dentistry, Brigham and Women's Hospital, Boston, Massachusetts, USA. Mucositis induced by antineoplastic drugs is an important, dose-limiting and costly side effect of cancer therapy. The ulcerative lesions which result are frequent systemic portals of entry for microorganisms which inhabit the mouth and consequently are often sources of systemic infection in the myelosuppressed patient. A number of clinical observations and the inconsistency of responses to a broad range of treatment modalities suggests a physiological complexity to mucositis which has not previously been comprehensively considered. We now propose a hypothesis as to the mechanism by which mucositis develops and resolves, which is based on four phases: an initial inflammatory/vascular phase; an epithelial phase; an ulcerative/bacteriological phase; and a healing phase. The role of cytokines as initiators and ampliers of the process is discussed, as is the potential influence of genetic factors in establishing risk and modifying the course of stomatotoxicity. PMID: 9659518 [PubMed - indexed for MEDLINE] 58. Cytokine. 1997 Aug;9(8):605-12. Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters. Sonis ST, Van Vugt AG, McDonald J, Dotoli E, Schwertschlag U, Szklut P, Keith J. Division of Oral Medicine Oral and Maxillofacial Surgery, and Dentistry, Brigham & Women's Hospital, Boston, MA 02115, USA. Ulcerative mucositis is a painful, debilitating and dose-limiting toxicity of cancer chemotherapy. Current treatment is largely palliative and no adequate preventive treatment exists. Recently, we reported that recombinant human(rh) interleukin 11 (IL-11) favourably modified the course of mucositis following a single stomatotoxic regimen of 5-fluorouracil in hamsters. Although potentially beneficial, the clinically relevant issue of mucositis and myelosuppression during multicourse chemotherapy treatment was not addressed. The present study was undertaken to evaluate the effect of rhIL-11 on two consecutive courses of mucositis and myelosuppression in hamsters. Ulcerative mucositis was induced using a standardized protocol consisting of 5-fluorouracil (60 mg/kg) on days 1 and 2 followed by superficial irritation of the buccal mucosa on day 4. Animals treated with 100 microg of rhIL-11 for 12 consecutive days following each regimen of chemotherapy experienced a reduction in the incidence, severity, and duration of mucositis, a reduction in weight loss, and less morbidity and mortality relative to control animals. Bone marrow cellularity and function was not adversely affected by rhIL-11 treatment. The present study is consistent with the potential use of rhIL-11 treating patients at risk of developing ulcerative mucositis while undergoing intensive multicourse chemotherapy treatment. PMID: 9245489 [PubMed - indexed for MEDLINE] 59. Oral Oncol. 1997 Jan;33(1):47-54. Transforming growth factor-beta 3 mediated modulation of cell cycling and attenuation of 5-fluorouracil induced oral mucositis. Sonis ST, Van Vugt AG, Brien JP, Muska AD, Bruskin AM, Rose A, Haley JD. Department of Oral Medicine, Brigham and Women's Hospital, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA. Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from damage to the epithelial cell layer. We have shown that transforming growth factor-beta 3 (TGF-beta 3) negatively regulates epithelial cell proliferation and reduces the incidence of oral mucositis. Here, we report the findings of a large study examining the effects of TGF-beta 3 administration in a hamster model on oral epithelial cell cycling in vivo, on oral mucositis, on weight retention and on survival. Topical application of TGF-beta 3 to the buccal mucosa significantly reduced basal cell proliferation, as measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and DNA ploidy. Administration of topical TGF-beta 3 prior to chemotherapy with 5-fluorouracil (5-FU) significantly reduced the severity of mucositis with respect to time, reduced chemotherapy-associated weight loss and increased survival. PMID: 9192553 [PubMed - indexed for MEDLINE] 60. J Oral Maxillofac Surg. 1996 Dec;54(12):1386-91; discussion 1391-2. Risk factors affecting hospital length of stay in patients with odontogenic maxillofacial infections. Peters ES, Fong B, Wormuth DW, Sonis ST. Division of Oral Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. PURPOSE: This study identified potential risk factors associated with increasing hospital length of stay (LOS) in patients with odontogenic maxillofacial infections. PATIENTS AND METHODS: One hundred twenty-eight patients admitted to Brigham and Women's Hospital by the Division of Oral Surgery between October 1, 1984 and March 31, 1995 with a maxillofacial infection of dental origin were retrospectively identified by a medical chart review. Linear regression techniques were used to explain the relationship between patient admission characteristics and LOS. Variables considered included age, gender, infection location, admission white blood count (WBC), admission temperature, antibiotic treatment during hospitalization, attending surgeon, insurance class, operating room use (ORU), and preexisting medical conditions associated with chronic immunosuppression. RESULTS: The following variables were found to significantly increase LOS: ORU (P = .007), preexisting medical conditions (P < .0001), admission temperature (P = .022), and deep infection (P = .063). CONCLUSION: LOS is best predicted on the basis of underlying medical conditions and location of the infection. PMID: 8957116 [PubMed - indexed for MEDLINE] 61. Transplantation. 1996 Nov 15;62(9):1278-85. Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease. Krenger W, Cooke KR, Crawford JM, Sonis ST, Simmons R, Pan L, Delmonte J Jr, Karandikar M, Ferrara JL. Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. Acute graft-versus-host disease (GVHD) is thought to be initiated by alloreactive type 1 T cells that secrete gamma-interferon (IFN-gamma). IFN-gamma induces the production of inflammatory cytokines, e.g., tumor necrosis factor-alpha and interleukin (IL)-1, which are the distal mediators of GVHD. We demonstrate that the transplantation of polarized type 2 murine T cells (i.e., cells secreting IL-4 but not IFN-gamma) together with T-cell-depleted bone marrow results in a significant increase in survival (P<0.001) after bone marrow transplantation across minor histocompatibility barriers (B10.BR-->CBA/J). Further analysis demonstrated that increased survival in recipients of polarized type 2 T cells correlated with diminished production of both IFN-gamma and tumor necrosis factor-alpha but with increases in IL-4 2 weeks after transplantation. Despite improved survival, histologic changes of GVHD were evident in oral mucosal and hepatic tissues at 7 weeks after bone marrow transplantation. These data provide further evidence that inflammatory cytokines in the immediate posttransplant period are pivotal to the development of mortality but that they do not correlate with individual target organ damage. PMID: 8932272 [PubMed - indexed for MEDLINE] 62. J Am Dent Assoc. 1996 Aug;127(8):1202-13. Recurrent aphthous ulcers: a review of diagnosis and treatment. Woo SB, Sonis ST. Harvard School of Dental Medicine, Boston, USA. Recurrent aphthous ulcers, or RAU--also called canker sores--are among the oral mucosal conditions that dentists and physicians see most commonly in their patients. Several systemic conditions are associated with oral aphthouslike ulcers, and aphthae themselves often are mistaken for recrudescent oral herpes simplex virus, or HSV, infections. This article will review RAU, describe systemic conditions associated with aphthous-like ulcerations and discuss the differences between RAU and recrudescent oral HSV infections. PMID: 8803396 [PubMed - indexed for MEDLINE] 63. Eur J Cancer B Oral Oncol. 1995 Jul;31B(4):258-60. A database for mucositis induced by cancer chemotherapy. Sonis ST, Costello KA. Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, Massachusetts, USA. Ulcerative mucositis has become an increasingly important toxicity of antineoplastic therapy. In an effort to establish mucositis risk prediction for specific cancer chemotherapy regimens, a 25 field database was developed. This paper describes the rationale and methodology for creation of the database and instructions for access to it via the Internet. PMID: 7492923 [PubMed - indexed for MEDLINE] 64. Cancer Res. 1994 Mar 1;54(5):1135-8. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3. Sonis ST, Lindquist L, Van Vugt A, Stewart AA, Stam K, Qu GY, Iwata KK, Haley JD. Division of Oral Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115. Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which appears to be a consequence of the rate of epithelial proliferation. The beta transforming growth factors have been shown to be negative regulators of epithelial cell proliferation. Here we show that transforming growth factor beta 3 administration reduced proliferation of oral epithelium in vitro and in vivo. Topical application of transforming growth factor beta 3 to the oral mucosa of the Syrian golden hamster prior to chemotherapy significantly reduced the incidence, severity, and duration of oral mucositis, reduced chemotherapy-associated weight loss, and increased survival. PMID: 8118793 [PubMed - indexed for MEDLINE] 65. Stem Cells. 1994;12 Suppl 1:79-89; discussion 89-90. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointestinal mucosal biology. Keith JC Jr, Albert L, Sonis ST, Pfeiffer CJ, Schaub RG. Genetics Institute, Inc., Cambridge, Massachusetts. Recombinant human interleukin 11 (rhIL-11) is a pleiotropic cytokine that stimulates bone marrow stem cells to proliferate and decreases intestinal mucosal injury produced by cytoablative drugs and radiation in animals. The effects of rhIL-11 were studied in a hamster model of oral mucositis and in two rat models of inflammatory bowel disease (IBD). Oral mucositis was induced in male Golden Syrian hamsters with 5-fluorouracil 60 mg/kg intraperitoneal, days 0 and 2. Peak mucositis occurred by day 10 in vehicle treated animals. rhIL-11, given twice daily subcutaneously, decreased the mucositis in a dose-dependent manner and increased animal survival at all doses tested. In two models of IBD, the acetic acid-induced acute colonic injury model in Sprague-Dawley rats and the transgenic Fischer 344 rats expressing human HLA-B27 and beta 2-microglobulin, rhIL-11 decreased the gross and microscopic damage in the colons of these animals. These data suggest that rhIL-11 exerts effects on the gastrointestinal mucosa which ameliorate responses to injurious stimuli. PMID: 7696971 [PubMed - indexed for MEDLINE] 66. Cancer. 1993 Sep 1;72(5):1612-7. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Woo SB, Sonis ST, Monopoli MM, Sonis AL. Brigham and Women's Hospital, Boston, MA 02115. BACKGROUND. Few longitudinal studies have investigated the onset, duration, and resolution of ulcerative mucositis in bone marrow transplant recipients. This study prospectively followed a group of such patients on a daily basis to obtain data on the incidence of ulcerative mucositis, location and duration of lesions, severity with different conditioning regimens, and the relationship of such mucositis to the absolute neutrophil count. METHODS. Fifty-nine bone marrow transplant recipients on prophylactic acyclovir were examined daily for 26 days after marrow infusion, and all oral ulcerative lesions were recorded. RESULTS. Oral ulcers occurred in 76.3% of patients, began at a mean of 5 days after marrow infusion (day + 5), and lasted for a median of 6 days. More than 90% of patients showed complete resolution of ulcers on or before day + 15, and all showed resolution when the absolute neutrophil count was > 500 cells/ml. Persistence of ulcers was noticed in patients who had oral graft-versus-host disease and in some patients who initially developed more severe ulcerations. Ninety-six percent of ulcers were located on nonkeratinized mucosa. CONCLUSIONS. Ulcerative mucositis occurs in about 75% of bone marrow transplant recipients in the absence of herpes simplex virus infection. Most lesions occur on nonkeratinized mucosae which are vulnerable to trauma, especially if such mucosae are rendered atrophic by conditioning regimens. Oral ulcers may persist beyond day + 15 and after recovery of the neutrophil count in patients who initially develop more severe ulcerations or in patients who develop graft-versus-host disease. PMID: 8348492 [PubMed - indexed for MEDLINE] 67. Oral Surg Oral Med Oral Pathol. 1992 Dec;74(6):749-55. Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Sonis ST, Costa JW Jr, Evitts SM, Lindquist LE, Nicolson M. Division of Dentistry, Brigham & Women's Hospital, Harvard School of Dental Medicine, Boston, Mass. Ulcerative mucositis is a common, bothersome, and dose-limiting complication of cancer chemotherapy. It has been hypothesized that mucosal susceptibility to the degenerative effects of stomatotoxic drugs is related to the renewal rate of the buccal epithelium. This study was undertaken to evaluate the effect of epidermal growth factor, a molecule known to stimulate epidermal cell division, on the course, frequency, and healing of ulcerative mucositis in an animal model. Golden Syrian hamsters were subjected to a standard mucositis-induction protocol with 5-fluorouracil. Osmotic pumps were implanted into a space between the retractor muscle and the platysma cervicale muscle, and delivered epidermal growth factor or placebo at a constant rate for 7 or 14 days. Epidermal growth factor increased oral mucosal breakdown in the face of antineoplastic therapy. The course and extent of mucositis was influenced by the timing of epidermal growth factor pump placement relative to the initiation of stomatotoxic therapy. These results support the hypothesis that the epithelial basal cell rate is one of the key elements in determining mucosal sensitivity to cancer chemotherapy. PMID: 1488231 [PubMed - indexed for MEDLINE] 68. Spec Care Dentist. 1992 Mar-Apr;12(2):71-3. Effect of medical status on dental procedure time. Hayes C, Sonis ST. Harvard School of Dental Medicine. The purpose of this study was to determine if treatment of medically compromised patients requires more time than that of healthy patients. The time taken to complete diagnostic and manipulative procedures was studied and compared for both groups. After an evaluation of 160 procedures on 108 patients, it was determined that no differences existed in the time taken to complete technical procedures between the two groups. However, the diagnostic and evaluation phase for moderately to severely compromised patients required twice as much time as that of healthy individuals. PMID: 1440121 [PubMed - indexed for MEDLINE] 69. Curr Opin Dent. 1991 Dec;1(6):715-7. The three H's are not enough. Sonis ST. Division of Dentistry, Brigham and Women's Hospital, University School of Dental Medicine, Boston. PMID: 1807472 [PubMed - indexed for MEDLINE] 70. J Am Dent Assoc. 1991 Jun;122(6):56-9. Lateral pharyngeal space abscess as a consequence of regional anesthesia. Kitay D, Ferraro N, Sonis ST. Brigham and Women's Hospital. Trismus may be a complication from local anesthesia. Patients with trismus of unknown cause after dental treatment should be evaluated thoroughly. The dentist should perform a complete examination and establish a differential diagnosis to avoid missing a serious or life-threatening infection. A right lateral pharyngeal space infection developed after a general restorative procedure that involved an inferior alveolar nerve injection on the same side. The patient's severe trismus required awake intubation, incision and drainage while the patient was under general anesthesia, treatment with antibiotics and ten days of hospitalization. PMID: 1676712 [PubMed - indexed for MEDLINE] 71. Cancer. 1990 Dec 1;66(11):2375-9. The role of herpes simplex virus in the development of oral mucositis in bone marrow transplant recipients. Woo SB, Sonis ST, Sonis AL. Harvard School of Dental Medicine, Brigham and Women's Hospital, Boston, MA 02115. Herpes simplex virus (HSV) has been implicated as a major etiologic factor in the development of ulcerative mucositis in bone marrow transplant (BMT) recipients. In this study, 60 patients who received BMTs were evaluated for at least 30 days post-transplant for ulcerative mucositis and the presence of culturable HSV. Fifty-nine patients received prophylactic acyclovir. Forty-six patients developed ulcerative lesions and 45 of these were culture negative for HSV. Neither the source of transplant (autologous versus allogenic) nor the HSV antibody status of the patient affected the frequency of mucositis. The conditioning regimen appeared to be the most significant factor contributing to the severity of ulcerative mucositis. While the majority of ulcers occurred on movable nonkeratinized mucosa in BMT recipients, the usual sites of reactivation of intraoral HSV are nonmovable, keratinized mucosa. We conclude that HSV is probably not a major etiologic agent of mucositis in BMT recipients and that acyclovir is an effective agent in preventing HSV reactivation. PMID: 2173971 [PubMed - indexed for MEDLINE] 72. Oral Surg Oral Med Oral Pathol. 1990 Apr;69(4):437-43. An animal model for mucositis induced by cancer chemotherapy. Sonis ST, Tracey C, Shklar G, Jenson J, Florine D. Division of Dentistry, Brigham and Women's Hospital, Boston, Mass. Mucositis induced by chemotherapy is a painful and often dose-limiting side effect of cancer therapy. Furthermore, loss of the integrity of the oral epithelium often provides a microbial portal of entry and leads to sepsis. The present study describes the first animal model for chemotherapy-induced mucositis. The combination of three intraperitoneal injections of 5-fluorouracil at 5-day intervals and superficial mechanical mucosal irritation resulted in clinical breakdown of the oral mucosa characterized by ulcerative mucositis in Golden Syrian hamsters. Both clinical and histologic evaluation demonstrated that these changes were similar to those described in human beings and followed a pattern influenced by the degree of myelosuppression. This model should be of significance in establishing the stomatotoxicity of new chemotherapeutic agents, in evaluating medicaments to treat mucositis, and in studying the influence of oral mucosal breakdown on sepsis in myelosuppressed persons. PMID: 2326035 [PubMed - indexed for MEDLINE] 73. NCI Monogr. 1990;(9):29-32. Oral complications of cancer therapies. Pretreatment oral assessment. Sonis ST, Woods PD, White BA. Division of Dentistry, Brigham and Women's Hospital, Boston, MA 02115. Individuals undergoing cancer therapy may be at risk for a wide variety of oral problems that can significantly affect morbidity and mortality. Pretreatment oral assessment of these patients is an opportunity to identify and eliminate potential sources of sepsis and irritation. While preliminary studies strongly support the efficacy of pretreatment oral screening programs, a number of issues have yet to be addressed relative to patient-related and cost-related outcomes. Such studies should provide specific data regarding the focus of oral screening for specific malignancies, forms of cancer therapy, and oral pathology. As the aggressiveness of cancer therapy increases, comprehensive oral evaluation with clinical, radiographic, and adjunctive components before treatment is warranted. PMID: 2342592 [PubMed - indexed for MEDLINE] 74. Nutr Cancer. 1989;12(4):371-80. In vivo and in vitro effects of beta-carotene and algae extracts in murine tumor models. Combs W, Sonis ST, Fitzgerald J, Tracy C, Wilson R. Department of Surgery, Brigham and Women's Hospital, Boston, MA. Phycotene, an algae extract with known antineoplastic activity, was demonstrated to prolong, but not sustain, an increased survival rate in a murine fibrosarcoma model when it was combined with immunotherapy. It was further shown that splenocytes from phycotene and beta-carotene-treated survivors could not confer protection to a fresh tumor cell challenge in virgin mice after adoptive transfer. In a series of cytotoxicity assays, phycotene combined with immunization was demonstrated to enhance cell-mediated and complement-dependent cytotoxicity in the first 14-21 days. However, after 21 days, the phycotene and immunization groups exhibited a decreased ability to mediate immune cytotoxicity compared with immunization-only controls. This may serve to explain the in vivo findings that while survival was increased early on in active immunization and phycotene-treated mice, it eventually dropped to the level of the active immunization controls. PMID: 2608541 [PubMed - indexed for MEDLINE] 75. Spec Care Dentist. 1988 May-Jun;8(3):106-8. An analysis of dental services based in the emergency room. Sonis ST, Valachovic RW. This study evaluated the utilization, cost-effectiveness, and marketing of emergency dental services in a 700-bed university-affiliated hospital. Sequential analysis of 445 emergency room dental visits was performed during a 3-month period. Services were most used on weekend days by patients who had chief symptoms lasting varying lengths of time (43% had them 21 days). The majority of patients sought care for relief of pain. A diagnosis of infection was made in 82% of the patients. An analysis of costs, revenues, marketing, and service design is included. PMID: 3152282 [PubMed - indexed for MEDLINE] 76. Int J Tissue React. 1987;9(2):105-14. The use of infrared thermography in the evaluation of oral lesions. White BA, Lockhart PB, Connolly SF, Sonis ST. We have attempted to quantify the degree of inflammation associated with oral lesions through the use of infrared thermography, since the increased vascularity associated with inflamed tissue might result in measurable increases in surface temperature. This would provide a better measure of the relief of pain and inflammation associated with cancer chemotherapy mucositis by an antiinflammatory drug such as benzydamine hydrochloride than the subjective pain scales now employed. One subject with normal oral mucosa and three subjects with oral lesions of varying aetiology were studied with a Hughes Series 4000 PROBEYE thermal video system utilizing an infrared imager and microprocessor. A 35-mm camera was used to obtain a colour photograph of each subject. Multiple thermograms were made in a temperature range of 30.0 degrees C to 34.2 degrees C at a sensitivity of 0.2 degrees C. Photographs were taken on different occasions to determine whether the temperature readings could be duplicated and to test the accuracy of each reading. The normal surface temperature of the control subject's mucosa was found to be significantly cooler than clinical areas of inflammation in patients with lesions induced by chemotherapy. The temperature of the areas of stomatitis was remarkably consistent (Subject C means 33.7 degrees C; Subject D means 33.9 degrees C). Interestingly, the necrotic center of a traumatic ulcer inhibited measurement of an underlying inflamed base and was thus equivalent in temperature to the normal control (Normal means 31.9 degrees C; Subject B necrotic lesion means 31.7 degrees C). These results suggest that infrared thermography may represent a means to assess quantitatively the degree of mucosal inflammation. Additional studies are in progress. PMID: 3610508 [PubMed - indexed for MEDLINE] 77. J Am Dent Assoc. 1986 Nov;113(5):783-6. The use of infrared thermography in the evaluation of oral lesions. White BA, Lockhart PB, Connolly SF, Sonis ST. This study was conducted to quantitate the degree of inflammation associated with oral lesions by using infrared thermography. It was reasoned that the increased vascularity associated with inflamed tissue may result in measurable increases in surface temperature. One subject with normal oral mucosa and three subjects with oral lesions of varying causes were studied with a thermal video system, using an infrared imager and microprocessor. A clinical photograph of each subject was obtained. Multiple thermograms were made in a temperature range of 30.0 C to 34.2 C at a sensitivity of 0.2 C. Photographs were taken on different occasions to determine whether the temperature readings could be duplicated and to test the accuracy of each reading. The normal surface temperature of the control subject's mucosa was significantly cooler than were the temperatures of the inflamed areas in the subjects with lesions induced by chemotherapy. The temperature of the areas of stomatitis was consistent (subject 3, mean = 33.7 C; subject 4, mean = 33.9 C). The necrotic center of a traumatic ulcer inhibited measurement of an underlying inflamed base and, thus, was equivalent to the control in temperature (subject 1 (control), mean = 31.9 C; subject 2 (necrotic lesion), mean = 31.7 C). These results suggest that infrared thermography may provide a means to quantitatively assess the degree of mucosal inflammation. PMID: 3465795 [PubMed - indexed for MEDLINE] 78. Oral Surg Oral Med Oral Pathol. 1986 Nov;62(5):524-8. Significance of the head and neck in late infection in renal transplant recipients. Stoufi ED, Sonis ST, Shklar G. The present study was undertaken to evaluate the overall significance of the mouth and contiguous structures as sites of late opportunistic infection in renal transplant recipients, to define the flora of such infections, and to determine factors that place patients at risk of infection. Of 323 patients who underwent renal transplants, 57% developed infection at least 1 month postoperatively. Sex, donor source, or age did not influence the risk of infection. Of the posttransplant infections, 30.6% occurred in the head and neck, 21.9% in the respiratory tract, 23.7% in the urinary tract, and 10% at sites of trauma. Of head and neck infections, 16.4% were bacterial, 20.5% were viral, and 21.9% were fungal. In the remainder a definitive causative organism could not be identified. These results emphasize that the head and neck area is a major site of late opportunistic infection in renal transplant recipients. PMID: 3537894 [PubMed - indexed for MEDLINE] 79. Oral Surg Oral Med Oral Pathol. 1986 Feb;61(2):139-41. Oral complications of multimodality therapy for advanced squamous cell carcinoma of head and neck. Archibald D, Lockhart PB, Sonis ST, Ervin TJ, Fallon BG, Miller D, Clark JR. Investigational treatment of advanced localized stage III or stage IV squamous cell carcinoma of the head and neck may include chemotherapy in addition to radiotherapy and surgery. Such therapy, while effective in eradicating local tumors, often produces considerable oral toxicity. In this study we reviewed the oral complications of 22 patients receiving multimodality cancer treatment. The addition of chemotherapy to the treatment regimen did not increase the incidence of complications (osteoradionecrosis, mucositis, xerostomia, radiation caries, or infection) when compared with historical controls receiving radiotherapy alone. Pretreatment dental evaluation and close follow-up of these patients are encouraged. PMID: 3457336 [PubMed - indexed for MEDLINE] 80. J Periodontol. 1985 Aug;56(8):470-9. Healing of spontaneous periodontal defects in dogs treated with xenogeneic demineralized bone. Sonis ST, Williams RC, Jeffcoat MK, Black R, Shklar G. This study was undertaken to histologically, clinically and radiographically evaluate the sequence of healing following implantation of bovine demineralized bone powder (DBP) into severe, spontaneous periodontal defects in beagle dogs. Eight dogs with documented severe periodontitis were treated surgically following initial debridement. One quadrant in each arch was treated with conventional flap surgery and the others were treated with surgery followed by DBP implantation. Animals received postoperative debridement and clinical and radiographic evaluation. Two dogs were sacrificed at 1, 3, 6 or 12 months postoperatively, and the jaws were evaluated histologically. Clinically, DBP was well tolerated by recipients. No evidence of localized inflammatory response or delayed hypersensitivity reaction was noted. Significant reductions in gingival inflammation were noted in both experimental and control sites at 1 month postoperatively compared to preoperative scores. Equivalent periodontal pocket reduction was noted between test and experimental sites and remained significant at 12 months. Radiographically, no differences were noted in the rate of bone loss between control and test sites. Histologic evaluation demonstrated the presence of DBP at 1 month following implantation, but the material was replaced with new bone by the next sacrifice period. Periodontal ligament fibers of standard orientation were seen extending from DBP-induced bone to the root surface by 1 month after implantation. An intact epithelial attachment appeared to be present 1 month after the implantation of DBP. No differences in root surfaces were detected between test and control groups. Ankylosis was a rare finding, noted equally between test and control sites. DBP did not appear to predispose to external root resorption. In later stages, histologic evidence of advancing periodontitis was noted equally in both control and experimental groups. While DBP successfully induced new bone formation, the inability to adequately maintain the periodontal tissues due to bacterial accumulation in this model combined with recurrent pocket formation, precluded any conclusion regarding long-term advantage. Based on these findings, clinical trials of this or similar materials are recommended. PMID: 3915013 [PubMed - indexed for MEDLINE] 81. J Oral Med. 1985 Apr-Jun;40(2):67-71. Benzydamine HCL in the management of chemotherapy-induced mucositis. I. Pilot study. Sonis ST, Clairmont F, Lockhart PB, Connolly SF. PMID: 3858465 [PubMed - indexed for MEDLINE] 82. J Surg Oncol. 1984 Apr;25(4):289-95. Successful immunotherapy in a murine metastasizing fibrosarcoma model. Cortes R, Correa LA, Behbehani AI, Sonis ST, Wilson RE. Antigenic differences were demonstrated between the primary murine fibrosarcoma and its metastases. Immunization with irradiated primary tumor cells (TC) protected C57B1/6J mice against subsequent challenge with those cells, but not against challenge with cells from pulmonary metastases (PMC). Mice immunized with irradiated PMC were protected from challenge with those cells, but not against challenge with TC. Mice with fibrosarcomas produced by the injection of 5 X 10(3) cells from the primary tumor were treated by resection of the tumor-bearing limb (Amp), Amp plus cyclophosphamide (Amp + Cy), Amp plus primary TC (Amp + TC), Amp plus primary TC and from its metastatic variant (Amp + TC + PMC), and with combinations of the last two groups with Cy. Although Amp + Cy improved survival, no animal lived 100 days and metastases increased as compared to controls. Immunotherapy significantly improved survival and decreased pulmonary metastases. Antigen combinations from primary and metastatic tumors resulted in significantly better survival than did a single preparation only from TC. Chemotherapy did not enhance the results obtained with immunotherapy and surgery. Immunity conferred in long-term survivors was permanent. PMID: 6717025 [PubMed - indexed for MEDLINE] 83. Oral Surg Oral Med Oral Pathol. 1983 Nov;56(5):483-6. Severe oral hemorrhage and sepsis following bone marrow transplant failure. Connolly SF, Lockhart PB, Sonis ST. Aplastic anemia is a failure of all the cellular components of the bone marrow and, untreated, usually results in death from bleeding and/or infection within 4 months. Treatment by bone marrow transplantation offers the only means of survival. When a bone marrow graft fails, the patient is extremely susceptible to severe infection and/or hemorrhage. In this case, a bone marrow transplantation in a 34-year-old white man with aplastic anemia failed. Among the medical problems that subsequently developed were severe, prolonged and life-threatening oral bleeding and infection. PMID: 6358996 [PubMed - indexed for MEDLINE] 84. J Oral Med. 1983 Jul-Sep;38(3):117-22. Clinical trial of demineralized bone powder in the treatment of periodontal defects. Sonis ST, Kaban LB, Glowacki J. PMID: 6355411 [PubMed - indexed for MEDLINE] 85. J Oral Med. 1983 Apr-Jun;38(2):58-61. Comparison of the nature and frequency of medical problems among patients in general, specialty and hospital dental practices. Sonis ST, Fazio R, Setkowicz A, Gottlieb D, Vorhaus C. PMID: 6242748 [PubMed - indexed for MEDLINE] 86. Inflammation. 1983 Mar;7(1):25-33. Interaction of Ia antigen-bearing polymorphonuclear leukocytes and murine splenocytes. Fitzgerald JE, Sonis ST, Rodrick ML, Wilson RE. Polymorphonuclear leukocytes (PMN) were induced in the peritoneum of a Balb/c mouse by ip injection of Fusobacterium nucleatum (FN) (greater than 95% PMN). A subpopulation of PMN harvested bore Ia surface antigens and stimulated a mixed lymphocyte reaction (MLR) when cultured with C57B1/6J splenocytes. The reaction was blocked by a short prior incubation of PMN with anti-Ia antibody or PMN cell depletion by the same antibody plus complement. The Ia antigen-bearing PMN were capable of antigenic modulation since incubation of PMN for 24 h rendered the cells incapable of stimulating an MLR. The Ia antigen-bearing PMN produced a soluble material that enhanced the phytohemagglutinin (PHA) response of murine splenocytes and the active material was a product of live cells since the supernatants contained no detectable lactate dehydrogenase activity. The data suggest that murine PMN subpopulations, defined by surface Ia antigen, can modulate mitogenic responses by production of an enhancing factor(s). PMID: 6220969 [PubMed - indexed for MEDLINE] 87. J Oral Med. 1982 Jul-Sep;37(3):80-3. Cavernous sinus thrombosis and brain abscess initiated and maintained by periodontally involved teeth. Goteiner D, Sonis ST, Fasciano R. PMID: 6958833 [PubMed - indexed for MEDLINE] 88. J Surg Res. 1982 Jul;33(1):17-22. The antigenicity of electrocauterized allogeneic tumor cells in mice. Devereux DF, Sonis ST, Tilney NL, Collins JJ Jr. PMID: 7087445 [PubMed - indexed for MEDLINE] 89. Cancer Treat Rep. 1982 Jun;66(6):1251-6. Oral complications of cancer chemotherapy: present status and future studies. Peterson DE, Sonis ST. PMID: 7083231 [PubMed - indexed for MEDLINE] 90. J Oral Med. 1982 Apr-Jun;37(2):38-41. Hematologic parameters as predictors of oral involvement in the presentation of acute leukemia. Stafford RF, Lockhart PB, Sonis AL, Sonis ST. PMID: 6980977 [PubMed - indexed for MEDLINE] 91. J Periodontol. 1982 Apr;53(4):231-8. An analysis of peripheral blood and salivary polymorphonuclear leukocyte function, circulating immune complex levels and oral status in patients with inflammatory bowel disease. Lamster IB, Rodrick ML, Sonis ST, Falchuk ZM. In an earlier case report, we described a 28-year-old man with active Crohn's disease and rapidly progressive alveolar bone loss, who presented with enhanced peripheral blood polymorphonuclear leukocyte activity as assessed by phagocytosis and lysis of a target bacterium. To assess the significance of this finding, peripheral blood polymorphonuclear leukocytes (PMN) from thirty patients with active or inactive inflammatory bowel disease (IBD) were examined for spontaneous and stimulated hexose monophosphate shunt (HMS) activity. Analysis revealed the PMN from active IBD patients displayed greater metabolic activity than PMN from inactive IBD patients, which in turn were more active than PMN from normal subjects. Since circulating immune complex (CIC) levels might be of importance in the in vivo activation of PMN, analysis of serum CIC levels via polyethylene glycol 6000 precipitation was carried out. This indicated that active IBD patients had higher levels of CIC activity then inactive IBD patients. Ten of these patients were evaluated for spontaneous HMS activity by salivary PMN. As compared to controls, comparable numbers of salivary PMN from IBD patients displayed an average of 45% less activity than control salivary PMN. Analysis of the oral status of 10 IBD patients referred to the Peter Bent Brigham Dental Clinic indicated that two patients had overt oral pathoses apparently attributable to IBD. These two patients also had the highest CIC levels observed in the 30 serum samples tested. PMID: 6951992 [PubMed - indexed for MEDLINE] 92. Inflammation. 1982 Mar;6(1):1-11. Effects of supernatants of polymorphonuclear neutrophils recruited by different inflammatory substances on mitogen responses of lymphocytes. Rodrick ML, Lamster IB, Sonis ST, Pender SG, Kolodkin AB, Fitzgerald JE, Wilson RE. Two different substances, glycogen and thioglycollate, were used to recruit early peritoneal exudate cells (4h). In the acute phase of the inflammatory response the cellular infiltrate is large, and the predominant cell (greater than 95%) is the polymorphonuclear neutrophil. Supernatant had differing effects on lymphocyte responses to the mitogens PHA and LPS, also carried out in serum-free media, depending on recruiting substance and time of culture. While glycogen-recruited PMN supernatant (GPMN-S) always enhanced splenocyte responses to PHA, thioglycollate-recruited cells (TPMN-S) did not produce an enhancing factor until the cells had been in culture for 24 h. Whereas GPMN-S enhanced the splenocyte response to LPS only after 1 or 4 h of culture, TPMN-S failed to have any significant effect. Thymocyte responses to PHA were facilitated by all supernatants. Dilution of the soluble PMN factors resulted in a suppressive effect on splenocyte responses to both PHA and LPS, regardless of whether PMN were recruited by the thioglycollate or glycogen or of the time of cell incubation. These results indicate that PMN-rich cell populations of different types of activity are recruited by glycogen and thioglycollate and that these cells produce factors capable of potentiating, enhancing, or suppressing responses to T- or B-cell mitogens by normal syngeneic lymphocytes. PMID: 7085040 [PubMed - indexed for MEDLINE] 93. Ann Dent. 1982 Winter;41(2):42-5. Comparison of the nature and frequency of medical problems among patients in general, specialty and hospital dental practices. Sonis ST, Fazio R, Setkowicz A, Gottlieb D, Vorhaus C. PMID: 6242461 [PubMed - indexed for MEDLINE] 94. J Dermatol Surg Oncol. 1981 Dec;7(12):1019-25. Alterations in the oral mucosa caused by chemotherapeutic agents. A histologic study. Lockhart PB, Sonis ST. Histologic changes in the oral mucosa of 120 specimens from 30 patients who had received chemotherapy for a variety of extra-oral malignancies were studied in an attempt to relate the phenomena to pharmacological toxicity of the chemotherapeutic agents and other factors. PMID: 7338583 [PubMed - indexed for MEDLINE] 95. J Periodontol. 1981 May;52(5):276-9. The presence of lymphoblasts in the gingival crevice of children with acute lymphoblastic leukemia. Sonis AL, Sonis ST. PMID: 6941013 [PubMed - indexed for MEDLINE] 96. J Oral Med. 1981 Apr-Jun;36(2):28-30. Bilateral necrotizing sialometaplasia: a case report. Stafford RF, Sonis ST, Shklar G. PMID: 6942128 [PubMed - indexed for MEDLINE] 97. Spec Care Dentist. 1981 Jan-Feb;1(1):18-21. Utilization of inpatient dental consultation services. Lockhart PB, Sonis ST. PMID: 6941500 [PubMed - indexed for MEDLINE] 98. Transplantation. 1980 Oct;30(4):244-50. Modification of in vitro and in vivo immune function by acute inflammatory cells. Lamster IB, Sonis ST, Mirando DM, Kolodkin AB, Rodrick ML, Wilson RE. The ability of adoptively transferred, syngeneic polymorphonuclear leukocyte-rich (PMNLr) inflammatory cells to influence lymphocyte-mediated cytotoxicity (LMC), complement-dependent cytotoxicity (CDC), and skin allograft survival was studied in a murine model. BALB/c mouse PMNLr, stimulated by i.p. injection of either glycogen (G/PMNLr) or thioglycollate (T/PMNLr), were transferred to other BALB/c mice at the time of primary or secondary immunization with a cellular alloantigen (C57BL/6 spleen cells) or after skin allografting (C57BL/6 tailskin). The metabolic activity of each PMNLr population was determined by measuring glucose utilization in the hexose monophosphate shunt. It appeared that metabolic activity of the T/PMNLr was significantly greater than that of the G/PMNLr. Our results indicate that, while the infusion of G/PMNLr tended to suppress the primary cell-mediated immune response and the secondary humoral immune response, the infusion of T/PMNLr stimulated both of these responses. Furthermore, i.p. infusion of mice with G/PMNLr at a time approximating grafting resulted in prolonged graft survival, but neither T/PMNLr nor syngeneic thymocytes effect graft survival. Our data demonstrate that both cellular and humoral immunity can be modified by acute inflammatory cells. The metabolic status of the acute inflammatory cells seems to be critical in determining their immunoregulatory potential. PMID: 7003842 [PubMed - indexed for MEDLINE] 99. J Periodontal Res. 1979 Sep;14(5):370-5. Evidence suggesting the presence of antigen-antibody complexes on the surface of salivary leukocytes. Sonis ST, Mirando DM, Lamster IB, Stelos P, Wilson RE. PMID: 161778 [PubMed - indexed for MEDLINE] 100. Oral Surg Oral Med Oral Pathol. 1979 Jul;48(1):21-8. Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy. Lockhart PB, Sonis ST. Patients undergoing cancer chemotherapy often suffer from oral complications as a result of their disease and its treatment. The effects of the chemotherapy on the bone marrow and oral mucosa, coupled with the patient's immunosuppressed state and altered oral microbial flora, predispose these patients to oral mucositis, infection, and hemorrhage. The oral mucosa appears to mirror the effects of the chemotherapy on the bone marrow, as there appears to be a direct relationship between the changing peripheral blood counts and the status of the oral mucosa. PMID: 313547 [PubMed - indexed for MEDLINE] 101. Clin Exp Immunol. 1979 May;36(2):285-91. Influence of supernatants from polymorphonuclear leucocytes on blastogenesis of syngeneic and allogeneic murine splenocytes. Lamster IB, Sonis ST, Mirando DM, Wilson RE. Supernatant was produced from activated peritoneal polymorphonuclear leucocyte-rich cell populations from different strains of mice. These supernatants were studied for their ability to modify spontaneous and mitogen-induced blastogenesis of syngeneic and allogeneic splenocytes. Our results indicate that polymorphonuclear leucocyte-rich cell cultures from two strains of mice, A/J and BALB/c, produced a supernatant that could enhance PHA-induced blastogenesis of syngeneic and allogeneic splenocytes. Cells from a third strain C57B1/6, did not produce an active supernatant. In general, the response by splenocytes from these three strains paralleled the production of active supernatant that we observed. The response to the active supernatant was dependent upon the mitogen stimulation of the splenocytes, the mitogen dilution and the supernatant activity. These functions are believed to be genetically determined. PMCID: PMC1537713 PMID: 477032 [PubMed - indexed for MEDLINE] 102. Arch Oral Biol. 1979;24(3):235-7. Capacity of human oral leucocytes to mediate antibody-dependent cell-mediated cytotoxicity. Sonis ST, Mirando D, Stelos P, Lamster IB. PMID: 289363 [PubMed - indexed for MEDLINE] 103. Surg Forum. 1979;30:362-4. Enhanced metabolic activity by polymorphonuclear leukocytes from patients with active inflammatory bowel disease. Lamster IB, Sonis ST, Wilson RE, Falchuk ZM. PMID: 538634 [PubMed - indexed for MEDLINE] 104. J Periodontol. 1978 Nov;49(11):585-91. Chlorhexidine-induced lingual keratosis and dysplasia in rats. Sonis ST, Clark WB, Shklar G. PMID: 364001 [PubMed - indexed for MEDLINE] 105. J Am Dent Assoc. 1978 Sep;97(3):468-72. Oral complications in patients receiving treatment for malignancies other than of the head and neck. Sonis ST, Sonis AL, Lieberman A. Oral complications in patients being treated for malignancies that were not in the head and neck were studied. Age, type of therapy, and type of malignancy were factors related to the prevalence of oral complications. Mucosal ulcerations, xerostomia, and bacterial and fungal infections were the most frequently encountered oral problems. The frequency of oral complications in these patients indicates the need for an awareness and involvement of dental practitioners in their management. PMID: 279602 [PubMed - indexed for MEDLINE] 106. Br J Cancer. 1977 Sep;36(3):307-12. Assessment of drug sensitivity of human leukaemic myeloblasts. II. The toxic effects of cytosine arabinoside on 125IUdR-labelled human leukaemic myeloblasts in mice. Sonis ST, Falcão R, MacLennan IC. Leukaemia cells from the peripheral blood and bone marrow of patients with acute myeloblastic leukaemia were labelled in vitro with [125I]5-iodo-2'-deoxy-uridine (IUdR). The myeloblasts were then injected into groups of mice and the survival of these cells estimated by measuring isotope loss, using whole-body counting. The isotope excretion from mice treated with various doses of cytosine arabinoside (Ara-C) and those not treated with drugs were compared. This comparison showed that the sensitivity of myeloblasts to the drug varies from patient to patient, and in one case was different for myeloblasts from bone marrow and from blood from the same patient. We compare the clinical responses of myeloblasts to Ara-C in 6 patients, who had high peripheral blood myeloblast counts, with the sensitivities of their myeloblasts to Ara-C in mice. This comparison indicates that the assay might be a useful way of predicting the response of leukaemic cells in patients to cytotoxic agents. PMCID: PMC2025424 PMID: 270373 [PubMed - indexed for MEDLINE] 107. Prostaglandins. 1977 Jan;13(1):87-96. Inhibition of lymphoma cell proliferation by supernatant from fibrosarcoma cultures: preliminary evidence that the inhibitory material is prostaglandin E. Sonis ST, Stelos P, Stylos WA, Wilson RE. Supernatants obtained from mouse fibrosarcoma cultures 48 hr after the addition of fresh medium contained dialyzable material which inhibited the proliferation of syngeneic lymphoma cells in vitro, as measured by 3H-thymidine incorporation. Three lines of evidence indicate that the supernatant inhibitory material is probably prostaglandin (PG) E. First, the supernatant and dialysis of the supernatant contained a substance with the same characteristics as PGE1 or PGE2 as detected by thin layer chromatography. Second, PGE2-treatment of lymphoma cells mimicked the inhibition of proliferation observed with supernatant inhibitory substance. Third, indomethacin, treatment of fibrosarcoma cultures reduced the amount of supernatant inhibitory substance present. PMID: 841109 [PubMed - indexed for MEDLINE] 108. Transplantation. 1976 Jul;22(1):52-60. The role of effector cells and antiserum in the inhibition of cell-mediated cytotoxicity of allogeneic tumor cells. Sonis ST, Stelos P, Fitzgerald MA, Bear SE, Wilson RE. Previous experiments in this laboratory demonstrated a progressive decrease in cell-mediated cytotoxicity (CMC) against allogeneic tumor cells by immune spleen cells from mice repeatedly immunized with those tumor cells. In the present study, immune spleen cells, obtained at specified intervals during the course of multiple immunizations of BALB/c mice with EL-4 lymphoma cells, were tested for CMC against EL-4 target cells pretreated with anti-EL-4 serum which had been obtained from singly or repeatedly immunized animals. Cytolysis of EL-4 cells was measured by a 51Cr-release assay. The results indicate that blocking of CMC in an allogeneic tumor model may occur by two pathways. First, antigen or antigen-antibody complexes present in the immunized animal may bind in vivo to the antigen receptor sites of of sensitized effector cells that are used in the in vitro CMC assay, thereby blocking their interaction with tumor cells. Second, immune serum that is added to the in vitro CMC assay may contain highly avid antibodies, as well as antigen-antibody complexes, that bind to tumor cells and thereby block interaction with sensitized effector cells. The identification of these elements may be of prognostic significance in certain clinical situations. PMID: 936284 [PubMed - indexed for MEDLINE] 109. Cell Immunol. 1976 May;23(2):297-308. Potentiation of cell-mediated lysis of xenogemeic tumor cells: the role of antiserum and effector cells. Sonis ST, Stelos P, Bancewicz J, Kolodkin A, Wilson RE. PMID: 1084229 [PubMed - indexed for MEDLINE] 110. Arch Oral Biol. 1975 Dec;20(12):787-90. The effect of methotrexate on experimental salivary gland neoplasm in rats. Shklar G, Sonis ST. PMID: 821459 [PubMed - indexed for MEDLINE] 111. Transplantation. 1975 Nov;20(5):399-403. The immune response of mice repeatedly injected with allogeneic tumor cells. Sonis ST, Stelos P, Bear SE, Fitzgerald MA, Wilson RE. The development and kinetics of cell-mediated cytotoxicity (CMC), antibody-mediated complement-dependent cytotoxicity (C'DC), and antibody-dependent cellular cytotoxicity (ADCC) were studied in an allogeneic model. Using microcytotoxic assays of 51Cr release from labeled EL-4 tumor cells, C'DC, ADCC, and CMC were measured at 14 intervals during the 77-day course of the experiment. The results obtained demonstrate the oscillating nature of the immune response. The rise and fall of activity was almost synchronous for the three functions studied. A generalized trend of increasing antibody-dependent functions and a simultaneous dampening of CMC was noted. PMID: 1209722 [PubMed - indexed for MEDLINE] 112. Cell Immunol. 1975 Apr;16(2):251-60. Contrasting effects of alloandtiserum and xenoantiserum on cell-mediated lysis of tumor cells. Sonis ST, Stelos P, Kopelman JD, Wilson RE. PMID: 1078791 [PubMed - indexed for MEDLINE] 113. Surg Forum. 1975;26:133-5. Successful immunotherapy with BCG as an adjunct to surgical resection for murine fibrosarcoma. Sonis ST, Stelos P, Wilson RE. PMID: 1216088 [PubMed - indexed for MEDLINE] http://www.hsdm.harvard.edu/faculty/faculty-sonis.html http://www.zoominfo.com/people/Sonis_Stephen_5470746.aspx Histórico e fotografia