Periodontal status and post‐transplantation complications following intensive periodontal treatment in patients underwent allogenic hematopoietic stem cell transplantation conditioned with myeloablative regimen

Abstract: Objectives: Evaluation of the periodontal status is necessary prior to management with high‐dose chemotherapy before hematopoietic stem cell therapy (HSCT). During medical therapy, pre‐existing periodontal conditions may exacerbate and cause local and systemic complications. When possible, maximal oral health should be achieved prior to engraftment. In this study, we aimed to determine the alterations occurred in the periodontal status of the patients after periodontal treatment and allogenic HSCT and evaluate the effect of intensive periodontal approach on the short‐term complications of HSCT. Methods: The alterations occurred in the periodontal tissues 3–4 weeks after periodontal treatment and after HSCT periods of 3 months for 29 patients treated with full‐mouth periodontal treatment completed in 24 h in addition to eradication of dental foci, and oral hygiene status were evaluated using pocket depth measurements, presence of bleeding on probing and plaque and gingival indices. The incidence and severity of acute graft‐versus‐host disease (GVHD) and oral mucositis (OM) were recorded. Duration of engraftment period and the episode of febrile neutropenia were also evaluated. Results: There were significant improvements in periodontal status after periodontal treatment (P < 0.001). There were 14 (48.3%) patients without acute GVHD and 17 (58.6%) patients with no sign of OM. The majority of OM was at grade II level. There was a negative relation that exists between the percentage of BOP (+) sites and presence of OM (r = ?0.518, P < 0.05). Conclusions: Together with a significant reduction in gingival inflammation and maintenance of the improvement in periodontal health, remarkable decrease in the incidence and severity of OM were observed.     

Radiation‐induced oral mucositis and periodontitis – proposal for an inter‐relationship

Virtually all patients who receive head and neck radiotherapy develop some degree of oral mucositis. Severe oral mucositis may necessitate an interruption of the course of radiotherapy and thus can serve as a dose‐limiting factor. Periodontitis is a host‐driven inflammatory response to a pathogenic bacterial biofilm in the subgingival environment, resulting in the progressive destruction of the tissues that support the teeth, specifically the gingiva, periodontal ligament and alveolar bone. This disease affects more than 50% of the population. Considering that radiation‐induced oral mucositis and periodontitis are both linked with continuing presence of systemic inflammation, they may be associated through a primed inflammatory response as proposed by the ‘two‐hit’ model. Alternatively, both conditions may be correlated as they represent a dysregulation of the inflammatory response. To date, no studies have looked into the association between these conditions. This review considers the current evidence that provides a rationale for proposing a link between periodontitis and oral mucositis.     

Evaluation of the effectiveness of olive oil to prevent chemotherapy induced oral mucositis: A randomized controlled clinical trial

ObjectivesThis study aimed to evaluate the effectiveness of topical application of olive oil either to delay chemotherapy induced oral mucositis (OM) or to alleviate its severity in Acute Lymphoblastic Leukemia children.Materials and methodsa randomized controlled clinical trial was conducted at Hematology-Oncology Department of Children's Hospital of Damascus University, Syria. 24 children suffering from acute lymphoblastic leukemia aged between 4 and 6 years old were randomly assigned into two groups, olive oil and sodium bicarbonate 5% (12 in each group).Preventive protocol started two days before the induction of chemotherapeutic drugs. Topical application was done by a sterilized spongeous stick in order to swab tongue, buccal mucosa, floor of the mouth, lips and hard palate, as those tissues of the mouth are susceptible to chemotherapy induced OM [1]. The study period was within induction and consolidation phases of chemotherapy. Oral mucosa was assessed weekly up to eight weeks by two external investigators using the World Health Organization grading scale.ResultsData was analyzed using Mann-Whitney U test. Based on the observed results, (OM) grades were with less severity in olive oil group than in sodium bicarbonate group with statistically significant difference reported from the 2 nd week of study phase. In addition, Mann-Whitney U test demonstrated that patients in olive oil group started (OM) later than those in sodium bicarbonate group with statistically significant difference (p = 0.022). As a result, olive oil retarded the beginning of oral mucositis (OM) compared with sodium bicarbonate.Conclusionsolive oil can be used topically on oral tissues to prevent chemotherapy induced (OM) in acute lymphoblastic leukemia children.     

Tongue surface model can predict radiation tongue mucositis due to intensity-modulated radiation therapy for head and neck cancer

Acute radiation tongue mucositis has a profound effect on talking and eating. We examined whether the dose–volume histogram obtained from the tongue surface model correlates with mucositis severity, and whether it is useful for predicting acute radiation tongue mucositis in patients with head and neck cancer treated with intensity-modulated radiation therapy. Thirty-six patients who received intensity-modulated radiation therapy for head and neck cancer were analysed for acute radiation tongue mucositis according to the Common Terminology Criteria for Adverse Events, version 4.0, as well as the Radiation Therapy Oncology Group scoring systems. The corresponding high-dose locations in anatomical sub-regions in the tongue surface model and the development of high-grade acute radiation tongue mucositis were compared. The mucositis sites coincided with the high-dose anatomical sub-regions in the tongue surface model. There was a clear dose–response relationship between the mean dose to the tongue and the acute radiation tongue mucositis Radiation Therapy Oncology Group grade. According to the dose–volume histogram, patients receiving 16.0–73.0 Gy to the tongue were susceptible to grade 2–3 toxicity. The tongue surface model can predict the site and severity of acute radiation tongue mucositis. In future, radiation treatment plans ccould be optimized using this model.     

Chemotherapy‐induced oral mucositis and associated infections in a novel organotypic model

Oral mucositis is a common side effect of cancer chemotherapy, with significant adverse impact on the delivery of anti‐neoplastic treatment. There is a lack of consensus regarding the role of oral commensal microorganisms in the initiation or progression of mucositis because relevant experimental models are non‐existent. The goal of this study was to develop an in vitro mucosal injury model that mimics chemotherapy‐induced mucositis, where the effect of oral commensals can be studied. A novel organotypic model of chemotherapy‐induced mucositis was developed based on a human oral epithelial cell line and a fibroblast‐embedded collagen matrix. Treatment of organotypic constructs with 5‐fluorouracil (5‐FU) reproduced major histopathologic characteristics of oral mucositis, such as DNA synthesis inhibition, apoptosis and cytoplasmic vacuolation, without compromising the three‐dimensional structure of the multilayer organotypic mucosa. Although structural integrity of the model was preserved, 5‐FU treatment resulted in a widening of epithelial intercellular spaces, characterized by E‐cadherin dissolution from adherens junctions. In a neutrophil transmigration assay we discovered that this treatment facilitated transport of neutrophils through epithelial layers. Moreover, 5‐FU treatment stimulated key proinflammatory cytokines that are associated with the pathogenesis of oral mucositis. 5‐FU treatment of mucosal constructs did not significantly affect fungal or bacterial biofilm growth under the conditions tested in this study; however, it exacerbated the inflammatory response to certain bacterial and fungal commensals. These findings suggest that commensals may play a role in the pathogenesis of oral mucositis by amplifying the proinflammatory signals to mucosa that is injured by cytotoxic chemotherapy.     

Aloin Inhibits Interleukin (IL)‐1β−Stimulated IL‐8 Production in KB Cells

Background: Interleukin (IL)‐1β, which is elevated in oral diseases including gingivitis, stimulates epithelial cells to produce IL‐8 and perpetuate inflammatory responses. This study investigates stimulatory effects of salivary IL‐1β in IL‐8 production and determines if aloin inhibits IL‐1β?stimulated IL‐8 production in epithelial cells. Methods: Saliva was collected from volunteers to determine IL‐1β and IL‐8 levels. Samples from volunteers were divided into two groups: those with low and those with high IL‐1β levels. KB cells were stimulated with IL‐1β or saliva with or without IL‐1 receptor agonist or specific mitogen‐activated protein kinase (MAPK) inhibitors. IL‐8 production was measured by enzyme‐linked immunosorbent assay (ELISA). MAPK protein expression involved in IL‐1β?induced IL‐8 secretion was detected by Western blot. KB cells were pretreated with aloin, and its effect on IL‐1β?induced IL‐8 production was examined by ELISA and Western blot analysis. Results: Saliva with high IL‐1β strongly stimulated IL‐8 production in KB cells, and IL‐1 receptor agonist significantly inhibited IL‐8 production. Low IL‐1β–containing saliva did not increase IL‐8 production. IL‐1β treatment of KB cells induced activation of MAPK signaling molecules as well as nuclear factor‐kappa B. IL‐1β?induced IL‐8 production was decreased by p38 and extracellular signal‐regulated kinase (ERK) inhibitor treatment. Aloin pretreatment inhibited IL‐1β?induced IL‐8 production in a dose‐dependent manner and inhibited activation of the p38 and ERK signaling pathway. Finally, aloin pretreatment also inhibited saliva‐induced IL‐8 production. Conclusions: Results indicated that IL‐1β in saliva stimulates epithelial cells to produce IL‐8 and that aloin effectively inhibits salivary IL‐1β–induced IL‐8 production by mitigating the p38 and ERK pathway. Therefore, aloin may be a good candidate for modulating oral inflammatory diseases.     

Oral mucositis in patients undergoing bone marrow transplantation

Thirty patients who received bone marrow transplantation treatment from HLA identical sibling donors for immunologic and malignant diseases were studied. In essentially all of the patients oral changes developed during the first 30 days following transplant. Oral symptoms frequently constituted the major complaints of the patients during the follow-up period. The oral changes included mucositis, xerostomia, pain, and bleeding. Mucositis was more severe and of longer duration when associated with herpes simplex infections and when optimal oral hygiene was not maintained. Xerostomia which accompanies engraftment was an early sign of acute graft-versus-host disease. A nonbrushing method of oral hygiene was effective in reducing the severity and duration of mucositis. This technique offers a short-term alternative to brushing in pancytopenic patients who are susceptible to bleeding or trauma.     

Orthodontic Force Increases Interleukin‐1β and Tumor Necrosis Factor‐α Expression and Alveolar Bone Loss in Periodontitis

Background: The present study aims to evaluate the effects of orthodontic movement (OM) on the periodontal tissues of rats with ligature‐induced periodontal disease. Methods: Eighty‐eight rats were divided into four groups: 1) negative control (sham operated); 2) periodontal disease; 3) OM; and 4) periodontal disease followed by OM (OMP). Rats were sacrificed 3 hours or 1, 3, or 7 days after OM commencement. Bone volume fraction (BVF) and bone mineral density (BMD) were assessed in hemimaxillae by microcomputed tomography analysis. Expression of the proinflammatory cytokines interleukin (IL)‐1β and tumor necrosis factor (TNF)‐α were evaluated in gingival samples by quantitative polymerase chain reaction and enzyme‐linked immunosorbent assay, and in the furcation region by immunohistochemistry analysis (IHC). Results: The OMP group had lower BVF and BMD levels compared to the other groups at day 7 (P <0.05). Maximum messenger ribonucleic acid expression of both cytokines was observed in the OMP group at day 1 (P <0.05). In the same period, all proteins were expressed in high levels for all test groups compared to the control group. The number of cells positive for IL‐1β and TNF‐α by IHC was highest in the OMP group at day 1, with progressive reduction thereafter. Conclusion: The results suggest that OM acts synergistically with periodontal disease in periodontal breakdown through upregulation of proinflammatory cytokines.     

造血干细胞移植预处理诱发口腔黏膜炎模型的建立

目的探讨建立造血干细胞移植预处理诱发口腔黏膜炎大鼠模型的可行性。方法采用马利兰和环磷酰胺预处理方案结合左颊黏膜搔刮建立大鼠口腔黏膜炎模型。设立模型组和对照组，从自然过程、口腔黏膜炎指数、血象、骨髓象、病理检查等指标动态观察口腔黏膜炎的发生、发展过程。结果模型组大鼠于第7天开始出现口腔黏膜炎表现，发生率为80．00％；口腔黏膜炎指数在第11天达到峰值（2．04±1.80），4级以上口腔黏膜炎占39．29％（11／28）；第18～21天病损基本恢复，期间大鼠体重持续下降，白细胞计数于第10天下降至最低点，骨髓增生度低下。结论成功建立了造血干细胞移植预处理诱发口腔黏膜炎的大鼠模型。     

Cancer therapy-related oral mucositis

Oral mucositis is a common side effect of cancer therapies, particularly radiation therapy for head and neck cancer and various forms of chemotherapy. It commonly results in severe oral pain that can compromise the duration and success of cancer management. Hospitalizations are common because patients lose the ability to take anything by mouth due to severe pain and must have alimentation supported during this period. Pain management usually requires potent narcotic analgesia. Cancer therapy-related oral mucositis is commonly described as the most significant and debilitating acute complication associated with radiation therapy and chemotherapy. Until recently, cancer therapy-induced oral mucositis was thought to be a process involving the epithelium only. Evidence is building that the process of oral mucositis involves far more than just the epithelium, but includes multiple cellular processes of the submucosa as well. Many strategies have been evaluated to prevent oral mucositis, but the data is confusing since it is often conflicting. Therapy with the growth factor, KGF1, appears promising, as it is the only medication currently approved by the FDA. A multifaceted approach that targets the entire mucositis process will probably be needed to optimize overall prevention.     

Oral health‐related quality of life among rural‐dwelling Indigenous Australians

Background: There is limited information on the impact of poor oral health on Indigenous Australian quality of life. This study aimed to determine the prevalence, extent and severity of, and to calculate risk indicators for, poor oral health‐related quality of life among a convenience sample of rural‐dwelling Indigenous Australians. Methods: Participants (n = 468) completed a questionnaire that included socio‐demographic, lifestyle, dental service utilization, dental self‐care and oral health‐related quality of life (OHIP‐14) factors. Results: The prevalence of having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ was 34.8%. The extent of OHIP‐14 scores was 1.88, while the severity was 15.0. Risk indicators for having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ included problem‐based dental attendance, avoiding dental care because of cost, difficulty paying a $100 dental bill and non‐ownership of a toothbrush. An additional risk indicator for OHIP‐14 extent was healthcare card ownership, while additional indicators for OHIP‐14 severity were healthcare card ownership and having had 5+ teeth extracted. Conclusions: Risk indicators for poor oral health‐related quality of life among this marginalized population included socio‐economic factors, dentate status factors, dental service utilization patterns, financial factors and dental self‐care factors.     

口炎清颗粒防治鼻咽癌患者放射性口腔炎的疗效观察

目的 观察口炎清颗粒对鼻咽癌患者放射性口腔炎的防治效果。方法 将60例鼻咽癌行适形调强放疗患者随机分为2组,口炎清组（30例）于放射治疗开始给予口炎清颗粒口服至放射治疗结束,对照组（30例）在放射治疗过程中出现2级及以上放射性口腔黏膜炎时,给予0.9%氯化钠注射液、利多卡因、地塞米松、维生素B12与维生素B2配制成漱口液含漱。采用全美放射肿瘤治疗协作组急性放射性黏膜炎的分级标准比较2组患者放射性口腔炎发生的时间、程度以及疼痛分级情况。结果 口炎清组和对照组放射性口腔炎出现的时间分别为（12.40±2.74）、（9.46±1.39） d,二者间差异有统计学意义（t=5.241,P<0.001）。口炎清组患者的疼痛分级、放射性口腔炎的分级比较均明显低于对照组,差异有统计学意义。结论 口炎清颗粒可延迟放射性口腔炎的发生时间,降低放射性口腔炎的严重程度,减轻患者疼痛,改善患者临床症状,有效防治鼻咽癌放疗引起的放射性口腔炎。     

Diagnosis and non‐surgical treatment of peri‐implant diseases and maintenance care of patients with dental implants – Consensus report of working group 3

The following consensus report is based on four background reviews. The frequency of maintenance visits is based on patient risk indicators, homecare compliance and prosthetic design. Generally, a 6‐month visit interval or shorter is preferred. At these visits, peri‐implant probing, assessment of bleeding on probing and, if warranted, a radiographic examination is performed. Diagnosis of peri‐implant mucositis requires: (i) bleeding or suppuration on gentle probing with or without increased probing depth compared with previous examinations; and (ii) no bone loss beyond crestal bone level changes resulting from initial bone remodelling. Diagnosis of peri‐implantitis requires: (i) bleeding and/or suppuration on gentle probing; (ii) an increased probing depth compared with previous examinations; and (iii) bone loss beyond crestal bone level changes resulting from initial bone remodelling. If diagnosis of disease is established, the inflammation should be resolved. Non‐surgical therapy is always the first choice. Access and motivation for optimal oral hygiene are key. The patient should have a course of mechanical therapy and, if a smoker, be encouraged not to smoke. Non‐surgical mechanical therapy and oral hygiene reinforcement are useful in treating peri‐implant mucositis. Power‐driven subgingival air‐polishing devices, Er: YAG lasers, metal curettes or ultrasonic curettes with or without plastic sleeves can be used to treat peri‐implantitis. Such treatment usually provides clinical improvements such as reduced bleeding tendency, and in some cases a pocket‐depth reduction of ≤ 1 mm. In advanced cases, however, complete resolution of the disease is unlikely.     

中药含服液防治放射性口腔炎的疗效观察

目的评价中医药防治放射性口腔炎的疗效。方法将134例鼻咽癌放疗后出现口腔黏膜炎的患者随机分成两组，以金银花、玄参、水牛角、麦冬等中药制剂含服治疗患者为实验组，复方硼砂溶液含漱治疗的患者作为对照组，按WHO放射性口腔黏膜反应标准记录患者的口腔黏膜炎程度。结果中药含服液治疗67例，出现Ⅰ、Ⅱ、Ⅲ、Ⅳ级口腔黏膜炎分别为37、21、6、3例：对照组67例，出现Ⅰ、Ⅱ、Ⅲ、Ⅳ级口腔黏膜炎分别为4、26、28、9例；两组比较差异具有显著性（P〈0．01）。结论中药含服液防治放射性口腔炎具有独特的疗效。     

Quantification of oral mucositis due to radiotherapy by determining viability and maturation of epithelial cells

BACKGROUND: An in-vitro assay has been developed for quantitative assessment of chemotherapy induced oral mucositis. In the present study this method was evaluated for assessment of irradiation mucositis at a cellular level. METHODS: Ten patients participated in this consecutive study. All patients were treated with conventional fractionated curative postoperative radiotherapy. Prior to, and weekly during, the irradiation course, oral washings were obtained to determine viability of epithelial cells by trypan blue dye exclusion. Maturation of epithelial cells was assessed from smears (Papanicolaou staining). The viability data were compared with the WHO-score for mucositis. RESULTS: Epithelial cell viability increased during the first three weeks of radiation (P = 0.04), and was seen earlier than the subjective mucosal changes with the WHO-score. Cell maturity shifted from immature and intermediate to mature (P = 0.03). CONCLUSIONS: The cell viability assay can be considered an objective method for following the development of irradiation mucositis, and seems to be more sensitive during the first three weeks of irradiation than the WHO-scoring method.     

Synthetic radiation‐inducible promoters mediated HSV‐TK/GCV gene therapy in the treatment of oral squamous cell carcinoma

Oral Diseases (2010) 16 , 445–452 Objective: To investigate the therapeutic effect of herpes simplex virus thymidine kinase (HSV‐TK) gene mediated by synthetic radiation‐inducible promoters in the treatment of oral squamous cell carcinoma (OSCC) in vitro and in vivo . Methods: The plasmids pcDNA3.1(+)E6‐HSV‐TK were constructed, in which the HSV‐TK genes were mediated by synthetic radiation‐inducible promoters. The recombined plasmids were transfected into the Tca8113 cells and golden hamster buccal carcinoma, respectively. Low‐dose radiotherapy was used to upregulate the HSV‐TK genes expression. HSV‐TK mRNA was assayed by RT‐PCR. Apoptosis and proliferating cell nuclear antigen were detected respectively by in situ end‐labeling and immunohistochemical method. Results: Compared with control group, the comparative survival rate of Tca8113 cells in HSV‐TK/GCV/IR group was markedly decreased and the golden hamster buccal carcinoma in HSV‐TK/GCV/IR group was obviously suppressed. Up‐regulation of HSV‐TK gene expression was found in the Tca8113 cells and in the golden hamster buccal carcinoma resulting from exposure to low‐dose irradiation. The apoptosis indexes in Tca8113 cells or golden hamster buccal carcinoma with irradiation were markedly higher than those without irradiation. At the same time, the proliferation indexes in Tca8113 cells or golden hamster buccal carcinoma with irradiation were markedly lower than those without irradiation. Conclusion: The results indicate that the synthetic radiation‐inducible promoters can serve as a molecular switch to adjust the expression of HSV‐TK gene in the treatment of OSCC, and low‐dose induction radiation can significantly improve therapeutic efficiency.     

Hypoxia inducible factor‐1α expression in areca quid chewing‐associated oral squamous cell carcinomas

Oral Diseases (2010) 16 , 696–701 Objectives: Hypoxia inducible factor (HIF)‐1α gene expression is mainly induced by tissue hypoxia. Overexpression of HIF‐1α has been demonstrated in a variety of cancers. The aim of this study was to compare HIF‐1α expression in normal human oral epithelium and areca quid chewing‐associated oral squamous cell carcinoma (OSCC) and further to explore the potential mechanisms that may lead to induce HIF‐1α expression. Methods: Twenty‐five OSCC from areca quid chewing‐associated OSCC and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N‐acetyl‐l ‐cysteine (NAC), AP‐1 inhibitor curcumin, extracellular signal‐regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms. Results: Hypoxia inducible factor‐1α expression was significantly higher in OSCC specimens than normal specimen (P < 0.05). Arecoline was found to elevate HIF‐1α expression in a dose‐ and time‐dependent manner (P < 0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline‐induced HIF‐1α expression (P < 0.05). Conclusions: Hypoxia inducible factor‐1α expression is significantly upregulated in areca quid chewing‐associated OSCC and HIF‐1α expression induced by arecoline is downregulated by NAC, curcumin, PD98059, and staurosporine.     

Salivary epidermal growth factor levels decrease in patients receiving radiation therapy to the head and neck

OBJECTIVE: The objective of this study was to assess changes in salivary epidermal growth factor (EGF) in patients receiving radiation therapy to the head and neck and to determine whether salivary EGF levels correlate with the severity of radiation-induced oral mucositis. STUDY DESIGN: Thirteen patients and 18 control subjects were enrolled in the study. Saliva was collected before, during (weekly), and after radiation therapy. Salivary total protein (TP) and EGF concentrations were measured and correlated with the severity of oral mucositis. The variability in normalized EGF (ngEGF/mgTP) values and mucositis scores were analyzed with analysis of covariance, and the adjusted correlation coefficient was calculated. RESULTS: EGF levels decreased (P =.004), whereas TP levels increased over time (P =.039). A strong correlation was seen with decreasing normalized EGF values and more severe mucositis (P =. 0001). CONCLUSION: A strong negative correlation between normalized EGF and mucositis severity suggests a possible role for EGF in the progression of radiation-induced mucosal breakdown.     

Microbiota and their role in the pathogenesis of oral mucositis

Oral mucositis in patients undergoing cancer therapy is a significant problem. Its prevalence ranges between 20 and 100%, depending on treatment type and protocols and patient‐based variables. Mucositis is self‐limiting when uncomplicated by infection. Unfortunately, the incidence of developing a local or systemic infection during the course of the treatment is very high. At this stage, it is unclear which role oral microbiota play in the onset, duration, and severity of oral mucositis. Nevertheless, there is growing interest in this underexplored topic, and new studies are being undertaken to unravel their impact on the pathogenesis of mucositis.     

The role of oral flora in the development of chemotherapy‐induced oral mucositis

Chemotherapy‐induced mucositis is considered to be a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. In the last 10 years, there have been significant advances in the understanding of mucositis pathobiology. At the basic level, it is now well‐understood that it is not just an epithelial process, but rather a complex interaction between epithelial and connective tissue compartments. There is also potential interaction between the oral microenvironment and the development of mucositis. Changes occur in the resident oral flora (commensal) throughout cancer treatment, and it is conceivable that these organisms and changes that occur may have an influence on the development of mucosal toxicity associated with cancer treatment. The aim of this review was to examine the potential contributions of oral microflora in the pathobiology of mucositis and identify pathways and interactions that could be targeted for therapeutic management of mucositis.