The 30th birthday of chronic ulcerative stomatitis: A systematic review.

OBJECTIVES: Chronic ulcerative stomatitis (CUS) is a chronic, ulcerative condition of the oral cavity, clinically and histologically similar to oral lichen planus (OLP), first described as a new disease entity in 1990 by Parodi et al. In this review, 30 years after our first description of CUS, we aimed to systematically review the literature of CUS cases reported ever since. METHODS: We present a systematic review of CUS literature cases, performed in compliance with the PRISMA statement. RESULTS: Of 125 retrieved articles, 20 satisfied inclusion criteria. These described 76 CUS cases, all presenting orally evident disease: erosions (55%), white lesions (49%), erythema (49%), ulcerations (34%) were the most frequent signs; 54% experienced discomfort/pain. Topographically, buccal mucosa (68%) and gingiva (54%) were the most affected locations, followed by tongue (42%), hard palate (27%), labial mucosa (22%), and widespread involvement (15%). Great diagnostic delay (6.3 years) was evidenced highlighting CUS is an entity too often misdiagnosed. Histopathology found lichenoid features (46%) and non-specific inflammation (54%). Extra-oral involvement was reported in 21%, especially as LP (69%). Of DIF, 97% were positive; 3% negative, compensated by positive IIF, permitting diagnosis. Of patients on steroids, only 12% reported therapeutic success; most steroid-non-responsive patients passed to antimalarials, with 91.66% success when used alone, 100% success in combination therapy. CONCLUSION: Dermatologists should suspect CUS in chronic steroid-unresponsive erosive/ulcerative stomatitis. In these cases, to diagnose CUS, the presence of stratified epithelium-specific antinuclear antibodies (SES-ANA) should be investigated through immunofluorescence. Once diagnosed, CUS can be treated with antimalarials, which are an effective treatment contrarily to corticosteroids.

A pilot study to evaluate the serum Alpha-1 acid glycoprotein response in cats suffering from feline chronic gingivostomatitis.

BACKGROUND: Feline chronic gingivostomatitis (FCGS) is a multifactorial immune-mediated disease that can lead to chronic pain, anorexia, and weight loss and has substantial health and welfare effects. Currently, the recommended treatment includes dental extractions to decrease the inflammatory stimulation associated with dental plaque. However, complete remission is observed in less than half of the cases, and the majority need comprehensive medical management. This study aimed to evaluate the serum levels of the acute phase protein alpha-1 acid glycoprotein (AGP) in cats with FCGS and to examine whether dental extractions contribute to a significant decrease in the systemic inflammatory response at two postoperative time points. RESULTS: AGP serum concentrations in the cats with FCGS were significantly higher at all time points than that in the control groups and were significantly correlated with the global caudal stomatitis score at day 0 but not at day 30 or 60. A significant improvement of some clinical scores, such as perceived comfort and global caudal stomatitis, was observed 60 days after the dental extraction. However, the levels of AGP did not significantly change over time. CONCLUSIONS: Cats with FCGS were more likely to have a systemic inflammatory response compared with age- and dental disease-matched controls. Dental extractions, in most cases, did not contribute to a significant decrease of AGP both at 30 and 60 days. Therefore, this study reinforces the need to pursue comprehensive medical management after dental extractions to attenuate the systemic inflammatory response as a result of this disease.

A Rat Model of Oral Mucositis Induced by Cancer Chemotherapy for Quantitative Experiments.

BACKGROUND/AIM: Oral mucositis, which occurs frequently in the treatment of cancer, is a major problem. In this study, we aimed to develop a rat model of oral mucositis induced by cancer chemotherapy for quantitative measurement. MATERIALS AND METHODS: A model animal of oral mucositis was prepared by injecting an acetic acid aqueous solution into the buccal mucosa of rats to which a 5-FU solution had been previously administered. The doses of 5-FU and acetic acid were examined, and a treatment experiment using Kenalog® was performed. RESULTS: The optimal dose of the 5-FU solution and the optimal concentration of the acetic acid aqueous solution were 40 mg/kg and 25%, respectively. Treatment with Kenalog® confirmed that this model mimics immunocompromised oral mucositis. CONCLUSION: Compared with a mouse model, oral mucositis can be easily observed in this model and provides a large amount of oral mucosal tissue.

Interleukin-10 and Interleukin-1ß Cytokines Expression in Leukocytes of Patients with Chronic Peri-Mucositis.

BACKGROUND The purpose of the present research is to analyze the effect of polyphenols and flavonoids substrat (PFS) from plants Calendula officinalis, Salvia fruticosa, Achillea millefolium, and propolis as immunomodulatory in the production of interleukin (IL)-1ß and IL-10 in peripheral blood leukocytes medium (PBLM) in patients who were diagnosed with mucositis of peri-implant tissue compared to patients with healthy implant tissue. It was hypothesized that IL-1ß and IL-10 contribute to the inflammation processes noticed in the diseases of peri-implant tissues. MATERIAL AND METHODS Sixty non-smoking patients were included in this study: patients with healthy implants (HP group) and patients with peri-implant mucositis (MP group). Peri-mucositis was diagnosed by radiologic and clinical examination. The PBLM from MP were treated with PFS at various concentrations. The levels of IL-10 and IL-1ß excreted by the PBLM stimulated and unstimulated with viable Porphyromonas gingivalis test-tube were committed by the enzyme amplified immunoassay sensitivity method. RESULTS Unstimulated and stimulated PBLM and treatment with 5.0 mg/mL or 10.0 mg/mL of PFS in the MP group produced significantly higher levels IL-10 (P<0.001) that analogous mediums of the HP group. The levels of IL-1ß decreased more considerably in the stimulated PBLM of the MP group than in those of HP group (P<0.001) after the treatment with PFS at only 10.0 mg/mL concentration. CONCLUSIONS Theses results suggest that the solution of PFS might offer a new potential for the development of a new therapeutic path to prevent and treat peri-implant mucositis.

A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL. METHODS: We assessed 25-hydroxyvitamin D (25(OH)D3) and 24,25-dihydroxyvitamin D (24,25(OH)2D3) levels in 99 children with ALL before the start of 4 × 5 g/m2 high-dose methotrexate (HD-MTX) (T0) and in 81/99 children after discontinuation of HD-MTX (T1). Two cutoff values for vitamin D deficiency exist: 25(OH)D3 levels < 30 and < 50 nmol/L. Oral mucositis was defined as grade ≥ 3 according to the National Cancer Institute Criteria. RESULTS: Vitamin D deficiency occurred in respectively 8% (< 30 nmol/L) and 33% (< 50 nmol/L) of the patients at T0, and more frequently in children > 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D3 levels during HD-MTX therapy was associated with developing severe oral mucositis (OR 1.6; 95% CI [1.1-2.4]). 25(OH)D3 and 24,25(OH)2D3 levels at T0 and the change in 24,25(OH)2D3 levels during therapy were not associated with the development of severe oral mucositis. CONCLUSIONS: This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D3 levels during MTX therapy was observed in children with ALL that developed severe oral mucositis.

RRM1 gene expression evaluated in the liquid biopsy (blood cfRNA) as a non-invasive, predictive factor for radiotherapy-induced oral mucositis and potential prognostic biomarker in head and neck cancer patients.

BACKGROUND: Intensified treatment of head and neck cancers (HNC): by radiotherapy (RTH) commonly combined with cytotoxic drugs is associated with oral mucositis (OM). Changes in the functioning of nucleotide synthesis pathway (RNR1, coded by RRM1 gene) can modulate the efficiency of cellular DNA repair mechanisms and influence the risk of occurrence and severity of OM in HNC patients after RTH. OBJECTIVE: The objective of this study was to evaluate the correlation between expression of RRM1 gene measured in free circulating RNA (cfRNA) and the risk of more severe OM and disease-free survival (DFS) and overall survival (OS) in patients undergoing RTH for HNC. METHODS: The study included 60 patients treated with RTH for HNC. RRM1 gene expression was examined in circulating RNA isolated from peripheral blood plasma (before treatment). RESULTS: High RRM1 gene expression was significantly associated with higher risk of grade 3 OM after 5 (OR = 4.97), 6 (OR = 4.33) and 7 (OR = 3.50) weeks of RTH. Expression of RRM1 gene was not significantly related with risk of DFS and OS shortening (however well separated Kaplan-Meier curves might suggest its potential prognostic impact). CONCLUSIONS: The evaluation of RRM1 gene expression in cfRNA allows for estimation of the risk of severe OM in patients subjected to RTH.

Plasma alpha-1-acid glycoprotein as a potential predictive biomarker for non-haematological adverse events of docetaxel in breast cancer patients.

CONTEXT: Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin. OBJECTIVE: To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians). MATERIALS AND METHODS: One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established. RESULTS: There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash. CONCLUSIONS: This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.

Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study.

PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

Determination of role of ceruloplasmin in oral potentially malignant disorders and oral malignancy-A cross-sectional study.

OBJECTIVES: In the process of carcinogenesis, lipid peroxidation and increased oxidative stress lead to changes in certain antioxidants. This study was aimed to assess and co-relate serum levels of ceruloplasmin in oral premalignancies and oral cancer so as to gauge its possible association with the process of carcinogenesis and to determine its role as tumor marker. MATERIAL AND METHODS: The study population comprised of 300 participants, equally divided into six study groups, that is, oral submucous fibrosis (OSMF), oral leukoplakia (OL), nicotina stomatitis (NS), oral malignancy (OM), controls (C), and healthy controls (HC); 5 ml of blood was collected from ante cubital vein from each participant. The serum was analyzed for ceruloplasmin levels using ERBA CHEM 5 PLUS semiautomated chemistry analyzer and diagnostic kit by turbidimetric immunoassay. RESULTS: There were total 242 males and 58 females, who were between 18 and 82 years of age, with a mean of 45.31 ± 13.97 years. The serum ceruloplasmin levels were significantly increased in OM, OSMF, OL, and NS groups as compared to C and HC groups (p < .001). No statistically significant difference was found in intragroup analysis of the disease groups (p > .05). CONCLUSION: Serum ceruloplasmin can be used as diagnostic marker for oral premalignant and malignant lesions.

Increased oral inflammation, leukocytes, and leptin, and lower adiponectin in overweight or obesity.

OBJECTIVES: The association between body mass index (BMI) and oral diseases was investigated, and levels of obesity-related inflammatory mediators were evaluated. SUBJECTS AND METHODS: Participants (n = 160) were clinically and radiographically examined for oral diseases. Blood profiles were recorded. Levels of adiponectin, leptin, and C-reactive protein (CRP) were measured. RESULTS: One hundred and thirteen (70.6%) participants had overweight or obese status (BMI ≥ 23.0 kg/m2 ). Sum of dental diseases and severe periodontitis were higher in overweight or obese individuals than in normal-weight participants (p = .037 and p = .002, respectively). A significant difference in oral mucosal disorders between normal weight and overweight or obesity was not found. Plasma leukocyte counts, liver enzymes, leptin, and CRP levels were increased while adiponectin levels were decreased in individuals with BMI≥23.0 kg/m2 compared with normal-weight participants. After adjusting for age, sex, fasting plasma glucose level, smoking, and exercise, obesity was associated with sum of dental diseases (ß = 0.239, p = .013), severe periodontitis (OR=4.52; 95% CI 1.37, 14.95, p = .013), adiponectin (ß = -0.359, p < .001), leptin (ß = 0.630, p < .001), and CRP levels (OR=12.66; 95% CI 3.07, 52.21, p < .001). CONCLUSION: Overweight or obese Thai people were related to an increase in inflammatory dental and periodontal diseases with an altered health profile and plasma inflammatory mediators.

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa.

BACKGROUND: Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. METHODS AND FINDINGS: Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5-6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. CONCLUSIONS: Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity.

Lights and shadows of dental implants: focus on mucositis and perimplantitis and their biological markers.

The increase in oral rehabilitation by means of dental implants has required an evolution of the related managing protocols and correct updating of the skills of dental professionals. Postsurgical management of the clinical case is aimed to stabilize the obtained results and preserve them from adverse conditions: a healthy implant prosthesis is maintained thanks to the huge number of consolidated protocols of oral hygiene. This practice plays a decisive role in the prevention of perimplant pathologies, forming a strong basis to ensure long implant life and avoid unnecessary and painful new surgical procedures. Furthermore, dental companies, in order to satisfy the new needs of professionals in oral hygiene, have produced new instrumentations and targeted drugs, in agreement to the cutting-edge scientific literature, thus creating a new market attracting huge interests in healthcare. The purpose of this topical review is to briefly comment on the state of the art of post-surgical dental implant management. This research is aimed to report the current protocols available to reduce the risk of oral diseases and prevent the progression of perimplant complications. Special focus has been dedicated to the most effective surgical and non-surgical protocols for treating mucositis and perimplantitis.

Ultrasensitive microfluidic array for serum pro-inflammatory cytokines and C-reactive protein to assess oral mucositis risk in cancer patients.

In addition to disease diagnostics, there is a need for biomarkers to predict severity of cancer therapy side effects such as oral mucositis. Oral mucositis is an inflammatory lesion of oral mucosa caused by high-dose chemotherapy and/or radiation that is especially prevalent during oral cancer treatment. We describe here a semi-automated, modular microfluidic immunoarray optimized for ultrasensitive detection of pro-inflammatory cytokines involved in pathobiology of oral mucositis. Our goal is to methodologically identify risk of mucositis early in oral cancer treatment, before the onset of lesions. Biomarkers include tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and C-reactive protein (CRP). Protein analytes were captured from serum in a capture chamber by 1-µm magnetic beads coated with antibodies and enzyme labels. Beads are then transported downstream to a detection chamber containing an eight-sensor array coated with glutathione-coated gold nanoparticles (GSH-AuNP) and a second set of antibodies to capture the beads with analyte proteins. In this first application of the immunoarray to four-protein multiplexed measurements, ultralow detection limits of 10-40 fg mL(-1) in 5 µL serum were achieved for simultaneous detection in 30 min. Mass detection limits were 2.5-10 zmol, as few as 1500 molecules. Accuracy and diagnostic utility of the arrays were demonstrated by correlation of levels of the four biomarker proteins in serum from head and neck cancer patients with results from standard ELISA. This approach may lead to rapid, low-cost estimates of projected risk for severity of oral mucositis in cancer patients to enable improved therapeutic management.

The relationship between oral mucositis and levels of pro-inflammatory cytokines in serum and in gingival crevicular fluid in allogeneic stem cell recipients.

PURPOSE: Oral mucositis (OM) is a severe side effect of conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). The aim of the present study was to investigate the relationship between oral mucositis and the levels of pro-inflammatory cytokines-both in serum and in gingival crevicular fluid (GCF), in relation to different conditioning regimens. METHODS: We analyzed the levels of pro-inflammatory cytokines IL-1ß, TNF-α, IL-6, and IL-7, as well as anti-inflammatory cytokine IL-10 in gingival crevicular fluid (GCF) and in serum from 43 HSCT patients. Twenty-five received reduced intensity conditioning (RIC) and 18 received myeloablative conditioning (MAC). Cytokine levels were determined in GCF and serum before the start of conditioning, and 1 week and 1 month after HSCT. All patients experienced OM with a median score of 2.1 and median peak on day 11. RESULTS: There was a significant correlation between OM and MAC (p = 0.035). There were no significant differences in GCF volume at the three time points examined. The levels of IL-6 in GCF increased 1 week after transplantation and then returned to baseline (p < 0.001). The levels of IL-10 in GCF decreased after HSCT (p < 0.001) and remained unchanged. The levels of IL-6 in serum significantly (p < 0.001) increased 1 week after HSCT and decreased to baseline levels after 1 month. The levels of IL-10 in serum significantly (p = 0.02) increased 1 month after HSCT. CONCLUSION: No correlations between cytokine levels in gingival crevicular fluid and oral mucositis were observed. There was a correlation between severity of OM score and increase in IL-6 in serum. No correlations between cytokine levels in gingival crevicular fluid and in serum were observed.

Oral status of patients submitted to autologous hematopoietic stem cell transplantation.

PURPOSE: Oral infection may be a source of bacteremia in patients undergoing hematopoietic stem cell transplant (HSCT). The aim of this study was to evaluate the relationship between patients with poor periodontal status and complications after HSCT. METHODS: A cohort of patients with hematological malignancies candidates for autologous HSCT was observed before and during the neutropenic phase of HSCT. A primary evaluation was performed before the HSCT procedure, including medical and socio-demographic data and physical examination (number of teeth and decayed, missing and filled teeth index (DMFT), oral mucosa, and full mouth periodontal assessment). During the neutropenic phase, data regarding the development of febrile neutropenia, bacteremia, and mucositis were also prospectively obtained. RESULTS: Forty-eight patients were included. The most common baseline disease was multiple myeloma (70 %). In the primary evaluations, the median DMFT was 13 (ranging 0-27), and periodontitis and gingivitis were present in 29 and 60 % of the patients, respectively. During the neutropenic phase of HSCT, fever occurred in 96 % of patients, and bacteremia was documented in 29 %. Coagulase-negative Staphylococcus was the most common isolated bacteria. Patients who developed bacteremia had a higher frequency of oral disorders compared with those without bacteremia, but it was not statistically significant. Oral mucositis affected 89.6 % of the patients, and patients with gingivitis or periodontal disorders had a high frequency of mucositis. CONCLUSIONS: The prevalence of oral pathologic conditions previous to HSCT procedures was very high in the studied population. A possible association was noted between previous gingivitis and the development of mucositis during the neutropenia of HSCT.

Efficacy of cyclosporine for chronic, refractory stomatitis in cats: A randomized, placebo-controlled, double-blinded clinical study.

Sixteen cats with chronic stomatitis, that had previously undergone premolar-molar or full-mouth extractions, were randomly assigned a group to receive 2.5 mg/kg cyclosporine or placebo orally twice daily Neither the clinician nor the clients were aware of the group assignments. Cats were evaluated prior to treatment and every 2 weeks for 6 weeks using a 30 point Stomatitis Disease Activity Index (SDAI) score. Mean improvement in SDAI scores among cats in the treatment group after 6 weeks was 52.7 %. This was significantty diffrent fom the mean improvement (12.2 %) of cats in the placebo group. During the 6 week study period, 7 of the 9 cats in the treatment group (77.8 %) showed a > 40 % improvement in SDAI score, while 1 of 7 cats in placebo group (14.3 %) showed a > 40 % improvement in SDAI score. This difference was statistically significant. Individual variability in the absorption of orally-administered cyclosporine was high. Trough whole-blood cyclosporine levels ranged firm 32.1 ng/ml to 1,576.2 ng/ml. At the end of the 6 week observation period, there was a statistically significant diference among cats with trough whole-blood cyclosporine levels >300 ng/ml (72.3 % improvement) compared with cats with cyclosporine levels < 300 ng/ml (28.2 % improvement). Whole-blood cyclosporine levels > 300 ng/ml were associated with significant improvement in oral inflammation in cats with chronic stomatitis that had previously undergone premolar-molar or fuill-mouth extraction.

Pretherapeutic plasma pro- and anti- inflammatory mediators are related to high risk of oral mucositis in pediatric patients with acute leukemia: a prospective cohort study.

OBJECTIVE: This prospective study evaluated clinical risk indicators as well as pro- and anti- inflammatory mediators at the time of malignancy diagnosis in relation to chemotherapy-related oral mucositis in pediatric population. METHODS: Patients (n = 104) under 18 years of age with primary malignancies and undergoing chemotherapy were included. Potential risk indicators were analyzed using binary logistic regression with oral mucositis as the outcome. In a subgroup (n = 35), plasma samples at the time of malignancy diagnosis were analyzed for inflammatory cytokines and an antimicrobial protein pro-LL-37 (hCAP18). RESULTS: In the multivariable model, type of malignancy diagnosis was significantly associated with oral mucositis, with highest risk of oral mucositis in patients with acute leukemia compared to those with lymphoma or solid tumors. At the time of malignancy diagnosis, plasma from patients with acute leukemia displayed higher concentrations (P<0.05) of IL-6, IL-8, IL-10, and TNF-α and lower levels of pro-LL-37 (P<0.001). CONCLUSIONS: The results imply that pretherapeutic high levels of inflammatory cytokines and low levels of pro-LL-37 in plasma might contribute to the high incidence of oral mucositis in patients with acute leukemia. These findings may add to our understanding of the predispositions to oral mucositis in children with malignancies.

The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial.

Oral mucositis (OM) is a complication of high-dose chemotherapy (HDC) followed by hematopoietic SCT (HSCT) with few effective treatments. Selenium has a cytoprotective role via the glutathione peroxidase (Glu.Px) enzyme and prevents chemotherapy-induced toxicities. We performed a double-blind, randomized, placebo-controlled study to evaluate the efficacy of selenium on the prevention of OM in 77 patients with leukemia, undergoing allogeneic HSCT. Thirty-seven patients received oral selenium tablets (200 mcg twice daily) from the starting day of HDC to 14 days after transplantation. OM was evaluated daily for 21 days after transplantation according to World Health Organization oral toxicity scale. The incidence of severe OM (grades 3-4) was significantly lower in the selenium group (10.8% vs 35.1%, P<0.05). We noted that the duration of objective OM (grades 2-4), excluding patient's self-declaration (grade 1), was significantly shorter in the selenium group (3.6±1.84 vs 5.3±2.2 days, P=0.014). Significant elevations in serum selenium level and plasma Glu.Px activity were observed 7 and 14 days after transplantation compared with baseline in the selenium group. We conclude that selenium can reduce the duration and severity of OM after HDC. Clinicaltrial.org ID: NCT01432873.

A phase I dose-escalation trial of high-dose melphalan with palifermin for cytoprotection followed by autologous stem cell transplantation for patients with multiple myeloma with normal renal function.

Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.