Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

The association and potentially destructive role of Th9/IL-9 is synergistic with Th17 cells by elevating MMP9 production in local lesions of oral lichen planus.

BACKGROUND: This study was to investigate association and potentially destructive role of Th9/IL-9 and their synergistic interaction with Th17 cells in elevating MMP9 production in local lesions of oral lichen planus (OLP) patients. METHODS: Oral mucosal tissues were obtained from OLP patients and healthy controls (HC) and then divided into an epithelial part (EP) or a lamina propria part (LP). Both EP and LP subsets were assessed for IL-9 and MMP9 mRNA levels by real-time quantitative PCR (qPCR). Flow cytometry was used to detect the CD4+ T helper subset Th9 (IL-9+ IL-17- CD4+ ) and Th17 (IL-9- IL-17+ CD4+ ) in co-cultured CD4+ Th cells and oral keratinocytes of OLP. IL-9, IL-17, and MMP9 in co-culture supernatant were detected by ELISA. RESULTS: The qPCR results demonstrated that IL-9 and MMP9 mRNA levels were positively correlated in OLP lesions, and both significantly elevated in EP and LP lesions of erosive type OLP. Th9 and Th17 cells were significantly elevated in co-cultures of CD4+ Th cells and keratinocytes, and MMP9, IL-9, and IL-17 levels were simultaneously increased. In vitro, recombinant human IL-17 treatment significantly enhanced MMP9 protein and mRNA levels, while a synergistic effect of IL-9 and IL-17 was not observed. However, further results showed Th17 cells, IL-17, and MMP9 were increased significantly when recombinant IL-9 was added to the cultured CD4+ T cells. CONCLUSION: This study demonstrated that Th9/IL-9 can induce elevated levels of MMP9 to aggravate OLP disease severity, which may occur directly through increasing Th17 levels or indirectly through a synergistic role with Th17.

Immunosuppression Induced by Chronic Inflammation and the Progression to Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is an aggressive, invasive malignancy of epithelial origin. The progression from premalignant lesions-oral leukoplakia (OLK) and oral lichen planus (OLP)-to OSCC involves complex inflammatory processes that have not been elucidated. We investigated the roles of inflammatory mediators and infiltrating immunocytes in the pathogenic progression of OLK and OLP to OSCC. The occurrence of regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs) and the expression of anti-inflammatory cytokines and proinflammatory cytokines were investigated in OLK, OLP, and OSCC tissues. Immunohistochemical staining of CD4, FOXP3, CD68, TGF-ß1, IL-10, IL-4, IFN-γ, and MCP-1 showed that the occurrence of Tregs and TAMs increased in parallel with disease progression in OLK and OSCC. IL-10 gradually increased during the early stages of OLK and in OSCC. Infiltrating IL-4+ macrophages were seen with increasing frequency in OLK tissue during the progression of oral dysplasia. Fewer TGF-ß1+ macrophages were seen in OSCC than in OLK and OLP. The expression of IFN-γ decreased gradually with the OLK development and had the lowest expression in OSCC. MCP-1 expression did not change significantly during the development of OSCC. The results suggested that the immunosuppression induced by chronic inflammation promotes tumorigenesis in OSCC, rather than initiating it.

Chemopreventive effect of modified zeng-sheng-ping on oral squamous cell carcinoma by regulating tumor associated macrophages through targeting tnf alpha induced protein 6.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck. Zeng-Sheng-Ping, composed of Sophora tonkinensis Gagnep., Bistorta officinalis Delarbre, Sonchus arvensis L., Prunella vulgaris L., Dioscorea bulbifera L., and Dictamnus dasycarpus Turcz., was regarded as an anti-cancer drug with significant clinical efficacy, but was discontinued due to liver toxicity. Our research group developed a modified Zeng-Sheng-Ping (ZSP-M) based on original Zeng-Sheng-Ping that exhibited high efficiency and low toxicity in preliminary investigations, although its pharmacodynamic mechanism is still unclear. Here, we aimed to elucidate the pharmacodynamic material basis of ZSP-M and investigate its chemopreventive effect on OSCC by modulating tumor associated macrophages (TAMs). METHODS: Components of ZSP-M were characterized using ultra-performance liquid chromatography-mass spectrometry. Chemopreventive effect induced by ZSP-M against experimental oral cancer was investigated using the 4-nitroquinoline N-oxide precancerous lesion mouse model. RNA sequencing analysis was used to gain a global transcriptional view of the effect of ZSP-M treatment. A cell co-culture model was used to study the targeted effect of ZSP-M on TAMs and the biological properties of OSCC cells and to detect changes in TAM phenotypes. The binding of ZSP-M active compounds to TNF alpha induced protein 6 (TNFAIP6) protein was analyzed by molecular docking and dynamic simulation. RESULTS: Forty main components of ZSP-M were identified, the most abundant of which were flavonoids. ZSP-M inhibited the degree of epithelial dysplasia in precancerous lesions by inhibiting the expression of the TNFAIP6 and CD163 proteins in the precancerous lesions of the tongue. ZSP-M inhibited proliferation, colony formation, migration and invasion of SCC7 cells by targeting TAMs. ZSP-M reduced the expression of CD163+ cells, inhibited the expression of TNFAIP6 protein, Arg1 mRNA and Il10 mRNA in TAMs, and reduced IL-10 cytokine release in the co-culture environment. This effect was maintained after the addition of recombinant TNFAIP6 protein. Computer simulations showed that trifolirhizin and maackiain are well-connected to TNFAIP6. CONCLUSIONS: ZSP-M counteracts the immunosuppressive action of TAMs by specific targeting of TNFAIP6, thereby exerting chemopreventive activity of OSCC.

Repurposing of yunnan baiyao as an alternative therapy for minor recurrent aphthous stomatitis.

The study was designed to evaluate the efficacy and safety of an herbal extract of Yunnan Baiyao formulated in toothpaste as an alternative therapy for minor RAS. A randomized, double-blind, placebo-controlled clinical trial (from March 2010 to March 2011) was conducted on a cohort of 227 minor RAS patients. The toothpaste containing Yunnan Baiyao was used twice daily as part of the patient's routine oral hygiene for 5 days. An assessment of ulcerative size and pain was recorded on day 0 (baseline), day 3, and day 5. Any noted adverse reactions were recorded. All data were analyzed using the SAS software 8.0. As a result, the toothpaste containing Yunnan Baiyao began to present noticeable effectiveness on ulcer healing (ulcer size) by day 3 (27.5% versus 15.8%, P < 0.05), which further improved by day 5 when compared to the placebo (66.4% versus 50.0%, P = 0.01). A significant difference in alleviating pain was noted on day 5 for those who used the toothpaste containing Yunnan Baiyao (66.4% versus 51.8%, P < 0.05). No side effects were noted as a result of the Yunnan Baiyao. Therefore, Yunnan Baiyao may provide an alternative therapy for minor ulcers by promoting healing.

NMR-based metabolomic approach to understanding Zeng-Sheng-Ping-induced hepatotoxicity, and identifying possible toxic constituents by LC-MS profiles.

Zeng-Sheng-Ping (ZSP) tablets, made from six Chinese herbs, are widely used in the chemoprevention and treatment of precancerous lesions in patients with gastrointestinal cancer. However, sporadic cases of liver injury have occurred. Herein, the serum metabolites in hamsters with ZSP-induced liver damage were analyzed by NMR-based metabolomics. Twelve metabolites associated with ZSP-induced hepatoxicity were identified. Amino acid metabolism and the urea cycle were significantly altered, and three associated amino acid metabolic enzymes (PAH, GS, and GLS) were further validated by ELISA. Therefore, 12 metabolites and 3 amino acid metabolic enzymes were proposed as potential biomarkers in ZSP-induced liver injury. The chemical constituents of ZSP tablets were profiled using liquid chromatography-mass spectrometry. The furanoids in two herbs, Dioscorea bulbifera L. and Dictamnus dasycarpus Turcz., were proposed to be the major hepatotoxic constituents in ZSP, leading to an improved preparation method with low hepatotoxicity for ZSP.

Difficult and complicated oral ulceration: an expert consensus guideline for diagnosis.

The complexity of oral ulcerations poses considerable diagnostic and therapeutic challenges to oral specialists. The expert consensus was conducted to summarize the diagnostic work-up for difficult and complicated oral ulcers, based on factors such as detailed clinical medical history inquiry, histopathological examination, and ulceration-related systemic diseases screening. Not only it can provide a standardized procedure of oral ulceration, but also it can improve the diagnostic efficiency, in order to avoid misdiagnosis and missed diagnosis.

Chemopreventive effect of modified zengshengping on oral cancer in a hamster model and assessment of its effect on liver.

Ethnopharmacological relevance Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors, seriously compromising patients' quality of life. Previous studies showed that Zengshengping (ZSP), a popular traditional Chinese medicine, has certain inhibiting effects on both oral precancerous lesions and OSCC. However, few reports underlined ZSP side effects such as liver toxicity, which limit its long-term application. Aim of the study was to evaluate the chemopreventive effect of a modified ZSPs formula on oral cancer in a hamster model. Its effect on hamster liver was also assessed. Materials and Methods The original medicine (ZSP-1) and other two formulas slightly different and called ZSP-2 and ZSP-3 were prepared ahead of time. DMBA (0.5%) was topically applied for 6 weeks to induce a premalignant lesion on hamsters' cheek pouch, then ZSP-1/2/3 were intragastrically administered for 8 weeks. Hamster treated with DMBA + each of the ZSPs represented the ZSP-1/2/3 groups, while those without ZSP-1/2/3 treatment represented the DMBA group. To assess the effect of ZSPs in the liver, intragastric administration of ZSP-1/2/3 was carried out to other groups of hamsters for 12 weeks and the blood was collected every two weeks to detect the hepatic function. Some of the hamsters were sacrificed at the end of 12 weeks, while the remaining animals were sacrificed after other 4 weeks to estimate the effect of ZSP-1/2/3 withdrawal on the liver. Results showed that tumor development in the ZSP-1/2/3 groups was less than that in DMBA group. BrdU, CD31 and COX-2 expression in the hyperplastic tissues was significantly lower in the ZSP-1/2/3 groups than that in the DMBA group. In addition, VEGF and COX-2 expression in ZSP-1/2/3 groups was lower while caspase-9 and p53 expression was higher than those in the DMBA group. Finally, PTEN expression in ZSP-1/2/3 groups was higher than that in the DMBA group. As regard the effect in the liver, ALP in the ZSP-1/2/3 groups was higher than that in the control group treated with an intragastric administration of ddH2O. After 4 weeks of withdrawal, the hamsters of the ZSP-3 group did not recover from the increase in ALP. Histopathology showed the presence of inflammatory lesions in each group after 12 weeks, especially in the ZSP-1/3 groups, and the number of apoptotic cells in the ZSP-3 group was higher than that in the other groups, without any recovery after withdrawal of the drug. At 12 weeks, the MDA in the ZSP-1 group was higher than that in the control group and the ZSP-2 group, but the difference disappeared after drug withdrawal because the MDA in the ZSP-1/3 groups decreased. Conclusions ZSP-2 possessed a chemopreventive effect against oral cancer by inhibiting inflammation, proliferation of tumor cells, generation of microvessels and by promoting tumor cell apoptosis. In addition, hepatotoxicity of ZSP-2, which might be related to oxidative stress injury, was reduced to some extent.

[Diagnostic accuracy of MALDI-TOF mass spectrum in identification of oral Candidiasis isolates].

PURPOSE: To investigate the diagnostic accuracy of matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in the identification of clinical oral Candida isolates. METHODS: In the first experiment, 170 suspected oral candidiasis patients were included. Unstimulated saliva was collected and cultured on solid plate (Sabouraud's agar) for 48 hours. Clinical isolates were analyzed by both PCR, which was used as golden standard, and MALDI-TOF MS. The diagnostic accuracy of MALDI-TOF MS for both C.albicans and non-C.albicans were investigated. In the second experiment, we tried to identify Candida isolates directly from positive liquid culture in a new cohort of 42 patients. MALDI-TOF MS identification of candida isolates were performed on positive liquid medium cultures directly. The data were analyzed using SPSS 18.0 software package. RESULTS: Totally, 230 clinical Candida isolates were isolated from 212 oral candidiasis patients enrolled. Out of the 230 analyzed clinical isolates, C. albicans (65.65%, 151/230) was the most frequently isolated species, followed by C. glabrata (11.74%, 27/230), and other candida species. The sensitivity and specificity of MALDI-TOF in identification of C. albicans were 93.33% and 92.73% respectively, and those for non-C. albicans were 83.64% and 89.2% respectively. Oral rinse followed by culturing in Sabouraud's liquid medium for 24 hours yield the diagnostic accuracy of 78.42% in MALDI-TOF MS identification. CONCLUSIONS: C. albicans is the most frequent Candida spp. in oral candidiasis. MALDI-TOF MS is an effective and rapid method for identification of Candida spp. The on-plate based method generate much higher diagnostic accuracy than liquid culture based one.

Delivery of mesenchymal stem cells-derived extracellular vesicles with enriched miR-185 inhibits progression of OPMD.

Oral leukoplakia is one of the most common oral potentially malignant disorders (OPMDs) and its malignant transformation to oral cancer is highly associated with chronic inflammation. Extracellular vesicles (EVs) or exosome-delivered microRNAs modulate inflammatory responses and alleviate irritations that predisposes to cancer. We previously reported that microRNA-185 (miR-185) was significantly decreased in the buccal tissue of patients with oral cancer. In this study, we utilized genetically modified mesenchymal stem cells (MSCs) derived EVs with high expression of miR-185 to pasted MSC-EV-miR-185 on buccal lesions in dimethylbenzanthracene (DMBA) induced OPMD model. We found that treatment with MSC-EV-miR-185 remarkably attenuated inflammation severity and significantly decreased the incidence and the number of dysplasia in the OPMD tissue. Immunohistochemistry showed significantly decreased expression of proliferation marker PCNA and angiogenic marker CD31 in the lesion treated with MSC-EV-miR-185. Furthermore, miR-185 specifically targeted Akt genes by promoting activation of the apoptotic pathway, confirmed by the increased levels of activated caspase-3 and 9. In conclusion, genetically modified MSC-derived EVs enriched with miR-185 alleviate inflammatory response, inhibit cell proliferation and angiogenesis, and induce cell apoptosis, suggesting that their potential role as a novel therapeutic option for OPMD.

IL-25 promotes Th2-type reactions and correlates with disease severity in the pathogenesis of oral lichen planus.

OBJECTIVE: The aim of the present study was to investigate the correlation between IL-25 expression and disease severity, and the potential immunoregulatory role of IL-25 expression in oral lichen planus (OLP). MATERIALS AND METHODS: The oral mucosal tissue samples obtained from OLP patients and healthy controls (HCs) were analyzed for IL-25 expression by real-time quantitative PCR (qPCR) and immunohistochemistry. Recombinant IL-25 was used to stimulate OLP patient-derived CD4 + T cells, and then IL-4 secretion and mRNA expression were evaluated by ELISA and qPCR, respectively. The efficiency of the siRNA-mediated knockdown of IL-25R expression in oral keratinocytes was determined by qPCR and Western blotting. Human oral keratinocyte cells were cultured with the recombinant human cytokines IL-25, IL-17 A and IL-17 F. The production of associated cytokines by keratinocytes was determined by qPCR. Statistical analyses of quantitative data were performed using SPSS software. RESULTS: The IL-25 and IL-4 mRNA levels were elevated and correlated significantly with each other in specific OLP subtype lesions compared to HCs, while the numbers of IL-25 positive cells were also increased in local OLP lesions as compared to HCs. In vitro culture with recombinant IL-25 could significantly promote CD4 + T cells from both subtypes of OLP to produce IL-4 mRNA and remarkably elevate supernatant IL-4 levels in reticular OLP CD4 + T cell cultures, which may be attributed to the elevated expression of IL-25R in local OLP lesions. Statistical analyses demonstrated that the simultaneously increased levels of IL-4, CXCL8 and CCL20 in keratinocytes were induced by IL-25 but not IL-17 A or IL-17 F. Decreasing IL-25R subunit expression by siRNA-mediated knockdown significantly blocked the expression of all cytokine-produced inflammatory mediators in oral keratinocytes. CONCLUSIONS: In OLP lesions, IL-25 can function to mediate the Th2 response in specific disease subtypes, which may be an important cause of OLP disease chronicity and persistent inflammation.

Quantitative prediction of oral cancer risk in patients with oral leukoplakia.

Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma. We have developed an oral cancer risk index using DNA index value to quantitatively assess cancer risk in patients with oral leukoplakia, but with limited success. In order to improve the performance of the risk index, we collected exfoliative cytology, histopathology, and clinical follow-up data from two independent cohorts of normal, leukoplakia and cancer subjects (training set and validation set). Peaks were defined on the basis of first derivatives with positives, and modern machine learning techniques were utilized to build statistical prediction models on the reconstructed data. Random forest was found to be the best model with high sensitivity (100%) and specificity (99.2%). Using the Peaks-Random Forest model, we constructed an index (OCRI2) as a quantitative measurement of cancer risk. Among 11 leukoplakia patients with an OCRI2 over 0.5, 4 (36.4%) developed cancer during follow-up (23 ± 20 months), whereas 3 (5.3%) of 57 leukoplakia patients with an OCRI2 less than 0.5 developed cancer (32 ± 31 months). OCRI2 is better than other methods in predicting oral squamous cell carcinoma during follow-up. In conclusion, we have developed an exfoliative cytology-based method for quantitative prediction of cancer risk in patients with oral leukoplakia.

The Efficacy and Safety of Miconazole Nitrate Mucoadhesive Tablets versus Itraconazole Capsules in the Treatment of Oral Candidiasis: An Open-Label, Randomized, Multicenter Trial.

BACKGROUND: Oral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment. METHODS: The study was a randomized, open-label, parallel-armed, multicenter clinical trial. Totally, 343 patients diagnosed with OC, who met the inclusion criteria, were randomly assigned to either a treatment group that received miconazole nitrate mucoadhesive tablets (10 mg) once daily or a control group that received itraconazole capsules (100 mg QD) for 2 weeks, and were followed up for 2 weeks. The clinical cure, improvement of clinical symptoms/signs, mycologic cure, and safety were evaluated. RESULTS: The mucoadhesive tablets (n = 171) did not show inferiority to itraconazole (n = 172) in the treatment of OC. At the end of the 14-day treatment, the clinical cure rates were 45.29% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.3472). At the end of the 14-day follow-up, the clinical cure rates were 51.18% and 41.76% in the miconazole and itraconazole groups, respectively (P = 0.0329). Adverse events occurred in 53 subjects (33 in the miconazole group and 20 in the itraconazole group). There was no statistical difference in the safety profile between miconazole and itraconazole (P = 0.0533). Thrombocytopenic purpura, although rare, occurred in one patient in the miconazole group and was considered a drug-related, severe adverse event. CONCLUSION: Miconazole nitrate mucoadhesive tablets may be as effective as systemic itraconazole capsule for OC treatment. Physicians should be cautious about thrombocytopenic purpura occurring as a rare and serious adverse event of miconazole nitrate. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-TRC-13003935.

Necrotizing gingivostomatitis and osteonecrosis associated with antithyroid drug propylthiouracil therapy.

A 43-year-old Chinese female had been diagnosed with hyperthyroidism 15 years ago. She was recently administered 150 mg/day propylthiouracil (PTU). After 3 weeks of PTU administration, she developed necrotizing stomatitis and osteonecrosis, most likely due to secondary effects from the PTU treatment. Her neutrophil count was reduced below normal to 0.24×10(9)/L but normalized after withdrawal of PTU therapy. About 1 month after onset, the patient came to our hospital and began to receive intravenous treatments of metronidazole and amoxicillin. Following review of her medical history and a series of clinical and laboratory examinations, the patient was diagnosed with secondary necrotizing gingivostomatitis and osteonecrosis possibly associated with PTU-induced agranulocytosis. One-year after treatment, the patient's oral manifestations remained unchanged. This case demonstrates the need for dental practitioners to more closely monitor oral symptoms in patients with hyperthyroidism treated with antithyroid drugs.

Inhibitory effects of Zengshengping fractions on DMBA-induced buccal pouch carcinogenesis in hamsters.

BACKGROUND: Zengshengping (ZSP) tablets had inhibitory effects on oral precancerous lesions by reducing the incidence of oral cancer. However, the severe liver toxicity caused by systemic administration of ZSP limits the long-term use of this anti-cancer drug. The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of extracts from ZSP, a Chinese herbal drug, on 7, 12-dimethlbenz(a)anthracene (DMBA) induced oral tumors in hamsters. The study also investigated the anti-cancer mechanisms of the ZSP extracts on oral carcinogenesis. METHODS: DMBA (0.5%) was applied topically to the buccal pouches of Syrian golden hamsters (6 - 8 weeks old) three times per week for six weeks in order to induce the development of oral tumors. Different fractions of ZSP were either applied topically to the oral tumor lesions or fed orally at varying dosages to animals with oral tumors for 18 weeks. Tumor volume was measured by histopathological examination. Tumor cell proliferation was evaluated by counting BrdU labeled cells and by Western blotting for mitogen-activated protein kinase (MAPK) protein levels. The protein levels of apoptosis marker Caspase-3 and regulator Bcl-2 protein were also measured by Western blotting. RESULTS: Topical application of DMBA to the left pouch of hamsters induced oral tumor formation. Animals treated with DMBA showed a loss in body weight while animals treated with ZSP maintained normal body weights. Both the ZSP n-butanol fraction and water fraction significantly reduced tumor volume by 32.6% (P < 0.01) and 22.9% (P < 0.01) respectively. Topical application of ZSP also markedly decreased the BrdU-positive cell numbers in oral tumor lesions and reduced the expression level of MAPK. In addition, ZSP promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production. CONCLUSION: The n-butanol and water fractions of ZSP are effective at inhibiting tumor cell proliferation and stimulating apoptosis in oral cancer suggesting that these fractions have chemopreventive effects on DMBA induced oral carcinogenesis.

Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs.

ZengShengPing (ZSP), a mixture of six medicinal herbs, has been reported to prevent esophageal squamous cell carcinoma (SCC) in human patients with dysplasia. This study was designed to investigate the chemopreventive effects of ZSP on oral cancer in animal models and human patients. In the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model, ZSP (6g/kgBW/day by gavage for 10 weeks) significantly reduced the number of visible tumor, the tumor volume, and the incidence of SCC (P<0.01). Two biomarkers associated with cell proliferation, silver stained nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)-labeling index, were also significantly suppressed by ZSP treatment (P<0.01). In the 4-nitroquinoline 1-oxide (4NQO)-induced oro-esophageal cancer model in mice, ZSP (10% in diet) also significantly reduced the incidence of tongue SCC from 55.2% (16/29) to 22.2% (6/27) (P<0.05), and slightly reduced the incidence of esophageal SCC from 34.5% (10/29) to 22.2% (6/27). Furthermore, in a randomized clinical trial on patients with oral leukoplakia, ZSP (4 tablets, 3 times per day for 8-12months) reduced the size of oral lesion in 67.8% (40/59) patients, whereas the placebo was effective in 17% (9/53) patients (P<0.01). Such an effect was associated with significant decrease of AgNOR and PCNA-labeling index. In summary, our studies have demonstrated the chemopreventive effects of ZSP on two animal models of oral cancer, and human patients with oral leukoplakia.

[Analysis of risk factors for carcinogenesis of oral leukoplakia].

OBJECTIVE: To investigate the risk factors for malignant transformation of oral leukoplakia. METHODS: A total of 409 cases with oral leukoplakia was retrospectively analyzed. Single factor test was first performed to examine the associations between oral leukoplakia's histopathological classification and each of risk factors including sex, age, systemic diseases, course of disease, clinical classification, site, size, numbers of lesion, alcohol and tobacco consumption, and symptom. Then the association of these selected factors with oral leukoplakia's histopathological classification was evaluated using multiple logistic regression analysis. RESULTS: Fifty-two cases of all 409 patients with oral leukoplakia (including 9 severe dysplasia) developed oral cancer. The ratio of malignant transformation was 12.7%. Sex, age, clinical type, site and symptom were chosen as risk factors incorporated into the multiple logistic regression models. The risk of mild-moderate dysplasia in female was 2.40 times as high as that in male. The risk of mild-moderate dysplasia of speckled leukoplakia was 2.81 times as high as that of homogeneous leukoplakia. The risk of mild-moderate dysplasia of dangerous site was 1. 98 times as high as that non-dangerous site. The risk of mild-moderate dysplasia with symptom was 1.84 times as high as that without symptom. The risk of severe dysplasia and oral cancer in female was 3.11 times as high as that in male. The risk of severe dysplasia and oral cancer of speckled (4.50 times), ulcerative (5.63 times), verrucous leukoplakia (4.09 times) were much higher than that of homogeneous leukoplakia. The risk of severe dysplasia and oral cancer in dangerous site was 2.79 times as high as in non-dangerous site. The risk of severe dysplasia and oral cancer in leukoplakia with symptom was 4.38 times as high as without symptom. CONCLUSIONS: The malignant transformation of oral leukoplakia is correlated to sex, clinical type, site and symptom.