Two by Two Factorial Design using Metformin and Curcumin for Second Primary Head and Neck Cancer Prevention Trial.

OBJECTIVE: The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors. METHODS: We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial. CONCLUSION: 2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly.

Can a cup a day keep cancer away? A systematic review exploring the potential of coffee constituents in preventing oral squamous cell carcinoma.

BACKGROUND: Coffee is one of the most consumed beverages in the world. Containing an abundance of bioactive molecules including polyphenols and flavonoids, the constituents of this beverage may exert antiproliferative, antioxidant and anti-inflammatory effects. METHODS: We conducted a systematic review to summarise the available evidence on the anticancer effects of coffee constituents and their potential therapeutic use for oral squamous cell carcinoma (OSCC). Studies were identified through a comprehensive search of OVID MEDLINE, OVID EMBASE and Web of Science, including articles from any year up to 15 May 2023. RESULTS: Of the 60 reviewed papers, 45 were in vitro, 1 was in silico and 8 were in vivo exclusively. The remaining studies combined elements of more than one study type. A total of 55 studies demonstrated anti-proliferative effects, whilst 12 studies also investigated migration and invasion of neoplastic cells. The constituents studied most frequently were quercetin and epigallocatechin gallate (EGCG), demonstrating various cytotoxic effects whilst also influencing apoptotic mechanisms in cancer cell lines. Dose-dependent responses were consistently found amongst the studied constituents. CONCLUSION: Whilst there was heterogeneity of study models and methods, consistent use of specific models such as SCC25 for in vitro studies and golden hamsters for in vivo studies enabled relative comparability. The constituents of coffee have gained significant interest over the last 30 years, particularly in the last decade, and present an area of interest with significant public health implications. Currently, there is a paucity of literature on utilization of active coffee constituents for the therapeutic treatment of oral cancers.

Inducible TgfbR1 and Pten deletion in a model of tongue carcinogenesis and chemoprevention.

Head and neck squamous cell carcinoma (HNSCC) is a significant public health problem, with a need for novel approaches to chemoprevention and treatment. Preclinical models that recapitulate molecular alterations that occur in clinical HNSCC patients are needed to better understand molecular and immune mechanisms of HNSCC carcinogenesis, chemoprevention, and efficacy of treatment. We optimized a mouse model of tongue carcinogenesis with discrete quantifiable tumors via conditional deletion of Tgfßr1 and Pten by intralingual injection of tamoxifen. We characterized the localized immune tumor microenvironment, metastasis, systemic immune responses, associated with tongue tumor development. We further determined the efficacy of tongue cancer chemoprevention using dietary administration of black raspberries (BRB). Three Intralingual injections of 500 µg tamoxifen to transgenic K14 Cre, floxed Tgfbr1, Pten (2cKO) knockout mice resulted in tongue tumors with histological and molecular profiles, and lymph node metastasis similar to clinical HNSCC tumors. Bcl2, Bcl-xl, Egfr, Ki-67, and Mmp9, were significantly upregulated in tongue tumors compared to surrounding epithelial tissue. CD4+ and CD8 + T cells in tumor-draining lymph nodes and tumors displayed increased surface CTLA-4 expression, suggestive of impaired T-cell activation and enhanced regulatory T-cell activity. BRB administration resulted in reduced tumor growth, enhanced T-cell infiltration to the tongue tumor microenvironment and robust antitumoral CD8+ cytotoxic T-cell activity characterized by greater granzyme B and perforin expression. Our results demonstrate that intralingual injection of tamoxifen in Tgfßr1/Pten 2cKO mice results in discrete quantifiable tumors suitable for chemoprevention and therapy of experimental HNSCC.

How to prevent human papillomavirus-related oropharyngeal cancer?

PURPOSE OF REVIEW: Human papillomavirus (HPV) is responsible of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in high-income countries. This significant epidemiological change requires several and diverse prevention strategies. RECENT FINDINGS: The cervical cancer prevention model is the paradigm of HPV-related cancer, and its success provides encouragement for the development of similar methods to prevent HPV-related OPSCC. However, there are some limitations that hinder its application in this disease. Here, we review the primary, secondary and tertiary prevention of HPV-related OPSCC and discuss some directions for future research. SUMMARY: The development of new and targeted strategies to prevent HPV-related OPSCC is needed since they could definitely have a direct impact on the reduction of morbidity and mortality of this disease.

Modulation of the oral glucocorticoid system during black raspberry mediated oral cancer chemoprevention.

Recent reports suggest that glucocorticoids (GCs), which can be synthesized in the oral mucosa, play an important role in cancer development. Therefore, the objectives of this study were to characterize the role of the oral GC system in oral cancer, and determine the effect of black raspberry (BRB) administration on GC modulation during oral cancer chemoprevention. We determined the expression of GC enzymes in various oral cancer cell lines, and investigated the role of the GC inactivating enzyme HSD11B2 on CAL27 oral cancer cells using siRNA mediated knockdown approaches. Using two in vivo models of oral carcinogenesis with 4-nitroquinoline 1-oxide carcinogen on C57Bl/6 mice and F344 rats, we determined the effect of BRB on GC modulation during head and neck squamous cell carcinoma chemoprevention. Our results demonstrate that HSD11B2, which inactivates cortisol to cortisone, is downregulated during oral carcinogenesis in clinical and experimental models. Knockdown of HSD11B2 in oral cancer cells promotes cellular proliferation, invasion and expression of angiogenic biomarkers EGFR and VEGFA. An ethanol extract of BRB increased HSD11B2 expression on oral cancer cells. Dietary administration of 5% BRB increased Hsd11b2 gene and protein expression and reduced the active GC, corticosterone, in cancer-induced mouse tongues. Our results demonstrate that the oral GC system is modulated during oral carcinogenesis, and BRB administration upregulates Hsd11b2 during oral cancer chemoprevention. In conclusion, our findings challenge the use of synthetic GCs in head and neck cancer, and support the use of natural product alternatives that potentially modulate GC metabolism in a manner that supports oral cancer chemoprevention.

Carcinoma epidermoide intraoral y factores de riesgo asociados: un estudio de casos y controles / Oral squamous cell carcinoma and associated risk factors: A case-control study

Introducción: El carcinoma epidermoide es la neoplasia maligna más frecuente de la cabeza y el cuello, por lo que un conocimiento adecuado sobre sus factores de riesgo podría disminuir su morbimortalidad. Objetivo: Identificar la asociación causal entre algunos factores de riesgo y la aparición del carcinoma epidermoide de la cavidad bucal. Métodos: Estudio observacional, analítico, de casos y controles en pacientes tratados en el servicio de cirugía maxilofacial del Hospital General Provincial Carlos Manuel de Céspedes entre el 1 de enero de 2018 y el 31 de diciembre de 2020. Para el análisis estadístico de los factores de riesgo se midió la fuerza de la asociación con el odds ratio y sus intervalos de confianza (IC 95 por ciento) y luego se realizó un análisis multivariado. Resultados: Se trabajó con 87 pacientes (29 casos y 58 controles). El 68,96 % (n = 20) de los casos fueron pacientes masculinos y su promedio de edad fue de 63,03 años. Las personas con antecedentes de consumo de alcohol tuvieron un riesgo 16 veces mayor de padecer la enfermedad (OR: 16,03). La higiene bucal deficiente (OR: 5,23; IC 95 por ciento: 1,18-23,29; p = 0,030) y la exposición a irritantes traumáticos (OR: 4,41; IC 95 por ciento: 1,01-19,23; p = 0,048) fueron también factores de riesgo. Conclusión: Existe una fuerte asociación entre la presencia de la enfermedad y el antecedente de consumo de alcohol, la exposición a irritantes traumáticos y la higiene bucal deficiente(AU)

Introduction: Squamous cell carcinoma is the most frequent neoplasm of the head and neck. An adequate knowledge about its risk factors could reduce its morbidity and mortality. Objective: To identify the causal association between some risk factors and the apparition of the oral squamous cell carcinoma. Methods: Observational, analytic and case-control study conducted with patients treated at Carlos Manuel de Céspedes Provincial General Hospital's maxillofacial surgery service between January 1, 2018 and December 31, 2020. For the statistical analysis of the risk factors, the strength of the association with the Odds Ratio and its confidence intervals (95 percent CI) was measured and later a multivariate analysis was performed. Results: The sample was comprised of 87 patients (29 cases and 58 controls). The 68.96 percent of the cases (n=20) were male patients and their average age was 63.03 years. People with history of alcohol consumption showed a 16 times greater risk (OR=16.03). Poor oral hygiene (OR: 5.23; CI 95 percent: 1.18-23.29; p=0.030) and traumatic irritants (OR: 4.41; CI 95 percent: 1.01-19.23; p=0.048) were risk factors too. Conclusion: A strong association between the disease and the antecedent of alcohol consumption, the exposition to traumatic irritating and the poor oral hygiene was identified(AU)

HPV-Induced Oropharyngeal Squamous Cell Carcinomas in Brazil: Prevalence, Trend, Clinical, and Epidemiologic Characterization.

BACKGROUND: Tobacco or human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent different clinical and epidemiologic entities. This study investigated the prevalence of HPV-positive and HPV-negative OPSCC in a reference cancer hospital in Brazil and its association with clinical and demographic data, as well as its impact on overall survival. METHODS: HPV infection was determined by p16-IHC in pre-treatment formalin-fixed paraffin-embedded samples from all patients with OPSCC diagnosed at Barretos Cancer Hospital between 2008 and 2018. The prevalence of HPV-positive cases and its temporal trend was assessed, and the association of clinical and demographic data with HPV infection and the impact on patient overall survival was evaluated. RESULTS: A total of 797 patients with OPSCC were included in the study. The prevalence of HPV-associated tumors in the period was 20.6% [95% confidence interval, 17.5-24.0] with a significant trend for increase of HPV-positive cases over the years (annual percentage change = 12.87). In a multivariate analysis, the variables gender, level of education, smoking, tumor sublocation, region of Brazil, and tumor staging had a significant impact in HPV positivity, and a greater overall survival (OS) was observed in HPV-positive patients (5-year OS: 47.9% vs. 22.0%; P = 0.0001). CONCLUSIONS: This study represents the largest cohort of Brazilian patients with OPSCC characterized according to HPV status. We report significant differences in demographics and clinical presentation according to HPV status, and an increasing trend in prevalence for HPV-induced tumors. IMPACT: These findings can potentially contribute to a better stratification and management of patients as well as assist in prevention strategies.

Precision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention.

OPINION STATEMENT: To date, there is no FDA-approved chemoprevention approach for tobacco-related HNSCC. Effective chemoprevention approaches validated in sufficiently powered randomized trials are needed to reduce the incidence and improve survival. In this review, we recap the challenges encountered in past chemoprevention trials and discuss emerging approaches, with major focus on green chemoprevention, precision prevention, and immunoprevention. As our current depth of knowledge expands in the arena of cancer immunotherapy, the field of immunoprevention is primed for new discoveries and successes in cancer prevention.

Local Anti-PD-1 Delivery Prevents Progression of Premalignant Lesions in a 4NQO-Oral Carcinogenesis Mouse Model.

Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti-PD-1 antibodies to prevent malignant progression of OPLs. PREVENTION RELEVANCE: Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.

Tacrolimus inhibits oral carcinogenesis through cell cycle control.

Tacrolimus (TAC, FK506) is a major calcineurin inhibitor and has been commonly used in treatments of patients with organ transplants and immune diseases. Moreover, tacrolimus is recommended by the treatment guidelines for oral potentially malignant disorders (OPMDs) such as oral lichen planus (OLP). However, whether tacrolimus increases the risk of cancer remains controversial. We observed that in a 4-Nitroquinoline N-oxide (4NQO)-induced oral carcinogenesis model, tacrolimus treatment was associated with a significantly lower ratio of cancer formation (52.94% vs. 90%) and a lower proportion of Ki67 and proliferation cell nuclear antigen (PCNA) -positive cells in lesion areas (P < 0.001). Liver, kidney, and lung functions of rats and the tumor immune microenvironment of the tongue were not affected. These observations suggest that tacrolimus blocked oral carcinogenesis through epithelial cell proliferation inhibition, independent of its immunosuppressive effects. As a processing factor, tacrolimus decreased tumor formation and cell proliferation in different stages of oral squamous cell carcinoma (OSCC) progression in vivo and in vitro. Furthermore, we investigated effects on the cell cycle and expression of related proteins. Tacrolimus induced G1/S phase arrest and significantly downregulated the expression of cyclinD1, cyclinE1, and c-Myc. These results suggest that tacrolimus induces G1/S phase arrest via inhibition of cyclinD1, cyclinE1, and c-Myc expression and retards oral cell carcinogenesis in vitro and in vivo. Thus, application of tacrolimus is a safe therapeutic strategy for treating OPMDs.

Laser Plume From Human Papillomavirus-Infected Tissue: A Systematic Review.

BACKGROUND: Laser procedures are becoming more prevalent across multiple medical specialties for a variety of indications. The plumes created by these lasers have raised concern for the dissemination of an infectious material. OBJECTIVE: To review and summarize the information on viral dissemination in laser plumes available in the literature. MATERIALS AND METHODS: Data Sources A systematic review was performed on English and non-English articles using the PubMed and the Cochrane databases. A manual search of bibliographies from relevant articles was also performed to collect additional studies. STUDY SELECTION: Only articles in the English language with full texts available that pertained to viral particles in laser plumes were included. Data Extraction Two authors performed independent article selections using predefined inclusion and exclusion criteria. RESULTS: There have been case reports of possible transmission of human papillomavirus (HPV) by inhalation of laser-produced aerosols. Multiple investigators have attempted to recreate this scenario in the laboratory to qualify this risk. Others have conducted clinical experiments to determine the presence of HPV in laser plumes. CONCLUSION: The current body of the literature suggests that laser surgeons are at a risk for HPV exposure by inhalation of laser-derived aerosols. We offer best practice recommendations for laser operators.

Recognition of oral potentially malignant disorders and transformation to oral cancer.

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

Beta-adrenergic blocker inhibits oral carcinogenesis and reduces tumor invasion.

PURPOSE: Beta-adrenergic signaling can influence cancer progression and the use of beta blockers as adjuvant drugs in oncologic patients has been suggested. However, the involvement of beta-adrenergic blockers in tumorigenesis is poorly understood. This study investigated the action of beta-adrenergic blocker propranolol on tumor onset using a preclinical model of chemically induced oral cancer. METHODS: Thirty-two male Wistar rats were subjected to daily subcutaneous injection of beta-blocker propranolol (10 mg/kg; SubQ), while another 32 rats received only a PBS injection (sham group). One week after starting propranolol treatment, all rats were submitted to chemical induction of oral carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). After 16 weeks, they were assessed for occurrence of oral squamous cell carcinoma (OSCC), in addition to measurement of tumor volume and thickness, and tissue levels of cytokines IL-6, TNF-alpha and IL-10 in the tumor microenvironment. RESULTS: Propranolol treatment reduced the occurrence of OSCC by 31%, 95% CI ( - 127, 216). Beta-adrenergic blocker significantly decreased thickness of OSCC when compared with PBS. Rats treated with propranolol exhibited a lower tumor volume when compared with control rats, but this result did not reach statistical significance. Tumors from propranolol-treated rats exhibited reduced concentrations of pro-inflammatory cytokines IL-6 and TNF-α. There was no difference in the IL-10 levels between tumors from propranolol- and sham-treated rats. CONCLUSION: Beta-adrenergic signaling may be one of the mechanisms associated with chemically induced oral carcinogenesis.

Application of a non-invasive oral brushing procedure based on bisulfite sequencing of a 13-gene panel to study high-risk OSCC patients.

BACKGROUND: A non-invasive sampling procedure for the early detection of Oral Squamous Cell Carcinoma (OSCC) based on DNA methylation analysis of a panel of 13 genes was applied in 4 different OSCC risk-group of patients. Aim of the study is to evaluate the between-group differences and the variables related to the methylation profile of each group. METHODS: Oral brushing samples were collected from 54 healthy subjects, 31 Oral Leukoplakia (OL) patients, 18 Oral Lichen Planus (OLP) patients and 26 patients previously treated for OSCC. Each sample was considered positive or negative in relation to a predefined cut-off value. RESULTS: None of the samples from 54 healthy subjects were positive, whereas 22/31 OL, 3/18 OLP and 8/26 surgically treated OSCC samples showed positive values with respect to the cut-off. In OL patients, dysplasia was the only variable significantly related to positive values: 10/10 OLs with high-grade dysplasia were positive with respect to 12/21 OLs without dysplasia (Chi 6.039, p< 0.05). CONCLUSION: DNA methylation analysis in epithelial cells collected by oral brushing seems to be a promising genetic method to distinguish lesions at high risk of developing OSCC. Larger population studies and an adequate follow-up period are necessary to confirm these preliminary data.

Cociente ganglionar como factor pronóstico de sobrevida. Recurrencia en carcinoma escamoso de cavidad oral / NODAL RATIO AS A PROGNOSTIC FACTOR OF SURVIVAL AND RECURRENCE IN ORAL SQUAMOUS CELL CARCINOMA

Antecedentes: El carcinoma escamoso de cavidad oral constituye una de las patologías de mayor frecuencia en cabeza y cuello. El tratamiento de elección es quirúrgico con altas tasas de control local. Sin embrago, se evidencian recidivas aún en etapas tempranas de la enfermedad, lo que lleva a la necesidad de identificar factores pronósticos confiables para mejorar la estadificación, tratamiento y seguimiento. El Cociente Ganglionar fue ratificado como herramienta pronóstica en otros tumores y validado en cavidad oral en un estudio multicéntrico dirigido por el Memorial Sloan Kettering Center de Nueva York. Objetivo: Validar en nuestro medio al Cociente ganglionar como factor pronóstico de sobrevida y recurrencia en carcinoma de cavidad oral. Lugar de aplicación: Hospital público de atención terciaria de tumores. Diseño: Cohorte Retrospectivo Institucional. Material y Métodos: Se recabó de manera retrospectiva información de historias clínicas, partes quirúrgicos e informes de anatomía patológica de un total de 92 pacientes. Se incluyeron aquellos con carcinoma escamoso de cavidad oral T 1-4 pN0-pN+ (pN1-2). Se calculó la sobrevida utilizando el método Kaplan-Meier y se realizó el análisis multivariado. Resultados: Un Cociente Ganglionar (CG.) mayor a 5% resultó estadísticamente significativo como factor pronóstico de sobrevida [HR 5,22(IC95% 1,86; 14;62) (p 0.002)] y recurrencia [HR 13.33 (IC95% 3.85; 46.16) No se evidenció diferencia pronóstica entre aquellos pacientes con vaciamientos pN0 y pN+ asociado a CG. menor a 5%. Pacientes pN1 y vaciamientos con recuento ganglionar total de 20 (1/20) podrían obtener un similar pronóstico al de pN0. Conclusiones: Fue posible ratificar al CG. como factor pronóstico y se plantea la posible utilidad del mismo en la indicación del tratamiento adyuvante

Background: Oral cavity squamous cell carcinoma is one of the most common pathologies in head and neck surgery. Surgery is the treatment of choice with high rates of locoregional control. However, recurrences are seen even in early stages of the disease. This explains the need of new prognostic factors to provide a better staging, treatment and follow up. Nodal Ratio has been validated as a prognostic tool in other tumors and in oral cavity in a multicentric study by Memorial Sloan Kettering Center of Nueva York. Objective: To validate the Nodal Ratio as a prognostic factor in terms of survival and recurrence in oral cavity carcinoma in our medium. Design: Institutional retrospective cohort. Setting: Tertiary Public Hospital for treatment of tumours. Population and Methods: We retrospectively review 92 patient´s information from clinic histories, surgical protocols and pathologic informs. Inclusion criteria were squamous cell histopathology, T1-4 and pN0-N+ (pN1-2) stage. We calculate survival with Kaplan-Meier method and multivariate analysis was done to determinate the independence value. Results: A Nodal Ratio higher than 5% was statistically significant as a prognostic factor of survival [HR 5,22(IC95% 1,86; 14;62) (p 0.002)] and recurrence [HR 13.33 (IC95% 3.85; 46.16) There was no prognostic difference between patients with pN0 dissections and those with pN+ dissections plus NR less than 5%. pN1 patients with nodal yields of 20 (1/20) or more could have the same forecast as a pN0. Conclusions: We were able to validate NR as a prognostic factor. We postulate the potential use in the indication of adjuvant therapy.

An Integrated Approach for Preventing Oral Cavity and Oropharyngeal Cancers: Two Etiologies with Distinct and Shared Mechanisms of Carcinogenesis.

Head and neck squamous cell carcinoma (HNSCC) was the 7th most common malignancy worldwide in 2018 and despite therapeutic advances, the overall survival rate for oral squamous cell carcinoma (OSCC; ∼50%) has remained unchanged for decades. The most common types are OSCC and oropharyngeal squamous cell carcinoma (OPSCC, survival rate ∼85%). Tobacco smoking is a major risk factor of HNSCC. In the developed world, the incidence of OSCC is declining as a result of tobacco cessation programs. However, OPSCC, which is also linked to human papillomavirus (HPV) infection, is on the rise and now ranks as the most common HPV-related cancer. The current state of knowledge indicates that HPV-associated disease differs substantially from other types of HNSCC and distinct biological differences between HPV-positive and HPV-negative HNSCC have been identified. Although risk factors have been extensively discussed in the literature, there are multiple clinically relevant questions that remain unanswered and even unexplored. Moreover, existing approaches (e.g., tobacco cessation, vaccination, and chemoprevention) to manage and control this disease remain a challenge. Thus, in this review, we discuss potential future basic research that can assist in a better understanding of disease pathogenesis which may lead to novel and more effective preventive strategies for OSCC and OPSCC.

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.

Dihydroartemisinin Prevents Distant Metastasis of Laryngeal Carcinoma by Inactivating STAT3 in Cancer Stem Cells.

BACKGROUND Accumulating evidence indicates that cancer stem cells (CSCs) are a minor subpopulation of cancer cells that may be the primary source of cancer invasion, migration, and widespread metastasis. MATERIAL AND METHODS We investigated the effects of dihydroartemisinin (DHA) on distant metastasis of laryngeal carcinoma and the relevant mechanism. In vitro, we used the Hep-2 human laryngeal squamous carcinoma cell line (Hep-2 cells) to assemble CSCs, using CD133 as the cell surface marker. Our data demonstrate that the CD133⁺ subpopulation of Hep-2 cells has greater invasion and migration capabilities than CD133⁻ cells. We also evaluated the effects of DHA, a newly defined STAT3 inhibitor, on the invasion and migration of CD133⁺ Hep-2 cells under hypoxia and IL-6 stimulation, both of which can activate STAT3 phosphorylation. RESULTS CSCs exhibited a significant decrease in the ability of migration and invasion upon the application of DHA, along with simultaneous alterations in related proteins, both in cultured cells and in xenograft tumors. The associated signaling proteins included phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-9 (MMP-9), and E-cadherin, which are closely involved in cancer invasion and metastasis. In vivo, we found that DHA can reduce lung metastasis formation caused by CSCs and prolong survival in mice, and can inhibit STAT3 activation, downregulate MMP-9, and upregulate E-cadherin in lung metastatic tumors. CONCLUSIONS Taken together, our findings indicate that CSCs possess stronger invasive and metastatic capabilities than non-CSCs, and DHA inhibits invasion and prevents metastasis induced by CSCs by inhibiting STAT3 activation.

Age at Initiation and Frequency of Screening to Prevent Esophageal Squamous Cell Carcinoma in High-risk Regions: an Economic Evaluation.

The aim of this study was to identify the economic screening strategies for esophageal squamous cell carcinoma (ESCC) in high-risk regions. We used a validated ESCC health policy model for comparing different screening strategies for ESCC. Strategies varied in terms of age at initiation and frequency of screening. Model inputs were derived from parameter calibration and published literature. We estimated the effects of each strategy on the incidence of ESCC, costs, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratios (ICERs). Compared with no screening, all competing screening strategies decreased the incidence of ESCC from 0.35% to 72.8%, and augmented the number of QALYs (0.002-0.086 QALYs per person) over a lifetime horizon. The screening strategies initiating at 40 years of age and repeated every 1-3 years, which gained over 70% of probabilities that was preferred in probabilistic sensitivity analysis at a $1,151/QALY willingness-to-pay threshold. Results were sensitive to the parameters related to the risks of developing basal cell hyperplasia/mild dysplasia. Endoscopy screening initiating at 40 years of age and repeated every 1-3 years could substantially reduce the disease burden and is cost-effective for the general population in high-risk regions.