Human papillomavirus, oropharyngeal cancer, and the latest vaccine: considerations for oral healthcare providers.

Human papillomavirus (HPV) is associated with both benign and malignant disorders, such as genital warts and a variety of cancers, including oropharyngeal squamous cell carcinomas (OPSCCs). The current 9-valent HPV vaccine (Gardasil 9) protects against high-risk strains that have been shown to cause OPSCC, and widespread vaccination should reduce the rate of all HPV-associated cancers. HPV-related OPSCCs differ from non-HPV-related OPSCCs in their clinical presentations and responsiveness to treatment. To provide oral healthcare providers with a basis for effective com-munication with patients, this article will examine the evolution of the HPV vaccination schedule and the role of the HPV vaccine in the prevention of OPSCCs.

Update on Oral and Oropharyngeal Cancers: A guide for oral health care providers.

Oral squamous cell carcinomas (OSCC) signs and symptoms may be first identified by dental hygienists during routine extra and intra-oral examinations. A comprehensive extra-oral and intra-oral examination during regular dental hygiene assessment is paramount to identifying oral potentially malignant disorders (OPMD) and cancerous lesions for timely referral and treatment. Integrating a systematic list of questions during the medical and dental assessment along with careful visual and tactile examinations is critical to identifying OPMDs and cancerous lesions. Understanding the relationship between oropharyngeal squamous cell carcinomas (OPSCC) and Human Papilloma Virus (HPV) and how vaccination can prevent HPV-related OPSCC is critical to providing evidence-based recommendations and care. The purpose of this report is to provide an update on current epidemiological trends of OSCC and OPSCC rates in the United States (US) and provide the latest evidence on what dental hygienists must know to improve health outcomes and mitigate the consequences of undiagnosed cancer. This report considers enduring challenges with the annual rise in OPSCC rates and the public health burden of HPV-related cancers in the US. Emphasis on regular, quality continuing education about OSCC and OPSCC is emphasized along with recommendations for evidence-based training.

[Translated article] Actinic Keratosis in Solid Organ Transplant Recipients: A Medical Literature Review.

Pharmacological immunosuppression in solid organ transplant recipients is a significant risk factor in the occurrence of actinic keratosis (AK) and later progression into squamous cell carcinomas (SCC). Treating clinical and preclinical lesions is mandatory in this group of patients due to the high changes of progression into SCC. On the other hand, prevention of AK should be considered because it plays a crucial role. Several studies have been published on immunocompetent patients, as well as on the management and prevention of AK, but not on immunosuppressed patients. This review aims to summarize the current knowledge on the management and prevention measures of AK in solid organ transplant recipients.

Oral intake of bucillamine, carvedilol, metformin, or phenformin does not protect against UVR-induced squamous cell carcinomas in hairless mice.

Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice.

Field Cancerization Therapies for the Management of Actinic Keratosis: An Updated Review.

Field cancerization theory highlights that the skin surrounding actinic keratoses (AK) is also at increased risk for possible malignant transformation; thus, field-directed treatments may both reduce the risk of AK recurrence and potentially reduce the risk of development of cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL), as well as topical treatments such as 5-fluorouracil (5-FU), diclofenac gel, piroxicam, imiquimod, and ingenol mebutate, have all shown higher efficacy than vehicle treatments. PDT is widely recognized for its high efficacy; however, concerns for associated pain have driven new studies to begin using alternative illumination and pretreatment techniques, including lasers. Among topical treatments, a combination of 5-FU and salicylic acid (5-FU-SA) has shown to be the most effective but also causes the most adverse reactions. Tirbanibulin, a new topical agent approved for use in 2020, boasts a favorable safety profile in comparison with imiquimod, 5-FU, and diclofenac. Meanwhile, ingenol mebutate is no longer recommended for the treatment of AKs due to concerns for increased risk of cSCC development. Moving forward, an increasing number of studies push for standardization of outcome measures to better predict risk of future cSCC and use of more effective measures of cost to better guide patients. Here, we present an updated and comprehensive narrative review both confirming the efficacy of previously mentioned therapies as well as highlighting new approaches to PDT and discussing the use of lasers and novel topical treatments for treatment of AK.

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.

Actinic Keratosis in Solid Organ Transplant Recipients: A Medical Literature Review. / Queratosis actínicas en pacientes trasplantados de órgano sólido: revisión de la literatura.

Pharmacological immunosuppression in solid organ transplant recipients is a significant risk factor in the occurrence of actinic keratosis (AK) and later progression into squamous cell carcinomas (SCC). Treating clinical and preclinical lesions is mandatory in this group of patients due to the high changes of progression into SCC. On the other hand, prevention of AK should be considered because it plays a crucial role. Several studies have been published on immunocompetent patients, as well as on the management and prevention of AK, but not on immunosuppressed patients. This review aims to summarize the current knowledge on the management and prevention measures of AK in solid organ transplant recipients.

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Phytochemicals targeting epidermal growth factor receptor (EGFR) for the prevention and treatment of HNSCC: A review.

Head and neck squamous cell carcinoma (HNSCC) develops from the mucosal epithelium of the oral cavity, pharynx, and larynx, and is the most common malignancy of the head and neck, the incidence of which continues to rise. The epidermal growth factor receptor is thought to play a key role in the pathogenesis of HNSCC. Inhibition of epidermal growth factor receptor has been identified as an effective target for the treatment of HNSCC. Many phytochemicals have emerged as potential new drugs for the treatment of HNSCC. A systematic search was conducted for research articles published in PubMed, and Medline on relevant aspects. This review provides an overview of the available literature and reports highlighting the in vitro effects of phytochemicals on epidermal growth factor in various HNSCC cell models and in vivo in animal models and emphasizes the importance of epidermal growth factor as a current therapeutic target for HNSCC. Based on our review, we conclude that phytochemicals targeting the epidermal growth factor receptor are potentially effective candidates for the development of new drugs for the treatment of HNSCC. It provides an idea for further development and application of herbal medicines for cancer treatment.

Skin cancer prevention - Recent advances and unmet challenges.

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in the world. Among many identified risk factors, immunosuppression is a major factor that contributes to cSCC development. Organ transplant recipients (OTRs) are at markedly increased risk of developing multiple cSCCs with a propensity for advanced metastatic disease, leading to significant morbidity and mortality. The severity of the cSCC phenotype in OTRs highlights the urgent need to identify effective preventive modalities in this population. Despite recent advances in skin cancer prevention (e.g., nicotinamide) and treatment (e.g., immune checkpoint blockade), these modalities have limited utility in OTRs due to the lack of efficacy or significant side effect. Topical treatments against precancerous skin lesions, actinic keratosis (AK), remain the primary strategy to prevent cSCC in OTRs, which also have significant deficiencies in this population. Herein, we review the epidemiology, risk factors, and current cSCC prevention strategies. We highlight the gaps and future clinical strategies to address cSCC risk in high-risk populations.

Spermidine Suppresses Oral Carcinogenesis through Autophagy Induction, DNA Damage Repair, and Oxidative Stress Reduction.

Autophagy has been proposed to play a dual role in cancer-as a tumor suppressor in early stages and oncogenic in late stages of tumorigenesis. This study investigated the role of autophagy in oral carcinogenesis using the model of oral squamous cell carcinoma (OSCC) induced by carcinogen 4-nitroquinoline 1-oxide (4NQO), mimicking molecular and histopathologic aspects of human OSCC. The induction of autophagy by spermidine (SPD) treatment reduced the severity of lesions and the incidence of OSCC in mice exposed to 4NQO. On the other hand, autophagy inhibition by chloroquine treatment had no protection. The comet assay indicated that SPD reduced 4NQO-induced DNA damage, likely related to the activation of DNA repair and the decrease of reactive oxygen species. As sphingolipid alterations have been reported in OSCC, sphingolipids in the tongue and plasma of animals were analyzed and plasma C16 ceramide levels were shown to increase proportionally to lesion severity, indicating its potential as a biomarker. Mice exposed to 4NQO plus SPD had lower levels of C16 ceramide than the 4NQO group, which indicated SPD's ability to prevent the 4NQO-induced carcinogenesis. Together, these data indicate that activation of autophagy has a tumor suppressor role during the early stages of oral carcinogenesis. Because of its ability to induce autophagy accompanied by reduced oxidative stress and DNA damage, SPD may have a protective action against chemically induced oral cancer.

A paradigm shift in the prevention and diagnosis of oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a widespread disease with only 50%-60% 5-year survival. Individuals with potentially malignant precursor lesions are at high risk. METHODS: Survival could be increased by effective, affordable, and simple screening methods, along with a shift from incisional tissue biopsies to non-invasive brush biopsies for cytology diagnosis, which are easy to perform in primary care. Along with the explainable, fast, and objective artificial intelligence characterisation of cells through deep learning, an easy-to-use, rapid, and cost-effective methodology for finding high-risk lesions is achievable. The collection of cytology samples offers the further opportunity of explorative genomic analysis. RESULTS: Our prospective multicentre study of patients with leukoplakia yields a vast number of oral keratinocytes. In addition to cytopathological analysis, whole-slide imaging and the training of deep neural networks, samples are analysed according to a single-cell RNA sequencing protocol, enabling mapping of the entire keratinocyte transcriptome. Mapping the changes in the genetic profile, based on mRNA expression, facilitates the identification of biomarkers that predict cancer transformation. CONCLUSION: This position paper highlights non-invasive methods for identifying patients with oral mucosal lesions at risk of malignant transformation. Reliable non-invasive methods for screening at-risk individuals bring the early diagnosis of OSCC within reach. The use of biomarkers to decide on a targeted therapy is most likely to improve the outcome. With the large-scale collection of samples following patients over time, combined with genomic analysis and modern machine-learning-based approaches for finding patterns in data, this path holds great promise.

Systemic Photoprotection in Melanoma and Non-Melanoma Skin Cancer.

Non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK), are the most common cancer diseases in the Caucasian race. If diagnosed late and improperly treated, BCC and SCC can become locally advanced and metastasize. Malignant melanoma (MM) is less frequent but more lethal than NMSC. Given the individual and social burdens of skin cancers, performing an adequate prevention is needed. Ultraviolet (UV) ray exposure is one of the main risk factors for skin cancer. Thus, the first-choice prevention strategy is represented by photoprotection that can be both topical and systemic. The latter consists of the oral administration of molecules which protect human skin against the damaging effects of UV rays, acting through antioxidant, anti-inflammatory, or immunomodulator mechanisms. Although several compounds are commonly used for photoprotection, only a few molecules have demonstrated their effectiveness in clinical trials and have been included in international guidelines for NMSC prevention (i.e., nicotinamide and retinoids). Moreover, none of them have been demonstrated as able to prevent MM. Clinical and preclinical data regarding the most common compounds used for systemic photoprotection are reported in this review, with a focus on the main mechanisms involved in their photoprotective properties.

Exploring cell competition for the prevention and therapy of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is characterized by the development of cancer in the esophageal squamous epithelium through a step-by-step accumulation of genetic, epigenetic, and histopathological alterations. Recent studies have demonstrated that cancer-associated gene mutations exist in histologically normal or precancerous clones of the human esophageal epithelium. However, only a small proportion of such mutant clones will develop ESCC, and most ESCC patients develop only one cancer. This suggests that most of these mutant clones are kept in a histologically normal state by neighboring cells with higher competitive fitness. When some of the mutant cells evade cell competition, they become "super-competitors" and develop into clinical cancer. It is known that human ESCC is composed of a heterogeneous population of cancer cells that interact with and influence their environment and neighbors. During cancer therapy, these cancer cells not only respond to therapeutic agents but also compete with each other. Therefore, competition between ESCC cells within the same ESCC tumor is a constantly dynamic process. However, it remains challenging to fine-tune the competitive fitness of various clones for therapeutic benefits. In this review, we will explore the role of cell competition in carcinogenesis, cancer prevention, and therapy, using NRF2, NOTCH pathway, and TP53 as examples. We believe that cell competition is a research area with promising targets for clinical translation. Manipulating cell competition may help improve the prevention and therapy of ESCC.

Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a group of malignancies, involving the oral cavity, pharynx, hypopharynx, larynx, nasal cavity, and salivary glands, that together compose the seventh most common cancer diagnosis worldwide. With 890,000 new cases and 450,000 deaths annually per GLOBOCAN estimates, HNSCC accounts for roughly 4.5% of cancer diagnoses and deaths. In the developing world, the incidence of HNSCC is growing with increasing consumption of tobacco (smoked or chewed), alcohol, and areca nut (betel quid). Alcohol and tobacco have a synergistic effect, with the heavy consumption of both increasing HNSCC risk 40-fold. In developed nations, HPV-related HNSCC surpasses tobacco- and alcohol-related disease. HPV-related HNSCC more commonly affects the oropharynx, hypopharynx, and larynx than the oral cavity, and is associated with a significantly longer median survival (130 months vs. 20 months). Discrepancies in etiology as well as disparities in lifestyle choices and access to healthcare may account for the greater incidence and poorer survival of HNSCC among minority and lower-socioeconomic-status communities in developed nations. Pharmacotherapy and counseling together have been shown to be effective in promoting smoking and alcohol cessation. Education on cancer risk and community engagement have reduced areca nut consumption in Asia as well as in diaspora communities. HPV vaccination, starting at age 11-12 for both sexes, has been shown to reduce the prevalence of high-risk HPV serologies and prevent pre-cancerous lesions of the cervix, vagina, and vulva. As of 2020, 58.6% of eligible adolescents in the US have received the full two-vaccine series. Increased adoption of vaccination, education on safe sex practices, and routine visual oral screening for high-risk patients would curb growing HNSCC incidence in developed nations.

Keratinocyte Carcinoma Chemoprevention With a Combination of Imiquimod, 5-Fluorouracil, and Tretinoin.

BACKGROUND: The incidence of keratinocyte carcinomas (KCs), comprising basal and squamous cell carcinomas, is rising in the United States. Chemoprevention is one modality by which patients can reduce the incidence of KCs. METHODS: We performed a retrospective review of 327 patients who employed a combination of imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream in a field therapy regimen over the face/ears or scalp for chemoprevention. RESULTS: Patients had dramatically lower odds of having KCs in the treatment location (face/ears or scalp) in the one-year period after field treatment than in the one-year period preceding field treatment (OR=0.06, 95% CI: [0.02, 0.15]). Patients were also at lower odds of having KCs in non-treated areas the year after field treatment than in the year preceding it (OR=0.25, 95% CI: [0.14, 0.42]). Additionally, fewer cryotherapy sessions were performed for actinic keratoses in the treatment areas in the year after treatment (mean=1.5, SD=1.21) than the year preceding treatment (mean=2.3, SD=0.99; t=11.68, P<0.001). CONCLUSIONS: A combination of imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream were effective at reducing the incidence of new KCs for at least one year. Individualized treatment application frequency allowed for increased patient adherence. Prospective studies evaluating combination topical treatments for chemoprevention of KCs are needed to further assess the treatment effects found in this study. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7334.

A multicenter case-control study comparing sun exposure habits and use of photoprotection measures in patients diagnosed with different types of skin cancer.

BACKGROUND: While skin cancer awareness programs have significantly furthered public understanding about the harmful effects of the sun, there is a disparity between photoprotection knowledge and protection practices. OBJECTIVE: To compare sun exposure habits and photoprotection measures in patients diagnosed with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma versus controls. METHODS: Multicentre case-control observational study carried out by 13 Spanish dermatologists between April 2020 and August 2022. Patients diagnosed with BCC, SCC, or melanoma were considered cases. The control group consisted of individuals with no history of skin cancer. RESULTS: Of the 254 cases (56.2% female; mean age, 62.67 ± 15.65), 119 (31.2%) had BCC, 62 (16.27%) SCC, and 73 (19.1%) melanoma. The control group consisted of 127 (33.33%) individuals. Avoiding sun exposure between 12:00 and 16:00 was the most commonly used photoprotection measure (habitually/always: 63.1%), followed by the use of sunscreen (habitually/always: 58.9%). Patients with melanoma were less likely to use clothing and shade to avoid sun exposure (p < .05), whereas those with BCC and SCC reported greater use of head coverings (p = .01). BCC and SCC groups reported greater sun exposure 15 years prior, whereas controls reported greater use of sunscreen. However, at the time of this study all groups reported using SPF ≥ 21, and the majority SPF > 50. No differences were observed in photoprotection measures between people with and without a previous history of skin cancer. CONCLUSIONS: We describe differences in photoprotection measures and sun exposure patterns among patients diagnosed with different skin tumor types. Whether these differences may influence the type of tumor each developed will require further investigation.

Etiology, diagnosis, treatment, and prevention of human papilloma virus-associated oropharyngeal squamous cell carcinoma.

Classical oropharyngeal squamous cell carcinoma (OPSCC) caused by alcohol consumption and smoking and HPV-associated OPSCC caused by human papillomavirus (HPV) infection have different etiologies, incidences, and prognoses. Therefore, the 8th American Joint committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM classifications propose distinguishing HPV-associated OPSCC from classical OPSCC and classifying it as an independent disease. Therefore, this review provides an overview of HPV-associated OPSCC from the perspectives of epidemiology, carcinogenesis, development, diagnosis, treatment, and prevention. The incidence of HPV-associated OPSCC is increasing. Although HPV vaccination has been shown to be effective at reducing the incidence of cervical cancer, it is still unclear how it affects the incidence of HPV-associated OPSCC. Additionally, the prognosis of patients with HPV-associated OPSCC is extremely favorable compared to that of patients with classical OPSCC. Therefore, patients with HPV-associated OPSCC may undergo reduced-dose therapy, although attempts to reduce treatment intensity should be carefully planned to ensure they do not compromise oncological outcomes, and large-scale trials aimed at reducing treatment intensity are ongoing.