Oral Tumors Research Articles

786. ANATOMICAL DISTRIBUTION OF HUMAN PAPILLOMAVIRUS INFECTION IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Human Papillomavirus (HPV) infection is a high-risk factor for many types of cancer development. The reported infectious rate in esophageal squamous cell carcinoma (ESCC) varies widely, ranging from 0% to 88.9%. It may be caused due to geographical location, sample size, and detection methods. In general, p16 expression is considered as a biomarker for HPV infection. However, the correlation between the p16 expression and HPV infectious status has been controversial. Methods Patients with ESCC underwent esophagectomy without neoadjuvant chemotherapy (NAC) from 2007 to 2021 were included. Three formalin-fixed paraffin-embedded blocks (oral side, tumor, and esophagogastric junction (EGJ)) from each surgical resected specimen were collected. p16 expression was examined by immunohistochemistry (labeling index ≥ 10% is defined as positive expression). The presence of HPV DNA was investigated by polymerase chain reaction. In addition, the anatomical distribution of HPV infection was investigated. Results A total of 158 patients with 417 samples were included. The positive expression rate of p16 was 3.6% (5/137), 19.2% (30/156) and 2.1% (3/146) in oral side, tumor, and EGJ, respectively. The HPV infectious rate was 7% (11/158), and six cases were detected in tumor site and the other 5 cases were detected in oral side or EGJ. In tumor tissue, HPV positive cases showed p16 positive, and the sensitivity and specificity for detecting HPV DNA by IHC of p16 were 100% and 84%, respectively. The HPV infection in ESCC specimens appears to be irregular. Conclusion This study is the largest sample size in Japan, demonstrating the p16 positive rate of 19.2% and HPV infectious rate of 7% in ESCC patients without NAC. IHC of p16 can be used as a screening examination for predicting HPV infection in ESCC because the false negative rate was 0%. In addition, we firstly reported the HPV infectious mapping in ESCC specimens, and it appears irregular and random.

Investigating EGFR, BRAF, and RAS Mutations in Oral and Cutaneous Squamous Cell Neoplasms: A Preliminary Report on Romanian Patients

Background: Head and neck cancers, and particularly, oral cancers have a complex pathogenesis that includes genetic mutations and epigenetic alterations which interfere with cellular signaling and can trigger tumor development. The purpose of this study was to reveal whether low-frequency hotspot mutations may be detected in a study lot with histopathological evidence of squamous cell carcinoma (SCC) of the oral mucosa and skin of the head and neck. Methods: Tumor biopsies from treatment naïve patients were tested for BRAF V600, NRAS G12/G13, NRAS Q61, KRAS Q61 mutations, and EGFR exon 19 deletions (Ex19Del) using droplet digital PCR (ddPCR). The tumors were also analyzed for EGFR T790M mutations by RT-PCR, using a CE-IVD validated kit, with a limit of detection of 0.05%. Results: None of the examined cases exhibited NRAS G12/G13, NRAS Q61, KRAS Q61, BRAF V600, or EGFR T790M mutations, indicating that these alterations are rare events in SCC pathogenesis. Interestingly, among the 12 specimens tested by ddPCR for EGFR Ex19Del, an HPV-negative cSCC tumor occurring in the parotid region tested positive for this drug-sensitizing mutation, offering unexplored therapeutic perspectives to the patient from whom it was collected. Conclusions: Our study highlights the important clinical implications of detecting low-frequency hotspot mutations in tumor biopsies by ddPCR. We believe that the ddPCR-assisted analysis of these mutations in larger SCC cohorts may provide us with mechanistic insights regarding their role in SCC pathogenesis and guide the development of novel therapeutic strategies for this problematic disease.

Clinicopathological risk factors of oral second primary tumours

BackgroundOral second primary tumours (SPTs) have a poor prognosis due to late-stage diagnosis. This study evaluates the demographic and clinicopathological risk predictors of SPTs. MethodsPatients with oral squamous cell carcinoma, carcinoma in situ, or severe dysplasia were accrued into the Oral Cancer Prediction Longitudinal study within one year post-curative treatment. Data on demographics, risk habits, and primary tumour characteristics were collected. Clinical follow-up included assessing the presence of second oral premalignant lesions (SOPLs), clinicopathological features, and the results from toluidine blue staining and fluorescence visualization. ResultsAmong 296 patients, 23 (8 %) developed SPTs. Older age at primary cancer diagnosis (P = 0.008) and a history of chewing tobacco or betel nut (P = 0.043) increased the risk of SPTs. Patients with primary tumours located at low-risk sites had an increased risk of SPTs (P = 0.004), which often presented at high-risk sites. The presence of SOPLs (P < 0.001), and multiple lesions (P = 0.017) significantly increased the risk of SPTs. Positive toluidine blue staining indicated a trend toward higher risk of SPTs, whereas fluorescence visualization did not. The median time to SPT diagnosis was 3.25 years post-treatment. ConclusionsIdentifying second or multiple oral premalignant lesions is critical for predicting the risk of SPTs regardless of their clinical or histological characteristics. Routine biopsy of these lesions should be prioritized to ensure timely diagnosis. Incorporating these risk predictors into clinical follow-up can enhance early cancer detection and improve patient outcomes.

Gene expression analysis of microRNA-1285 in the South Indian oral squamous cell carcinoma population.

Oral squamous cell carcinoma (OSCC) is the most common oral malignant tumor, which has poor prognosis. The traditional investigative modality is invasive biopsy which is the gold standard for diagnosis. In recent years, alternative methods like non-invasive biomarkers have been studied for their potential role in early diagnosis and prognosis. Among them, microRNAs (miRNAs or miRs) are short non-coding RNAs that regulate gene expression in various diseases, including OSCC. Several miRNAs are being researched as non-invasive biomarkers as well as novel therapeutic targets in the treatment of OSCC. MiR expression can be upregulated or downregulated in OSCC. Among the reported miRNAs, miR-1285 is an important miRNA found to be involved in OSCC. The aim of the current study was to quantify the levels of miR-1285 in OSCC samples and to validate their potential role as biomarkers for OSCC detection. Sixteen samples of cancer tissue and normal tissue were evaluated from a total of 25 patients, in the study, conducted in the Department of Oral and Maxillofacial Surgery. The tissues were processed for H&E staining and gene expression analysis of miR-1285. The samples were collected after proper informed consent from the patients. Total RNA isolated was reverse transcribed into cDNA which was used in the gene expression analysis using qRT-PCR. The histopathological examination confirmed the OSCC cases and the gene expression analysis revealed that miR-1285 was significantly downregulated in OSCC tissues. Since miR-1285 showed significant difference between the OSCC and normal tissues it could be postulated as a potential biomarker and therapeutic target for OSCC. Further in-vitro and in-vivo studies could validate their functional role in OSCC.

Oral granular cell tumor: a collaborative clinicopathological study of 61 cases.

Granular Cell Tumor (GCT) is an uncommon benign lesion in the oral cavity whose pathogenesis remains poorly understood. Due to their infrequent occurrence and similarity to other oral lesions, they are often forgotten during the initial clinical diagnosis. Therefore, understanding its prevalence, clinical and pathological characteristics is crucial for an accurate diagnosis and adequate management. All cases diagnosed as GCTs in six Brazilian and Argentinian oral diagnostic centers were re-evaluated by HE staining, and clinical, demographic, and histopathological data were collected and evaluated. The series comprised 45 female (73.8%) and 16 male (26.2%), with a 2.8:1 female-to-male ratio and a mean age of 35.3 ± 16.9 years (range: 7-77 years). Most cases occurred on the tongue (n = 49; 81.6%) and presented clinically as asymptomatic papules or nodules (n = 50; 89.3%) with a normochromic (n = 25; 45.5%) or yellowish (n = 11; 20.0%) coloration and sizes ranging from 0.2 to 3.0cm (mean ± SD: 1.40 ± 0.75cm). Morphologically, most tumors were characterized by a poorly delimited proliferation (n = 52; 88.1%) of cells typically rounded to polygonal containing abundant, eosinophilic, finely granular cytoplasm. Pustulo-ovoid bodies of Milian were identified in all lesions (n = 61; 100%). Entrapment of skeletal striated muscle (n = 44; 72.1%) and nerve fibers (n = 42; 68.9%) were common findings. Pseudoepitheliomatous hyperplasia (PEH) was observed in 23 cases (39.0%). In only 27.7% of cases (n = 13) there was agreement between the clinical and histopathological diagnosis. Outcome information was available from 16 patients (26.2%), with clinical follow-up ranging from 4 to 36 months (mean 13.3 months), and none developed local recurrence. The clinical and histopathological features of GCTs were consistent with those described in previous studies. In general, these lesions have a predilection for the lateral region of the tongue in adult women. It is essential to consider GCTs in the differential diagnosis of yellow or normochromic papules and nodules in the oral cavity. Histopathological evaluation is essential for the definitive diagnosis and the prognosis is excellent.

31 Videolaryngoscope-assisted flexible intubation (VAFI) in a patient with airway obstruction due to a giant oral tumour. A case report

31 Videolaryngoscope-assisted flexible intubation (VAFI) in a patient with airway obstruction due to a giant oral tumour. A case report

Chitosan-based mucoadhesive films loaded with curcumin for topical treatment of oral cancer

This study aimed to develop mucoadhesive chitosan-based films capable of enhancing the curcumin penetration into the oral mucosa to treat oral cancers. We developed three films containing medium molecular weight chitosan (190–310 KDa) and other excipients (polyvinyl alcohol, Poloxamer®407, and propylene glycol) that have proven to be compatible with each other and with curcumin in thermal analyses. The films were smooth, flexible, and precipitates free, with uniform weight and thickness, pH compatible with the oral mucosa, resistance to traction, and entrapped curcumin in a high proportion. They also exhibited necessary swelling and mucoadhesion for tissue adherence. Ex vivo penetration studies proved that the films significantly increased the penetration of curcumin into the oral mucosa compared to control, even when the mucosa was subjected to a condition of simulated salivation. Curcumin exhibited cytotoxic activity in vitro in the two head and neck cancer cell lines (FaDu, SCC-9) at doses close to those found in penetration studies with the films. When combined with radiotherapy, curcumin demonstrated superiority over single doses of radiotherapy at 4, 8, and 12 Gy. Therefore, the developed films may represent a promising alternative for the topical treatment of oral tumors.

Metastatic Renal-Cell Carcinoma of the Oro-Facial Tissues: A Comprehensive Review of the Literature with a Focus on Clinico–Pathological Findings

Background: Metastatic tumors of the oro-facial tissuesare rare, with an incidence ranging between 1% and 8% of all oral malignant tumors. Generally reported with a peak of incidence in the 5–7th decades but possibly occurring at any age, metastases may represent the first sign of an occult cancer or manifest in patients with an already known history of a primary carcinoma, mostly from the lungs, kidney, prostate, and colon/rectum in males, and the uterus, breast, lung, and ovary in females. In the oro-facial tissues, the most involved sites are the oral mucosa, gingiva/jawbones, tongue, and salivary glands. Methods: A broad and deep literature review with a comprehensive analysis of the existing research on oro-facial metastases from renal-cell carcinoma (RCC) was conducted by searching the most used databases, with attention also paid to the clear-cell histological variant, which is the most frequent one. Results: Among the 156 analyzed studies, 206 cases of oro-facial metastases of renal cancer were found in patients with an average age of 60.9 years (145 males, 70.3%; 61 females, 29.6%). In almost 40% of the cases, metastasis represented the first clinical manifestation of the primary tumor, and 122 were histologically diagnosed as clear-cell renal-cell carcinoma (ccRCC) (59.2%). The tongue was involved in most of the cases (55 cases, 26.7%), followed by the gingiva (39 cases, 18.9%), mandible (35 cases, 16.9%), maxilla (23 cases, 11.1%), parotid gland (22 cases, 10.6%), buccal mucosa (11 cases, 5.3%), lips (7 cases, 3.3%), hard palate (6 cases, 2.8%), soft palate, masticatory space, and submandibular gland (2 cases, 0.9%), and lymph nodes, tonsils, and floor of the mouth (1 case, 0.4%). Among the 122 ccRCCs (84 males, 68.8%; 38 females, 31.1%), with an average age of 60.8 years and representing in 33.6% the first clinical manifestation, the tongue remained the most frequent site (31 cases, 25.4%), followed by the gingiva (21 cases, 17.2%), parotid gland (16 cases, 13.1%), mandibular bone (15 cases, 12.2%), maxillary bone (14 cases, 11.4%), buccal mucosa and lips (6 cases, 4.9%), hard palate (5 cases, 4%), submandibular gland and soft palate (2 cases, 1.6%), and lymph nodes, tonsils, oral floor, and masticatory space (1 case, 0.8%). The clinical presentation in soft tissues was mainly represented by a fast-growing exophytic mass, sometimes accompanied by pain, while in bone, it generally presented as radiolucent lesions with ill-defined borders and cortical erosion. Conclusions: The current comprehensive review collected data from the literature about the incidence, site of occurrence, age, sex, and survival of patients affected by oro-facial metastases from renal-cell carcinoma, with particular attention paid to the cases diagnosed as metastases from clear-cell renal-cell carcinoma, which is the most frequent histological variant. Clinical differential diagnosis is widely discussed to provide clinicians with all the useful information for an early diagnosis despite the effective difficulties in recognizing such rare and easily misdiagnosed lesionsTheir early identification represents a diagnostic challenge, especially when the clinical work-up is limited to the cervico–facial region. Nevertheless, early diagnosis and recently introduced adjuvant therapies may represent the key to better outcomes in such patients. Therefore, general guidelines about the clinical and radiological identification of oro-facial potentially malignant lesions should be part of the cultural background of any dentist.

A Whole-Transcriptomic Analysis of Canine Oral Melanoma: A Chance to Disclose the Radiotherapy Effect and Outcome-Associated Gene Signature.

Oral melanoma (OM) is the most common malignant oral tumour among dogs and shares similarities with human mucosal melanoma (HMM), validating the role of canine species as an immunocompetent model for cancer research. In both humans and dogs, the prognosis is poor and radiotherapy (RT) represents a cornerstone in the management of this tumour, either as an adjuvant or a palliative treatment. In this study, by means of RNA-seq, the effect of RT weekly fractionated in 9 Gray (Gy), up to a total dose of 36 Gy (4 weeks), was evaluated in eight dogs affected by OM. Furthermore, possible transcriptomic differences in blood and biopsies that might be associated with a longer overall survival (OS) were investigated. The immune response, glycosylation, cell adhesion, and cell cycle were the most affected pathways by RT, while tumour microenvironment (TME) composition and canonical and non-canonical WNT pathways appeared to be modulated in association with OS. Taking these results as a whole, this study improved our understanding of the local and systemic effect of RT, reinforcing the pivotal role of anti-tumour immunity in the control of canine oral melanoma (COM).

Comprehensive analysis of risk factors for flap necrosis in free flap reconstruction of postoperative tissue defects in oral and maxillofacial tumors

Free flap reconstruction for postoperative tissue defects in oral and maxillofacial tumors is a critical component of reconstructive surgery. Identifying risk factors for flap necrosis is essential for improving surgical outcomes and patient quality of life. A retrospective study was conducted on patients who underwent free flap reconstruction between January 2020 and December 2023. Patients were included if they had comprehensive medical records and at least a six-month follow-up. We excluded those with a history of flap necrosis, uncontrolled systemic diseases, non-adherence to postoperative care, or concurrent malignancy treatments. Data on demographics, comorbidities, flap characteristics, and operative details were collected and analyzed using univariate analysis and logistic regression tests. Univariate analysis did not find a significant correlation between flap necrosis and factors such as hyperlipidemia, lymph node metastasis, or flap type. However, diabetes mellitus, oral infections, and albumin levels below 35 g/L were significantly associated with flap necrosis. Multivariate logistic regression showed diabetes mellitus increased the odds of flap necrosis by approximately ninefold, and oral infection increased it by over tenfold. Diabetes mellitus, oral infection, and low albumin levels are significant risk factors for flap necrosis in free flap reconstruction after oral and maxillofacial surgery. Prompt identification and management of these factors are crucial to mitigate the risk of flap necrosis.

Current status and influencing factors of fear of surgery in patients with oral and maxillofacial tumors.

This study aimed to investigate the incidence and severity of surgical fear in patients with oral and maxillofacial tumors. The survey participants were composed of patients with oral and maxillofacial tumors, who were scheduled to undergo surgery. A general information questionnaire, the Surgical Fear Questionnaire (SFQ), the Patient Health Questionnaire (PHQ)-9, and the Generalized Anxiety Disorder (GAD)-7 score were used for the investigation. A total of 203 patients were investigated. Among them, 85.22% had fear of surgery. The median score of SFQ was 20, and the quartile was (6, 36). The patients were categorized into none, mild, moderate, and severe groups according fear level. Gender, diabetes, obvious discomfort before surgery, PHQ-9, and GAD-7 scores were the variables with statistical difference in each fear level. Multifactor analysis showed that women were more likely to have moderate and severe fear than men (OR=2.19, P=0.03; OR=2.72, P=0.01), patients with obvious preoperative discomfort symptoms were more inclined to have no fear (OR=4.73, P=0.02), and patients with diabetes were more likely to have severe fear (OR=3.33, P=0.02). The incidence rates of depression and anxiety were 31.03% and 24.63%, respectively. The incidence of anxiety and depression in patients with severe fear was 40.00%. Surgical fear was moderately positively correlated with anxiety (r=0.491, P<0.001) and depression (r=0.514, P<0.001). The fear of surgery in patients with oral and maxillofacial tumors is common and distributed in all levels. Medical staff can screen and assess patients with moderate and severe fear of surgery in accordance with the influencing factors and implement targeted interventions to reduce fear of surgery, anxiety, and depression on the basis of the source of fear.

Decoding Oral Carcinogenesis and Tumor Progression in Whole Cigarette Smoke Exposure: A Systematic Review.

This systematic review aims to highlight the molecular mechanisms by which whole cigarette smokeaffects oral carcinogenesis and its progression in human oral cells, based on evidence from original research articles published in the literature. A literature search was conducted using three databases: Web of Science, Scopus, and PubMed from May to June 2024. The articles were screened, and the data were extracted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (2020). The included studies were subsequently evaluated using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool for bias factors. From the 14 included studies, two types of cell lines were frequently utilized: human oral mucosal epithelial cells or oral squamous cell carcinoma cells. In these cell lines, one of three forms of exposure was applied: cigarette smoke, its extract, or condensate. The mechanism of oral carcinogenesis and tumor progression includes aberrations in the heme metabolic pathway, modulation of miRNA-145, NOD1 and BiP expression, MMP-2, MMP-9, and cathepsin modulation, abnormal TSPO binding, RIP2-mediated NF-κB activation, MZF1-mediated VEGF binding, and activation of the RAGE signaling pathway. In conclusion, cigarette smoke significantly influences the development and progression of oral squamous cell carcinoma, based on the evidence highlighted in human oral cells. While previous studies have focused on specific carcinogens and pathways, this review added to our understanding of the overall impact of whole cigarette smoke on oral carcinogenesis at the molecular and cellular levels.

Investigating the Effect of Smoking on Transcriptomics of Primary Oral Cavity Tumors using the Gene Expression Omnibus Dataset

Investigating the Effect of Smoking on Transcriptomics of Primary Oral Cavity Tumors using the Gene Expression Omnibus Dataset

Impact of Adjuvant Radiotherapy Setting on Quality-of-Life in Head and Neck Squamous Cell Carcinoma.

To determine differences in post-treatment QoL across treatment settings in patients receiving adjuvant radiation therapy for head and neck squamous cell carcinoma (HNSCC). This was a prospective observational cohort study of patients with HNSCC initially evaluated in a head and neck surgical oncologic and reconstructive clinic at an academic medical center (AMC). Participants were enrolled prior to treatment in a prospective registry collecting demographic, social, and clinical data. Physical and social-emotional QoL (phys-QoL and soc-QoL, respectively) was measured using the University of Washington-QoL questionnaire at pre-treatment and post-treatment visits. A cohort of 177 patients, primarily male and White with an average age of 61.2 ± 11.2 years, met inclusion criteria. Most patients presented with oral cavity tumors (n = 132, 74.6%), had non-HPV-mediated disease (n = 97, 61.8%), and were classified as Stage IVa (n = 72, 42.8%). After controlling for covariates, patients treated at community medical centers (CMCs) reported a 7.15-point lower phys-QoL compared with those treated at AMCs (95% CI: -13.96 to -0.35, p = 0.040) up to 12 months post-treatment. Additionally, patients who were treated at CMCs had a 5.77-point (-11.86-0.31, p = 0.063) lower soc-QoL score compared with those treated at an AMC, which was not statistically significant. This study revealed that HNSCC patients treated with radiation at AMCs reported significantly greater phys-QoL in their first-year post-treatment compared to those treated at CMCs, but soc-QoL did not differ significantly. Further observational studies are needed to explore potential factors, including treatment planning and cancer resource engagement, behind disparities between AMCs and CMCs. 3 Laryngoscope, 134:3645-3655, 2024.

Hedgehog/Gli2 signaling triggers cell proliferation and metastasis via EMT and wnt/β-catenin pathways in oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC) is the most lethal oral malignant tumor, however, clinical outcomes remain unsatisfactory. The Hedgehog/Gli2 pathway plays a pivotal role in tumor progression, yet the regulatory mechanism governing its involvement in the malignant evolution process of OSCC remains elusive. MethodsOSCC animal tissue samples were used to detect the activation of the Hedgehog/Gli2 pathway in OSCC. Based on the clinical information of oral cancer patients in TCGA database, the role of this pathway in patients was analyzed, and the activation status of this pathway was verified in human OSCC cells. After activating or inhibiting the Hedgehog pathway, the effects of this pathway on the biological function of OSCC cells and its regulatory mechanism were examined. Interfering the expression of Gli2, a key transcription factor in this pathway, revealed the role of Hedgehog/Gli2 pathway in the malignant evolution of OSCC cells. ResultsThe Hedgehog pathway exhibits abnormal activation in animal models of OSCC. Clinical data from TCGA demonstrate a significant enrichment of the Hedgehog pathway in patients with OSCC, and Gli2, a key downstream factor of this pathway, is closely associated with the occurrence and progression of OSCC. Cellular studies have revealed aberrant activation of this pathway in human OSCC cells, which exerts its function by modulating the activation of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathways. Subsequent investigations further confirm the pivotal involvement of Gli2 in the Hedgehog pathway activation, underscoring its potential as a therapeutic target for inhibiting malignant proliferation and metastasis of OSCC cells through modulation of EMT and Wnt/β-catenin pathways. ConclusionThe Hedgehog/Gli2 pathway induces EMT and activates Wnt/β-catenin pathway to trigger the malignant proliferation and metastasis of OSCC cells, and Gli2 plays a key role in this process, which suggests that targeting Gli2 may be a promising therapeutic strategy for inhibiting the proliferation and metastasis of OSCC.

Impact of various nutritional interventions on the physical and mental state of patients undergoing surgery for oral and maxillofacial tumor: guiding patients' informed choices.

To compare the effects of oral nutritional supplements (ONS), parenteral nutrition (PN), and enteral nutrition (EN) on the recovery of patients who underwent oral and maxillofacial surgery. The shared decision-making process assigned 37, 56, and 35 patients to the ONS, PN, and EN groups, respectively. Details such as demographic data, duration of hospitalization, cost of nutritional therapy, nutritional assessments, patients' satisfaction, and compliance, Hamilton Anxiety Rating Scale (HAM-A) score, and relevant biochemical indices were systematically recorded and compared between the groups. Patients with healthier biochemical indices and physical states at baseline, including a higher body mass index, preferred ONS. Patients using dentures and those with medical insurance often chose EN, while patients with recurrent disease preferred PN. Patients receiving EN had a similar duration of hospitalization to patients receiving ONS and also had the lowest nutritional costs. Patients receiving ONS had higher lymphocyte counts and levels of hemoglobin, albumin, and C-reactive protein. Patients in the PN group had elevated levels of serum potassium, chlorine, and sodium, while those receiving EN reported higher HAM-A scores, indicating greater anxiety than their counterparts. Predischarge surveys showed higher satisfaction and compliance in the PN and ONS groups than in the EN group. The PN group reported more adverse symptoms. At 7days post-discharge, patients with EN reported a greater feeling of well-being. ONS is the optimal choice for patients in good preoperative conditions, while PN is preferred during disease recurrence or when financially feasible. EN is suitable for patients using dentures or those with limited finances despite its potential psychological discomfort. Future studies with increased sample sizes and longer follow-up duration are necessary to corroborate our findings. The Trial Registration Number is ChiCTR2100049547. The date of registration isAugust 2, 2021.

Triterpene-Based Prodrug for Self-Boosted Drug Release and Targeted Oral Squamous Cell Carcinoma Chemotherapy.

Chemotherapy is one of the main treatments for oral squamous cell carcinoma (OSCC), especially as a combined modality approach with and after surgery or radiotherapy. Limited therapeutic efficiency and serious side effects greatly restrict the clinical performance of chemotherapeutic drugs. The development of smart nanomedicines has provided new research directions, to some extent. However, the involvement of complex carrier compositions inevitably brings biosafety concerns and greatly limits the "bench-to-bed" translation of most nanomedicines reported. In this study, a carrier-free self-assembled prodrug was fabricated by two triterpenes (glycyrrhetinic acid, GA and ginsenoside Rh2, Rh2) isolated from medicinal plants, licorice, and ginseng, for the targeted and highly effective treatment of OSCC. Reactive oxygen species (ROS) self-supplied molecule TK-GA2 was synthesized with ROS-responsive thioketal linker and prodrug was prepared by a rapid-solvent-exchange method with TK-GA2 and Rh2. After administration, oral tumor cells transported large amounts of prodrugs with glucose ligands competitively. Endogenous ROS in oral tumor cells then promoted the release of GA and Rh2. GA further evoked the generation of a large number of ROS to help self-boosted drug release and increase oxidative stress, synergistically causing tumor cell apoptosis with Rh2. Overall, this carrier-free triterpene-based prodrug might provide a preeminent opinion on the design of effective chemotherapeutics with low systemic toxicity against OSCC.

Immune cell topography of head and neck cancer

BackgroundApproximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of...

Long-term toxicity and efficacy of FLASH radiotherapy in dogs with superficial malignant tumors.

FLASH radiotherapy (RT) has emerged as a promising modality, demonstrating both a normal tissue sparing effect and anticancer efficacy. We have previously reported on the safety and efficacy of single fraction FLASH RT in the treatment of oral tumors in canine cancer patients, showing tumor response but also a risk of radiation-induced severe late adverse effects (osteoradionecrosis) for doses ≥35 Gy. Accordingly, the objective in this study was to investigate if single fraction high dose FLASH RT is safe for treating non-oral tumors. Privately-owned dogs with superficial tumors or microscopic residual disease were included. Treatment was generally delivered as a single fraction of 15-35 Gy 10 MeV electron FLASH RT, although two dogs were re-irradiated at a later timepoint. Follow-up visits were conducted up to 12 months post-treatment to evaluate treatment efficiency and adverse effects. Fourteen dogs with 16 tumors were included, of which nine tumors were treated for gross disease whilst seven tumors were treated post-surgery for microscopic residual disease. Four treatment sites treated with 35 Gy had ulceration post irradiation, which was graded as severe adverse effect. Only mild adverse effects were observed for the remaining treatment sites. None of the patients with microscopic disease experienced recurrence (0/7), and all patients with macroscopic disease showed either a complete (5/9) or a partial response (4/9). Five dogs were euthanized due to clinical disease progression. Our study demonstrates that single fraction high dose FLASH RT is generally safe, with few severe adverse effects, particularly in areas less susceptible to radiation-induced damage. In addition, our study indicates that FLASH has anti-tumor efficacy in a clinical setting. No osteoradionecrosis was observed in this study, although other types of high-grade adverse effects including ulcer-formations were observed for the highest delivered dose (35 Gy). Overall, we conclude that osteoradionecrosis following single fraction, high dose FLASH does not appear to be a general problem for non-oral tumor locations. Also, as has been shown previously for oral tumors, 30 Gy appeared to be the maximum safe dose to deliver with single fraction FLASH RT.

Might photobiomodulation therapy interfere with the frequency of severe mucositis and oral candidiasis? A retrospective analysis in patients with head and neck carcinoma.

Considering the tumor in the oral cavity or the oropharynx and nasopharynx region might be an aggravating factor for oral mucositis (OM) manifestation, the present study aimed to evaluate whether the location of the tumor and the use of photobiomodulation therapy (PBMT) might affect the frequency of oral candidiasis (OC) during radiotherapy (RT) and/or chemotherapy (CT) treatments. The medial records of seventy-four patients with head and neck cancer treated in a public service from 2016 to 2019 were evaluated. All these patients were submitted to RT in an accumulated dose of 48 to 70Gy of radiation. Data about OM and OC were collected and presented according to the application of a therapeutic protocol with laser photobiomodulation (PBMT) to control oral mucositis, or not (No-PBM), and the location of tumor (head and neck or oral cavity). In the PBMT group patients, a low-power laser device composed of InGaAlP diode (maximum output power of 86.7mW, active tip area of 0.1256cm2, and continuous wavelength of 660nm), was applied to the lips (three points each), right and left jugal mucosa (three points each), the limit between hard and soft palate (three points), buccal floor/sublingual gland (one point), lateral edge of the tongue (three points on each side), and back of the tongue (six points), three times weekly, for 5weeks. The dosimetry used in each application was 2J for 3s, thus totaling 56J. The correlation between clinical characteristics such as age, tumor size (T), metastatic lymph node (N), number of RT and CT sessions, candidiasis, and OM were analyzed. Mucositis grades 1 and 2 were the most common among all patients, especially before the 12th radiotherapy session, regardless of the treatment with PBM (p > 0.05). Additionally, no difference in the grade of OM and OC was significantly observed when comparing the two laser therapy groups. OC was more frequent after the 12th radiotherapy session in all groups. Nonetheless, OM and OC had a different correlation regarding to tumor location (head and neck and oral cavity) being PBMT a positive therapy to delay OM. It was observed a positive and statistically significant correlation between tumors at oral cavity and OM, regardless PBMT (R = 0.84, p < 0.05 to PBMT and R = 0.13, p < 0.05 to No-PBM). Otherwise, OC was positively correlated to local metastasis in patients with oral tumors undergoing PBMT (R = 0.84, p < 0.05). Patients with oral cavity tumor presented more OM, especially high grades, then patients with tumors in other regions of the head and neck, which seems to be related to the irradiation parameters of radiotherapy and/or with the limitation of conduction of PBMT in tumor areas. OM and OC were not changed by PBMT, although it helped to reduce the incidence of severe cases of OM.