OBJECTIVE: To obtain detailed understanding on the gene regulation of natural compounds in altering prognosis of head and neck squamous cell carcinomas (HNSC). METHODS: Gene expression data of HNSC samples and peripheral blood mononuclear cells (PBMCs) of HNSC patients were collected from Gene Expression Omnibus (GEO). Differential gene expression analysis of GEO datasets were achieved by the GEO2R tool. Common differentially expressed gerres (DEGs) were screened by comparing DEGs of HNSC with those of PBMCs. The combination was further analyzed for regulating pathways and biological processes that were affected. RESULTS: Totally 110 DEGs were retrieved and identified to be involved in biological processes related to tumor regulation. Then 102 natural compounds were screened for a combination such that the expression of all 110 commonly DEGs was altered. A combination of salidroside, ginsenoside Rd, oridonin, britanin, and scutellarein was chosen. A multifaceted, multi-dimensional tumor regression was showed by altering autophagy, apoptosis, inhibiting cell proliferation, angiogenesis, metastasis and inflammatory cytokines production. CONCLUSIONS This study has helped develop a unique combination of natural compounds that will markedly reduce the propensity of development of drug resistance in tumors and immune evasion by tumors. The result is crucial to developing a combinatorial natural therapeutic cocktail with accentuated immunotherapeutic potential.
Humans ; Leukocytes, Mononuclear ; Head and Neck Neoplasms/drug therapy* ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Immunotherapy ; Prognosis

Oral squamous cell carcinoma (OSCC) is a prevalent malignant tumor affecting the head and neck region (Leemans et al., 2018). It is often diagnosed at a later stage, leading to a poor prognosis (Muzaffar et al., 2021; Li et al., 2023). Despite advances in OSCC treatment, the overall 5-year survival rate of OSCC patients remains alarmingly low, falling below 50% (Jehn et al., 2019; Johnson et al., 2020). According to statistics, only 50% of patients with oral cancer can be treated with surgery. Once discovered, it is more frequently at an advanced stage. In addition, owing to the aggressively invasive and metastatic characteristics of OSCC, most patients die within one year of diagnosis. Hence, the pursuit of novel therapeutic drugs and treatments to improve the response of oral cancer to medication, along with a deeper understanding of their effects, remains crucial objectives in oral cancer research (Johnson et al., 2020; Bhat et al., 2021; Chen et al., 2023; Ruffin et al., 2023).
Humans ; Mouth Neoplasms/pathology* ; Carcinoma, Squamous Cell/metabolism* ; Luteolin/therapeutic use* ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Head and Neck Neoplasms/drug therapy* ; Cell Line, Tumor

Objective: To evaluate the roles of G Protein-Coupled Receptor 68 (GPR68) and tumor infiltrating lymphocytes (TIL) in TPF-(paclitaxel, cisplatin and 5-fluorouracil) induced chemotherapy for middle-advanced hypopharyngeal squamous cell carcinomas. Methods: A total of 31 patients with middle-advanced hypopharyngeal squamous cell carcinoma before TPF-inducted chemotherapy were enrolled from September 2012 to November 2017 in Beijing Tongren Hospital, Capital Medical University, including 28 males and 3 females, aged 43 to 71 years old. The expression of GPR68 and tumor infiltrating CD4⁺and CD8⁺T cells before chemotherapy was detected by immunohistochemical staining, and the relationships between GPR68 expression and clinical features, chemotherapy efficacy and overall survival (OS) were analyzed using t-test. Results: After 3 cycles of chemotherapy, there were 4, 14, 10 and 3 patients respectively with complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The positive rates of GPR68 and CD8 were 25% and 40% respectively in the effective group (CR+PR), while 50% and 15% in the ineffective group (SD+PD), with statistically significant differences between two groups (t=5.17 and 12.86,P<0.001). Linear regression analysis showed that GPR68 was negatively correlated with CD8⁺T cells (r=-0.64,P<0.001). There was no significant correlation between the CD4 expression and TPF efficacy (P>0.05). The mean OS was 12.5 months in patients with high-expressed GPR68 and 25.0 months in patients with low-expressed GPR68, with a statistically significant difference (P=0.005). And mean OS was 25.0 months in patients with high-expressed CD8 and 14.5 months in low-expressed CD8, with a statistically significant difference (HR=2.58, P=0.019). Cox regression analysis showed that GPR68 and CD8⁺T cells were significant prognostic factors (OR(95%CI)=3.27(2.46-5.97) and 1.53(0.78-1.82), all P<0.05), while CD4 had no significant effect on prognosis (P>0.05). Conclusion: GPR68 and CD8⁺T cells are expected to be biomarkers for evaluating the efficacy and prognosis of TPF-induced chemotherapy in patients with middle-advanced hypopharyngeal squamous cell carcinoma.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Cisplatin ; Female ; Fluorouracil ; Head and Neck Neoplasms/drug therapy* ; Humans ; Induction Chemotherapy ; Lymphocytes, Tumor-Infiltrating ; Male ; Middle Aged ; Prognosis ; Receptors, G-Protein-Coupled ; Squamous Cell Carcinoma of Head and Neck

OBJECTIVE: To investigate the characteristics of pathogen infection and to establish a prediction model of infections in oral squamous cell carcinoma patients undergoing surgery with free flap reconstruction. METHODS: The retrospective cohort study consisted of 1 596 patients undergoing tumor resection and free flap reconstruction for oral squamous cell carcinoma from January 2018 to December 2020. According to the postoperative infection, the patients were divided into the infected group (n=154) and non-infected group (n=1 442). The characteristics of pathogens were analyzed in the infected patients. The primary outcome variable was postoperative infection, and Logistic regression was used to determine risk factors of the infection. The prediction model was established and the discriminatory accuracy of the model was evaluated using receiver operating characteristic (ROC) curve. RESULTS: Totally 154 cases were infected in the 1 596 cases undergoing surgery with free flap reconstruction, and the infection rate was 9.65%. The most frequent sites of infection were the surgical wound and respiratory tract. A total of 268 pathogens were isolated and cultured, including 240 strains of Gram-negative bacteria, accounting for 89.55%, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae; 23 strains of Gram-positive bacteria, accounting for 8.58%, mainly Enterococcus faecalis and Staphylococcus aureus; and 5 strains of fungi, accounting for 1.87%. The isolated Pseudomonas aeruginosa had high resistant rate to imipenem and meropenem, and was sensitive to antibiotics, such as ciprofloxacin. The isolated Staphylococcus aureus had high resistant rate to erythromycin and clindamycin, and was sensitive to vancomycin. According to the multivariate Logistic analysis, four independent variables were significantly associated with an increased risk of postoperative infection (P < 0.05): clinical N category≥1, the American Society of Anesthesiologists (ASA) grade ≥2, tracheotomy and length of hospital stay >13 d. The prediction model was established based on these factors and the expression of the risk prediction model was as follows: predicted probability value P=1/(1+e^-a), a=-0.803+0.674×(clinical N category ≥1)+0.518×(the ASA grade ≥2)+0.918×(tracheotomy)+1.581×(length of hospital stay >13 d), Hosmer-Lemeshow χ²=10.647, P=0.223, the degree of fitting of the model was good. The area under the ROC curve was 0.818 and 95%CI of the model for predicting infection was 0.789-0.846. CONCLUSION Oral squamous cell carcinoma patients undergoing surgery with free flap reconstruction are prone to have a high incidence of postoperative infection and Gram-negative bacteria are the main pathogens causing an infection. The established prediction model is of good predictive effect. Rational antimicrobial use coupled with awareness of infection control measures is paramount to reduce the incidence of postoperative infection in the oral squamous cell carcinoma patients undergoing surgery with free flap reconstruction.
Anti-Bacterial Agents/therapeutic use* ; Carcinoma, Squamous Cell/surgery* ; Drug Resistance, Bacterial ; Free Tissue Flaps ; Head and Neck Neoplasms ; Humans ; Microbial Sensitivity Tests ; Mouth Neoplasms/surgery* ; Retrospective Studies ; Squamous Cell Carcinoma of Head and Neck/drug therapy*

Immune checkpoint inhibitors (ICIs) present significant efficacy in the treatment of malignant tumors, and they have been approved as the first-line of treatment for various cancers. Pembrolizumab monotherapy or combined with chemotherapy has been recommended by domestic and foreign guidelines for the first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma. Although ICIs represent a milestone in the treatment of head and neck squamous cell carcinoma, potential problems still need to be addressed, such as the selection of the efficacy predictors for ICIs, the evaluation of the tumor response to ICIs, and the treatment of immune hyperprogression and immune-related adverse events. Therefore, to form a relatively unified understanding of ICIs treatment for head and neck squamous cell carcinoma, we integrated the clinical experience of multi-disciplinary experts of head and neck cancers on the basis of current clinical hot issues and finally developed this consensus.
Humans ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Immune Checkpoint Inhibitors ; Consensus ; Neoplasm Recurrence, Local/pathology* ; Head and Neck Neoplasms/drug therapy*

Adenosquamous cell carcinoma of tonsil is a rare lesion of head and neck and is often misdiagnosed as squamous cell carcinoma. It has a very aggressive clinical pattern. We encountered a patient with an adenosquamous cell carcinoma of tonsil and performed various treatment modalities including surgical resection, radiation therapy, chemotherapy but the patient expired two years after the first diagnosis. Such case has never been reported earlier in Korea. Herein, we present this rare case with a review of related literature.
Carcinoma, Adenosquamous ; Carcinoma, Squamous Cell ; Diagnosis ; Drug Therapy ; Head ; Humans ; Korea ; Neck ; Palatine Tonsil

After FDA approval of cetuximab at 2006, receptor tyrosine kinase, including an epidermal growth factor receptor, blocking agents have been evaluated for head and neck squamous cell carcinoma (HNSCC). Agents targeting PI3K/Akt/mTOR, IL-6/JAK/STAT3, vascular endothelial growth factor receptor, and cyclin D-CDK-4/6-INK4/Rb pathway have developed. Most of them have failed to demonstrate better treatment outcome in recurrent and/or metastatic (R/M) HNSCC than conventional chemotherapy. Since a pivotal role of PD-1/PD-L1 pathway in immunological tumor microenvironment was revealed, the immune checkpoint inhibitors, including pembrolizumab and nivolumab, have opened new paradigm of cancer treatment modality and propagates other immune-based therapies for R/M HNSCC. Various types of combination trials consisting of immunotherapy with other class of immunotherapy, targeted agents, radiation therapy, or conventional chemotherapy have been under investigation to improve treatment outcome. Biomarker studies to find an optimal candidate for the newly developed agents are accompanied. These clinical trials lead to tailored approach based on immunotherapy with precision medicine is expected to lead to promising results.
Carcinoma, Squamous Cell ; Cetuximab ; Cyclins ; Drug Therapy ; Epithelial Cells ; Head ; Immunotherapy ; Molecular Targeted Therapy ; Neck ; Precision Medicine ; Protein-Tyrosine Kinases ; Receptor, Epidermal Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Treatment Outcome ; Tumor Microenvironment

Radiotherapy (RT) is a mainstay in the treatment of head and neck squamous cell carcinoma (HNSCC). For locally advanced HCSCC, concurrent chemoradiotherapy (CCRT) benefits HCSCC patients in terms of better survival and loco-regional control. In this study, we evaluated changes in oral microbiota in patients, who received CCRT for head and neck cancer. Oral rinsed samples were weekly collected before and during CCRT and at 4 weeks following treatment from HNSCC patients, who had received 70 Gy of radiation delivered to the primary sites for over 7 weeks and concurrent chemotherapy. Oral microbiota changes in three patients were analyzed by next-generation sequencing using 16S rRNA 454 pyrosequencing. On an average, 15,000 partial 16S rRNA gene sequences were obtained from each sample. All sequences fell into 11 different bacterial phyla. During early CCRT, the microbial diversity gradually decreased. In a patient, who did not receive any antibiotics during the CCRT, Firmicutes and Proteobacteria were the most abundant phylum. During the early CCRT, proteobacteria gradually decreased while Firmicutes increased. During the late CCRT, firmicutes gradually decreased while Bacteroides and Fusobacteria increased. In all the patients, yellow complex showed a gradual decrease, while orange and red complex showed a gradual increase during the CCRT. At 4 weeks after CCRT, the recovery of oral microbiota diversity was limited. During CCRT, there was a gradual increase in major periodontopathogens in association with the deterioration of the oral hygiene. Henceforth, it is proposed that understanding oral microbiota shift should provide better information for the development of effective oral care programs for patients receiving CCRT for HNSCC.
Anti-Bacterial Agents ; Bacteroides ; Carcinoma, Squamous Cell ; Chemoradiotherapy ; Citrus sinensis ; Drug Therapy ; Epithelial Cells ; Firmicutes ; Fusobacteria ; Genes, rRNA ; Head and Neck Neoplasms ; Head ; Humans ; Microbiota ; Neck ; Oral Hygiene ; Proteobacteria ; Radiotherapy

PURPOSE: To evaluate the prognostic value of 18F-fluorodeoxyglucose positron-emission tomography (FDG PET) with computed tomography (CT) before and during radiotherapy (RT) in patients with head and neck cancer. METHODS: Twenty patients with primary head and neck squamous cell carcinoma were enrolled in this study, of whom 6 had oropharyngeal cancer, 10 had hypopharyngeal cancer, and 4 had laryngeal cancer. Fifteen patients received concurrent cisplatin and 2 received concurrent cetuximab chemotherapy. FDG PET/CT was performed before RT and in the 4th week of RT. The parameters of maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor were measured, and the prognostic significance of each was analyzed with the Cox proportional hazards model. RESULTS: Higher TLG (>19.0) on FDG PET/CT during RT was a poor prognostic factor for overall survival (OS) (p = 0.001) and progression-free survival (PFS) (p = 0.007). In the multivariate analysis, TLG during RT as a continuous variable was significantly associated with OS and PFS rate (p = 0.023 and p = 0.016, respectively). Tumor response worse than partial remission at 1 month after RT was another independent prognostic factor for PFS (p = 0.024). CONCLUSIONS: Higher TLG of the primary tumor on FDG PET/CT during RT was a poor prognostic factor for OS and PFS in patients with head and neck cancer.
Carcinoma, Squamous Cell ; Cetuximab ; Cisplatin ; Disease-Free Survival ; Drug Therapy ; Glycolysis ; Head and Neck Neoplasms ; Head ; Humans ; Hypopharyngeal Neoplasms ; Laryngeal Neoplasms ; Multivariate Analysis ; Neck ; Oropharyngeal Neoplasms ; Positron-Emission Tomography ; Positron-Emission Tomography and Computed Tomography ; Proportional Hazards Models ; Radiotherapy ; Tumor Burden

Prognosis in relapsed metastatic head and neck squamous cell cancer (RM-HNSCC) is dismal. Platinum based chemotherapy in combination with Cetuximab is used in first-line setting, while no further validated options are available at progression. Immunotherapy has produced durable clinical benefit in some patients with RM-HNSCC although the premises are several patients are nonresponders. Studies are ongoing to determine predictive factors and the ideal setting/combination of novel immunotherapies. In this paper, we discuss the past and present of immunotherapy in head and neck cancer and provide an up-to-date information regarding the potential ways to improve immunotherapy outcomes in HNSCC.
Biomarkers ; Carcinoma, Squamous Cell ; Cetuximab ; Drug Therapy ; Epithelial Cells* ; Head and Neck Neoplasms ; Head* ; Humans ; Immunotherapy* ; Neck* ; Neoplasms, Squamous Cell* ; Platinum ; Prognosis ; Tumor Escape