The small extracellular vesicle-mediated intercellular transformation of CXCR1Low to CXCR1High tumour cells promotes the progression of head and neck squamous cell carcinoma.

The heterogeneity of tumour cells enables cancers to dynamically adapt to microenvironmental stresses during progression. However, the mechanism underlying the transformation and intercellular communication between heterogeneous tumour cells has remained elusive. Here, we report a "contagion model" that mediates intercellular transformation between heterogeneous tumour cells which facilitates tumour progression. Initially identifying heterogeneous expression of CXCR1, a receptor for interleukin-8, in head and neck squamous cell carcinoma (HNSCC) tumour cells, we found that CXCR1High tumour cells had higher abilities for migration and invasion. Following interleukin-8-mediated activation, CXCR1High cells transformed CXCR1Low cells into CXCR1High cells through the secretion of small extracellular vesicles (sEVs), which increased the proportion of CXCR1High cells and facilitated tumour progression. Mechanistically, we demonstrate that sEVs derived from interleukin-8-activated CXCR1High cells contain high levels of ATP citrate lyase (ACLY), which acetylates NF-κB p65 and facilitates its nuclear translocation to transcribe CXCR1 in CXCR1Low cells. That process could be inhibited by Bempedoic acid, an FDA-approved ACLY-targeted drug. Taken together, our study reveals an sEV-mediated transformation of CXCR1Low to CXCR1High cells that promotes HNSCC progression. This provides a new paradigm to explain the dynamic changes of heterogeneous tumour cells, and identifies Bempedoic acid as a potential drug for HNSCC treatment.

Comprehensive clinical, genome and transcriptomic analysis of primary ghost cell odontogenic carcinoma.

OBJECTIVES: There is currently no comprehensive genome-wide description of the primary ghost cell odontogenic carcinoma (GCOC), hindering our understanding of pathogenesis. We herein present a case with comprehensive clinical, genome and transcriptomic analysis. These will serve as the first comprehensive molecular atlas for primary GCOC. A 58-year-old male underwent subtotal resection with prosthetic restoration. Genome sequencing (WGS) detected previously identified CTNNB1 mutation with novel alterations of MAP3K, EP300, and 22q11.21 region. Transcriptome results showed significant involvement of cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway. These results need to be compared with more GCOCs for more accurate clinical guidance.

Tumor-derived extracellular vesicles in the immune microenvironment of head and neck squamous cell carcinoma: Foe or future?

Head and neck squamous cell carcinoma (HNSCC) is considered a "cold tumor" due to its suppressive immune microenvironment, and is associated with a poor prognosis. Tumor-derived extracellular vesicles (EVs) play an essential role in the tumor microenvironment and mediate intercellular communications. EVs have been proven to be key immune regulators involved in antitumor immune responses and escape from immune surveillance. Tumor-derived EVs favor the formation of an immunosuppressive tumor microenvironment by regulating the differentiation, proliferation and activation of innate and adaptive immune effector cells, as well as myeloid cells, acting as a "foe" in the microenvironment. However, EVs are also valuable for predicting and improving the prognosis of HNSCC, and represent hope for future treatments. In this review, we summarize the impact of HNSCC-derived EVs on the immune microenvironment, describe their roles as biomarkers and for drug delivery in disease monitoring and treatment. We provide insights into important areas for future research and identify potential therapeutic targets for HNSCC treatment.

The significance of elective neck dissection for patients with T2N0M0 OSCC at different ages.

BACKGROUND: The aim of this study was to determine the significance of elective neck dissection (END) for patients of different ages with T2N0M0 oral squamous cell carcinoma (OSCC) and sought to analyze the reasons behind it and its value for clinical guidance. METHODS: This study enrolled 391 patients with T2N0M0 OSCC who were surgically treated in our hospital and were divided into young-, moderate-, and advanced-age groups according to our previous study. The Chi-square test and Kaplan-Meier analysis were performed for statistical analysis. RESULTS: Compared with moderate- and advanced-age patients, young patients with T2N0M0 OSCC had higher lymph node metastasis rates and lymph node ratios. Therefore, END significantly improved the recurrence (p = 0.001) and survival (p = 0.001) for young patients, but not for moderate-age patients. Advanced-age patients even benefit from watchful waiting. END significantly improved recurrence and survival in young patients with smoking or alcohol consumption habits. CONCLUSIONS: END improved the prognosis of young patients, and it was related to their higher metastasis rate. However, advanced-age patients benefited from the wait-and-see policy. END is essential for the young patients with smoking or drinking habit, it is also highly recommended for nonsmokers and nondrinkers.

Tumour-stroma ratio is a valuable prognostic factor for oral tongue squamous cell carcinoma.

OBJECTIVE: The objectives of this study were to estimate the prognostic value of the tumour-stroma ratio (TSR) and tumour budding (TB) in oral tongue squamous cell carcinoma (OTSCC) and to establish a reliable model to predict the outcome of OTSCC patients. METHODS: A total of 103 patients surgically treated at our hospital were enrolled in this study. Chi-square tests, Kaplan-Meier analyses and Cox proportional hazards regression models were performed for statistical analysis. RESULTS: Fifty-six patients were categorized as stroma-rich, and 47 patients were categorized as stroma-poor. Only pathological grade was associated with the TSR (p = 0.017). Kaplan-Meier analysis showed that stroma-rich, high-intensity budding and high risk groups were associated with worse prognosis. The Cox regression model showed that the TSR was an independent risk factor for OTSCC patients prognosis, and the high risk group was also related to poor prognosis (p < 0.05). TB was significantly associated with poor prognosis but was not an independent risk factor. CONCLUSIONS: We found that patients in the stroma-rich group had a worse long-term prognosis. The TSR is an independent risk factor for OTSCC patients' outcome. In addition, a risk model that combined the TSR and TB proved to be valuable for predicting OTSCC patients' outcome.

Family history of cancer is associated with poorer prognosis in oral squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to investigate the prognostic value of the family history of cancer (FHC) in predicting survival and clinicopathological features in oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: This single-institution study utilized data from 610 patients undergoing surgery from 2014 to 2020 that was prospectively collected and cataloged for research purposes. All patients underwent standard surgery with/without radiotherapy or chemoradiotherapy. We statistically evaluated whether FHC was associated with changes in disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Among 610 patients, 141 (23.1%) reported a family history of cancer. The distribution of clinicopathological characteristics was balanced between FHC-positive and FHC-negative OSCC patients. FHC-positive patients had decreased DFS (p = 0.005) and DSS (p = 0.018) compared to FHC-negative patients. CONCLUSIONS: FHC-positive OSCC patients have a poorer prognosis. FHC positivity is an independent predictor of negative outcomes based on DFS and DSS. FHC should be a consideration in screening, evaluating, counseling, and treating OSCC patients.

The modified vermilion border-marionette line approach: A management for buccal cancer with wider indications and higher satisfaction.

OBJECTIVE: The purpose of this study is to explore the effects of modified vermilion border-marionette line (MVBML) approach on postoperative facial scar, nerves injury, and prognosis of patients with buccal squamous cell carcinoma (BSCC). PATIENTS AND METHODS: This is a single-center, prospective cohort study that enrolled 80 patients with BSCC from June 2015 to December 2020. According to the different surgical approaches, the patients were divided into two groups: the lower lip median (LLM) approach group and the MVBML approach group. RESULTS: The results showed that the appearance (p = 0.003), scar consciousness (p < 0.001) and satisfaction with appearance (p = 0.001) of patients in the MVBML group were significantly better than those in the LLM group, and the difference was more obvious in elderly group. Statistical analysis of postoperative nerves injury showed that the MVBML group had a lower risk of facial and mental nerves injury than the LLM group, and there was a significant statistical difference in mental nerve injury between the two groups (p < 0.001). Through Kaplan-Meier survival analysis, we found no significant difference in disease-specific survival (p = 0.47) or disease-free survival (p = 0.70) between the LLM approach group and the MVBML approach group. CONCLUSIONS: The MVBML surgical approach is worthy of advancement for the surgical treatment of BSCC.

Comprehensive complication index: A new reporting standard for postoperative complications of free-flap reconstruction in head and neck cancer patients.

OBJECTIVE: We aimed to validate and evaluate the comprehensive complication index (CCI) as a measure of postoperative complications (POCs) in the patients with head and neck squamous cell carcinoma (HNSCC) who had undergone free-flap reconstruction. STUDY DESIGN: A single-center, prospective cohort study was conducted on the patients with primary HNSCC treated between 2015 and 2020. RESULTS: Of 443 patients, 177 experienced POCs (40.0%). According to the new CCI, 93 patients had severe POCs (score ≥26.2; 21.0%), and only 76 patients were classified as having severe POCs (grade ≥III; 17.2%) according to the traditional Clavien-Dindo classification (CDC). The patients with CCI scores ≥26.2 had a higher rate of major adverse short-term outcomes, such as prolonged length of the hospital stay after surgery, excessive medical costs, and the need for transfusion. Importantly, the Kaplan-Meier analysis revealed a lower overall survival rate for patients with severe complications (CCI score ≥26.2, P = .038). However, no statistically significant differences were observed between CDC grades III or above and overall survival (P = .100). CONCLUSIONS: The CCI can be used to evaluate POCs of free-flap reconstruction in patients with HNSCC. It performed more accurately than the CDC in short- and long-term outcome prediction and risk factor identification.

The application of salvage surgery improves the quality of life and overall survival of extensively recurrent head and neck cancer after multiple operation plus radiotherapy.

Objectives: The prognosis, choice of reconstruction and the quality of life (QOL) after salvage surgery (SS) for extensively locoregional recurrent/metastatic head and neck cancer (R/M HNC) is an important issue, but there are few reports at present. Materials and methods: We analyzed extensively locoregional R/M HNC patients from March 1, 2015, to December 31, 2021 who underwent SS with latissimus dorsi or pectoralis major musculocutaneous flaps. QOL were accessed using QLQ-H&N35 and UW-QOL questionnaire. Wilcoxon signed-rank test was used to compare difference between pre- and post-QOL and Kaplan-Meier curves were used in estimate overall survival (OS) and disease-free survival (DFS). The literature review summarized recent 10 years clinical trials of nonoperative treatment in R/M head and neck cancer. Results: 1362 patients were identified and 25 patients were analyzed after screened. Median age at surgery was 59 years (range 43-77), 15/25(60%) were male and 22/25(88%) chose latissimus dorsi flap. Better mean pain score after applying massive soft tissue flaps revealed relief of severe pain(p<0.001) which strongly associated with improvement of QOL. The improved mean overall QOL score after surgery revealed a better QOL(p<0.001). As of June 1, 2022, 11/25 (44%) of the patients were alive. The 1-year, 2-year OS after SS was 58.4% and 37.2%, while the 1-year, 2-year DFS was 26.2% and 20.9%. The median OS of our study was better than nonoperative treatment of 11 included clinical trials. Conclusions: R/M HNC patients underwent SS can obtain survival benefit. The application of massive soft tissue flap in SS could significantly enhance the QOL for patients with extensively locoregional R/M HNC, especially by relieving severe pain.

Lactate secreted by PKM2 upregulation promotes Galectin-9-mediated immunosuppression via inhibiting NF-κB pathway in HNSCC.

Pyruvate kinase M2 as a key rate-limiting enzyme in glycolysis, it plays a critical role in metabolic reprogramming and carcinogenesis. However, whether PKM2 can promote immunosuppressive microenvironment formation remains unknown in head and neck squamous cell carcinoma (HNSCC). PKM2 expression was detected using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of Galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. The mechanism of lactate regulating Galectin-9 expression through NF-κB signaling was explored in vitro. Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. The glycolysis and glycolytic capacity are significantly decreased after PKM2 silencing. Lactate secretion induced by PKM2 significantly promotes migration and invasion capacity. Furthermore, a positive correlation between PKM2 and Galectin-9 expression is observed in HNSCC tissues. The induction of Galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor. Mechanically, lactate impeded the suppressive transcriptional complex formation of NF-κB and histone deacetylase 3 (HDAC3), which released the transcription of Galectin-9 mediated by NF-κB signaling. Our findings demonstrate that lactate produced by PKM2 upregulation promotes tumor progression and Galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-Galectin-9 axis might be a potential therapeutic target in HNSCC.

The interaction of interleukin-8 and PTEN inactivation promotes the malignant progression of head and neck squamous cell carcinoma via the STAT3 pathway.

Interleukin-8 (IL-8) expression correlates with poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. In this study, we found that overexpression of IL-8 correlated with poor outcome in HNSCC patients. IL-8 significantly increased cellular proliferation, migration, and invasion ability both in vitro and in vivo, which could be blocked by a CXCR1/2 inhibitor. IL-8 promoted the expression of MMP2, MMP9, snail, and vimentin in HNSCC cells. Furthermore, IL-8 could inactivate PTEN via phosphorylation, and then inactivated PTEN affected the phosphorylation of STAT3. Recombinant PTEN that internalized in cytoplasm decreased the expression of phosphorylated STAT3, while knockdown of PTEN led to the increased expression of phosphorylated STAT3. A STAT3 inhibitor could reverse the upregulation of invasion-associated proteins mediated by IL-8 stimulation. Furthermore, overexpression of snail and inactivated PTEN jointly promoted the autocrine effect of IL-8 on tumor cells. Last, there were positive correlations between IL-8 and snail, vimentin expression in HNSCC tissues. In summary, our study demonstrates that PTEN acts as a novel "molecular switch" to regulate IL-8/STAT3 signaling, promoting the progression of HNSCC, and indicating that this pathway may be a potential therapeutic target for HNSCC.

Hypoxia-induced MFAP5 Promotes Tumor Migration and Invasion via AKT Pathway in Head and Neck Squamous Cell Carcinoma.

Objective: Microfibrillar-associated protein 5 (MFAP5) is highly expressed in many types of cancers. Our previous study has observed that overexpression of MFAP5 was correlated with lymph nodes metastasis and poor prognosis in head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism is poorly understood. Materials and methods: The MFAP5 expression is detected under hypoxia condition. HNSCC cell lines are transfected with MFAP5-expressing lentivirus vector to establish stable overexpression model. Wound-healing, migration and invasion assay are used to determine the effect of MFAP5 on HNSCC and metastasis-related proteins are examined by Western blot. In vivo lung metastasis assays are conducted by the tail vein injection. In addition, immunohistochemistry is applied to analyze the correlation of MFAP5, hypoxia-induced factor-1 α (HIF-1α), and vimentin in 84 HNSCC patients' tissue samples. Results: Firstly, MFAP5 expression can be markedly induced under hypoxia condition in HNSCC cell lines. Cell lines with MFAP5 overexpression has a significant higher ability of migration and invasion. In addition, in vivo assay observes that overexpression of MFAP5 can promote tumor lung metastasis. Furthermore, MFAP5 facilitates this process by activating epithelial-mesenchymal transition (EMT) program via AKT pathway in HNSCC cell lines. The pro-metastatic effect of MFAP5 can be reversed by MK2206, an AKT phosphorylation inhibitor. Lastly, the positive correlation among HIF-1α, MFAP5 and vimentin from tissue samples and TCGA dataset are also observed in HNSCC. Conclusion: Our study demonstrates MFAP5 plays a critical role in hypoxia-induced EMT program via AKT pathway in HNSCC, which would be a very promising therapeutic target.

The impact of age on oral squamous cell carcinoma: A longitudinal cohort study of 2,782 patients.

BACKGROUND: The purposes of this study were to assess the influence of age on oral squamous cell carcinoma patients and sought to analyze the reasons that may contribute to this difference. METHODS: This study enrolled 2,782 patients included 2,443 patients in a retrospective cohort to find the influence of age and 339 patients in a prospective cohort to testify these findings. The patients were divided into young age-group (≤40 years old), moderate age-group (41-75 years old), and advanced age-group (>75 years old). All patients were diagnosed as oral squamous cell carcinoma and were surgically treated in our hospital. Chi-square test, Kaplan-Meier analysis, and Cox proportional-hazards regression model were performed for statistical analysis. RESULTS: Younger patients started smoking (p < 0.001) and drinking (p < 0.001) earlier than the older patients and consumed more tobacco (p = 0.005) and alcohol (p = 0.156). Patients with advanced age had worse outcomes in both recurrence (p = 0.002) and survival (p < 0.001). They also had more severe comorbidity (p < 0.001) and were more likely to receive conservative treatment (p = 0.011). CONCLUSIONS: Compared with young patients, older patients had worse prognosis, and it was related with their more severe comorbidity and received more conservative treatment. Young adults smoking and drinking earlier and heavier than old patients, it may relate with their occurrence of oral squamous cell carcinoma.

Relationship between body mass index and outcomes for patients with oral squamous cell carcinoma.

OBJECTIVE: The purpose of our study was to investigate body mass index (BMI) as a prognostic factor and to examine the relationship between pretreatment BMI and oral squamous cell carcinoma (OSCC) outcomes in northern Chinese patients. METHODS: This retrospective study enrolled 633 patients with OSCC who underwent surgery between 2004 and 2014. RESULTS: Most baseline characteristics (gender, sites, smoking history, comorbidity, hypertension, T stage, clinical features, perineural invasion, flap reconstruction) were differentiated by BMI groups. Overall, the Kaplan-Meier curves indicated no significant relationship between BMI and disease-free survival (DFS) or disease-specific survival (DSS). Interestingly, obese patients exhibited higher risks of recurrence and death than normal-weight patients (DFS: HR: 1.86, 95% CI: 1.16-2.96; DSS: HR: 2.04, 95% CI: 1.08-3.86). However, postoperative complications occurred more frequently in underweight patients than in normal-weight patients. CONCLUSIONS: Obesity may contribute to a higher recurrence rate and a worse prognosis in OSCC patients than in normal-weight patients in northern China. However, underweight patients have a higher risk of postoperative complications.

[Primary acinic cell carcinoma in mandible: a case report].

Acinic cell carcinoma is a relatively rare salivary gland tumor predominantly occurring in the major glands. Therefore, acinic cell carcinoma rarely occurs in the mandible. In this study, a case of primary acinic cell carcinoma of the mandible was reported, and relevant literature was reviewed. The etiology, clinical symptom, image and histological features, diagnosis, treatment, and prognosis of acinic cell carcinoma in the mandible were discussed.

Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients With Head and Neck Squamous Cell Carcinoma.

BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) remains controversial. Additionally, there is no standardized approach or cutoff value for evaluating TIL levels. The aim of this study was to establish a feasible method and criterion to assess TIL levels for future clinical practice and research use and to explore the relationship between TIL levels and prognosis. PATIENTS AND METHODS: This retrospective cohort study reviewed the records and pathological sections of 202 patients with HNSCC who were surgically treated at Beijing Stomatological Hospital, Capital Medical University, from January 1998 to January 2011. The predictor variable was the TIL level. The main outcome assessment parameters were disease-free survival (DFS) and disease-specific survival (DSS). RESULT: The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level. A cutoff value equal to 70% could be taken as a threshold for TIL assessment, with a TIL level higher than 70% associated with a better prognosis (DFS rate: 51.9%, P = .018; DSS rate: 59.3%, P = .049). The Cox regression model showed that the TIL level was an independent prognostic factor for DFS (hazard ratio (HR): 0.786, 95% CI: 0.618-0.999, P = .049). CONCLUSION: The TIL level is closely related to the prognosis of patients with HNSCC. A threshold value of 70% is appropriate for TIL assessment, as patients with a TIL level higher than 70% show a better prognosis. Thus, the TIL level might serve as an independent predictor for HNSCC recurrence.