Mechanism of sensitivity to cisplatin, docetaxel, and 5-fluorouracil chemoagents and potential erbB2 alternatives in oral cancer with growth differentiation factor 15 overexpression.

The aim of this study was to: (a) explore the potential mechanism of cancer cell sensitivity to cisplatin, docetaxel, and 5-fluorouracil (TPF) in oral squamous cell carcinoma (OSCC) patients overexpressing growth differentiation factor 15 (GDF15); and (b) identify potential alternative agents for patients who might not benefit from inductive TPF chemotherapy. The results indicated that OSCC cells overexpressing GDF15 were sensitive to TPF through a caspase-9-dependent pathway both in vitro and in vivo. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential GDF15-binding protein, which was verified by coimmunoprecipitation. Growth differentiation factor 15 overexpression promoted OSCC cell proliferation through erbB2 phosphorylation, as well as downstream AKT and Erk signaling pathways. When GDF15 expression was blocked, the phosphorylation of both the erbB2 and AKT/Erk pathways was downregulated. When OSCC cells with GDF15 overexpression were treated with the erbB2 phosphorylation inhibitor, CI-1033, cell proliferation and xenograft growth colony formation were significantly blocked (P < .05). Thus, GDF15-overexpressing OSCC tumors are sensitive to TPF chemoagents through caspase-9-dependent pathways. Growth differentiation factor 15 overexpression promotes OSCC proliferation through erbB2 phosphorylation. Thus, ErbB2 inhibitors could represent potential targeted drugs or an alternative therapy for OSCC patients with GDF15 overexpression.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma.

BACKGROUND: Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. RESULT: Here, intelligent "theranostic" platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. CONCLUSION: In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions.

Stathmin guides personalized therapy in oral squamous cell carcinoma.

The survival benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy in oral squamous cell carcinoma (OSCC) patients is not satisfactory. Previously, we identified that stathmin, a microtubule-destabilizing protein, is overexpressed in OSCC. Here, we further investigated its role as a biomarker that impacts on OSCC chemosensitivity. We analyzed the predictive value of stathmin on TPF induction chemotherapy and its impact on OSCC cell chemosensitivity. Then, we further investigated the therapeutic effects of the combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors in vitro and in vivo. We found that OSCC patients with low stathmin expression benefited from TPF induction chemotherapy, while OSCC patients with high stathmin expression could not benefit from TPF induction chemotherapy. Stathmin overexpression promoted cellular proliferation and decreased OSCC cell sensitivity to TPF treatment. In addition, inhibition of the PI3K-AKT-mTOR signaling pathway decreased stathmin expression and phosphorylation. The combination therapy of TPF chemotherapy and PI3K-AKT-mTOR inhibitors exhibited a potent antitumor effect both in vitro and in vivo. Therefore, stathmin can be used as a predictive biomarker for TPF induction chemotherapy and a combination therapy regimen based on stathmin expression might improve the survival of OSCC patients.

High-risk lymph node ratio predicts worse prognosis in patients with locally advanced oral cancer.

BACKGROUND: To investigate the prognostic value of lymph node ratio (LNR), as well as the correlation with docetaxel, cisplatin, and 5-FU (TPF) induction chemotherapy, in patients with locally advanced oral squamous cell carcinoma (OSCC). METHODS: Two-hundred and forty-five patients from a phase 3 trial involving TPF induction chemotherapy in stage III/IVA OSCC patients (NCT01542931) were enrolled in this study between 2008 and 2010. The clinical and pathological data were collected and analyzed. The cutoff value for LNR was calculated on the receiver operating characteristic (ROC) curve. Univariate and multivariate Cox regression models, and Kaplan-Meier method were used for survival analysis. RESULTS: According to the ROC curve, the cutoff value for LNR was 7.6%. With a median follow-up period of 80 months, the OSCC patients with high-risk LNR (> 7.6%), or positive extranodal extension (ENE) had significantly worse clinical outcomes than patients with low-risk LNR (≤7.6%) or negative ENE. Multivariate analysis on pathological covariates showed that only high-risk LNR was an independent negative predictive factor for survival (P < .05). The cutoff value of LNR of 7.6% was also verified with the similar results using an open TCGA database, high-risk LNR indicating worse overall survival (P < .001) and disease-free survival (P < .001). CONCLUSION: Oral squamous cell carcinoma patients with high-risk LNR have a worse clinical outcome than patients with low-risk LNR. High-risk LNR is an independent negative predictive factor for clinical outcome in patients with locally advanced OSCC.

Clinical Application of Temporary External Fixator for Immediate Mandibular Reconstruction.

Immediate mandibular reconstruction is always necessary for the patients receiving segmental mandibulectomy to recover the facial contour and function of occlusion. When 3D modeling is unavailable, temporary external fixator is necessary to maintain the occlusion relationship and facial contour. In this study, we introduce the clinical application of temporary external fixator for immediate mandibular reconstruction in patients receiving segmental mandibulectomy, which consists of 2 anchor claws, 2 all-round retentive arms, and 1 central locking structure. From August 2016 to September 2017, temporary external fixator was applied in 13 patients. Clinical data of gender, age, surgical procedure, duration of operation, and clinical outcomes were recorded and analyzed. Among the 13 patients, there were 4 men and nine women whose ages ranged from 21 to 64 (mean 47.7) years old. There were 9 benign and 4 malignant lesions. All lesions expended at the buccal side of mandible. 12 fibular flaps and 1 vascularized iliac bone graft were used. The mandibular defect ranged from 6 to 14 (mean 10) cm. The operation duration of surgery ranged from 5 to 10 (mean 7) hours. All flaps survived with primary healing. The occlusion and facial contour were good, without significant changes of the length of mandibular body and width of mandible before and after surgery. No functional sequelae were noted at the donor sites. From these results, the temporary external fixator is easy to operate; the surgical procedure is simple and time-saving for surgeon when 3D modeling is unavailable. The indication for temporary external fixator usage is the mandibular lesion growing outward to cheek soft tissue.

Mutation allele frequency threshold does not affect prognostic analysis using next-generation sequencing in oral squamous cell carcinoma.

BACKGROUND: With the development of sequencing technologies, there may be some disputes on sequencing analysis. The aim of this study was to investigate different allele frequency thresholds of mutations in targeted genes on prognostic analyses using a panel of cancer associated gene exons (CAGE) in oral squamous cell carcinoma (OSCC). METHODS: Forty-six patients were included in this study. Twelve genes were sequenced and analyzed using next-generation sequencing from formalin-fixed paraffin-embedded tissues. Allele frequency thresholds of 10, 5, and 3% were used for prognostic analyses. RESULTS: With a mean sequence depth of 3199-fold, 99% of CAGE were represented by at least 10 reads. Ninety-four non-synonymous (missense [70.2%], nonsense [11.7%], splice site [10.6%], and insertion/deletion [7.5%]) mutations were detected in 40 OSCC patients with an allele frequency threshold of 10%. TP53 (78.3%), NOTCH1 (30.4%), CASP8 (13.0%), CDKN2A (10.9%), and CDH1 (6.5%) were the most frequently mutated genes. Using allele frequency thresholds of 10, 5, and 3%, there were no significant differences in clinical outcomes between patients with non-synonymous mutations and wild type genotypes. CONCLUSIONS: TP53, NOTCH1, CASP8, CDKN2A, and CDH1 are the most frequently mutated genes in OSCC patients. The allele frequency threshold used in this study does not affect the results of clinical outcome analysis.

Decreased expression of glutathione S-transferase pi correlates with poorly differentiated grade in patients with oral squamous cell carcinoma.

BACKGROUND: Glutathione S transferase pi (GSTP1) is a member of phase II detoxification enzymes as a major regulator of cell signaling in response to stress, hypoxia, growth factors, and other stimuli. The clinical role of GSTP1 in cancer is still unclear. The aim of this study was to investigate the serum GSTP1 level in patients with oral squamous cell carcinoma (OSCC) and the GSTP1 expression in tissue samples from patients with OSCC and OSCC lines. METHODS: One hundred and sixty-six patients with OSCC and 120 normal persons were used to screen potential serum peptide biomarkers using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Serum GSTP1 concentration was detected in 18 patients with OSCC and 18 normal persons using ELISA. Immunohistochemistry was used to detect GSTP1 expression in tissue samples from twenty-eight OSCC patients. Western blot and real-time PCR were used to detect GSTP1 expression in nine OSCC lines. RESULTS: Decreased GSTP1 concentration was found in the patients with OSCC compared with the normal persons by MALDI-TOF-MS, which was then confirmed by ELISA (P = 0.019). Decreased GSTP1 mRNA level and protein expression were also found in the OSCC lines. Decreased GSTP1 expression was found correlating with pathological differentiation grade in the tissue samples from OSCC patients, a lower GSTP1 expression indicating a poorer pathological differentiation grade (P = 0.041). CONCLUSIONS: These results suggest that decreased GSTP1 expression in patients with OSCC and a lower GSTP1 expression indicating a poorer pathological differentiation grade in OSCC tissue samples.

Elevated level of serum growth differentiation factor 15 is associated with oral leukoplakia and oral squamous cell carcinoma.

BACKGROUND: Although molecular mechanism of growth differentiation factor 15 (GDF15) in tumorigenesis of oral squamous cell carcinoma (OSCC) is not clear, the diagnostic and prognostic value of serum GDF15 detection has been noticed. However, serum GDF15 levels in patients with oral leukoplakia and GDF15 as a potential predictive biomarker for response to induction chemotherapy in patients with OSCC have not been reported. METHODS: Pretreatment serum GDF15 concentration was detected using an enzyme-linked immunosorbent assay in 30 healthy persons, 24 patients with oral leukoplakia, and 60 patients with OSCC. RESULTS: Serum GDF15 concentration was significantly higher in patients with oral leukoplakia and OSCC, compared with healthy controls (F = 13.701, df = 2, P < 0.001). From a diagnostic standpoint, a cutoff value of 346.9 ng/l of serum GDF15 concentration was calculated using receiver operating characteristic curve, with a sensitivity of 0.750, specificity of 0.867, Youden's Index of 0.617, and area under curve of 0.863. From a prognostic standpoint, patients with serum GDF15 concentration <346.9 ng/l had an improved 3-year disease-free survival rate (64.3% vs 56.5%) compared with those above 346.9 ng/l, but the difference was not statistically significant. A decreased concentration of GDF15 (<346.9 ng/l) showed a predictive trend toward an improved response to induction chemotherapy compared with elevated concentration with clinical response rates of 100% and 71.4%, respectively, but the difference was not significant. CONCLUSION: Elevated GDF15 level may be not only a diagnostic biomarker for oral leukoplakia, but also a prognostic/predictive biomarker associated with decreased survival and diminished response to induction chemotherapy for patients with OSCC.

Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

Low Annexin A1 expression predicts benefit from induction chemotherapy in oral cancer patients with moderate or poor pathologic differentiation grade.

BACKGROUND: The benefit of induction chemotherapy in locally advanced oral squamous cell carcinoma (OSCC) remains to be clearly defined. Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients and biomarker development might lead to identification of the patients whose tumors are to respond to a particular treatment. Annexin A1 may serve as a biomarker for responsiveness to induction chemotherapy. The aim of this study was to investigate Annexin A1 expression in pre-treatment biopsies from a cohort of OSCC patients treated with surgery and post-operative radiotherapy or docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery and post-operative radiotherapy. Furthermore we sought to assess the utility of Annexin A1 as a prognostic or predictive biomarker. METHODS: Immunohistochemical staining for Annexin A1 was performed in pre-treatment biopsies from 232 of 256 clinical stage III/IVA OSCC patients. Annexin A1 index was estimated as the proportion of tumor cells (low and high, <50% and ≥50% of stained cells, respectively) to Annexin A1 cellular membrane and cytoplasm staining. RESULTS: There was a significant correlation between Annexin A1 expression and pathologic differentiation grade (P=0.015) in OSCC patients. The proportion of patients with low Annexin A1 expression was significantly higher amongst those with moderate/poorly differentiated tumor (78/167) compared to those with well differentiated tumor (18/65). Multivariate Cox model analysis showed clinical stage (P=0.001) and Annexin A1 expression (P=0.038) as independent prognostic risk factors. Furthermore, a low Annexin A1 expression level was predictive of longer disease-free survival (P=0.036, HR=0.620) and locoregional recurrence-free survival (P=0.031, HR=0.607) compared to high Annexin A1 expression. Patients with moderate/poorly differentiated tumor and low Annexin A1 expression benefited from TPF induction chemotherapy as measured by distant metastasis-free survival (P=0.048, HR=0.373) as well as overall survival (P=0.078, HR=0.410). CONCLUSIONS: Annexin A1 can be used as a prognostic biomarker for OSCC. Patients with moderate/poorly differentiated OSCC and low Annexin A1 expression can benefit from the addition of TPF induction chemotherapy to surgery and post-operative radiotherapy. Annexin A1 expression can potentially be used as a predictive biomarker to select OSCC patients with moderate/poorly differentiated tumor who may benefit from TPF induction chemotherapy.

Induction chemotherapy in patients with resectable head and neck squamous cell carcinoma: a meta-analysis.

BACKGROUND: Induction chemotherapy has been investigated as a possible strategy to shrink or downstage locally advanced head and neck cancers, providing opportunity to remove the lesions completely after induction chemotherapy, especially in the patients with resectable advanced disease. The aim of this study was to investigate the definitive effect of induction chemotherapy in patients with resectable head and neck squamous cell carcinoma. METHODS: A meta-analysis of randomized trials (1965-2011) was performed on the impact of induction chemotherapy on survival, disease control, and toxicity in this population of patients. Kaplan-Meier curves were read by Engauge-Digitizer. Data combining was performed using RevMan. RESULTS: Fourteen trials (2099 patients) were involved in this analysis. There was no significant difference on overall survival, disease free survival, or locoregional recurrence between the patients treated with and without induction chemotherapy (P >0.05). However, the patients treated with induction chemotherapy had a lower rate of distant metastasis by 8% (95% confidence interval 1%-16%, P = 0.02) than those treated without induction chemotherapy. In patients with laryngeal cancer, comparing to radical surgery, the larynx could be preserved in responders to induction chemotherapy without survival decease (P >0.05). Induction chemotherapy-associated death was 0%-5%. CONCLUSIONS: Based on the results above, there is a significant benefit of induction chemotherapy on decreasing distant metastasis in patients with resectable head and neck squamous cell carcinoma. In patients with laryngeal cancer, induction chemotherapy provides larynx preservation in responders to induction chemotherapy.

[Experimental investigation of vincristine on chemosensitivity through Stathmin regulation in oral squamous cell carcinoma].

PURPOSE: Our previous studies have found that Stathmin, a microtubule depolymerizing protein, is a potential biomarker to guide locally advanced oral squamous cell carcinoma (OSCC) induction chemotherapy. This study further explored the regulatory effect of vincristine on Stathmin and its potention as an alternative chemotherapy drug. METHODS: Stathmin overexpressed and knockdown stable cell lines were constructed. Cell proliferation, q-PCR, Western blot, subcutaneous xenograft and other experimental methods were used to value the regulatory effect of vincristine on Stathmin. The differences were statistically analyzed with SPSS 23.0 software package. RESULTS: Vincristine inhibited the expression of Stathmin in OSCC cell lines. The sensitivity to vincristine was increased in Stathmin overexpressed OSCC cell lines. Vincristine had potent anti-tumor effect for OSCC cell line xenografts with higher Stathmin expression. CONCLUSIONS: Vincristine is a potential alternative chemotherapeutic agent for OSCC with higher Stathmin expression.

A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma.

Novel neoadjuvant therapy regimens are warranted for oral squamous cell carcinoma (OSCC). In this phase I trial (NCT04393506), 20 patients with locally advanced resectable OSCC receive three cycles of camrelizumab (200 mg, q2w) and apatinib (250 mg, once daily) before surgery. The primary endpoints are safety and major pathological response (MPR, defined as ≤10% residual viable tumour cells). Secondary endpoints include 2-year survival rate and local recurrence rate (not reported due to inadequate follow-up). Exploratory endpoints are the relationships between PD-L1 combined positive score (CPS, defined as the number of PD-L1-stained cells divided by the total number of viable tumour cells, multiplied by 100) and other immunological and genomic biomarkers and response. Neoadjuvant treatment is well-tolerated, and the MPR rate is 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃10 achieve MPR. Post-hoc analysis show 18-month locoregional recurrence and survival rates of 10.5% (95% CI: 0%-24.3%) and 95% (95% CI: 85.4%-100.0%), respectively. Patients achieving MPR show more CD4+ T-cell infiltration than those without MPR (P = 0.02), and decreased CD31 and ɑ-SMA expression levels are observed after neoadjuvant therapy. In conclusion, neoadjuvant camrelizumab and apatinib is safe and yields a promising MPR rate for OSCC.

Clinical management of peripheral ameloblastoma.

Peripheral ameloblastoma is a rare epithelial odontogenic tumor, limited to the soft tissues of the gingiva or oral mucosa. Peripheral ameloblastoma represents approximately 2% to 10% of all ameloblastomas. It is always considered to be benign, but occasionally it may be locally aggressive or with malignant potential. In this article, we report 3 new cases of benign peripheral ameloblastoma and further discuss the clinical management of this disease.

Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma.

Apatinib is an oral tyrosine kinase inhibitor that targets VEGFR2 signaling and shows potent antitumor effects in various cancers. In this study, we explored the efficacy of apatinib against oral squamous cell carcinoma (OSCC). The relationships between VEGFR2 protein expression and clinical variables were investigated in OSCC patients. OSCC tissues had higher VEGFR2 levels than paracancerous tissues. Compared to patients with low VEGFR2 expression, patients with high VEGFR2 expression had poorer overall survival (OS) and disease-free survival (DFS). Apatinib significantly induced G0/G1 phase arrest and apoptosis, inhibited cell growth and colony formation ability, and blocked autophagic flux by downregulating p-AKT and p-mTOR signaling via the VEGFR2/AKT/mTOR pathway in vitro. Moreover, the inhibition of ERK phosphorylation increased apatinib-induced apoptosis in vitro and in vivo. Apatinib synergized with SCH772984 to achieve a more significant suppression of tumor growth than individual treatment, suggesting the combination of apatinib and SCH772984 as a potent OSCC therapy.

A therapeutic approach with combination of interferon-gamma and autophagy inhibitor for oral squamous cell carcinoma.

Former clinical trials and experimental research have indicated that Interferon-gamma therapy does not achieve an ideal effect in solid tumors. Autophagy has been associated with tumor chemoresistance. The aim of this study was to explore the efficacy of Interferon-gamma and autophagy inhibitor in the combination treatment of oral squamous cell carcinoma. Interferon-gamma-induced apoptosis was evaluated by the expression of relative proteins (cleaved-PARP and caspase-3) and flow cytometry. Interferon-gamma induced autophagy was assessed by the expression of Beclin1, LC3B, and P62. The synergistic effect of interferon-gamma and autophagy inhibitor (chloroquine) was evaluated in vitro and in vivo. Interferon-gamma induced anti-proliferation, apoptosis, and autophagy in oral squamous cell carcinoma cells. Autophagy-related protein 5 was a key feature in Interferon-gamma-induced autophagy flux. Interferon-gamma and chloroquine had obvious synergistic effects on cellular growth inhibition and apoptosis promotion in oral squamous cell carcinoma cells and xenograft models. Our findings suggest that Interferon-gamma-induced autophagy plays a cellular protective role, and blocking autophagy flux can promote Interferon-gamma mediated oral squamous cell carcinoma cell apoptosis. The combination of Interferon-gamma and autophagy inhibitors represents a novel strategy for oral squamous cell carcinoma therapy.

Anti-tumor effect of carrimycin on oral squamous cell carcinoma cells in vitro and in vivo.

PURPOSE: Carrimycin is a newly synthesized macrolide antibiotic with good antibacterial effect. Exploratory experiments found its function in regulating cell physiology, proliferation and immunity, suggesting its potential anti-tumor capacity. The aim of this study is to investigate the anti-tumor effect of carrimycin against human oral squamous cell carcinoma cells in vitro and in vivo. METHODS: Human oral squamous cell carcinoma cells (HN30/HN6/Cal27/HB96 cell lines) were treated with gradient concentration of carrimycin. Cell proliferation, colony formation and migration ability were analyzed. Cell cycle and apoptosis were assessed by flow cytometry. The effect of carrimycin on OSCC in vivo was investigated in tumor xenograft models. Immunohistochemistry, western blot assay and TUNEL assays of tissue samples from xenografts were performed. The key proteins in PI3K/AKT/mTOR pathway and MAPK pathway were examined by western blot. RESULTS: As the concentration of carrimycin increased, the proliferation, colony formation and migration ability of OSCC cells were inhibited. After treating with carrimycin, cell cycle was arrested in G0/G1 phase and cell apoptosis was promoted. The tumor growth of xenografts was significantly suppressed. Furthermore, the expression of p-PI3K, p-AKT, p-mTOR, p-S6K, p-4EBP1, p-ERK and p-p38 were down-regulated in vitro and in vivo. CONCLUSIONS: Carrimycin can inhibit the biological activities of OSCC cells in vitro and in vivo, and regulate the PI3K/AKT/mTOR and MAPK pathways.

Diffuse-type tenosynovial giant cell tumor of the temporomandibular joint with skull base invasion: a report of 22 cases with literature review.

OBJECTIVES: The aim of this study was to retrospectively analyze the clinical characteristics, surgical treatment, and prognosis of patients with diffuse-type tenosynovial giant cell tumor (D-TGCT) involving the temporomandibular joint (TMJ) and the skull base. STUDY DESIGN: A retrospective study was performed in patients with D-TGCT involving the TMJ and the skull base at our institute from April 2009 to August 2018. Data on clinical characteristics, surgical treatment, and prognosis were collected and analyzed. A literature search on D-TGCT involving the TMJ was conducted and the data analyzed. RESULTS: The study included 22 patients (14 males and 8 females), with an average age of 44 years. The main symptoms were headache and hearing limitation, accompanied by a swelling in the TMJ area. Magnetic resonance imaging (MRI) showed low signals on T1- and T2-weighted images. All lesions were completely removed. Temporal bone flap, titanium mesh, and temporal muscle flap were used for reconstruction. The recurrence rate was 4.5%. In the literature, 115 cases were reported. Surgery alone was performed in 88 cases; postoperative radiotherapy was performed in 19 cases; the tumor recurrence rates were 9.1% and 15.8% for the 2 procedures, respectively. All patients were alive at the end of the follow-up period. CONCLUSIONS: D-TGCT involving the TMJ and the skull base is a locally aggressive but benign lesion necessitating complete resection and has a good prognosis.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.