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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.

Background Annexin A1, a member of the Annexin superfamily, has been shown to play a vital role in a broad range of molecular and cellular processes. This study aims to explore the relationship between the Annexin A1 expression and the clinical response to cisplatin, docetaxel and 5‐fluorouracil (TPF) as induction chemotherapy in patients with oral squamous cell carcinoma (OSCC). Methods This study recruited two hundred thirty‐two patients from a III/IVA OSCC trial. Immunohistochemistry was used to assess the level of Annexin A1 expression. Overexpression and knockdown methods in HB96, HN4 and CAL27 cell lines were used to assess the role of Annexin A1 in the neoplastic cellular response to chemotherapy. Results We found that reduced expression of Annexin A1 conferred a prognostic benefit from induction chemotherapy based on the TPF drug combination in patients with moderately/poorly differentiated disease. Using an in vitro model, we found that low Annexin A1 enhanced cellular proliferation by activating the EGFR/AKT signalling pathway and inhibiting p27 expression. Furthermore, low Annexin A1 initiated a significant decrease in cell viability after treatment with TPF agents. In addition, downregulation of Annexin A1 promoted apoptosis induced by docetaxel, cisplatin and 5‐fluorouracil, and upregulation of Annexin A1 inhibited apoptosis. Conclusion Annexin A1 may be of prognostic value in patients with locally advanced OSCC who are managed with TPF chemotherapy, as low Annexin A1 promotes chemosensitivity to TPF chemotherapy in oral cancer cells via enhanced caspase‐dependent apoptosis.

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. Graphic abstract

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.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.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.Vincristine is a potential alternative chemotherapeutic agent for OSCC with higher Stathmin expression.

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

Novel neoadjuvant therapy regimens are needed to improve the outcomes of patients with locally advanced resectable oral squamous cell carcinoma (OSCC). We conducted a prospective, open-label, single-arm trial (n = 21, NCT04393506) to determine the safety and feasibility of neoadjuvant camrelizumab (an anti-PD-1 antibody) plus apatinib (a VEGFR inhibitor) for locally advanced resectable OSCC. The primary endpoints were safety and major pathological response (MPR). Neoadjuvant camrelizumab plus apatinib was well-tolerated and the MPR rate was 40% (8/20), meeting the primary endpoint. All five patients with CPS ˃ 10 had MPR. Additionally, patients achieving MPR showed more CD4+ T cell infiltration and a higher CD8+/FoxP3+ ratio than those without MPR (p < 0.05), and decreased CD31 and ɑ-SMA expression were observed after neoadjuvant therapy. Our findings demonstrate that neoadjuvant therapy with a chemo-free combination of camrelizumab and apatinib is safe and yields a promising MPR rate, supporting further trials.

e18067 Background: In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), major pathological response (MPR) to neoadjuvant therapy may translate into improved survival. The combination of anti-PD-1 and chemotherapy as neoadjuvant protocol has not been well reported in OSCC. Methods: The prospective single arm trial (NCT04473716) was performed to evaluate the neoadjuvant therapy with anti-PD-1 (Toripalimab) and chemotherapy (albumin paclitaxel/cisplatin) in OSCC patients at clinical stage III and IVA (AJCC 2018). The patients received two cycles (21 days each) of intravenous albumin paclitaxel (260mg/m2), cisplatin (75mg/m2) and Toripalimab (240mg) on day 1 and day 22. Radical surgery was performed within two weeks after neoadjuvant therapy. Post-operative radiotherapy/chemoradiotherapy was performed within 1.5 months after surgery. The primary endpoints were MPR and safety. Primary tumors were assessed for the percentage of residual viable tumor cells on HE staining, and tumor with no more than 10% viable tumor cell was considered as MPR. Results: From Nov. 2020 to Apr. 2021, 20 patients were enrolled, including 16 males and 4 females, at clinical stage III (16) and IVA (4). They aged from 19 to 75 (median 54) years . The primary tumor site was eight tongue, six mouth floor, three gingiva, two retromolar trigone and one buccal mucosa. The neoadjuvant therapy was well-tolerated with low incidence of grade 3-4 adverse events (AEs) including 5% grade 4 neutropenia, 10% grade 3 leukopenia, 5% grade 3 neutropenia, hypokalemia, vomiting, and rash each. Common grade 1-2 AEs included baldness/rash/itch/pain/fatigue, AST/ALT/uric acid elevation, nausea/vomiting/diarrhea, hyperbilirubinemia, proteinuria, neutropenia/leukopenia. All AEs were relieved after expectant treatment, the subsequent standard treatment was not delayed. According to pathological evaluation, the MPR rate was 60% (12/20), including 30% (6/20) pCR. According to RECIST 1.1, radiological evaluation on neoadjuvant therapy showed two CR, ten PR, seven SD and one PD. It was significantly consistent between pathological and radiological evaluation in linear regression analysis ( P＜0.0001). Combined positive score (CPS) of PD-L1 expression in biopsy was evaluated in 19 patients, MPR was archived in all 4 patients with CPS≥10, in 6 out of 8 patients (75%) with CPS≥1, and in 5 out of 11 patients (45.5%) with CPS < 1. Conclusions: Neoadjuvant therapy with combination of Toripalimab, albumin paclitaxel, and cisplatin in resectable OSCC patients is safe and well-tolerated, with high MPR rate. Clinical trial information: NCT04473716.

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.

Background: Former clinical trials and experimental research have indicated that interferon-gamma (IFNγ) 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 IFNγ and autophagy inhibitor in the combination treatment of oral squamous cell carcinoma (OSCC). Method: IFNγ-induced apoptosis was evaluated by the expression of relative proteins (cleaved-PARP and caspase-3) and flow cytometry. IFNγ-induced autophagy was assessed by the expression of Beclin1, LC3B, and P62. The synergistic effect of IFNγ and autophagy inhibitor (chloroquine) was evaluated in vitro and in vivo.Findings: IFNγ induced anti-proliferation, apoptosis, and autophagy in OSCC cells. Autophagy-related protein 5 (ATG5) was a key feature in IFNγ-induced autophagy flux. IFNγ and chloroquine had obvious synergistic effects on cellular growth inhibition and apoptosis promotion in OSCC cells and xenograft models. Interpretation: Our findings suggest that IFNγ-induced autophagy plays a cellular protective role, and blocking autophagy flux can promote IFNγ-mediated OSCC cell apoptosis. The combination of IFNγ and autophagy inhibitors represents a novel strategy for OSCC therapy.

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. Electronic supplementary material The online version of this article (10.1186/s12885-018-4481-8) contains supplementary material, which is available to authorized users.

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., The evaluation of stathmin in biopsy tissues has potential as a clinical tool for predicting the outcomes of oral cancer patients undergoing docetaxel, cisplatin, and 5‐fluorouracil (TPF) induction chemotherapy. Combination of TPF chemotherapy and PI3K signaling pathway inhibitors showed potent inhibition of oral cancer cells and xenografts, in which stathmin is highly expressed. Therefore, we are exploring personalized strategies of stathmin expression‐based induction chemotherapy in oral cancer.

Summary Background & aims This study aimed to evaluate the prognostic value of the body mass index (BMI), as well as the association with docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Methods This retrospective study enrolled 253 patients with locally advanced OSCC between 2008 and 2010 based on our previous prospective, randomized, phase 3 trial ( NCT01542931 ). Univariate and multivariate Cox regression models, and the Kaplan–Meier method were used for survival analyses. Results Among the 253 patients, the BMI at the time of clinical diagnosis ranged from 13.16 to 34.66 kg/m2. Smoking status among patients showed a marked correlation with a higher BMI status at the time of clinical diagnosis (tobacco status: P Conclusion The BMI at the time of clinical diagnosis was showed to be an independent predictive factor for patients with locally advanced OSCC. Compared with normoweight patients, underweight patients may have worse clinical outcomes, while overweight and obese patients have a better prognosis. A normal BMI in clinical stage IVA OSCC patients predicts significant OS and DMFS benefits of TPF induction chemotherapy.

6052 Background: In patients with locally advanced oral squamous cell carcinoma (LAOSCC), major pathologic response (MPR) to induction therapy may translate into improved survival. The induction therapy using chemo-free drugs, such as the combination of anti-PD1 and anti-VEGFR drugs, has not been well issued in LAOSCC. Methods: A prospective single arm trial (NCT04393506) has been performed to evaluate the induction therapy of anti-PD1 and anti-VEGFR protocol in LAOSCC patients at clinical stage III and IVA. The patients received three cycles of intravenous Camrelizumab (PD-1 antibody, 200mg) on d1, d15, d29; and oral Apatinib (anti-VEGFR inhibitor, 250mg) daily, initiating on d1, ending on the 5th day before surgery. Radical surgery was planned on d42-d45. Post-operative radiotherapy was planned within 1.5 months after surgery, based on clinical and pathological stage. The primary endpoints were MPR and safety; primary tumors were assessed for the percentage of residual viable tumor that was identified on HE staining, and tumors with no more than 10% viable tumor cells were considered as MPR. This study has been approved by institutional ethics committee at Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine. Results: From April to December 2020, 21 patients were enrolled in this trial, and one patient withdraw from the trial at the beginning of treatment. The induction therapy was well-tolerated with no grade 3-4 toxicity or serve induction therapy-related AEs. One patient required surgery delay for 7 days due to unexplainable cTnI elevation. One patient put off Camrelizumab for 14 days due to grade 2 thrombocytopenia. One patient suspended Apatinib for 21 days due to grade 2 Hyperbilirubinemia. The induction therapy did not effect on the subsequent standard treatment. MPR rate was 40% (8/20), including 5% (1/20) pCR. Radiological evaluation of response to induction therapy showed 3 PR, 10 SD, 5 PD and 2 NA. Weak correlation was found between pathologic and radiological evaluation on induction therapy. Combined positive score (CPS) of PD-L1 expression in biopsy was evaluated in 19 patients; all 4 patients with CPS≥ 20 had MPR, 3 out of 11 patients with 1≤CPS < 20 had MPR, and 1 out of 4 patients with CPS < 1 had MPR. Conclusions: The chemo-free protocol of induction therapy using Camrelizumab and Apatinib is safe and well-tolerated for the patients with LAOSCC. The MPR rate is much higher using the anti-PD1 and anti-VEGFR protocol than the traditional induction chemotherapy protocol in LAOSCC. Clinical trial information: NCT04393506.

e18542 Background: To explore the mechanism of sensitivity to docetaxel, cisplatin, and 5-fluorouracil (TPF) chemoagents in patients with oral squamous cell carcinoma (OSCC) and growth differentiation factor 15 (GDF15) overexpression recruited in a TPF induction chemotherapy trial; and to explore potential alternative agents for patients who might not benefit from TPF induction chemotherapy. Methods: GDF15-overexpression and silenced OSCC cells were used to investigate sensitivity to TPF chemoagents in vitro and in vivo. Immunoprecipitation combined with mass spectrometry was used to screen out the possible receptor for GDF15, and associated signaling pathways were detected after intervention with the possible receptor of GDF15. The efficacy of an inhibitor of the phosphorylation of the possible GDF15 receptor was evaluated by treatment of GDF15-overexpression OSCC cells in vitro and in vivo. Results: Overexpression of GDF15 in OSCC cell lines and xenografts lead to an increase of chemotherapeutics sensitivity on apoptosis effects induced by docetaxel, cisplatin and 5-fluorouracil, through a caspase -dependent pathway. Immunoprecipitation combined with mass spectrometry revealed that the erbB2 protein was a potential binding protein of GDF15, as verified by coimmunoprecipitation. When GDF15 was overexpressed, the phosphorylation of erbB2 and downstream PI3K/AKT and MAPK/ERK pathways was significantly upregulated, but was downregulated when GDF15 expression was interfered. The erbB2 phosphorylation inhibitor CI1033 significantly inhibited the proliferation and colony-forming ability of GDF15-overexpression OSCC cells as well as the growth of xenografts. CI1033 might be used as a potential targeted drug or alternative of TPF chemoagents for OSCC patients with GDF15 overexpression. Conclusions: OSCC with GDF15 overexpression exhibit sensitivity to TPF chemoagents through a caspase-dependent pathway. ErbB2 phosphorylation inhibitors might be used as potential targeted drugs or an alternative of TPF chemoagents for OSCC patients with GDF15 overexpression.

Objective The aim of this study was to analyze myopericytoma in the oral and maxillofacial region in terms of clinical appearance, diagnosis, treatment, and outcomes. Study Design Data on 5 new patients with myopericytoma in the oral and maxillofacial region treated at our department were collected and analyzed. Results There were 2 males and 3 females (age range 10–62 years; mean age 43.8 years). All of the 5 patients presented with masses showing benign biologic behavior. Imaging examinations with use of computed tomography or magnetic resonance imaging showed heterogeneous regions with internal contrast-enhancement or cystic change in 3 cases. All of the patients underwent surgery. Histologic examination showed a broad morphologic spectrum characterized by concentric and perivascular growth of ovoid, plump spindled, and/or round myoid tumor cells. Immunohistochemical examination showed positive staining for vimentin and smooth muscle actin, and negative for CD34 and desmin. During the follow-up period (8–56 months), there was no tumor recurrence. Conclusions Myopericytoma in the oral and maxillofacial region always exhibits benign biologic behavior and a heterogeneous region with internal contrast-enhancement or cystic change on imaging examinations. Surgery is the first choice of treatment and results in good clinical outcomes.

Background To evaluate the computed tomographic features and create a prediction model for clinical diagnosis of adenoid cystic carcinoma (ACC) in the palate with intact mucosa. Methods From March 2016 to May 2018, 102 patients with palatal tumors and intact mucosa, including 28 patients with a pathological diagnosis of ACC after surgery, were enrolled in this study. The patients’ clinical symptoms, computed tomographic features and pathological diagnoses were recorded and analyzed. Independent predictors of ACC were determined by using univariate analysis and multivariate logistic regression, and the discrimination and calibration of the prediction model was evaluated, and internal validation was performed. Results Univariate analysis of patients showed that ACC patients were more likely than non-ACC patients to be older (P = 0.019); to have palatine bone destruction (P

Table S6. Correlation between NOTCH1 non-synonymous mutation and baseline characteristics in patients with oral squamous cell carcinoma. (DOCX 19Â kb)

Table S5. Correlation between TP53 non-synonymous mutation and baseline characteristics in patients with oral squamous cell carcinoma. (DOCX 19Â kb)

Table S1. Non-synonymous mutations (threshold of allele frequency of â Ľ10%) in the cancerous tissues from oral squamous cell carcinoma patients. (DOCX 22Â kb)

Table S7. Correlation between CAPS8 non-synonymous mutation and baseline characteristics in patients with oral squamous cell carcinoma. (DOCX 19Â kb)

Table S2. Non-synonymous mutations (threshold of allele frequency of â Ľ5%) in the cancerous tissues from oral squamous cell carcinoma patients. (DOCX 23Â kb)

Table S3. Non-synonymous mutations (threshold of allele frequency of â Ľ3%) in the cancerous tissues from oral squamous cell carcinoma patients. (DOCX 24Â kb)

Table S4. Validation of TP53 mutations by Sanger sequencing in patients with oral squamous cell carcinoma. *NA: the DNA is not available. (DOCX 16Â kb)

Background The aim of this study was to investigate the oncogenic function and regulatory mechanism of stathmin in oral squamous cell carcinoma (OSCC). Methods Two-dimensional electrophoresis and liquid chromatography-tandem mass chromatography were applied to screen differentiated proteins during carcinogenesis in OSCC. Cell Counting Kit-8 (CCK-8) assays, colony formation, migration, flow cytometry, immunofluorescence and a xenograft model were used to detect the function of stathmin. The correlation between stathmin and p53 expression was analyzed using immunohistochemistry. Mutant/wild type p53 plasmids and small interfering RNA were used to examine the regulation of stathmin. Chromatin immunoprecipitation assays and luciferase assays were performed to detect the transcriptional activation of stathmin by p53. Results Overexpression of stathmin was screened and confirmed in OSCC patients and cell lines. Silencing expression of stathmin inhibited proliferation, colony formation and migration and promoted apoptosis. Poly ADP ribose polymerase (PARP) and cyclin-dependent kinase 1 (cdc2) were activated after silencing the expression of stathmin. Suppression of tumorigenicity was also confirmed in vivo. Mutant p53 transcriptionally activated the expression of stathmin in HN6 and HN13 cancer cells, but not in HN30 cells harboring wild type p53. Conclusions These results suggest that stathmin acts as an oncogene and is transcriptionally regulated by mutant p53, but not by wild-type p53. Stathmin could be a potential anti-tumor therapeutic target in OSCC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0575-4) contains supplementary material, which is available to authorized users.

Objective The aim of this study was to analyze tuberculosis (TB) in the oral cavity according to clinical appearance, clinical differential diagnosis, treatment, and outcome. Study Design We enrolled 11 patients with TB in the oral cavity between November 2012 and November 2016. Glossal lymphoid TB was excluded. Clinical symptoms, auxiliary examinations, treatments, and outcomes were recorded and analyzed. Results The study population comprised 6 men and 5 women, with a mean age of 59 years. Five patients presented with ulcer, 5 with a mass, and 1 with osteomyelitis. Excisional biopsy was performed in 3 patients, mass resection in 7, and curettage of mandibular lesion in 1. After pathologic diagnosis of TB in the oral cavity in 8 patients; 6 of them underwent purified protein derivative examination, and 4 of them had positive results and received drug therapy. The mean follow-up period was 24.9 months, and there was no recurrence. Conclusions TB in the oral cavity is rare and has no specific clinical features. Pathology, acid-fast staining, polymerase chain reaction, and DNA testing for Mycobacterium tuberculosis are useful for final diagnosis. Surgery is recommended as the treatment of choice to achieve good clinical outcomes.

Our previous phase 3 trial (NCT01542931) failed to demonstrate improved survival when docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy was introduced prior to surgery and postoperative radiotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). The aim of the present study was to investigate the long-term predictive value of GDF15 expression for potential personalized treatment strategies in OSCC. A total of 256 patients with stage III/IVA OSCC from our phase 3 trial were enrolled in the present study. Immunohistochemical staining against GDF15 was performed in the biopsy samples from 230/256 patients. Kaplan-Meier analysis, followed by the log-rank test, and the Cox proportional hazards model were used for outcome analysis using the statistical SPSS 18.0 software package for Windows. Among the 230 patients, low GDF15 expression was detected in 68 patients and high GDF15 expression was detected in 162 patients. With a median follow-up period of 67 months, the patients with low GDF15 expression exhibited a higher survival rate than those with high GDF15 expression, including 5-year overall survival (73.4 vs. 57.7%; P=0.059), 5-year disease-free survival (64.5 vs. 49.2%; P=0.033), 5-year locoregional recurrence-free survival (66.0 vs. 51.5%; P=0.043) and 5-year distant metastasis-free survival (73.4 vs. 56.6%; P=0.038) rates. Furthermore, the cT3/4N0M0 patients with high GDF15 expression benefited significantly from TPF induction chemotherapy, including overall survival (HR=0.233; P=0.02), disease-free survival (HR=0.296; P=0.014), locoregional recurrence-free survival (HR=0.347; P=0.035) and distant metastasis-free survival (HR=0.212; P=0.013) rates. The results of the present study suggested that elevated GDF15 expression may be used as a long-term prognostic biomarker for poor clinical outcomes in patients with locally advanced OSCC. Elevated GDF15 expression in cT3/4N0M0 patients predicts significant long-term benefit of survival from TPF induction chemotherapy.

6040 Background: A randomized phase 3 trial failed to demonstrate a survival advantage for TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in the overall study population of patients with locally advanced and resectable oral squamous cell carcinoma (OSCC). It is possible that personalized TPF-based induction chemotherapy might improve outcomes in biomarker-defined subsets of patients. Methods: Immunohistochemical staining against stathmin was performed in pre-treatment biopsy specimens in 170 OSCC patients from our randomized trial. Chemoresistance to TPF chemotherapy drugs regulated by stathmin expression was investigated. The anti-cancer activity of TPF chemotherapy drugs alone, a combination of TPF drugs and PI3K-AKT-mTOR pathway inhibitors, and vincristine were investigated using in vitro and in vivo OSCC models. Results: OSCC patients with low stathmin expression benefited from TPF induction chemotherapy in terms of overall survival (HR = 0.102, 95% CI:0.013-0.781, P = 0.028), disease-free survival (HR = 0.070, 95% CI:0.009-0.525, P = 0.010), locoregional recurrence-free survival (HR = 0.070, 95% CI:0.009-0.524, P = 0.010), and distant metastasis-free survival (HR = 0.101, 95% CI:0.013-0.767, P = 0.027). Stathmin overexpression promoted cellular proliferation and chemoresistance to TPF drugs in OSCC (P < 0.05). PI3K pathway inhibitors decreased stathmin expression and phosphorylation, and improved the chemosensitivity to TPF drugs in vitro and in vivo (P < 0.05). Vincristine decreased stathmin expression and phosphorylation, and OSCC lines were significantly sensitive to vincristine in vitro and in vivo (P < 0.01). Conclusions: Our results suggest a potential personalized TPF induction chemotherapy on the basis of stathmin expression in OSCC patients: patients with low stathmin expression in the biopsy samples are suggested to receive TPF induction chemotherapy followed by surgical resection and post-operative radiotherapy. For patients with stathmin overexpression PI3K inhibitor is a good choice to improve the inductive effect of TPF chemotherapy drugs; vincristine is a potential alternative for a chemotherapy drug when a patient is chemoresistant to or unsuitable to receive TPF chemotherapy drugs; however, more clinical trials are warranted to verify this optimization protocol.

e18034Background: A phase 3 trial (NCT01542931) demonstrated failure to improve survival when docetaxel, cisplatin, and 5-fluorouracil (TPF) based induction chemotherapy was added to standard thera...

Rosai-Dorfman disease (RDD), also named sinus histiocytosis with massive lymphadenopathy, is a rare, idiopathic, and benign disorder that classically presents as a painless massive bilateral cervical lymphadenopathy. In cases of extranodal presentations, such as cutaneous RDD, it may not involve the classic manifestation. The diagnosis is usually made by histopathologic analysis. Surgery is suggested in the cases of significant cosmetic deformity or when there is fatal or functional obstruction. We reported a case of extranodal RDD that recurred in the infraorbital region postoperatively.