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PDF file - 746K, Forest plot of overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival in OSCC patients treated with surgery and post-operative radiotherapy with and without TPF induction chemotherapy.

PDF file - 81K, Supplemental table S1: Survival comparison between the cN2 patients treated with and without TPF induction chemotherapy. Supplemental table S2: Univariate Cox model analysis. Supplemental table S3: Multivariate Cox model analysis with interaction analysis. Supplemental table S4: Correlation between cyclin D1 expression and response to TPF induction chemotherapy. Supplemental table S5: Survival comparison between the cN2 patients treated with and without TPF induction chemotherapy according to cyclin D1 expression.

Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients with cancer with biomarker detection. To investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma (OSCC) who were treated in a prospective, randomized, phase III trial evaluating standard treatment with surgery and postoperative radiotherapy preceded or not by induction docetaxel, cisplatin, and 5-fluorouracil (TPF), immunohistochemical staining for cyclin D1 was conducted in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival (OS; P = 0.001), disease-free survival (P = 0.005), locoregional recurrence-free survival (P = 0.003), and distant metastasis-free survival (DMFS; P = 0.002) compared with high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater OS (P = 0.025) and DMFS (P = 0.025) when compared with high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy. Mol Cancer Ther; 12(6); 1112–21. ©2013 AACR.

PDF file - 3255K, Subgroup analysis of overall survival, disease-free survival, locoregional recurrence-free survival and distant metastasis free-survival in 232 OSCC patients with low and high cyclin D1 expression

PDF file - 2826K, Overall survival (A), disease-free survival (B), locoregional recurrence-free survival (C), and distant metastasis-free survival (D) in 232 OSCC patients with low and high cyclin D1 expression.

PDF file - 10421K, Immunohistochemical staining for cyclin D1, negative (A), weak positive (B), and strong positive staining (C), original magnification �200.

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 Patients with locally advanced oral squamous cell carcinoma (OSCC) failed to benefit from docetaxel, cisplatin and 5-fluorouracil (TPF) neoadjuvant chemotherapy prior to surgery and postoperative radiotherapy in our previous phase 3 trial (NCT01542931). The aim of the present study was to explore the prognostic value of Ki67 expression for individualized TPF neoadjuvant therapy. Methods Immunohistochemical staining of Ki67 was performed in the biopsies before treatment in the experimental arm of our previous phase 3 trial. A total of 65 patients with Ki67 expression below 25% or above 50% were retrospectively reviewed in this study. Kaplan‑Meier analysis, log-rank test and Cox proportional hazards model were used for survival analysis. Results Among the 65 patients enrolled in the study, the patients with high Ki67 expression (n = 41) before treatment exhibited higher overall survival (OS) (P = 0.041) and distant metastasis–free survival (DMFS) (P = 0.049) than those with low expression (n = 24). The 5-year OS of the two groups were 70.7% and 45.8% respectively (high vs low). Cox proportional hazards model showed that high Ki67 expression before TPF neoadjuvant chemotherapy had a positive impact on the OS (HR = 0.399, 95% CI: 0.178–0.893, P = 0.025). Conclusions High Ki67 expression before treatment could predict the survival benefits from TPF neoadjuvant chemotherapy prior to standard therapy in patients with locally advanced OSCC, which could act as a biomarker for individualized treatment.

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.

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.

Background and purposeThe 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 methodsPublished 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.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) 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&nbsp

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) 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 (CLRT(P)) 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 CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-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.

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.

How to improve the effects of treatment on patients with oral squamous cell carcinoma (OSCC) has always been the focus of clinical and basic studies. The standardized diagnosis and treatment of malignant tumors aim to improve the effects of treatment, and individualized treatment based on standardized diagnosis and treatment may further improve these effects. On the basis of the existing guidelines for the diagnosis and treatment of patients with OSCC, this study explored the opportunities and challenges of standardized and individualized diagnosis and treatment of OSCC. These challenges and opportunities were related to the updates of clinical and pathological staging system, surgical margins, and neck dissection in patients with OSCC at early stage and preoperative induction therapy and postoperative adjuvant treatment in patients with advanced OSCC. This study also shared ideas on clinical studies of OSCC to optimize the existing treatment schemes, improve the treatment effects, and enhance the guidelines.如何提高口腔鳞状细胞癌（OSCC）患者的疗效，一直是临床与基础研究的重点。恶性肿瘤规范化诊治的目的就是提高疗效，而在规范化诊治基础上的个体化治疗，有可能进一步提高疗效。本文在OSCC现有诊治指南的基础上，针对OSCC临床分期的更新内容、外科治疗的肿瘤手术切缘、早期OSCC的颈部淋巴结清扫、局晚期OSCC术前诱导治疗和术后辅助治疗等方面，探讨OSCC的规范化和个体化诊治的机遇与挑战，分享临床研究思路，旨在优化现有治疗方案、提高治疗效果、完善治疗指南。.

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.

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.

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.

To investigate the mechanism of ANXA1 in TPF chemotherapy of oral squamous cell carcinoma (OSCC).ANXA1 overexpression and low-expression cell lines were constructed. The role of ANXA1 in TPF chemotherapy was analyzed by cell proliferation, cytotoxicity test, real-time PCR and Western blot, and the mechanism of ANXA1 in TPF chemotherapy through EMT (epithelial-mesenchymal transition) pathway was discussed. The data were analyzed with SPSS 18.0 software package.After overexpression of ANXA1, cell growth rate decreased, cell cycle slowed down, sensitivity to TPF-induced drugs decreased, and EMT occurred in OSCC. After underexpression of ANXA1, cell growth rate increased, cell cycle accelerated, sensitivity to TPF chemotherapeutic drugs increased, and reverse EMT occurred in OSCC.In TPF chemotherapy of OSCC, overexpression of ANXA1 results in EMT of cells, which leads to decreased chemosensitivity.

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.

// Xi Yang 1 , Kailiu Wu 1 , Siyi Li 1 , Longwei Hu 1 , Jing Han 1 , Dongwang Zhu 1 , Xuerui Tian 1 , Wei Liu 1 , Zhen Tian 2 , Laiping Zhong 1 , Ming Yan 1 , Chenping Zhang 1 , Zhiyuan Zhang 1 1 Department of Oral & Maxillofacial - Head & Neck Oncology, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China 2 Department of Oral Pathology, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China Correspondence to: Chenping Zhang, email: zhang.chenping@hotmail.com Zhiyuan Zhang, email: zhangzy0502@qq.com Keywords: potential marker, metastasis and prognosis, tongue cancer, microarray Received: May 30, 2016 Accepted: September 20, 2016 Published: October 04, 2016 ABSTRACT The purpose of this study is to identify candidate genes that could predict prognosis of early-stage tongue squamous cell carcinoma (TSCC) and its occult cervical lymphatic metastasis by large-scale gene expression profiling. Tumor tissue and matched normal mucosa samples were collected from patients with TSCC and analyzed with Affymetrix HTA2.0 high-density oligonucleotide array. Differentially expressed genes in TSCC with cervical lymph node metastasis (CLNM) were further analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes for their functions and related pathways. A total of 107 differentially expressed genes ( p < 0.05) were identified by microarray in TSCC samples with CLNM (n = 6) compared to those without CLNM (n = 6). Genes involved in the cell-matrix adherens junction and migration function including MFAP5, TNNC1, MGP, FBFBP1 and FBXO32 were selected and validated by RT-PCR in TSCC samples ( n = 32). Of the five genes, MFAP5 and TNCC1 expressions were further validated by immohistochemistry ( n = 61). The significant positive correlation between MFAP5 and TNNC1 expression (p

Induction chemotherapy has been previously demonstrated to downgrade locally advanced or aggressive cancers and increase the likelihood of primary lesion eradication. Based on our previous phase 3 trial on TPF (docetaxel, cisplatin and fluorouracil) induction chemotherapy in patients with oral squamous cell carcinoma (OSCC), in which short-term prognostic and predictive values of cyclin D1 expression were reported, the present study aimed to determine the long-term predictive value of cyclin D1 expression in the same patients with OSCC who were eligible to receive TPF induction chemotherapy. In addition, the present study investigated the potential association between cyclin D1 expression and chemosensitivity to TPF agents during OSCC cell intervention, and the underlying apoptotic mechanism of action. In total, 232 patients with locally advanced OSCC from our previous trial with a median follow-up of 5 years were included for survival analysis using the Kaplan-Meier method and the log-rank test in the present study, where cyclin D1 expression in their tissues was detected by immunohistochemistry. Cyclin D1 knockdown, cytotoxicity assays assessing the efficacy of the TPF chemotherapeutic agents and measurements of caspase-3 and PARP activity in HB96, CAL27 and HN30 cell lines were performed. Patients with OSCC in the low cyclin D1 expression group exhibited significantly superior long-term clinical outcomes compared with those in patients in the high cyclin D1 expression group [overall survival (OS), P=0.001; disease-free survival, P=0.003; local recurrence-free survival, P=0.004; distant metastasis-free survival (DMFS), P=0.001]. Furthermore, patients with stage clinical nodal stage 2 (cN2) OSCC in the high cyclin D1 expression group benefitted from TPF induction chemotherapy (OS, P=0.024; DMFS, P=0.024), whilst patients with cN2 OSCC in the low cyclin D1 expression group did not benefit from this chemotherapy. Overexpression of cyclin D1 expression was found to enhance chemosensitivity to TPF chemotherapeutic agents in OSCC by mediating caspase-3-dependent apoptosis. Based on these findings, TPF induction chemotherapy can benefit patients with cN2 OSCC and high cyclin D1 expression in terms of long-term survival from compared with standard treatment. In addition, OSCC cell lines overexpressing cyclin D1 are more sensitive to TPF chemotherapeutic agents in a caspase-3-dependent manner (clinical trial. no. NCT01542931; February 2012).

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)

// Jie Ma 1, * , Xiao Tang 1, * , Wen-wen Sun 1 , Ying Liu 1 , Yi-ran Tan 1 , Hai-long Ma 1 , Dong-wang Zhu 1 , Min Wang 1 , Li-zhen Wang 2 , Jiang Li 2 , Yao-yao Tu 1 , Chen-ping Zhang 1 , Zhi-yuan Zhang 1 , Lai-ping Zhong 1 1 Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shangai, China 2 Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shangai, China * These authors have contributed equally to this work Correspondence to: Lai-ping Zhong, e-mail: zhonglp@hotmail.com Yao-yao Tu, e-mail: tuyaoyao1117@163.com Keywords: growth differentiation factor 15, mutation, oral squamous cell carcinoma, prognosis Received: July 18, 2015 Accepted: October 06, 2015 Published: October 19, 2015 ABSTRACT Purpose: To investigate the mutation status of growth differentiation factor 15 (GDF15) in patients with oral squamous cell carcinoma (OSCC), as well as the prognostic value of missense GDF15 mutations. Patients and methods: Formalin-fixed paraffin-embedded biopsy samples from 46 OSCC patients were involved in this study. GDF15 and TP53 mutations were sequenced using the Ion Torrent Personal Genome Machine, GDF15 protein expression was detected using immunohistochemistry. Torrent Suite Software v.3.6, Integrative Genomics Viewer; v.2.3, statistical software SPSS18.0 for Windows were used for analysis. All hypothesis-generating tests were two-sided at a significance level of 0.05. Results: Twenty-nine GDF15 mutations were identified in 19 out of 46 patients (41.3%), including eighteen missense mutations, two nonsense mutations and nine synonymous mutations. The patients with missense GDF15 mutations had poorer prognostic outcomes than those with wild-type GDF15, including overall survival ( P = 0.035), disease-free survival ( P = 0.032), locoregional recurrence-free survival ( P = 0.015), and distant metastasis-free survival ( P = 0.070). Missense GDF15mutations was an independent increased risk factor of overall survival ( HR = 5.993, 95% CI:1.856–19.346, P = 0.003), disease-free survival ( HR = 3.764, 95% CI:1.295–10.945, P = 0.015), locoregional recurrence-free survival ( HR = 4.555, 95% CI:1.494–13.889, P = 0.008), and distant metastasis-free survival ( HR = 4.420, 95% CI:1.145–13.433, P = 0.009). Conclusions: Patients with missense GDF15 mutations have significantly poorer outcomes than those with wild-type GDF15, missense GDF15 mutations could be used as an independent increased risk factor of poor prognosis in OSCC patients.

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

The aim of this study is to eliminate more cancer cells by promoting them from quiescence into cell cycle or by changing their molecular events, leading them to be sensitive to radiation or chemotherapy. Protein phosphatase 2A plays an important role in many cellular functions and regulates various biological processes. It is unclear that LB1, which is an inhibitor of protein phosphatase 2A, has enhanced anticancer activity on chemotherapy (cisplatin and 5-fluorourcil) and radiation in head and neck squamous cell carcinoma (HNSCC). Herein, we performed both in vitro and in vivo studies to determine the anticancer activity of LB1 on chemotherapy and radiation in HNSCC, with detection of p53 expression, AKT and MDM2 phosphorylation. In vitro studies indicated that, LB1 could significantly enhance the cytotoxicity of cisplatin, 5-fluorourcil, and radiation; LB1 could also significantly enhance the treatment effect of cisplatin in nude mice. The anticancer activity of LB1 was mediated by increased AKT phosphorylation and decreased p53 expression with increased MDM2 phosphorylation, especially when combined with cisplatin. Our data suggest a strategy of improving treatment effect through the enhanced anticancer activity of LB1 on cisplatin-based chemotherapy and radiation in HNSCC.