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.

Clinical retrospective analysis with a predictive model for diffused-tenosynovial giant cell tumors of the temporomandibular joint.

BACKGROUND: This study aimed to find out the characteristics in relation to tumor recurrence in diffused-tenosynovial giant cell tumor of temporomandibular joint and to develop and validate the prognostic model for personalized prediction. METHODS: From April 2009 to January 2021, patients with diffused-tenosynovial giant cell tumor of temporomandibular joint at a single center were included in this study. The clinical features and local recurrence-free survival were assessed through the expression of the Ki-67 index and colony-stimulating factor 1 receptor expression. Both univariate and multivariate analyses were performed on the prognostic factors for local recurrence-free survival. An independent predictor nomogram and pertinent tumor characteristics were included. RESULTS: The retrospective study enrolling seventy eligible patients at the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. During the follow-up time, eleven patients suffered tumor recurrence. Age was an independent risk factor for local recurrence-free survival (P = 0.032). The Ki-67 index varied significantly in different sites (P = 0.034) and tumor volume (P = 0.017). Multivariate logistic regression was used to develop the prediction model using both statistical significance and prognostic indicators. The C-index of the nomogram based on age, site, Ki-67, and colony-stimulating factor 1 receptor was 0.833. These variates provided good predicted accuracy for a nomogram on local recurrence-free survival. Diffused-tenosynovial giant cell tumor from the temporomandibular joint is extremely uncommon, and certain clinical traits are linked to the tumor proliferation index. CONCLUSIONS: We identified the risk indicators and developed a nomogram in this study to forecast the likelihood of local recurrence-free survival in patients with diffused-tenosynovial giant cell tumor from temporomandibular joint.

Design, synthesis and anti-inflammatory activity study of lansiumamide analogues for treatment of acute lung injury.

Acute lung injury (ALI) is an inflammation-mediated respiratory disease with a high mortality rate. Medications with anti-inflammatory small molecules have been demonstrated in phase I and II clinical trials to considerably reduce the ALI mortality. In this study, two series of lansiumamide analogues were designed, synthesized, and evaluated for anti-inflammatory activity for ALI treatment. We found that compound 8n exhibited the best anti-inflammatory activity through inhibiting LPS-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in Raw264.7 cells and activating the Nrf2/HO-1 pathway. Furthermore, we discovered in a LPS-induced ALI mice model that compound 8n significantly reduced the infiltration of inflammatory cells into lung tissue to achieve the effect of protecting lung tissues and improving ALI. Additionally, our mice model study revealed that compound 8n had a good expectorant effect. These results consistently support that lansiumamide analogue 8n represents a new class of anti-inflammatory agents with potential as a lead compound for further development into a therapeutic drug for ALI treatment.

Design, Synthesis and Antifungal Activities of Novel Pyrazole Analogues Containing the Aryl Trifluoromethoxy Group.

On the basis of the three-component synthetic methodology developed by us, a total of twenty-six pyrazole compounds bearing aryl OCF3 were designed and synthesized. Their chemical structures were characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry. These compounds were evaluated systematically for antifungal activities in vitro against six plant pathogenic fungi by the mycelium growth rate method. Most of the compounds showed some activity against each of the fungi at 100 µg/mL. Compounds 1t and 1v exhibited higher activity against all the tested fungi, and 1v displayed the highest activity against F. graminearum with an EC50 value of 0.0530 µM, which was comparable with commercial pyraclostrobin. Structure-activity relationship analysis showed that, with respect to the R1 substituent, the straight chain or cycloalkyl ring moiety was a key structural moiety for the activity, and the R2 substituent on the pyrazole ring could have significant effects on the activity. Simple and readily available pyrazoles with potent antifungal activity were obtained, which are ready for further elaboration to serve as a pharmacophore in new potential antifungal agents.

Neoadjuvant immunochemotherapy for locally advanced resectable oral squamous cell carcinoma: a prospective single-arm trial (Illuminate Trial).

BACKGROUND: Locally advanced oral squamous cell carcinoma (LAOSCC) is associated with a high rate of recurrence and poor survival. Given the recent successes of neoadjuvant immunochemotherapy (NAICT) in solid tumors, it is promising to use this treatment modality to achieve a better pathological response and improve the survival of LAOSCC, and clinical evidence is needed to assess its safety and efficacy. PATIENTS AND METHODS: A prospective trial of NAICT with toripalimab (PD-1 inhibitor) and albumin paclitaxel/cisplatin (TTP) was conducted in patients with clinical stage III and IVA OSCC. Intravenous albumin paclitaxel (260 mg/m 2 ), cisplatin (75 mg/m 2 ), and toripalimab (240 mg) were given in sequence on day 1 of each 21 day cycle for two cycles, followed by radical surgery and risk-adapted adjuvant (chemo)radiotherapy. The primary endpoints were safety and major pathological response (MPR). Targeted next generation sequencing and multiplex immunofluorescence were performed to assess clinical molecular characteristics and the tumor immune microenvironment in the pre-NAICT and post-NAICT tumor samples. RESULTS: Twenty patients were enrolled. NAICT was well-tolerated with a low incidence of grades 3-4 adverse events in three patients. The completion rates of NAICT and subsequent R0 resection were 100%. The MPR rate was 60%, including a 30% pathological complete response. MPR was achieved in all four patients with a combined positive score of PD-L1>10. The density of tertiary lymphatic structure in post-NAICT tumor samples predicted the pathological response to NAICT. During the median 23-month follow-up, the disease-free survival was 90%, and the overall survival was 95%. CONCLUSIONS: NAICT with the TTP protocol in LAOSCC is feasible and well tolerated, with a promising MPR and no obstruction on subsequent surgery. This trial is supportive of further randomized trials using NAICT in LAOSCC.

Can adjuvant radiotherapy be omitted for oral cavity cancer patients who received neoadjuvant therapy and surgery? A retrospective cohort study.

BACKGROUND: Surgery and postoperative adjuvant therapy comprise the standard treatment for locally advanced resectable oral squamous cell carcinoma (LAROSCC), while preoperative neoadjuvant therapy is being explored without sufficient confirmation of improved survival. De-escalation regimens after neoadjuvant therapy, such as those omitting adjuvant radiotherapy, may provide comparable or better outcomes, suggesting rigorous assessment of adjuvant therapy outcomes is needed in LAROSCC patients. The authors thus performed this retrospective study in LAROSCC patients who received neoadjuvant therapy and surgery, to compare the outcomes for overall survival (OS) and locoregional recurrence-free survival (LRFS) between the adjuvant radiotherapy (radio) and nonradiotherapy (nonradio) cohorts. MATERIALS AND METHODS: Patients diagnosed with LAROSCC who received neoadjuvant therapy and surgery were enrolled and divided into radio and nonradio cohorts to determine whether adjuvant radiotherapy could be omitted after neoadjuvant therapy and surgery. RESULTS: From 2008 to 2021, 192 patients were enrolled. No significant differences were found in OS or LRFS between the radio and nonradio patient cohorts. The 10-year estimated OS rates were 58.9 versus 44.1% in radio versus nonradio cohorts, while 10-year estimated LRFS rates were 55.4 versus 48.2%, respectively. For clinical stage III patients, 10-year OS rates were 62.3 versus 62.6% (radio vs. nonradio), and estimated 10-year LRFS rates were 56.5 versus 60.7% (radio vs. nonradio). Multivariate Cox regression modeling of postoperative variables showed pathologic response of primary tumor and pathologic regional lymph nodes staging were associated with survival, while the adjuvant radiotherapy exposure was not included in the model due to nonsignificance. CONCLUSION: These findings support further prospective evaluation of adjuvant radiotherapy omission, and suggest that de-escalation trials are warranted for LAROSCC surgery patients who received neoadjuvant therapy.

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.

Diagnosis and management of hypoglossal nerve-derived schwannoma in the floor of mouth: a case series.

BACKGROUND: Schwannomas or neurilemmomas are well-encapsulated, benign, solitary, and slow-growing tumors that originate from Schwann cells of the nerve sheath. Extracranial schwannoma is reported to have a relatively high incidence in the tongue while an extremely low incidence in the floor of mouth. In the current study, we presented the first case series of hypoglossal nerve-derived schwannoma in the floor of mouth in Asia. METHODS: A retrospective study of 9 surgical cases of hypoglossal nerve-derived schwannoma in the floor of mouth was performed. The patient and tumor characteristics were evaluated by physical, radiological and pathological examination. Details of operation and complications were also recorded. RESULTS: Hypoglossal nerve-derived schwannoma in the floor of mouth showed a well-defined boundary with a firm texture, smooth surface and good mobility on palpation. The median maximum diameter of the tumors was 4.3 cm (range 2.8-7.0 cm). The median operative time and bleeding volumes were 89.4 min (range 47-180 min) and 99.2 mL (range 15-200 mL), respectively. All cases received complete surgical excision. CONCLUSION: In this study, we presented the diagnosis and management of hypoglossal nerve-derived schwannoma in the floor of mouth for the first time in Asia. The study provided us with a recommendation for consideration of the diagnosis of hypoglossal schwannoma when a patient presents with a mass in the floor of mouth.

[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.

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.

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.

Decreased Annexin A1 expression enhances sensitivity to docetaxel, cisplatin and 5-fluorouracil combination induction chemotherapy in oral squamous cell carcinoma.

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.

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.

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.

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.

Cyclin D1 overexpression enhances chemosensitivity to TPF chemotherapeutic agents via the caspase-3 pathway in oral cancer.

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).

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.

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.

Normal BMI predicts the survival benefits of inductive docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced oral squamous cell carcinoma.

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 < 0.001). The distribution of clinical nodal (cN) stage was significantly different, as patients with higher BMIs generally had earlier cN stages (P < 0.021) among the different BMI groups. The Kaplan-Meier analysis showed that the BMI was significantly correlated with overall survival (OS, P = 0.004), disease-free survival (DFS, P = 0.005), locoregional recurrence-free survival (LRFS, P = 0.003) and distant metastasis-free survival (DMFS, P = 0.007). When the BMI was included in the multivariate Cox regression model adjusted for potentially confounding clinical variables, the BMI was shown to be an independent predictive factor of OS (P = 0.015), DFS (P = 0.015), LRFS (P = 0.009), and DMFS (P = 0.023). The TPF group showed better 5-year clinical survival rates than the control group when analyzing patients with a normal BMI (OS: 64.2% vs. 55.9%; DFS: 54.7% vs. 46.4%; LRFS: 56.6% vs. 49.6%; DMFS: 64.2% vs. 56.0%), but no significant difference was observed. Subgroup survival analysis indicated that patients with a normal BMI and clinical stage IVA disease who accepted TPF induction chemotherapy had a significantly improved OS (HR: 0.425, 95% CI: 0.187-0.966, P = 0.035) and DMFS (HR: 0.425, 95% CI: 0.187-0.966, P = 0.034). 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.

[The effect and mechanism of ANXA1 on TPF chemosensitivity in oral squamous cell carcinoma].

PURPOSE: To investigate the mechanism of ANXA1 in TPF chemotherapy of oral squamous cell carcinoma (OSCC). METHODS: 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. RESULTS: 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. CONCLUSIONS: In TPF chemotherapy of OSCC, overexpression of ANXA1 results in EMT of cells, which leads to decreased chemosensitivity.