Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy for incurable head and neck cancer.

OBJECTIVES: We aimed to evaluate the outcomes of the Radiation Therapy Oncology Group 8502 "QUAD shot" regimen using volumetric modulated arc therapy (VMAT) for incurable head and neck cancer (HNC). MATERIALS AND METHODS: We included 105 patients with HNC in the study, undergoing at least one QUAD shot regimen cycle. We planned the radiotherapy using VMAT with 6 MV photons. One QUAD shot cycle included 14.8 Gy in 4 fractions with at least 6-hour intervals over 2 consecutive days, repeated every 3-6 weeks up to 3 cycles. RESULTS: We completed 1, 2, and 3 cycles in 11 (10 %), 17 (16 %), and 77 (73 %) patients, respectively. We concurrently performed systemic therapy in 13 (12 %) patients. Tumor response was observed in 92 (88 %) patients and at least one symptom relief in 51 (71 %) of 72 patients. We observed an overall response (tumor response or symptom relief) in 98 (93 %) patients with all patients who completed 3 cycles achieving it. The median overall survival (OS) was 6.8 months. Our multivariate analysis revealed that non-squamous cell carcinoma (p < 0.001), T category of 0-2 (p = 0.021), and 3 QUAD shot cycles (p < 0.001) were independent prognostic factors of better OS. We observed Grade 3 toxicity in 2 (2 %) patients while no ≥ Grade 4 acute or ≥ Grade 3 late toxicity. CONCLUSIONS: The QUAD shot regimen using VMAT exerts appropriate palliative effect in patients with incurable HNC. Treatment with higher QUAD shot cycle number would be recommended for better treatment outcomes.

Sicca syndrome during ipilimumab and nivolumab therapy for metastatic renal cell carcinoma.

Introduction: Dry mouth is the main symptom of sicca syndrome, which rarely occurs as an immune-related adverse event. Here we report a case of sicca syndrome caused by immune checkpoint inhibitor treatment. Case presentation: A 70-year-old man was diagnosed with left renal cell carcinoma after radical left nephrectomy. Nine years later, computed tomography revealed a metastatic nodule in the upper left lung lobe. Subsequently, ipilimumab and nivolumab were administered for recurrent disease. After 13 weeks of treatment, xerostomia and dysgeusia were noted. Salivary gland biopsy revealed lymphocyte and plasma cell infiltration in the salivary glands. Sicca syndrome was diagnosed and pilocarpine hydrochloride was prescribed without corticosteroids, with continuation of immune checkpoint inhibitor therapy. The symptoms alleviated after 36 weeks of treatment, with shrinkage of the metastatic lesions. Conclusion: We experienced sicca syndrome caused by immune checkpoint inhibitors. Sicca syndrome improved without steroids and the immunotherapy could be continued.

FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells.

Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression in OSCC cell lines, including CRR cell lines and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell lines. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In a xenograft model and clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific small interfering RNA (siRNA) treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions, as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.

Macroglossia in rapidly progressive inclusion body myositis.

Inclusion body myositis (IBM) is a refractory muscle disease characterized by inflammatory and degenerative features in myofibers. Macroglossia is common in systemic amyloid light chain amyloidosis; however, no reports have been published on patients with IBM. We encountered a female patient with clinicopathologically defined IBM who exhibited relatively rapid progression of dysphagia, gait disturbance, and macroglossia. Muscle biopsy demonstrated endomysial mononuclear inflammatory infiltrates, fiber necrosis and regeneration with rimmed vacuoles, and sarcoplasmic inclusions of p62. Tongue biopsy demonstrated fiber degeneration with fatty replacement and fibrosis, nonnecrotic fibers surrounded and invaded by mononuclear cells, and sarcoplasmic dotlike inclusions of p62. Based on the parotid gland, lip, and muscle biopsy, she was diagnosed as having IBM with Sjögren's syndrome. She was treated with steroid pulse and intravenous immunoglobulin therapy followed by oral administration of prednisolone, which resulted in temporary clinical improvement. Macroglossia might be an indicator of immunotherapy effectiveness.

An oncolytic virus as a promising candidate for the treatment of radioresistant oral squamous cell carcinoma.

We evaluated the usefulness of an oncolytic virus (Suratadenoturev; OBP-301) against radioresistant oral squamous cell carcinoma. We confirmed the expression of human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor in cell lines. Also, we examined the potential presence in a patient who has received existing therapy that is amenable to treatment with OBP-301. We evaluated: (1) the antitumor effects of OBP-301 alone and in combination with radiotherapy on radioresistant cell lines, (2) the molecular mechanism underlying the radiosensitizing effect and cell death increased by the combination therapy, and (3) the antitumor effect of the combination therapy in vivo using xenograft models (a radioresistant cell line-derived xenograft in mouse and a patient-derived xenograft). Human telomerase reverse transcriptase and the coxsackievirus and adenovirus receptor were expressed in all cell lines. OBP-301 decreased the proliferative activity of these cell lines in a concentration-dependent manner, and significantly enhanced the antitumor effect of irradiation. Phosphorylated STAT3 and its downstream molecules, which correlated with apoptosis and autophagy, showed significant changes in expression after treatment with OBP-301. The combination therapy exerted a significant antitumor effect versus radiotherapy alone in both xenograft models. Combination of OBP-301 with radiotherapy exerts a synergistic effect and may represent a promising treatment for radioresistant oral squamous cell carcinoma.

Potential use of EGFR-targeted molecular therapies for tumor suppressor CYLD-negative and poor prognosis oral squamous cell carcinoma with chemoresistance.

BACKGROUND: Tumor suppressor CYLD dysfunction by loss of its expression, triggers malignant transformation, especially drug resistance and tumor invasion/metastasis. Although loss of CYLD expression is significantly associated with poor prognosis in a large variety of tumors, no clinically-effective treatment for CYLD-negative cancer patients is available. METHODS: We focused on oral squamous cell carcinoma (OSCC), and sought to develop novel therapeutic agents for CYLD-negative cancer patients with poor prognosis. CYLD-knockdown OSCC cells by using CYLD-specific siRNA, were used to elucidate and determine the efficacy of novel drug candidates by evaluating cell viability and epithelial-mesenchymal transition (EMT)-like change. Therapeutic effects of candidate drug on cell line-derived xenograft (CDX) model and usefulness of CYLD as a novel biomarker using patient-derived xenograft (PDX) model were further investigated. RESULTS: CYLD-knockdown OSCC cells were resistant for all currently-available cytotoxic chemotherapeutic agents for OSCC, such as, cisplatin, 5-FU, carboplatin, docetaxel, and paclitaxel. By using comprehensive proteome analysis approach, we identified epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, played key roles in CYLD-knockdown OSCC cells. Indeed, cell survival rate in the cisplatin-resistant CYLD-knockdown OSCC cells was markedly inhibited by treatment with clinically available EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib. In addition, gefitinib was significantly effective for not only cell survival, but also EMT-like changes through inhibiting transforming growth factor-ß (TGF-ß) signaling in CYLD-knockdown OSCC cells. Thereby, overall survival of CYLD-knockdown CDX models was significantly prolonged by gefitinib treatment. Moreover, we found that CYLD expression was significantly associated with gefitinib response by using PDX models. CONCLUSIONS: Our results first revealed that EGFR-targeted molecular therapies, such as EGFR-TKIs, could have potential to be novel therapeutic agents for the CYLD-negative OSCC patients with poor prognosis.

The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation.

Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of critical antioxidant proteins, was recently demonstrated to play a key role in cancer progression. Resistance to radiotherapy is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about the association between Nrf2 and radioresistance in OSCC. Two OSCC cell lines (SAS and HSC-2) and their clinically relevant radioresistant (CRR) clones (SAS-R, HSC-2-R) were used. The effects of Nrf2 downregulation on radiosensitivity and the involvement of glycolysis in Nrf2-mediated radioresistance were evaluated. Immunohistochemistry of phosphorylated Nrf2 (p-Nrf2) was performed in 110 patients with OSCC who underwent preoperative chemoradiotherapy and surgery. Nrf2 was stably upregulated in CRR cells in vitro and in a mouse xenograft model. Moreover, elevated Nrf2 expression was associated with radioresistance. The enhancement of Nrf2-dependent glycolysis and glutathione synthesis was involved in the development of radioresistance. Additionally, p-Nrf2 expression was closely related to the pathological response to chemoradiotherapy, and its expression was predictive of prognosis in patients with advanced OSCC. Our results suggest that Nrf2 plays an important role in the radioresistance of OSCC accompanied by metabolic reprogramming. Targeting Nrf2 antioxidant pathway may represent a promising treatment strategy for highly malignant OSCC.

Naringenin potentiates anti-tumor immunity against oral cancer by inducing lymph node CD169-positive macrophage activation and cytotoxic T cell infiltration.

The CD169+ macrophages in lymph nodes are implicated in cytotoxic T lymphocyte (CTL) activation and are associated with improved prognosis in several malignancies. Here, we investigated the significance of CD169+ macrophages in oral squamous cell carcinoma (OSCC). Further, we tested the anti-tumor effects of naringenin, which has been previously shown to activate CD169+ macrophages, in a murine OSCC model. Immunohistochemical analysis for CD169 and CD8 was performed on lymph node and primary tumor specimens from 89 patients with OSCC. We also evaluated the effects of naringenin on two murine OSCC models. Increased CD169+ macrophage counts in the regional lymph nodes correlated with favorable prognosis and CD8+ cell counts within tumor sites. Additionally, naringenin suppressed tumor growth in two murine OSCC models. The mRNA levels of CD169, interleukin (IL)-12, and C-X-C motif chemokine ligand 10 (CXCL10) in lymph nodes and CTL infiltration in tumors significantly increased following naringenin administration in tumor-bearing mice. These results suggest that CD169+ macrophages in lymph nodes are involved in T cell-mediated anti-tumor immunity and could be a prognostic marker for patients with OSCC. Moreover, naringenin is a new potential agent for CD169+ macrophage activation in OSCC treatment.

Laterality on FDG-PET/CT in clinically node-negative early-stage oral squamous cell carcinoma: a retrospective analysis of patients with late neck metastasis.

This study aimed to assess the role of preoperative 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) for predicting late neck metastasis in clinically node-negative (cN0) early-stage oral squamous cell carcinoma (OSCC). We retrospectively investigated the standardized uptake value (SUV) parameters in patients with late neck metastasis based on the neck node level. The study population consisted of 16 patients with cT1N0 or cT2N0 oral SCC who were evaluated with dual-phase FDG-PET/CT and were treated with local resection of the primary tumor and watchful waiting for neck management. The SUV at each level was measured on the early and delayed images, and the laterality of the SUV was calculated. The laterality on the delayed images significantly differed between positive and negative pairs at the levels Ib (p = 0.002) and IIb (p = 0.013); a cut-off value of 1.4 yielded a true-positive rate of 50% and a false-positive rate of 6%. The laterality of FDG-uptake should be used to stratify the risk for nodal-level metastasis.

Extracellular vesicles derived from radioresistant oral squamous cell carcinoma cells contribute to the acquisition of radioresistance via the miR-503-3p-BAK axis.

Despite advancements in treatments, oral squamous cell carcinoma (OSCC) has not significantly improved in prognosis or survival rate primarily due to the presence of treatment-resistant OSCC. The intercellular communication between tumour cells is a molecular mechanism involved in acquiring OSCC treatment resistance. Extracellular vesicles (EVs) and encapsulated miRNAs are important mediators of intercellular communication. Here, we focused on EVs released from clinically relevant radioresistant (CRR) OSCC cells. Additionally, we evaluated the correlation between miRNA expression in the serum samples of patients who showed resistance to radiotherapy and in EVs released from CRR OSCC cells. We found that EVs released from CRR OSCC cells conferred radioresistance to radiosensitive OSCC cells via miR-503-3p contained in EVs. This miR-503-3p inhibited BAK and impaired the caspase cascade to suppress radiation-induced apoptosis. Furthermore, OSCC cells with BAK knockdown had increased radioresistance. Additionally, the expression of circulating miR-503-3p in patients with OSCC was correlated with a poor treatment response and prognosis of radiotherapy. Our results provide new insights into the relationship between EVs and the radioresistance of OSCC and suggest that the miR-503-3p-BAK axis may be a therapeutic target and that circulating miR-503-3p is a useful prognostic biomarker in the radiotherapy of OSCC.

miR-30a attenuates drug sensitivity to 5-FU by modulating cell proliferation possibly by downregulating cyclin E2 in oral squamous cell carcinoma.

We aimed to determine the functional role of the miRNA, which affects drug sensitivity to 5-FU in oral squamous cell carcinoma (OSCC), using two types of 5-FU-resistant and parental OSCC cell lines. MiRNA microarray data showed that miR-30a was significantly upregulated in two resistant cell lines. Therefore, we investigated the effects and molecular mechanism of miR-30a on 5-FU sensitivity. Stable overexpression of miR-30a in parental OSCC cells decreased cell proliferation and attenuated drug sensitivity to 5-FU. Cell cycle analysis indicated that miR-30a overexpression increased the proportion of G1 phase cells and decreased the proportion of S phase cells. MiR-30a knockdown using siRNA reversed the effects of miR-30a overexpression. DNA microarray analysis using miR-30a-overexpressing cell lines and a TargetScan database search showed that cyclin E2 (CCNE2) is a target of miR-30a. A luciferase reporter assay confirmed that a miR-30a mimic interacted with the specific binding site in the 3' UTR of CCNE2. CCNE2 knockdown with siRNA in OSCC cells yielded decreased drug sensitivity to 5-FU, similar to miR-30a overexpressing cells. These findings suggest that miR-30a in OSCC may be a novel biomarker of 5-FU-resistant tumors, as well as a therapeutic target for combating resistance.

Re-evaluating the clinical significance of serum p53 antibody levels in patients with oral cancer in Japanese clinical practice.

TP53 gene mutations can lead to mutant p53 protein accumulation in cancer cells, thereby inducing the production of serum antip53 antibodies (Ap53Ab) in patients with various types of cancer. The aim of the present study was to re-evaluate the clinicopathological and prognostic significance of Ap53Ab using the Ap53Ab ELISA kit, approved by the Japanese Health Insurance System in 2007. Ap53Ab was measured as a tumor marker in 94 patients with oral squamous cell carcinoma (OSCC), by subjecting paraffin-embedded sections obtained from biopsy specimens to immunohistochemical analysis to confirm p53 expression. The associations among Ap53Ab status, p53 expression and clinical significance in OSCC were examined. A total of 23% of the patients were Ap53Ab-positive. Ap53Ab status was found to be significantly associated with p53 expression status in primary tumors (P=0.027), clinical T-category, pathological N-category and pathological stage (P=0.04, P=0.010 and P=0.013, respectively). Kaplan-Meier curve analysis revealed that Ap53Ab status was significantly associated with poor disease-free survival (DFS; P=0.043), and Cox regression analysis revealed that Ap53Ab status was a significant prognostic factor for DFS in patients with OSCC (hazard ratio=2.807; 95% confidence interval: 1.029-7.160; P=0.044). These results suggested that Ap53Ab measurement may reflect the p53 mutation status and an aggressive malignant phenotype, and it may serve as a useful predictive marker candidate for OSCC in clinical practice.

Colonization of distant organs by tumor cells generating circulating homotypic clusters adaptive to fluid shear stress.

Once disseminated tumor cells (DTCs) arrive at a metastatic organ, they remain there, latent, and become seeds of metastasis. However, the clonal composition of DTCs in a latent state remains unclear. Here, we applied high-resolution DNA barcode tracking to a mouse model that recapitulated the metastatic dormancy of head and neck squamous cell carcinoma (HNSCC). We found that clones abundantly circulated peripheral blood dominated DTCs. Through analyses of multiple barcoded clonal lines, we identified specific subclonal population that preferentially generated homotypic circulating tumor cell (CTC) clusters and dominated DTCs. Despite no notable features under static conditions, this population significantly generated stable cell aggregates that were resistant to anoikis under fluid shear stress (FSS) conditions in an E-cadherin-dependent manner. Our data from various cancer cell lines indicated that the ability of aggregate-constituting cells to regulate cortical actin-myosin dynamics governed the aggregates' stability in FSS. The CTC cluster-originating cells were characterized by the expression of a subset of E-cadherin binding factors enriched with actin cytoskeleton regulators. Furthermore, this expression signature was associated with locoregional and metastatic recurrence in HNSCC patients. These results reveal a biological selection of tumor cells capable of generating FSS-adaptive CTC clusters, which leads to distant colonization.

Postoperative delirium in patients undergoing tumor resection with reconstructive surgery for oral cancer.

Many attempts have been made to identify the risk factors for postoperative delirium, but this has proved difficult due to its complex morbidity. Furthermore, there is little information on postoperative delirium in patients undergoing tumor resection and reconstructive surgery for oral cancer. The aim of the current study was to investigate the incidence of and risk factors for postoperative delirium in patients undergoing resection and reconstructive surgery for oral cancer. The present study included 104 patients with pedicle or free flap reconstruction. Postoperative delirium developed in 22 (21.2%) of these patients. The mean time to onset of postoperative delirium was 2.5±1.0 days and the duration of delirium was 1.9±1.2 days. Univariate analysis demonstrated that the occurrence of postoperative delirium was significantly correlated with operating time (P=0.033), duration of anesthesia (P=0.039), amount of blood loss (P=0.027), method of reconstruction (P=0.008), type of flap used (P=0.009) and time until postoperative ambulation (P=0.0008). Low postoperative red blood cell count (P=0.004), hemoglobin (P=0.004) and hematocrit (P=0.004) were significantly associated with delirium, but preoperative blood test results were not. The multiple logistic regression analysis of these risk factors revealed that the only significant correlation that remained was between postoperative delirium and the time to ambulation after surgery (P=0.005). Since 2009, the Department of Oral and Maxillofacial Surgery, Kumamoto University Hospital has promoted ambulation after the first two postoperative days for patients with oral cancer undergoing tumor resection with reconstruction, and the occurrence of postoperative delirium has decreased from 29.2 to 14.0%. The results of the current study suggest that early postoperative ambulation in patients who undergo reconstructive surgery for oral cancer is effective for preventing postoperative delirium.

Can MRI-derived depth of invasion predict nodal recurrence in oral tongue cancer?

OBJECTIVES: To evaluate the prognostic value of preoperative radiological findings for nodal recurrence in clinically node-negative (cN0) patients with oral tongue squamous cell carcinoma (SCC). METHODS: The study population consisted of 52 patients with cT1-2N0 oral tongue SCC classified according to the 7th edition of the Union for International Cancer Control (UICC) staging system. The subjects had undergone preoperative radiological examinations, including magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography. All patients were treated with local resection and watchful waiting for neck management. Using an unpaired t test, Pearson's chi-squared test, and the Kaplan-Meier method, the MRI-derived depth of invasion (DOI), the standardized uptake value (SUV) on FDG-PET, and the T stage according to the 7th and 8th UICC were assessed as prognostic factors. RESULTS: The MRI-derived DOI was recorded as ≤ 5 mm in 24 patients and > 5 mm in 28 patients. During the follow-up period, nine patients exhibited nodal recurrence, with the MRI-derived DOI being significantly higher in patients with positive than in those with negative (p = 0.011). The SUV was not significant. Five-year cumulative nodal recurrence probabilities were 4.5% for patients with an MRI-derived DOI ≤ 5 mm, while it was 32.1% for > 5 mm (p = 0.013). Although the T classifications were not significant, none of our patients whose T stage according to the 8th UICC was T1 suffered nodal recurrence. CONCLUSIONS: MRI-derived DOI can predict nodal recurrence, while preoperative information may assist in treatment planning for oral tongue SCC.

The Tumour Suppressor CYLD Is Required for Clathrin-Mediated Endocytosis of EGFR and Cetuximab-Induced Apoptosis in Head and Neck Squamous Cell Carcinoma.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and is a target for the therapeutic antibody cetuximab (CTX). However, because only some patients have a significant clinical response to CTX, identification of its predictive biomarkers and potentiation of CTX-based therapies are important. We have recently reported a frequent downregulation of cylindromatosis (CYLD) in primary HNSCC, which led to increased cell invasion and cisplatin resistance. Here, we show that CYLD located mainly in lipid rafts was required for clathrin-mediated endocytosis (CME) and degradation of the EGFR induced by EGF and CTX in HNSCC cells. The N-terminus containing the first cytoskeleton-associated protein-glycine domain of CYLD was responsible for this regulation. Loss of CYLD restricted EGFR to lipid rafts, which suppressed CTX-induced apoptosis without impeding CTX's inhibitory activity against downstream signalling pathways. Disruption of the lipid rafts with cholesterol-removing agents overcame this resistance by restoring CME and the degradation of EGFR. Regulation of EGFR trafficking by CYLD is thus critical for the antitumour activity of CTX. Our findings suggest the usefulness of a combination of cholesterol-lowering drugs with anti-EGFR antibody therapy in HNSCC.

Role of serum amylase and salivary cytokines in oral complications during chemoradiotherapy.

OBJECTIVES: To investigate whether serum amylase can predict the recovery of salivary volume and determine the correlation of the level of cytokines, including epidermal growth factor, hepatocyte growth factor and keratinocyte growth factor, with oral mucositis during chemoradiotherapy for oral cancer. SUBJECTS AND METHODS: This study included 84 patients treated with preoperative chemoradiotherapy followed by curative surgery, following a phase II study protocol. We measured and analysed the correlation of the stimulated saliva volume, serum amylase and cytokines in resting saliva at baseline and 1 month after chemoradiotherapy with oral mucositis levels. RESULTS: We observed a negative correlation between the serum amylase level at the beginning of chemoradiotherapy and the stimulated saliva volume at 1 month after chemoradiotherapy (p = .03). Epidermal growth factor in resting saliva was significantly reduced after chemoradiotherapy (p < .01). The incidence of severe oral mucositis during chemoradiotherapy was significantly higher and negatively associated with the epidermal growth factor and keratinocyte growth factor levels (p = .04, p = .05). CONCLUSIONS: The serum amylase level at the beginning of chemoradiotherapy may be a predictor of the recovery of the saliva volume. Furthermore, cytokines such as epidermal growth factor and keratinocyte growth factor in resting saliva affect the development of oral mucositis during chemoradiotherapy.

Compositional Shift of Oral Microbiota Following Surgical Resection of Tongue Cancer.

Salivary microbiota is considered a source of microorganisms for the respiratory and digestive tracts, and a trigger for diseases in these distant organs. Meanwhile, the microbiota on the tongue surface is thought to be a major source of salivary microbiota. Therefore, surgical resection of the tongue for definitive treatment of oral cancer could drastically change the salivary bacterial balance and virulence. Here, we investigated the shift of the salivary microbiota following surgical resection in patients with tongue cancer. The stimulated saliva samples were collected from 25 tongue cancer patients pre- and post-resection of the tongue, and bacterial density and composition was determined using quantitative PCR analysis and 16S ribosomal RNA (rRNA) gene sequencing, respectively. Although no significant difference in the total bacterial density in saliva pre- and post-surgery was observed, the bacterial composition significantly differed according to the analysis of similarity. Among predominant operational taxonomic units (OTUs) with ≥1% of relative abundance, the proportions of OTUs corresponding to Streptococcus salivarius, Prevotellamelaninogenica, and Prevotellahisticola were significantly decreased following the tongue resection. On the other hand, the proportions of OTUs corresponding to Lautropiamirabilis, Neisseriaflava, Streptococcussanguinis, and Fusobacterium nucleatum, known to be inhabitants of dental plaque, were significantly increased. These results suggest that surgical resection of the tongue causes a compositional shift of the salivary microbiota, characterized by an increase in bacterial species derived from dental plaque, including periodontal pathogens. These results suggest the necessity of more careful and frequent postoperative oral care after surgical resection of tongue cancer.

Onodera's prognostic nutritional index correlates with tumor immune environment and survival in patients with oral squamous cell carcinoma undergoing chemoradiotherapy.

Pretreatment nutritional and immunological status is useful for predicting survival outcomes for various types of malignant tumors. Our objective was to determine the impact of the pretreatment Onodera's prognostic nutritional index (OPNI) on outcomes of patients who underwent definitive chemoradiotherapy for advanced oral squamous cell carcinoma (OSCC). We reviewed 47 patients treated for OSCC with definitive chemoradiotherapy (CRT) at our institution between January 2004 and December 2011. We determined the OPNI according to the following formula: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per µL). We determined the optimum OPNI cut-off through a receiver operating characteristic analysis. We analyzed the associations between OPNI status and various clinicopathological features and evaluated the effects of OPNI on the prognosis. We examined the relationships between OPNI and systemic inflammatory response parameters and analyzed intratumoral CD8+ T cells and their correlation with OPNI. The optimum OPNI cut-off was 42.7. A Kaplan-Meier curve analysis revealed that low OPNI was significantly associated with poor overall survival and cause-specific survival. The multivariate analysis revealed that low OPNI was independently correlated with poor 5 year overall survival and cause-specific survival. OPNI was significantly correlated with systemic inflammatory response parameters. Intratumoral CD8+ T cell counts in primary tumors were significantly lower for low OPNI than for high OPNI. The present data demonstrate that pretreatment OPNI is a valuable independent prognostic indicator of overall and cause-specific survival in advanced OSCC following definitive CRT. OPNI might reflect the tumor immune microenvironment characterization in OSCC.

Microsecretory adenocarcinoma of the hard palate: A case report of a recently described entity.

We report a case of microsecretory adenocarcinoma of the hard palate. The patient is a 37-year-old woman with a 15 mm submucosal tumor, which was incidentally found by her primary care dentist, in her hard palate. Preoperative magnetic resonance imaging revealed a tumor exhibiting high signal on T2-weighted image, which was gradually enhanced on dynamic study. Histologically, the tumor border was ill-defined without fibrous capsule and adjoined minor salivary gland with permeative infiltration at the tumor periphery. The tumor comprised intercalated duct-like cells with polygonal narrow eosinophilic to clear cytoplasm and small, uniform oval nuclei. These cells formed small infiltrative microcysts, tubules and fascicular cords collecting pale basophilic secretions and small vacuoles setting in an abundant fibromyxoid stroma. The tumor cells were positive for CK AE1+AE3, S-100 protein, and p63, while are completely negative for p40, alpha-SMA, and calponin. The MEF2C-SS18 fusion was identified by reverse transcriptase-polymerase chain reaction followed by Sanger sequencing. The combination of characteristic histology, immunophenotype, and presence of MEF2C-SS18 fusion indicated the diagnosis of microsecretory adenocarcinoma of the hard palate, an entity described only recently. Post-operative course was uneventful and there was no evidence of disease at 4 months after surgery.