Indications for sentinel lymph node biopsy in node-negative oral cancers.

BACKGROUND: We aimed to define the indications for sentinel lymph node biopsy (SLNB), the third option for cervical treatment in oral cancer with negative cervical lymph nodes. METHODS: The greatest depth of invasion (DOI) and long diameter (LD) of the primary site were used as exposures. SLN metastasis was considered the outcome. RESULTS: In three trials conducted between 2009 and 2016, 158 patients were eligible and reassigned to this study group. The scatterplot based on the respective values of DOI and LD would eventually be divided into three sections. In cases of sections T1, T2, and T3, the proportions of SLN metastasis positivity were 21.3%, 35.3%, and 51.2%, respectively. In certain cases of T1 with 2 mm < DOI ≤ 5 mm and 8 mm < LD ≤ 20 mm, the proportion of SLN metastasis positivity was 40.9%. CONCLUSIONS: SLNB-navigated or assisted neck dissection can be added as an effective procedure for N0 neck control.

Identification of novel oncogenes in oral cancer among elderly nonsmokers.

OBJECTIVES: In recent years, an increase in oral cancer among elderly nonsmokers has been noted. The aim of this study was to identify novel oncogenes in oral cancer in older nonsmokers. MATERIAL AND METHODS: Whole-exome sequencing (WES) data from 324 oral cancer patients were obtained from The Cancer Genome Atlas. Single nucleotide variants (SNVs) and insertions/deletions (INDELs) were extracted from the WES data of older patients. Fisher's exact test was performed to determine the specificity of variants in these genes. Finally, SNVs and INDELs were identified by target enrichment sequencing. RESULTS: Gene ontology analysis of 112 genes with significant SNVs or INDELs in nonsmokers revealed that nonsynonymous SNVs in HECTD4 were significantly more frequent in nonsmokers than in smokers by target enrichment sequencing (p = .02). CONCLUSIONS: Further investigation of the function of HECTD4 variants as oncogenes in older nonsmokers is warranted.

A retrospective analysis of tumor infiltrating lymphocytes in head and neck squamous cell carcinoma patients treated with nivolumab.

Nivolumab, an immune checkpoint inhibitor is the first-line therapy for platinum-resistant recurrent/metastatic head and neck cancer, and highly effective for some patients. However, no factors have been identified that could predict response or prognosis after nivolumab administration. We retrospectively investigated the association between tumor infiltrating lymphocytes (TILs) of initial pathology and prognosis in patients treated with nivolumab. Twenty-eight patients with human papilloma virus and Epstein-Barr virus unrelated head and neck squamous cell carcinoma were enrolled. CD8+cells, FoxP3+cells and FoxP3-CD4+cells in the tumoral and peritumoral stromal area and PD-L1 were measured. In result, FoxP3-CD4+TIL, FoxP3+TIL, and CD8+TIL were not correlated with survival in either intratumoral and stromal area. In univariate analysis, objective response was significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.006, respectively). PD-L1 was also significant prognostic factor both in progression-free survival and overall survival (p = 0.01, 0.01, respectively). ECOG Performance status was a significant prognostic factor in overall survival (p = 0.0009). In the combined analysis of stromal CD8+TIL and PD-L1, PD-L1 positive with high stromal CD8+TIL subgroups had a better prognosis than PD-L1 negative with low stromal CD8+TIL subgroups in progression-free survival (p = 0.006). Although these results require a further investigation, PD-L1 and ECOG Performance status and the combination of stromal CD8+TIL and PD-L1 positivity have potential as useful prognostic markers in patients of virus unrelated head and neck squamous cell carcinoma treated with nivolumab.

Predicting the radiosensitivity of HPV-negative oropharyngeal squamous cell carcinoma using miR-130b.

BACKGROUND: Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma shows a higher rate of radiation resistance than HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Radioresistant HPV-negative OPSCC is associated with unfavourable outcomes, but validated prognostic biomarkers remain lacking. AIMS/OBJECTIVES: This study investigated biomarkers for radioresistant HPV-negative OPSCC. MATERIAL AND METHODS: The Cancer Genome Atlas included miRNA sequence and mRNA sequence data from 528 HNSCC tumours. Of these, we used gene expression data for HPV-negative head and neck squamous cell carcinoma for which data were available on the effects of radiation, and compared miRNA sequence and mRNA sequence data between radioresistant and radiosensitive groups. We subsequently estimated downstream miRNA from the results. Finally, we validated miRNAs related to the outcomes of radiotherapy in our clinical cases. RESULTS: Investigation of miRNA sequence revealed expression of miR-130b as the greatest difference between radiosensitive and radioresistant groups. We subsequently evaluated miR-130b expression in our clinical OPSCC cases. Values of miR-130b >5.372 (low expression), determined from receiver operating characteristic curve analyses, were associated with significantly longer progression-free survival and overall survival (p = .006, p = .04, respectively). CONCLUSIONS AND SIGNIFICANCE: Our results suggest that miR-130b has potential as a biomarker for the radiosensitivity of HPV-negative OPSCC.

Acquired Hemophilia A Presenting as Massive Postoperative Bleeding in a Patient with Oral Squamous Cell Carcinoma.

Acquired hemophilia A (AHA) is an extremely rare and serious bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Approximately, 10% of patients with AHA have an underlying malignancy. We report on a 46-year-old man with AHA and advanced oral cancer who presented with massive bleeding after surgery. Preoperative blood coagulation tests showed no abnormalities. He underwent radical tumor resection followed by reconstruction using a free rectus abdominal musculocutaneous flap. Massive subcutaneous hemorrhage developed in his neck and abdomen on the first postoperative day. The hemorrhage remained uncontrolled, despite embolization of the responsible vessels. Subsequent laboratory data showed prolonged activated partial thromboplastin time and decreased FVIII levels. On the basis of his clinical course and the presence of the FVIII inhibitor, we speculated that the patient suffered from AHA. We administered recombinant activated factor VII and prednisolone, after which the spontaneous bleeding stopped and the subcutaneous hemorrhage resolved. A review of the literature identified only three previous documented cases of AHA associated with head and neck cancer. This case indicates that AHA should not be ruled out in patients with uncontrolled postoperative bleeding, while attempting to ensure bleeding control and preventing potentially catastrophic fatal consequences.

Nivolumab-related tracheobronchial chondritis: Extremely rare manifestation of an immune-related adverse effect.

BACKGROUND: Programmed death-1 checkpoint inhibitors, such as nivolumab, have successfully been utilized for recurrent or metastatic squamous cell carcinoma of the head and neck; however, their use may be associated with immune-related adverse effects (irAEs). METHODS: We describe a case of tracheobronchial chondritis as a rare irAE in a 72-year-old man with multiple pulmonary metastases of hypopharyngeal squamous cell carcinoma treated with nivolumab, who was seen with a 2-week history of fever, nonproductive cough, and dyspnea. RESULTS: CT revealed a thickened tracheobronchial wall and narrowed intraluminal space resulting in respiratory symptoms, despite significant clinical response of the metastases. He was clinically diagnosed with tracheobronchial chondritis and treated successfully by steroid therapy. His diagnosis was confirmed by a positive serum anti-collagen type 2 antibody test. CONCLUSIONS: In addition to interstitial lung disease, tracheobronchial chondritis should be considered as a possible irAE in patients with acute respiratory symptoms after nivolumab administration.

Functional characterization of a germline ETV6 variant associated with inherited thrombocytopenia, acute lymphoblastic leukemia, and salivary gland carcinoma in childhood.

Germline pathogenic ETV6 variants have been discovered in families with inherited thrombocytopenia and predisposition to hematological and solid malignancies. We present a patient with short stature who was initially diagnosed with chronic immune thrombocytopenia. Subsequently, the patient developed acute lymphoblastic leukemia, followed by mammary analog secretory carcinoma. Sequencing analysis identified an ETV6 c.641C > T (p.Pro214Leu) germline variant. The variant protein exhibited attenuated nuclear localization, increased protein degradation, and reduced transcription repression function. Our findings suggest that the ETV6 gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in patients with pathogenic ETV6 variants.

Podoplanin is an efficient predictor of neck lymph node metastasis in tongue squamous cell carcinoma with low tumor budding grade.

The current study investigated the efficacy of podoplanin expression in tumor budding cells as a predictor of neck lymph node metastasis (NLM) in patients with tongue squamous cell carcinoma (SCC) of low tumor budding grade (TBG). A total of 99 patients with early T-stage tongue SCC of any clinical N status who received the initial curative treatment were enrolled. The association between podoplanin expression and NLM was immunohistochemically analyzed, with a focus on tongue SCC with low TBG. The disease-specific survival (DSS) rate was 77% at 5 years, and a significant difference was observed between the NLM-positive and NLM-negative groups, and between the low (n=77) and high (n=22) TBG groups. In the low TBG group, there was a significant difference in DSS between the NLM-positive and NLM-negative groups. The multivariate analysis showed that lymphatic vessel invasion (ly) [odds ratio (OR)=11.5, 95% confidence interval (CI): 1.50-87.6; P=0.02] and podoplanin expression (OR=7.07, 95% CI: 1.80-27.7; P=0.005) were significantly correlated with NLM. Furthermore, negative predictive values (NPV) of ly and podoplanin expression for NLM were 75% and 88%, respectively. Considering the balance of stratification case number adding to ratio, NLM-negative prediction by podoplanin was more significant than that by ly for the low TBG group. The results of the present study demonstrated that podoplanin expression in tumor budding is an independent and efficient predictor of NLM in the tongue SCC with low TBG. The low TBG and podoplanin-negative cases may be candidates for the wait and watch policy, therefore, reducing inappropriate elective neck lymph node dissections.

In Vitro Study of the Anti-cancer Effect of Alternate-day 5-Fluorouracil in Head and Neck Cancer Cells.

BACKGROUND/AIM: We have previously reported that alternate-day S-1 had comparable effects and milder adverse events than the respective consecutive-day regimen in head and neck cancer (HNC) patients. The aim of this study was to investigate the anticancer effects of both regimens and underlying mechanisms in vitro. MATERIALS AND METHODS: Two head and neck squamous cell carcinoma (HNSCC) cell lines were treated with 5-FU given on an alternate-day or consecutive-day schedule. The relative inhibition (RI) of tumor growth was calculated. Cell cycle distributions and cyclin expression following 5-FU treatment were analyzed. RESULTS: The RI of both regimens was almost identical. The percentage of cells in S phase was significantly increased in the alternate-day group compared to the consecutive-day group (p<0.001). CONCLUSION: The cytotoxic effect of alternate-day was equivalent to that of consecutive-day. S-phase arrest was more prominently observed with the alternate-day regimen, which may help maintain 5-FU sensitivity in head and neck cancer cells.

Importance of tumor budding grade as independent prognostic factor for early tongue squamous cell carcinoma.

BACKGROUND: Factors involved in neck lymph node metastasis (NLM) and prognosis of early tongue squamous cell carcinoma (SCC) remain unknown. METHODS: We analyzed disease-specific survival (DSS) and NLM including tumor budding grade (TBG) among 64 patients with cT1/2N0 tongue SCC. RESULTS: Univariate analysis of DSS of primary lesions uncovered significant differences in new cT, pT, new pT, pDiameter, venous infiltration, and TBG. Multivariate analysis selected only TBG3 as a predictor of NLM (odds ratio, 9.55; 95% confidence interval [CI], 1.80-50.8; P = .008), and a prognostic factor for DSS (hazard ratio, 4.41; 95% CI, 1.34-14.5; P = .02). CONCLUSION: The sole predictor of NLM and the prognosis of early tongue SCC was TBG, indicating that it might help to select overwhelming risk patients.

Significance of PD-L1 Expression in Tongue Cancer Development.

Aims: Immunohistochemistry of PD-L1 has been recently established as a surrogate method to predict if immunotherapy targeting PD-L1/PD-1 has a significant effect on suppression of cancers such as lung non-small cell carcinoma, melanoma, and renal cell carcinoma. Here we performed immunohistochemistry for PD-L1 expression in squamous cell carcinoma (SCC) of the tongue to investigate the potential correlation between PD-L1 expression and clinicopathological factors and whether PD-L1 expression would be associated with prognosis. Methods: Tissue microarray cores of paraffin-embedded blocks from 135 cases with surgically resected tongue SCC were immunohistochemically analysed for PD-L1 expression. Results: We observed a positive correlation between PD-L1 expression and tongue SCC pT1 and pT2 tumours, but a negative correlation with pT2, pT3 and pT4 tumours. We also observed a positive correlation with lymph node metastasis. However, no positive correlation was demonstrated between PD-L1 expression and overall survival. Conclusions: PD-L1 tends to be overexpressed at the early stage of tongue SCC, showing a close correlation with initial development of tongue. However, PD-L1 expression may not affect prognosis.

Prognostic role of epiregulin/amphiregulin expression in recurrent/metastatic head and neck cancer treated with cetuximab.

BACKGROUND: Cetuximab combined with chemoradiotherapy chemotherapy is the standard therapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, survival benefit is limited. The purpose of this study was to investigate the expression of epiregulin (EREG) and amphiregulin (AREG), as predictive prognostic markers for the efficacy of cetuximab combined with chemotherapy in R/M HNSCC. METHODS: We conducted a retrospective analysis of 37 patients diagnosed with R/M HNSCC. Tumor samples were analyzed for EREG and AREG mRNA gene expression, and clinical outcomes evaluated. RESULTS: Values of EREG and AREG were associated with significantly longer overall survival (OS) (P = .03 and P = .01, respectively), as well as progression-free survival (PFS) (P = .04 and P = .04, respectively). Multivariate analysis revealed that AREG expression was significantly associated with OS and PFS. CONCLUSIONS: Patients with recurrent/metastatic HNSCC with higher EREG and AREG gene expression appear to benefit more from cetuximab combined with chemoradiotherapy chemotherapy than those with lower expression.

Correlation of Inflammatory Markers, Survival, and COX2 Expression in Oral Cancer and Implications for Prognosis.

Objective Peripheral blood-derived inflammation-based scores, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and the combination of platelet count and NLR, have recently been proposed as prognostic markers in solid tumors. The purpose of this study was to investigate the validity of inflammatory markers as predictive prognostic factors for locally advanced oral squamous cell carcinoma (OSCC). In addition, we evaluated the potential correlation between systemic inflammation and local expression of COX2. Study Design Retrospective chart review and histologic analysis. Setting Tertiary referral academic center. Subjects and Methods We conducted a retrospective analysis of 94 patients with advanced OSCC treated with surgery at our hospital between 2007 and 2015. The relationship among patient survival, systemic inflammatory markers, and local COX2 expression was evaluated. Local COX2 expression in surgical specimens was measured by immunohistochemistry. Results High NLR and high PLR were associated with significantly shorter overall survival and cancer-specific survival. Multivariate analysis revealed that cN stage, NLR, and postoperative radiation/chemoradiation were significantly associated with overall survival and cancer-specific survival. PLR and combination of platelet count and NLR were significantly correlated with tumor expression of COX2. Finally, patients with cN2 stage disease and high local COX2 expression had a significantly worse prognosis than other patient groups. Conclusion Pretreatment inflammatory markers are useful as prognostic factors in advanced OSCC. Our study suggests that local COX2 may be affected by systemic inflammation and that the prognostic impact of COX2 expression depends on host factors and tumor characteristics.

Human papillomavirus and p16 protein expression as prognostic biomarkers in mobile tongue cancer.

OBJECTIVES: The objectives were to determine the prevalence of human papillomavirus (HPV) in mobile tongue cancer (MTC) and evaluate associations and survival. MATERIALS AND METHODS: Patients who underwent surgical resection as primary treatment for MTC (n = 127) were retrospectively evaluated. Formalin-fixed paraffin-embedded (FFPE) specimens were assessed for p16 and p53 by immunohistochemistry; for HPV DNA by nested multiplex polymerase chain reaction (PCR) using two pairs of consensus primers (MY09-MY11 and GP5+-GP6+); and for E6 and E7 oncogenes from 13 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, 66, and 68) by real-time reverse transcription PCR (RT-PCR). RESULTS: There were 18 (14.2%) p16-positive, 45 (35.4%) p53-positive, 9 (7.1%) HPV DNA-positive, and 7 (5.5%) E6 and/or E7 mRNA-positive tumors, but the correlation of all pairs was poor. There was no demographic or histopathologic association with HPV status. Cause-specific survival was significantly better with p16-positive than with p16-negative tumors (p = .037). CONCLUSIONS: The prevalence of HPV and p16 positivity was relatively low and p16 status was a poor surrogate marker for HPV status. The results showed the importance of p16 expression in prognosticating mobile tongue cancer.

PD-L1 Expression Confers Better Prognosis in Locally Advanced Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Clinical trials with therapies targeting immune checkpoint molecules have shown promising results in several tumor types. However, the predictive and prognostic values of these immunological factors for locally advanced oral squamous cell carcinomas (LAOSCC) remain unclear. Our purpose was to evaluate the expression and prognostic value of programmed cell death-ligand1 (PD-L1) and PD-L2 and to correlate their expression with the degree of infiltration by CD8+ cells in LAOSCC. PATIENTS AND METHODS: A total of 84 patients with LAOSCC were included. PD-L1, PD-L2 and CD8 expression was detected in the tumor tissue using immunohistochemistry and was tested for correlation with clinical outcome. RESULTS: PD-L1 and PD-L2 were expressed in 52.4% and 23.8% of LAOSCC cases, respectively. PD-L1 positivity was significantly associated with superior disease-free (p=0.024) and overall (p=0.008) survival of the patients and retained significance in multivariate analysis. PD-L1 positivity was correlated with CD8 density. CONCLUSION: PD-L1 expression was associated with CD8+ tumor-infiltrating lymphocytes and better outcome in patients with LAOSCC.

Inhibition of epithelial-mesenchymal transition by cetuximab via the EGFR-GEP100-Arf6-AMAP1 pathway in head and neck cancer.

BACKGROUND: Despite improved survival by the addition of a monoclonal antibody against epidermal growth factor receptor (EGFR), cetuximab, to chemotherapy or radiotherapy for squamous cell carcinoma of the head and neck (SCCHN), cetuximab by itself is not a potent antiproliferative agent against SCCHN. We aimed to elucidate working mechanism of cetuximab in SCCHN. METHODS: The effect of cetuximab on the proliferation, migration, invasion, epithelial-mesenchymal transition, and signaling events downstream of the EGFR were investigated in 4 SCCHN cell lines. The in vivo efficacy of cetuximab was evaluated in a xenotransplant model. RESULTS: Cetuximab inhibited migration, invasion, epithelial-mesenchymal transition, and lymph node metastasis by suppressing EGFR-GEP100-Arf6-AMAP1 pathway, but it did not inhibit cancer cell proliferation. CONCLUSION: The improved survival by the addition of cetuximab is likely to be attributable to the antiepithelial-mesenchymal transition action of cetuximab via inhibiting EGFR-GEP100-Arf6-AMAP1 pathway. © 2016 Wiley Periodicals, Inc. Head Neck 39: 476-485, 2017.

Prognostic role of the combination of platelet count and neutrophil-lymphocyte ratio in patients with hypopharyngeal squamous cell carcinoma.

Hypopharyngeal squamous cell carcinoma (HPSCC) is an aggressive disease with poor prognosis; but has no established biomarkers on the order of human papilloma virus and p16 in oropharyngeal carcinoma. This study investigated pre-treatment serum markers, including the combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) as a prognosis predictor in patients with HPSCC treated in our hospital. We retrospectively reviewed electronic medical records of 118 consecutive patients treated with curative intent at our hospital between 2007 and 2013. Of these 118 patients, we enrolled 100 patients for whom we had sufficient data to analyze relationships between clinico-laboratory characteristics and survival, including the prognostic significance of pre-treatment serum markers and previous reported clinical factors. Multivariate analysis of clinico-laboratory characteristics associated COP-NLR with cancer-specific survival, as were lymph node metastases. Kaplan-Meier analysis and log-rank tests showed that the COP-NLR could stratify those patients into three independent groups (P = 0.003). COP-NLR might be a useful predictor of survival in patients with HPSCC.

[Emergency Care System in Otolaryngology].

Otolaryngologists play a very important role in the field of emergency care in otolaryngology because their field requires a particular expertise in dealing with a variety of diseases. However, the emergency medical service system at night or during holidays has not yet been completely organized. Clarification of the present problems is essential to improve our emergency medical service system. Thus, we investigated the present state of otolaryngological emergency care in Tokyo and in Kyorin University Hospital. In Tokyo, outpatient clinics and hospitals see the emergency patients in the otolaryngology field by rotation during holidays. More than 13,000 patients were referred to the outpatient clinics, and more than 2, 000 patients were referred to the hospitals per year using this emergency care system. There are some problem with this system. One is that patients have to rush to a hospital in consecutive holidays and the other is that only a few clinics and hospitals see patients at night. Otolaryngologists have to regard these problem as an otolaryngologist-wide issue. For both public administration or academic societies a site for discussion needs to be provided.