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Background The aim of the study was to explore the treatment outcomes and prognostic factors for patients with previously irradiated but unresectable recurrent head and neck squamous cell carcinoma (rHNSCC) treated by stereotactic body radiotherapy (SBRT) plus cetuximab at a single institute in Taiwan. Methods From February 2016 to March 2019, 74 patients with previously irradiated but unresectable rHNSCC were treated with SBRT plus cetuximab. All patients received irradiation to the gross tumor and/or nodal area with 40-50 Gy in five fractions, with each fraction interval ≥ 2 days over a 2-week period by using the CyberKnife M6 machine. An18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan was performed before treatment for treatment target delineation (n = 74) and 2 months later for response evaluation (n = 60). The median follow-up time was 9 months (range 1-36 months). Results The treatment response rate was complete response: 25.0%, partial response: 41.7%, stable disease: 11.7%, and progressive disease: 21.7% based on the criteria of the Response Evaluation Criteria in Solid Tumors (n = 72) and complete metabolic response: 21.7%, partial metabolic response: 51.7%, stable metabolic disease: 13.3%, and progressive metabolic disease: 13.3% based on PET-CT (n = 60), respectively. The 1-/2-year overall survival (OS) and progression-free survival (PFS) rates were 42.8%/22.0% and 40.5%/19.0%, respectively. In the logistic regression model, a re-irradiation interval > 12 months was observed to be the only significant prognostic factor for a favorable treatment response. In the Cox proportional hazards model, a re-irradiation interval > 12 months and gross tumor volume (GTV) ≦ 50 ml were favorable prognostic factors of OS and PFS. Conclusion SBRT plus cetuximab provides a promising salvage strategy for those patients with previously irradiated but unresectable rHNSCC, especially those with a re-irradiation interval > 12 months or GTV ≦ 50 ml.

Background Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) has been identified as a histone 3 lysine 27 (H3K27) demethylase and acted as a tumor suppressor gene or oncogenic function. The current study was to explore the significance of UTX in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. Methods A total of 148 OTSCC patients who underwent surgical resection were identified, including 64 patients (43%) with overexpression of UTX and 84 patients (57%) harboring low expression of UTX. We also used two OTSCC cell lines, SAS and Cal 27, to determine the modulation of cancer. Chi-square test was used to investigate the difference of categorical variables between the groups; survival outcome was analyzed using the Kaplan–Meier method in univariate analysis, and a Cox regression model was performed for multivariate analyses. Results Univariate and multivariate analyses showed overexpression of UTX were significantly related to worse disease-free survival (P = 0.028) and overall survival (P = 0.029). The two OTSCC cell lines were treated with GSK-J4, a potent inhibitor of UTX, and transwell migration and invasion assays showed an inhibitory effect with a dose-dependent manner. In addition, western blot analyses also revealed the inhibition of cell cycle and epithelial-mesenchymal transition. Conclusion Our study suggests that UTX plays an important role in the process of OTSCC and overexpression of UTX may predict poor prognosis in OTSCC patients who received surgical resection.

Background To evaluate the longitudinal changes of quality of life (QoL) and survival in patients with nasopharyngeal carcinoma (NPC) treated by volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT). Methods One hundred and forty non-distant metastatic NPC patients treated by VMAT (n = 66) or IMRT (n = 74) with simultaneously integrated boost between March 2013 and December 2015 at a single institute were analyzed. QoL was prospectively assessed by the EORTC QLQ-C30 and HN35 questionnaires at the four time points: before RT, RT 42.4 Gy (20 fractions), and 3, 12 months after RT. Results The 3-year locoregional relapse-free survival, distant metastasis-free survival, failure-free survival, and overall survival rates were 96.6, 89.4, 86.1%, and 87.4 for the VMAT group, respectively, compared with 91.4, 90.0, 79.8, and 91.3% for the IMRT group (p value > 0.05). The pattern of QoL changes was similar between the VMAT and IMRT group. No statistically or clinically significant difference in all the QoL scales was observed between VMAT and IMRT group at each time point. Compared to before RT, we observed statistically (p Conclusion The study provides the evidence that the tumor control, survival and changes of QoL is compatible for NPC patients treated by VMAT versus IMRT.

Oral cavity cancer is a common cancer type that presents an increasingly serious global problem. Oral squamous cell carcinoma (OSCC) accounts for90% oral cancer cases. No biomarker tests are currently available for management of this cancer type in clinical practice. Previously, we validated matrix metalloproteinase-1 (MMP1) as one of the most promising salivary biomarkers for OSCC detection. Development of a convenient, rapid and high-throughput assay should further facilitate application of salivary MMP1 measurement for early detection of OSCC. The present study aimed to develop a workflow comprising dry saliva spot (DSS) sampling and immunoenrichment-coupled MALDI-TOF MS (immuno-MALDI) analysis to quantify salivary MMP1. We generated recombinant MMP1 protein and anti-peptide antibodies against MMP1, which were used to optimize the procedures of the entire workflow, including DSS sampling, on-paper protein digestion and elution, KingFisher magnetic particle processor-assisted immuno-enrichment and MALDI-TOF MS analysis. The established workflow was applied to measure salivary MMP1 levels in DSS samples from 5 healthy donors and 9 OSCC cases. The newly developed workflow showed good precision (intra-day and inter-day variations10%) and accuracy (80-100%) in quantification of MMP1 in DSS samples, with the limit of quantification at 3.07 ng/ml. Using this assay, we successfully detected elevated salivary MMP1 levels (ranging from 5.95 to 242.52 ng/ml) in 7 of 9 OSCC cases while MMP1 was not detectable in samples from the 5 healthy donors. In comparison, the traditional immunoassay was not effective in measuring MMP1 in DSS samples, highlighting the significant advantage of our immuno-MALDI assay. The DSS sampling format confers high flexibility and convenience of collection, storage and delivery of saliva specimens and the KingFisher-assisted immuno-MALDI analysis renders the assay as suitable for high-throughput screening. By combining the two features, the workflow developed in this study should facilitate improvement of molecular diagnostic tests for OSCC using salivary MMP1 as a biomarker.

Background: There are still oral cancer patients without surgery. To improve the survival, it is necessary to know the causes of the oral cancer patients without surgery. Methods: 23,217 patients with a newly-diagnosed oral cancer in Taiwan Cancer Registry (TCR) database between 2011 and 2015 were enrolled. Data from TCR database named “Reason for No Surgery of Primary Site” were extracted for analysis of the causes of those without surgery. Overall survival plots were presented using the Kaplan–Meier method with log-rank test. Results: 3263 (14%) patients did not received surgery. Among them, there were 720 patients (group 3) without surgery although surgery was advised, 154 patients (group 2) because of poor condition or death before surgery, and 2389 patients (group 1) because of other causes. Twenty-four percent of the patients with surgery were treated one month and more after diagnosis. The 5-year overall survival rates were 68.7%, 25.2%, 9.1% and 17.3% for surgery group, group 3, 2 and 1, respectively (p

Simple Summary Even after the implementation of intensity-modulated radiotherapy (IMRT), nasopharyngeal cancer (NPC) survivors may continue to exhibit several physical symptoms that negatively affect long-term quality of life (QoL). An NPC patient cohort study (n = 682) was conducted to examine the potential mediating effect of QoL (evaluated at multiple treatment-related time points) on the cancer stage–mortality association. Patients with advanced NPC exhibited low global health QoL and high QoL-HN35 symptom pre-IMRT, 3 months post-IMRT, and 2 years post-IMRT. Global health QoL and QoL-HN35 symptom scores 2 years after IMRT explained 49.4% and 39.4% of the excessive effect of advanced NPC on mortality risk. Our findings indicate that global health QoL and QoL-HN35 symptom 2 years after IMRT are key mediators of the relationship between advanced NPC and high mortality. These findings emphasize the significance of QoL-HN35 symptom and global health QoL-associated medical support and care for patients with NPC who received IMRT. Abstract Background: Quality of life (QoL) attained before, during, or after treatments is recognized as a vital factor associated with therapeutic benefits in cancer patients. This nasopharyngeal cancer (NPC) patient longitudinal study assessed the relationship among QoL, cancer stage, and long-term mortality in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Patients and Methods: The European Organization for Research and Treatment of Cancer (EORTC) core QoL questionnaire (QLQ-C30) and the head and neck cancer-specific QoL questionnaire module (QLQ-HN35) were employed to evaluate four-dimensional QoL outcomes at five time points: pre- (n = 682), during (around 40 Gy) (n = 675), 3 months (n = 640), 1 year (n = 578) and 2 years post-IMRT (n = 505), respectively, for 682 newly diagnosed NPC patients treated between 2003 and 2017 at a single institute. The median followed-up time was 7.5 years, ranging from 0.3 to 16.1 years. Generalized estimating equations, multivariable proportional hazards models, and Baron and Kenny’s method were used to assess the investigated effects. Results: Advanced AJCC stage (III–IV) patients revealed a 2.26-fold (95% CI—1.56 to 3.27) higher covariate-adjusted mortality risk than early-stage (I–II) patients. Compared with during IMRT, advanced-stage patients had a significantly low global health QoL and a significantly high QoL-HN35 symptom by a large magnitude at pre-, 3 months, and 2 years post-IMRT. QoL scales at pre-IMRT, 1 year, and 2 years post-IMRT were significantly associated with mortality. The effect changes of mortality risk explained by global health QoL, QoL-C30, and QoL-HN35 symptom were 5.8–9.8% at pre-IMRT but at 2 years post-IMRT were 39.4–49.4% by global health QoL and QoL-HN35 symptoms. Conclusions: We concluded advanced cancer stage correlates with a long-term high mortality in NPC patients treated with IMRT and the association is partially intermediated by QoL at pre-IMRT and 2 years post-IMRT. Therefore, QoL-HN35 symptom and global health QoL-dependent medical support and care should be focused and tailored at 2 years post-IMRT.

This study aims to evaluate the relationship between human ribophorin II (RPN2) and the effect of treatment using induction therapy with docetaxel, cisplatin, and fluorouracil (TPF) for p-16 negative locally advanced head and neck squamous cell carcinoma (HNSCC). A total of 203 patients with locally advanced p-16 negative HNSCC who received induction chemotherapy with TPF at the Kaohsiung Chang Gung Memorial Hospital between 2009 and 2014 were enrolled. Immunohistochemistry (IHC) for RPN2 was examined and correlated with treatment outcome. Our study showed that RPN2 overexpression was significantly correlated with a poor response to induction chemotherapy with TPF. Both RPN2 overexpression and clinical N1 to N3 stages represented adverse prognostic factors for progression-free survival (PFS) and overall survival (OS). RPN2 might be a predictive marker for treatment response to induction chemotherapy. Further clinical trials are needed to determine the therapeutic significance of RPN2 in patients with HNSCC.

Janus kinase 2 (JAK2) is a member of the JAK family that transduces cytokine-mediated signals via the JAKs/STATs (signal transducer and activator of transcription proteins) pathway, which plays an important role in many inflammatory diseases. This study investigates the association of p-JAK2 and JAK2-associated cytokines from nasal polyp (NP) tissue with disease severity, and evaluates the p-JAK2-mediated STATs in chronic rhinosinusitis (CRS) with NP. Sixty-one CRSwNP patients with nasal polyps undergoing endoscopic sinus surgery were enrolled, while the turbinate tissues from 26 nasal obstruction patients were examined as the control group. Elevated levels of p-JAK2 were detected in CRSwNP, and significantly correlated with scores of disease severity (LMK-CT, TPS, and SNOT-22). Expressions of the JAK2-associated cytokines, such as IL-5, IL-6, IL-13, G-CSF, and IFN-γ were significantly higher in CRSwNP than in the controls, while the levels of IL-5, IL-6, IL-13, or G-CSF had positive correlation with scores of disease severity. Moreover, markedly increased expression of p-STAT3 in CRSwNP was observed relative to the control. Taken together, these data showed that the JAK2-associated cytokines including IL-6 and G-CSF may stimulate JAK2 phosphorylation to activate p-STAT3, indicating an association with disease severity and supporting its development of JAK2 inhibitor as a potential therapeutic agent for CRS.

Background To investigate the toxicity, changes of quality of life (QOL), and survival for patients with nasopharyngeal cancer (NPC) treated by concurrent chemoradiotherapy (CCRT) with simultaneously integrated boost volumetric-modulated arc therapy (SIB-VMAT). Methods A total of 68 NPC patients treated by CCRT with SIB-VMAT technique were collected. QOL was longitudinally assessed by the EORTC QLQ-C30 and HN35 questionnaires at the 4 time points: baseline, 42.4 Gy (20 fractions), and 3, 12 months after CCRT. Results The 4-year locoregional relapse free, distant metastasis free, failure free, and overall survival rates were 97.0%, 86.4%, 82.0%, and 88.1%, respectively. The 4-year cumulative incidence rate of late toxicities with grade 3 or more was 3.0%. One year after CCRT, most QOL scales, except some oral related symptoms, recovered to baseline level. Conclusion CCRT with SIB-VMAT produces excellent locoregional control, few severe late toxicity, and good general health status for NPC patients.

Objectives microRNA (miRNA) expression patterns have provided new insight as biomarkers of prognosis as well as novel therapeutic targets for several neoplasms. However, the role of exosomal miRNA in the prognosis of oral squamous cell carcinoma (OSCC) has not yet been completely clarified. Paired primary tumor and normal oral epithelial cells from OSCC patients were obtained, and the exosomal miRNA profiles between them were compared by miRNA microarray analysis. The miRNA levels in the serum exosomes of OSCC patients were verified by real-time quantitative reverse transcription PCR (qRT-PCR) analysis. Finally, the biological functions and the potential as a prognostic marker of the selected miRNA candidates were analyzed in the OSCC cells and patients, respectively. Results Exosomal miR-155 and miR-21 were significantly upregulated, and exosomal miR-126 was dramatically downregulated in the primary OSCC cells and the serum of OSCC patients. In the analysis of oncogenic behaviors, coculture with either miR-155-rich or miR-21-rich exosomes could promote cell proliferation and invasion accompanied with downregulation of PTEN and Bcl-6 tumor suppressors. Moreover, treatment with miR-126-rich exosomes inhibited oncogenic behaviors and oncogene EGFL7 expression in OSCC cells. Finally, exosomal miR-126 was reduced in the serum of the late-staged OSCC patients, and downregulation of blood exosomal miR-126 was associated with poor survival in OSCC patients. Conclusion Exosomal miR-155 and miR-21 are oncogenic miRNAs which suppress PTEN and Bcl-6 expression, and exosomal miR-126 acts as a tumor suppressor which downregulates EGFL7 in OSCC. Furthermore, blood exosomal miRNAs may serve as biomarkers for the diagnosis and prognosis of OSCC.

Patients with advanced head and neck squamous cell carcinoma (HNSCC) usually show a dismal prognosis. It is this worthwhile to develop new, effective therapeutic regimens for these patients, such as molecular targeted therapy, which is promising as an alternative or combination treatment for HNSCC. The mammalian target of rapamycin (mTOR) pathway, which plays an important role in the carcinogenesis of HNSCC, is the most frequently activated, and is thus worthy of further investigation. In this study, two human HNSCC cell lines, FaDu and SAS, were evaluated for cell growth with trypan blue staining and tumor growth using an orthotopic xenograft model. The immunohistochemical expression of mTOR in the subcutaneous xenograft model and the inhibitory effects of docetaxel on the growth and state of activation of the PI3K/mTOR pathway were also evaluated and examined by colony formation and Western blot, respectively. Cell proliferation and migration were measured by water-soluble tetrazolium salt (WST-1) and OrisTM cell migration assay, respectively. Furthermore, the effects of rapamycin and BEZ235, a phosphatidylinositol 3-kinases (PI3K) and mTOR inhibitor in combination with docetaxel or CCL20 were evaluated in the FaDu and SAS cells. The results showed that the expression of mTOR was significantly higher in the SAS and FaDu xenograft models than in the control. Docetaxel treatment significantly suppressed HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. Additionally, when administered in a dose-dependent fashion, mTOR inhibitors inhibited the growth and migration of the HNSCC cells. This combination was synergistic with docetaxel, resulting in almost complete cell growth and migration arrest. In conclusion, docetaxel significantly inhibited HNSCC cell proliferation and migration in vitro via the PI3K/mTOR/CCL-20 signaling pathway. The synergistic and additive activity of mTOR inhibitors combined with docetaxel shows potential as a new treatment strategy for HNSCC.

The current trend in cardio-oncology places major emphasis on circulatory toxicity induced by cancer therapy. Whether malignancy itself is a direct contributing factor to cardiovascular dysfunctions and baroreflex dysregulation in patients with cancer, however, has rarely appeared in literature. The present study addressed this largely overlooked aspect of cardio-oncology by evaluating blood pressure, heart rate and baroreflex functionality before and after curative surgery in patients with oral cavity squamous cell carcinoma (OSCC). We found that these patients exhibited reduced baroreflex-mediated sympathetic vasomotor tone and augmented cardiac vagal baroreflex, and such inherent anomalies were readily reversed to levels of healthy controls after surgical removal of the primary tumor. It is concluded that by being more prone to hypotension and bradycardia, anomalous baroreflex functionality causally induced by malignancy predisposes patients with cancer to detrimental cardiovascular abnormalities that may be further exacerbated by cancer therapy.

BACKGROUND Nasopharyngeal carcinoma (NPC) is a common type of head and neck cancer in Asia. Adverse effects occur in over 90% of NPC patients treated with radiotherapy or chemoradiation. Angiotensin II receptor blockers (ARBs) are commonly used to treat hypertension without serious adverse effects. However, the anticancer activity of ARBs in NPC remains unclear. METHODS We investigated the survival impacts of ARBs among NPC patients in a retrospective study. The anticancer effects and related signaling pathways of the ARBs valsartan and losartan were also evaluated in vitro and in vivo. RESULT A total of 927 patients with NPC who had hypertension were enrolled in the study, 272 (29.3%) of whom received ARBs. Kaplan-Meier analysis revealed that patients who used ARBs had higher rates of 5-year overall survival (OS; 87.8% vs 75.1%; P = .002) and disease-specific survival (DSS; 95.4% vs 77.7%; P < .001) than those who did not receive this treatment. Additionally, ARBs inhibited cell proliferation and induced apoptosis by increasing levels of cleaved caspase-3, cleaved caspase-9, and cytochrome C; the cell population in the sub-G1 phase; and caspase-3 activity in NPC-TW01 cells. ARBs inhibited tumor growth and angiogenesis via apoptosis in an NPC xenografts model. Interestingly, ARBs inhibited phosphorylation of PI3K/AKT signaling in vitro and in vivo, which is markedly attributed to their antitumor effects in NPC. CONCLUSION These data indicate that ARBs not only improve 5-year OS and DSS among patients with NPC but also exert antiproliferative and antiangiogenesis effects by inducing apoptosis in NPC, supporting that ARBs may be promising agents for treatment of NPC.

Hui-Ching Chuang,1,2 Ming-Hsien Tsai,1,2 Yu-Tsai Lin,1,2 Ming-Huei Chou,3,4 Tai-Lin Huang,2,5 Tai-Jan Chiu,2,5 Hui Lu,1 Fu-Min Fang,2,6 Chih-Yen Chien1,2,7 1Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3The Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Center for General Education, Cheng-Shiu University, Kaohsiung, Taiwan; 5Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 7Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, TaiwanCorrespondence: Chih-Yen Chien Email cychien3965@adm.cgmh.org.twPurpose: This study aimed to investigate the clinical impacts of the pretreatment peripheral blood ratios of lymphocytes, monocytes and neutrophils among patients with hypopharyngeal cancer/laryngeal cancer.Patients and Methods: A total of 141 people with cases of hypopharyngeal cancer/laryngeal cancer were enrolled to evaluate the clinical impacts of the systemic inflammation response index (SIRI), neutrophil–lymphocyte ratio (NLR) and lymphocyte–monocyte ratio (LMR) in pretreatment blood among patients with laryngeal/hypopharyngeal cancer between January 2012 and December 2014.Results: Those patients with higher pretreatment LMR (> 2.99) showed a significantly higher 5-year complete response rate (CR) (69% vs 31%) than those with lower LMR (≤ 2.99, p = 0.006). Additionally, those patients with lower pretreatment SIRI (< 3.26) showed a significantly higher 5-year CR (90% vs 10%) than those with higher SIRI (≥ 3.26, p < 0.001). Patients with higher LMR had better 5-year overall survival (OS) (p = 0.01) and 5-year progression-free (PFS) (p = 0.005) rates than those with lower LMR in univariate analysis. Patients with lower SIRI had better 5-year OS (p < 0.001) and 5-year PFS (p < 0.001) than those with higher SIRI in univariate analysis. In the Cox regression analysis, SIRI (HR = 1.941, [95% CI: 1.223– 3.081], p = 0.005) and N classification (HR = 2.203, [95% CI: 1.327– 3.657], p = 0.002) were independent variables of 5-year OS. In addition, SIRI (HR= 2.127, [95% CI: 1.214– 3.725], p = 0.008), T classification (HR = 2.18, [95% CI: 1.072– 4.433], p = 0.031), and N classification (HR = 2.329, [95% CI: 1.395– 3.889], p = 0.001) were independent variables of 5-year PFS.Conclusion: Pretreatment SIRI is superior to LMR in predicting treatment response and clinical outcomes among patients with laryngeal/hypopharyngeal cancer treated by CRT/RTO. SIRI may be adopted in the treatment of laryngeal/hypopharyngeal cancer by CRT/RTO.Keywords: head and neck squamous cell carcinoma, hypopharyngeal cancer, laryngeal cancer, systemic inflammation response index, neutrophil–lymphocyte ratio, lymphocyte–monocyte ratio

Background Systemic inflammation and nutritional status both play roles in the survival of cancer patients. Therefore, it is important to understand the effects of prognostic nutritional index (PNI) and lymphocyte-to-monocyte ratio (LMR) on the survival of patients with advanced p16-negative oropharyngeal cancer. Methods A total of 142 patients diagnosed with advanced p16-negative oropharyngeal cancer between 2008 and 2015 were enrolled in this study. All patients received primary treatment with definite concurrent chemoradiotherapy (CCRT). Optimal cutoff values for PNI and LMR were determined using receiver operating characteristic curves for survival prediction. Survival rates for different level of PNI and LMR were estimated and compared using Kaplan–Meier method and log-rank test to see if there were significant effects on these end points, including 5-year overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) rates. The effects of PNI and LMR on survival were assessed using Cox regression model adjusted for other prognostic factors. Results The results showed the optimal cutoff values for PNI and LMR were 50.5 and 4.45, respectively. A high PNI (≧50.5) was significantly improved the 5-year OS. A low LMR ( Conclusions Elevated pretreatment PNI and LMR are both favorable prognosticators in advanced p16-negative oropharyngeal cancer patients undergoing CCRT.

ObjectiveTo determine the predictive factors of postoperative hospital stay and total hospital medical cost among patients who underwent total laryngectomy.MethodsA total of 213 patients who underwent total laryngectomy in a tertiary referral center for tumor ablation were enrolled retrospectively between January 2009 and May 2018. Statistical analyses including Pearson's chi-squared test were used to determine whether there was a significant difference between each selected clinical factors and outcomes. The outcomes of interest including postoperative length of hospital stay and inpatient total medical cost. Logistic regression analyses were performed to reveal the relationship between clinical factors and postoperative length of hospital stay or total inpatient medical cost.ResultsPreoperative radiotherapy (p = 0.007), method of wound closure (p < 0.001), postoperative serum albumin level (p = 0.025), and postoperative serum hemoglobin level (p = 0.04) were significantly associated with postoperative hospital stay in univariate analysis. Postoperative hypoalbuminemia (odds ratio [OR]: 2.477; 95% confidence interval [CI]: 1.189-5.163; p = 0.015) and previous radiotherapy history (OR 2.194; 95% CI: 1.228-3.917; p = 0.008) are independent predictors of a longer postoperative hospital stay in multiple regression analysis. With respect to total inpatient medical cost, method of wound closure (p < 0.001), preoperative serum albumin level (p = 0.04), postoperative serum albumin level (p < 0.001), and history of liver cirrhosis (p = 0.037) were significantly associated with total inpatient medical cost in univariate analysis. Postoperative hypoalbuminemia (OR: 6.671; 95% CI: 1.927-23.093; p = 0.003) and microvascular free flap reconstruction (OR: 5.011; 95% CI: 1.657-15.156; p = 0.004) were independent predictors of a higher total inpatient medical cost in multiple regression analysis.ConclusionsPostoperative albumin status is a significant factor in predicting prolonged postoperative hospital stay and higher inpatient medical cost among patients who undergo total laryngectomy. In this cohort, the inpatient medical cost was 48% higher and length of stay after surgery was 35% longer among hypoalbuminemia patients.

ObjectiveDepression is a common comorbidity in cancer patients. This study aimed to compare the prevalence and associated factors of depressive disorder between patients with head and neck cancer (HNC) and those with lung cancer (LC).DesignThis study used a cross-sectional design with consecutive sampling.SettingA medical centre (Kaohsiung Chang Gung Memorial Hospital, Taiwan).ParticipantsPatients for the study were recruited from the HNC and LC outpatient clinic and inpatient ward from March 2016 to February 2018. Patients with HNC and LC were enrolled and assessed using the Mini International Neuropsychiatric Interview (MINI).Primary and secondary outcome measuresThe primary outcome was psychiatric diagnoses assessed using the MINI. The secondary outcomes were psychological well-being assessed using the Beck Anxiety Inventory, Taiwanese Depression Questionnaire, Brief Fatigue Inventory, Numeric Pain Rating Scale and the List of Threatening Experiences Questionnaire.ResultsIn total, 113 HNC patients and 104 LC patients were recruited for the study. The most common psychiatric comorbidity of HNC patients was alcohol use disorder (49.6%), followed by adjustment disorder (20.4%) and depressive disorder (11.5%). The most common psychiatric comorbidity of LC patients was depressive disorder (25.0%), followed by adjustment disorder (17.3%), alcohol use disorder (3.8%) and insomnia disorder (3.8%). Among HNC patients, a self-harm history was positively associated with depression (OR=11.91; 95% CI, 1.47 to 96.83), and a higher educational level was negatively associated with depression (OR=0.77; 95% CI, 0.66 to 0.91). Among LC patients, severity of stressor (OR=2.78; 95% CI, 1.50 to 5.15) and severity of anxiety (OR=1.18; 95% CI, 1.04 to 1.34) were two significant factors associated with depression.ConclusionWe reported the prevalence and associated factors of depression between patients with HNC and those with LC. Clinicians should be aware of this comorbidity and the associated risk factors, and conduct intervention programmes to prevent these cancer patients from developing depression.

Background This study evaluated the treatment outcomes of the primary surgery (PS) or concurrent chemoradiotherapy (CCRT) as the initial treatment for hypopharyngeal squamous cell carcinoma (HPSCC). Methods This retrospective cohort study included patients with stages III–IV HPSCC from four tertiary referral centers consecutively enrolled from 2003 to 2012; of them, 213 (32.6%) and 439 (67.4%) had received PS and CCRT as their primary treatments, respectively. The 5-year overall survival (OS) and disease-free survival (DFS) rates were analyzed using the Kaplan–Meier method and Cox regression models. Results In patients undergoing PS and CCRT, OS rates were 45.0% and 33.1% (p < 0.001), respectively, and DFS rates were 36.2% and 28.9% (p = 0.003), respectively. In subgroup analysis, in patients with stage IVA HPSCC, PS was associated with higher OS rate (p = 0.002), particularly in those with T4 or N2 classification (p = 0.021 and 0.002, respectively). Multivariate analysis indicated that stage IVA HPSCC, stage IVB HPSCC, and CCRT were independent adverse prognostic factors for OS rate (p = 0.004, < 0.001, and 0.014, respectively). Furthermore, in patients with stage IVA HPSCC aged ≥ 65 years and with N2 classification, CCRT was significantly associated with lower OS rates than was PS (p = 0.027 and 0.010, respectively). Conclusions In patients with advanced HPSCC, PS was significantly associated with better prognosis than CCRT. PS could be a favorable primary treatment modality for the management of patients with stage IVA HPSCC, particularly those aged ≥ 65 years and with T4 and N2 classification.

Esophageal squamous cell carcinoma (ESCC) and head/neck squamous cell carcinoma (HNSCC) are very common cancers worldwide, and there is higher incidence of synchronous ESCC/NSCC in Taiwan. The aim of the current study was to investigate the efficacy of different chemotherapy regimens in patients with locally advanced synchronous ESCC/HNSCC who received curative concurrent chemoradiotheapy (CCRT). A total of 75 patients were identified and assigned to one of two groups: 45 patients receiving cisplatin/5-fluorouracil (5-FU) regime in one group and 30 patients receiving a weekly cisplatin regime in the other. Overall survival (OS) was calculated from the date of diagnosis of the ESCC or HNSCC to the date of death from any cause or the most recent follow-up. Kaplan&ndash, Meier curves and log-rank tests were used to estimate OS and differences between the two groups, respectively. There was no significant difference in the analysis of OS between the cisplatin/5-FU and the weekly cisplatin groups. However, patients that interrupted their CCRT were found to have worse OS compared to those without interruptions (5.4 months versus 18.8 months, p = 0.002). In subgroup analysis, patients without interruptions of CCRT had a better OS than those with interruptions in the cisplatin/5-FU group (13.0 months versus 5.4 months, p = 0.041) as well as in the weekly cisplatin group (21.4 months versus 5.0 months, p = 0.017). Interruption of CCRT was the only independently poor prognostic factor of OS in the univariate and multivariate (hazard ratio 0.18, p &lt, 0.001) analyses. Most interruption of CCRT resulted from adverse events (AEs) or serious AEs. Although there was no significant difference in the incidence of AEs between these two groups, lower incidence of adverse events was mentioned in the weekly cisplatin group. Our study suggests that interruption of CCRT is an independently poor prognostic factor of OS, and that completion of CCRT without interruption is more important than the choice of chemotherapeutic regimen for patients with synchronous ESCC/HNSCC.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population‐based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra‐nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause‐specific survival (CSS), local‐regional relapse‐free survival (LRFS), and distant metastasis‐free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P 70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.

Objectives Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with various cancers. However, it remains unclear whether ARBs confer a survival benefit on patients with oral squamous cell carcinoma (OSCC). Here, we assessed the associations between ARB use and survival in patients with OSCC of different stages. Materials and methods This was a 10-year retrospective cohort study of OSCC patients. We enrolled 7,558 patients diagnosed with oral cancer between January 2007 and December 2017 whose details had been entered into the Chang Gung Research Database. Seven hundred and fourteen patients were recruited from the Chang Gung Research Database after performing 1:1 propensity score-matching between ARB users and non-users. Cox’s regression models with adjusted covariates were employed to detect factors influencing the survival rates of patients with OSCC. Results Kaplan-Meier analysis revealed that the overall survival (OS) rate of 180-day ARB users increased (p = 0.038). Cox’s regression models indicated that ARB use, younger patients, early-stage OSCC, and patients without diabetes mellitus were independently prognostic of improved OS. Increased OS was more prominent in 180-day ARB users in stage III, Iva, and IVb categories. Conclusions ARB use for more than 180 days is associated with an increased survival rate and is a positive, independent prognostic factor in patients with OSCC. A further two-arm study should be conducted to confirm the clinical usefulness of ARBs in OSCC patients.

Obstructive sleep apnea (OSA), a breathing disorder characterized by repetitive collapse of the pharyngeal airway during sleep, can cause intermittent hypoxemia and frequent arousal. The evaluation of dynamic tongue motion not only provides the biomechanics and pathophysiology for OSA diagnosis, but also helps doctors to determine treatment strategies for these patients with OSA. The purpose of this study was to develop and verify a dedicated tracking algorithm, called the modified optical flow (OF)-based method, for monitoring the dynamic motion of the tongue base in ultrasound image sequences derived from controls and patients with OSA. The performance of the proposed method was verified by phantom and synthetic data. A common tracking method, the normalized cross-correlation method, was included for comparison. The efficacy of the algorithms was evaluated by calculating the estimated displacement error. All results indicated that the modified OF-based method exhibited higher accuracy in verification experiments. In the human subject experiment, all participants performed the Müller maneuver (MM) to simulate the contour changes of the tongue base with a negative pharyngeal airway pressure in sleep apnea. Ultrasound image sequences of the tongue were obtained during 10 s of a transition from normal breathing to the MM, and these were measured using the modified OF-based method. The results indicated that the displacement of the tongue base during the MM was larger in the controls than in the patients with OSA (p 0.05); the calculated areas of the tongue in the controls and patients with OSA were 24.9 ± 3.0 and 27.6 ± 3.3 cm

Background Margin status and lymph node metastasis are the most important prognostic factors for oral cancers. However, while adequate surgical resection is crucial for local control and prognosis, the definition of clear margins has long been a subject of debate. In this study, we analyzed data from a nationwide population-based cancer registry database and evaluated the impact of surgical margins on cancer-specific survival (CSS) and overall survival (OS) as well as the optimal cutoff of adequate surgical margins. Methods This analysis included all cases of oral cancer diagnosed from 2011 to 2017 that were reported to the Taiwan Cancer Registry database. The staging system was converted from American Joint Committee on Cancer (AJCC) version 7 to AJCC version 8. Kaplan–Meier analysis and Cox proportional-hazards regression were performed to identify covariates that were significantly associated with CSS and OS. Results Between 2011 and 2017, 15,654 of a total of 36,091 cases diagnosed with oral cancers were included in the final analyses. Advanced N stage, positive margins, and advanced T stage are the leading risk factors for poor CSS and OS. When surgical margins were subdivided into 1-mm intervals from 5 mm to positive margin, we found that surgical margins Conclusions This is the first nationwide, population-based cohort to revisit the question of the adequate surgical margins for oral cancers. We conclude that surgical margins ≥4 mm and ≥5 mm are adequate for good CSS and OS, respectively.

Background Inflammation plays a role in the development of cancer. This study aims to analyze the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological determinants in early-stage (cT1/T2N0) tongue cancer. Materials and methods A total of 262 patients were selected from our institute’s cancer database between 2004 and 2011. Optimal cutoff value of NLR and lymph node density (LND) were determined statistically using receiver operating characteristic curve analysis for survival prediction. The 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) rates were estimated using the Kaplan–Meier method. Results The results showed that, in this cohort, the optimal cutoff value of NLR was 2.95 and for LND, it was 0.031. Patients with NLR ≥2.95 correlated significantly with positive N classification (P=0.011), T2 classification (P=0.007), positive perineural invasion (P5 mm (P=0.005). The 5-year OS among patients with NLR 0.031 compared to those with LND

Summary Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade tumor of the salivary glands made up of clear cells that form cords and nests in hyalinized stroma. To date, primary HCCCs of the paranasal sinus have not been described. This article presents 2 cases of HCCC of the maxillary sinus with unusual glandular formation and lymphoplasmacytic stroma in case 1 and a characteristic solid nest pattern and fibrocellular and hyalinized stroma in case 2. Immunohistochemical studies excluded myoepithelial origin and sinonasal renal cell–like adenocarcinomas. Negativity for p63 and p40 in case 1 ruled out a squamous cell origin. Both cases showed a rearranged EWSR1 gene. Reverse-transcription polymerase chain reaction detected EWSR1-ATF1 fusion gene transcripts, and Sanger sequencing confirmed an EWSR1 exon 11 fused in-frame to ATF exon 3.

The aim of this study is to investigate soft tissue disorders of affected shoulders after nerve-sparing selective neck dissection (SND) in patients with head and neck cancers (HNCs) by sonography. Eighteen HNCs patients with shoulder disability after SND were enrolled. Shoulder motions, pain, and the sonographic findings were measured and analyzed. Significantly decreased flexion, abduction, and increased pain were found on affected shoulders compared with normal shoulders. There were significant decrease in thickness of trapezius muscle (p=0.001), abnormal findings of supraspinatus tendon (p=0.022), and subdeltoid bursa (p=0.018) on surgical side. The ratio of trapezius muscle atrophy was related to shoulder pain (p=0.010). Patients with subdeltoid abnormalities had significant limitation on shoulder flexion and abduction. Abnormalities of supraspinatus tendon and subdeltoid bursa on sonography and trapezius muscle atrophy may play a key role in shoulder pain and shoulder flexion and abduction limitations.

BACKGROUND: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). METHODS: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. RESULTS: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). "Fear of the cancer returning" (39%) and "dry mouth" (37%) were most common. Twenty-five percent (524) reported less than good QOL. CONCLUSION: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL. peerReviewed

Background: Nox4 has been reported to promote tumor progression of various types of cancer through many different pathways. The current study was designed to evaluate the prognostic significance of Nox4 in patients with oral tongue squamous cell carcinoma (OTSCC) receiving surgical resection. Methods: We retrospectively analyzed the 161 patients with OTSCC treated with surgical resection, including 81 patients with high expression of Nox4 and 80 patients with low expression of Nox4. Two OTSCC cell lines, SAS and SCC4, were used to investigate the proliferation activity. Results: The univariate and multivariable analyses showed that negative nodal metastasis and low expression of Nox4 were significantly associated with superior disease-free survival (DFS) and overall survival (OS). Western blotting analysis indicated that Nox4 was highly expressed in these two OTSCC cell lines and knockdown of Nox4 was successful by transfecting with Nox4 shRNA. In addition, these cell lines were also treated with a Nox4 inhibitor (GKT-137831) and the results showed GKT-137831 could inhibit the proliferation of OTSCC tumor cells in a dose-dependent manner. Conclusion: Our study suggests that Nox4 plays an important role in disease progression of OTSCC and Nox4 overexpression is a poor prognostic factor for patients with OTSCC who received surgical resection.

This study investigated the therapeutic benefit of radical resection (SRR) for clinical T4b oral cavity squamous cell carcinoma (OSCC) with partial or complete response after radical chemoradiotherapy (CRT).At the authors' institution, 79 patients with newly diagnosed non-metastatic T4b OSCC were treated with CRT from January 2009 to December 2014. All of them were irradiated using intensity-modulated radiotherapy (IMRT), with a radical dose (median 70 Gy; range 66-76 Gy) in the gross tumor area. Of the 65 cases achieving partial or complete response after CRT, 33 were treated further with SRR and 32 with adjuvant chemotherapy or observation. The locoregional control (LRC), overall survival (OS), and cancer-free survival (CFS) rates were compared between the two groups.The 3-year LRC, OS, and CFS rates were respectively 72.3, 75.1, and 72.6 % in the SRR group compared with 32.8, 47.7, and 44.3 % in the non-SRR group (p0.05). Multivariate analysis showed that SRR was the only statistically significant prognostic factor related to LRC, OS, and CFS. For those with SRR, pathologic downstaging was observed in 27 cases (81.8 %). Perioperative flap failure was observed in three cases (9.2 %) and neck wound necrosis in four cases (12.1 %).For T4b OSCC, incorporating SRR in the therapy is technically safe and has survival benefit, with a significant response after CRT applied by IMRT, with a radical dose in the gross tumor area.

Oral squamous cell carcinoma (OSCC) accounts for &gt, 90% of cases of oral cancer, including cancer at the lip and oral cavity and cancer at the oropharynx. Most OSCCs develop from oral potentially malignant disorders (OPMDs), which consist of heterogeneous lesions with different malignant transformation potentials that make early detection of OSCC a challenge. Using a targeted mass spectrometry-based assay to compare multiple candidate proteins, we previously identified matrix metalloproteinase-1 (MMP-1) as one of the most promising salivary OSCC biomarkers. To explore the clinical utility of MMP-1 in OSCC detection, we developed an in-house, sensitive enzyme-linked immunosorbent assay (ELISA) for measuring MMP-1 content, and tested it on saliva samples from 1160 subjects (313 healthy controls, and 578 OPMD and 269 OSCC patients) collected at two medical centers. Salivary MMP-1 levels measured by our in-house ELISA significantly discriminated OSCC patients from non-cancerous groups. A receiver operating characteristic curve analysis showed that MMP-1 was effective in separating non-cancer groups from patients with OSCCs at the oral cavity. Additionally, salivary MMP-1 levels in oral cavity cancer patients were highly correlated with tumor progression (tumor size, lymph node metastasis, and overall stage). Collectively, our results indicate that salivary MMP-1 is an effective biomarker for OSCC that can be sensitively detected using our newly developed ELISA. The newly developed MMP-1 ELISA may be used as a new adjunctive tool to aid in detecting and monitoring OSCC.

BACKGROUND Distinguishing benign complications after concurrent chemoradiotherapy (CCRT) from a local residual tumor in advanced head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge. In this study, we propose criteria when considering physiological uptake patterns on F-18-fluorodeoxyglucose (FDG) PET/CT in patients with advanced HNSCC after CCRT. METHODS We retrospectively reviewed FDG PET/CT images of 62 patients with advanced HNSCC, which were taken within 16 weeks following CCRT. Visual interpretation criteria were rated by three nuclear medicine physicians, independently, according to the uptake patterns of the primary site. The Cohen k coefficient was calculated to assess inter-reader agreement. The histology of the primary site within a 1 month of the PET/CT study was used as the gold standard for sensitivity, specificity, positive predictive value and negative predictive value. RESULTS PET/CT was arranged at a median interval of 10.5 weeks (range 4-16 weeks) after CCRT, and the pathologic residual rate was 55.7% at the primary site. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of identifying residual disease were 91.1%, 50.0%, 68.9%, 82.3%, and 72.6%, respectively, by the previously established criteria, and 88.2%, 92.9%, 93.8%, 86.7%, and 90.3%, respectively, by our physiology-based criteria. Our visual rating criteria corrected 12 of 14 (84.6%) false-positive results from the established criteria, while two more false-negative cases identified with our criteria were proven to be small residual tumors. CONCLUSIONS By incorporating physiological changes following CCRT, our visual rating criteria improved the accuracy of the currently used FDG PET/CT visual rating system, especially the number of false-positive cases with advanced HNSCC after CCRT.

The highest incidence of nasopharyngeal carcinoma (NPC) is in southeast China, including Taiwan. Many side effects have been observed following radiation therapy with chemotherapy; hence, exploring new treatment modalities for NPC is an important future direction. Angiotensin-(1–7) [Ang-(1–7)] is an endogenous heptapeptide hormone and important component of the renin–angiotensin system that acts through both the Mas receptor and AT2 receptor, exhibiting anti-proliferative and anti-angiogenic properties in cancer cells. However, the anti-cancer activity of Ang-(1–7) related to autophagy in NPC remains largely debated. The effects and signaling pathway(s) involved in the Ang-(1–7)/Mas receptor axis in NPC were investigated both in vitro and in vivo. Ang-(1–7) inhibited cell proliferation, migration, and invasion in NPC-TW01 cells. Ang-(1–7) induced autophagy by increasing the levels of the autophagy marker LC3-II and by enhancing p62 degradation via activation of the Beclin-1/Bcl-2 signaling pathway with involvement of the PI3K/Akt/mTOR and p38 pathways in vitro study. In addition, pre-treatment with Ang-(1–7) inhibited tumor growth in NPC xenografts by inducing autophagy, suggesting a correlation between PI3K/Akt/mTOR pathway inhibition and the abovementioned anti-cancer activities. However, no autophagy was observed following Ang-(1–7) post-treatment. Taken together, these data indicate that Ang-(1–7) plays a novel role in autophagy downstream signaling pathways in NPC, supporting its potential as a therapeutic agent for alleviation the incidence of NPC and preventive treatment of recurrent NPC. Key messages Ang-(1–7) inhibits cell proliferation, migration, and invasion by activating autophagyAng-(1–7)pre-treatment inhibits tumor growth via autophagy by suppressing PI3K/Akt/mTOR pathway.Ang-(1–7) may provide a novel preventative treatment for NPC and recurrent NPC Electronic supplementary material The online version of this article (10.1007/s00109-018-1704-z) contains supplementary material, which is available to authorized users.

Background To scrutinize the pretreatment prognosticators on survival and late toxicities in a homogenous cohort of nasopharyngeal carcinoma (NPC) patients treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT). Methods A total of 219 non-distant metastatic NPC patients consecutively treated by SIB-IMRT at a single institute were collected. The pretreatment factors including the socio-demographic variables, TNM stages, gross tumor volume (GTV), Epstein-Barr virus (EBV)-DNA, and hematologic inflammatory markers were analyzed. Cox model was used to screen the prognostic factors of late toxicities and four survival outcomes including locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), failure-free survival (FFS), and overall survival (OS). Results Statistically significant inter-correlations were observed between the values of EBV-DNA, some hematologic inflammatory markers, GTV, and N classification. The 5-year LRRFS, DMFS, FFS, and OS rates were 87.9%, 89.4%, 79.4%, and 81.3%, respectively. Multivariate analysis revealed that advanced N classification (N2–3 vs. N0–1) remained the only significant negative prognosticator for all the four survival outcomes. An increased monocyte percentage and a decreased lymphocyte-to-monocyte ratio were significantly associated with poorer FFS and OS, respectively. Larger GTV was observed to be predictive of poorer LRRFS. Patients with T3–4 (HR: 3.5, 95% CI: 1.0–12.1, p = 0.048) or higher GTV (HR: 1.006, 95% CI: 1.001–1.011, p = 0.027) were associated with higher incidence of radiation neuropathy. Conclusion N classification remains the most significant survival predictor for NPC patients treated by SIB-IMRT after adjusting these biomarkers. GTV impacts not only on locoregional control but also radiation neuropathy.

BackgroundPoor nutritional status among patients with advanced stage head and neck squamous cell carcinoma (HNSCC) is common. Albumin is a common indicator of nutritional status and has been shown to be a predictor of oncological outcomes and perioperative morbidity. This study aims to determine the prognostic value of the serum albumin level among patients with advanced HNSCC undergoing surgery with simultaneous free flap reconstruction.MethodsA total of 233 patients with advanced head and neck cancer undergoing tumor resection and immediate microvascular free flap reconstruction in a tertiary referral center were enrolled retrospectively between January 2009 and December 2011. Statistical analyses including Pearson’s chi-squared test were used to determine whether there was a significant difference between each selected clinical factors and postoperative major wound infection. Multiple regression analysis was performed to reveal the relationship between postoperative major wound infection and clinical factors. Kaplan–Meier curves and multivariate Cox regression were applied to analyse survival outcome for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS).ResultsPostoperative serum albumin level (p p = 0.018) in univariate analysis. Multiple regression analysis showed a higher risk of postoperative major wound infection among patients with postoperative hypoalbuminemia than in their counterparts (odds ratio [OR] 9.811, 95% CI [2.288–42.065],p = 0.002). Patients with a tumor located over the hypopharynx experienced increased risk of postoperative major wound infection (OR 2.591, 95% CI [1.095–6.129],p = 0.030). With respect to oncological outcomes, preoperative serum albumin level is a significant independent prognostic factor for overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS).ConclusionsPostoperative hypoalbuminemia is a useful indicator for the development of postoperative complications. In addition, preoperative hypoalbuminemia is a negative prognostic factor for patients who have undergone tumor excision and free flap reconstruction for the advanced stage of HNSCC.

Objective This study aimed to assess the outcomes of administering negative-pressure wound therapy (NPWT) in patients immediately following free flap reconstruction after head and neck cancer surgery and radical neck lymph node dissection. The outcomes were compared with those of patients who received conventional wound care (CWC). Methods A retrospective analysis was performed for 58 patients with head and neck cancer who underwent free flap reconstruction after tumor ablation and radical neck dissection between February 1, 2016, and October 31, 2016. All reconstructions were performed by the same plastic surgeon. Charts were reviewed for patient demographics, comorbidities, cancer type, operation time, flap type, postoperative drainage volume, complication rates, length of hospital stay, and wound outcomes. Results No significant difference was observed between patients receiving NPWT and CWC regarding operation time and drainage volume from the vacuum ball. After the application of NPWT, no patients experienced flap failure or developed a wound infection. Significantly fewer patients receiving NPWT developed complications (9.7% vs. 37.0%; P = 0.025) and developed infections (0.0% vs. 14.8%; P = 0.041) compared with those receiving CWC. Conclusion On the basis of fewer associated complications and infections, this study supports the immediate use of NPWT after free flap reconstruction in patients who have undergone head and neck cancer ablation and radical neck lymph node dissection. Level of evidence 4. Laryngoscope, 2478-2482, 2018.

CD105 is rich in endothelium cells and is involved in angiogenesis. Higher microvascular density of tumor is also related to the prognosis in a variety of cancers. In this present study, patients with positive N classification, advanced T classification, advanced TNM stage, extracapsular spread of lymph nodes (ECS), and perineural invasion had significantly higher levels of peripheral vein (pCD105) and venous return from tumor (tCD105) in 71 patients with OSCC compared to 13 healthy volunteers. Those with higher pCD105 or tCD105 levels had significantly poorer 5-year disease-specific survival rate (DDS) and overall survival rate (OS). The tCD105 and pCD105 levels and ECS were the independent prognostic factors by the multivariate analysis according to the Cox regression model in 5-year DDS and OS rate. SAS and SCC4 cells treated with CD105 showed the increase in migration, invasion, and proliferation in vitro and in vivo. Furthermore, CCL20 expression participated in CD105-elicited cell motility in oral cancer cells. In conclusion, higher level of circulating CD105 is related to adverse pathological features among patients with OSCC. It is also a useful marker for evaluating the prognosis and targeting therapeutics of OSCC.

Objectives:This study aimed to identify the pattern of post-operative drainage following partial superficial parotidectomy with and without the use of a bipolar vessel-sealing device.Methods:Of the 49 patients undergoing parotidectomies, a bipolar vessel-sealing device was used for 20. Predictive factors included in the analysis were age, sex, body weight, operating time, tumour pathology, and diabetes mellitus, hypertension and smoking status.Results:In multivariate analyses, body weight (p = 0.026) and non-use of a bipolar vessel-sealing device (p = 0.009) were significantly associated with increased post-operative drainage after 24 hours. There was also a trend towards increased drainage in diabetic patients. Operating times were significantly shorter in the bipolar vessel-sealing device group.Conclusion:Although 24-hour drainage appears adequate for most patients, in obese and diabetic individuals there is a risk of requiring increased drainage. Therefore, the drain should be left in place for a longer period. The bipolar vessel-sealing device is safe and time-efficient, and decreases the post-operative drainage period.

Background The purpose of this study was to investigate late toxicities and quality of life (QOL) of patients with nasopharyngeal carcinoma (NPC) with long-term survival after treatment by intensity-modulated radiotherapy (IMRT) versus non-IMRT. Methods An observational, cross-sectional study of QOL and late toxicities was conducted in 242 patients with NPC with survival of >5 years after treatment with IMRT (n = 100) or non-IMRT (n = 142) by using physician-assessed toxicities (Common Terminology Criteria for Adverse Events [CTCAE] version 4) and the patient-reported European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC QLQ-C30) and the Head and Neck 35-questions (EORTC QLQ-C30-H&N35) module. Results The IMRT group had both statistically (p

Background This study evaluated the significance of mammalian target of rapamycin (mTOR) activation on the prognosis of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) receiving induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF). Methods Immunohistochemistry (IHC) for phosphorylated-mTOR and phosphorylated-p70 ribosomal S6 protein kinase (p70S6K) examined in 107 patients with locally advanced HNSCC receiving TPF was correlated with treatment outcome. The effect of mTOR inhibition on HNSCC cell lines was investigated in vitro and in vivo. Results Phosphorylated-mTOR expression was independently significantly associated with response to TPF, progression-free survival (PFS), and overall survival (OS). In cell lines and xenograft models, mTOR inhibitor, everolimus, enhanced the effect of docetaxel. Conclusion In patients with locally advanced HNSCC treated with TPF, phosphorylated-mTOR expression was independently associated with prognosis. In vitro and in vivo, concomitant inhibition of mTOR enhanced the effect of docetaxel. Our findings suggest the potential of mTOR as a therapeutic target for locally advanced HNSCC. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

Objectives/Hypothesis Perineural invasion (PNI), lymphovascular invasion (LVI), and extracapsular spread (ECS) of lymph nodes are adverse histopathologic factors among patients with oral cancer. We analyzed the clinical impact of the combination of PNI, LVI, and ECS among patients with oral cancer. Study Design Retrospective analysis of patients with oral cancer that was treated primarily with surgery with at least 5 years of follow-up data in a tertiary referral center. Methods In total, 554 patients diagnosed with oral cavity squamous cell carcinoma who underwent operations consecutively between 2006 and 2008 in our hospital were enrolled. Clinical characteristics, 5-year survival rates, and local/regional control rates were analyzed. Results There were 41 females and 513 males. Patients with PNI, LVI, or ECS presented pathologically had 5-year overall survival rates of 58.4%, 50.4%, and 31.4%, respectively. Patients with both ECS and PNI or both ECS and LVI presented had 5-year overall survival rates of 31.5% and 22.2%, respectively. Patients presenting with triple-positive status (PNI, LVI, and ECS) had only a 20.0% 5-year overall survival rate. The 5-year local/regional control rate for patients with both ECS and PNI or both ECS and LVI was 26% and 44.4%, respectively; for all three factors, it was 26.7%. Conclusion Patients with triple-positive status (PNI, LVI, ECS), ECS and PNI, or ECS and LVI experienced very low 5-year local/regional control rates, 5-year overall, and disease-specific survival rates. Novel interventions are necessary to improve these clinical outcomes. Level of Evidence 4. Laryngoscope, 125:E300–E305, 2015

Pluchea indica is used in traditional medicine for the treatment of lumbago, ulcer, tuberculosis and inflammation. The anti-cancer activities and the underlying molecular mechanisms of the ethanolic extracts of P. indica root (PIRE) were characterized in the present study. PIRE strongly inhibited the viability of the human nasopharyngeal carcinoma cells (NPC-TW 01 and NPC-TW 04) in a time- and dose-dependent manner. Migration of cancer cells was also suppressed by PIRE. In addition, PIRE significantly increased the occurrence of the cells in sub-G1 phase and the extent of DNA fragmentation in a dose-dependent manner, which indicates that PIRE significantly increased apoptosis in NPC cells. The apoptotic process triggered by PIRE involved up-regulation of pro-apoptotic Bax protein and down-regulation of anti-apoptotic Bcl-2 protein, consequently increasing the ratios of Bax/Bcl-2 protein levels. Moreover, the p53 protein was up-regulated by PIRE in a concentration-dependent manner. Therefore, PIRE could induce the apoptosis-signaling pathway in NPC cells by activation of p53 and by regulation of apoptosis-related proteins.

Oral cancer is one of the most common cancers worldwide, and there are currently no biomarkers approved for aiding its management. Although many potential oral cancer biomarkers have been discovered, very few have been verified in body fluid specimens in parallel to evaluate their clinical utility. The lack of appropriate multiplexed assays for chosen targets represents one of the bottlenecks to achieving this goal. In the present study, we develop a peptide immunoaffinity enrichment-coupled multiple reaction monitoring-mass spectrometry (SISCAPA-MRM) assay for verifying multiple reported oral cancer biomarkers in saliva. We successfully produced 363 clones of mouse anti-peptide monoclonal antibodies (mAbs) against 36 of 49 selected targets, and characterized useful mAbs against 24 targets in terms of their binding affinity for peptide antigens and immuno-capture ability. Comparative analyses revealed that an equilibrium dissociation constant (KD) cut-off value < 2.82 × 10−9 m could identify most clones with an immuno-capture recovery rate >5%. Using these mAbs, we assembled a 24-plex SISCAPA-MRM assay and optimized assay conditions in a 25-μg saliva matrix background. This multiplexed assay showed reasonable precision (median coefficient of variation, 7.16 to 32.09%), with lower limits of quantitation (LLOQ) of 50 ng/ml for 14, 7 and 3 targets, respectively. When applied to a model saliva sample pooled from oral cancer patients, this assay could detect 19 targets at higher salivary levels than their LLOQs. Finally, we demonstrated the utility of this assay for quantification of multiple targets in individual saliva samples (20 healthy donors and 21 oral cancer patients), showing that levels of six targets were significantly altered in cancer compared with the control group. We propose that this assay could be used in future studies to compare the clinical utility of multiple oral cancer biomarker candidates in a large cohort of saliva samples.

Conventional therapeutic processes in patient with OSCC are associated with several unfavorable effects leading to patients with poor survival rate. Metformin has been shown to protect against a variety of specific diseases, including cancer. However, the precise roles and mechanisms underlying the therapeutic effects of metformin on OSCC remain elusive. In the current study, in vitro and xenograft model experiments revealed that metformin inhibited growth and metastasis of oral cancer cells. Importantly, metformin-restrained tumorigenesis of oral cancer was accompanied with strong decrease of both Aurora-A and Late SV40 Factor (LSF) expressions. Furthermore, LSF contributed to Aurora-A-elicited malignancy behaviors of oral cancer via binding to the promoter region of Aurora-A. A significant correlation was observed between LSF and Aurora-A levels in a cohort of specimens of oral cancer. These findings showed that a novel LSF/Aurora-A-signaling inhibition supports the rationale of using metformin as potential OSCC therapeutics.

Objectives The purpose of this study is to determine the prevalence and clinical impact of human papillomavirus (HPV) related laryngeal squamous cell carcinoma (LSCC). Methods A total of 106 LSCC patients who underwent primary surgical resection with or without adjuvant radiotherapy/chemoradiotherapy were enrolled retrospectively. Tumors collected from paraffin-embedded samples were used for HPV detection by polymerase chain reaction and in situ hybridization technique. Clinicopathological parameters were recorded for analysis. Results The prevalence of HPV in patients with LSCC was 13.2% in our series and 12 out of 14 (85.7%) HPV-positive tumors were HPV-16. The patients with HPV-positive tumors were older (p = 0.042), less local/regional recurrence (p = 0.037) and non-smoker (p = 0.068). There was no significant difference in the 5-year overall survival (OS) (p = 0.8056) between HPV-positive and -negative tumors. The patients with HPV-positive tumors had a better 5-year disease-specific survival (DSS) (100% vs. 84.8%, p = 0.1485), although the difference did not reach statistical significance. However, the local/regional control rate was significantly better in HPV-positive tumors than in HPV-negative tumors (100% vs. 75%, p = 0.0494). Conclusions A low prevalence of HPV infection in our series suggests that HPV is not a major cause of LSCC. However, a 100% local/regional control rate and DSS were observed in HPV-positive tumors. This finding suggests a different tumor behavior between HPV-positive and HPV-negative LSCC. Further research with a larger sample size is necessary to confirm our observations.

The present study investigated clinical outcomes and prognostic factors of patients with locally advanced synchronous esophageal squamous cell carcinoma (ESCC) and head/neck squamous cell carcinoma (HNSCC) receiving curative concurrent chemoradiotherapy (CCRT), and determined whether synchronous ESCC/HNSCC patients had worse prognosis compared to isolated ESCC patients. Using propensity score matching method, we compared 60 locally advanced synchronous ESCC/HNSCC patients with 60 matched isolated ESCC patients. Compared to 60 matched isolated ESCC patients, synchronous ESCC/HNSCC patients had significantly worse prognosis (13.5 months versus 17.2 months, P = 0.01), more grade 3–4 CCRT toxicity, and higher percentage of CCRT interruption. For synchronous ESCC/HNSCC group, the 1-year and 2-year survival rates were 52% and 13%, respectively. Univariate analysis showed that early ESCC stage, non-T4b disease, and salvage operations were significantly associated with superior survival. In multivariate analysis, ESCC stage represented an independent prognosticator. For chemotherapy regimen during CCRT, cisplatin/5-fluorouracil had significantly more grade 3–4 mucositis/esophagitis and neutropenia than weekly cisplatin. In conclusion, synchronous ESCC/HNSCC patients receiving curative CCRT have worse prognosis and poorer compliance of CCRT compared to isolated ESCC patients. For these patients, ESCC stage and T4b disease were significantly associated with clinical outcomes, and salvage operation may improve overall survival.

The landscape of human papillomavirus (HPV) infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P < 0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16,18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P < 0.0001). There was no statistically significant difference in HPV16,18 prevalence in non-oropharyngeal cancer by race (P = 0.682). With regard to the pattern of HPV16,18 status and p16 expression, White patients had the highest proportion of HPV16,18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0 and 22.6%, respectively) [P < 0.0001]. Our findings suggest that the pattern of HPV16,18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

Objective The purpose of this study is to examine the prevalence and risk factors of depressive disorder in caregivers of patients with head and neck cancer. Methods Study subjects were recruited from a multidisciplinary outpatient clinic for head and neck cancer in a medical center from February to July 2012. Caregivers of patients with head and neck cancer were enrolled and assessed using the Structured Clinical Interview for the DSM-IV, Clinician Version, the Short Form 36 Health Survey, and the Family APGAR index. The main aim of the study was to examine the difference in demographic data and clinical characteristics between the caregivers with and without depressive disorders. In addition, a stepwise forward model of logistic regression was used to test the possible risk factors. Results One hundred and forty-three caregivers were included in the study. The most prevalent psychiatric disorder was depressive disorder (14.7%), followed by adjustment disorder (13.3%). Nearly one-third of the caregivers had a psychiatric diagnosis. By using logistic regression analysis, it was found that unemployment (odds ratio (OR) = 3.16; 95% CI, 1.04–9.68), lower social functioning (OR = 1.43; 95% CI, 1.18–1.72), and lower educational level (OR = 1.16; 95% CI, 1.01–1.34) were significant risk factors for the depressive disorder. Conclusions The clinical implication of our results is the value of using the standardized structured interview for early diagnosis of depressive disorder in caregivers of head and neck cancer patients. Early screening and management of depression in these caregivers will raise their quality of life and capability to care patients. Copyright © 2014 John Wiley & Sons, Ltd.

// Chih-Yen Chien 1,2,* , Hsin-Ting Tsai 1,2,7,* , Li-Jen Su 3 , Hui-Ching Chuang 1,2 , Li-Yen Shiu 4 , Chao-Cheng Huang 2,5 , Fu-Min Fang 2,6 , Chun-Chieh Yu 7 , Huei-Ting Su 7 , and Chang-Han Chen 1,2,7 1 Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Kaohsiung Chang Gung Head and Neck Oncology Group, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Taiwan 3 Graduate Institute of Systems Biology and Bioinformatics, National Central University, Jhongli, Taiwan 4 Department of Medical Research, Cell Therapy and Research Center, E-Da Hospital, I-shou University, Kaohsiung, Taiwan 5 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung Taiwan 6 Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung Taiwan 7 Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Taiwan * The authors contributed this study equally Correspondence: Chang-Han Chen, email: // Keywords : HNSCC, Aurora-A, osteopontin, CD44, ERK Received : February 5, 2014 Accepted : April 11, 2014 Published : April 11, 2014 Abstract The clinical significances, cellular effects, and molecular mechanisms by which Aurora-A mediate its invasive effects in HNSCC are still unclear. Here, we found that Aurora-A expression is significantly higher in tumor tissues on 14-microarray of HNSCC in Oncomine-databases. The activity of Aurora-A was not only found in HNSCC specimens, but also significantly correlated with advanced-T-classification, positive-N-classification, TNM-stage and the poor 5-year survival rate. HNSCC-microarray profile showed that osteopontin and Aurora-A exhibited positive correlation. Stimulation of HNC cells with osteopontin results in an increase in Aurora-A expression where localized at the centrosome. Functionally, Aurora-A had the abilities to stimulate cell motility in HNC cells through increase ERK1/2 activity under osteopontin stimulation. Conversely, depletion of Aurora-A expression by siRNAs suppressed ERK1/2 activity as well as inhibition of cell invasiveness. Treatment with anti-CD44 antibodies in HNC cells not only caused a decrease of mRNA/protein of Aurora-A and ERK1/2 activity upon osteopontin stimulation, but also affected the abilities of Aurora-A-elicited cell motility. Finally, immunohistochemical/Western-blotting analysis of human aggressive HNSCC specimens showed a significant positively correlation between osteopontin-Aurora-A and ERK1/2. These findings suggest that Aurora-A is not only an important prognostic factor but also a new therapeutic target in the osteopontin/CD44/ERK pathway for HNSCC treatment.