Radiogenomic markers enable risk stratification and inference of mutational pathway states in head and neck cancer.

PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.

Expression of inhibitors of apoptosis proteins in salivary gland adenoid cystic carcinoma: XIAP is an independent marker of impaired cause-specific survival.

OBJECTIVES: Inhibitors of apoptosis proteins are crucial to carcinogenesis since their expression results in evasion of apoptosis. Overexpression of inhibitors of apoptosis has repeatedly been associated with resistance to treatment and poor prognosis in various cancers. The role of inhibitors of apoptosis in adenoid cystic carcinoma of the salivary gland is still unclear. The aim of this study was to investigate the expression of inhibitors of apoptosis and their potential prognostic value in adenoid cystic carcinoma. DESIGN, SETTING AND PARTICIPANTS: Forty-nine patients, diagnosed with adenoid cystic carcinoma of the salivary gland between 1996 and 2016, were retrospectively included in this study. The expression of cIAP1, cIAP2, XIAP, Birc6, Livin and Survivin was assessed using immunohistochemistry, and their association of survival and prognosis was evaluated during a median follow-up of 6.4 years. MAIN OUTCOME MEASURE: Cause-specific survival and recurrence-free survival rates. RESULTS: XIAP, cIAP2, Livin and nuclear Survivin showed high expression levels in adenoid cystic carcinoma in most patients. There was no significant association of cIAP1, cIAP2, Livin, Birc6 and Survivin with outcome. However, high XIAP expression was associated with worse cause-specific survival and worse response to radiotherapy and proved to be an independent marker in multivariable analysis. CONCLUSION: Our data indicate that high expression of XIAP may be used as a prognosticator for poor survival and poor response to radiotherapy in adenoid cystic carcinoma patients.

Prognostic value of advanced lung cancer inflammation index in head and neck squamous cell carcinoma.

PURPOSE: The advanced lung cancer inflammation index (ALI) is a useful tool for prediction of outcome in several malignancies. However, to date, its significance in head and neck cancer patients has not been evaluated. METHODS: We retrospectively analyzed data from 93 patients who were diagnosed with head and neck squamous cell carcinoma (HNSCC) and treated with surgical resection and postoperative radiotherapy between 2002 and 2012. The aim of this study was to investigate whether the preoperative ALI is a prognostic indicator for disease-free survival and overall survival in HNSCC patients. RESULTS: A low ALI was significantly associated with a worse 5-year disease-free survival (47.0 vs. 83.5%, p < 0.001), and overall survival (44.4 vs. 73.6%, p = 0.008). Multivariate analysis showed that low ALI was independently associated with disease-free survival (p < 0.001) and overall survival (p = 0.02). CONCLUSION: The ALI could serve as an easily available prognostic indicator for disease-free and overall survival prediction in patients with HNSCC.

Rising incidences of Warthin's tumors may be linked to obesity: a single-institutional experience.

PURPOSE: Recently, there has been an increase in the number of reported Warthin's tumors, but few risk factors have been described for this benign tumor. Yet, smoking is the only evidently identified risk factor. Obesity and the metabolic syndrome are causally linked to or a risk factor for a variety of diseases. Therefore, we analyzed whether metabolic syndrome, including obesity, might influence the incidence of Warthin's tumors. METHODS: In this retrospective study, we evaluated 197 patients with Warthin's tumor. We assessed the tumor size, the body mass index (BMI), comorbidities related to the metabolic syndrome, and cigarette and alcohol consumption. Additionally, we evaluated several blood parameters and their influence. RESULTS: Warthin's tumor patients had a significantly higher BMI in comparison to patients with other benign parotid gland tumors (29.1 versus 26.2, p < 0.0001). The rate of metabolic syndrome-associated comorbidities was higher in Warthin's tumor patients (62.4% versus 35.2%, p < 0.0001). CONCLUSION: Our results might be the first step to recognize obesity and its consequences as a co-driver in the formation of Warthin's tumors. Nevertheless, further studies are requested to validate our results and to answer the question whether obesity or the metabolic syndrome are integrally linked to Warthin's tumors.

Preoperative plasma fibrinogen as a predictive factor for post-tonsillectomy haemorrhage.

OBJECTIVES: To assess whether preoperative plasma fibrinogen is able to predict severe post-tonsillectomy haemorrhage. STUDY DESIGN: Retrospective chart review. METHODS: We included 456 patients who underwent tonsillectomy between 2008 and 2013. Preoperative plasma fibrinogen levels (PFL) were assessed in patients who developed severe bleeding requiring surgical revision under general anesthesia compared to those with uneventful postoperative courses. RESULTS: 414 (90.8%) had no severe post-tonsillectomy haemorrhage. In contrast, 42 (9.2%) patients needed surgical hemostasis. PFL were significantly higher (P = .023) in patients with a severe bleeding. Univariate Cox-regression analysis revealed that elevated preoperative fibrinogen represents a significant worse (P = .003; HR 2.66; 95% CI 1.38-5.10) prognostic factor for postoperative bleeding. Even at multivariable analysis, increased PFLs were a significantly worse prognostic factor for post-tonsillectomy haemorrhage (P = .016; HR 15.4; 95% CI 0.01-0.6). High preoperative PFL was associated with significantly higher risk for post-tonsillectomy haemorrhage within the first 31 days after surgery (65% vs 90%; P = .002). Moreover, accurate negative predictive value (NPV) of 95.1% pointed out that PFL could be used as a reliable preoperative screening marker. CONCLUSIONS: Elevated PFL represents an independent worse prognostic factor for severe bleeding after tonsillectomy and could be helpful to identify patients at higher risk for PTH.

PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis - impact on clinical outcome.

AIMS: Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients' clinical outcome. METHODS AND RESULTS: Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease-free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD-1-expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD-1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)-negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD-1-expressing lymphocytes (P = 0.0412) and PD-L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. CONCLUSIONS: Our results characterise the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.

6-shogaol induces apoptosis and enhances radiosensitivity in head and neck squamous cell carcinoma cell lines.

Ginger (Zingiber officinale Roscoe) is used for a wide array of conditions in traditional medicine in Asia, but little is known about the effect on head and neck cancer. In this study, the effect of two major pharmacologically active compounds of ginger, 6-gingerol and 6-shogaol, were studied on head and neck cancer cell lines. Furthermore, experiments in combination with established treatment methods for head and neck cancer were performed. Proliferation assays showed a dose-dependent reduction of cell viability. Flow cytometry analysis revealed the induction of apoptosis. Western blot analysis indicated that the antiapoptotic protein survivin was suppressed after treatment. Although a combination of 6-shogaol with cisplatin exhibited no synergistic effect, the combination with irradiation showed a synergistic reduction of clonogenic survival. In conclusion, ginger compounds have many noteworthy effects on head and neck cancer cell lines. In particular, the enhancement of radiosensitivity is remarkable.

Impact of anatomic origin of primary squamous cell carcinomas of the nasal cavity and ethmoidal sinus on clinical outcome.

PURPOSE: Since squamous cell carcinomas (SCCs) of the nasoethmoidal complex are rare and aggressive malignancies, the purpose of this study was to evaluate whether anatomic subsites of SCCs of the nasal cavity and ethmoid sinuses affect clinical outcome. METHODS: We retrospectively analyzed data from 47 patients with primary SCCs of the nasal cavity and ethmoid sinuses who were treated at the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, between 1993 and 2018. The impact of anatomic subsites of nasoethmoidal SCCs was evaluated with respect to tumor and nodal classification, disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: Of the 47 cases, 17 SCCs (36.2%) originated from lateral nasal wall followed by 13 (27.7%) tumors of the edge of naris to mucocutaneous junction, 11 (23.4%) SCCs of the nasal septum, 3 tumors of the nasal floor (6.4%) and 3 SCCs of the ethmoid sinuses (6.4%), respectively. SCCs of the nasal septum were associated with significantly higher rates of neck node metastasis (p = 0.007), which represented a significantly worse prognostic factor for DSS (HR 7.87; p < 0.001). Moreover, advanced tumor stage (HR 5.38; p = 0.014) and tumor origin of nasal septum (HR 4.05; p = 0.025) were also significantly worse prognostic factors for DSS. Fourteen patients (29.8%) developed recurrent disease, including eight local (17.0%), five regional (10.6%) and one distant (2.1%) recurrence. Elective neck dissection (ND) was associated with lower (0 vs. 20.0%) but not significantly different regional and distant DFS (p = 0.075). CONCLUSION: Anatomic origin of nasal SCC has significant impact on clinical outcome. SCCs of the nasal septum were associated with higher rates of positive neck nodes and worse outcome.

Overexpression of DCLK1 is predictive for recurrent disease in major salivary gland malignancies.

Salivary gland carcinomas are a rare malignancy. Therefore, little is known about biomarkers and cancer stem cells in salivary gland malignancies. Double cortin-like kinase 1 (DCLK1) is a promising therapeutic target and cancer stem cell marker, predominantly investigated in pancreatic and colorectal cancer. The purpose of this study was to investigate the expression of DCLK1 in major and minor salivary gland carcinomas and its influence on survival. We examined a total of 80 patients with major or minor salivary gland cancer in this retrospective study. Immunohistochemistry with anti-DCLK1 antibody was applied to assess the expression of DCLK1. Moreover, we evaluated the impact of DCLK1 on overall and disease-free survival. DCLK1 expression could be detected in 66.3 % of all examined cases. Overexpression of DCLK1 was associated with reduced overall and disease-free survival in patients with major salivary gland cancer. Disease-free survival reached statistical significance (p = 0.0107). However, expression of DCLK1 had no influence on survival in patients with minor salivary gland cancer. Since treatment of recurrent disease in oncologic patients is utterly challenging, DCLK1 may be a promising prognostic biomarker that helps to identify patients with a high risk for recurrence of major salivary gland carcinoma.

The prognostic significance of ß-catenin, cyclin D1 and PIN1 in minor salivary gland carcinoma: ß-catenin predicts overall survival.

Minor salivary gland carcinoma is a rare and heterogeneous type of cancer. Molecular prognostic and predictive markers are sparse. The aim of this study was to identify new prognostic and predictive markers in minor salivary gland carcinoma. 50 tissue samples of carcinomas of the minor salivary glands (adenoid cystic carcinoma n = 23, mucoepidermoid carcinoma n = 12, adenocarcinoma n = 10, carcinoma ex pleomorphic adenoma n = 2, salivary duct carcinoma n = 1, clear cell carcinoma n = 1, basal cell carcinoma n = 1) were immunohistochemically stained for ß-catenin, cyclin D1 and PIN1. Expression patterns were analyzed and correlated to clinical outcome of 37 patients with complete clinical data. High expression of membranous ß-catenin was linked to significantly better overall survival in patients with adenoid cystic carcinoma (log rank test, χ (2) = 13.3, p = .00397, Bonferroni corrected p = .024). PIN1 and cyclin D1 did not show any significant correlation to patients' clinical outcome. Expression of ß-catenin in adenoid cystic carcinoma of the minor salivary glands significantly correlates with better overall survival. Hence, evaluation of ß-catenin might serve as a clinical prognostic marker.

Improved survival in HPV/p16-positive oropharyngeal cancer patients treated with postoperative radiotherapy.

INTRODUCTION: In the literature, HPV infection and/or p16 positivity have been consistently demonstrated to correlate with improved response rates in oropharyngeal squamous cell carcinoma (OPSCC) patients treated with primary radiotherapy (RT) alone and in combination with chemotherapy. However, the exact role of HPV/p16 positivity in patients treated with postoperative RT is still unclear. METHODS: We analyzed tumor samples for HPV-DNA and p16 expression and correlated these variables with treatment outcome in a series of 63 consecutively treated oropharyngeal cancer patients (95% stage III/IV). HPV and p16 analysis were performed using validated test systems. Survival was estimated by the Kaplan-Meier method. Cox proportional hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. RESULTS: Expression of p16 or high-risk HPV-DNA was detected in 60.3% and 39.6% of the tumors, respectively. p16 expression [overall survival (OS) at 2 years: 91%] as well as HPV infection (OS at 2 years: 95%) was associated with improved OS. Mean survival in p16-positive patients was 112 months compared to 64.6 months in case of p16 negativity. All HPV-positive tumors stained positive for p16. In a multivariable analysis, p16 positivity was associated with improved OS and with disease-free survival. CONCLUSION: p16 expression and HPV infection are strongly associated with the outcome of postoperatively irradiated OPSCC patients. HPV and p16 double-negative OPSCC patients should be regarded as a distinct "very high-risk patient group" that may benefit from intensified or novel treatment combinations.

Assessment of caroverine as a potential chemotherapeutical agent in HNSCC cell lines.

Since the prognosis of head and neck squamous cell carcinoma (HNSCC) still remains poor, identifying novel chemotherapeutic agents is of outmost importance. The anticancer potential of quinoxalines has been described in various tumor entities. Caroverine, also a quinoxaline derivative, has been shown to suppress tumor promotion factors. The aim of this study was to evaluate the effect of caroverine on HNSCC cell lines. The HNSCC cell lines SCC9, SCC25, CAL27, and FaDu were incubated with caroverine alone or in combination with cisplatin, 5-fluorouracil (5-FU) or cetuximab. Cell viability was measured using the CCK-8 assay. The murine 3T3 fibroblast cell line was used to address tissue specificity. Apoptosis was visualized by immunohistochemistry. Caroverine showed a dose-dependent growth inhibition in all cell lines, IC50 values ranged from 75.69 to 179.80 µM. This effect was increased when caroverine was combined with cetuximab or 5-FU. Immunohistochemistry displayed more apoptosis after caroverine treatment compared to controls. Furthermore, caroverine alone had no growth inhibitory effect on 3T3 cells. For the first time, this study provides evidence that caroverine may serve as a supportive drug in the treatment of HNSCC patients.

HS-173, a selective PI3K inhibitor, induces cell death in head and neck squamous cell carcinoma cell lines.

BACKGROUND: The selective PI3K (Phosphatidylinositol 3-kinase) inhibitor HS-173 has anticancer activity in non-small cell lung cancer and pancreatic cancer cells. Of all head and neck squamous cell carcinomas (HNSCC) 20% harbor specific mutations in the genome. The aim of this study was to investigate the effect of HS-173 on HNSCC cell lines. METHODS: The cell lines SCC25, CAL27 and FaDu were incubated with HS-173. Its antiproliferative effect was determined using the CCK­8 cell proliferation assay. Combined incubation with cisplatin was performed and combination index analysis was conducted. To investigate its effect on radiotherapy, cells were irradiated with 2, 4, 6 and 8 Gy, respectively. Synergistic effects of radiation and HS-173 were measured by proliferation assays and clonogenic survival. RESULTS: The use of HS-173 induced significant reduction of cell proliferation across all cell lines. Most interestingly, it showed a synergistic effect with cisplatin treatment. Clonogenic survival revealed a radiosensitizing effect in CAL27 and FaDu cells. The HS-173 caused significant induction of apoptosis in SCC25 and FaDu cells. CONCLUSION: The selective PI3K inhibitor HS-173 is a potent chemosensitizing and also radiosensitizing drug in treatment of HNSCC cell lines and could be an effective treatment in PI3K-mutated HNSCC.

PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis.

Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group (n = 34) by immunohistochemistry. Kaplan-Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA (p = 0.0001) and the Austrian cohort (p = 0.02), associated with a negative anamnesis for alcohol consumption (p = 0.009) and tobacco smoking (p = 0.02) and poorer overall survival (univariate p = 0.02, multivariate p< 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both p < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.

Intraparotid and cervical lymph nodes metastasis in primary parotid gland carcinoma-impact on clinical outcome.

OBJECTIVE: The aim of this study was to investigate the prognostic value of evaluation of intraparotid and cervical lymph node metastases in primary parotid cancer. STUDY DESIGN: A retrospective medical chart review and histopathologic evaluation of all patients surgically treated for primary parotid cancer during the period 1993 to 2010 was performed. The presence and ratio of intraparotid and cervical lymph node metastases were assessed and determined as primary predictor variables. Overall survival (OS) and disease-free survival (DFS) were defined as primary outcome variables. RESULTS: In total, 50 patients were included. The presence of pathologic cervical lymph nodes (P = .005) and a high cervical lymph node ratio (LNR) (P = .0001) had a significant association with worse OS. Worse DFS was found in patients with a high cervical LNR (P = .001) and intraparotid lymph node metastases (P = .029). In high-grade carcinoma, a high LNR showed worse DFS (P = .05). A high cervical LNR (P = .012) and resection margin status (P = .002) were identified as independent prognostic markers for OS and the presence of intraparotid lymph nodes for DSS (P = .05). CONCLUSIONS: Evaluation of patterns of lymph node metastases provides additional prognostic value in patients with primary parotid gland cancer.

Impact of pretherapeutic neutrophil-to-lymphocyte ratio, serum albumin, body-mass index, and advanced lung cancer inflammation index on clinical outcome in sinonasal squamous cell carcinoma.

BACKGROUND: Squamous cell carcinoma of the nasal cavity and paranasal sinuses is a rare and aggressive cancer entity with poor survival rates. Data on this group of head and neck tumors are scarce. Inflammation and cachexia-based markers and their impact on clinical outcome have been studied in several cancer groups. The aim of this study was to evaluate their prognostic potential in sinonasal squamous cell carcinoma. PATIENTS AND METHODS: This retrospective analysis included all patients treated for sinonasal squamous cell carcinoma at a tertiary referral center between 2002 and 2015. Patients were divided into groups with low and high pretherapeutic values based on the values of serum albumin (ALB, median 41.6 g/l), neutrophil-to-lymphocyte ratio (NLR, median 3.5), body-mass index (BMI, median 24.7), or advanced lung cancer inflammation index (ALI, median 29.5). Main outcome measures were overall survival (OS) and disease-free survival (DFS). Statistical analysis included calculation of survival differences using log-rank tests, hazard ratios (HR), and respective 95% confidence intervals (CI). RESULTS: 41 patients were included. Low ALB values did not influence OS (median OS not reached in both groups; p = 0.59, HR = 0.75, CI = 0.3-2.1) or DFS (median DFS 0.9 years vs 2.2 years; p = 0.6, HR = 0.8, CI = 0.4-1.8). High NLR was significantly associated with worse OS rates (median OS not reached vs 1.7 years, p = 0.02, HR = 3.4, CI = 1.0-108) but with no influence on DFS (median DFS 3.1 years vs 0.8 years; p = 0.15, HR = 1.8, CI = 0.8-4.2). Similar results were observed for patients with low ALI (median OS 1.7 years vs not reached; p = 0.03, HR = 0.3, CI = 0.1-0.9 and median DFS 0.8 years vs 2.2 years; p = 0.58, HR = 0.8, CI = 0.3-1.8). BMI was the strongest prognosticator in our study. Low pretherapeutic BMI was linked to significantly worse OS (median OS 1.4 years vs not reached; p = 0.003, HR = 0.2, CI = 0.0-0.6) and DFS (median DFS 0.8 years vs not reached; p = 0.02, HR = 0.4, CI = 0.2-0.8). In multivariate analysis BMI was revealed as an independent marker for OS (p = 0.015). No marker reached the level of significance in regard to DFS in multivariate analysis. CONCLUSION: Pretherapeutic BMI had a superior prognostic value in patients with sinonasal squamous cell carcinoma in comparison with other tested variables. BMI may be a simple tool for estimating clinical outcome in SNSCC. However, larger studies are necessary to validate our results.

Epithelial stem cell marker LGR6 expression identifies a low-risk subgroup in human papillomavirus positive oropharyngeal squamous cell carcinoma.

OBJECTIVES: R-Spondins (RSPOs) and leucine-rich repeat-containing G-protein coupled receptors (LGRs) play a critical role in embryonic and cancer development through potentiation of WNT/ß-catenin signaling, but their prognostic significance in head and neck squamous cell carcinoma (HNSCC) is still unclear. HNSCC is a group of neoplasms that include, amongst others, oropharyngeal squamous cell carcinoma (OPSCC), some of which are induced by human papillomavirus (HPV). We aimed to investigate the potential prognostic value of RSPO2 and LGR4/5/6 on overall survival (OS) and disease-free survival (DFS) in HNSCC patients. METHODS: We examined RSPO and LGR expression by means of immunohistochemistry in 126 HNSCC patients. Furthermore, in order to validate our findings externally, we examined RSPO2 and LGR6 mRNA expression levels using independent secondary datasets. RESULTS: The five-year OS of our cohort was 59.6%. RSPO2 and LGR4/5/6 expression were not associated with OS or DFS in multivariable analyses. Within the HPV+ cases (n = 26, 33%), however, we observed a difference in OS by RSPO2 expression (5-year OS: RSPO+ 45.4% vs. RSPO2- 84.6%) and LGR6 expression (5-year OS: LGR6+ 52.9% vs. LGR6-100%). Evidence for an interaction of HPV status with RSPO2 and LGR6 was found for OS. Relative to HPV+/LGR6- patients, HPV+/LGR6+ patients were 12 times more likely to die. These results were replicated in the second dataset. CONCLUSION: Our results indicated that the expression status of LGR6 had an influence on the aggressiveness of HPV+ OPSCC, potentially making this receptor a useful marker for identifying patients with a high risk of death.

Cross-sectional study on the occurrence of Frey's syndrome following superficial parotidectomy or extracapsular dissection.

BACKGROUND: Most studies that examine postoperative outcomes after parotidectomy in patients with benign parotid gland tumors are based on retrospective chart reviews. Data about long-term results in patients with parotid gland surgery with patient contact are still sparsely published. METHODS: During the period of 1960-2005, a total of 127 patients underwent either extracapsular dissection (ECD) or superficial parotidectomy (SP) and were available for interview. Patients were questioned about their postoperative outcome after parotid gland surgery. RESULTS: The mean follow-up was 21.5 years. A total of 42 and 85 patients underwent ECD and SP, respectively. No significant differences were observed in the rates of permanent facial paralysis (SP 1.2% vs. ECD 7.1%; p = 0.1053) or recurrence (SP 4.7% vs. ECD 11.9%; p = 0.1557), and Frey's syndrome was diagnosed only after SP (10.6% vs. 0% after ECD, p = 0.0293). Frey's syndrome was detected more often compared to retrospective chart analysis. CONCLUSION: We conclude that Frey's syndrome is underdiagnosed after SP without standardized follow-up examinations. Long-term follow-up should be applied to detect and treat gustatory sweating.

AF1q Expression Associates with CD44 and STAT3 and Impairs Overall Survival in Adenoid Cystic Carcinoma of the Head and Neck.

Salivary gland malignancies of the head and neck form a heterogeneous group. Adenoid cystic carcinomas are an aggressive entity of salivary gland malignancies characterized by frequent distant metastases and poor response to radio- and chemotherapy. AF1Q is a MLL fusion partner, which can activate Wnt and STAT3 signaling. Recently, overexpression of AF1q has been identified as a poor prognosticator in patients of different malignancies. A total of 46 patients with adenoid cystic carcinoma were immunohistochemically evaluated for expression of AF1q and clinical outcome was analyzed in this context. Additionally, STAT3 and the Wnt downstream target CD44 were investigated and correlated with AF1q. AF1q was overexpressed in 52.2%. Overexpression of AF1q was associated with poorer overall survival (p = 0.03). Additionally, lymph node metastases and solid tumor parts were more frequently observed in AF1qhigh patients (p = 0.07 and 0.05, respectively). AF1q did not influence the occurrence of distant metastases. Expression of AF1q was associated with higher levels of STAT3 and CD44 (p = 0.003 and 0.006, respectively). AF1q is a novel prognostic marker for poor overall survival in adenoid cystic carcinoma patients. The deleterious effects on survival may be a result of promotion of the STAT3 and Wnt pathway.