Lymphocyte-to-Monocyte Ratio Might Serve as a Prognostic Marker in Young Patients with Tongue Squamous Cell Carcinoma.

BACKGROUND: Young patients with tongue squamous cell carcinoma (TSCC) mostly lack typical prognostic markers and face a dire prognosis. The aim of this study was to analyze the prognostic relevance of lymphocyte-to-monocyte ratio (LMR) in TSCC patients, with a special emphasis on patients under 45 years. METHODS: This retrospective study included all patients primarily treated for TSCC. The prognostic relevance of LMR was investigated in terms of predicting the overallsurvival (OS) and disease-free survival (DFS). RESULTS: A total of 74 patients were included and the young cohort (<45 years) comprised 27 individuals. The mortality and recurrence rates were 39.2% (n = 29) and 37.8% (n = 28), respectively. OS and DFS were significantly shorter in the low LMR group within the whole cohort. Furthermore, low LMR was associated with worse prognosis, particularly inferior OS (median OS 1.7 vs. 14.6 years, p = 0.0156) and worse DFS (median DFS 0.8 years vs. not reached, p = 0.0405) in the young patient cohort. CONCLUSIONS: Our results reveal that pretreatment LMR might become a prognostic tool for young TSCC patients, especially due to its availability. However, further studies on larger cohorts are necessary to validate our results.

The dual role of autophagy in HPV-positive head and neck squamous cell carcinoma: a systematic review.

PURPOSE: Human papilloma virus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) displays distinct epidemiological, clinical, and molecular characteristics compared to the negative counterpart. Alterations in autophagy play an important role in cancer, and emerging evidence indicates an interplay of autophagy in HNSCC carcinogenesis and tumor promotion. However, the influence of HPV infection on autophagy in HNSCC has received less attention and has not been previously reviewed. Therefore, we here aimed to systematically review the role of autophagy explicitly in HPV+ HNSCC. METHODS: Studies accessible in PubMed, Embase, Scopus, and Web of Science investigating HNSCC, highlighting the molecular biological differences between HPV- and HPV+ HNSCC and its influences on autophagy in HNSCC were analyzed according to the PRISMA statement. A total of 10 articles were identified, included, and summarized. RESULTS: The HPV16 E7 oncoprotein was reported to be involved in the degradation of AMBRA1 and STING, and to enhance chemotherapy-induced cell death via lethal mitophagy in HNSCC cells. Autophagy-associated gene signatures correlated with HPV-subtype and overall survival. Additionally, immunohistochemical (IHC) analyses indicate that high LC3B expression correlates with poor overall survival in oropharyngeal HNSCC patients. CONCLUSION: HPV may dampen general bulk autophagic flux via degradation of AMBRA1 but may promote selective autophagic degradation of STING and mitochondria. Interpretations of correlations between autophagy-associated gene expressions or IHC analyses of autophagy-related (ATG) proteins in paraffin embedded tissue with clinicopathological features without biological validation need to be taken with caution.

The ATR inhibitor berzosertib acts as a radio- and chemosensitizer in head and neck squamous cell carcinoma cell lines.

Alterations in the DNA damage response play a crucial role in radio- and chemoresistance of neoplastic cells. Activation of the Ataxia telangiectasia and Rad3-related (ATR) pathway is an important DNA damage response mechanism in head and neck squamous cell carcinoma (HNSCC). Berzosertib, a selective ATR inhibitor, shows promising radio- and chemosensitizing effects in preclinical studies and is well tolerated in clinical studies. The aim of this study was to elucidate the effect of berzosertib treatment in combination with radiation and cisplatin in HNSCC. The HNSCC cell lines Cal-27 and FaDu were treated with berzosertib alone and in combination with radiation or cisplatin. Cell viability and clonogenic survival were evaluated. The effect of combination treatment was evaluated with the SynergyFinder or combination index. Apoptosis was assessed via measurement of caspase 3/7 activation and migration was evaluated using a wound healing assay. Berzosertib treatment decreased cell viability in a dose-dependent manner and increased apoptosis. The IC50 of berzosertib treatment after 72 h was 0.25-0.29 µM. Combination with irradiation treatment led to a synergistic increase in radiosensitivity and a synergistic or additive decrease in colony formation. The combination of berzosertib and cisplatin decreased cell viability in a synergistic manner. Additionally, berzosertib inhibited migration at high doses. Berzosertib displays a cytotoxic effect in HNSCC at clinically relevant doses. Further evaluation of combination treatment with irradiation and cisplatin is strongly recommended in HNSCC patients as it may hold the potential to overcome treatment resistance, reduce treatment doses and thus mitigate adverse events.

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis.

Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Early on-treatment C-reactive protein and its kinetics predict survival and response in recurrent and/or metastatic head and neck cancer patients receiving first-line pembrolizumab.

PURPOSE: First-line immune checkpoint blockade has improved the prognosis of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), but response rates remain low. In this study, we aimed to investigate the prognostic value of CRP and its early kinetics to predict response and survival in R/M HNSCC. METHODS: A total of 87 patients who received first-line pembrolizumab for R/M HNSCC were analyzed. Three-fold cross-validation was used to estimate cut-off points of CRP at baseline and on-treatment (day 40 ± 10). Treatment response and survival were analyzed according to early CRP kinetics. The neutrophil-to-lymphocyte ratio (NLR) was used as a benchmark for the prognostic performance of CRP. RESULTS: On-treatment CRP below 2 mg/dl, 4x the upper limit of normal (ULN), was associated with increased overall survival (OS), while on-treatment CRP below 3 mg/dl (6x ULN) was correlated with a higher disease control rate (DCR) and increased progression-free survival (PFS). CRP flare-responders and CRP responders showed a higher DCR and longer PFS than CRP non-responders. An NLR above 6 was a negative prognosticator for progression. In multivariable analysis, on-treatment CRP prevailed as the only significant prognosticator for OS (HR: 4.97, CI95%: 2.18-11.32, p < 0.001) and PFS (HR: 2.07, CI95%: 1.07-3.99, p = 0.030). CONCLUSION: On-treatment CRP was identified as a prognostic biomarker for objective response and survival in R/M HNSCC patients receiving first-line pembrolizumab and could be easily incorporated into clinical practice as a widely available and cost-effective biomarker.

Low free triiodothyronine and immune-related hyperthyroidism are associated with overall and progression-free survival in head and neck squamous cell carcinoma treated with pembrolizumab.

INTRODUCTION: Thyroid function is frequently impaired in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In patients treated with pembrolizumab, immune-related adverse events (irAEs) of the thyroid are common. However, the prognostic significance of baseline and on-treatment thyroid dysfunction is currently unclear. METHODS: This study included 95 patients who received pembrolizumab for R/M HNSCC between 2016 and 2022. Baseline thyroid status, according to serum hormone levels, and irAEs were assessed. Univariable and multivariable Cox regression analyses were performed for overall survival (OS) and progression-free survival (PFS). Furthermore, the best overall response according to the prognostic groups was examined. RESULTS: Low fT3 (HR: 2.52, p = 0.006), immune-related hyperthyroidism (HR: 0.11, p = 0.038), ECOG performance status ≥2 (HR: 3.72, p = 0.002), and platinum-refractory disease (HR: 3.29, p = 0.020) were independently associated with OS. Furthermore, immune-related hyperthyroidism was associated with longer PFS (HR: 0.13, p = 0.007), a higher objective response rate (83% vs. 31%, p = 0.018), and a higher disease control rate (100% vs. 43%, p = 0.008). Thyroid-related autoantibodies were elevated in 40% of thyroid irAEs cases with available measurements. Out of 16 thyroid irAEs, 15 occurred in patients with fT3 above the lower limit of normal. CONCLUSION: Low fT3 was associated with worse OS. Immune-related hyperthyroidism was correlated with both improved OS and PFS. Baseline fT3 assessment and close on-treatment monitoring of serum thyroid levels may be valuable for risk stratification in R/M HNSCC patients receiving pembrolizumab.

High USP4 mRNA is associated with an HPV-positive status in head and neck squamous cell carcinoma patients.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is among the most common cancers in the world with a low survival rate and common diagnosis at late stages. Deubiquitination of proteins is involved in tumor growth, metastasis, apoptosis, and immunosuppressive pathways. The impact of the ubiquitin-specific protease (USP4) on survival was only scarcely investigated so far. The goal of our research was to analyze the association of USP4 expression with prognosis and clinicopathological features in HNSCC. METHODS: USP4 mRNA levels were derived from The Cancer Genome Atlas (TCGA) for a cohort of 510 patients. Protein expression of USP4 was analyzed by immunohistochemistry in a second cohort of 113 patients. Associations between USP4 levels and overall survival, disease-free survival and clinicopathological data were analyzed. RESULTS: High levels of USP4 mRNA were associated with prolonged overall survival in univariable analysis. There was no more association with survival after correction for the confounders HPV, stage and smoker status. High USP4 mRNA levels were linked to a lower T-stage, the patient's age at diagnosis, and a positive HPV status. USP4 protein levels were not associated with prognosis or other features. CONCLUSION: Since high USP4 mRNA was not an independent prognostic marker, we assume that the association is a result of the correlation of high USP4 mRNA with an HPV-positive status. Therefore, further investigation of USP4 mRNA and its association with the HPV status of HNSCC patients is warranted.

Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma.

OBJECTIVES: The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro. MATERIALS AND METHODS: TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment. RESULTS: Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects. CONCLUSION: Our results indicate a high risk of death in tumorTGFBR1+ |stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.

ß-CATENIN is a positive prognostic marker for HPV-positive head and neck squamous cell carcinoma.

PURPOSE: The evolutionary-conserved Wnt/ß-CATENIN (WBC) pathway has been implicated in the pathogenesis of different solid malignant tumors. We evaluated the prognostic relevance of ß-CATENIN, a pivotal mediator of WBC activation, in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). METHODS: We analyzed if patients with HPV-positive HNSCC from the "The Cancer Genome Atlas" (TCGA cohort, n = 41) can be stratified based on their CTNNB1 mRNA expression. Moreover, in a tissue microarray (TMA) of primary tumor sections from HPV-positive HNSCC patients treated in a tertiary academic center (in-house cohort, n = 31), we evaluated the prognostic relevance of ß-CATENIN expression on protein level. RESULTS: In silico mining of CTNNB1 expression in HPV-positive HNSCC revealed that high CTNNB1 expression was linked to better overall survival (OS, p = 0.062). Moreover, high ß-CATENIN expression was significantly associated with a better OS in our in-house cohort (p = 0.035). CONCLUSION: Based on these findings, we postulate that ß-CATENIN expression could serve (potentially in conjunction with other WBC pathway members) as a marker for better survival outcomes in patients with HPV-positive HNSCC. However, it is evident that future studies on bigger cohorts are warranted.

The Geriatric Nutritional Risk Index (GNRI) as a Prognostic Biomarker for Immune Checkpoint Inhibitor Response in Recurrent and/or Metastatic Head and Neck Cancer.

Malnutrition is a frequent comorbidity in head and neck cancer patients and has been shown to impair immunotherapy response in other cancer types. The geriatric nutritional risk index (GNRI) assesses malnutrition using the patient's ideal weight, actual weight, and serum albumin. The aim of this study was to evaluate the prognostic relevance of malnutrition as determined by the GNRI for the response to immunotherapy in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). A total of 162 patients with R/M HNSCC who received immune checkpoint inhibitors were included. The associations between the GNRI and progression-free survival (PFS), overall survival (OS), and the disease control rate (DCR) were computed. Univariable analysis showed worse PFS for GNRI ≤ 98 (p < 0.001), ECOG performance status (PS) ≥ 2 (p = 0.012), and enteral (p = 0.009) and parenteral (p = 0.015) nutritional supplementation, and worse OS for GNRI < 92 (p < 0.001), ECOG PS ≥ 2 (p < 0.001), and enteral (p = 0.008) and parenteral (p = 0.023) nutritional supplementation. In our multivariable model, GNRI ≤ 98 (p = 0.012) and ECOG PS ≥ 2 (p = 0.025) were independent prognostic factors for PFS. For OS, GNRI < 92 (p < 0.001) and ECOG PS ≥ 2 (p < 0.001) were independent prognostic factors. A GNRI ≤ 98 was significantly associated with a lower DCR compared to a GNRI > 98 (p = 0.001). In conclusion, our findings suggest that the GNRI may be an effective predictor for response to immunotherapy in R/M HNSCC.

In vitro effects of gamma-secretase inhibition in HPV-positive and HPV-negative head and neck squamous cell carcinoma.

BACKGROUND: New chemotherapy agents are warranted for head and neck squamous cell carcinoma (HNSCC), particularly for incidence-rising HPV-positive tumors. Based on the evidence of Notch pathway involvement in cancer promotion and progression, we aimed to gain insights into the in vitro antineoplastic effects of gamma-secretase inhibition in HPV-positive and -negative HNSCC models. METHODS: All in vitro experiments were conducted in two HPV-negative (Cal27 and FaDu) and one HPV-associated HNSCC cell line (SCC154). The influence of the gamma-secretase inhibitor PF03084014 (PF) on proliferation, migration, colony forming, and apoptosis was assessed. RESULTS: We observed significant anti-proliferative, anti-migratory, anti-clonogenic, and pro-apoptotic effects in all three HNSCC cell lines. Furthermore, synergistic effects with concomitant radiation were observable in the proliferation assay. Interestingly, effects were slightly more potent in the HPV-positive cells. CONCLUSION: We provided novel insights into the potential therapeutic relevance of gamma-secretase inhibition in HNSCC cell lines in vitro. Therefore, PF may become a viable treatment option for patients with HNSCC, particularly for patients with HPV-induced malignancy. Indeed, further in vitro and in vivo experiments should be conducted to validate our results and decipher the mechanism behind the observed anti-neoplastic effects.

The prognostic role of PSMD14 in head and neck squamous cell carcinoma.

PURPOSE: PSMD14 is an essential protein for proteasomal degradation. Inhibition of this protein disrupts homeostasis and inhibits cancer cell viability. Overexpression of PSMD14 was associated with advanced cancer characteristics and a worse prognosis in various carcinomas. This study aimed to analyze PSMD14 copy number variation, mRNA and protein expression in HNSCC, and its role as an independent prognostic biomarker. METHODS: PSMD14 mRNA expression and copy number variations were analyzed in "The Cancer Genome Atlas (TCGA)" in 510 patients. Protein expression was evaluated using immunohistochemistry in a second cohort including 115 patients. PSMD14 levels were analyzed for correlation with clinicopathological data, overall and disease-free survival. RESULTS: PSMD14 mRNA expression and copy number variation were high in 44 and 50% of patients, respectively. Protein expression of PSMD14 was high in 56%. In both cohorts, high PSMD14 levels were associated with advanced staging. High PSMD14 mRNA expression was additionally associated with a worse prognosis in univariable analysis. However, after correction for possible confounders, PSMD14 mRNA was not an independent prognostic marker. CONCLUSION: PSMD14 is commonly expressed in HNSCC patients and associated with advanced stages. High expression of PSMD14 mRNA was associated with a worse outcome. However, this may be a result of the association of PSMD14 with poor prognosticators. Based on our study, further evaluation of PSMD14 as a prognostic marker and potential therapeutic target is warranted.

Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro.

Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.

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.

A new nomogram to predict oncological outcome in laryngeal and hypopharyngeal carcinoma patients after laryngopharyngectomy.

BACKGROUND: To create nomograms for better prediction of the oncological outcome in advanced laryngeal (LxCAs) or hypopharyngeal (HpxCAs) cancer after laryngopharyngectomy. MATERIALS: 239 patients who underwent total laryngectomy or laryngopharyngectomy due to LxCA (52.7%) or HpxCA (47.3%) were included in this study. Based on clinical risk factors (tumor site, lymph node involvement, salvage setting), we created nomograms for prediction of disease-specific survival (DSS) and disease-free survival (DFS). RESULTS: HpxCAs showed a higher rate of lymph node involvement (p < 0.001), a 2.47-fold higher risk of a 2nd head and neck cancer (p = 0.009) and significantly worse loco-regional control rates (p = 0.003) compared to LxCAs. Positive neck nodes and salvage procedures were associated with significantly worse outcome. Nomograms demonstrated that hypopharyngeal tumors with positive neck nodes in salvage situations had the worst oncological outcome with a 5-year DSS of 15-20%. CONCLUSIONS: The oncological outcome is worse in hypopharyngeal carcinomas and could be easily quantified by our nomograms that are based on tumor site, lymph node involvement and salvage situation.

Survival Outcome in True Carcinoma of Unknown Primary (tCUP) with p16 + Cervical Metastasis

Abstract Introduction Age and lymph node ratio have been attributed as independent predictors for survival and recurrence in carcinoma of unknown primary (CUP). Objective The purpose of this study was to analyze the prognostic value of p16 overexpression for CUP in the absence of true primary (TP). Methods The study involved 43 patients who underwent therapeutic lymph node dissection (LND) from 2000 to 2015 after all the diagnostic work up for CUP. Immunohistochemistry for p16 overexpression was performed. Cox proportional hazard regression analysis was used to analyze the prognostic impact on 5-year overall survival (OS) and recurrence-free survival (RFS). Results The male-to-female ratio was 5.1:1, with a median age of 62 years. The clinicopathological data, except for p16 overexpression, did not differ significantly in terms of 5-year OS and RFS. The Cox regression analysis proposed p16 positivity to be an independent prognosticator of regional recurrence-free survival (RRFS) (hazard ratio [HR] 6.180, p = 0.21). The median time to recurrence and death were 10 and 25 months, respectively. Conclusion Cervical metastasis with p16 overexpression is a significant prognostic factor of improved RFS after surgery in CUP. The prognostic significance of lymph node p16 positivity should be further studied.

Evaluation of the Prognostic Capacity of a Novel Survival Marker in Patients with Sinonasal Squamous Cell Carcinoma.

Sinonasal squamous cell carcinoma (SNSCC) is a malignant tumor associated with poor survival, and easily obtainable prognostic markers are of high interest. Therefore, we aimed to assess the prognostic value of a novel survival index (SI) combining prognostic values of clinical (T and N classifications and invasion across Ohngren's line), inflammatory (neutrophil-to-lymphocyte ratio), and nutritional (albumin and body-mass index) markers. All patients with primarily treated SNSCC between 2002 and 2020 (n = 51) were included. Each of the six SI components was stratified into a low- (0) and high-risk (1) categories. Subsequently, the cohort was stratified into low- (SI of 0-2) and high-risk SI groups (SI of 3-6). Overall survival (OS) and disease-free survival (DFS) were compared between patients with low- and high-risk SI. The log-rank test was used to test for statistical significance. Overall, the mortality rate was 41.2% (n = 21), and the recurrence rate was 43.1% (n = 22). We observed significantly better OS in patients with low-risk SI (n = 24/51, 47.1%, mean OS: 7.9 years, 95% confidence interval (CI): 6.3-9.6 years) than in high-risk SI (n = 27/51, 52.9%, mean OS: 3.4 years, 95% CI: 2.2-4.5 years; p = 0.013). Moreover, we also showed that patients with low-risk SI had a longer DFS than patients with high-risk SI (mean DFS: 6.4, 95% CI: 4.8-8.0 vs. mean DFS: 2.4 years, 95% CI 1.3-3.5, p = 0.012). The SI combines the prognostic capacity of well-established clinical, radiologic, inflammatory, and nutritional prognosticators and showed prognostic potential in our cohort of SNSCC patients.

Protein Expression of Folate Receptor Alpha in Adenoid Cystic Carcinoma of the Head and Neck.

Purpose: Folate receptor alpha (FRα) is overexpressed in various cancer entities while expression in normal tissue is limited. Thus, FRα is an attractive target in cancer therapy. Currently, various therapeutic and diagnostic approaches are under investigation in clinical trials. The aim of this study was to assess the expression and clinical relevance of FRα in adenoid cystic carcinoma of the head and neck. Patients and Methods: In this retrospective cohort study, 43 patients with adenoid cystic carcinoma (ACC) of the head and neck were included. FRα expression was analyzed in tumor tissue and tumor-free margin in a tissue microarray using immunohistochemical staining. Protein levels were correlated with clinical parameters. Results: FRα staining was positive in 47% of ACC patients. The tumor-free margin was positive in 22%. Patients with positive tumor tissue showed positive margin staining in 55%. FRα expression was not associated with the clinical parameters (sex, age, staging, grading, perineural invasion, lymphovascular invasion). Conclusion: FRα expression is common in ACC of the head and neck. Therefore, FRα should be further evaluated as a therapeutic target in ACC.

Evaluation of the External Jugular Vein Overlying the Sternocleidomastoid Muscle as Venous Lymph-Node Flap.

BACKGROUND: Until recently, vascularized lymph-node flaps were based on arterial and venous donor vessels. Now, venous lymph-node flaps form a novel promising concept in the treatment of advanced-stage lymphedema. In preliminary studies, the external jugular vein has shown promising results as a venous lymph-node flap. However, nothing is known about the number of lymph nodes adjacent to the external jugular vein. METHODS: Standardized specimens of the external jugular vein and surrounding fatty tissue directly overlying the sternocleidomastoid muscle were obtained during routine neck dissection. Histologic evaluation was performed in order to evaluate for the presence of lymph nodes within the tissue. RESULTS: A total of 20 specimens were evaluated. There was no vein in 4 of the samples. We found lymph nodes in 9 of the remaining 16 samples. In 7 samples, lymph nodes were absent. CONCLUSION: Our results suggest that the vein directly overlying the sternocleidomastoid muscle may not be the ideal candidate for a venous lymph-node flap.

The radiosensitizing effect of ß-Thujaplicin, a tropolone derivative inducing S-phase cell cycle arrest, in head and neck squamous cell carcinoma-derived cell lines.

BACKGROUND: Resistance to radiotherapy is a common cause of treatment failure in advanced head and neck squamous cell carcinoma (HNSCC). ß-Thujaplicin, a natural tropolone derivative, acts as an anti-cancer agent and has recently been shown to radiosensitize non-HNSCC cancer cells. However, no data is currently available on its radiosensitizing potential in HNSCC. METHODS: To investigate the effect of ß-Thujaplicin and irradiation in HNSCC cell lines CAL27 and FADU, we performed a cell viability assay, colony forming assay, flow cytometry for cell cycle analysis and a wound healing assay. Drug-irradiation interaction was analyzed using a zero-interaction potency model. RESULTS: Treatment with ß-Thujaplicin led to a dose-dependent decrease in cell viability and enhanced the effect of irradiation. Clonogenic survival was inhibited with synergistic drug-irradiation interaction. ß-Thujaplicin further led to S-phase arrest and increased the sub-G1 population. Moreover, combined ß-Thujaplicin and irradiation treatment had a higher anti-migratory effect compared to irradiation alone. CONCLUSIONS: ß-Thujaplicin acts as a radiosensitizer in HNSCC cell lines. Further evaluation of its use in HNSCC therapy is warranted.