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Purpose: Amplification of the 11q13 region is a frequent event in human cancer. The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene.Experimental Design: To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon.Results: Using array-based comparative genomic hybridization analysis, we detected a region of ∼1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser194 phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser194 phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest.Conclusion: Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy.

Supplementary Materials and Methods; Supplementary Table S1.

OBJECTIVE: To determine the diagnostic value of measuring squamous cell carcinoma antigen (SCC-Ag) and cancer antigen 15-3 (CA15-3) concentrations in fine-needle aspiration (FNA) samples for the detection of squamous cell carcinoma (SCC) metastases in cervical lymph nodes.STUDY DESIGN: A prospective study with patients consecutively included between November 2018 and May 2021.SETTING: A tertiary head and neck oncologic center.METHODS: Out of 138 patients, SCC-Ag concentrations were analyzed in 168 FNA cervical lymph node samples and CA15-3 in 152 samples. Results were compared with FNA cytology (FNAC) or definitive histology to establish sensitivity and specificity rates.RESULTS: For the detection of cervical SCC lymph node metastases, SCC-Ag measurement had an 89.4% sensitivity and 79.3% specificity at a cutoff concentration of 0.1 µg/L. Measurement of CA15-3 concentration in addition to SCC-Ag concentration did not lead to improved accuracy for the detection of SCC. In histology-confirmed cases, FNAC had an 80.0% sensitivity and 100% specificity, as opposed to 93.3% and 57.1%, respectively, for SCC-Ag.CONCLUSION: Measurement of SCC-Ag concentration for detection of SCC lymph node metastases has a sensitivity at least comparable to FNAC and could be used as a relatively cheap screening tool in samples with nondiagnostic or indeterminate FNAC results or when multiple lymph nodes are sampled. However, SCC-Ag in FNA samples has a lower specificity than FNAC assessed by pathologists experienced in head and neck oncology. Addition of CA15-3 measurement did not lead to improved accuracy.

BACKGROUND AND PURPOSE: Geriatric impairments and frailty are highly prevalent in patients with head and neck cancer (HNC). This study investigated the association of frailty and outcomes of geriatric assessment (GA) with radiation-induced toxicity (RIT) in patients undergoing (chemo)radiotherapy ((C)RT) for HNC.MATERIALS AND METHODS: Between October 2014 and April 2016, patients with HNC were prospectively included in OncoLifeS, an institutional data-biobank. Before treatment initiation, patients underwent GA and frailty screening (Groningen Frailty Indicator and Geriatric 8). The main outcome of this study was RIT (weight loss, mucositis, salivary gland inflammation, oral pain, sore throat, hoarseness, dry mouth, dysgeusia, dysphagia and general pain) according to the common terminology criteria of adverse events (CTCAE) version 4.0. Linear mixed models were performed, to analyse factors associated with increasing mean RIT over time during the treatment period.RESULTS: 160 patients were included. 114 (71.3%) were male and the mean age was 66.1 years. Age ≥ 65 (β = 0.03(95 %CI = 0.01;0.05), p = 0.01), regional RT (β = 0.05(95 %CI = 0.02;0.09), p = 0.004), and concurrent chemotherapy (β = 0.04(95 %CI = 0.02;0.07), p = 0.001), were independent factors associated with increasing toxicity during the 7-week treatment period, adjusted for relevant covariates. None of the single items of GA, as well as the frailty screening instruments, were associated with increasing RIT.CONCLUSION: In this study, frailty and GA were not associated with additional RIT during treatment. These results suggest that (C)RT is equally tolerated in frail and non-frail patients, with respect to acute RIT. RT could be a suitable alternative to surgery in selected frail patients.

Objective: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins.Materials and Methods: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology.Results: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range −6.1 to 12.8 mm) than for FMI (0.9 mm, range −3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy.Conclusion: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons.

Objective: To evaluate expression of the potential molecular imaging targets glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) in comparison to classical epidermal growth factor receptor (EGFR) in previously untreated head and neck cancer primary tumors and corresponding lymph node metastases, and in lymph node metastases after initial (chemo)radiotherapy. Methods: Primary tumors and lymph node metastases of 38 patients who underwent primary resection of head and neck squamous cell carcinoma (HNSCC) were selected. In addition, lymph node metastases from salvage surgery after (chemo)radiotherapy from 22 patients with HNSCC were selected. Immunohistochemical staining for EGFR, VEGF and GPNMB was performed, after which protein expression was scored using H-scores (percentage of positive tumor cells multiplied by staining intensity ranging from 0 to 2). Primary tumors and lymph node metastases with an H-score ≥5 were considered positive, after which sensitivity rates were calculated. Groups were compared using the Mann-Whitney U test for non-parametric data with post-hoc Bonferroni corrections. Results: In untreated primary HNSCC the sensitivity was 86.8% for EGFR (median H-score 60), 92.1% for VEGF (median 60), and 100% for GPNMB (median 100). In previously untreated lymph node metastases the sensitivity was 81.6% for EGFR (median 30), 86.8% for VEGF (median 65), and 100% for GPNMB (median 118). In lymph node metastases after initial (chemo)radiotherapy, sensitivity was 86.4% for EGFR (median 95) and 100% for GPMB (median 100). VEGF sensitivity could not reliably be evaluated in these lymph nodes due to nonspecific staining in all tissue slides. GPNMB expression was significantly higher compared to EGFR in untreated primary HNSCC (p = .009 and p < .001, respectively) and lymph node metastases (p < .001 for both). Conclusion: GPNMB shows better tumor-specific receptor expression in both sensitivity and H-scores compared to EGFR and VEGF in immunohistochemistry. VEGF performed comparable to EGFR in untreated HNSCC and lymph node metastases. GPNMB could therefore be a new potential imaging target based on these immunohistochemical results. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Saskia H. Hanemaaijer, Gyorgy B. Halmos, Max J. Witjes, Bernard F.A.M. van der Laan, Rudolf S. Fehrmann, Sjoukje F. Oosting, Boudewijn E. Plaat. Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6261.

Objective: Head and neck squamous cell carcinoma (HNSCC) can intraoperatively be visualized by fluorescence molecular imaging (FMI) using fluorophores conjugated to HNSCC specific antibodies. Currently, the epidermal growth factor receptor (EGFR) is used as a target. Targets more specific for HNSCC would reduce background signal, resulting in a higher tumor to background ratio. We aimed to identify new potential targets for FMI in HNSCC. Methods: Publicly available transcriptomic data were collected. A biostatistical method known as Transcriptional Adaptation to Copy Number Alterations (TACNA) profiling was applied, which captures the downstream effects of copy number alterations (CNAs) on mRNA levels, which we used to predict the overexpression on the protein level. By comparing gene expression profiles of HNSCC and normal oral mucosa, genes overexpressed explicitly in HNSCC were identified. Potential targets were selected based on the degree of overexpression, plasma membrane expression, and cross expression in other tissues in the head and neck region. Next, the expression of potential targets of TACNA results on mRNA level were validated on the protein level and compared to EGFR expression using immunohistochemistry (IHC). Subsequently, paired biopsies of HNSCC, adjacent suspicious mucosa, and healthy mucosa of the same patients were stained. Receptor expression was evaluated using H-scores (i.e., percentage of positive cells combined with staining intensity). Results: TACNA profiling was applied on 111 samples of healthy oral mucosa and 410 HNSCC comparing expression levels of 19,635 genes. The newly identified membrane-bound targets were glucose transporter 1 (GLUT-1), placental cadherin (P-cadherin), and monocarboxylate transporter 1 (MCT-1). The three targets were evaluated by IHC in a total of 31 patients, of which 8 had oropharyngeal, 7 hypopharyngeal, and 16 laryngeal carcinomas. GLUT-1 had a median H-score of 175, P-cadherin 140, and MCT-1 40. GLUT-1 and P-cadherin were significantly higher compared to EGFR, with a median H-score of 90 (p < .001). GLUT-1 receptor expression was also seen on erythrocytes, while P-cadherin expression was seen in the basal layer of normal epithelium. This can complicate its use in FMI. Conclusion: TACNA profiling results were successfully validated in immunohistochemistry as a first step in the search for new specific FMI targets in HNSCC. GLUT-1 and P-cadherin show promising results with significantly higher receptor expression than EGFR. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Bernard F.A.M. van der Laan, Max J.H. Witjes, Sjoukje F. Oosting, Rudolf S. Fehrmann, Boudewijn E. Plaat. Identification of molecular imaging targets specific for head and neck squamous cell carcinoma by transcriptional adaptation to copy number alterations profiling: Digital data translated to protein expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6260.