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Objective: To assess whether narrow band imaging (NBI) detects fields of cancerisation around suspicious lesions in the upper aerodigestive tract, which were undetected by white light imaging (WLI)., Methods: In 96 patients with laryngeal and pharyngeal lesions suspicious for malignancy, 206 biopsies were taken during laryngoscopy: 96 biopsies of suspicious lesions detected by both WLI and NBI (WLI+/NBI+), 60 biopsies adjacent mucosa only suspicious with NBI (WLI-/NBI+), and 46 biopsies of NBI and WLI unsuspicious mucosa (WLI-/NBI-) as negative controls. Optical diagnosis according to the Ni-classification was compared with histopathology., Results: Signs of (pre)malignancy were found in 88% of WLI+/NBI+ biopsies, 32% of WLI-/NBI+ biopsies and 0% in WLI-/NBI- (p < .001). In 58% of the WLI-/NBI+ mucosa any form of dysplasia or carcinoma was detected., Conclusion: The use of additional NBI led to the detection of (pre)malignancy in 32% of the cases, that would have otherwise remained undetected with WLI alone. This highlights the potential of NBI as a valuable adjunct to WLI in the identification of suspicious lesions in the upper aerodigestive tract., (© 2024 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Purpose: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR)., Materials and Methods: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r)., Results: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively)., Conclusion: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC., Competing Interests: Declaration of competing interest Boudewijn E.C. Plaat has a consultancy role for and has received unrestricted research grants from Olympus Medical Systems EU. Bert van der Vegt reports honoraria received by UMCG for expertise or scientific advisory board/consultancy (on request): Visiopharm, Philips, MSD/Merck, Daiichi-Sankyo/AstraZeneca; Speaker's fee from Visiopharm, Diaceutics, MSD/Merck. All unrelated to this publication. Sjoukje F. Oosting reports research grants from Novartis (2009), Pfizer (2011) and Celldex Therapeutics (2015); a speakers fee from Merck, and consultancy fees from Genmab, Merck, and Bristol Myers Squibb (all paid to the institution). The other authors have no other funding, financial relationships, or conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Intraoperative fluorescence imaging (FI) of head and neck squamous cell carcinoma (HNSCC) is performed to identify tumour-positive surgical margins, currently using epidermal growth factor receptor (EGFR) as imaging target. EGFR, not exclusively present in HNSCC, may result in non-specific tracer accumulation in normal tissues. We aimed to identify new potential HNSCC FI targets., Materials and Methods: Publicly available transcriptomic data were collected, and a biostatistical method (Transcriptional Adaptation to Copy Number Alterations (TACNA)-profiling) was applied. TACNA-profiling captures downstream effects of CNAs on mRNA levels, which may translate to protein-level overexpression. Overexpressed genes were identified by comparing HNSCC versus healthy oral mucosa. Potential targets, selected based on overexpression and plasma membrane expression, were immunohistochemically stained. Expression was compared to EGFR on paired biopsies of HNSCC, adjacent macroscopically suspicious mucosa, and healthy mucosa., Results: TACNA-profiling was applied on 111 healthy oral mucosa and 410 HNSCC samples, comparing expression levels of 19,635 genes. The newly identified targets were glucose transporter-1 (GLUT-1), placental cadherin (P-cadherin), monocarboxylate transporter-1 (MCT-1), and neural/glial antigen-2 (NG2), and were evaluated by IHC on samples of 31 patients. GLUT-1 was expressed in 100 % (median; range: 60-100 %) of tumour cells, P-cadherin in 100 % (50-100 %), EGFR in 70 % (0-100 %), MCT-1 in 30 % (0-100 %), and NG2 in 10 % (0-70 %). GLUT-1 and P-cadherin showed higher expression than EGFR (p < 0.001 and p = 0.015)., Conclusions: The immunohistochemical confirmation of TACNA-profiling results showed significantly higher GLUT-1 and P-cadherin expression than EGFR, warranting further investigation as HNSCC FI targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Boudewijn E.C. Plaat has a consultancy role for and has received unrestricted research grants from Olympus Medical Systems EU. Bert van der Vegt reports honoraria received by UMCG for expertise or scientific advisory board/consultancy (on request): Visiopharm, Philips, MSD/Merck, Daiichi-Sankyo/AstraZeneca; Speaker’s fee from Visiopharm, Diaceutics, MSD/Merck. All unrelated to this publication. Sjoukje F. Oosting reports research grants from Novartis (2009), Pfizer (2011) and Celldex Therapeutics (2015); a speakers fee from Merck, and consultancy fees from Genmab, Merck, and Bristol Myers Squibb (all paid to the institution). The other authors have no other funding, financial relationships, or conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fibre-optic laryngoscopy is still widely used in daily clinical practice; however, high-definition laryngoscopy using narrow band imaging could be more reliable in characterising pharyngeal and laryngeal lesions., Methods: Endoscopic videos were assessed in a tertiary referral hospital by 12 observers with different levels of clinical experience. Thirty pairs of high-definition laryngoscopy with narrow band imaging and fibre-optic laryngoscopy videos were judged twice, with an interval of two to four weeks, in a random order. Inter- and intra-observer reliability, sensitivity and specificity were calculated in terms of detecting a malignant lesion and a specific histological entity, for beginners, trained observers and experts., Results: Using high-definition laryngoscopy with narrow band imaging, inter-observer reliability for detecting malignant lesions increased from moderate to substantial in trained observers and experts (high-definition laryngoscopy with narrow band imaging κ = 0.66 and κ = 0.77 vs fibre-optic laryngoscopy κ = 0.51 and κ = 0.56, for trained observers and experts respectively) and sensitivity increased by 16 per cent., Conclusion: Inter-observer reliability increased with the level of clinical experience, especially when using high-definition laryngoscopy with narrow band imaging.

Objective: Assessing whether the additional use of narrow-band imaging (NBI) in transoral laser surgery (TOLS) for early laryngeal cancer improves clinical outcomes., Study Design: Randomized controlled trial, performed between September 2015 and November 2022., Setting: A tertiary referral hospital in The Netherlands., Methods: TOLS was carried out in 113 patients. The procedure was performed with white light imaging (WLI, n = 56) alone, or combined with NBI (n = 57). Patients received frequent follow-up laryngoscopy. Resection margin status, recurrence rate, and recurrence-free survival at 12 months, 18 months, and after study termination (maximum 86 months) were analyzed., Results: Thirty-one cases in the WLI group had a positive resection margin, versus 16 in the NBI group (p = .002). After 12 months, the recurrence-free survival was 92%: 87% for WLI versus 96% for NBI, p = .07. The recurrence rate was 7/56 (13%) for WLI, versus 2/57 (4%) for NBI, p = .09. After 18 months, the recurrence-free survival was 84% for WLI versus 96% for NBI, p = .02. The recurrence rate was 9/56 (16%) for WLI, versus 2/57 (4%) for NBI, p = .02. After study termination, the recurrence-free survival was 71% for WLI versus 83% for the NBI group (p = .08). The recurrence rate was 16/56 for WLI, versus 10/57 for NBI (p = .16)., Conclusion: The additional use of NBI during TOLS significantly decreased the number of positive resection margins. Although not statistically significant at all time points, patients treated with NBI-supported TOLS showed a lower recurrence rate and better recurrence-free survival. Further studies in larger patient groups are needed to confirm these results., (© 2023 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Purpose: Treatment decision-making in advanced-stage laryngeal squamous cell carcinoma (LSCC) is difficult due to the high recurrence rates and the desire to preserve laryngeal functions. New predictive markers for radiosensitivity are needed to facilitate treatment choices. In early stage glottic LSCC treated with primary radiotherapy, expression of hypoxia (HIF-1α and CA-IX) and proliferation (Ki-67) tumour markers showed prognostic value for local control. The objective of this study is to examine the prognostic value of tumour markers for hypoxia and proliferation on locoregional recurrent disease and disease-specific mortality in a well-defined cohort of patients with locally advanced LSCC treated with primary, curatively intended radiotherapy., Methods: In pre-treatment biopsy tissues from a homogeneous cohort of 61 patients with advanced stage (T3-T4, M0) LSCC primarily treated with radiotherapy, expression of HIF-1α, CA-IX and Ki-67 was evaluated with immunohistochemistry. Demographic data (age and sex) and clinical data (T- and N-status) were retrospectively collected from the medical records. Cox regression analysis was performed to assess the relation between marker expression, demographic and clinical data, and locoregional recurrence and disease-specific mortality., Results: Patients with high expression of HIF-1α developed significantly more often a locoregional recurrence (39%) compared to patients with a low expression (21%) (p = 0.002). The expression of CA-IX and Ki-67 showed no association with locoregional recurrent disease. HIF-1α, CA-IX and Ki-67 were not significantly related to disease-specific mortality. Clinical N-status was an independent predictor of recurrent disease (p < 0.001) and disease-specific mortality (p = 0.003). Age, sex and T-status were not related to locoregional recurrent disease or disease-specific mortality., Conclusion: HIF-1α overexpression and the presence of regional lymph node metastases at diagnosis were independent predictors of locoregional recurrent disease after primary treatment with curatively intended radiotherapy in patients with locally advanced LSCC., (© 2023. The Author(s).)

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., (© 2022 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Purpose: As a result of rapid tumor growth in head and neck squamous cell carcinoma (HNSCC), delay in treatment initiation can result in tumor progression and inferior outcome. Especially older and frail patients are prone to develop adverse events. The aim of this study was to assess the effect of delay on development of adverse events and recurrence in older HNSCC patients., Materials and Methods: This cohort study with prospectively collected data included all newly diagnosed, curatively treated HNSCC patients (≥60 years) between 2015 and 2017. Time-to-treatment interval and geriatric domains were assessed. Adverse events were defined as postoperative complications (Clavien-Dindo classification) and acute radiation-induced toxicity (Common Terminology Criteria of Adverse Events). Multivariable regression models were performed, using adverse events and recurrence as outcome variables., Results: A total of 245 patients were included. Median time-to-treatment was 26 days for surgery patients and 40 days for radiotherapy patients (p < 0.001). Delayed treatment initiation was not associated with postoperative complications or acute radiation-induced toxicity. Delay was significantly associated with recurrence risk within two years after treatment initiation in a model adjusted for stage and tumor location in patients treated with initial surgery (HR:4.1, 95%CI:1.2-14.0, p = 0.024). For patients treated with radiotherapy, delay was not significantly associated with recurrence risk., Conclusion: Delayed treatment initiation was independently associated with increased recurrence risk in patients treated with initial surgery. Delay was not associated with short-term adverse events. These findings highlight the importance of establishing fast-track care pathways to minimize delays and improve especially long-term outcome., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti., Methods: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated., Results: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass., Conclusion: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

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., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Head and neck squamous cell carcinomas (HNSCC) are rapidly developing tumours, and substantial delay in treatment initiation is associated with decreased overall survival. The effect of delay on health-related quality of life (HRQOL) is unknown. The aim of this study was to assess the impact of delay on QOL and overall survival., Methods: Patients with mucosal HNSCC were prospectively included. HRQOL and 2-year overall survival were analysed using linear mixed-model analyses and cox regression, respectively. Delay was defined as care pathway interval (CPI) of ≥30 days between first consultation and treatment initiation., Results: Median CPI was 39 days for the 173 patients included. A trend towards higher HRQOL-scores (indicating better HRQOL) during 2-year follow-up for patients with delay in treatment initiation was visible in the adjusted models (HRQOL summary score-β: 2.62, 95% CI: 0.57-4.67, p = 0.012). Factors associated with decreased overall survival were moderate comorbidities (HR: 5.10, 95% CI: 1.65-15.76, p = 0.005) and stage-IV tumours (HR: 12.37, 95% CI: 2.81-54.39, p = 0.001). Delay was not associated with worse overall survival., Conclusion: Timely treatment initiation is challenging, especially for patients with advanced tumours and initial radiotherapy treatment. Encountering delay in treatment initiation did not result in clinically relevant differences in HRQOL-scores or decreased overall survival during 2-year follow-up., (© 2022 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Objectives/hypothesis: Early-stage laryngeal squamous cell carcinoma (LSCC) has yielded local control rates of 75% after radiotherapy. DNA methylation, in which DNA methyltransferases play an important role, has influence on tumorigenesis. In this study, we investigated the association between the expression of DNA methyltransferase 1 (DNMT1) and local control in early-stage LSCC treated with radiotherapy., Study Design: Retrospective cohort study., Methods: We analyzed a well-defined homogeneous series of 125 LSCC patients treated with radiotherapy with curative intent. The association of immunohistochemical expression of DNMT1 with local control was evaluated using Cox proportional hazard regression models., Results: With a median follow-up of 58 months, 29 local recurrences (23%) were observed. On univariate analysis, worse local control was associated with high DNMT1 expression (hazard ratio [HR] 2.57, 95% confidence interval [CI] 1.10-6.01). Also, higher T-stage (HR 2.48, 95% CI 1.06-5.80) and positive N-status (HR 2.62, 95% CI 1.06-6.47) were associated with worse local control. Multivariate Cox regression demonstrated that high DNMT1 (HR 2.81; 95% CI 1.20-6.58) was independently associated with worse local control., Conclusions: We found an association between high DNMT1 expression and worse local control in a homogeneous well-defined cohort of early-stage LSCC patients treated with definitive radiotherapy. The association between DNA methylation status as determined by DNMT1 expression and local control suggests that DNMT1 acts as a potential prognostic tumor marker in treatment decision-making in early-stage laryngeal carcinoma., Level of Evidence: NA Laryngoscope, 132:801-805, 2022., (© 2021 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In recent clinical practice, an increasing number of elderly patients suffering from head and neck squamous cell carcinoma (HNSCC) of unknown pathophysiology is observed. The majority of HNSCC patients can roughly be divided into three subcategories. First, a small group of young patients who present with variants of genomic aberrations and inheritable diseases like Fanconi anaemia. Second, an increasing population of HPV-related HNSCCs that are regarded as genomic stable tumours with a more favourable prognosis. Though HPV-related tumours used to be more common among younger males, a notable rise in the elderly population is observed. The third subcategory, that of HPV-negative tumours, has been shown to be more heterogeneous with involvement of a variety of oncogenic pathways related to lifestyle factors like smoking and alcohol consumption, often seen in middle-aged males. Some of these pathways could be related to age, such as TP53 alterations, EGFR activation, apoptotic pathway alterations and field cancerization., Conclusions: In this narrative review, we provide an overview of established and newly discovered age-specific pathophysiological mechanisms underlying HNSCC. We propose a fourth subcategory of patients with a suspected different pathophysiology: elderly (HPV-negative) HNSCC patients without a history of tobacco and alcohol consumption. In this subcategory, carcinogenesis seems to be a multi-step process based on genomic instability, immunosenescence, cell cycle disruption and telomere shortening. To conclude, we discuss suggestions for future research to fill the knowledge gap about age-dependent HNSCC carcinogenesis., (© 2022. Springer Nature Switzerland AG.)

Purpose: New energy-based sutureless vessel ligation devices, such as the Thunderbeat (Olympus Medical Systems Corp., Tokyo, Japan), could reduce operative time and limit blood loss in head and neck surgery; however, efficacy and safety in major head and neck surgery have not been investigated in a prospective, randomized study., Methods: This prospective, double-arm, randomized controlled trial consisted of two parts: total laryngectomy (TL) and neck dissection (ND). Thirty patients planned for TL were randomized in two groups. For the ND part, forty-two operative sides were likewise randomized. In both parts, Thunderbeat was used in addition to the standard instrumentation in the intervention groups, while only standard instrumentation was used in the control groups. Primary outcome values were blood loss, operative time and complication rate., Results: For the TL part there was no difference in mean blood loss (p = 0.062), operative time (p = 0.512) and complications (p = 0.662) between both hemostatic techniques. For the neck dissection part, there was a reduction in blood loss (mean 210 mL versus 431 mL, p = 0.046) and in operative time (median 101 (IQR 85-130) minutes versus 150 (IQR 130-199) minutes, p = 0.014) when Thunderbeat was used. There was no difference in complication rate between both hemostatic systems (p = 0.261)., Conclusion: The Thunderbeat hemostatic device significantly reduces operative blood loss and operative time for neck dissections, without increase in complications. In TL, blood loss using Thunderbeat was comparable with the standard technique, but the operative time tended to be shorter., Trial Registration: UMCG Research Register, Reg. no. 201700041, date of registration: 18/1/2017., (© 2021. The Author(s).)

Importance: Accumulation of geriatric deficits, leading to an increased frailty state, makes patients susceptible for decline in health-related quality of life (HRQOL) after treatment for head and neck cancer (HNC)., Objective: To assess the association of single and accumulated geriatric deficits with HRQOL decline in patients after treatment for HNC., Design, Setting, and Participants: Between October 2014 and May 2016, patients at a tertiary referral center were included in the Oncological Life Study (OncoLifeS), a prospective data biobank, and followed up for 2 years. A consecutive series of 369 patients with HNC underwent geriatric assessment at baseline; a cohort of 283 patients remained eligible for analysis, and after 2 years, 189 patients remained in the study. Analysis was performed between March and November 2020., Interventions or Exposures: Geriatric assessment included scoring of the Adult Comorbidity Evaluation 27, polypharmacy, Malnutrition Universal Screening Tool, Activities of Daily Living, Instrumental Activities of Daily Living (IADL), Timed Up & Go, Mini-Mental State Examination, 15-item Geriatric Depression Scale, marital status, and living situation., Main Outcomes and Measures: The primary outcome measure was the Global Health Status/Quality of Life (GHS/QOL) scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Differences between patients were evaluated using linear mixed models at 3 months after treatment (main effects, β [95% CI]) and declining course per year during follow-up (interaction × time, β [95% CI]), adjusted for baseline GHS/QOL scores, and age, sex, stage, and treatment modality., Results: Among the 283 patients eligible for analysis, the mean (SD) age was 68.3 (10.9) years, and 193 (68.2%) were male. Severe comorbidity (β = -7.00 [-12.43 to 1.56]), risk of malnutrition (β = -6.18 [-11.55 to -0.81]), and IADL restrictions (β = -10.48 [-16.39 to -4.57]) were associated with increased GHS/QOL decline at 3 months after treatment. Severe comorbidity (β = -4.90 [-9.70 to -0.10]), IADL restrictions (β = -5.36 [-10.50 to -0.22]), restricted mobility (β = -6.78 [-12.81 to -0.75]), signs of depression (β = -7.08 [-13.10 to -1.06]), and living with assistance or in a nursing home (β = -8.74 [-15.75 to -1.73]) were associated with further GHS/QOL decline during follow-up. Accumulation of domains with geriatric deficits was a major significant factor for GHS/QOL decline at 3 months after treatment (per deficient domain β = -3.17 [-5.04 to -1.30]) and deterioration during follow-up (per domain per year β = -2.74 [-4.28 to -1.20])., Conclusions and Relevance: In this prospective cohort study, geriatric deficits were significantly associated with HRQOL decline after treatment for HNC. Therefore, geriatric assessment may aid decision-making, indicate interventions, and reduce loss of HRQOL., Trial Registration: trialregister.nl Identifier: NL7839.

Background: In this feasibility study we aimed to evaluate the value of previously reported molecular tumor biomarkers associated with lymph node metastasis in oral squamous cell carcinoma (OSCC) to optimize neck strategy selection criteria., Methods: The association between expression of cortactin, cyclin D1, FADD, RAB25, and S100A9 and sentinel lymph node status was evaluated in a series of 87 (cT1-2N0) patients with OSCC treated with primary resection and SLNB procedure., Results: Tumor infiltration depth and tumor pattern of invasion were independent prognostic markers for SLN status, while none of the tumor makers showed a better prognostic value to replace SLNB as neck staging technique in the total cohort. However, in the subgroup of patients with pT1N0 OSCC, cortactin expression (OR 16.0, 95%CI 2.0-127.9) was associated with SLN classification., Conclusions: Expression of cortactin is a promising immunohistochemical tumor marker to identify patients at low risk that may not benefit from SLNB or END., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective/hypothesis: Comparing detection and extension of malignant tumors by flexible laryngoscopy in the outpatient setting with laryngoscopy under general anesthesia using both White Light Imaging (WLI) and Narrow Band Imaging (NBI)., Study Design: Prospective study., Methods: Two hundred and thirty-three patients with laryngeal and pharyngeal lesions underwent flexible and rigid laryngoscopy, with both WLI and NBI. Extension of malignant lesions (n = 132) was compared between both techniques in detail., Results: Sensitivity of NBI during flexible endoscopy (92%), was comparable with that of WLI during rigid endoscopy (91%). The correlation of tumor extension between flexible and rigid laryngoscopy was high (r s  = 0.852-0.893). The observed tumor extension was significantly larger when using NBI in both settings. The use of NBI during flexible laryngoscopy leads to upstaging (12%) and downstaging (2%) of the T classification., Conclusions: NBI during flexible laryngoscopy could be an alternative to WLI rigid endoscopy. NBI improves visualization of tumor extension and accuracy of T staging., Level of Evidence: 3 Laryngoscope, 131:E2222-E2231, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: We aimed to evaluate the association between frailty screening and geriatric assessment (GA) on short term adverse events in patients treated for head and neck cancer (HNC) for the first time in a prospective study., Materials and Methods: Newly diagnosed HNC patients undergoing curative treatment were prospectively included in OncoLifeS, a data biobank. Prior to the start of treatment, frailty was assessed with a GA, Groningen Frailty Indicator (GFI) and Geriatric-8 (G8). The GA included comorbidity (Adult Comorbidity Evaluation - 27), nutritional status (Malnutrition Universal Screening Tool), functional status ((instrumental) Activities of Daily Living), mobility (Timed Up & Go), psychological (Geriatric Depression Scale 15) and cognitive (Mini Mental State Examination) measures. Clinically relevant postoperative complications (Clavien-Dindo ≥ grade 2) and acute radiation-induced toxicity (Common Terminology Criteria for Adverse Events version 4.0 ≥ grade 2) were defined as outcome measures. Univariable and multivariable logistic regression analyses were performed, yielding odds ratios (ORs) and 95% confidence intervals (95%CIs)., Results: Of the 369 included patients, 259 patients were eligible for analysis. Postoperative complications occurred in 41/148 (27.7%) patients and acute radiation-induced toxicity was present in 86/160 (53.7%) patients. Number of deficit domains of GA (OR = 1.71, 95%CI = 1.14-2.56), GFI (OR = 2.54, 95%CI = 1.02-6.31) and G8 (OR5.59, 95%CI = 2.14-14.60) were associated with postoperative complications, but not with radiation-induced toxicity., Conclusion: Frailty and restrictions in geriatric domains were associated with postoperative complications, but not with radiation-induced acute toxicity in curatively treated HNC patients. The results of this prospective study further emphasizes the importance of geriatric evaluation, particularly before surgery., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aims to analyse differences in fiberoptic laryngoscopy (FOL) versus high definition laryngoscopy (HDL) by examining videolaryngoscopy images by a large group of observers with different levels of clinical expertise in ear, nose and throat (ENT) medicine., Methods: This study is a 111 observer paired analysis of laryngoscopy videos during an interactive presentation. During a National Meeting of the Dutch Society of ENT/Head and Neck Surgery, observers assessed both FOL and HDL videos of nine cases with additional clinical information. Observers included 41 ENT consultants (36.9%), 34 ENT residents (30.6%), 22 researchers with Head and Neck interest (19.8%) and 14 with unspecified clinical expertise (12.6%). For both laryngoscopic techniques, sensitivity, specificity, positive and negative predictive value and diagnostic accuracy were determined for identifying a normal glottis, hyperkeratosis, radiotherapy adverse effects and squamous cell carcinoma. The sensitivities for FOL and HDL were analysed with regard to the different levels of clinical expertise., Results: The overall sensitivity for correctly identifying the specific histological entity was higher in HDL (FOL 61% vs HDL 66.3%, p < 0.05). HDL was superior to FOL in identifying a normal glottis (FOL 68.1% vs HDL 91.6%, p < 0.01) and squamous cell carcinoma (FOL 70.86% vs HDL 79.41%, p = 0.02). Residents and researchers with Head and Neck interest diagnosed laryngeal lesions more correctly with HDL (p < 0.05)., Conclusions: In a large population of observers with different levels of clinical expertise, HDL is superior to FOL in identifying laryngeal lesions.

Introduction: Life expectancy is rising and consequently also the number of older patients with head and neck cancer. Different treatment regimens are often applied for older patients. The aim of this study is to investigate how treatment patterns and survival rates have changed over the past 20 years in older patients with head and neck squamous cell carcinoma (HNSCC)., Materials: Patient and tumour characteristics, treatment and 5-year survival data from the Netherlands Cancer Registry of patients aged ≥60 years diagnosed with HNSCC in 1990-1995 and 2010-2015 were compared using chi-square test and relative survival analysis., Results: Data of 14,114 patients were analyzed. Oral cavity cancer treatment did not change over time, while survival improved from 54% to 58% (p = 0.03). Oropharyngeal and hypopharyngeal cancer treatment shifted towards non-surgical, with survival improving from 31% to 51% (p < 0.01) and 26% to 34% (p < 0.01), respectively. Laryngeal cancer treatment changed towards surgery in stage I and non-surgical treatment in stage III and IV disease. Survival in laryngeal cancer stage I remained stable and favorable at a relative survival rate of around 90%. Survival non-significantly changed from 54% to 49% for stage III disease and from 37% to 33% for disease., Conclusion: Relative survival increased for all head and neck cancer sites in older patients, except for laryngeal cancer. For oropharyngeal, hypopharyngeal and advanced laryngeal cancer, a shift towards non-surgical treatment modalities was observed., Competing Interests: Declarations of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Distant metastasis (DM) in patients with head and neck squamous cell carcinoma (HNSCC) is uncommon, but strongly deteriorates prognosis. Controversy exists regarding age as a predictor for the presence and development of DM. The aim of this study was to investigate age and other predictors for DM in HNSCC patients., Methods: From 1413 patients diagnosed with a primary HNSCC between 1999 and 2010 in a tertiary referral centre, patient, disease and pathological characteristics were extracted from patient files. Uni- and multivariable Cox regression analyses were performed to identify risk factors for DM as primary outcome., Results: DM occurred in 131 (9.3%) patients, of which 27 (1.9%) were diagnosed simultaneously with the primary tumour, 27 (1.9%) were diagnosed synchronous, and 77 (5.4%) were diagnosed metachronous. The most common site of DM was lung (51.1%), followed by bone (19.1%) and liver (11.5%). Multivariable analysis identified male gender (HR = 1.95, 95% CI 1.23-3.10) hypopharyngeal tumours (HR = 3.28, 95% CI 1.75-6.14), advanced T-stage (HR = 1.61, 95% CI 1.09-2.38), poor differentiation grade (HR = 2.49, 95% CI 1.07-5.78), regional lymph node metastasis (HR = 5.35, 95% CI 3.25-8.79) and extranodal extension of regional lymph nodes metastasis (HR = 3.06, 95% CI 1.39-6.72) as independent prognostic factors for the presence or development of DM. No relation with age was found., Conclusion: Age is not related to the presence or development of DM. This study emphasizes the importance of screening for DM, especially in males, patients with hypopharyngeal tumours, advanced T-stage, histopathological poor differentiation grade, regional lymph node metastasis and extranodal extension.

Objective: To evaluate expression of potential molecular imaging targets epidermal growth factor receptor (EGFR), glycoprotein nonmetastatic melanoma protein B (GPNMB), and vascular endothelial growth factor (VEGF) in lymph nodes (LNs) with or without head and neck squamous cell carcinoma (HNSCC) metastases after (chemo)radiation., Study Design: Retrospective study comparing receptor expression in paired lymph nodes after initial treatment., Setting: A tertiary referral hospital., Subjects and Methods: Salvage neck dissection specimens of 40 patients treated with (chemo)radiation were selected. LNs that contained viable tumor, reactive changes after initial treatment, and normal LNs were analyzed using immunohistochemically determined H-scores and by calculating sensitivity and specificity rates and positive/negative predictive values (PPVs/NPVs)., Results: EGFR expression was found in 86% and GPNMB expression in 100% of the LNs with viable tumor. VEGF expression was present in all lymph node types. For EGFR, the sensitivity rate was 86%, and specificity rate was 81%. For GPNMB, these were 100% and 75%, respectively. PPV of EGFR was 61.8% and NPV was 98.2%. These were 56.4% and 100% for GPNMB, respectively., Conclusion: In residual or recurrent HNSCC lymph node metastases, both EGFR and GPNMB show tumor-specific expression in immunohistochemistry, which may prove useful in future molecular imaging in salvage neck dissections. Immunohistochemically detected VEGF expression indicates that this target is not feasible for imaging purposes in salvage surgery. Therefore, GPNMB could be a new potential imaging target showing comparable results to EGFR in immunohistochemistry.

Objective: To determine the effect of frailty on Health Related Quality of Life (HRQoL) after treatment for Head and Neck Cancer (HNC)., Materials and Methods: Patients were prospectively included in OncoLifeS, a data-biobank. Before treatment, patients underwent geriatric screening, including the Groningen Frailty Indicator (GFI) and Geriatric 8 (G8). Patients' HRQoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) at three, six, twelve and twenty four months after treatment. Linear mixed models were used for statistical analysis. All models were adjusted for baseline HRQoL values, relevant confounders at baseline and yielded estimates (β), 95% confidence intervals and p-values., Results: 288 patients were included. The mean age was 68.4 years and 68.8% were male. During follow-up, 84 patients had tumor recurrence and 66 died. Response to EORTC-QLQ-C30 ranged from 77.3% to 87.8%. Frail patients, defined by GFI, had significantly worse Global Health Status/Quality of Life (GHS/QoL) (β = -8.70(-13.54;-3.86), p < 0.001), physical functioning (β = -4.55(-8.70;-0.40), p < 0.032), emotional functioning (β = -20.06(-25.65;-15.86), p < 0.001), and social functioning (β = -8.44(-13.91;-2.98), p < 0.003) three months after treatment compared to non-frail patients. Furthermore, frail patients had a significantly worse course of GHS/QoL (β = -7.47(-11.23;-3.70), p = 0.001), physical functioning (β = -3.28(-6.26;-0.31), p = 0.031) and role functioning (β = -7.27(-12.26;-2.28), p = 0.005) over time, compared to non-frail patients. When frailty was determined by G8, frailty was significantly associated with worse GHS/QoL (β = -6.68(-11.00;-2.37), p = 0.003) and emotional functioning (β = -5.08(-9.43;-0.73), p = 0.022) three months after treatment., Conclusion: Frail patients are at increased risk for decline in HRQoL, and further deterioration during follow-up after treatment for HNC., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS)., Methods: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index., Results: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively., Conclusion: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance., (© 2020 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: In early stage laryngeal squamous cell carcinoma (LSCC) radiotherapy with curative intent is a major treatment modality. TNM classification is used to define patients eligible for radiotherapy. Studies in early stage glottic LSCC identified several predictive biomarkers associated with local control. However, we recently reported that this predictive value could not be confirmed in supraglottic LSCC., Objective: To examine whether clinical behavior and protein expression patterns of these biomarkers differ between glottic and supraglottic LSCC., Study Design: Retrospective cohort study., Methods: Tumor tissue sections of 196 glottic and 80 supraglottic T1-T2 LSCC treated primarily with RT were assessed immunohistochemically for expression of pAKT, Ki-67 and β-Catenin. Expression data of HIF-1α, CA-IX, OPN, FADD, pFADD, Cyclin D1, Cortactin and EGFR in the same cohort of glottic and supraglottic LSCC, were retrieved from previously reported data. The relationship between glottic and supraglottic sublocalization and clinicopathological, follow-up, and immunohistochemical staining characteristics were evaluated using logistic regression and Cox regression analyses., Results: Glottic LSCC were correlated with male gender (P = .001), hoarseness as a primary symptom (P < .001), T1 tumor stage (P < .001), negative lymph node status (P < .001), and an older age at presentation (P = .004). Supraglottic LSCC patients developed more post-treatment distant metastasis when adjusted for gender, age, and T-status. While supraglottic LSCC was associated with higher expression of HIF-1α (P = .001), Cortactin (P < .001), EGFR (P < .001), and Ki-67 (P = .027), glottic LSCC demonstrated higher expression of CA-IX (P = .005) and Cyclin D1 (P = .001)., Conclusion: Differences in clinicopathological and immunohistochemical staining characteristics suggest that T1-T2 glottic and supraglottic LSCC should be considered as different entities., Level of Evidence: N/A. Laryngoscope, 2020., (© 2020 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: Most early stage laryngeal squamous cell carcinomas (LSCC) are treated with radiotherapy. Discovery of new biomarkers are needed to improve prediction of outcome after radiotherapy and to identify potential targets for systemic targeted therapy. The ataxia telangiectasia mutated (ATM) gene plays a critical role in DNA damage response induced by ionizing radiation., Methods: The prognostic value of immunohistochemical expression of pATM, pChk2, and p53 were investigated in 141 patients with T1-T2 LSCC curatively treated with external beam radiotherapy. Uni- and multivariable Cox regression analyses were performed to examine the relation between expression levels of markers and local control., Results: Local control was significantly worse in cases with high levels of pATM (HR 2.14; 95% CI, 1.08-4.24; P = .03). No significant associations with local control were found for pChk2 and p53 expression. The association of high pATM expression with poor local control was only found for supraglottic LSCC (HR 10.9; 95% CI, 1.40-84.4; P = .02)., Conclusion: Our findings suggest a potential role for ATM in response to radiotherapy in early stage supraglottic LSCC and imply ATM inhibition as a possibility to improve response to radiotherapy., Level of Evidence: NA Laryngoscope, 130: 1954-1960, 2020., (© 2020 The Authors. The Laryngoscope published by Wiley Periodicals, Inc. on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance., Objective of the Review: The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy., Type of Review: Systematic review., Search Strategy: PubMed, Embase, Cochrane Library., Evaluation Method: A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers., Results: A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy., Conclusions: Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy., (© 2020 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Background: We aimed to assess feasibility of self-completion of the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) by head and neck cancer patients, and to assess self-reported increased awareness regarding malnutrition risk after self-completion., Methods: Participants were randomized to complete the PG-SGA SF by paper or app. Feasibility was assessed by time needed to complete the PG-SGA SF, perceived difficulty, and help needed during completion. Participants were asked if they knew what malnutrition was (yes/no) and if they could define "malnutrition." They were also asked 9 questions on whether they perceived increased awareness of malnutrition risk after having completed the PG-SGA SF and 2 on their intention to change lifestyle habits., Results: Of all participants (n = 59; 65.9 ± 12.6 years; 73% male), 55% completed the PG-SGA SF paper version and 46% the Pt-Global app. Median time needed for self-completion of the PG-SGA SF was 2 minutes 41 seconds (interquartile range: 1 minute 49 seconds-3 minutes 50 seconds). Forty-eight percent needed help with completion, indicating acceptable feasibility. Participants who completed the Pt-Global app needed help significantly more often (66%; 21/32) than those who completed the PG-SGA SF paper version (26%; 7/27) (P = 0.005). All difficulty scores were excellent. For 7/9 questions on malnutrition risk awareness, >50% of the participants answered positively., Conclusion: The results of this study show that self-completion of the PG-SGA SF by head and neck cancer patients is feasible and that awareness regarding malnutrition risk may increase after completing the PG-SGA SF., (© 2019 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals, Inc. on behalf of American Society for Parenteral and Enteral Nutrition.)

Background: To determine time of onset and risk of hypothyroidism after total laryngectomy (TL) with and without (hemi)thyroidectomy in relation to treatment regimen, that is, preoperative radiotherapy (RT-TL), postoperative radiotherapy (TL-RT), and postoperative re-irradiation (RT-TL-RT)., Methods: Retrospective review of 128 patients treated by RT-TL (51 patients), TL-RT (55 patients), and RT-TL-RT (22 patients). Risk of hypothyroidism was determined by multivariable Cox regression analysis and euthyroid survival was calculated using Kaplan-Meier method., Results: Hypothyroidism developed in 69 (54%) patients. The median onset of hypothyroidism was later (P < .01) and the risk of hypothyroidism was lower (hazard ratio 0.49; P = .014) in the TL-RT group compared to both other treatment regimens. Euthyroid survival did not differ between the treatment regimens. Two years euthyroid survival was 24% with and 61% without (hemi)thyroidectomy (P < .001)., Conclusions: Patients treated with TL-RT have later onset of hypothyroidism. Higher risk for hypothyroidism is associated with salvage TL after radiotherapy and (hemi)thyroidectomy., (© 2019 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Objectives: Endoscopic imaging techniques and endoscopic endonasal surgery (EES) expertise have evolved rapidly. Only few studies have assessed the effect of three-dimensional (3D) endoscopy on endoscopic sinus surgery (ESS). The present study aimed to objectively and subjectively assess the additional value of 3D high-definition (HD) endoscopy in ESS., Design: A randomized crossover study of endoscopic surgery performance, using five ESS tasks of varying complexity, performed on Thiel embalmed human specimens., Setting: Simulated surgical environment., Participants: Thirty participants, inexperienced in ESS., Main Outcome Measures: Performance was assessed using video imaging, surgical navigation and questionnaires. Main outcome measures were as follows: efficiency (defined by time to task completion), distance covered inside the nose, average velocity towards target, accuracy (measured by error rate), and subjective assessment of endoscope characteristics., Results: During ESS tasks, both efficiency and accuracy did not differ significantly between 2D HD and 3D HD endoscopy. Subjectively, imaging characteristics of the 3D HD endoscope were rated significantly better., Conclusions: ESS performance of inexperienced participants was not significantly improved by the use of 3D HD endoscopy during ESS tasks, although imaging characteristics of the 3D HD endoscope were rated significantly better. Surgical field characteristics and surgical techniques are likely to influence any additional value of 3D HD endoscopy., (© 2019 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Objectives: Ambiguous results have been reported on the predictive value of the Ki-67 proliferation index (Ki-67 PI) regarding local control (LC) and survival after primary radiotherapy (RT) in early-stage laryngeal squamous cell cancer (LSCC). Small study size, heterogenic inclusion, variations in immunostaining and cut-off values are attributing factors. Our aim was to elucidate the predictive value of the Ki-67 PI for LC and disease-specific survival (DSS) using a well-defined series of T1-T2 LSCC, standardised automatic immunostaining and digital image analysis (DIA)., Methods: A consecutive and well-defined cohort of 208 patients with T1-T2 LSCC treated with primary RT was selected. The Ki-67 PI was determined using DIA. Mann-Whitney U-tests, logistic and Cox regression analyses were performed to assess associations between Ki-67 PI, clinicopathological variables, LC and DSS., Results: In multivariate Cox regression analysis, poor tumour differentiation (HR 2.20; 95% CI 1.06-4.59, P = .04) and alcohol use (HR 2.84, 95% CI 1.20-6.71; P = .02) were independent predictors for LC. Lymph node positivity was an independent predictor for DSS (HR 3.16, 95% CI 1.16-8.64; P = .03). Ki-67 PI was not associated with LC (HR 1.59; 95% CI 0.89-2.81; P = .11) or DSS (HR 0.98; 95% CI 0.57-1.66; P = .97). In addition, continuous Ki-67 PI was not associated with LC (HR 2.03; 95% CI 0.37-11.14, P = .42) or DSS (HR 0.62; 95% CI 0.05-8.28; P = .72)., Conclusion: The Ki-67 PI was not found to be a predictor for LC or DSS and therefore should not be incorporated in treatment-related decision-making for LSCC., (© 2019 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Objectives: High definition laryngoscopy (HDL) could lead to better interpretation of the pharyngeal and laryngeal mucosa than regularly used fiberoptic laryngoscopy (FOL). The primary aim of this study is to quantify the diagnostic advantage of HDL over FOL in detecting mucosal anomalies in general, in differentiating malignant from benign lesions and in predicting specific histological entities. The secondary aim is to analyse image quality of both laryngoscopes., Design: Retrospective paired analysis with multiple observers evaluating endoscopic videos simulating daily clinical practice., Setting: A tertiary referral hospital., Participants: In 36 patients, both FOL and HDL videos were obtained. Six observers were provided with additional clinical information, and 36 FOL and HDL videos were evaluated in a randomised order., Main Outcome Measures: Sensitivity, specificity, positive and negative predictive value and diagnostic accuracy of observers using both flexible laryngoscopes were calculated for detection of mucosal lesions in general and uncovering malignant lesions. Sensitivities were calculated for prediction of specific histological entities. Image quality (scale 1-10) was assessed for both flexible laryngoscopes., Results: HDL reached higher sensitivity compared to FOL for detection of mucosal abnormalities in general (96.0% vs 90.4%; P = .03), differentiating malignant from benign lesions (91.7% vs 79.8%; P = .03) and prediction of specific histological entities (59.7% vs 47.2%; P < .01). Image quality was judged better with HDL in comparison with FOL (mean: 8.4 vs 5.4, P < .01)., Conclusions: HDL is superior to FOL in detecting mucosal anomalies in general, malignancies and specific histological entities. Image quality is considered as superior using HDL compared to FOL., (© 2019 The Authors. Clinical Otolaryngology published by John Wiley & Sons Ltd.)

Objective: We aimed to compare frailty status between patients with head and neck cancer (HNC) and other solid malignancies., Methods: Data collection was prospective, and the following were compared between cohorts at baseline: patient and tumour characteristics, Charlson Comorbidity Index (CCI), Groningen Frailty Indicator (GFI), Mini Mental State Examination (MMSE), Activities of Daily Living (ADLs), Instrumental ADLs (IADLs), Timed Up and Go (TUG) and Quality of Life (QoL). Univariate and multivariate logistic regression analyses were performed, and odds ratios (ORs) with their 95% confidence intervals (95% CIs) were estimated., Results: In total, 242 patients with HNC and 180 with other oncology diagnoses were enrolled, of whom 32.6% and 21.8% were frail according to the GFI respectively. Comorbidity scores were not significantly different between the cohorts (7.4% vs. 13.1%; OR 0.54; 95% CI 0.28-1.02). In the univariate analysis, the GFI was significantly worse in the HNC cohort (OR 1.74; 95% CI 1.11-2.71). However, in the multivariate analysis, the MMSE, TUG and global QoL were significantly worse in the HNC cohort, with ORs of 20.03 (95% CI 2.44-164.31), 11.56 (95% CI 1.86-71.68) and 0.98 (95% CI 0.97-1.00) respectively., Conclusion: Patients with HNC appear to be frailer than patients with other solid malignancies despite comparable levels of comorbidity., (© 2019 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Introduction: As cutaneous head and neck malignancies are highly prevalent especially in older patients, the risk of surgical complications is substantial in this potentially vulnerable population. The objective of this study was to evaluate the value of geriatric assessment of this population with respect to postoperative complications., Methods: Patients were prospectively included in OncoLifeS, a databiobank. Before surgery, patients underwent a geriatric assessment including multiple validated screening tools for frailty, comorbidity, polypharmacy, nutrition, functional status, social support, cognition and psychological status. Postoperatively, complications (Clavien-Dindo ≥ grade II) were registered. Uni- and multivariable logistic regression analyses were performed yielding odds ratios (ORs) and 95% confidence intervals (95%CIs)., Results: 151 patients undergoing surgery for cutaneous head and neck malignancies were included in this study (mean age 78.9 years, 73.5% male). In a multivariable analysis, frailty measured by the Geriatric 8 (G8) (OR = 6.34; 95%CI:1.73-23.25) was the strongest independent predictor of postoperative complications, among other predictors such as major treatment intensity (OR = 2.73; 95%CI:1.19-6.26) and general anesthesia (OR = 4.74; 95%CI:1.02-22.17), adjusted for age and sex., Conclusion: Frailty, measured by G8, is the strongest predictor of postoperative complications in patients undergoing surgery for cutaneous head and neck malignancies in addition to treatment intensity and type of anesthesia. Geriatric screening on multiple domains is recommended for patients with cutaneous malignancies undergoing head and neck surgery is recommended, as this population includes old patients and frequently suffers postoperative complications., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: The purpose of this study was to determine the additional diagnostic value of squamous cell carcinoma antigen (SCC-Ag) in cervical lymph node fine needle aspiration (FNA) samples for the detection of regional metastases of head and neck squamous cell carcinoma (HNSCC)., Methods: In 149 FNA samples of 114 patients, SCC-Ag concentration was retrospectively analyzed and associated with diagnosis to establish a cutoff concentration in relation to sensitivity and specificity of HNSCC detection., Results: SCC-Ag was elevated in lymph nodes from patients with HNSCC compared to lymph nodes from other patients (P < 0.01). With 0.3 μg/L as the cutoff concentration, SCC-Ag has 96% sensitivity for detecting HNSCC., Conclusions: SCC-Ag in FNA is a reliable test for detecting HNSCC in cervical lymph nodes., (© 2019 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Objectives: The patients' perspective on health has become increasingly important when assessing treatment outcomes. Recently, the Endoscopic Endonasal Sinus and Skull Base Surgery Questionnaire (EES-Q) was developed to determine the impact of endoscopic endonasal surgery on health-related quality of life (HRQoL). The aim of this study was to evaluate the test-retest reliability, construct validity and responsiveness of the EES-Q., Design: Prospective cohort study., Setting: University Medical Center Groningen, tertiary referral hospital, the Netherlands., Participants: One hundred patients who underwent endoscopic endonasal surgery because of sinus or anterior skull base pathology., Main Outcome Measures: Test-retest reliability, construct validity and responsiveness., Results: The EES-Q domains exhibited good test-retest reliability (ICC > 0.90). Construct validity was corroborated by significant positive and negative correlations between the EES-Q and the Sino-Nasal Outcome Test-22 (SNOT-22) and postoperative health status (P < 0.01) respectively. The correlation between the social EES-Q domain and the ability to move and perform usual activities (EuroQol-5D-3L [EQ-5D-3L]) was significant positive (P < 0.01). In patients with paranasal sinus pathology, the EES-Q was responsive to clinical change (Cohen's d = 0.6)., Conclusion: The EES-Q is a reliable and acceptable responsive disease-specific HRQoL instrument. The expected construct validity of the EES-Q is supported by the results in this study. Inconveniences in social functioning had the greatest negative impact on postoperative health status rating. This reflects the importance of a multidimensional HRQoL assessment after EES. The results indicate that the EES-Q is a promising disease-specific tool for the HRQoL assessment after endoscopic endonasal sinus or anterior skull base surgery., (© 2019 John Wiley & Sons Ltd.)

Objectives: The aim of this study was to establish the prognostic value of the epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression on local control in patients with early stage supraglottic laryngeal squamous cell carcinoma (LSCC) treated with radiotherapy only., Study Design: Retrospective cohort study., Methods: Immunohistochemical staining for EGFR and PTEN was performed on pretreatment biopsies of a selected well-defined homogeneous group of 52 patients with T1-T2 supraglottic LSCC treated with radiotherapy between 1990 and 2008. Kaplan-Meier analysis and univariate and multivariate Cox Regression analyses were performed to correlate clinical data and expression levels of EGFR and PTEN with local control., Results: Kaplan-Meier survival analysis and Cox Regression analysis showed a significant association between PTEN expression and local control (hazard ratio [HR] = 3.26, 95% confidence interval [CI] = 1.14-9.33, P = .027) and between lymph node status and local control (HR = 3.60, 95% CI = 1.26-10.31, P = .017). Both were independent prognostic factors in a multivariate analysis (HR = 3.28, 95% CI = 1.14-9.39, P = .027 and HR = 3.62, 95% CI = 1.26-10.37, P = .017, respectively). There was no significant association between EGFR expression and local control (HR = 1.32, 95% CI = 1.17-10.14, P = .79)., Conclusion: This study showed an association between both high PTEN expression and the presence of lymph node metastasis and deteriorated local control in early stage supraglottic LSCC treated with radiotherapy., Level of Evidence: NA.

Objectives: The aim of this study was to determine and compare the incidence of long- and short-term complications of percutaneous dilatation tracheotomies (PDT) and surgical tracheotomies (ST)., Design: A single-centre retrospective study., Participants: 305 patients undergoing a tracheotomy (PDT or ST) in the University Medical Center Groningen from 2003 to 2013 were included. Data were gathered from patient files., Main Outcome Measures: Short-term and long-term complications including tracheal stenosis., Results: The incidence of short- and long-term complications, including tracheal stenosis, was similar in both groups. Analysis of a small high-risk subgroup showed no difference in long-term complications., Conclusions: The rate of short- and long-term complications, including tracheal stenosis, is equal in PDT and ST. PDT is a safe alternative for ST in selected patients.

Objective: 18F FDG-PET is superior to other imaging techniques in revealing residual laryngeal cancer after radiotherapy. Unfortunately, its specificity is low, due to FDG uptake in inflammation and in anaerobic conditions. PET imaging with the amino acid-based radiopharmaceutical C11-methionine (MET) should be less influenced by post-radiation conditions. The aim of this study was to investigate the potential of MET in diagnosing recurrent laryngeal cancer after radiotherapy as compared to 18F-FDG., Methods: Forty-eight patients with a clinical suspicion of local residual disease at least 3 months after completion of radiotherapy or chemoradiotherapy for a T2-4 laryngeal carcinoma, along with an indication for direct laryngoscopy, were included. They received MET-PET and FDG-PET prior to the direct laryngoscopy. One senior nuclear medicine physician assessed both the FDG-PET and MET-PET images visually for the degree of abnormal uptake. The gold standard was a biopsy-proven recurrence 12 months after PET. The nuclear physician had no access to the medical charts and was blinded to the results of the other PET. Sensitivity, specificity and positive and negative predictive value were calculated., Results: The sensitivity of FDG was 77.3% and the specificity 56.0% after the conservative reading, with these values equalling 54.5% and 76.0% for MET. The positive predictive value of FDG was 60.7% and the negative predictive value 73.7%. The PPV of MET was 66.7%, and the NPV was 65.5%. The McNemar test within diseased (sensitivity comparison) shows a p-value of 0.125, and the McNemar test within non-diseased (specificity comparison) shows a P-value of 0.180., Conclusion: MET-PET is not superior to FDG-PET in terms of identifying recurrent laryngeal cancer., (© © 2018 The Authors. Clinical Otolaryngology Published by John Wiley & Sons Ltd.)

Background: Trismus occurs frequently in patients with head and neck cancer. Determining the prevalence and associated factors of trismus would enable prediction of the risk of trismus for future patients., Methods: Based on maximal mouth opening measurements, we determined the prevalence of trismus in 730 patients with head and neck cancer. Associated factors for trismus were analyzed using univariate analyses and multivariate logistic regression analyses. Based on the regression model, a calculation tool to predict trismus was made., Results: Prevalence of trismus was 23.6%. Factors associated with trismus were: advanced age; partial or full dentition; tumors located at the maxilla; mandible; cheek; major salivary glands; oropharynx; an unknown primary; a free soft tissue transfer after surgery; reirradiation; and chemotherapy., Conclusion: About one-fourth of patients with head and neck cancer develop trismus. Based on prevalence and associated factors of trismus, a simple calculation tool predicts the risk of trismus in these patients., (© 2018 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Objectives: The primary goal was to study the diagnostic potential of narrow-band imaging (NBI), and the secondary goal was to evaluate the most common mistakes when using and interpreting NBI., Design: Retrospective study., Setting: University Medical Center Groningen, tertiary referral hospital, the Netherlands., Participants: Three hundred and seventy patients who underwent rigid endoscopy of the upper aerodigestive tract. Two observers assessed all lesions. Twelve observers assessed a selection of 100 lesions. All observers were provided with both white light imaging and NBI., Main Outcome Measures: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and reasons for insufficient photograph quality., Results: When using NBI, the sensitivity, specificity, PPV, NPV and accuracy for detecting invasive carcinoma, carcinoma in situ or high-grade dysplasia were 92%, 68%, 61%, 94% and 77%, respectively. In multiple-observer analysis, values were 76%, 58%, 53%, 83% and 65% with the evaluation strictly based on type V patterns of Ni's classification, vs 83%, 68%, 64%, 85% and 74% when evaluation was also based on lesion-specific clinical characteristics. Lesions that caused misinterpretations were leukoplakia, papillomas and mucosal lesions after irradiation. In total, 185 photographs were assessed to be of suboptimal quality due to blurring (36%), bleeding (6%), insufficient zooming (15%) and/or insufficient lighting (17%)., Conclusion: NBI is a relatively reliable screening method for detecting malignancy. Evaluation based on Ni's classification alone is not sufficient. To optimise NBI photograph quality, we recommend sufficient zooming and prevention of bleeding, blurring and inadequate lighting., (© 2018 John Wiley & Sons Ltd.)

Background: Head and neck cancers are fast growing tumours that are complex to diagnose and treat. Multidisciplinary input into organization and logistics is critical to start treatment without delay. A multidisciplinary first-day consultation (MFDC) was introduced to reduce throughput times for patients suffering from head and neck cancer in the care pathway. In this mixed method study we evaluated the effects of introducing the MFDC on throughput times, number of patient hospital visits and compliance to the Dutch standard to start treatment within 30 calendar-days., Methods: Data regarding 'days needed for referral', 'days needed for diagnostic procedures', 'days to start first treatment', and 'number of hospital visits' (process indicators) were retrieved from the medical records and analysed before and after implementation of the MFDC (before implementation: 2007 (n = 21), and after 2008 (n = 20), 2010 (n = 24) and 2013 (n = 24)). We used semi-structured interviews with medical specialists to explore a sample of outliers., Results: Comparing 2007 and 2008 data (before and after MFDC implementation), days needed for diagnostic procedures and to start first treatment reduced with 8 days, the number of hospital visits reduced with 1.5 visit on average. The percentage of new patients treated within the Dutch standard of 30 calendar-days after intake increased from 52 to 83%. The reduction in days needed for diagnostic procedures was sustainable. Days needed to start treatment increased in 2013. Semi-structured interviews revealed that this delay could be attributed to new treatment modalities, patients needed more time to carefully consider their treatment options or professionals needed extra preparation time for organisation of more complex treatment due to early communication on diagnostic procedures to be performed., Conclusions: A MFDC is efficient and benefits patients. We showed that the MFDC implementation in the care pathway had a positive effect on efficiency in the care pathway. As a consequence, the extra efforts of four specialist disciplines, a nurse practitioner, and a coordinating nurse seeing the patient together during intake, were justified. Start treatment times increased as a result of new treatment modalities that needed more time for preparation.

Background: For patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) palliative treatment options that improve overall survival are limited. The prognosis in this group remains poor and there is an unmet need for new therapeutic options. An emerging class of therapeutics, targeting tumor-specific antigens, are antibodies bound to a cytotoxic agent, known as antibody-drug conjugates (ADCs). The aim of this study was to prioritize ADC targets in HNSCC., Methods: With a systematic search, we identified 55 different ADC targets currently targeted by registered ADCs and ADCs under clinical evaluation. For these 55 ADC targets, protein overexpression was predicted in a dataset containing 344 HNSCC mRNA expression profiles by using a method called functional genomic mRNA profiling. The ADC target with the highest predicted overexpression was validated by performing immunohistochemistry (IHC) on an independent tissue microarray containing 414 HNSCC tumors., Results: The predicted top 5 overexpressed ADC targets in HNSCC were: glycoprotein nmb (GPNMB), SLIT and NTRK-like family member 6, epidermal growth factor receptor, CD74 and CD44. IHC validation showed combined cytoplasmic and membranous GPNMB protein expression in 92.0% of the cases. Strong expression was seen in 65.9% of the cases. In addition, 86.5% and 67.7% of cases showed ≥5% and >25% GPNMB positive tumor cells, respectively., Conclusions: This study provides a data-driven prioritization of ADCs targets that will facilitate clinicians and drug developers in deciding which ADC should be taken for further clinical evaluation in HNSCC. This might help to improve disease outcome of HNSCC patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)