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Introduction: There is a lack of comprehensive and uniform data on head and neck paragangliomas (HNPGLs), and research is challenging due to its rarity and the involvement of multiple medical specialties. To improve current research data collection, we initiated the Head and Neck Paraganglioma Registry (HNPGL Registry). The aim of the HNPGL Registry is to a) collect extensive data on all HNPGL patients through a predefined protocol, b) give insight in the long term outcomes using patient reported outcome measures (PROMs), c) create uniformity in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future (randomized) research., Methods and Analysis: The HNPGL Registry is designed as a prospective longitudinal observational registry for data collection on HNPGL patients and carriers of (likely) pathogenic variants causative of HNPGLs. All patients, regardless of the received treatment modality, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition a survey containing the EuroQol 5D-5L (EQ-5D-5L), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Modified Fatigue Impact Scale (MFIS), Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH), Cancer Worry Scale (CWS) and Hospital Anxiety and Depression Scale (HADS) will be sent periodically. The registry protocol was approved by the Medical Ethical Review Board of the University Medical Center Utrecht., Conclusion: The HNPGL Registry data will be used to further establish the optimal management for HNPGL patients and lay the foundation for guideline recommendations and the outline of future research., Competing Interests: NO authors have competing interests, (Copyright: © 2024 de Bresser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To assess whether there are differences in the effects of time to treatment interval (TTI) on patient survival for head and neck cancer (HNC) sites in order to provide evidence that can support decision-making regarding prioritizing treatment., Materials and Methods: Patients in the Netherlands with a first primary HNC without distant metastasis between 2010 and 2014 were included for analysis (N = 10,486). TTI was defined as the time from pathologic diagnosis to the start of initial treatment. Overall survival (OS), cox regression analyses and cubic spline hazard models were calculated and visualized., Results: Overall, the hazard of dying was higher (HR = 1.003; 95 % CI 1.001-1.005) with each additional day until treatment initiation. The pattern, as visualized in cubic spline graphs, differed by site the hazard increased more steeply with increasing TTI for oral cavity cancer. For oropharyngeal and laryngeal cancer, a slight increase commenced after a longer TTI than for oral cavity cancer, while there was hardly an increase in hazard with increasing TTI for hypopharyngeal cancer., Conclusion: The relationship between longer TTI and decreased survival was confirmed, but slight variations in the pattern of the hazard of dying by TTI by tumour site were observed. These findings could support decisions on prioritizing treatment. However, other aspects such as extent of treatment and quality of life should be investigated further so this can also be included., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

(1) Background: Chemoradiotherapy (CRT) for head and neck cancer (HNC) is associated with severe toxicity resulting in fatigue and weight loss, including loss of skeletal muscle mass. Exercise interventions might positively affect physical fitness and quality of life. Sufficient adherence and compliance rates are necessary for optimal effects. This study aimed to gain insight into expectations and experiences and factors influencing adherence, retention and compliance of HNC patients participating in exercise intervention during CRT. (2) Methods: Consecutive participants were invited for semi-structured interviews, conducted pre- and post-intervention. A deductive approach was used to identify themes and factors influencing adherence, retention and compliance. (3) Results: Thematic saturation was reached after interviewing 14 patients pre-intervention. Five themes were identified: planning and time management, treatment toxicity, motivation to exercise, exercise intervention and supervision by a physiotherapist. The intensity of the treatment schedule and treatment toxicity were important barriers. Facilitators mentioned were physical and emotional benefits, social support as well as the simplicity and home-based setting of the intervention. (4) Conclusions: A personalised approach, considering the individual facilitators and barriers of HNC patients, is important to increase adherence, retention and compliance to exercise intervention and to reap the optimal effects of the program.

Objective: To investigate utilization of mental healthcare among head and neck cancer (HNC) patients from diagnosis to 2 years after treatment, in relation to psychological symptoms, mental disorders, need for mental healthcare, and sociodemographic, clinical and personal factors., Methods: Netherlands Quality of life and Biomedical Cohort study data as measured before treatment, at 3 and 6 months, and at 1 and 2 years after treatment was used (n = 610). Data on mental healthcare utilization (iMCQ), psychological symptoms (Hospital Anxiety and Depression Scale, Cancer Worry Scale), mental disorders (CIDI interview), need for mental healthcare (Supportive Care Needs Survey Short-Form 34, either as continuous outcome indicating the level of need or dichotomized into unmet need (yes/no)) and several sociodemographic, clinical and personal factors were collected. Factors associated with mental healthcare utilization were investigated using generalized estimating equations (p < 0.05)., Results: Of all HNC patients, 5%-9% used mental healthcare per timepoint. This was 4%-14% in patients with mild-severe psychological symptoms, 4%-17% in patients with severe psychological symptoms, 15%-35% in patients with a mental disorder and 5%-16% in patients with an unmet need for mental healthcare. Among all patients, higher symptoms of anxiety, a higher need for mental healthcare, lower age, higher disease stage, lower self-efficacy and higher social support seeking were significantly associated with mental healthcare utilization., Conclusion: Mental health care utilization among HNC patients is limited, and is related to psychological symptoms, need for mental healthcare, and sociodemographic, clinical and personal factors., (© 2023 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schaeffers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Early-stage glottic cancer can be treated with radiotherapy only. Modern radiotherapy solutions allow for individualized dose distributions, hypofractionation and sparing of organs at risk. The target volume used to be the entire voice box. This series describe the oncological outcome and toxicity of individualized vocal cord-only hypofractionated radiotherapy for early stage (cT1a-T2 N0)., Methods: Retrospective cohort study with patients treated in a single center between 2014 and 2020., Results: A total of 93 patients were included. Local control rate was 100% for cT1a, 97% for cT1b and 77% for cT2. Risk factor for local recurrence was smoking during radiotherapy. Laryngectomy-free survival was 90% at 5 years. Grade III or higher late toxicity was 3.7%., Conclusion: Vocal cord-only hypofractionated radiotherapy appears to be oncologically safe in early-stage glottic cancer. Modern, image-guided radiotherapy led to comparable results as historical series with very limited late toxicity., (© 2023. The Author(s).)

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas., Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation., Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC., Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation., Funding: This work was funded by Oncode PoC 2018-P0003., Competing Interests: Declaration of interests H.C.’s full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is inventor of several patents related to organoid technology, is a co-founder of Xilis, Inc., and is currently an employee of Roche, Basel. E.D. is inventor on a patent related to head and neck organoid technology. R.M. is currently an employee of Roche Products, Welwyn. S.M.W. holds unrestricted research grants from Bayer, Pfizer, Roche, MSD, Amgen, and AstraZeneca, all paid to the UMCG., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The projected increase in life expectancy over the next few decades is expected to result in a rise in age-related diseases, including cancer. Head and neck cancer (HNC) is a worldwide health problem with high rates of morbidity and mortality. In this report, we have critically reviewed the literature reporting the management of older patients with HNC. Older adults are more prone to complications and toxicities secondary to HNC treatment, especially those patients who are frail or have comorbidities. Thus, this population should be screened prior to treatment for such predispositions to maximize medical management of comorbidities. Chronologic age itself is not a reason for choosing less intensive treatment for older HNC patients. Whenever possible, also older patients should be treated according to the best standard of care, as nonstandard approaches may result in increased treatment failure rates and mortality. The treatment plan is best established by a multidisciplinary tumor board with shared decision-making with patients and family. Treatment modifications should be considered for those patients who have severe comorbidities, evidence of frailty (low performance status), or low performance status or those who refuse the recommendations of the tumor board., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: The adequate surgical margin for local control of buccal mucosa squamous cell carcinoma (BMSCC) is under debate. This study investigates surgical margins and other factors associated with local recurrence free survival (LRFS) in a large cohort of BMSCC patients., Methods: Multiple factors were evaluated retrospectively in 97 patients with BMSCC. Cox-regression and Kaplan-Meier curves were used for analysis., Results: The local recurrence rate was 23%. The tumor-free margin was <5.0 mm in 89% of the patients and the deep margin was significantly more often inadequate. Multivariate analysis associated pT3-classification, former smokers, tumor-free margin status, and postoperative (chemo)radiation (PO(ch)RT) with local recurrence. Re-resections did not improve LRFS in patients with <5.0 mm tumor-free margins., Conclusions: Adequate tumor-free margins are pivotal for LRFS of BMSCC. PO(ch)RT, not re-resection, can improve LRFS in patients with <5.0 mm tumor-free margins., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Image-guided surgery could help obtain clear (≥5.0 mm) resection margins. This feasibility study investigated ultrasound-guided resection accuracy of buccal mucosa squamous cell carcinoma (BMSCC)., Methods: MRI and ultrasound measurements of tumor thickness were compared to histology in 13 BMSCC-patients. Ultrasound measured margins (at five locations) on the specimen were compared to the corresponding histological margins., Results: Accuracy of in- and ex-vivo ultrasound (mean deviation from histology: 1.6 mm) for measuring tumor thickness was comparable to MRI (mean deviation from histology: 2.6 mm). The sensitivity to detect clear margins using ex-vivo ultrasound was low (48%). If an ex-vivo ultrasound cutoff of ≥7.5 mm would be used, the sensitivity would increase to 86%., Conclusions: Ultrasound-guided resection of BMSCC's is feasible. In- and ex-vivo ultrasound measure tumor thickness in BMSCC accurately. We recommend ≥7.5 mm resection margins on ex-vivo ultrasound to obtain histological clear margins. Additional research is required to establish the effect of 7.5 mm ultrasound cutoff., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: Chemoradiotherapy (CRT) for head and neck cancer (HNC) is associated with high toxicity that adversely affects physical functioning, body composition, fatigue, quality of life and treatment outcomes. Exercise interventions during treatment might counteract these negative effects. We therefore assessed the feasibility of an exercise programme for HNC patients during CRT., Methods: Forty patients were offered a tailored 10-week endurance and resistance training with supervised and home-based sessions. Feasibility endpoints were (1) adherence (main outcome): ≥60% attendance; (2) recruitment: ≥30%; (3) retention rate: ≥85% and (4) compliance rate: ≥60%. Physical performance, muscle strength, body composition, quality of life and fatigue were assessed pre- and post-intervention., Results: Overall adherence was 54%. The recruitment rate was 36%, and the retention rate was 65%. Compliance to the supervised intervention protocol was 66%. Statistically significant decreases were found in mean grip strength, fat-free mass and clinically relevant deteriorations on several domains of quality of life, and fatigue subscales were found., Conclusion: We conclude that this exercise programme for HNC patients during CRT in its current form is feasible for only a minority of patients. We suggest adaptations to improve adherence and retention rates for a definitive multicentre trial., Trial Registration: This study is registered at the Netherlands Trial Register (NTR7305), 6 June 2018, retrospectively registered., (© 2022 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

The aim of this meta-analysis was to determine the diagnostic test accuracy of sentinel lymph node biopsy (SLNB) in patients with oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma (SCC). For this purpose, MEDLINE, EMBASE, and Web of Science were searched from inception to March 8, 2022. Included were studies evaluating diagnostic test accuracy of SLNB to identify cervical lymph node metastases with elective neck dissection or follow-up as reference. A bivariate generalized linear mixed model approach was used for the meta-analysis. Nineteen studies were eligible, evaluating 377 cases in total. The pooled estimates of sensitivity and negative predictive value were 0.93 (95% CI: 0.86-0.96) and 0.97 (95% CI: 0.94-0.98), respectively. The excellent accuracy of SLNB justifies a place in the diagnostic workup of patients with larynx and pharynx SCC. Randomized trials are required to demonstrate oncologic safety and benefits on treatment related morbidity and quality of life when omitting elective neck treatment based on SLNB., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Background: Skeletal muscle mass (SMM) and chronic inflammation are associated with postoperative complications and survival., Methods: Patients with head and neck cancer (HNC) undergoing microvascular free flap reconstruction were included. SMM and neutrophil-to-lymphocyte ratio (NLR) were measured and their association with treatment outcomes analyzed., Results: Five hundred and fifty-four patients were included. Predictors for complications were elevated NLR in all flaps (OR 1.5), low SMM in radial forearm flap (OR 2.0), and elevated NLR combined with low SMM in fibula flap surgery (OR 4.3). Patients with solely elevated NLR were at risk for flap-related complications (OR 3.0), severe complications (OR 2.2), and when combined with low SMM for increased length of hospital stays (LOS) (+3.9 days). In early-stage HNC, low SMM (HR 2.3), and combined elevated NLR with low SMM (HR 2.6) were prognostics for decreased overall survival., Conclusions: SMM and NLR are predictive for poor outcomes in patients with HNC undergoing microvascular reconstruction., (© 2022 The Authors. Head & Neck published by Wiley Periodicals LLC.)

This study aimed to assess the prognostic value of intratumoral CD57+ cells in head and neck squamous cell carcinoma (HNSCC) and to examine the reproducibility of these analyses using QuPath. Pretreatment biopsies of 159 patients with HPV-negative, stage III/IV HNSCC treated with chemoradiotherapy were immunohistochemically stained for CD57. The number of CD57+ cells per mm 2 tumor epithelium was quantified by two independent observers and by QuPath, software for digital pathology image analysis. Concordance between the observers and QuPath was assessed by intraclass correlation coefficients (ICC). The correlation between CD57 and clinicopathological characteristics was assessed; associations with clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves. The patient cohort had a 3-year OS of 65.8% with a median follow-up of 54 months. The number of CD57+ cells/mm 2 tumor tissue did not correlate to OS, DFS, or LRC. N stage predicted prognosis (OS: HR 0.43, p = 0.008; DFS: HR 0.41, p = 0.003; LRC: HR 0.24, p = 0.007), as did WHO performance state (OS: HR 0.48, p = 0.028; LRC: 0.33, p = 0.039). Quantification by QuPath showed moderate to good concordance with two human observers (ICCs 0.836, CI 0.805-0.863, and 0.741, CI 0.692-0.783, respectively). In conclusion, the presence of CD57+ TILs did not correlate to prognosis in advanced stage, HPV-negative HNSCC patients treated with chemoradiotherapy. Substantial concordance between human observers and QuPath was found, confirming a promising future role for digital, algorithm driven image analysis., (© 2022. The Author(s).)

Purpose: Evidence suggests that patients' skeletal muscle mass (SMM) can predict the patients at risk for cisplatin dose-limiting toxicities (DLT). Cisplatin is currently dosed on body surface area (BSA). The predictive value of SMM for cisplatin DLT in patients with locally advanced head and neck cancer (LA-HNC) is investigated., Methods: Patients with LA-HNC treated with cisplatin-based chemoradiotherapy (CRT) were included. SMM was measured using pre-treatment scans. Logistic regression analysis was performed to identify the predictive impact of low SMM for DLT., Results: In total, 343 patients were included of which 199 patients (58.0%) had low SMM and 154 patients (44.9%) experienced cisplatin DLT. In multivariate analysis, low SMM at diagnosis was the only predictive factor for DLT (HR 1.8, 95% CI 1.1-2.9)., Conclusions: Low SMM was associated with an increased risk of DLT. Trials are needed to investigate cisplatin dosing with consideration of SMM rather than solely BSA., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The aim of this registry-based cohort study was to evaluate the potential role of endoscopic esophageal surveillance for esophageal second primary tumors (ESPTs) in Western patients with head and neck squamous cell carcinoma (HNSCC)., Methods: Outcomes were cumulative incidence and risk factors for ESPTs and its effect on overall survival., Results: A total of 47 ESPTs were observed in 1,708 patients with HNSCC, with 10-year cumulative incidence (95% confidence interval) of 2.9% (2.1-3.7). Alcohol and HNSCC location were significant predictors for ESPTs. ESPTs significantly increased the risk of dying (adjusted hazard ratio 3.36, 95% confidence interval 2.16-5.22)., Discussion: Endoscopic esophageal surveillance of Western patients with HNSCC with high risk of ESPTs seems justified., (Copyright © 2022 by The American College of Gastroenterology.)

Objective: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1α] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON)., Materials and Methods: Immunohistochemical staining was performed for HIF-1α and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1α expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker., Results: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1α and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1α expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR., Conclusion: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1α and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival., Material and Methods: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010-2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis., Results: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68-1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63-3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48-4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found., Conclusion: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions., (© 2022. The Author(s).)

Purpose of Review: The aim of this review is to discuss recent studies on the assessment of sarcopenia and its predictive and prognostic value in head and neck cancer (HNC) patients., Recent Findings: There is increasing evidence that low skeletal muscle mass (SMM), often named sarcopenia, can easily be assessed on cross-sectional imaging of the head and neck and is associated with chemotherapy (dose limiting) and radiotherapy toxicity and survival., Summary: SMM measurement at the level of the third cervical vertebra (C3) on routine computed tomography and magnetic resonance imaging is easy and robust to perform. Several studies have shown a significantly higher incidence of cisplatin dose limiting toxicity in HNC patients with a low SMM. In HNC patients pretreatment low SMM is associated with acute and late toxicity and adverse events of radiotherapy, complications of major head and neck surgery and decreased disease-specific and overall survival. This information can be used for individualized treatment planning in HNC patients with low SMM., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patients with head and neck cancer (HNC) are usually confronted with functional changes due to the malignancy itself or its treatment. These factors typically affect important structures involved in speech, breathing, chewing, swallowing, and saliva production. Consequently, the intake of food will be limited, which further contributes to loss of body weight and muscle mass, anorexia, malnutrition, fatigue, and anemia. This multifactorial condition can ultimately lead to cancer cachexia syndrome. This study aims to examine the treatment of cachexia in HNC patients., Methods: We systematically searched OvidMedline, PubMed, Scopus, and Web of Science for articles examining the treatment of cachexia in HNC., Results: A total of nine studies were found, and these suggested interventions including nutritional, pharmacologic, therapeutic exercise, and multimodal approaches. The nutritional intervention includes essential components such as dietary counseling, oral nutritional supplements, and medical nutritional support. Individualized nutritional interventions include oral, enteral (feeding tubes i.e., percutaneous endoscopic gastrostomy [PEG], nasogastric tube [NGT]) and parenteral nutrition. The pharmacologic interventions aim at increasing the appetite and weight of cachectic patients. Therapeutic exercise and increased physical activity can help to enhance the synthesis of muscle protein, reducing inflammation and the catabolic effects of cachexia syndrome., Conclusion: Owing to the multifactorial nature of this syndrome, it is expected that the management approach should be multi-interventional. Early implementation of these interventions may help to improve survival and quality of health and life of cachectic HNC patients., (© 2022. The Author(s).)

Objectives: This study analyzes the influence of the surgical setting, i.e. resection under local anesthesia versus resection under general anesthesia, on surgical margins in tumor resection of stage I and II oral squamous cell carcinoma (OSCC)., Materials and Methods: Retrospective study on tumor resections of stage I or II OSCC performed between 2014 and 2020. Potential predictors associated with surgical margins were identified. Multinomial logistic regression was used to analyze the effect of type of anesthesia on surgical margins, adjusted for potential predictors., Results: In total, 109 cases were included: 54 tumor resections were performed under local anesthesia and 55 under general anesthesia. Histopathological examination showed 19 clear surgical margins, 54 close surgical margins, and 36 positive surgical margins. Compared to resection under general anesthesia, resection under local anesthesia increased the risk of close margins (adjusted OR = 6.26; 95 %CI 1.66-23.58; p = .01) and positive margins (adjusted OR = 6.81; 95 %Cl 1.70-27.27; p = .01). Tumor resection of the floor of mouth, buccal mucosa, gingiva, retromolar trigone, hard palate, and soft palate had a higher risk of close and positive margins than tumor resection of the tongue. Tumor resection of the tongue under local anesthesia was associated with an increased risk of positive margins compared to resection under general anesthesia., Conclusion: Tumor resection under local anesthesia of stage I and II OSCC increases the risk of close and positive surgical margins compared to tumor resection under general anesthesia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inevitably, the emergence of COVID-19 has impacted non-COVID care. Because timely diagnosis and treatment are essential, especially for patients with head and neck cancer (HNC) with fast-growing tumours in a functionally and aesthetically important area, we wished to quantify the impact of the COVID-19 pandemic on HNC care in the Netherlands., Material and Methods: This population-based study covered all, in total 8468, newly diagnosed primary HNC cases in the Netherlands in 2018, 2019 and 2020. We compared incidence, patient and tumour characteristics, primary treatment characteristics, and time-to-treatment in the first COVID-19 year 2020 with corresponding periods in 2018 and 2019 (i.e. pre-COVID)., Results: The incidence of HNC was nearly 25% less during the first wave (n = 433) than in 2019 (n = 595) and 2018 (n = 598). In April and May 2020, the incidence of oral cavity and laryngeal carcinomas was significantly lower than in pre-COVID years. There were no shifts in tumour stage or alterations in initial treatment modalities. Regardless of the first treatment modality and specific period, the median number of days between first visit to a HNC centre and start of treatment was significantly shorter during the COVID-19 year (26-28 days) than pre-COVID (31-32 days, p < 0.001)., Conclusion: The incidence of HNC during the Netherlands' first COVID-19 wave was significantly lower than expected. The expected increase in incidence during the remainder of 2020 was not observed. Despite the overloaded healthcare system, the standard treatment for HNC patients could be delivered within a shorter time interval., Competing Interests: Conflict of interest None., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC., Methods: We performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m 2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity., Results: A total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p < 0.005). In a simulation, patients with a low SMM (<25.8 kg) were predicted to reach higher-bound cisplatin concentrations., Conclusion: We found an association between cisplatin pharmacokinetics and SMM; however, this relationship was also seen between cisplatin pharmacokinetics and other body composition descriptors., Competing Interests: Conflict of interest statement The authors Najiba Chargi, Laura Kuijsten-Molenaar, Laura F.J. Huiskamp, Lot A. Devriese, Remco de Bree and Alwin D.R. Huitema of the manuscript The association of cisplatin pharmacokinetics and skeletal muscle mass in head and neck cancer patients: the prospective PLATISMA study have no conflict of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess variations in nutritional interventions during chemoradiotherapy (CRT) among the Dutch Head and Neck Oncology centres (HNOCs)., Methods: An online questionnaire about nutritional interventions and dietetic practices was sent to 14 oncology dietitians of the HNOCs., Results: The response rate was 93%. The number of scheduled dietetic consultations varied from two to seven during CRT. Most centres (77%) reported using a gastrostomy for tube feeding in the majority of patients. Gastrostomies were placed prophylactically upon indication (39%) or in all patients (15%), reactive (15%), or both (31%). For calculating energy requirements, 54% of the dietitians used the Food and Agriculture Organization/World Health Organization and United Nations University (FAO/WHO/UNU) formula and 77% uses 1.2-1.5 g/kg body weight for calculating protein requirements. Almost half of the centres (46%) reported to remove the gastrostomy between 8 and 12 weeks after CR. Most centres (92%) reported to end dietary treatment within 6 months after CRT., Conclusion: This study shows substantial variation in dietetic practice, especially in the use of a gastrostomy for tube feeding, between the HNOCs. There is a need for concise dietetic guidelines., (© 2021 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Background & Aims: Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF ≥ 4 weeks and would benefit from prophylactic gastrostomy insertion., Methods: A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency ≥4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose-volume parameters were calculated., Results: The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency ≥4 weeks were 81.8% and 42.3% respectively., Conclusions: We developed and externally validated a prediction model to estimate TF-dependency ≥4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice., Competing Interests: Conflict of interest Anna C.H. Willemsen, Annemieke Kok, Jan Paul de Boer, Remco de Bree, Chantal M.L. Driessen, Johannes H.A.M. Kaanders, Rebecca T. Karsten, Sander M.J. van Kuijk, Roy I. Lalisang, Arash Navran, Susanne R. Pereboom, Annemie M.W.J. Schols, Chris H.J. Terhaard, and Ann Hoeben declare that they have no conflict of interest. Laura W.J. Baijens. Consulting or advisory role: Phagenesis Limited, member of the Independent FEES Review Committee for the PhINEST study. Lot A. Devriese. Consulting or advisory role: MSD, Bristol Myers Squibb. Frank J.P. Hoebers. Consulting or advisory role: Bristol Myers Squibb. Carla M.L. van Herpen. Consulting or advisory role: Bayer, Bristol Myers Squibb, MSD, Regeneron, TRK Fusion Cancer Medical. Research Funding: Astra Zeneca, Bristol Myers Squibb, MSD, Merck, Ipsen, Novartis, Sanofi, France., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Low skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose-limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings., Methods: Consecutive LA-HNSCC patients treated with primary CRT with high-dose cisplatin were retrospectively included. SMM was measured on pre-treatment CT-imaging. A cumulative cisplatin dose below 200 mg/m 2 was defined as CDLT., Results: One hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56-10.23], p = 0.01) and an eGFR of 60-70 ml/min (OR 5.40 [95% CI 1.57-18.65], p < 0.01) were predictors for CDLT., Conclusion: Pre-treatment low SMM is associated with CDLT in LA-HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization., (© 2021 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Introduction: In addition to classical endpoints such as survival and complication rates, other outcomes such as quality of life and functional status are increasingly recognized as important endpoints, especially for elderly patients. However, little is known about the long-term effect of surgery with regard to these other outcomes. Our aim is to investigate the functional status and self-reported health status of patients ≥ 70 years one year after surgery for head and neck cancer., Methods: We present one-year follow-up data of patients ≥ 70 year who underwent surgery for HNC. During an interview by telephone, functional status was evaluated by using the Katz-15 Index of Independence questionnaire including six items covering basic Activities of Daily Living (ADL) and nine items covering Instrumental Activities of Daily Living (IADL). Measurements were compared with those obtained preoperatively., Results: In total, 126 patients were included and eventually we collected follow-up data of 68 patients. There was a statistically significant decrease in functional status on the total Katz-15 and on the IADL questionnaire scores one year after surgery (mean 1.34 versus 2.42,p-value 0.00 and mean 1.21 versus 1.94,p-value 0.00). There was no significant change concerning ADL dependence (p-value 0.18) and cognitive status (p-value 0.11). The self-reported health status improved postoperatively, although not statistically significantly so (mean 67.36 versus 71.25,p-value 0.12)., Conclusion: Approximately-one year after surgery for HNC, there is a significant decline in functional status indicating a higher level of dependency., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The inherent variability in performing specific surgical procedures for head and neck cancer remains a barrier for accurately assessing treatment outcomes, particularly in clinical trials. While non-surgical modalities for cancer therapeutics have evolved to become far more uniform, there remains the challenge to standardize surgery. The purpose of this review is to identify the barriers in achieving uniformity and to highlight efforts by surgical groups to standardize selected operations and nomenclature. While further improvements in standardization will remain a challenge, we must encourage surgical groups to focus on strategies that provide such a level., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Approximately 70-80% of patients with cT1-2N0 oral squamous cell carcinoma (OSCC) ultimately prove to have no cancer in the cervical lymphatics on final pathology after selective neck dissection. As a result, sentinel lymph node biopsy (SLNB) has been adopted during the last decade as a diagnostic staging method to intelligently identify patients who would benefit from formal selective lymphadenectomy or neck irradiation. While not yet universally accepted, SLNB is now incorporated in many national guidelines. SLNB offers a less invasive alternative to elective neck dissection (END), and has some advantages and disadvantages. SLNB can assess the individual drainage pattern and, with step serial sectioning and immunohistochemistry (IHC), can enable the accurate detection of micrometastases and isolated tumor cells (ITCs). Staging of the neck is improved relative to END with routine histopathological examination. The improvements in staging are particularly notable for the contralateral neck and the pretreated neck. However, for floor of mouth (FOM) tumors, occult metastases are frequently missed by SLNB due to the proximity of activity from the primary site to the lymphatics (the shine through phenomenon). For FOM cancers, it is advised to perform either elective neck dissection or superselective neck dissection of the preglandular triangle of level I. New tracers and techniques under development may improve the diagnostic accuracy of SLNB for early-stage OSCC, particularly for FOM tumors. Treatment of the neck (either neck dissection or radiotherapy), although limited to levels I-IV, remains mandatory for any positive category of metastasis (macrometastasis, micrometastasis, or ITCs). Recently, the updated EANM practical guidelines for SLN localization in OSCC and the surgical consensus guidelines on SLNB in patients with OSCC were published. In this review, the current evidence and results of SLNB in early OSCC are presented., (© 2020. The Author(s).)

Objectives: Patients with head and neck cancer (HNC) have a risk of sarcopenia which is associated with adverse health outcomes. Frailty is also associated with adverse outcomes and is diagnosed by a comprehensive geriatric assessment (CGA). Because a CGA is time-consuming and not all patients benefit from it, frailty screening questionnaires are used to select patients for CGA. Sarcopenia measurement may be a biomarker for frailty. Our objective was to examine the association between sarcopenia and a frailty screening questionnaire., Materials and Methods: In this single-center retrospective study, 150 patients (≥ 60-years old) with HNC were reviewed. Sarcopenia was defined as the combination of reduced handgrip strength and loss of skeletal muscle mass, calculated as skeletal muscle index (SMI), according to the EWGSOP-criteria. Frailty screening was performed using the Geriatrics 8 (G8) questionnaire., Results: The 150 patients included 101 men and 49 women. Frail patients were more likely to be sarcopenic at diagnosis. G8 frailty score showed a significant though weak correlation with SMI. Univariate regression analysis with frailty as a dependent variable distinguished comorbidity score, handgrip strength, SMI, and sarcopenia as significant. These variables were subjected to a multivariate analysis in which comorbidity score and SMI remained significant., Conclusion: There is an association between sarcopenia and the G8 frailty screening questionnaire. Therefore, sarcopenia measurement could be interchangeable with the G8 frailty screening questionnaire. Further research should compare the gold standard for frailty, i.e. CGA, with sarcopenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hypoxia is a negative prognostic factor in head and neck squamous cell carcinomas. Under hypoxia, the hypoxia-inducible factor (HIF)-1a transcription factor is overexpressed. We investigated whether there were site differences in HIF-1a expression and its effect on patient outcomes per subsite., Design/method: A total of 941 patients with HNSCC in the squamous cell carcinoma of the oropharynx (OPSCC, n = 302), oral cavity (OSCC, n = 391), or larynx (LSCC, n = 248) were included. Expression of HIF-1a in tissue samples was investigated using immunohistochemistry. Overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) were analyzed., Results: HIF-1a expression was higher in OSCC than in LSCC and OPSCC. High HIF-1a expression led to worse prognosis in OPSCC (OS P = .029, DFS P = .085) and LSCC (OS P = .041, DFS P = .011) and better in OSCC (OS P = .055, DFS P = .012). There was no association between HIF-1a and LRC., Conclusions: High HIF-1a expression is related to poor outcome in OPSCC and LSCC and better outcome in OSCC., (© 2020 Wiley Periodicals LLC.)

Objectives: To assess (I) correlations between diffusion-weighted (DWI), intravoxel incoherent motion (IVIM), dynamic contrast-enhanced (DCE) MRI, and 18 F-FDG-PET/CT imaging parameters capturing tumor characteristics and (II) their predictive value of locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy., Methods: Between 2014 and 2018, patients with histopathologically proven HNSCC, planned for curative (chemo) radiotherapy, were prospectively included. Pretreatment clinical, anatomical, and functional imaging parameters (obtained by DWI/IVIM, DCE-MRI, and 18 F-FDG-PET/CT) were extracted for primary tumors (PT) and lymph node metastases. Correlations and differences between parameters were assessed. The predictive value of LRFS and OS was assessed, performing univariable, multivariable Cox and CoxBoost regression analyses., Results: In total, 70 patients were included. Significant correlations between 18 F-FDG-PET parameters and DWI-/DCE volume parameters were found (r > 0.442, p < 0.002). The combination of HPV (HR = 0.903), intoxications (HR = 1.065), PT ADC GTV (HR = 1.252), K trans (HR = 1.223), and V e (HR = 1.215) was predictive for LRFS (C-index = 0.546; p = 0.023). N-stage (HR = 1.058), HPV positivity (HR = 0.886), hypopharyngeal tumor location (HR = 1.111), ADC GTV (HR = 1.102), ADC mean (HR = 1.137), D* (HR = 0.862), K trans (HR = 1.106), V e (HR = 1.195), SUV max (HR = 1.094), and TLG (HR = 1.433) were predictive for OS (C-index = 0.664; p = 0.046)., Conclusions: Functional imaging parameters, performing DWI/IVIM, DCE-MRI, and 18 F-FDG-PET/CT, yielded complementary value in capturing tumor characteristics. More specific, intoxications, HPV-negative status, large tumor volume-related parameters, high permeability (K trans ), and high extravascular extracellular space (V e ) parameters were predictive for adverse locoregional recurrence-free survival and adverse overall survival. Low cellularity (high ADC) and high metabolism (high SUV) were additionally predictive for decreased overall survival. These different predictive factors added to estimated locoregional and overall survival., Key Points: • Parameters of DWI/IVIM, DCE-MRI, and 18F-FDG-PET/CT were able to capture complementary tumor characteristics. • Multivariable analysis revealed that intoxications, HPV negativity, large tumor volume and high vascular permeability (K trans ), and extravascular extracellular space (Ve) were complementary predictive for locoregional recurrence. • In addition to predictive parameters for locoregional recurrence, also high cellularity (low ADC) and high metabolism (high SUV) were complementary predictive for overall survival.

Purpose: The emerge of improved personalized treatment adaptations and outcome prediction is accompanied with increasing non-invasive assessments in early treatment phase, leading to increased patient burden. This study assessed the adherence of patients with head and neck squamous cell carcinoma (HNSCC) to undergo pretreatment and research-related intratreatment imaging, and assessed which factors caused drop-out., Method: Between 2013 and 2019, advanced-staged HNSCC patients were prospectively included, underwent (chemo) radiotherapy with curative intent and planned for both pre-treatment and intratreatment sequential 18F-FDG-PET/CT, 18F-FDG-PET/MRI and thereafter MRI (including DWI/DCE). Drop-out-factors were described as healthcare-related (logistics and imaging-system defects) and patient-related (psychological, physical, not-specified). Common Toxicity Criteria (CTC) were routinely scored by radiation/medical oncologists throughout the first 3 weeks, and compared between patient drop-outs and who complete imaging., Results: Ninety-seven patients (mean age 61 ± 6.8 years) were included; 95 patients (97.9%) underwent pretreatment imaging and 63 (64.9%) intratreatment imaging. For 18F-FDG-PET/CT, 18F-FDG-PET/MRI and MRI pretreatment drop-outs were 2, 10 and 3 patients and for intratreatment drop-outs were 34, 39 and 35 patients, respectively. Patient-related drop-out-factors were physical (n = 16, e.g. dysphagia), psychological (n = 6, e.g. claustrophobia) and non-specified (n = 12). Healthcare-related drop-out-factors were logistics (n = 6) and 18F-FDG-PET/CT-/MRI-system defects (n = 2). The CTC mucosal toxicity was significantly higher (p = 0.023) at week 2 of (chemo)radiotherapy in patient drop-outs than with complete imaging., Conclusions: The drop-out frequency of advanced-staged HNSCC patients for imaging during (chemo)radiotherapy in a research-setting was high and mainly patient-related. Treatment of patient-related inconveniences, communication of rationale and healthcare-related imaging protocol efficiency improvements may contribute to improved adherence., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer., Materials and Methods: Native T1-weighted images of four independent, retrospective (2005-2013), patient cohorts (n = 102, n = 76, n = 89, and n = 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC)., Results: In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (p < 0.001)., Conclusions: MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters., Key Points: • MRI radiomics can predict overall survival and relapse-free survival in oral and HPV-negative oropharyngeal cancer. • MRI radiomics provides additional prognostic information to known clinical variables, with the best performance of the combined models. • Variation in MRI vendors and acquisition protocols did not influence performance of radiomic prognostic models.

Objective: To evaluate the potential role of head and neck oncologic surgeons in environmental protection, sustainability of health-care systems and avoidance of procedures contributing to climate change in the future., Review Methods: This literature review searched for relevant literature about the relevance of waste in surgical head and neck oncology practice and the innovative alternatives to decrease its effect on environment., Conclusions: Head and neck oncologic surgeons have a role in environmental protection, sustainability of health-care systems and avoidance of procedures contributing to climate change in the future. However, there exist only limited data on waste management and other procedures in surgical oncology to promote these practices., Implications for Practice: By increasing awareness of the corresponding issues of waste production within the healthcare environment, head and neck surgeons can have a pioneering role in considering how to reduce, recycle and reuse in a more efficient manner. As research in this field accumulates, healthcare providers can engage both managers and clinicians in this process. It remains imperative to provide these professionals opportunities for their work force to rethink current practices in a manner that prioritizes environmentally sustainable head and neck surgical practices., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Treatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC., Methods: After histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990-2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model., Results: Sixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1-70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33-72 vs 12%, IQR 1-70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04)., Conclusion: CXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine factors associated with local recurrence (LR) of oral squamous cell carcinoma involving the maxillae (MSCC) and overall survival (OS) after salvage treatment., Subjects and Methods: Retrospective study of MSCC operated between 2000 and 2015. Kaplan-Meier survival and Cox regression were used for analysis of MSCC-associated clinical and histopathological factors., Results: Ninety-five patients were included. LR occurred in 24% of patients. Vascular invasion significantly increased the risk of LR (hazard ratio 4.595, P = .003). Local salvage surgery, in the area of the original tumor, significantly prolonged OS, compared to palliative treatment (P = .001) and extensive salvage surgery (P = .013). Extensive salvage surgery, requiring resection of adjacent facial structures, did not prolong OS compared to palliative treatment (P = .186)., Conclusions: MSCC with vascular invasion has higher risk of LR. Salvage surgery may prolong OS in small recurrences but might have dubious value for larger recurrences infiltrating adjacent facial structures., (© 2020 The Authors. Head & Neck published by Wiley Periodicals, Inc.)

Background & Aims: Chemoradiation and bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often comes with high toxicity rates, interfering with oral intake and leading to temporary tube feeding (TF) dependency. High-quality scientific evidence for indicators of prophylactic gastrostomy insertion is not available. The aim of this retrospective cohort study was to develop a prediction model to identify patients who need prophylactic gastrostomy insertion, defined as the expected use of TF for at least four weeks., Methods: Four-hundred-fifty LAHNSCC patients receiving CRT/BRT with curative intent between 2013 and 2016 were included in the study. Primary outcome was TF-dependency for four weeks or longer. Patient, tumor, and treatment characteristics were extracted from the medical records and their effects on the use of TF were analyzed using univariable and multivariable analysis. The prediction model was internally validated using bootstrapping techniques., Results: Sixty-five percent (294/450 patients) required TF for four weeks or longer. Variables included in the model were: body mass index and adjusted diet at start of CRT/BRT, percentage weight change at baseline, World Health Organization performance status, tumor subsite, TNM-classification, CRT/BRT, mean radiation dose on the contralateral submandibular and parotid gland. The corrected Area Under the Curve after internal validation was 72.3%, indicating good discriminative properties of the prediction model., Conclusions: We developed and internally validated a prediction model that is intended to estimate TF-dependency for at least four weeks in LAHNSCC patients treated with CRT/BRT. This model can be used as a tool to support personalized decision making on prophylactic gastrostomy insertion., Competing Interests: Conflict of Interest None declared., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Treatment options for advanced head and neck adenoid cystic carcinoma (AdCC) are limited. Prostate-Specific Membrane Antigen (PSMA), a transmembrane protein that is known for its use in diagnostics and targeted therapy in prostate cancer, is also expressed by AdCC. This study aimed to analyse PSMA expression in a large cohort of primary, recurrent and metastasized AdCC of the head and neck., Methods: One hundred ten consecutive patients with histologically confirmed AdCC in the period 1990-2017 were included. An analysis was made of clinical details, revised pathology and semiquantitative immunohistochemical expression of PSMA on tissue microarray and whole slides. Associations of PSMA expression with clinicopathological parameters were explored and survival was analysed by multivariate Cox-proportional Hazard analysis., Results: PSMA expression was present in 94% of the 110 primary tumours, with a median of 31% positive cells (IQR 15-60%). Primary tumours (n = 18) that recurred (n = 15) and/or had metastases (n = 10) demonstrated 40, 60 and 23% expression respectively. Expression was not independently related to increased pathological stage, tumour grade, and the occurrence of locoregional recurrence or metastasis. After dichotomization, only primary tumour PSMA expression ≤10% appeared to be associated with reduced 10-years recurrence-free survival (HR 3.0, 95% CI 1.1-8.5, p = .04)., Conclusions: PSMA is highly expressed in primary, recurrent and metastatic AdCC of the salivary and seromucous glands. PSMA expression has no value in predicting clinical behaviour of AdCC although low expression may indicate a reduced recurrence-free survival. This study provides supporting results to consider using PSMA as target for imaging and therapy when other diagnostic and palliative treatment options fail.

Background: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed., Methods: SUV body weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127)., Results: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV 70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV 50 /SUV liver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV 70 and SUV 50 /SUV liver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV 70  = 0.93, SUV 50 /SUV liver  = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant)., Conclusion: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV 70 threshold 2.2) prove robust, yet ratios (SUV 50 /SUV liver , threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria., Trial Registration: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.

Aim: This study aimed to evaluate the presence and prognostic value of tumor-infiltrating T cells in the tumor epithelium in advanced stage, HPV-negative head and neck squamous cell carcinoma (HNSCC) patients treated with primary chemoradiotherapy using digital pathology., Methods: Pre-treatment biopsies from 80 oropharyngeal, 52 hypopharyngeal, and 29 laryngeal cancer patients were collected in a tissue microarray (TMA) and immunohistochemically stained for T-cell markers CD3, CD4, CD8, FoxP3, and PD1, and for immune checkpoint PD-L1. For each marker, the number of positive tumor-infiltrating lymphocytes (TILs) per mm 2 tumor epithelium was digitally quantified and correlated to overall survival (OS), disease-free survival (DFS), and locoregional control (LRC), as well as to clinicopathological characteristics. Differences in clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan-Meier curves., Results: The patient cohort had a 3-year OS of 58%, with a median follow-up of 53 months. None of the T-cell markers showed a correlation with OS, DFS or LRC. A low N stage was correlated to a better prognosis (OS: HR 0.39, p = 0.0028, DFS: HR 0.34, p =  < 0.001, LRC: HR 0.24, p = 0.008). High TIL counts were more often observed in PD-L1-positive tumors (p < 0.05)., Conclusion: This study showed an objective, digital pathology-aided method to assess TILs in the tumor epithelium. However, it did not provide evidence for a prognostic role of the presence of CD3 + , CD4 + , CD8 + , FoxP3 + , and PD1 + TILs in the tumor epithelium of advanced stage, HPV-negative HNSCC patients treated with primary chemoradiotherapy.

Background: The optimal evidence-based prophylactic antibiotic regimen for surgical site infections following major head and neck surgery remains a matter of debate., Methods: Medline, Cochrane, and Embase were searched for the current best evidence. Retrieved manuscripts were screened according to the PRISMA guidelines. Included studies dealt with patients over 18 years of age that underwent clean-contaminated head and neck surgery (P) and compared the effect of an intervention, perioperative administration of different antibiotic regimens for a variable duration (I), with control groups receiving placebo, another antibiotic regimen, or the same antibiotic for a different postoperative duration (C), on surgical site infection rate as primary outcome (O) (PICO model). A systematic review was performed, and a selected group of trials investigating a similar research question was subjected to a random-effects model meta-analysis., Results: Thirty-nine studies were included in the systematic review. Compared with placebo, cefazolin, ampicillin-sulbactam, and amoxicillin-clavulanate were the most efficient agents. Benzylpenicillin and clindamycin were clearly less effective. Fifteen studies compared short- to long-term prophylaxis; treatment for more than 48 h did not further reduce wound infections. Meta-analysis of five clinical trials including 4336 patients, where clindamycin was compared with ampicillin-sulbactam, implied an increased infection rate for clindamycin-treated patients (OR = 2.73, 95% CI 1.50-4.97, p = 0.001)., Conclusion: In clean-contaminated head and neck surgery, cefazolin, amoxicillin-clavulanate, and ampicillin-sulbactam for 24-48 h after surgery were associated with the highest prevention rate of surgical site infection.

Purpose of Review: Electrochemotherapy (ECT) is increasingly used in different settings in head and neck cancer patients when conventional treatment options are not available., Recent Findings: Recent improvements of electroporation and ECT include new advanced electrode probes, the combination with intratumorally injected supraphysiological doses of calcium and an update of the standard operating procedures., Summary: ECT is a treatment modality that combines administration of a chemotherapeutic drug, for example, bleomycin, with electroporation therapy (EPT). EPT uses brief, high-intensity, pulsed electrical currents to enhance the uptake of cytotoxic drugs by producing a transient increase in cell wall permeability. ECT increases the effect of cytostatic drugs, is independent on histology of the lesion, enables treatment to previously treated areas, preserves healthy tissue, has no significant side effects (low-dose chemotherapy) and enables repeated treatments. ECT can be combined with other treatment modalities and is an addition to the current treatment options of head and neck cancer. ECT is not only able to palliate symptoms but can also provide complete responses and curation.

Background: Second primary tumors (SPTs) are a common cause of reduced life expectancy in patients treated for head and neck cancer (HNC). This phenomenon forms an area to be addressed during posttreatment follow-up., Methods: We conducted a systematic review of literature following PRISMA guidelines, from 1979 to 2019, to investigate incidence of SPTs, synchronous, and metachronous, in HNC population., Results: Our review includes data of 456 130 patients from 61 articles. With a minimum follow-up of 22 months, mean incidence of SPTs was 13.2% (95% CI: 11.56-14.84): 5.3% (95% CI: 4.24-6.36) for synchronous SPTs and 9.4% (95% CI: 7.9-10.9) for metachronous SPTs. The most frequent site for SPTs was head and neck area, followed by the lungs and esophagus., Conclusion: Although with wide variations between studies, the rate of SPTs in HNC patients is high. Given the impact in the prognosis, we must develop strategies for the early diagnosis of SPTs., (© 2019 Wiley Periodicals, Inc.)

Objectives: Pretreatment identification of radio-insensitive head and neck squamous cell carcinomas (HNSCC) would affect treatment modality selection. The apparent diffusion coefficient (ADC) of a tumor could be a predictor of local recurrence. However, little is known about its prognostic value next to known factors such as clinical T-stage. The aim of the present study is to determine the added value of pretreatment ADC to clinical T-stage as a prognostic factor for local recurrence., Methods: This retrospective cohort study included 217 patients with HNSCC treated with (chemo)radiotherapy between April 2009 and December 2015. All patients underwent diffusion-weighted MRI prior to treatment. Median ADC values of all tumors were obtained using a semi-automatic delineation method. Univariate models containing ADC and T-stage were compared with a multivariable model containing both variables., Results: Fifty-eight patients experienced a local recurrence within 3 years. On average, the ADC value in the group of patients with a recurrence was 1.01 versus 1.00 (10 -3  mm 2 /s) in the group without a recurrence. Univariate analysis showed no significant association between tumor ADC and local recurrence within 3 years after (chemo)radiotherapy (p = 0.09). Cox regression showed that clinical T-stage was an independent predictor of local recurrence and adding ADC to the model did not increase its performance., Conclusion: Pretreatment ADC has no added value as a prognostic factor for local recurrence to clinical T-stage., Key Points: • Pretreatment identification of head and neck squamous cell carcinoma patients who do not benefit from (chemo)radiotherapy could improve personalized cancer care. • The apparent diffusion coefficient (ADC) obtained from diffusion-weighted MRI has been reported to be a prognostic factor for local recurrence. • In this study, ADC has no added value as a prognostic factor compared with clinical T-stage.

Purpose: Stepped care (SC), consisting of watchful waiting, guided self-help, problem-solving therapy, and psychotherapy/medication is, compared to care-as-usual (CAU), effective in improving psychological distress. This study presents secondary analyses on subgroups of patients who might specifically benefit from watchful waiting, guided self-help, or the entire SC program., Methods: In this randomized controlled trial, head and neck and lung cancer patients with distress (n = 156) were randomized to SC or CAU. Univariate logistic regression analyses were performed to investigate baseline factors associated with recovery after watchful waiting and guided self-help. Potential moderators of the effectiveness of SC compared to CAU were investigated using linear mixed models., Results: Patients without a psychiatric disorder, with better psychological outcomes (HADS: all scales) and better health-related quality of life (HRQOL) (EORTC QLQ-C30/H&N35: global QOL, all functioning, and several symptom domains) were more likely to recover after watchful waiting. Patients with better scores on distress, emotional functioning, and dyspnea were more likely to recover after guided self-help. Sex, time since treatment, anxiety or depressive disorder diagnosis, symptoms of anxiety, symptoms of depression, speech problems, and feeling ill at baseline moderated the efficacy of SC compared to CAU., Conclusions: Patients with distress but who are relatively doing well otherwise, benefit most from watchful waiting and guided self-help. The entire SC program is more effective in women, patients in the first year after treatment, patients with a higher level of distress or anxiety or depressive disorder, patients who are feeling ill, and patients with less speech problems., Trial: NTR1868.