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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. [ABSTRACT FROM AUTHOR]

Simple Summary: Many head and neck cancer patients report sexual problems. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. This effect seems to differ between men and women. Men reported change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction, while women reported change in desire, arousal, and orgasm. These findings are helpful to improve information on sexuality and sexual care in head and neck cancer patients. The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women. [ABSTRACT FROM AUTHOR]

Objective: Head and neck cancer care is highly complex, and multidisciplinary team meetings (MDTs) are vital for improved outcomes. In the Netherlands, head and neck cancer care is practiced in eight high-volume head and neck oncologic centers (HNOC) and six affiliated hospitals preferred partner (PP) centers. Patients treated in the PP are presented and discussed in the HNOC. To evaluate the importance of these mandatory and decisive steps in decision making, we have assessed the changes in treatment. Materials and methods: Retrospective evaluation of head and neck cancer patients referred between January 2011 and October 2018 for a MDT evaluation to the HNOC was conducted. The differences in MDT recommendation were classified with regards to major and minor changes. Results: Management recommendation(MR) changed after 113 of 515 MDT discussions within the PP (487 patients; 22%), of which 86 cases (16%) were major changes. In 67 cases (59.3%), escalation of management was recommended, while in 43 cases (38.1%) de-escalation was recommended. Conclusion: There was a high rate of change of MRs, when comparing the PP recommendations with the HNOC recommendations. Since patient and tumor characteristics seem unable to predict these changes, we recommend all patients be seen for a clinical presentation, revision of diagnostics, and MDT discussion in a high volume HNOC. [ABSTRACT FROM AUTHOR]

Background:. At present, the prognostic prediction in advanced oral cavity squamous cell carcinoma (OCSCC) is based on the tumor-node-metastasis (TNM) staging system, and the most used imaging modality in these patients is magnetic resonance image (MRI). With the aim to improve the prediction, we developed an MRI-based radiomic signature as a prognostic marker for overall survival (OS) in OCSCC patients and compared it with published gene expression signatures for prognosis of OS in head and neck cancer patients, replicated herein on our OCSCC dataset. Methods: For each patient, 1072 radiomic features were extracted from T1 and T2-weighted MRI (T1w and T2w). Features selection was performed, and an optimal set of five of them was used to fit a Cox proportional hazard regression model for OS. The radiomic signature was developed on a multi-centric locally advanced OCSCC retrospective dataset (n = 123) and validated on a prospective cohort (n = 108). Results: The performance of the signature was evaluated in terms of C-index (0.68 (IQR 0.66–0.70)), hazard ratio (HR 2.64 (95% CI 1.62–4.31)), and high/low risk group stratification (log-rank p < 0.001, Kaplan-Meier curves). When tested on a multi-centric prospective cohort (n = 108), the signature had a C-index of 0.62 (IQR 0.58–0.64) and outperformed the clinical and pathologic TNM stage and six out of seven gene expression prognostic signatures. In addition, the significant difference of the radiomic signature between stages III and IVa/b in patients receiving surgery suggests a potential association of MRI features with the pathologic stage. Conclusions: Overall, the present study suggests that MRI signatures, containing non-invasive and cost-effective remarkable information, could be exploited as prognostic tools. [ABSTRACT FROM AUTHOR]

Simple Summary: Social eating problems may affect lives of people with head and neck cancer (HNC) during and after (chemo)radiotherapy treatment. This study aimed at investigating if people with HNC experience social eating problems from diagnosis up to 24 months after (chemo)radiotherapy and if their change over time is associated with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. We found that social eating problems worsened three months after treatment and improved to baseline levels up to 24 months. The change in social eating problems over time was associated with swallowing, nutritional status, tumor subsite, age, muscle strength, hearing problems, and depressive symptoms. Results are relevant to research and clinical practice for improving personalized supportive care targeting social eating problems. This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6–24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients' features. [ABSTRACT FROM AUTHOR]

Purpose: Mucoepidermoid carcinoma (MEC) of the head and neck is a prevalent malignant salivary gland tumour with a reported good outcome. The aim of this study was to report the outcome in our centre. Methods: A retrospective chart analysis with survival analyses was performed combined with fluorescence in situ hybridization (FISH) analysis to assess CRTC1/3 MAML 2 fusion gene presence. Results: Sixty-four cases of MEC were identified. Median age at presentation was 51.4 years with a predominance for parotid gland involvement. Five, 10- and 20- year disease-free survival was 98%, 90% and 68%, respectively. Overall survival was 94%, 90% and 64%, respectively. Local recurrence was seen up to 14 years after primary diagnosis; distant metastases were diagnosed up to 17 years later. The overall recurrence rate was less than 20 per cent. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit. Conclusion: MEC of the head and neck has a favorable outcome with the exception of high-grade MEC. PNI and nodal involvement are not rare. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit. The tendency for late onset of loco-regional and distant recurrence should not be underestimated. [ABSTRACT FROM AUTHOR]

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients. Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses. Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs. Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: This study assessed the course of fear of cancer recurrence (FCR) in patients newly diagnosed with head and neck cancer (HNC), identified FCR trajectories and factors associated with FCR trajectories. Methods: Six hundred and seventeen HNC patients from the NET‐QUBIC cohort study completed the Cancer Worry Scale‐6 at diagnosis, 3 and 6 months post‐treatment. FCR trajectories were identified using Latent Class Growth Analysis. Associations were explored between FCR trajectories and baseline demographic and medical variables, coping and self‐efficacy. Results: Overall, FCR decreased slightly between baseline and 3 months post‐treatment and remained stable up to 6 months. Two FCR trajectories were identified: "high stable" (n = 125) and "low declining" (n = 492). Patients with high stable FCR were younger, reported more negative adjustment, passive coping, and reassuring thoughts, and less avoidance. Conclusions: The majority of HNC patients have low declining FCR after diagnosis, but one in five patients experience persistent high FCR up to 6 months post‐treatment. [ABSTRACT FROM AUTHOR]

Background: Longitudinal observational cohort studies in cancer patients are important to move research and clinical practice forward. Continued study participation (study retention) is of importance to maintain the statistical power of research and facilitate representativeness of study findings. This study aimed to investigate study retention and attrition (drop-out) and its associated sociodemographic and clinical factors among head and neck cancer (HNC) patients and informal caregivers included in the Netherlands Quality of Life and Biomedical Cohort Study (NET-QUBIC).Methods: NET-QUBIC is a longitudinal cohort study among 739 HNC patients and 262 informal caregivers with collection of patient-reported outcome measures (PROMs), fieldwork data (interview, objective tests and medical examination) and biobank materials. Study retention and attrition was described from baseline (before treatment) up to 2-years follow-up (after treatment). Sociodemographic and clinical characteristics associated with retention in NET-QUBIC components at baseline (PROMs, fieldwork and biobank samples) and retention in general (participation in at least one component) were investigated using Chi-square, Fisher exact or independent t-tests (p< 0.05).Results: Study retention at 2-years follow-up was 80% among patients alive (66% among all patients) and 70% among caregivers of patients who were alive and participating (52% among all caregivers). Attrition was most often caused by mortality, and logistic, physical, or psychological-related reasons. Tumor stage I/II, better physical performance and better (lower) comorbidity score were associated with participation in the PROMs component among patients. No factors associated with participation in the fieldwork component (patients), overall sample collection (patients and caregivers) or PROMs component (caregivers) were identified. A better performance and comorbidity score (among patients) and higher age (among caregivers) were associated with study retention at 2-years follow-up.Conclusions: Retention rates were high at two years follow-up (i.e. 80% among HNC patients alive and 70% among informal caregivers with an active patient). Nevertheless, some selection was shown in terms of tumor stage, physical performance, comorbidity and age, which might limit representativeness of NET-QUBIC data and samples. To facilitate representativeness of study findings future cohort studies might benefit from oversampling specific subgroups, such as patients with poor clinical outcomes or higher comorbidity and younger caregivers. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune checkpoint inhibitors (ICI) has improved treatment outcomes in many cancer types and has focused attention on cancer immunity and the role of the tumor microenvironment (TME). Studies into efficacy of immunotherapy and TME are generally restricted to tumors in one anatomical location, while the histological type may have substantial influence on the contexture of the TME, perhaps more so than anatomical location, and subsequently to the response to immunotherapy. This review aims to focus on the TME in ICI‐treated tumors of the same histological type, namely carcinogen‐induced squamous cell carcinoma developing within the aerodigestive tract, at three locations, i.e. head and neck (HNSCC), esophagus (ESCC) and lung (LUSC). [ABSTRACT FROM AUTHOR]

Purpose: Before and after treatment for head and neck cancer (HNC), many patients have problems with mastication, swallowing, and salivary flow. The aim of this study was to investigate the association between objective test outcomes of mastication, swallowing, and salivary flow versus patient-reported outcomes (PROs) measuring mastication-, swallowing-, and salivary flow–related quality of life. Methods: Data of the prospective cohort "Netherlands Quality of Life and Biomedical Cohort Study" was used as collected before treatment, and 3 and 6 months after treatment. Spearman's rho was used to test the association between objective test outcomes of the mixing ability test (MAT) for masticatory performance, the water-swallowing test (WST) for swallowing performance, and the salivary flow test versus PROs (subscales of the EORTC QLQ-H&N35, Swallow Quality of Life questionnaire (SWAL-QoL-NL) and Groningen Radiation-Induced Xerostomia (GRIX)). Results: Data of 142 patients were used, and in total, 285 measurements were performed. No significant correlations were found between the MAT or WST and subscales of the EORTC QLQ-H&N35. Significant but weak correlations were found between the MAT or WST and 4 subscales of the SWAL-QoL-NL. Weak to moderate correlations were found between the salivary flow test and GRIX at 3 and 6 months after treatment, with the highest correlation between salivary flow and xerostomia during the day (Spearman's rho = − 0.441, p = 0.001). Conclusion: The association between objective test outcomes and PROs is weak, indicating that these outcome measures provide different information about masticatory performance, swallowing, and salivary flow in patients with HNC. [ABSTRACT FROM AUTHOR]

PURPOSE: Under common therapeutic regimens, the prognosis of human papillomavirus (HPV)–positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models. METHODS: Patients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model. RESULTS: The study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster (P =.00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster. CONCLUSION: The rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this pretest–posttest study was to investigate the reach and effects of My Changed Body (MyCB), an expressive writing activity based on self-compassion, among head and neck cancer (HNC) survivors. Methods: This pilot study had a pretest–posttest design. HNC survivors received an invitation to complete a baseline survey on body image-related distress. At the end of the survey, HNC survivors were asked if they were interested in the intervention study. This entailed the writing activity and a survey 1 week and 1 month post-intervention. The reach was calculated by dividing the number of participants in the intervention study, by the number of (1) eligible HNC survivors and (2) those who filled in the baseline survey. Linear mixed models were used to analyze the effect on body image-related distress. Logistic regression analysis was used to investigate factors associated with the reach and reduced body image-related distress. MyCB was evaluated using study-specific questions. Results: The reach of MyCB was 15–33% (depending on reference group) and was associated with lower education level, more social eating problems, and fewer wound healing problems. Among the 87 participants, 9 (10%) showed a clinically relevant improvement in body image-related distress. No significant effect on body image-related distress was found. Self-compassion improved significantly during follow-up until 1 month post-intervention (p=0.003). Users rated satisfaction with MyCB as 7.2/10. Conclusion: MyCB does not significantly improve body image-related distress, but is likely to increase self-compassion, which sustains for at least 1 month. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) patients often suffer from distress attributed to their cancer diagnosis which may disturb their sleep. However, there is lack of research about poor sleep quality among newly diagnosed HNC patients. Therefore, our aim was to investigate the prevalence and the associated factors of poor sleep quality among HNC patients before starting treatment.Materials and Methods: A cross-sectional study was conducted using the baseline data from NET-QUBIC study, an ongoing multi-center cohort of HNC patients in the Netherlands. Poor sleep quality was defined as a Pittsburgh Sleep Quality Index (PSQI) total score of > 5. Risk factors examined were sociodemographic factors (age, sex, education level, living situation), clinical characteristics (HNC subsite, tumor stage, comorbidity, performance status), lifestyle factors, coping styles, and HNC symptoms.Results: Among 560 HNC patients, 246 (44%) had poor sleep quality before start of treatment. Several factors were found to be significantly associated with poor sleep: younger age (odds ratio [OR] for each additional year 0.98, 95% CI 0.96-1.00), being female (OR 2.6, 95% CI 1.7-4.1), higher passive coping style (OR 1.18, 95% CI 1.09-1.28), more oral pain (OR 1.10, 95% CI 1.01-1.19), and less sexual interest and enjoyment (OR 1.13, 95% CI 1.06-1.20).Conclusion: Poor sleep quality is highly prevalent among HNC patients before start of treatment. Early evaluation and tailored intervention to improve sleep quality are necessary to prepare these patients for HNC treatment and its consequences. [ABSTRACT FROM AUTHOR]

Purpose: To develop a European White Paper document on oropharyngeal dysphagia (OD) in head and neck cancer (HNC). There are wide variations in the management of OD associated with HNC across Europe. Methods: Experts in the management of specific aspects of OD in HNC across Europe were delegated by their professional medical and multidisciplinary societies to contribute to this document. Evidence is based on systematic reviews, consensus-based position statements, and expert opinion. Results: Twenty-four sections on HNC-specific OD topics. Conclusion: This European White Paper summarizes current best practice on management of OD in HNC, providing recommendations to support patients and health professionals. The body of literature and its level of evidence on diagnostics and treatment for OD in HNC remain poor. This is in the context of an expected increase in the prevalence of OD due to HNC in the near future. Contributing factors to increased prevalence include aging of our European population (including HNC patients) and an increase in human papillomavirus (HPV) related cancer, despite the introduction of HPV vaccination in various countries. We recommend timely implementation of OD screening in HNC patients while emphasizing the need for robust scientific research on the treatment of OD in HNC. Meanwhile, its management remains a challenge for European professional associations and policymakers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 mm2 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. [ABSTRACT FROM AUTHOR]

Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8+ T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8+T-cells: HR = 2.2, p < 0.05; CD8+T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8+ T-cell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Concurrent chemoradiation (CRT) with high-dose cisplatin is associated with significant acute and late toxicities, including acute kidney injury (AKI). The aims of this study were to investigate the incidence of AKI in patients with LA-SCCHN during and after treatment with high-dose cisplatin-based CRT, to identify risk factors for cisplatin-induced AKI, and to describe the impact of AKI on long-term renal function and treatment outcomes.Methods: This is a retrospective cohort study with measurements of renal function before CRT, weekly during CRT, every 1 or 2 days during hospitalizations, and 3 and 12 months after CRT in patients with LA-SCCHN. AKI was defined as increase in serum creatinine (sCr) of ≥1.5 times baseline or by ≥0.3 mg/dL (≥26.5 μmol/L) using the Kidney Disease Improving Global Outcomes (KDIGO) classification. Logistic regression models were estimated to analyze renal function over time and to identify predictors for AKI.Results: One hundred twenty-four patients completed all measurements. AKI was reported in 85 patients (69%) with 112 episodes of AKI. Sixty of 85 patients experienced 1 AKI episode; 20 patients experienced ≥2 AKI episodes. Ninety-three (83%) AKI episodes were stage 1, 13 (12%) were stage 2, and 6 (5%) AKI episodes were stage 3. Median follow-up time was 29 months (Interquartile Range, IQR 22-33). Hypertension (Odds Ratio, OR 2.7, 95% Confidence Interval, CI 1.1-6.6; p = 0.03), and chemotherapy-induced nausea and vomiting (CINV; OR 4.3, 95% CI 1.6-11.3; p = 0.003) were associated with AKI. In patients with AKI, renal function was significantly more impaired at 3 and 12 months post-treatment compared to patients without AKI. AKI did not have a negative impact on treatment outcomes.Conclusion: AKI occurred in 69% of patients with LA-SCCHN undergoing CRT with high-dose cisplatin. Long-term renal function was significantly more impaired in patients with AKI. Hypertension and CINV are significant risk factors. Optimizing prevention strategies for CINV are urgently needed. [ABSTRACT FROM AUTHOR]

Dysphagia represents one of the most serious adverse events after curative-intent treatments with a tremendous impact on quality of life in patients with head and neck cancers. Novel surgical and radiation therapy techniques have been developed to better preserve swallowing function, while not negatively influencing local control and/or overall survival. This review focuses on the current literature of swallowing outcomes after curative treatment strategies. Available results from recent studies relevant to this topic are presented, demonstrating the potential role of new treatment modalities for early- and intermediate-stage oropharyngeal cancers. Based on this, we present the rationale and design of the currently active EORTC 1420 "Best of" trial, and highlight the potential of this study to help prioritizing either surgery- or radiation-based treatment modalities for the treatment of oropharyngeal cancer in the future. [ABSTRACT FROM AUTHOR]

Background: Patients with head and neck cancer (HNC) are vulnerable to fear of cancer recurrence (FCR) and psychiatric morbidity. We investigated the prevalence of high FCR and demographic, clinical, psychological, and psychiatric factors associated with high FCR prior to the start of the treatment. Methods: In a cross‐sectional substudy of the large ongoing prospective NET‐QUBIC study questionnaires and psychiatric interviews of 216 patients newly diagnosed with HNC were analyzed. Results: High FCR was observed in 52.8% of patients and among those 21.1% also had a lifetime history of selected anxiety or major depressive disorder. FCR was not related to any clinical characteristics; however, younger age, higher anxiety symptoms, introversion, greater needs for support regarding sexuality, and being an exsmoker were significantly associated with higher FCR. Conclusion: Factors associated with high FCR provide us with a better conceptual understanding of FCR in patients newly diagnosed with HNC. [ABSTRACT FROM AUTHOR]

Objective: To systematically review the literature on factors associated with a clinical diagnosis of depression or symptoms of depression (depression) among head and neck cancer (HNC) patients.Methods: The search was conducted in PubMed, PsycINFO, and CINAHL. Studies were included if they investigated factors associated with depression among HNC patients, they were of prospective or longitudinal nature, and English full text was available. The search, data extraction, and quality assessment were performed by two authors. Based on the data extraction and quality assessment, the level of evidence was determined.Results: In total, 35 studies were included: 21 on factors associated with depression at a single (later) time point, 10 on the course of depression, and four on both. In total, 77 sociodemographic, lifestyle, clinical, patient-reported outcome measures, and inflammatory factors were extracted. Regarding depression at a single time point, there was strong evidence that depression at an earlier time point was significantly associated. For all other factors, evidence was inconclusive, although evidence suggests that age, marital status, education, ethnicity, hospital/region, sleep, smoking, alcohol, surgery, treatment, tumor location, and recurrence are not important associated factors. Regarding the course of depression, we found inconclusive evidence for all factors, although evidence suggests that gender, age, chemotherapy, pain, disease stage, treatment, and tumor location are not important associated factors.Conclusion: Depression at an earlier time point is significantly associated with depression later on. Several sociodemographic and clinical factors seem not to be important factors associated with depression. For other factors, further research is warranted. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess patient-reported levels of physical activity (PA) and its associations with health-related quality of life (HRQoL) adjusted for important demographic, lifestyle-related, and clinical factors, among head and neck (HNC) survivors.Methods: This cross-sectional study included 116 HNC survivors. PA was assessed with the Physical Activity Scale for the Elderly (PASE) and HRQoL with the EORTC-QLQ-C30 and EORTC-HN35. Associations were studied using univariable and multivariable regression analyses.Results: Median PASE score was 100.3 (interquartile range 65.1;170.8) of which 54% were household, 34% leisure-time, and 12% occupational activities. Younger HNC survivors had higher levels of PA. Higher PA was significantly associated with higher global QoL (p < 0.05). Findings for physical function, role function, social function, fatigue, and pain were in line, but not statistically significant (0.05 ≤ p < 0.10).Conclusions: Among HNC survivors, a large proportion of PA consists of household activities. Younger HNC survivors had higher PA levels, and higher PA levels were associated with higher HRQoL. [ABSTRACT FROM AUTHOR]

Background We examined the assumption in conventional teaching about metastatic adenoid cystic carcinoma (ACC) being an indolent type of disease. Methods A single center analysis of 105 cases of ACC was performed. Radiographs were reviewed and tumor response to chemotherapy was measured. Distant disease-free survival (DDFS) and time to death since distant metastases diagnosis were analyzed. Results Forty-two percent of the patients were diagnosed with distant metastases. DDFS showed significant negative associations with advanced T classification, N+ classification, solid type tumor, and positive surgical margins. Distant metastases (91%) developed in the first 5 years after presentation. Median distant metastatic survival was 13.8 months. The most frequent organ sited was the lung. Solid type ACC showed a preponderance for multiorgan metastases (17/28; 61%). Distant metastases seemed not to occur in case of clear surgical margins. Solid type ACC had a significant poorer survival after development of distant metastases. Conclusion Metastatic ACC is not always an indolent disease. © 2016 Wiley Periodicals, Inc. Head Neck 39: 456-463, 2017 [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to assess the interobserver variability in chest computed tomography (CT) and whole body 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) screening for distant metastases in head and neck squamous cell carcinoma (HNSCC) patients.Procedure: Chest CT and whole body FDG-PET of 69 HNSCC patients with high-risk factors who underwent screening for distant metastases were analyzed. All scans were independently read by two experienced radiologists or nuclear physicians who were blinded to the other examinations and follow-up results.Results: A kappa of 0.516 was found for assessment of size on CT. Kappa values for origin and susceptibility of 0.406 and 0.512 for CT and 0.834 and 0.939 for PET were found, respectively. The overall conclusions had a kappa of 0.517-0.634 for CT and 0.820-1.000 for PET.Conclusions: In screening for distant metastases in HNSCC patients with high-risk factors, chest CT readings had a reasonable to substantial agreement, while PET readings showed an almost perfect agreement. These findings suggest that for optimal assessment in clinical practice, PET most often can be scored by one observer, but CT should probably more often be scored by different observers in consensus or combined with PET. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable early prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring. Early tumoral changes can be captured by functional imaging (DWI/IVIM/DCE/18F-FDG-PET-CT) parameters, which allow for the construction of accurate patient-specific prognostic models for locoregional recurrence-free survival, distant metastasis-free survival and overall survival. We also present clinical applicable risk stratification in high/medium/low risks for these patient outcomes. This can enable personalized treatment (adaptation) management early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring. Background: Patients with locally-advanced head and neck squamous cell carcinoma (HNSCC) have variable responses to (chemo)radiotherapy. A reliable prediction of outcomes allows for enhancing treatment efficacy and follow-up monitoring. Methods: Fifty-seven histopathologically-proven HNSCC patients with curative (chemo)radiotherapy were prospectively included. All patients had an MRI (DW,-IVIM, DCE-MRI) and 18F-FDG-PET/CT before and 10 days after start-treatment (intratreatment). Primary tumor functional imaging parameters were extracted. Univariate and multivariate analysis were performed to construct prognostic models and risk stratification for 2 year locoregional recurrence-free survival (LRFFS), distant metastasis-free survival (DMFS) and overall survival (OS). Model performance was measured by the cross-validated area under the receiver operating characteristic curve (AUC). Results: The best LRFFS model contained the pretreatment imaging parameters ADC_kurtosis, Kep and SUV_peak, and intratreatment imaging parameters change (Δ) Δ-ADC_skewness, Δ-f, Δ-SUV_peak and Δ-total lesion glycolysis (TLG) (AUC = 0.81). Clinical parameters did not enhance LRFFS prediction. The best DMFS model contained pretreatment ADC_kurtosis and SUV_peak (AUC = 0.88). The best OS model contained gender, HPV-status, N-stage, pretreatment ADC_skewness, D, f, metabolic-active tumor volume (MATV), SUV_mean and SUV_peak (AUC = 0.82). Risk stratification in high/medium/low risk was significantly prognostic for LRFFS (p = 0.002), DMFS (p < 0.001) and OS (p = 0.003). Conclusions: Intratreatment functional imaging parameters capture early tumoral changes that only provide prognostic information regarding LRFFS. The best LRFFS model consisted of pretreatment, intratreatment and Δ functional imaging parameters; the DMFS model consisted of only pretreatment functional imaging parameters, and the OS model consisted ofHPV-status, gender and only pretreatment functional imaging parameters. Accurate clinically applicable risk stratification calculators can enable personalized treatment (adaptation) management, early on during treatment, improve counseling and enhance patient-specific post-therapy monitoring. [ABSTRACT FROM AUTHOR]

Background Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal linings of the upper aerodigestive tract. HNSCC may develop in large preneoplastic fields, which are in most cases invisible, but can be detected microscopically and by genetic analysis. Methods Cells of mucosal tissue biopsies were cultured and genetically analyzed. Genetic changes in established preneoplastic cultures were compared to the corresponding tumor and surgical margins. Results Of 45 mucosal tissue biopsies taken from primary tumor resection specimen, 26 were successfully cultured and could be genetically analyzed. In 1 culture, genetic changes were found and an immortalized preneoplastic cell line was obtained with genetic changes that were also found in a surgical margin of the corresponding specimen. Conclusion Our data show that noninvasive fields surrounding HNSCC may consist of immortalized preneoplastic cell clones. Our preneoplastic cell line is a valuable tool to develop and test treatment strategies for precursor fields in patients with HNSCC. © 2012 Wiley Periodicals, Inc. Head Neck, 2013 [ABSTRACT FROM AUTHOR]

Background Extranodal spread (ENS) of tumors is widely used as a prognosticator for patients with head and neck cancer and is used as an indicator for postoperative treatment. However, the histopathologic agreement among pathologists on the assessment of the presence or absence of this criterion has never been studied. Methods The interobserver and intraobserver agreement among 10 pathologists on the diagnosis of ENS in 41 tumor-positive lymph nodes was evaluated. Results The kappa value of the interobserver agreement among pathologists varied between 0.14 and 0.75, the overall kappa value was 0.42 and 0.49 in the 2 scoring sessions. The intraobserver kappa value varied between 0.49 and 0.95. Conclusion The intraobserver and interobserver agreement among pathologists in the assessment of the presence of ENS was low in metastatic lymph nodes in the neck. Because of the widely accepted prognostic significance and therapeutic consequences of ENS, there is a need for internationally accepted reproducible criterion for the histopathologic assessment of ENS in metastatic lymph nodes in the neck. © 2011 Wiley Periodicals, Inc. Head Neck, 2011 [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined molecular risk factors for the local relapse (LR) in treated head and neck squamous cell carcinoma (HNSCC). Markers used for molecular grading were the number of Ki-67 positive cells, the number of 53 immunopositive cells, and loss of heterozygosity (LOH) at 17p, 9p and 3p. The study found that the presence of a genetically defined preneoplastic region, or field, is significantly associated with LR.

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins. Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters. A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p<0.001), and the group of patients with histopathological tumor-free surgical margins (p=0.001). This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising. [ABSTRACT FROM AUTHOR]

The immunosuppressive character of head and neck cancers may explain the relatively low response rates to antibody therapy targeting a tumor antigen, such as cetuximab, and anti-PD-1 checkpoint inhibition. Immunostimulatory agents that overcome tumor-derived inhibitory signals could augment therapeutic efficacy, thereby enhancing tumor elimination and improving patient survival. Here, we demonstrate that cetuximab treatment combined with immunostimulatory agonists for Toll-like receptor (TLR) 2 induces profound immune responses. Natural killer (NK) cells, isolated from healthy individuals or patients with head and neck cancer, harbored enhanced cytotoxic capacity and increased tumor-killing potential in vitro. Additionally, combination treatment increased the release of several pro-inflammatory cytokines and chemokines by NK cells. Tumor-bearing mice that received cetuximab and the TLR2 ligand Pam3CSK4 showed increased infiltration of immune cells into the tumors compared to mice that received cetuximab monotherapy, resulting in a significant delay in tumor growth or even complete tumor regression. Moreover, combination treatment resulted in improved overall survival in vivo. In conclusion, combining tumor-targeting antibody-based immunotherapy with TLR stimulation represents a promising treatment strategy to improve the clinical outcomes of cancer patients. This treatment could well be applied together with other therapeutic strategies such as anti-PD-(L)1 checkpoint inhibition to further overcome immunosuppression. [ABSTRACT FROM AUTHOR]

Several techniques have been developed to reconstruct oral and pharyngeal defects following surgery, in order to restore function and cosmesis. These are primary closure, skin grafts, local transposition of skin, mucosa and/or muscle, regional flaps and free vascularized flaps. Because of the ‘bulky’, pedicled nature and problems with the donor area of locoregional flaps, and consequently frequently unsatisfactory functional results, free vascularized flaps have gained popularity during the last decade. The authors review the current options available to give physicians, who are not experienced in the field of reconstruction in the head and neck, an impression of the range of techniques available for reconstruction of oral and pharyngeal defects following tumor resection. For reconstruction of oral cavity and pharyngeal defects, fasciocutaneous (e.g. radial forearm and anterolateral thigh flaps) and myocutaneous free flaps (e.g. rectus abdominis and latissimus dorsi) have proven to be very reliable. Free vascularized osteocutaneous flaps (e.g. fibula and iliac crest) permit reconstructive options for bony defects of the mandible or maxilla that can be adapted to a variety of defects. Depending on the site, size and involved tissues of the surgical defect and patient factors, a variety of reconstructive options are available. For both soft tissue and bony defects of the upper aerodigestive tract, microvascular free flaps provide good functional outcomes. [ABSTRACT FROM AUTHOR]

Background. The use of microvascular free flaps is currently the favored method for the reconstruction of defects after resection of head and neck cancer. The flap most commonly used for head and neck reconstruction is the free radial forearm flap, but the less popular infrahyoid flap represents a good alternative in selected cases. This flap has proven to be helpful in the reconstruction of a wide range of moderate-sized head and neck defects. Methods. We reviewed a series of 13 patients with defects resulting from cancer of the head and neck, who underwent infrahyoid flap reconstruction as an alternative to free radial forearm flap. The series includes 12 squamous cell carcinomas arising from the oral cavity and oropharynx, and 1 Merkel cell carcinoma of the submental skin. In the harvesting of the flap, the technical modifications recently suggested by Dolivet et al were used in all cases. Furthermore, another technical change has been introduced so creating a new infrahyoid facio-myocutaneous flap (IHFMCF). The surgical technique is described in detail. Results. No total or partial flap necrosis was experienced. All reconstructions healed quickly without wound complications and with good functional results. The healing process in the donor site was excellent in every case with good aesthetic results. Conclusions. The IHFMCF is a versatile, reliable, and convenient flap suitable for repairing small and medium-sized defects of the oral cavity and oropharynx and obviates the need for a microvascular reconstruction. © 2007 Wiley Periodicals, Inc. Head Neck 29, 2007 [ABSTRACT FROM AUTHOR]

In the absence of large-scale randomized trials evaluating dissection versus observation of the involved neck after neoadjuvant chemoradiotherapy, there is a need to collect data that will either support or ultimately refute a role for planned posttreatment neck dissection. A significant percentage of patients with extensive (N2 or N3) neck disease who demonstrate a complete response to chemoradiation therapy may harbor residual occult metastases, and identification of this subset of patients remains a clinical challenge. Because surgical salvage rates are greatly diminished when occult nodal disease becomes clinically manifest, planned posttreatment neck dissection is advocated but may not be necessary in all patients. The role of positron emission tomography chemoradiotherapy (PET-CT) in this scenario remains unproven but holds promise in being able to identify which patients may be harboring residual disease in the neck after chemoradiotherapy. The implementation of as yet unidentified molecular tumor markers in combination with PET-CT may ultimately prove to be effective in identifying patients who will best benefit from posttherapy neck dissection. Correlation of imaging results and pathologic node status will be important in determining the accuracy and, therefore, the value of this imaging modality for predicting the presence or absence of residual disease. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX–XXX, 2005 [ABSTRACT FROM AUTHOR]

Background: Transcriptionally active high-risk human papilloma viruses (HPVs), particularly HPV type 16 (HPV16), are found in a subset of head and neck squamous-cell carcinomas (HNSCCs). HPV16-associated carcinogenesis is mediated by expression of the viral E6 and E7 oncoproteins, which cause deregulation of the cell cycle by inactivating p53 and pRb, respectively. We tested the hypothesis that HPVassociated HNSCCs display a pattern of genetic alterations different from those of HNSCCs without HPV DNA. Methods: Polymerase chain reaction-based assays were used to examine 143 consecutive HNSCCs (106 of the oral cavity and 37 of the oropharynx) for the presence of HPV DNA and for viral E6 and/or E7 messenger RNA (mRNA) expression. The HPV DNA- and E6 and E7 mRNA-positive HNSCCs and an equal number of HPV DNA-negative HNSCCs were further analyzed for mutations in TP53, the gene encoding p53, and for allelic loss of 28 microsatellite markers at chromosome arms 3p, 6q, 8p, 9p, 13q, 17p, and 18q, including markers located in regions of chromosome arms 9p and 17p that harbor genes involved the p53 and pRb pathways. All statistical tests were two-sided. Results: Twenty-four (16.7 %) of the 143 HNSCCs were positive for HPV16 DNA, and 12 of these HNSCCs (8.4% of total number) expressed E6 and E7 mRNAs. None of the HPV DNA- and E6/E7 mRNA-positive tumors had TP53 gene mutations, whereas nine (75 %) of the 12 HPV DNA-negative tumors had such mutations (P<.001). Compared with the HPV DNA-negative HNSCCs, the E6/E7 mRNA-positive HNSCCs had statistically significantly lower levels of allelic loss for 13 of the 15 markers on 3p, 9p, and 17p. Conclusions: HNSCCs with transcriptionally active HPV16 DNA are characterized by occasional chromosomal loss, whereas HNSCCs lacking HPV DNA are characterized by gross deletions that involve whole or large parts of chromosomal arms and that already occur early in HNSCC development. These distinct patterns of genetic alterations suggest that HPV16 infection is an early event in HNSCC development. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients that suffer from advanced head and neck cancer have a low average survival chance. Improving prognosis could improve this survival rate as it may help in clinical decision making. Radiomics features calculated from images of the tumour describe tumour size, shape, and pattern. These characteristics may be linked to patient survival, which is investigated in this paper. We combined radiomics features with other biomarkers of survival of 809 patients to make a prognosis before treatment. We then compared the predicted prognosis with the actual outcome to see how well our model performs. Our model was able to make three distinct risk groups of low-, medium-, and high-survival patients. With these findings, doctors may make a better judgement of treatment and follow-up per patient, which might improve clinical outcomes. Background: Locoregionally advanced head and neck squamous cell carcinoma (HNSCC) patients have high relapse and mortality rates. Imaging-based decision support may improve outcomes by optimising personalised treatment, and support patient risk stratification. We propose a multifactorial prognostic model including radiomics features to improve risk stratification for advanced HNSCC, compared to TNM eighth edition, the gold standard. Patient and methods: Data of 666 retrospective- and 143 prospective-stage III-IVA/B HNSCC patients were collected. A multivariable Cox proportional-hazards model was trained to predict overall survival (OS) using diagnostic CT-based radiomics features extracted from the primary tumour. Separate analyses were performed using TNM8, tumour volume, clinical and biological variables, and combinations thereof with radiomics features. Patient risk stratification in three groups was assessed through Kaplan–Meier (KM) curves. A log-rank test was performed for significance (p-value < 0.05). The prognostic accuracy was reported through the concordance index (CI). Results: A model combining an 11-feature radiomics signature, clinical and biological variables, TNM8, and volume could significantly stratify the validation cohort into three risk groups (p < 0∙01, CI of 0.79 as validation). Conclusion: A combination of radiomics features with other predictors can predict OS very accurately for advanced HNSCC patients and improves on the current gold standard of TNM8. [ABSTRACT FROM AUTHOR]

Objectives Subjects and Methods Results Conclusion Robotic transoral mucosectomy of the base of tongue was introduced as a diagnostic procedure in patients treated for head and neck cancer with unknown primary (CUP), increasing the identification rate of the primary tumour. For the treatment of CUP, a considerable percentage of patients require adjuvant (chemo)radiation. The aim of this study was to investigate swallowing outcomes among CUP patients after TORS and adjuvant treatment.A systematic review was carried out on studies investigating the impact of TORS and adjuvant treatment on swallowing‐related outcomes among CUP patients In addition, a cross‐sectional study was carried out on swallowing problems (measured using the SWAL‐QOL questionnaire) among CUP patients in routine care who visited the outpatient clinic 1–5 years after TORS and adjuvant treatment.The systematic review (6 studies; n = 98) showed that most patients returned to a full oral diet. The cross‐sectional study (n = 12) showed that all patients were able to return to a full oral diet, nevertheless, 50% reported swallowing problems in daily life (SWAL‐QOL total score ≥14).Although after TORS and adjuvant treatment for CUP a full oral diet can be resumed, patients still experience problems with eating and drinking in daily life. [ABSTRACT FROM AUTHOR]

Background: Radiomics is aimed at image-based tumor phenotyping, enabling application within clinical-decision-support-systems to improve diagnostic accuracy and allow for personalized treatment. The purpose was to identify predictive 18-fluor-fluoro-2-deoxyglucose (18F-FDG) positron-emission tomography (PET) radiomic features to predict recurrence, distant metastasis, and overall survival in patients with head and neck squamous cell carcinoma treated with chemoradiotherapy. Methods: Between 2012 and 2018, 103 retrospectively (training cohort) and 71 consecutively included patients (validation cohort) underwent 18F-FDG-PET/CT imaging. The 434 extracted radiomic features were subjected, after redundancy filtering, to a projection resulting in outcome-independent meta-features (factors). Correlations between clinical, first-order 18F-FDG-PET parameters (e.g., SUVmean), and factors were assessed. Factors were combined with 18F-FDG-PET and clinical parameters in a multivariable survival regression and validated. A clinically applicable risk-stratification was constructed for patients' outcome. Results: Based on 124 retained radiomic features from 103 patients, 8 factors were constructed. Recurrence prediction was significantly most accurate by combining HPV-status, SUVmean, SUVpeak, factor 3 (histogram gradient and long-run-low-grey-level-emphasis), factor 4 (volume-difference, coarseness, and grey-level-non-uniformity), and factor 6 (histogram variation coefficient) (CI = 0.645). Distant metastasis prediction was most accurate assessing metabolic-active tumor volume (MATV)(CI = 0.627). Overall survival prediction was most accurate using HPV-status, SUVmean, SUVmax, factor 1 (least-axis-length, non-uniformity, high-dependence-of-high grey-levels), and factor 5 (aspherity, major-axis-length, inversed-compactness and, inversed-flatness) (CI = 0.764). Conclusions: Combining HPV-status, first-order 18F-FDG-PET parameters, and complementary radiomic factors was most accurate for time-to-event prediction. Predictive phenotype-specific tumor characteristics and interactions might be captured and retained using radiomic factors, which allows for personalized risk stratification and optimizing personalized cancer care. Trial registration: Trial NL3946 (NTR4111), local ethics commission reference: Prediction 2013.191 and 2016.498. Registered 7 August 2013, https://www.trialregister.nl/trial/3946 [ABSTRACT FROM AUTHOR]

• Platinum-based CRT for HPV-neg HNSCC has unique treatment course and outcome pattern. • CRT is often too toxic, in ∼35% of patients the cisplatin-dose plan needed changes. • Switching to carboplatin when cisplatin is too toxic seems not beneficial for OS (HR 1.49 vs HR 1.59). • Development of DM was strongly associated with boosting method (SEQ vs SIB; OR 1.91). Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11–3.26; p = 0.02). Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study. [ABSTRACT FROM AUTHOR]

Summary: The relatively modest survival of patients surgically treated for advanced HNSCC can partly be explained by the development of local relapse. It is important that surgeons are able to predict which patients are at high risk to develop local relapse, since clinical management can be tailored. Local relapse after resection of a primary HNSCC is easily explained, when tumour is detected in the surgical margins and thus residual tumour is likely to remain in the patient, but the pathobiology is more complex in cases where the margins are histologically tumour-free. Molecular studies indicate that there are two different mechanisms responsible in these cases. First, small clusters of residual tumour cells that are undetectable on routine histopathological examination (known as minimal residual cancer: MRC) proliferate and this forms the basis of recurring cancer. A second cause of relapse is a remaining field of preneoplastic cells that is struck by additional genetic hits leading to invasive cancer. It is likely that within this field, that can be over 7cm in diameter, the primary carcinoma has also emerged. Despite careful histopathological examination of the surgical margins of the primary carcinoma, it is at present not reliably possible to predict which patient will develop local relapse. Herein we focus on new developments regarding the analysis of margins, causes of local relapse, and how novel molecular techniques can be of help in a more accurate risk assessment. Critical analysis of the studies that have been published thus far shows that there is a list of promising markers, based on protein expression (immuno-histochemistry) and nucleic acid analysis. Further studies should be focused on validation and assessment of the clinical utility of these markers. Margin analysis should reveal whether one is dealing with residual cancer cells that might be treated by post-operative radiotherapy or with preneoplastic fields that remained behind. For this latter entity, there is no intervention available at present, except for a more intensive surveillance. [Copyright &y& Elsevier]

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers.Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%).Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible.Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients. [ABSTRACT FROM AUTHOR]

Intravoxel incoherent motion (IVIM) imaging is increasingly applied in the assessment of head and neck cancer (HNC). Our purpose was to determine the diagnostic and prognostic performance of IVIM in HNC by performing a critical review of the literature. Pubmed and EMBASE were searched until May 2016. Study and patients characteristics, imaging protocol and diagnostic or prognostic outcomes were extracted by 2 independent reviewers. The studied IVIM parameters were diffusion coefficient (D), pseudodiffusion coefficient (D∗), and perfusion fraction (f). We included 10 diagnostic studies, 5 prognostic studies and 2 studies assessing both. Studies were very heterogeneous in terms of applied b-values, imaging protocols, outcome measurements and reference standards; therefore we did not perform a meta-analysis. The most commonly used sequence was "spin-echo planar imaging". A median of 10.5 b-values (range, 3-17) were used. All but three studies included at least 4 b-values below b=200s/mm2. By combining IVIM-parameters squamous cell carcinomas, lymphomas, malignant salivary gland tumors, Warthin's tumors and pleomorphic adenomas could be differentiated with a sensitivity of 85-87% and specificity of 80-100%. Low pre-treatment D or f and an increase in D during treatment were associated with a favorable response to treatment. D∗ appeared to be the parameter with the lowest prognostic value. Future research should focus on finding the optimal IVIM protocol, using uniformly accepted study methods and larger patient populations. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT). Methods and materials: The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method. Results: The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82. For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84. Conclusions: Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly. [Copyright &y& Elsevier]

Summary: The detection of distant metastases is critical for prognostication and for the choice of treatment in patients with head and neck squamous cell carcinoma (HNSCC). Pretreatment screening for distant metastases should be conducted particularly for patients with high risk factors, prior to locoregional treatment decisions. Different diagnostic techniques are discussed. Unfortunately, most studies lack sufficient follow-up to reliably assess false-negative results. Moreover, the designs of most studies vary substantially with regard to homogeneity of groups (tumor types and stages), timing (pretreatment, follow-up) and definition of risk factors (patient selection). Therefore, only a few studies are comparable. The combination of F-18 fluoro-d-glucose-positron emission tomography (FDG-PET) and a dedicated CT (at least of the chest) is the most important imaging protocol at the present time. Eventually, whole-body-MRI (WB-MRI) may possibly replace PET-CT for screening patients for distant metastases. [ABSTRACT FROM AUTHOR]

Summary: Currently, selection of lymph nodes for ultrasound-guided-fine-needle-aspiration cytology (USgFNAC) in patients with HNSCC relies mainly on size of lymph nodes. This retrospective study was undertaken to assess the potential value of size, laterality, level and changes in size as criteria for selection of nodes that need to be aspirated during follow-up of patients. We aim to reduce the number of unnecessary aspirations being performed without decreasing accuracy of USgFNAC. Eighty-one patients with oral cavity carcinoma (OCC) were eligible for observation-policy regarding treatment of the neck and received transoral excision of OCC. Selection of nodes for fine-needle-aspiration-cytology (FNAC) was based on size criterion. Localization (side and level) and size of aspirated lymph nodes were scored. Data on treatment and follow-up were collected and analyzed to assess the value of the used criteria. During follow-up all 17 positive nodes were found, of which 16 were ipsilateral. Contralateral metastasis was found in a patient with ipsilateral metastasis and a tumor crossing the midline. Minimal axial diameter (MAD) of all positive nodes was larger than 5.0mm in level II or 4.0mm in other levels. Follow-up aspirations in patients with OCC performed in the neck by USgFNAC can be reduced by 56% without increasing false-negative lymph nodes if follow-up aspirations would only be performed on the ipsilateral neck in lymph nodes with a MAD of 5mm in level II and 4mm in other levels or larger and in lymph nodes with rapid change of diameter. [ABSTRACT FROM AUTHOR]

Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. Strong prognostic indicators that predict development of distant metastases are the presence and number of lymph node metastases in the neck, and extranodal spread. Recently, it was shown in several studies that also the presence of disseminated tumor cells (DTC) in the bone marrow predicts development of distant metastases. We have investigated whether protein signatures could be detected in primary HNSCC that distinguish tumors that disseminate into the bone marrow from those that do not. Therefore, DTC-positive and -negative primary HNSCC tumors were analyzed by 2D-DIGE. A signature consisting of 51 differential protein spots was identified upon stratification for bone marrow status, which allowed a correct classification of DTC-positive and DTC-negative HNSCC tumors in 95% of cases, using hierarchical clustering. The most prominent feature within this signature was the down-regulation of CK19 in DTC-positive tumors. Our data show that tumor cell dissemination to the bone marrow, the onset of hematogenic metastasis, can be deduced from the protein profile in the primary tumor. The highly significant down-regulation of CK19 supports a model of epithelial–mesenchymal transition for tumors that show a high proclivity for hematogenic dissemination. [Copyright &y& Elsevier]

Summary: Radiation may cause radiation-induced cancers after a long latency period. In a group of 111 patients surgically treated for hypopharyngeal carcinoma, patients previously treated with radiotherapy for tuberculosis in the neck were compared to patients without previous radiotherapy. Seven patients (7.4%) underwent radiotherapy (median age 15years) and developed a hypopharyngeal carcinoma (median age 70years, median latency period 54.4year). Considering this long latency period and the localisation in the previous radiation field these tumours can be classified as potentially radiation-induced carcinomas. Patients with potentially radiation-induced carcinomas were significantly older when the hypopharyngeal carcinoma was diagnosed (p =0.048), were more frequently females (p =0.05) and had a worse 5-year regional control rate (p =0.048). When radiotherapy is considered in young patients the risk of induction of tumours has to be kept in mind. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have revealed an important and intriguing role for human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC). There are indications that the prevalence of HPV-positive HNSCC has recently increased, and genetic analyses point to a completely distinct class of HNSCCs. Most studies suggest that patients with this type of tumour have a better prognosis and some argue that an adjusted therapeutic approach is needed. One crucial point in the research of HNSCC–HPV involvement has often been neglected, which is the lack of a standardised assay to detect HPV. This has resulted in a considerable variation in the frequency of HPV-positive tumours between studies reported thus far. Especially for PCR-based tests, the risk exists that the assay is too sensitive and detects virus without implying a causal involvement in HNSCC. A reliable algorithm to detect a clinically relevant HPV infection in formalin-fixed paraffin embedded tissue has recently become available. Here, we address important biological and analytical aspects of HPV involved in the development of HNSCC and it is emphasised that a standardised HPV assay is a prerequisite for assessing the clinical importance of a HPV infection in HNSCC. [Copyright &y& Elsevier]