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Objectives: Diagnosing adenoid cystic carcinoma (AdCC) is challenging due to histopathological variability and similarities with other tumors. In AdCC pathogenesis, the cellular myeloblastosis gene (c-MYB) often exhibits a MYB::NFIB fusion from a reciprocal translocation. This study aimed to assess the predictive accuracy of MYB immunohistochemistry for detecting this translocation compared to fluorescence in situ hybridization (FISH)., Study Design: This study included 110 AdCC patients (1999-2017) from two Dutch head and neck centers using tissue microarrays and full slides. Median MYB expression levels by immunohistochemistry were compared based on translocation status by FISH, and differences within clinicopathological parameters were examined. An immunohistochemical cut-off was established to estimate the translocation., Results: MYB immunohistochemistry was available in 90/110 patients, with a median expression of 27%. FISH was interpretable in 79/108 tumors, identifying MYB::NFIB fusion in 44 (56%). Among 62 patients with both MYB expression and translocation data, the fusion was present in 38 (61%). These tumors had higher MYB expression (30%) than nontranslocated tumors (6%); P = .02. A 60% MYB expression cut-off yielded 100% specificity for detecting the translocation but had no prognostic value., Conclusions: Although MYB protein expression alone lacks diagnostic precision, protein expression >60% predicted the MYB::NFIB fusion in all tumors., Competing Interests: DECLARATIONS OF INTEREST None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest.

Concomitant chemoradiotherapy (CRT) is extensively used as primary organ preservation treatment for selected advanced laryngeal squamous cell carcinomas (LSCC). The oncologic outcomes of such regimens are comparable to those of total laryngectomy followed by adjuvant radiotherapy. However, the management of loco-regional recurrences after CRT remains a challenge, with salvage total laryngectomy being the only curative option. Furthermore, the decision whether to perform an elective neck dissection (END) in patients with rN0 necks, and the extent of the neck dissection in patients with rN + necks is still, a matter of debate. For rN0 patients, meta-analyses have reported occult metastasis rates ranging from 0 to 31 %, but no survival advantage for END. In addition, meta-analyses also showed a higher incidence of complications in patients who received an END. Therefore, END is not routinely recommended in addition to salvage laryngectomy. Although some evidence suggests a potential role of END for supraglottic and locally advanced cases, the decision to perform END should weigh benefits against potential complications. In rN + patients, several studies suggested that selective neck dissection (SND) is oncologically safe for patients with specific conditions: when lymph node metastases are not fixed and are absent at level IV or V. Super-selective neck dissection (SSND) may be an option when nodes are confined to one level. In conclusion, current evidence suggests that in rN0 necks routine END is not necessary and that in rN + necks with limited nodal recurrences SND or a SSND could be sufficient., Competing Interests: Declaration of competing interest In relation to the manuscript “Treatment of the neck in residual/recurrent advanced primary laryngeal cancer after chemoradiotherapy” submitted for publication to the European Journal of Surgical Oncology, the authors state that they have not conflicts of interest to disclose., (© 2024 Published by Elsevier Ltd.)

Objective: The aim of this project is to create an interactive online patient decision aid (PDA) for oropharyngeal cancer (OPSCC) patients, eligible for transoral (robotic) surgery with an ultimate goal to assist both physicians and patients in making treatment choices., Materials and Methods: Following the International Patient Decision Aid Standards, a mixed-methods approach was employed. The study involved semi-structured in-depth interviews with patients and physicians, thinking-out-loud sessions, and study-specific questionnaires. Thematic coding and analysis were conducted on verbatim transcriptions of audio-recorded interviews., Results: The PDA drafts were evaluated by twenty OPSCC survivors and twenty multidisciplinary specialists. Significant revisions were made after phase 1 to enhance readability and reduce text, whilst incorporating videos and graphics. Following all phases, both patients and specialists rated the PDA as comprehensible, feasible, and a valuable addition to regular counseling., Conclusion: This study showcases the development of a PDA for early stage oropharyngeal cancer patients considering surgery and radiotherapy options. The decision aid emphasizes the disparities in short- and long-term side effects between the two treatments. Patients and physicians found the decision aid to be understandable, user-friendly, and helpful for future patients. The PDA is available on https://beslissamen.nl/., 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 © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Evidence to support Epstein-Barr virus (EBV)-directed population nasopharyngeal carcinoma (NPC) screening has been growing. Familial aggregation is a well-recognized phenomenon in endemic regions. This systematic review summarizes the role of EBV-directed screening in individuals with a positive family history (FH+) of NPC., Methods: We searched four electronic databases from their inception to October 2021. We included studies on individuals with FH+ of NPC who had undergone EBV-directed investigations, with no restriction in the testing methods or analytic techniques. The primary and secondary outcomes were EBV positivity rates and NPC incidence rates, respectively. Meta-analyses were performed using the random-effect model., Results: Ten cross-sectional studies (n = 7436) and three cohort studies (n = 4306) were included. The pooled relative risk (RR) of EBV positivity between individuals with and without FH+ of NPC were 2.79 (95 % CI 1.37-5.68, p = 0.005) for viral capsid antigen (VCA) IgA, 3.09 (95 % CI 0.65-14.83, p = 0.16) for Epstein-Barr nuclear antigen (EBNA1) IgA, and 1.76 (95 % CI 1.04-2.96, p = 0.03) for combined EBNA1/VCA IgA. In the three cohort studies, the NPC incidence rates ranged from 90.2 to 266 per 100 000 person-years with high proportions of early-stage diseases. FH+ individuals who were EBV-positive had a 2.5 to 30.7-fold risk of NPC development compared to their EBV-negative counterparts., Conclusion: Family members of NPC patients had significantly higher EBV positivity rates than the general population. FH+ individuals who are EBV-positive had high risks of developing NPC. Familial screening using EBV serology may facilitate early NPC detection in endemic areas., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Surgical removal of squamous cell carcinoma of the tongue (SCCT) with tumour-free margin status (≥5 mm) is essential for loco-regional control. Inadequate margins (<5 mm) often indicate adjuvant treatment, which results in increased morbidity. Ultrasound (US)-guided SCCT resection may be a useful technique to achieve more adequate resection margins compared to conventional surgery. This study evaluates the application and accuracy of this technique., Methods: Forty patients with SCCT were included in a consecutive US cohort. During surgery, the surgeon aimed for a 10-mm echographic resection margin, while the tumour border and resection plane were captured in one image. Ex-vivo US measurements of the resection specimen determined whether there was a need for an immediate re-resection. The margin status and the administration of adjuvant treatment were compared those of with a consecutive cohort of 96 tongue cancer patients who had undergone conventional surgery. A receiver operating characteristic analysis was done to assess the optimal margin of ex-vivo US measurements to detect histopathologically inadequate margins., Results: In the US cohort, the frequency of free margin status was higher than in the conventional cohort (55% vs. 16%, p < 0.001), and the frequency of positive margins status (<1 mm) was lower (5% vs. 15%, respectively, p < 0.001). Adjuvant radiotherapy was halved (10% vs. 21%), and the need for re-resection was comparable (10% vs. 9%). A cut-off value of 8 mm for ex-vivo measurements prevented histopathologically inadequate margins in 76%., Conclusion: US-guided SCCT resections improve margin status and reduce the frequency of adjuvant radiotherapy., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

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 & 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.)

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.)

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the feasibility and merits of a complete magnetic approach for a sentinel lymph node biopsy (SLNB) procedure in oral cancer patients., Materials and Methods: This study included ten oral cancer patients (stage cT1-T2N0M0) scheduled for elective neck dissection (END). Superparamagnetic iron oxide nanoparticles (SPIO) were administered peritumorally prior to surgery. A preoperative MRI was acquired to identify lymph nodes (LNs) with iron uptake. A magnetic detector was used to identify magnetic hotspots prior, during, and after the SLNB procedure. The resected sentinel LNs (SLNs) were evaluated using step-serial sectioning, and the neck dissection specimen was assessed by routine histopathological examination. A postoperative MRI was acquired to observe any residual iron., Results: Of ten primary tumors, eight were located in the tongue, one floor-of-mouth (FOM), and one tongue-FOM transition. SPIO injections were experienced as painful by nine patients, two of whom developed a tongue swelling. In eight patients, magnetic SLNs were successfully detected and excised during the magnetic SLNB procedure. During the END procedure, additional magnetic SLNs were identified in three patients. Histopathology confirmed iron deposits in sinuses of excised SLNs. Three SLNs were harboring metastases, of which one was identified only during the END procedure. The END specimens revealed no further metastases., Conclusion: A complete magnetic SLNB procedure was successfully performed in eight of ten patients (80% success rate), therefore the procedure seems feasible. Recommendations for further investigation are made including: use of anesthetics, magnetic tracer volume, planning preoperative MRI, comparison to conventional technique and follow-up., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: The guided self-help exercise program called In Tune without Cords (ITwC) is effective in improving swallowing problems and communication among patients treated with a total laryngectomy (TL). This study investigated the cost-utility and cost-effectiveness of ITwC., Materials and Methods: Patients within 5 years after TL were included in this randomized controlled trial. Patients in the intervention group (n = 46) received access to the self-help exercise program with flexibility, range-of-motion and lymphedema exercises, and a self-care education program. Patients in the control group (n = 46) received access to the self-care education program only. Healthcare utilization (iMCQ), productivity losses (iPCQ), health status (EQ-5D-3L, EORTC QLU-C10D) and swallowing problems (SwalQol) were measured at baseline, 3- and 6-months follow-up. Hospital costs were extracted from medical files. Mean total costs and effects (quality-adjusted life-years (QALYs) or SwalQol score) were compared with regression analyses using bias-corrected accelerated bootstrapping., Results: Mean total costs were non-significantly lower (-€685) and QALYs were significantly higher (+0.06) in the intervention compared to the control group. The probability that the intervention is less costly and more effective was 73%. Sensitivity analyses with adjustment for baseline costs and EQ-5D scores showed non-significantly higher costs (+€119 to +€364) and QALYs (+0.02 to +0.03). A sensitivity analysis using the QLU-C10D to calculate QALYs showed higher costs (+€741) and lower QALYs (-0.01) and an analysis that used the SwalQol showed higher costs (+€232) and higher effects (improvement of 6 points on a 0-100 scale)., Conclusion: ITwC is likely to be effective, but possibly at higher expenses., Trial Registration: NTR5255., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Geriatric 8 (G8) has proven to be one of the most sensitive frailty-screening tools for older patients with cancer undergoing systemic treatment. In this study we validated whether the G8 is also suitable for identifying impairments in their comprehensive geriatric assessment (CGA) in older patients with cancer undergoing surgery. Thereby, we investigated the differences in postoperative outcomes between the fit and frail patients classified by the G8., Methods: Patients ≥70 years with a surgery indication because of a (suspected) malignant disease were prospectively enrolled. In all patients, a CGA was performed. The G8 results were assessed in parallel. The diagnostic value of the G8 was determined by comparing the result with the CGA as a reference test. Deficits in CGA was defined as ≥ two impairments of the CGA. Postoperative complications were retrospectively obtained from the medical record and compared between the fit and frail patients., Results: In total, 143 patients were enrolled. The sensitivity, specificity, and negative predictive value of the G8 were 82% (95% CI 70-91), 63% (95% CI 52-73), and 85% (95% CI 75-91). In the patients with an impaired G8, a significantly prolonged hospital stay, higher rate of delirium, and higher 1-year mortality rate were seen., Conclusion: The G8 is a simple and useful screening tool for identifying deficits in CGA in older patients with cancer requiring surgery. Second, we concluded that patients with an impaired G8 are more at risk for a complicated recovery from surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Squamous cell carcinoma of the tongue (SCCT) is preferably treated by surgery. Free resection margins (≥5 mm) provide local control and disease-free survival. However, close (1-5 mm) and positive margins (<1 mm) are frequently encountered. We present our first experience of in-vivo ultrasound (US) guided SCCT resections followed by ex-vivo US control on the resection specimen to obtain free margins. We compare the results with those from a hisorical cohort of 91 conventionally treated SCCT patients., Materials and Methods: Ten patients with SCCT were included in a consecutive US-cohort. We aimed for a 5-10 mm margin during surgery, while we visualized the resection plane on US. Ex-vivo US measurements on the resection specimen determined whether there was any need for an immediate re-resection. US measurements were then compared with histopathology. Histopathological margins were compared with a consecutive cohort of 91 patients who had undergone conventional surgery for a SCCT., Results: In the US cohort, 70% of the margins were free. In the conventional cohort, this figure was 17% (P = 0.005). US predicted minimal histopathological margin distance with a mean ± SD error of 1.9 ± 1.8 mm. The mean ± SD of the histopathological overall submucosal/deep margin distance was 7.9 ± 2.1 mm in the US cohort and 7.0 ± 2.2 mm in the conventional cohort (P = 0.188). Ex-vivo examination through use of US indicated an immediate re-resection, which prevented local adjuvant treatment., Conclusion: Use of US-guided SCCT resection is feasible and improves margin control., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

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: Complete resection of tongue cancer is necessary to achieve local control. Unfortunately, deep resection margins are frequently inadequate. To improve deep margin control, accurate knowledge of tumour thickness is pivotal. Magnetic resonance imaging (MRI) and intraoral ultrasound (ioUS) are frequently applied for tumour staging. This study explores the accuracy of these techniques to estimate depth of invasion., Materials and Methods: The data of patients with a T1-2 tongue cancer that had been treated surgically between 2014 and 2018 were retrospectively analysed. Measurements that had been taken by either MRI or ioUS were compared with those taken during histopathology., Results: A total of 83 patients with tongue cancer had undergone a pre-operative MRI and 107 had been studied through an ioUS. Tumour thickness measured by MRI (r = 0.72) and ioUS (r = 0.78) correlated significantly (p < 0.001) with histopathological depth of invasion (DOI). In tumours with a DOI of 0-10 mm, MRI has a mean absolute difference with histopathology of 3.1 mm (SD 3.2 mm) and ioUS of 1.6 mm (SD 1.3 mm). In tumours with a DOI greater than 10 mm, MRI has a mean absolute difference of 3.5 mm (SD 3.0 mm) and ioUS of 4.7 mm (SD 3.5 mm)., Conclusion: Estimation of histopathological DOI in tongue cancers with DOI till 10 mm is very accurate through use of ioUS. ioUS tends to underestimate DOI in tumors exceeding 10 mm DOI. MRI tends to overestimate DOI in both thin and thick tumours. Since ultrasound measurements can be performed during surgery, ioUS could potentially guide the surgeon in the achievement of adequate resection margins., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is a common malignancy of the head and neck region. OSCC has a relatively low survival rate and the incidence of the disease is increasing in some geographic areas. Staging and grading of OSCC are established prerequisites for management, as they influence risk stratification and are the first step toward personalized treatment. The current AJCC/UICC TNM staging (8th edition, 2017) of OSCC has included significant modifications through the incorporation of depth of invasion in the T stage and extracapsular spread/extranodal extension in the N stage. Further modifications for AJCC 8 have been suggested. On the other hand, the World Health Organization (WHO) classification (4th edition, 2017) still endorses a simple, differentiation-based histopathologic grading system of OSCC (despite its low prognostic value) and ignores factors such as tumor growth pattern and dissociation, stromal reactions (desmoplasia, local immune response), and tumor-stroma ratio. The various controversies and possible developments of the current staging and grading criteria of OSCC are briefly discussed in this update together with possible applications of artificial intelligence in the context of screening and risk stratification., 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 © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Objective: To investigate the effectiveness of a guided self-help exercise program on swallowing, speech, and shoulder problems in patients treated with total laryngectomy (TL)., Materials and Methods: This randomized controlled trial included patients treated with TL in the last 5 years. Patients were randomized into the intervention group (self-help exercise program with flexibility, range-of-motion and lymphedema exercises and self-care education program) or control group (self-care education program). Both groups completed measurements before and 3 and 6-months after randomization. The primary outcome was swallowing problems (SWAL-QOL). Secondary outcomes were speech problems (SHI), shoulder problems (SDQ), self-management (patient activation: PAM) and health-related quality of life (HRQOL: EORTC QLQ-C30/H&N35). Adherence was defined as moderate-high in case a patient exercised >1 per day. Linear mixed model analyses were conducted to investigate the effectiveness of the intervention and to investigate whether neck dissection, treatment indication (primary/salvage TL), time since treatment, severity of problems, and preferred format (online/booklet) moderated the effectiveness., Results: Moderate-high adherence to the exercise program was 59%. The intervention group (n = 46) reported less swallowing and communication problems over time compared to the control group (n = 46) (p-value = 0.013 and 0.004). No difference was found on speech, shoulder problems, patient activation and HRQOL. Time since treatment moderated the effectiveness on speech problems (p-value = 0.025): patients within 6 months after surgery benefitted most from the intervention. Being treated with a neck dissection, treatment indication, severity of problems and format did not moderate the effectiveness., Conclusion: The guided self-help exercise program improves swallowing and communication., Trial Registration: NTR5255., Competing Interests: Declaration of Competing Interest IV obtained funding for research related to In Tune without Cords from the Michel Keijzer Fund (institutional funding). The other authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this era of information technology, big data analysis is entering biomedical sciences. But what is big data, where do they come from and what can we do with it? In this commentary, the main sources of big data are explained, especially in (head and neck) oncology. It also touches upon the need to integrate various sources of clinical, pathological and quality-of-life data. It discusses some initiatives in linking of such datasets on a nation-wide scale in the Netherlands. Finally, it touches upon important issues regarding governance, FAIRness of data and the need to bring into place the necessary infrastructures needed to fully exploit the full potential of big data sets in head and neck cancer., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neopharyngeal stenosis is a recognized sequela of total laryngectomy (TL). We aim to investigate the incidence of stenosis requiring dilation, risk factors for stenosis and complications of dilation., Methods: Retrospective cohort study of patients undergoing TL in two dedicated head and neck centers in the Netherlands., Results: A total of 477 patients, (81% men, median age of 64 at TL) were included. Indication for TL was previously untreated primary tumor in 41%, salvage following (chemo)radiotherapy (CRT) in 44%, dysfunctional larynx in 9% and a second primary tumor in 6%. The cumulative incidence of dilatation at 5 years was 22.8%, and in total 968 dilatations were performed. Median number of dilations per patient was 3 (range 1-113). Female gender, a hypopharynx tumor, and (C)RT before or after the TL were significantly associated with stenosis requiring dilation. We observed 8 major complications (0.8%) predominantly during the first dilation procedures. Use of general anesthesia is a risk factor for complications. The most frequent major complication was severe esophageal perforation (n = 6 in 5 patients)., Conclusion: The cumulative incidence of pharyngeal stenosis needing dilation was 22.8% at 5 years. Roughly half of these patients could be treated with a limited number of dilations, the rest however needed ongoing dilations. Major complications are rare (0.8%) but can be life threatening. General anesthetics is a risk factor for complications, and complications occurred predominantly during the first few dilations procedures. This should alert the physician to be extra careful in new patients., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 1994 a decision analysis, based on the literature and utility ratings for outcome by a panel of experienced head and neck physicians, was presented which showed a threshold probability of occult metastases of 20% to recommend elective treatment of the neck. It was stated that recommendations for the management of the cN0 neck are not immutable and should be reconfigured to determine the optimal management based on different sets of underlying assumptions. Although much has changed and is published in the almost 25 years after its publication, up to date this figure is still mentioned in the context of decisions on treatment of the clinically negative (cN0) neck. Therefore, we critically reviewed the developments in diagnostics and therapy and modeling approaches in the context of decisions on treatment of the cN0 neck. However, the results of studies on treatment of the cN0 neck cannot be translated to other settings due to significant differences in relevant variables such as population, culture, diagnostic work-up, follow-up, costs, institutional preferences and other factors. Moreover, patients may have personal preferences and may weigh oncologic outcomes versus morbidity and quality of life differently. Therefore, instead of trying to establish "the" best strategy for the cN0 neck or "the" optimal cut-off point for elective neck treatment, the approach to optimize the management of the cN0 neck would be to develop and implement models and decision support systems that can serve to optimize choices depending on individual, institutional, population and other relevant variables., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This systematic review gives an extensive overview of the current state of functional imaging during (chemo)radiotherapy to predict locoregional control (LRC) and overall survival (OS) for head and neck squamous cell carcinoma. MEDLINE and EMBASE were searched for literature until April 2018 assessing the predictive performance of functional imaging (computed tomography perfusion (CTp), MRI and positron-emission tomography (PET)) within 4 weeks after (chemo)radiotherapy initiation. Fifty-two studies (CTp: n = 4, MRI: n = 19, PET: n = 26, MRI/PET: n = 3) were included involving 1623 patients. Prognostic information was extracted according the PRISMA protocol. Pooled estimation and subgroup analyses were performed for comparable parameters and outcome. However, the heterogeneity of included studies limited the possibility for comparison. Early tumoral changes from (chemo)radiotherapy can be captured by functional MRI and 18 F-FDG-PET and could allow for personalized treatment adaptation. Lesions showed potentially prognostic intratreatment changes in perfusion, diffusion and metabolic activity. Intratreatment ADC mean increase (decrease of diffusion restriction) and low SUV max (persistent low or decrease of 18 F-FDG uptake) were most predictive of LRC. Intratreatment persistent high or increase of perfusion on CT/MRI (i.e. blood flow, volume, permeability) also predicted LRC. Low SUV max and total lesion glycolysis (TLG) predicted favorable OS. The optimal timing to perform functional imaging to predict LRC or OS was 2-3 weeks after treatment initiation., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is used for detection and (re)staging of prostate cancer. However, healthy salivary, seromucous, and lacrimal glands also have high PSMA-ligand uptake. This study aimed to describe physiologic PSMA-ligand uptake distribution characteristics in the head and neck to aid in PSMA PET/CT interpretation and to identify possible new clinical applications for PSMA-ligand imaging., Study Design: Thirty consecutive patients who underwent PSMA PET/CT for prostate cancer were evaluated. Tracer maximum standardized uptake values (SUV max ) in the salivary, seromucous, and lacrimal glands were determined visually and quantitatively. Overall and intraindividual variations were reported., Results: All gland locations had increased tracer uptake. The mean SUV max  ± standard deviation varied: parotid 12.3 ± 3.9; submandibular 11.7 ± 3.5; sublingual 4.5 ± 1.9; soft palate 2.4 ± 0.5; pharyngeal wall 4.3 ± 1.3; nasal mucosa 3.4 ± 0.9; supraglottic larynx 2.7 ± 0.7; and lacrimal 6.2 ± 2.2. The parotid had the largest overall variation in SUV max (5.2-22.9), and the sublingual glands had the largest mean intraindividual difference (18.1%)., Conclusions: Major and minor salivary and seromucous glands consistently have high PSMA-ligand uptake. Minor gland locations can be selectively visualized by this technique for the first time. This provides potential new applications such as quantification of present salivary gland tissues and individualization of radiotherapy for head and neck cancer or lutetium-177-PSMA radionuclide treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adequate treatment of lymph node metastases is essential for patients with head and neck squamous cell carcinoma (HNSCC). However, there is still no consensus on the optimal surgical treatment of the neck for patients with a clinically positive (cN+) neck. In this review, we analyzed current literature about the feasibility of selective neck dissection (SND) in surgically treated HNSCC patients with cN + neck using the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. From the reviewed literature, it seems that SND is a valid option in patients with cN1 and selected cN2 neck disease (non-fixed nodes, absence of palpable metastases at level IV or V, or large volume ->3 cm-multiple lymph nodes at multiple levels). Adjuvant (chemo) radiotherapy is fundamental to achieve good control rates in pN2 cases. The use of SND instead a comprehensive neck dissection (CND) could result in reduced morbidity and better functional results. We conclude that SND could replace a CND without compromising oncologic efficacy in cN1 and cN2 cases with the above-mentioned characteristics., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Early oral cancer is preferably treated by surgery. Its complete removal is essential for locoregional control and disease-free survival. Inadequate resection margins require adjuvant therapy such as re-resection or (chemo)radiation, that causes extra morbidity and oral discomfort. Intraoral ultrasonography (US) is reported to be of value in determining tumor thickness. Intraoperative visualization of the tumor may facilitate the resection and ensure adequate surgical margins. Furthermore, accurate prediction of tumor thickness could help determine the treatment strategy of the clinically node-negative neck, as thickness and depth of invasion are predictors of cervical metastasis as well as prognosticators of survival. The 8th edition of the American Joint Committee on Cancer staging system for oral squamous cell carcinoma has included depth of invasion as parameter for cT-stage. The aim of this review is to analyze the accuracy of intraoral US in determining tumor thickness in oral cancer. A systematic search was conducted, and the quality of the included papers was assessed using the QUADAS-2 tool for diagnostic accuracy studies. Subsequently, a meta-analysis was performed on the available individual participant data of 240 patients. Most of the twelve included studies focused on T1-2 tongue cancer (n = 129). Meta-analysis showed a high correlation in tumor thickness within this subgroup as measured by intraoral US and histopathology (r = 0.82, p < .001), with minor overestimation of 0.5 mm on US. It is concluded that intraoral US is very accurate in determining tumor thickness in early oral tongue cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: Diffusion weighted imaging (DWI) is a frequently performed MRI sequence in cancer patients. While previous studies have shown the clinical value of the apparent diffusion coefficient (ADC) for response prediction and response monitoring, less is known about the biological background of ADC. In the tumor microenvironment, hypoxia and increased proliferation of tumor cells contribute to resistance to (radio-)therapy, while high T-cell influx is related to better prognosis. We investigated the correlation between these three tissue characteristics and ADC in 20 oropharyngeal squamous cell carcinoma patients., Materials and Methods: 20 patients with oropharyngeal squamous cell carcinoma (OPSCC) who underwent 1.5 T MRI, including DWI were included in this pilot study. Corresponding formalin-fixed paraffin-embedded tumor tissues were immunohistochemically analyzed for protein expression of hypoxia-inducible factor 1a (HIF-1a), Ki-67 and CD3. Expression of these markers was correlated with ADC., Results: ADC negatively correlated with Ki-67 expression (p = .024) in tumor cells. There was a significant negative correlation between ADC and CD3-positive cell count (p = .009). No correlation was observed between HIF-1a expression and ADC., Conclusion: This study suggests that ADC reflects characteristics of tumor cells as well as the surrounding microenvironment. Interestingly, high tumor proliferation (a negative prognostic factor) and high T-cell influx (a beneficial prognostic factor) are both associated with a lower ADC. Further studies should be performed to correlate ADC to these histological characteristics in relation to previously known factors that affect ADC, to gain further knowledge on the role of DW-MRI in diagnostics and personalized medicine., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Liquid biopsy is a minimally invasive detection method for molecular biomarkers in body fluids which may serve as a novel tool in management of head and neck cancer. The purpose of this systematic review is to outline the current status of liquid biopsy in head and neck squamous cell carcinoma (HNSCC) patients by systematically identifying and qualifying all published studies on the diagnostic or prognostic value of cell-free nucleic acids detection for posttreatment disease monitoring and/or disease outcome. A search was performed in PubMed, EMBASE, and Cochrane Library. Thirty articles met the inclusion criteria for further analysis. Study and patient characteristics, molecular analysis method and treatment or prognostic outcomes were extracted. Seventeen studies investigated circulating miRNAs in blood. Of these studies, 16 found statistically significant results for a total of 24 different candidate miRNAs for prognostication or treatment monitoring. The remaining studies investigated circulating tumor DNA by targeting somatic mutations, allelic imbalances, hypermethylation, or HPV-DNA. Of these studies, 2 found a statistically significant association between nucleic acid levels (tumor DNA targeted by allelic imbalances and HPV-DNA) in blood and/or saliva and prognostic outcome. One study found significantly different pre- and posttreatment levels of mitochondrial DNA in serum. Despite large differences among these studies in both design and results, individual results are promising and provide ground for more large-scale studies with standardized serial assessment of patient samples in the future., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Diagnosing residual malignancy after (chemo)radiotherapy presents a diagnostic challenge because of overlapping symptoms and imaging characteristics. We assessed the added diagnostic value of diffusion-weighted imaging (DWI) to positron emission tomography combined with computed tomography (PET-CT) in patients with head and neck squamous cell carcinoma (HNSCC) with residual fluorodeoxyglucose ( 18 F-FDG) uptake at the primary tumor site 3 months after (chemo)radiotherapy., Study Design: For this retrospective study from January 2010 to June 2012, 22 cases (median patient age of 61 years; range 41-77 years) were included for analysis. Both PET-CT and magnetic resonance imaging (MRI), including DWI, were performed as part of the institutional protocol and were qualitatively assessed for the presence of residual malignancy at the primary tumor site., Results: The sensitivity and specificity of PET-CT were 100% and 47%, respectively. For DWI, sensitivity and specificity were 80% and 82%, respectively. When DWI was added to PET-CT with residual 18 F-FDG uptake, and only a positive read on both PET-CT and DWI was considered to be overall positive, sensitivity remained 80% (95% confidence interval [CI] 28%-99%), and specificity was 88% (95% CI 64%-99%)., Conclusions: In this pilot study of the selected patients with residual 18 F-FDG uptake at the primary tumor site 3 months after (chemo)radiotherapy, we demonstrated that the addition of DWI to PET-CT has the potential to increase the specificity of the response evaluation with limited decrease in sensitivity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Low skeletal muscle mass (SMM) or sarcopenia is emerging as an adverse prognostic factor for chemotherapy dose-limiting toxicity (CLDT) and survival in cancer patients. Our aim was to determine the impact of low SMM on CDLT in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with primary radiochemotherapy (RCT)., Patients and Methods: Consecutive patients diagnosed with LA-HNSCC and treated with primary RCT between 2007 and 2011 in our center were included. Clinical variables were retrospectively retrieved and SMM was measured at the level of the third cervical vertebra using pre-treatment head and neck CT-scans. After determining a cut-off value for low SMM, multivariate analysis was performed to identify prognostic factors for CDLT., Results: Of 112 patients included, 30.4% experienced CDLT. The optimal cut-off value for low SMM as a predictor of CDLT was ≤43.2cm 2 /m 2 . Using this cut-off, 54.5% patients had low SMM. Patients with low SMM experienced CDLT more frequently than patients with normal SMM (44.3% vs. 13.7%, p<0.001) and received a higher dose of chemotherapy/kg lean body mass (estimated from SMM, p=0.044). At multivariate analysis, low SMM was independently inversely associated with CDLT (OR 0.93, 95%CI: 0.88-0.98). Patients experiencing CDLT had a lower overall survival than patients who did not (mean 36.6vs. 54.2months, p=0.038)., Conclusion: Low SMM is an independent risk factor for CDLT in LA-HNSCC patients treated with primary RCT. Pre-therapeutic estimation of SMM using routine CT-scans of the head and neck region may identify patients at risk of CDLT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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/mm 2 . 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., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The management of the clinically node negative (N0) neck in patients with squamous cell carcinoma of the maxilla (MSCC) is a matter of debate. In this retrospective cohort study the incidence of occult metastases is determined in clinically N0 MSCCs, as well as histopathological factors associated with occult metastases., Patients and Methods: 95 patients with clinically N0 MSCCs had maxillectomy. 18 patients with elective treatment of the neck were excluded. The remaining 77 patients followed a 'watch and wait' strategy for the neck and were included in this study. The incidence of occult metastases was calculated and Cox regression analysis was used to assess the predictive and prognostic value of clinical and histopathological parameters., Results: Occult metastases occurred in 14.3% (11/77) in the whole cohort and in 19.0% (11/58) in T2-T4 clinically N0 MSCC. Patients with T4 clinically N0 MSCC, showed the highest rate of occult metastases (24.1%). 45.5% of the occult metastases developed in the contralateral neck. The hazard ratio to develop occult metastasis was 5.39 (p=0.017) for perineural growth and 11.12 (p=0.003) for perivascular invasion. Salvage for cervical recurrence was poor at 40%., Conclusion: We recommend elective treatment of the neck or improved diagnostics to detect occult metastases in T2-T4 clinically N0 MSCC or when the biopsy specimen shows perineural growth or perivascular invasion. Since the contralateral neck was involved in 45.5% of the regional recurrences, we emphasize the importance of bilateral neck management. Improved diagnostics, like sentinel node biopsy, could possibly further reduce occult metastatic disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Patients with head and neck cancer (HNC) have a higher risk of malnutrition and sarcopenia, which is associated with adverse clinical outcome. As abdominal CT-imaging is often used to detect sarcopenia, such scans are rarely available in HNC patients, possibly explaining why no studies investigate the effect of sarcopenia in this population. We correlated skeletal muscle mass assessed on head and neck CT-scans with abdominal CT-imaging., Methods: Head and neck, and abdominal CT-scans of trauma (n=51) and HNC-patients (n=52) were retrospectively analyzed. On the head and neck CT-scans, the paravertebral and sternocleidomastoid muscles were delineated. On the abdominal CT-scans, all muscles were delineated. Cross-sectional area (CSA) of the muscles at the level of the C3 vertebra was compared to CSA at the L3 level using linear regression. A multivariate linear regression model was established., Results: HNC-patients had significantly lower muscle CSA than trauma patients (37.9 vs. 45.1cm 2 , p<0.001, corrected for sex and age). C3 muscle CSA strongly predicted L3 muscle CSA (r=0.785, p<0.001). This correlation was stronger in a multivariate model including sex, age and weight (r=0.891, p<0.001)., Discussion: Assessment of skeletal muscle mass on head and neck CT-scans is feasible and may be an alternative to abdominal CT-imaging. This method allows assessment of sarcopenia using routinely performed scans without additional imaging or additional patient burden. Identifying sarcopenic patients may help in treatment selection, or to select HNC patients for physiotherapeutic or nutritional interventions to improve their outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Assessment of the impact of a sentinel node biopsy (SNB)-based strategy in cT1/T2 N0 oral cancer on the course of health related quality of life, psychological distress, and shoulder disability, and evaluation of the patients' perspective on neck management strategies., Study Design: Fifty-two patients (39 SNB negative; 13 SNB positive) completed the European Organization for Research and Treatment of Cancer (EORTC) questionnaires-QLQ-C30 and QLQ-H&N35, and the HADS, IES, and SDQ questionnaires at baseline, after SNB diagnosis and at 6 months of follow-up. Objective shoulder measurements were performed after 2 years and interviews were conducted after 4.5 months of follow-up., Results: All the scores of the questionnaires were not significantly different between SNB negative and SNB positive patients. Objective shoulder functioning was similar. Most patients preferred a SNB-based strategy to an elective neck dissection strategy., Conclusions: The impact of a SNB-based strategy in patients with cT1/T2 N0 oral cancer is comparable for SNB-negative and SNB-positive patients in terms of health-related quality of life, psychological distress and shoulder functioning. Most patients preferred the SNB-based strategy over the elective neck dissection strategy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To calculate the cost-utility of different strategies for the detection of occult lymph node metastases in cT1-T2N0 oral cancer., Methods: A decision tree followed by a Markov model was designed to compare the cost-utility of the following strategies: (a) USgFNAC (ultrasound guided fine needle aspiration cytology), (b) SLNB (sentinel lymph node biopsy), (c) USgFNAC and, if negative, SLNB (d) END (elective neck dissection). Data was collected from 62 patients in four Dutch head and neck centres. Utilities were measured with the EQ5D questionnaire and resource use was recorded from patient charts. Costs were calculated from a hospital perspective. Uncertainty was explored with scenario analyses and probabilistic sensitivity analyses., Results: With a 5- or 10-year time horizon, SLNB results in the highest number of additional quality-adjusted life years (QALYs, 0.12 and 0.26, respectively) for the smallest additional costs (€56 and €74, respectively) compared to USgFNAC. With a lifetime horizon END results in the highest number of additional QALYs (0.55) for an additional €1.626 per QALY gained compared to USgFNAC. When we make different assumptions regarding the duration of disutilities (⩾5 years) or the improvement (⩾3%) of sensitivity of SLNB, SLNB is the most favourable strategy from all time horizons., Conclusion: SLNB is a good diagnostic strategy to evaluate cT1-T2N0 oral cancer. SLNB is the preferred strategy in a 5- or 10-year time horizon. From a lifetime horizon, END may be preferred. SLNB may become the optimal strategy from all time horizons if its sensitivity can be slightly improved., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Early oral cavity squamous cell carcinoma (OCSCC) management appears to vary both within and between countries. Variation in practice can be an indicator of absence of evidence-based management and may negatively influence survival and morbidity. The exact variation and the relationship to differences in guidelines are unknown. This study aimed to report on these variations in the Netherlands, UK, and USA, and to evaluate them., Methods: Information regarding the variation in OCSCC management strategies was obtained from a questionnaire sent to representatives of head and neck cancer centers in the Netherlands, UK, and USA. Within-country and between-country variations were also assessed in light of the different guidelines., Results: In total, representatives of 45 centers completed the questionnaire; 10 from the Netherlands, 26 from the UK and 9 from the USA. Our results demonstrate a distinct variation in the diagnoses, treatment and follow-up of OCSCC, both within and between countries. Only a small amount of variation between countries could be linked to differences in guidelines., Conclusions: There is high variation in the management of the neck in OCSCC. There seem to be a need for direct evidence about optimal management decisions to establish more evidence-based management and uniform practice., (Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Purpose: Due to the rarity and the variety of histological types of sinonasal cancers, there is a paucity of data regarding strategy for their optimal treatment. Generally, outcomes of advanced and higher grade tumors remain unsatisfactory, despite the employment of sophisticated surgical approaches, technical advances in radiation techniques and the use of heavy ion particles. In this context, we critically evaluated the role of systemic therapy as part of a multidisciplinary approach to locally advanced disease., Results: Induction chemotherapy has shown encouraging activity and could have a role in the multimodal treatment of patients with advanced sinonasal tumors. For epithelial tumors, the most frequently employed chemotherapy is cisplatin, in combination with either 5-fluorouracil, taxane, ifosfamide, or vincristine. Only limited experiences with concurrent chemoradiation exist with sinonasal cancer. The role of systemic treatment for each histological type (intestinal-type adenocarcinoma, sinonasal undifferentiated carcinoma, sinonasal neuroendocrine carcinoma, olfactory neuroblastoma, sinonasal primary mucosal melanoma, sarcoma) is discussed., Conclusions: The treatment of SNC requires a multimodal approach. Employment of systemic therapy for locally advanced disease could result in better outcomes, and optimize the therapeutic armamentarium. Further studies are needed to precisely define the role of systemic therapy and identify the optimal sequencing for its administration in relation to local therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The aim of this report is to describe the history of sentinel node biopsy in head and neck cancer. Sentinel node biopsy is a minimally invasive technique to select patients for treatment of metastatic lymph nodes in the neck. Although this procedure has only recently been accepted for early oral cancer, the first studies on visualization of the cervical lymphatic vessels were reported in the 1960s. In the 1980s mapping of lymphatic drainage from specific head and neck sites was introduced. Sentinel node biopsy was further developed in the 1990s and after validation in this century the procedure is routinely performed in early oral cancer in several head and neck centers. New techniques may improve the accuracy of sentinel node biopsy further, particularly in difficult subsites like the floor of mouth., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Pretreatment screening on distant metastases is particularly useful in head and neck squamous cell carcinoma (HNSCC) patients with high risk factors., Methods: In a retrospective study of 88 patients with previously identified clinical high risk factors the predictive value of standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) in the primary tumor and in the lymph node metastases for the development of distant metastases was examined. Different SUVs corrected for plasma glucose levels and body mass index were calculated and analysed in different patient groups: all patients (n=88), patients with a follow up >6months (n=73), not previously treated patients (n=51) and not previously treated patients with a follow up >6months (n=40)., Results: Twenty-four of the 88 (27%) high risk HNSCC patients were diagnosed with distant metastases during screening and follow up. No correlation was found between different SUVs of the primary tumor and lymph nodes metastases and the development of distant metastases., Conclusion: SUVs of primary tumor and lymph node on FDG-PET are not predictive for distant metastases in a (selected) group of patients with already high risk factors for distant metastases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: Evaluation of accuracy and interobserver variation of diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDGPET-CT) to detect residual lymph node metastases after chemoradiotherapy (CRT) in advanced staged head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: Retrospectively, routinely performed DW-MRI (n=73) and 18F-FDG-PET-CT (n=58) 3months after CRT in HNSCC-patients with advanced nodal disease (N2-N3) were assessed by two radiologists and two nuclear medicine physicians (individually and in consensus). Imaging was scored dichotomously and on a five-point Likert scale. We also explored different scenarios for the potential added value of DW-MRI to PET-CT using the consensus Likert scale. Histopathology and a follow-up of 9months after CRT served as reference standard., Results: Five patients (7%) had residual regional disease. DW-MRI showed a sensitivity of 60% and a specificity of 93%, vs. 100% and 84% for PET-CT, respectively. DW-MRI and PET-CT observers had 'moderate' and 'substantial' interobserver agreement (κ=0.58 and κ=0.64, respectively) with the dichotomous system. The combination of PET-CT and DW-MRI showed a sensitivity of 100% and a specificity of 95%., Conclusion: The high sensitivity of PET-CT authorizes a neck dissection in all patients with a positive test result and the high specificity of DW-MRI justifies avoidance of invasive neck dissections if the test is negative. Interobserver agreement varied as a function of test positivity criteria. Adding DW-MRI to PET-CT seemed to increase the specificity of PET-CT alone, thereby ensuring that less patients are exposed to unnecessary neck dissections., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Purpose: Previously identified high risk factors for development of distant metastases are: three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases, locoregional tumor recurrence and second primary tumors. The aims of this study were to validate these specific risk factors and to investigate the impact of time (i.e. during screening or follow-up) of detection of distant metastases on survival., Material and Methods: From a total of 301 HNSCC patients with high risk factors who were scheduled for extensive treatment and underwent pretreatment screening on distant metastases using chest CT and/or whole body PET(-CT) (in some patients combined with whole body MRI), the high risk factors, the development and time point of distant metastases and survival were analyzed., Results: Forty-four percent developed distant metastases. Multivariate analysis revealed that bilateral lymph node metastases is the strongest predictive factor. Locoregional recurrence and second primary tumor were the risk factors associated with the lowest cumulative incidence. However, if the risk factor locoregional recurrence was split into local and regional recurrences, regional recurrence became a high risk factor. The more high risk factors a patient had the lower the 5-year distant metastases free survival was. Patients with distant metastases detected pretreatment has a significant worse survival (corrected for lead time bias) compared to patients with distant metastases diagnosed during follow-up., Conclusions: The validity of three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6cm, low jugular lymph node metastases and regional recurrence as high risk factors for the development of distant metastases was confirmed. If more high risk factors are present the cumulative incidence of distant metastases increases significantly. The detection of distant metastases by pretreatment screening worsens the overall survival as compared to distant metastases detected during follow-up., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Rationale: Inadequate intraoperative visualization of the sentinel node can hamper its harvest. Freehand SPECT is a 3D tomographic imaging modality based on the concepts of SPECT, which can be used for intraoperative visualization and navigation towards the sentinel node in order to improve its localization and removal during surgery., Patients and Methods: The use of freehand SPECT was evaluated during 66 sentinel node biopsy procedures in early stage oral cancer patients. Intraoperative detection of sentinel nodes was compared with preoperative identified sentinel nodes on lymphoscinitigraphic examination. Additional value of freehand SPECT was subjectively scored by the surgeon directly following the biopsy procedure., Results: Freehand SPECT was able to detect 94% of sentinel nodes intraoperatively. Most sentinel nodes not detected (7 out of 9) were located in level I of the neck. Freehand SPECT appeared to be of additional value for facilitating the intraoperative detection of the sentinel node in 24% of procedures., Conclusion: The use of the freehand SPECT system is feasible in the intraoperative detection of sentinel nodes in early stage oral cancer. Freehand SPECT provides helpful information facilitating the SN biopsy procedure in a quarter of cases. However, freehand SPECT cannot detect all SNs which are located in the vicinity of the injection site., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This systematic review gives an extensive overview of the current state of perfusion-weighted magnetic resonance imaging (MRI) for head and neck squamous cell carcinoma (HNSCC). Pubmed and Embase were searched for literature until July 2014 assessing the diagnostic and prognostic performance of perfusion-weighted MRI in HNSCC. Twenty-one diagnostic and 12 prognostic studies were included for qualitative analysis. Four studies used a T2(∗) sequence for dynamic susceptibility (DSC)-MRI, 29 studies used T1-based sequences for dynamic contrast enhanced (DCE)-MRI. Included studies suffered from a great deal of heterogeneity in study methods showing a wide range of diagnostic and prognostic performance. Therefore we could not perform any useful meta-analysis. Perfusion-weighted MRI shows potential in some aspects of diagnosing HNSCC and predicting prognosis. Three studies reported significant correlations between hypoxia and tumor heterogeneity in perfusion parameters (absolute correlation coefficient |ρ|>0.6, P<0.05). Two studies reported synergy between perfusion-weighted MRI and positron emission tomography (PET) parameters. Four studies showed a promising role for response prediction early after the start of chemoradiotherapy. In two studies perfusion-weighted MRI was useful in the detection of residual disease. However more research with uniform study and analysis protocols with larger sample sizes is needed before perfusion-weighted MRI can be used in clinical practice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer., Patients and Methods: Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology. Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS)., Results: Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5 months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p=0.916, OS: p=0.134, DSS: p=0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%., Conclusion: SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck., (Copyright © 2014 Elsevier Ltd. All rights reserved.)