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Background Patterns of nodal involvement in adenoid cystic carcinoma (ACC) of the head and neck have not been sufficiently assessed to guide a decision of prophylactic neck dissection (ND). The objective of this study is to analyse the influence of ND on event-free survival (EFS) for patients with cN0 ACC. Patients and methods A multicentre prospective study was conducted between 2009 and 2018. Patients presenting cN0 non-metastatic ACC on any site, and who received surgery on the tumour, were included. EFS was the main judgement criterion. A comparative survival analysis between the groups that received a ND versus those that did not was performed, using a propensity score. Analyses were carried out using the R software. Results Between 2009 and 2018, 322 patients with cN0 ACC were included, out of which 58% were female. The average age was 53 years. Tumours were in minor salivary glands in 58% of cases, and 52% had T3/T4 stages. ND was performed on 46% of patients. Out of them, seven had histological lymph node invasion, out of which six had tumour infiltration in the mucosa of oral cavity. After propensity score, the median EFS for N0 patients with ND was 72 months (95% Confidence Interval (CI) [48–81]), compared to 73 months (95% CI [52–85]) for patients without ND (HR = 1.33; 95% CI [0.82–2.16]; p = 0.2). Conclusion ND of cN0 patients does not provide any benefit on EFS, which suggests that its application on such patients is not necessary.

International audience; ObjectiveTo assess long-term quality of life (QoL) and psycho-social outcomes, and to determine their predictive factors after oropharyngeal cancer (OPC) surgery and radial forearm free-flap (RFFF) reconstruction.MethodsPatients who had undergone OPC surgery and RFFF reconstruction who were still alive and disease-free at least 1 year after surgery were enrolled in this prospective multicentric study. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Core (QLQ-C30) and Head and Neck Cancer (QLQ-H&N35) QoL questionnaires, the Voice Handicap Index (VHI-10) questionnaire and the Hospital Anxiety and Depression Scale (HADS). The level of dysphagia was evaluated using the Dysphagia Handicap Index (DHI) and the Dysphagia Outcomes and Severity Scale (DOSS). Predictive factors of these clinical outcomes were determined in univariate and multivariate analysis.ResultsA total of 58 patients were included in this study. Long-term QoL and functioning scales scores were well-preserved (all superior to 70%). Main persistent symptoms were fatigue, reduced sexuality and oral function-related disorders (swallowing, teeth, salivary and mouth-opening problems). HADS anxiety and depression scores were 7.2 and 5.4, respectively. Twenty-one (36%) patients presented an anxiodepressive disorder (HADS global score ≥ 15). Among the 21 patients who were still working before surgery, 11 (52%) had returned to work at the time of our study. The HADS global score (p < 0.001) was the main predictor of QoL, VHI-10 and DOSS scores.ConclusionsPsychological distress is the main determinant of long-term QoL and is therefore of critical importance in the multidisciplinary management of OPC patients.

Contains fulltext : 246727.pdf (Publisher’s version ) (Open Access) 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. 12 p.

Objectives: To examine whether adolescents exceed recommended noise exposure limits when using personal listening devices (PLDs) and to investigate the relationship between objectively measured PLD use and hearing thresholds Study Design: Cross-sectional study. Setting: This study was embedded within an ongoing prospective birth cohort study in Rotterdam, the Netherlands. Data were collected from May 2017 to September 2019. Methods: A smartphone application was developed to measure daily noise exposure from PLDs. Listening habits were monitored among 314 adolescents with a mean age of 13 years 7 months (SD, 5 months), of whom 51.6% were male. Hearing acuity was measured by pure tone audiometry, and tympanometry was performed in both ears. Results: Within the study group, 2.2% adolescents exceeded the recommended daily noise dose (85 dBA as an 8-hour time-weighted average) among all days when the application was active and 9.9% when among only the listening days. No significant correlation was found between the daily noise dose from PLDs and pure tone thresholds. Conclusions: The majority of adolescents exhibited listening habits that could be considered safe. As noise-induced hearing loss develops slowly over time, it could be that the effects of PLD use on hearing are not evident yet in this young population with a relatively short duration of PLD use.

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV‐status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV‐infections, figures on HPV‐attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid‐based workflow to assess HPV‐prevalence in a consecutive cohort of 1016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16‐immunohistochemistry (p16‐IHC) as surrogate marker for transforming HPV‐infection and independent prognosticator. All OCSCC‐patients diagnosed between 2008 and 2014 at two Dutch university medical centers were included (N = 1069). Formalin‐fixed, paraffin‐embedded (FFPE)‐samples of 1016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE‐blocks and tested for HPV. P16‐IHC was performed on 580 OCSCCs, including all HPV‐positive tumors. From 940 samples (92.5%), nucleic acids were of sufficient quality for HPV‐testing. In total, 21 (2.2%) OCSCCs were HPV DNA‐positive. All HPV DNA‐positive tumors were E6 mRNA‐positive and considered as true HPV‐positive. There was no difference in survival between HPV‐positive and HPV‐negative OCSCCs. In total, 46 of 580 (7.9%) OCSCCs were p16‐immunopositive, including all HPV‐positive tumors. Survival was comparable in p16‐positive and p16‐negative OCSCCs. To conclude, HPV‐prevalence is very low in OCSCC and neither HPV‐status nor p16‐status affects outcome. Based on these data, determining HPV‐status in OCSCC seems irrelevant for clinical management., What's new? While human papillomavirus (HPV)‐infection is prognostic for oropharyngeal squamous cell carcinoma (OCSCC), its role and prognostic impact in OCSCC remain uncertain. In the present study, nucleic acid‐based HPV‐testing of a cohort of 1016 tumor samples collected from OCSCC patients diagnosed between 2008 and 2014 reveals very low HPV‐prevalence in OCSCC. In addition, no difference was found in survival between HPV‐positive and HPV‐negative tumors. The findings indicate that HPV is uncommon in OCSCC and, when present, has no impact on survival, providing new and important insight into the ongoing debate regarding the role of HPV in OCSCC.

Purpose This study investigated the effects of psychosocial working conditions on mental health-related long-term sickness absence and whether distress, work satisfaction, burnout, engagement, and work ability mediated the associations between psychosocial working conditions and mental health-related long-term sickness absence. Methods This cohort study included 53,833 non-sick listed workers who participated in occupational health surveys between 2010 and 2013. The effects of the individual psychosocial working conditions on mental long-term sickness absence were analyzed using univariable and multivariable logistic regression analyses. Mediation analyses were performed to examine the mediating role of distress, burnout, work satisfaction, engagement, and work ability between psychosocial working conditions and mental long-term sickness absence. The mediation analyses were performed using structural equation modeling. Results Role clarity, cognitive demands, emotional demands, work variety, learning opportunities, and co-worker support were related to mental health-related long-term sickness absence after adjustment for other working conditions. The relationship between emotional demands and mental health-related long-term sickness absence was the strongest, OR 1.304 (p Conclusions Psychosocial working conditions are related to mental health-related long-term sickness absence. After correction for other working conditions, the association between emotional demands and mental health-related long-term sickness absence was the strongest. Psychosocial working conditions are indirectly related to mental health-related long-term sickness absence through mediation by distress, work satisfaction, and work ability.

Objectives: Tinnitus is a common hearing-related disorder, which may have a large impact on daily life. With aging populations worldwide, it is important to gain insight in the occurrence of tinnitus at older ages and to understand its relationship with age-related hearing loss. We investigated the prevalence of tinnitus among a general aging population, across age strata and hearing status. Study Design: Cross-sectional. Setting: The population-based Rotterdam Study. Methods: A total of 6098 participants underwent tinnitus assessment, and 4805 had additional hearing assessment. We determined tinnitus prevalence per 5-year age groups. Hearing impairment was defined as ≥25–dB HL worse ear pure tone average (0.5, 1, 2, 4 kHz). We investigated with multivariable logistic regression the association between hearing impairment and tinnitus. Tinnitus handicap was assessed in 663 participants with daily tinnitus via the Tinnitus Handicap Inventory–screening version (THI-s). Results: Tinnitus was prevalent in 21.4% (n = 1304). Prevalent tinnitus was evenly distributed over 5-year age groups. Participants with hearing impairment were more likely to have tinnitus (odds ratio, 2.27; 95% CI, 1.92-2.69) as compared with those without hearing impairment. The median THI-s score was 4 (interquartile range, 0-10), indicating a slight handicap, and 14.6% of the participants reported a moderate or severe handicap (THI-s ≥16). Conclusions: In a general elderly population, 1 in 5 persons has tinnitus. Of those with tinnitus, for 1 per 10 persons, the presence of tinnitus interfered with daily life. Participants with hearing impairment were twice as likely to have tinnitus. Despite the age-dependent occurrence of hearing impairment, no such age dependency was found for tinnitus.

Research question: How does follicle distribution evolve in the human ovarian cortex between the ages of 20 and 35 years? Design: Fragments of ovarian cortex from women undergoing unilateral oophorectomy for fertility preservation were obtained for quantitative histological assessment, including recording the two-dimensional coordinates of the follicles. Data were analysed using spatial statistical methods. Results: A total of 53 ovarian cortex tissue samples, containing 1–803 follicles each, were obtained from 14 women aged 20–35 years. Primordial and transitory follicles lay in a clustered manner in the human ovarian cortex, with an average cluster radius of around 270 µm (95% confidence interval 154–377 µm; n = 49). Follicle density declined with age (P = 0.006, n = 13), and the distance from the nearest neighbouring follicle increased (P = 0.004, n = 13). Cluster radius decreased with age (P = 0.02, n = 13), but the degree of clustering tended to increase (P = 0.11, n = 13). In the majority of the samples, follicles at different stages lay in different clusters (P < 0.05, n = 13). Conclusions: This study shows that primordial and transitory follicles lie in different clusters in the human ovarian cortex. Spatio-temporal computer simulation suggests that interfollicular signals may hinder follicle loss and may therefore drive clustered follicle distribution. In clinical practice, the woman's age should be taken into account when assessing follicle density, as follicle distribution is increasingly clustered with advancing age.

Contains fulltext : 231712.pdf (Publisher’s version ) (Open Access) BACKGROUND: Oncokompas is a web-based self-management application that supports cancer survivors to monitor their health-related quality of life (HRQOL) and symptoms, and to obtain personalised feedback and tailored options for supportive care. In a large randomised controlled trial among survivors of head and neck cancer, colorectal cancer, and breast cancer and (non-)Hodgkin lymphoma, Oncokompas proved to improve HRQOL, and to reduce several tumour-specific symptoms. Effect sizes were however small, and no effect was observed on the primary outcome patient activation. Therefore, this study aims to explore which subgroups of cancer survivors may especially benefit from Oncokompas. MATERIALS AND METHODS: Cancer survivors (n = 625) were randomly assigned to the intervention group (access to Oncokompas, n = 320) or control group (6 months waiting list, n = 305). Outcome measures were HRQOL, tumour-specific symptoms, and patient activation. Potential moderators included socio-demographic (sex, age, marital status, education, employment), clinical (tumour type, stage, time since diagnosis, treatment modality, comorbidities), and personal factors (self-efficacy, personal control, health literacy, Internet use), and patient activation, mental adjustment to cancer, HRQOL, symptoms, and need for supportive care, measured at baseline. Linear mixed models were performed to investigate potential moderators. RESULTS: The intervention effect on HRQOL was the largest among cancer survivors with low to moderate self-efficacy, and among those with high personal control and those with high health literacy scores. Cancer survivors with higher baseline symptom scores benefitted more on head and neck (pain in the mouth, social eating, swallowing, coughing, trismus), and colorectal cancer (weight) specific symptoms. DISCUSSION: Oncokompas seems most effective in reducing symptoms in head and neck cancer and colorectal cancer survivors who report a higher burden of tumour-specific symptoms. Oncokompas seems most effective in improving HRQOL in cancer survivors with lower self-efficacy, and in cancer survivors with higher personal control, and higher health literacy.

RationalePaediatric laryngotracheal stenosis (LTS) is often successfully corrected with open airway surgery. However, respiratory and vocal sequelae frequently remain. Clinical care and surgical interventions could be improved with better understanding of these sequelae.ObjectiveThe objective of this cross-sectional study was to develop an upper airway MRI protocol to obtain information on anatomical and functional sequelae post-LTS repair.MethodsForty-eight patients (age 14.4 (range 7.5–30.7) years) and 11 healthy volunteers (15.9 (8.2–28.8) years) were included. Spirometry and static and dynamic upper airway MRI (3.0 T, 30 min protocol) were conducted. Analysis included assessment of postoperative anatomy and airway lumen measurements during static and dynamic (inspiration and phonation) acquisitions.Main resultsGood image quality without artefacts was achieved for static and dynamic images in the majority of MRIs. MRI showed vocal cord thickening in 80.9% of patients and compared with volunteers, a significant decrease in vocal cord lumen area (22.0 (IQR 17.7–30.3) mm2 vs 35.1 (21.2–54.7) mm2, p=0.03) but not cricoid lumen area (62.3±27.0 mm2 vs 66.2±34.8 mm2, p=0.70). Furthermore, 53.2% of patients had an A-frame deformation at site of previous tracheal cannula, showing lumen collapse during inspiration. Dynamic imaging showed incomplete vocal cord abduction during inspiration in 42.6% and incomplete adduction during phonation in 61.7% of patients.ConclusionsStatic and dynamic MRI is an excellent modality to non-invasively image anatomy, tissue characteristics and vocal cord dynamics of the upper airways. MRI-derived knowledge on postsurgical LTS sequelae might be used to improve surgery.

OBJECTIVE: As part of the value-based healthcare programme in our hospital, a set of patient-reported outcome measures was developed together with patients and implemented in the dedicated Turner Syndrome (TS) outpatient clinic. This study aims to investigate different aspects of health-related quality of life (HR-QoL) and psychosocial functioning in women with TS in order to establish new possible targets for therapy.DESIGN/PARTICIPANTS: A comprehensive set of questionnaires (EQ-5D, PSS-10, CIS-20, Ferti-QoL, FSFI) was developed and used to capture different aspects of HR-QoL and psychosocial functioning in a large cohort of adult women with Turner syndrome. All consecutive women, ≥18 years, who visited the outpatient clinic of our tertiary centre were eligible for inclusion.RESULTS: Of the eligible 201 women who were invited to participate, 177 women (age 34 ± 12 years, mean ± SD) completed at least one of the validated questionnaires (88%). Women with TS reported a lower health-related quality of life (EQ-5D: 0.857 vs 0.892, P = .003), perceived more stress (PSS-10:14.7 vs 13.3; P = .012) and experienced increased fatigue (CIS-20: P < .001) compared to the general Dutch population. A relationship between noncardiac comorbidities (eg diabetes, orthopaedic complaints) and HR-QoL was found (R = .508).CONCLUSIONS: We showed that TS women suffer from impaired HR-QoL, more perceived stress and increased fatigue compared to healthy controls. A relationship between noncardiac comorbidities and HR-QoL was found. Especially perceived stress and increased fatigue can be considered targets for improvement of HR-QoL in TS women.

BACKGROUND: Language is a complex neurodevelopmental phenomenon. Approximately 45% of children born very preterm (VP) show mild-to-severe language problems throughout childhood. Nevertheless, in most hospitals in Europe language functions are not routinely assessed at follow-up.OBJECTIVE: To give clear indications for extensive language assessment in school-aged children born VP, based on routinely assessed intelligence and behavioral problems.METHOD: Language functions of 63 10-year-old children born VP (RESULTS: The mean language score was significantly lower than the verbal intelligent quotient (VIQ; mean difference = 6.4, p < .001, d=.48) and the mean vocabulary knowledge (mean difference = 9.3, p < .001, d=.70). Besides, VIQ (β = .649, p = .001) and performance IQ (PIQ; β = .260, p = .035) were significantly associated with language scores. Significant predictors of language scores were number of days of assisted ventilation (β = -.592, p = .015) and mother's vocabulary knowledge (β =.473, p = .014), rather than mother's educational level (β =.139, p = .956).CONCLUSIONS: Children born VP had language problems that were not expected from their significantly higher VIQ and vocabulary knowledge. Clinicians assessing these children should be aware of possible language problems, which cannot be detected with a simple vocabulary task. Our findings provide evidence of the need for adequate language assessments by a speech-language pathologist in children born VP, especially in those with VIQ scores in the low average range.

Background Head and Neck cancer (HNC) is characterized by significant mortality and morbidity. Treatment is often invasive and interferes with vital functions, resulting in a delicate balance between survival benefit and deterioration in quality of life (QoL). Therefore, including prognostic information during patient counseling can be of great importance. The first aim of this study was to explore HNC patients’ preferences for receiving prognostic information: both qualitative (general terms like “curable cancer”), and quantitative information (numbers, percentages). The second aim of this study was to explore patients’ views on “OncologIQ”, a prognostic model developed to estimate overall survival in newly diagnosed HNC patients. Methods We conducted a single center qualitative study by organizing five focus groups with HNC patients (n = 21) and their caregivers (n = 19), categorized in: 1) small laryngeal carcinomas treated with radiotherapy or laser, 2) extensive oral cavity procedures, 3) total laryngectomy, 4) chemoradiation, 5) other treatments. The patients’ perspective was the main focus. The interview guide consisted of two main topics: life-expectancy and the prognostic model OncologIQ. All focus groups were recorded, transcribed and coded. Themes were derived using content analysis. Results While all patients considered it somewhat to very important to receive information about their life-expectancy, only some of them wanted to receive quantitative information. Disclosing qualitative prognostic information like “the cancer is curable” would give enough reassurance for most patients. Overall, patients thought life-expectancy should not be discussed shortly after cancer diagnosis disclosure, as a certain time is needed to process the first shock. They had a stronger preference for receiving prognostic information in case of a poor prognosis. Prognostic information should also include information on the expected QoL. The pie chart was the most preferred chart for discussing survival rates. Conclusions The participants found it important to receive information on their life-expectancy. While most patients were enough reassured by qualitative prognostic information, some wanted to receive quantitative information like OncologIQs’ estimates. A tailor-made approach is necessary to provide customized prognostic information. A clinical practice guideline was developed to support professionals in sharing prognostic information, aiming to improve shared decision making and patient-centered care.

Objective: To investigate the variance in reported prevalence rates of permanent neonatal hearing impairment (HI) worldwide.Design: A systematic review and meta-analysis was performed on reported p...

Fluorescence molecular endoscopy (FME) is an emerging technique in the field of gastroenterology that holds potential to improve diagnosis and guide therapy, by serving as a 'red-flag' endoscopic imaging technique. Here, we investigated the safety, feasibility and optimal method of administration of EMI-137, targeting c-Met, during FME in Barrett's Esophagus (BE) and report several outcome parameters for early phase FME studies. Methods: FME was performed in 15 Barrett's neoplasia patients. EMI-137 was administered to three cohorts of five patients: 0.13 mg/kg intravenously (IV); 0.09 mg/kg IV or topically at a dose of 200 μg/cm BE (n=1) or 100 μg/cm BE (n=4). Fluorescence was visualized in vivo, quantified in vivo using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy and correlated to histopathology and immunohistochemistry. EMI-137 localization was assessed using fluorescence microscopy. Results: FME using different IV and topical doses of EMI-137 appeared to be safe and correctly identified 16/18 lesions, although modest target-to-background ratios were observed (median range of 1.12-1.50). C-Met overexpression varied between lesions, while physiological expression in the stomach-type epithelium was observed. Microscopically, EMI-137 accumulated around the neoplastic cell membranes. We identified several outcome parameters important for the validation of EMI-137 for FME: 1) the optimal administration route; 2) optimal dose and safety; 3) in vivo FME contrast; 4) quantification of intrinsic fluorescence; 5) ex vivo correlation of fluorescence, histopathology and target expression; and 6) microscopic tracer distribution. Conclusions: C-Met targeted FME using EMI-137 may not be the ideal combination to improve BE surveillance endoscopies, however the identified outcome parameters may serve as a valuable guidance for designing and performing future early phase clinical FME studies, independent of which fluorescent tracer is investigated.

Mesenchymal stem cells (MSC) are promising candidates for use as a biological therapeutic. Since locally injected MSC disappear within a few weeks, we hypothesize that efficacy of MSC can be enhanced by prolonging their presence. Previously, encapsulation in alginate was suggested as a suitable approach for this purpose. We found no differences between the two alginate types, alginate high in mannuronic acid (High M) and alginate high in guluronic acid (High G), regarding MSC viability, MSC immunomodulatory capability, or retention of capsule integrity after subcutaneous implantation in immune competent rats. High G proved to be more suitable for production of injectable beads. Firefly luciferase-expressing rat MSC were used to track MSC viability. Encapsulation in high G alginate prolonged the presence of metabolically active allogenic MSC in immune competent rats with monoiodoacetate-induced osteoarthritis for at least 8 weeks. Encapsulation of human MSC for local treatment by intra-articular injection did not significantly influence the effect on pain, synovial inflammation, or cartilage damage in this disease model. MSC encapsulation in alginate allows for an injectable approach which prolongs the presence of viable cells subcutaneously or in an osteoarthritic joint. Further fine tuning of alginate formulation and effective dosage for might be required in order to improve therapeutic efficacy depending on the target disease.

Introduction As hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain. Methods A total of 1086 dementia-free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population-based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016-2017) and magnetic resonance imaging of the brain (2011-2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts. Results Hearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus. Conclusion Our results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes.

RATIONALE: A substantial number of breast cancer patients with an overexpression of the human epidermal growth factor receptor 2 (HER2) have residual disease after neoadjuvant therapy or become resistant to trastuzumab. Photodynamic therapy (PDT) using nanobodies targeted to HER2 is a promising treatment option for these patients. Here we investigate the in vitro and in vivo antitumor efficacy of HER2-targeted nanobody-photosensitizer (PS) conjugate PDT. METHODS: Nanobodies targeting HER2 were obtained from phage display selections. Monovalent nanobodies were engineered into a biparatopic construct. The specificity of selected nanobodies was tested in immunofluorescence assays and their affinity was evaluated in binding studies, both performed in a panel of breast cancer cells varying in HER2 expression levels. The selected HER2-targeted nanobodies 1D5 and 1D5-18A12 were conjugated to the photosensitizer IRDye700DX and tested in in vitro PDT assays. Mice bearing orthotopic HCC1954 trastuzumab-resistant tumors with high HER2 expression or MCF-7 tumors with low HER2 expression were intravenously injected with nanobody-PS conjugates. Quantitative fluorescence spectroscopy was performed for the determination of the local pharmacokinetics of the fluorescence conjugates. After nanobody-PS administration, tumors were illuminated to a fluence of 100 J∙cm-2, with a fluence rate of 50 mW∙cm-2, and thereafter tumor growth was measured with a follow-up until 30 days. RESULTS: The selected nanobodies remained functional after conjugation to the PS, binding specifically and with high affinity to HER2-positive cells. Both nanobody-PS conjugates potently and selectively induced cell death of HER2 overexpressing cells, either sensitive or resistant to trastuzumab, with low nanomolar LD50 values. In vivo, quantitative fluorescence spectroscopy showed specific accumulation of nanobody-PS conjugates in HCC1954 tumors and indicated 2 h post injection as the most suitable time point to apply light. Nanobody-targeted PDT with 1D5-PS and 1D5-18A12-PS induced significant tumor regression of trastuzumab-resistant high HER2 expressing tumors, whereas in low HER2 expressing tumors only a slight growth delay was observed. CONCLUSION: Nanobody-PS conjugates accumulated selectively in vivo and their fluorescence could be detected through optical imaging. Upon illumination, they selectively induced significant tumor regression of HER2 overexpressing tumors with a single treatment session. Nanobody-targeted PDT is therefore suggested as a new additional treatment for HER2-positive breast cancer, particularly of interest for trastuzumab-resistant HER2-positive breast cancer. Further studies are now needed to assess the value of this approach in clinical practice.

Using tissue microarrays, it was shown that membranous C-terminal MET immunoreactivity and ectodomain (ECD) shedding are associated with poor prognosis in oral cancer. Seen the potential diagnostic value, extrapolation of these results to whole-tissue sections was investigated. Because MET orchestrates epithelial-to-mesenchymal transition (EMT), the results were benchmarked to loss of E-cadherin, a readout for EMT known to be associated with poor prognosis. C-terminal MET, N-terminal MET, and E-cadherin immunoreactivities were examined on formalin-fixed paraffin-embedded parallel sections of 203 oral cancers using antibody clones D1C2, A2H2-3, and NCH-38. Interantibody and intra-antibody relations were examined using a novel scoring system, nonparametric distribution, and median tests. Survival analyses were used to examine the prognostic value of the observed immunoreactivities. Assessment of the three clones revealed MET protein status (no, decoy, transmembranous C-terminal positive), ECD shedding, and EMT. For C-terminal MET-positive cancers, D1C2 immunoreactivity is independently associated with poor overall survival (hazard ratio [HR] = 2.40; 95% confidence interval [CI] = 1.25 to 4.61; and P = 0.008) and disease-free survival (HR = 1.83; 95% CI = 1.07-3.14; P = 0.027). For both survival measures, this is also the case for ECD shedding (43.4%, with HR = 2.30; 95% CI = 1.38 to 3.83; and P = 0.001 versus HR = 1.87; 95% CI = 1.19-2.92; P = 0.006) and loss of E-cadherin (55.3%, with HR = 2.21; 95% CI = 1.30 to 3.77; and P = 0.004 versus HR = 1.90; 95% CI = 1.20-3.01; P = 0.007). The developed scoring system accounts for MET protein status, ECD shedding, and EMT and is prognostically informative. These findings may contribute to development of companion diagnostics for MET-based targeted therapy.

This study aimed to determine the ability of single fiber reflectance (SFR) spectroscopy incorporated in endoscopic ultrasound fine needle biopsy (EUS-FNB) procedures in the pancreas to distinguish benign and malignant pancreatic tissue in patient with pancreatic masses suspected for malignancy. Methods: This study was designed as a prospective observational single center study and included consecutive adult patients, who were scheduled for EUS-FNB of a solid pancreatic mass suspected for pancreatic ductal adenocarcinoma (PDAC). In total, seven optical parameters, derived from the absorption acquired spectra, were analyzed: blood volume fraction (BVF), microvascular saturation, average vessel diameter, bilirubin concentration (BIL), Mie amplitude, Mie slope and Rayleigh amplitude. Results: Forty-five patients with a suspicious pancreatic lesion undergoing EUS-FNB were included, of which most of the patients (N=34) were ultimately diagnosed with PDAC. Finally, 27 out of 45 (60.0%) patients were used for the final analysis of the optical parameters. The median (IQR) BVF differed significantly in benign compared to malignant tissue (0.86 [0.30-2.03] and 4.49 [1.28-15.47]; p=0.046). Combining BVF and BIL to a new parameter (Theta) improved the discrimination between PDAC and benign pancreatic tissue (p=0.026). The area under the curve of Theta was 0.84, resulting in a 92.8%, 75.0%, 97.5%, 50.0% and 91.3% sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for detection of PDAC. Conclusion: Differentiation between PDAC and benign pancreatic tissue using SFR spectroscopy during EUS-FNB procedures is promising. Future work should focus on comparing the diagnostic performance combining SFR spectroscopy with EUS-FNB and EUS-FNB alone.

Summary Objective Synovium contains multipotent progenitor/stromal cells (MPCs) with potential to participate in cartilage repair. Understanding the identity of these MPCs will allow their therapeutic potential to be fully exploited. Hence this study aimed to identify primary synovial MPCs and characterize them in the context of cartilage regeneration. Methods Primary MPC/MPC-subset specific markers in synovium were identified by FACS analysis of uncultured cells. MPC-subsets from human synovium obtained from patients undergoing total knee arthroplasty were FACS sorted, cultured, immunophenotyped and chondrogenically differentiated. The anatomical localization of MPCs in synovium was examined using immunohistochemistry. Finally, the presence of these MPC subsets in healthy synovium obtained from human organ donors was examined. Results A combination of CD45, CD31, CD73 and CD90 can isolate two distinct MPC-subsets in synovium. These MPC-subsets, freshly isolated from synovium, did not express CD45 or CD31, but expressed CD73. Additionally, a sub-population of CD73+ cells also expressed CD90. CD45−CD31−CD73+CD90− cells were significantly more chondrogenic than CD45−CD31−CD73+CD90+ cells in the presence of TGFβ1. Interestingly, reduced chondrogenic ability of CD73+CD90+ cells could be reversed by the addition of BMP2, showing discrete chondrogenic factor requirements by distinct cell-subsets. In addition, these MPCs had distinct anatomical localization; CD73 was expressed both in intimal and sub-intimal region while CD90 was enriched in the sub-intimal region. We further demonstrated that these subsets are also present in healthy synovium. Conclusions We provide indications that primary MPCs in synovial intima and sub-intima are phenotypically and functionally distinct with different chondrogenic properties.

OBJECTIVES: Recent studies have shown an association between poorer hearing thresholds and smaller brain tissue volumes in older adults. Several underlying causal mechanisms have been opted, with a sensory deprivation hypothesis as one of the most prominent. If hearing deprivation would lead to less brain volume, hearing aids could be hypothesized to moderate this pathway by restoration of hearing. This study aims to investigate whether such a moderating effect of hearing aids exists. DESIGN: The authors conducted a cross-sectional study involving aging participants of the population-based Rotterdam Study. Hearing aid use was assessed by interview and hearing loss was quantified using pure-tone audiometry. Total brain volume, gray matter and white matter volume and white matter integrity [fractional anisotropy (FA) and mean diffusivity] were measured using magnetic resonance imaging. Only participants with a pure tone average at 1, 2, and 4 kHz (PTA1,2,4) of ≥35 dB HL were included. Associations of hearing loss with brain volume and global measures of white matter integrity were analyzed using linear regression, with hearing aid use and interaction between hearing aid use and PTA1,2,4 included as independent variables. Models were adjusted for age, sex, time between audiometry and magnetic resonance imaging, level of education, and cardiovascular risk factors. RESULTS: Out of 459 included participants with mean age (range) 70.4 (52 to 92) 41% were female. Distributions of age and sex among hearing aid users (n = 172) did not significantly differ from those without hearing aids. PTA1,2,4 was associated with lower FA, but not with a difference in total brain volume, gray matter volume, white matter volume, or mean diffusivity. Interaction between hearing aid use and PTA1,2,4 was not associated with FA or any of the other outcome measures. Additional analysis revealed that interaction between hearing aid use and age was associated with lower FA. CONCLUSIONS: We found no evidence for a moderating effect of hearing aids on the relationship between hearing loss and brain structure in a population of older adults. However, use of hearing aids did appear as an effect modifier in the association between age and white matter integrity. Future longitudinal research is needed to clarify these results.

OBJECTIVES: To investigate associations between testosterone and patient reported sexual problems and need for sexual care in head and neck cancer patients at time of diagnosis and 6 months after treatment.PATIENTS AND METHODS: Data and samples were used of 40 patients (20 men, 20 women) before and 6 months after treatment. Outcome measures were total testosterone level (TT) and free testosterone index (FTI), testosterone insufficiency (TI), the EORTC QLQ-HN35 Sexuality subscale, the subscales of the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), and the Sexuality subscale of the Short-Form Supportive Care Needs Survey (SCNS-SF34).RESULTS: In men, higher FTI before treatment was significantly associated with better IIEF Orgasm (p = 0.020) and at 6 months follow-up with IIEF Desire (p = 0.019). Before treatment, insufficient testosterone was present in 5 males (25%) and in 3 at follow-up (15%) (2 patients who had TI before treatment plus one). In women, higher TT at follow-up was significantly associated with better EORTC Sexuality (p = 0.031) and FSFI Satisfaction (p = 0.020); FTI at follow-up was associated with FSFI Satisfaction (p = 0.012). Before treatment, TI was present in 2 women (10%) and in 3 (15%) at follow-up (the same 2 patients plus one).CONCLUSION: This pilot study showed that testosterone seems to be associated with patient reported sexual outcomes among male and female head and neck cancer patients. It is estimated that 10-25% of HNC patients may have testosterone insufficiency before treatment and/or at 6 months after treatment.

Ajay T Bakas,1 Aniel Sewnaik,1 Jaclyn van Straaten,2 Robert J Baatenburg de Jong,1 Francesco US Mattace-Raso,2 Harmke A Polinder-Bos2 1Department of Otorhinolaryngology, Erasmus MC University Cancer Institute, Rotterdam, the Netherlands; 2Division of Geriatric Medicine, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the NetherlandsCorrespondence: Ajay T BakasDepartment of Otorhinolaryngology, Erasmus MC University Cancer, Institute, Rotterdam, the NetherlandsTel +31-10-7040704Email a.bakas@erasmusmc.nlPurpose: The multidimensional prognostic index (MPI) is a prognostic model derived from the comprehensive geriatric assessment (CGA) which can predict 1-year mortality risk in elderly individuals. We hypothesized that the MPI also reflects the degree of frailty and thus will correlate with established measures of frailty. Therefore, the aim of this study is to explore whether the MPI-score is a measure of frailty in older head and neck cancer patients and is associated with several physical functioning measurements.Patients and Methods: From November 2019 to July 2020, a prospective cohort study enrolled patients with head and neck cancer aged ≥ 70 years, and patients < 70 years with an abnormal G8 score. The MPI-score ranged from 0 to 1 and was categorized in MPI-stage 1 (≤ 0.33, non-frail); MPI-stage 2 (0.34– 0.66, mildly frail), and MPI-stage 3 (≥ 0.67, severe frail). Pearson’s correlation coefficient and multivariable linear regression were used to study the association between MPI-score and the physical functioning measurements handgrip strength, gait speed, and the timed up and go test (TUGT).Results: A total of 163 patients were included. One hundred four (63.8%) patients were categorized as non-frail according MPI-stage 1, and 59 (36.2%) patients as mildly or severe frail (n=55 MPI-stage 2; n=4 MPI-stage 3, respectively). A higher MPI-score was significantly associated with lower hand grip strength (B − 0.49 [95% CI − 0.71; − 0.28] p< 0.001), lower gait speed (B − 0.41 [95% CI − 0.55; − 0.25] p< 0.001), and a slower TUGT (B 0.53 [95% CI 0.66; 0.85] p< 0.001).Conclusion: Almost one-third of the included patients with head and neck cancer was mild or severe frail. A higher MPI-score, indicating higher degree of frailty, was associated with worse physical performance by lower handgrip strength, gait speed, and a slower TUGT. Thus, the MPI reflects the degree of frailty.Keywords: comprehensive geriatric assessment, sarcopenia, head and neck cancer, multidimensional prognostic index, elderly

Objectives: To elucidate the association between tinnitus and brain tissue volumes and white matter microstructural integrity. Design: Two thousand six hundred sixteen participants (mean age, 65.7 years [SD: 7.5 years]; 53.9% female) of the population-based Rotterdam Study underwent tinnitus assessment (2011 to 2014) and magnetic resonance imaging of the brain (2011 to 2014). Associations between tinnitus (present versus absent) and total, gray, and white matter volume and global white matter microstructure were assessed using multivariable linear regression models adjusting for demographic factors, cardiovascular risk factors, depressive symptoms, Mini-Mental State Examination score, and hearing loss. Finally, potential regional gray matter density and white matter microstructural volume differences were assessed on a voxel-based level again using multivariable linear regression. Results: Participants with tinnitus (21.8%) had significantly larger brain tissue volumes (difference in SD, 0.09; 95% confidence interval, 0.06 to 0.13), driven by larger white matter volumes (difference, 0.12; 95% confidence interval, 0.04 to 0.21) independent of hearing loss. There was no association between tinnitus and gray matter volumes nor with global white matter microstructure. On a lobar level, tinnitus was associated with larger white matter volumes in each lobe, not with gray matter volume. Voxel-based results did not show regional specificity. Conclusions: We found that tinnitus in older adults was associated with larger brain tissue volumes, driven by larger white matter volumes, independent of age, and hearing loss. Based on these results, it may be hypothesized that tinnitus potentially has a neurodevelopmental origin in earlier life independent of aging processes.

Key Points Question Can a model be developed for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients newly diagnosed with oropharyngeal cancer, incorporating clinical, oncologic, and imaging data? Findings In this prognostic study, model predictions for 5-year overall survival demonstrated excellent discrimination in cohort study training data for models with and without imaging variables. This model appeared to possess good calibration and well stratified patients in terms of likely outcomes among many competing events. Meaning This prognostic model and web-based application may serve as a useful tool to provide clinicians, researchers, and patients with oropharyngeal cancer robust, individualized prognostic estimations., Importance Recent insights into the biologic characteristics and treatment of oropharyngeal cancer may help inform improvements in prognostic modeling. A bayesian multistate model incorporates sophisticated statistical techniques to provide individualized predictions of survival and recurrence outcomes for patients with newly diagnosed oropharyngeal cancer. Objective To develop a model for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients with newly diagnosed oropharyngeal cancer, incorporating clinical, oncologic, and imaging data. Design, Setting, and Participants In this prognostic study, a data set was used comprising 840 patients with newly diagnosed oropharyngeal cancer treated at a National Cancer Institute–designated center between January 2003 and August 2016; analysis was performed between January 2019 and June 2020. Using these data, a bayesian multistate model was developed that can be used to obtain individualized predictions. The prognostic performance of the model was validated using data from 447 patients treated for oropharyngeal cancer at Erasmus Medical Center in the Netherlands. Exposures Clinical/oncologic factors and imaging biomarkers collected at or before initiation of first-line therapy. Main Outcomes and Measures Overall survival, locoregional recurrence, and distant metastasis after first-line cancer treatment. Results Of the 840 patients included in the National Cancer Institute–designated center, 715 (85.1%) were men and 268 (31.9%) were current smokers. The Erasmus Medical Center cohort comprised 300 (67.1%) men, with 350 (78.3%) current smokers. Model predictions for 5-year overall survival demonstrated good discrimination, with area under the curve values of 0.81 for the model with and 0.78 for the model without imaging variables. Application of the model without imaging data in the independent Dutch validation cohort resulted in an area under the curve of 0.75. This model possesses good calibration and stratifies patients well in terms of likely outcomes among many competing events. Conclusions and Relevance In this prognostic study, a multistate model of oropharyngeal cancer incorporating imaging biomarkers appeared to estimate and discriminate locoregional recurrence from distant metastases. Providing personalized predictions of multiple outcomes increases the information available for patients and clinicians. The web-based application designed in this study may serve as a useful tool for generating predictions and visualizing likely outcomes for a specific patient., This prognostic study reports on the development of a model including factors used in establishing an individualized prognosis for locoregional recurrence, distant metastasis, and survival in patients with oropharyngeal cancer.

This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2‐q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow‐up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family.

Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma ...

Background: Voice outcome was assessed in patients with extended T1 and limited T2 glottic carcinoma, treated with a unilateral type III or a bilateral type II resection according to the European Laryngological Society (ELS) classification. Methods: Objective evaluation (acoustic and aerodynamic parameters), perceptual evaluation (GRBAS), and patients' self-assessment (voice handicap index [VHI]) were performed before and 1 year after treatment. Results were evaluated according to ELS resection type and the involvement of the anterior commissure. Results: The majority of voice parameters in all resection subgroups showed an improvement of the mean score 1 year postoperatively. Grade of dysphonia varied between 1.15 and 1.66 postoperatively and VHI score varied from 23.3 to 24.5. Conclusion: Voice outcome after ELS unilateral type III or a bilateral type II resection for extended T1 and limited T2 glottic carcinoma is good with mild to very moderate perceptive dysphonia and low self-reported voice impairment.

Background The objectives of this study are to determine the incidence and survival rate of patients with head and neck squamous cell carcinoma (HNSCC) with multiple primary tumors (MPT) in the HN‐region, lung, or esophagus. Methods Patient and tumor specific data of 1372 patients with HNSCC were collected from both the national cancer registry and patient records to ensure high‐quality double‐checked data. Results The total incidence of MPTs in the HN‐region, lung, and esophagus in patients with HNSCC was 11% (149/1372). Patients with lung MPTs and esophageal MPTs had a significant worse 5‐year survival than patients with HN‐MPTs (29%, 14%, and 67%, respectively, P

Articular cartilage is frequently injured by trauma or osteoarthritis, with limited and inadequate treatment options. We investigated a new strategy based on hydrogel-mediated delivery of a locked nucleic acid microRNA inhibitor targeting miR-221 (antimiR-221) to guide in situ cartilage repair by endogenous cells. First, we showed that transfection of antimiR-221 into human bone marrow-derived mesenchymal stromal cells (hMSCs) blocked miR-221 expression and enhanced chondrogenesis in vitro. Next, we loaded a fibrin/hyaluronan (FB/HA) hydrogel with antimiR-221 in combination or not with lipofectamine carrier. FB/HA strongly retained functional antimiR-221 over 14 days of in vitro culture, and provided a supportive environment for cell transfection, as validated by flow cytometry and qRT-PCR analysis. Seeding of hMSCs on the surface of antimiR-221 loaded FB/HA led to invasion of the hydrogel and miR-221 knockdown in situ within 7 days. Overall, the use of lipofectamine enhanced the potency of the system, with increased antimiR-221 retention and miR-221 silencing in infiltrating cells. Finally, FB/HA hydrogels were used to fill defects in osteochondral biopsies that were implanted subcutaneously in mice. FB/HA loaded with antimiR-221/lipofectamine significantly enhanced cartilage repair by endogenous cells, demonstrating the feasibility of our approach and the need to achieve highly effective in situ transfection. Our study provides new evidence on the treatment of focal cartilage injuries using controlled biomaterial-mediated delivery of antimicroRNA for in situ guided regeneration.

Introduction Swallowing problems in children with a tracheostomy tube seem to be a common problem, although exact prevalence is not known. The aim of this study is to identify the prevalence and type of swallowing problems in children with a tracheostomy tube. Methods We retrospectively included 44 children having a tracheostomy tube at Erasmus MC-Sophia Children's hospital. Assessment by a specialized speech and language therapist, the Modified Evans Blue Dye test, Video Fluoroscopic Swallowing Study and a Fiber-optic Endoscopic Evaluation of Swallowing were reviewed with regard to the different phases of swallowing, in particular signs of aspiration. Results In our cohort, 31 (70%) children with a tracheostomy tube presented with problems in the oral and/or the pharyngeal phase of swallowing. Overall 19 (43%) children aspirated. Conclusions The majority of children with a tracheostomy tube have swallowing problems in the different swallowing phases with a high risk for aspiration.

ObjectivesIn the management of patients with bleeding peptic ulcers, recurrent bleeding is associated with high mortality. We investigated if added angiographic embolisation after endoscopic haemostasis to high-risk ulcers could reduce recurrent bleeding.DesignAfter endoscopic haemostasis to their bleeding gastroduodenal ulcers, we randomised patients with at least one of these criteria (ulcers≥20 mm in size, spurting bleeding, hypotensive shock or haemoglobinResultsBetween January 2010 and July 2014, 241 patients were randomised (added angiographic embolisation n=118, standard treatment n=123); 22 of 118 patients (18.6%) randomised to angiography did not receive embolisation. In an intention-to-treat analysis, 12 (10.2%) in the embolisation and 14 (11.4%) in the standard treatment group reached the primary endpoint (HR 1.14, 95% CI 0.53 to 2.46; p=0.745). The rate of reinterventions (13 vs 17; p=0.510) and deaths (3 vs 5, p=0.519) were similar. In a per-protocol analysis, 6 of 96 (6.2%) rebled after embolisation compared with 14 of 123 (11.4%) in the standard treatment group (HR 1.89, 95% CI 0.73 to 4.92; p=0.192). None of 96 patients died after embolisation compared with 5 (4.1%) deaths in the standard treatment group (p=0.108). In a posthoc analysis, embolisation reduced recurrent bleeding only in patients with ulcers≥15 mm in size (2 (4.5%) vs 12 (23.1%); p=0.027).ConclusionsAfter endoscopic haemostasis, added embolisation does not reduce recurrent bleeding.Trial registration numberNCT01142180.

Objectives Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs. Methods Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1. Results Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs. Conclusion This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.

Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphological and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated (1) enhanced Wnt/β-catenin signaling, (2) a broad spectrum of degrees of epithelial to mesenchymal transition (EMT) activation including hybrid E/M states (partial EMT) with highly plastic features, and (3) high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and β-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically distinct cellular states and to underlie the phenotypic plasticity of colon cancer cells.

Background Patients with primary oesophageal squamous cell carcinoma are at risk of developing multiple primary tumours in the upper aero digestive tract. To date, most studies are performed in the Asian population. We aimed to evaluate the risk of multiple primary tumours in the upper aero digestive tract and stomach in patients with oesophageal squamous cell carcinoma in a Western population. Methods We performed a nationwide, retrospective cohort study in collaboration with the Netherlands Cancer Registry. Patients with primary oesophageal squamous cell carcinoma, diagnosed between 2000 and 2016, were included. Primary endpoints were synchronous and metachronous multiple primary tumour risk. Results The cohort consisted of 9058 patients, diagnosed with oesophageal squamous cell carcinoma (male: 57.3%, median age 67 years). In 476 patients (5.3%), 545 multiple primary tumours have been diagnosed. Most of them were located in the head and neck region (49.5%). Among all multiple primary tumours, 329 (60.4%) were diagnosed synchronously (, Key Summary A minimum of one out of 20 patients with oesophageal squamous cell carcinoma (ESCC) in a Western population develops multiple primary tumours (MPTs).Most MPTs were detected in the head and neck region, and were detected synchronously with a higher risk than in the general population.Screening for both synchronous and metachronous MPTs in patients with primary ESCC should be considered.

Study objectives To study the pattern of upper airway collapse in patients with CPAP failure by performing DISE while administering CPAP therapy and to determine the reason for CPAP failure accordingly. Methods This observational retrospective study comprised 30 patients diagnosed with OSA and CPAP failure, who underwent DISE while administering CPAP therapy. During DISE, the upper airway was assessed with and without CPAP therapy using the VOTE classification. Additionally, a jaw thrust maneuver was performed, in order to mimic the effect of an additional mandibular advancement device (MAD) in combination with CPAP therapy. Consequently, the outcome of DISE was translated into a clinically relevant categorization. Results Eleven patients (37%) had a persistent anteroposterior (AP) collapse, including a collapse at velum, tongue base, or epiglottis level and multilevel collapse. Eight patients (27%) had a floppy epiglottis. Five patients (17%) had a persistent complete concentric collapse (CCC) and three patients had a persistent laryngeal collapse (10%). In three patients (10%), no airway collapse was found after CPAP administration. Conclusions Based on the results of the reported study, in most cases, the potential cause of CPAP failure can be determined by this new diagnostic method. Consequently, suggestions can be made for additional therapy.

Objectives: To identify possibly distinct acute otitis media (AOM) trajectories in childhood and identify determinants associated with specific AOM trajectories. To explore which child will become prone to recurrent AOM episodes and which will not. Design: Population-based prospective cohort study among 7863 children from birth until 10 years and their mothers. Methods: This study was embedded in the Generation R Study: a population-based prospective cohort study. Data on AOM and determinants were collected by repeated parental questionnaires. Distinct AOM trajectories within the population were identified with latent-class analyses. Next, using multivariate analysis we checked whether specific determinants were associated with specific trajectories. Results: Three distinct trajectories were identified; that is, non–otitis prone, early AOM—that is children who suffered AOM episodes until 3 years of age but not beyond, and persistent AOM—that is children who remained otitis-prone. Male gender (OR: 1.26, CI: 1.11-1.43) and day-care attendance (OR: 1.31, CI: 1.06-1.60) were associated with increased odds of early AOM. Breastfeeding was beneficial for children in both the early-AOM and persistent-AOM trajectories (OR: 0.78 and 0.77, respectively). Birth in the summer or autumn as compared with birth in the spring decreased odds of AOM only in the persistent-AOM trajectory. Half of all AOM-prone children recovered after the age of 3 years. Conclusion: Specific determinants are associated with different AOM trajectories. Future research is needed to better predict which child will remain otitis-prone and which recovers after the age of 3 years to better tailor treatment towards the needs of the individual child.

Purpose The eHealth self-management application ‘Oncokompas’ was developed to support cancer survivors in monitoring health-related quality of life (HRQOL) and symptoms, and obtaining personalized feedback and options for supportive care. The aim of this study was to assess the cost-utility of Oncokompas compared with care as usual (CAU) among cancer survivors. Methods Survivors were randomly allocated to the intervention or control group. Direct (non-)medical, indirect non-medical costs, and HRQOL were measured at 3- and 6-month follow-up, using iMTA Medical Consumption and Productivity Costs and the EuroQol-5D questionnaires. Mean cumulative costs and quality-adjusted life-years (QALYs) were compared between both groups. Results In total, 625 survivors were randomized into intervention (n = 320) or control group (n = 305). Base case analysis showed that incremental costs from a societal perspective were − €163 (95% CI, − 665 to 326), and incremental QALYs were 0.0017 (95% CI, − 0.0121 to 0.0155) in the intervention group compared with those in the control group. The probability that, compared with CAU, Oncokompas is more effective was 60%, less costly 73%, and both more effective and less costly 47%. Sensitivity analyses showed that incremental costs vary between − €40 and €69, and incremental QALYs vary between − 0.0023 and − 0.0057. Conclusion Oncokompas is likely to be equally effective on utilities, and not more expensive than CAU, and will therefore contribute to sustainable cancer survivorship care in a (cost-)effective manner. Implications for Cancer Survivors Oncokompas seems to improve HRQOL and reduces the burden of several tumour-specific symptoms, while costs from a societal perspective are similar to CAU.

Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.

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.

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p &lt, 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p &lt, 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.

Fluorescence molecular endoscopy (FME) is an emerging technique that has the potential to improve the 22% colorectal polyp detection miss-rate. We determined the optimal dose-to-imaging interval and safety of FME using EMI-137, a c-Met-targeted fluorescent peptide, in a population at high risk for colorectal cancer. Methods: We performed in vivo FME and quantification of fluorescence by multidiameter single-fiber reflectance/single-fiber fluorescence spectroscopy in 15 patients with a dysplastic colorectal adenoma. EMI-137 was intravenously administered (0.13 mg/kg) at a 1-, 2- or 3-h dose-to-imaging interval (n = 3 patients per cohort). Two cohorts were expanded to 6 patients on the basis of target-to-background ratios. Fluorescence was correlated to histopathology and c-Met expression. EMI-137 binding specificity was assessed by fluorescence microscopy and in vitro experiments. Results: FME using EMI-137 appeared to be safe and well tolerated. All dose-to-imaging intervals showed significantly higher fluorescence in the colorectal lesions than in surrounding tissue, with a target-to-background ratio of 1.53, 1.66, and 1.74 for the 1-, 2-, and 3-h cohorts, respectively, and a mean intrinsic fluorescence of 0.035 vs. 0.023 mm-1 (P < 0.0003), 0.034 vs. 0.021 mm-1 (P < 0.0001), and 0.033 vs. 0.019 mm-1 (P < 0.0001), respectively. Fluorescence correlated with histopathology on a macroscopic and microscopic level, with significant c-Met overexpression in dysplastic mucosa. In vitro, a dose-dependent specific binding was confirmed. Conclusion: FME using EMI-137 appeared to be safe and feasible within a 1- to 3-h dose-to-imaging interval. No clinically significant differences were observed among the cohorts, although a 1-h dose-to-imaging interval was preferred from a clinical perspective. Future studies will investigate EMI-137 for improved colorectal polyp detection during screening colonoscopies.

Objective Free fatty acids (FAs) may influence cartilage metabolism and osteoarthritis (OA) disease progression. It is not clearly studied which FAs are present in the synovial fluid of knee joints and whether there are differences in FA content between nonsymptomatic and OA knee joints. The aim of this study was to investigate the presence of different types of FAs in synovial fluid of both OA- and nonsymptomatic control joints, and to analyze differences between both groups. Design A total of 23 synovial fluid samples were collected from patients with end-stage knee OA undergoing total knee replacement, with approval of the medical ethical committee. As controls, 6 synovial fluid samples were obtained from postmortem donors without any history of joint disease or arthritis. Measurement of free FA concentration was done by mass spectrometry for saturated FAs (SFA), monounsaturated FAs (MUFA), and omega-3 and omega-6 polyunsaturated FAs (n-3 PUFAs and n-6 PUFAs). Results Our measurements demonstrated the presence of SFAs, MUFAs, n-3 and n-6 PUFAs in synovial fluid of both nonsymptomatic and OA knee joints. The n-6/n-3 ratio was significantly lower in the OA group ( P = 0.0005). Arachidonic acid (n-6 PUFA) concentrations were also lower in OA synovial fluid ( P = 0.01), while tetracosadienoic acid ( P = 0.0001) and nervonic acid ( P = 0.001) (MUFAs) were higher in synovial fluid of patients with knee OA. Conclusion Synovial fluid contains a broad spectrum of free FAs. The FAs profile differs between OA and control subjects, including a tendency for less n-6 FAs in OA joints.

Background Tinnitus is a prevalent auditory disorder that frequently co-occurs with hearing loss. It is suggested that tinnitus might have negative impact on speech perception. However, studies thus far have not been able to disentangle tinnitus, hearing loss, and speech in noise intelligibility. We therefore investigated whether there is an association between tinnitus and speech understanding in noise, independent of hearing loss. Methods Of 4,211 participants from the population-based Rotterdam Study (mean age 67.8 [SD 8.9], 57.3% female) data was available on tinnitus, pure-tone audiometry, and digits in noise test. We compared the speech reception threshold in noise (SRTn) in participants with and without tinnitus for the whole population as well as for subgroups stratified for average hearing threshold in 10-dB strata. Additionally, we regressed tinnitus on SRTn with a multivariable regression model, adjusting for sex, age, highest achieved education, and cognitive function. Results Participants with tinnitus (20.8%) had a higher SRTn (-3.6 dB [SD 3.7] versus -4.6 dB [SD 3.1]). This difference remained only in the subgroups of participants with hearing loss, between 0.6 and 0.8 dB difference in the SRTn for the different subgroups. In the fully adjusted model tinnitus was associated with 0.2 dB (95% CI 0.00, 0.39) SRTn increase. Conclusion We have shown that tinnitus is associated with speech intelligibility in noise, but it is a small effect, only found in people with co-occurring hearing loss.

Supplemental Digital Content is available in the text., Objectives: To understand the varying levels of daily cochlear implant (CI) use in children, previous studies have investigated factors that may be of influence. The objective of this study was to investigate the degree with which new child-related and environment-related characteristics were associated with consistent CI use. Design: The design of this study was retrospective. Data were reviewed of 81 children (51% females, mean age 6.4 years with a range of 1.3 to 17.7 years) who received a CI between 2012 and 2019. Developmental status, quantified burden of comorbidity, hearing experience, and hearing environment were investigated for correlation with consistency in daily CI use. The CIs datalog was used to objectively record the wearing times. Associations were examined using univariate correlation analyses and a linear regression analysis. Results: On average, the CI was worn 8.6 hr per day and 59% of the children wore it more than 8 hr daily. The latter children’s hearing performance was significantly higher than that of the others. Consistency in CI use correlated significantly with the child-related characteristics chronological age, nonverbal intelligence quotient (IQ), American Society of Anesthesiologists physical status class, pre CI acoustic experience, CI experience, and one of the environment related characteristics “parental communication mode.” In a multivariate linear regression model, consistency in CI use was significantly dependent on nonverbal IQ and parental communication mode. These together accounted for 47% of the variation in daily CI use. Conclusions: The findings indicate that children with lower nonverbal IQ scores and low exposure to oral communication by their parents are at risk of inconsistent CI use.

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.

Importance: Children with severe hearing loss are known to have more behavioral problems and may perform worse at school than children without. Few large-scale studies of slight to mild hearing loss are available.Objective: To examine the relevance of slight to mild hearing loss by studying its association with behavioral problems and school performance.Design, Setting, and Participants: This cross-sectional study was performed within an ongoing prospective birth cohort study in Rotterdam, the Netherlands. Participants were part of a population-based sample of children. Between ages 9 and 11 years, 5355 children underwent audiometric and behavioral evaluations. Children were excluded if they had missing data for either audiometry or both outcomes. Data were collected from April 2012 through October 2015. Data were analyzed from March to June 2018.Exposures: Audiometric evaluation included pure-tone audiometry tests and speech-in-noise testing.Main Outcomes and Measures: Child behavior was rated by the primary caregiver using the Child Behavior Checklist at ages 9 to 11 years (n = 4471). School performance was measured with a standardized test at age 12 years (n = 2399).Results: The final sample included 4779 participants who were a mean (SD) age of 9.8 (0.3) years. The sample had nearly equal distribution between boys (n = 2200; 49.2%) and girls (n = 2271; 50.8%). Associations of hearing thresholds with behavioral problems differed between boys and girls. Among boys, higher pure-tone hearing thresholds at low frequencies were associated with higher total problem, social problem, and attention problem scores (total problems for the better-hearing ear: β = 0.01; 95% CI, 0-0.02). Higher speech reception thresholds were associated with higher attention problem scores among girls (β = 0.04; 95% CI, 0-0.08). Higher speech reception thresholds were associated with poorer school performance scores for both boys and girls (β = -0.06; 95% CI, -0.10 to -0.02).Conclusions and Relevance: Higher hearing thresholds during pure-tone audiometric and speech-in-noise testing were associated with higher behavioral problem scores and poorer school performance. This supports the relevance of slight to mild hearing loss with these outcomes in school-aged children.