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Counter, S. A., Buchanan, L. H., Ortega, F., Jacobs, A. B. & Laurell, G. (2017). Assessment of the Brainstem- Mediated Stapedius Muscle Reflex in Andean Children Living at High Altitudes. High Altitude Medicine & Biology, 18(1), 37-45.
Open this publication in new window or tab >>Assessment of the Brainstem- Mediated Stapedius Muscle Reflex in Andean Children Living at High Altitudes
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2017 (English)In: High Altitude Medicine & Biology, ISSN 1527-0297, E-ISSN 1557-8682, Vol. 18, no 1, 37-45 p.Article in journal (Refereed) Published
Abstract [en]

This study examined the physiological thresholds, amplitude growth, and contraction duration of the acoustic stapedius reflex (ASR) in Andean children aged 2-17 years living at altitudes of 2850m (Altitude I Group) and 3973m (Altitude II Group) as part of a general medical assessment of the health status of the children. The brainstem-mediated ASR reveals the integrity of the neuronal components of the auditory reflex arc, including the cochlea receptors, eight cranial nerves, and brainstem neural projections to the cochlear nuclei, bilateral superior olivary nuclei, facial nerve nuclei, and facial nerve and its stapedius branch. Uncrossed (ipsilateral) and crossed (contralateral) ASR thresholds (ASRT), ASR amplitude growth (ASRG) function, and ASR muscle contraction duration (decay/ fatigue) (ASRD) were measured noninvasively with 500, 1000 Hz and broadband (bandwidth = 125-4000 Hz) noise stimulus activators using a middle ear immittance system. Oxygen saturation (SaO(2)) level and heart rate were measured in a subsample of the study group. Statistical analyses revealed that the Altitude I and Altitude II groups had ASRT, ASRG function, and ASRD rates comparable to children at sea level and that the two groups were not significantly different for any of the ASR measures. No significant association was found between SaO(2) or heart rate and ASRT, growth, and muscle fatigue rate. In conclusion, the assessment of the ASR in children in the high-altitude groups revealed normal function. Furthermore, the results indicate no adverse oto-physiological effects of altitude on the brainstem-mediated ASR at elevations between 2850 and 4000m and suggest normal middle ear and auditory brainstem function.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2017
Keyword
altitude, Andean, auditory, brainstem, children, hearing, hypoxia, stapedius reflex
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-320300 (URN)10.1089/ham.2016.0082 (DOI)000397571000005 ()27860516 (PubMedID)
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2017-04-18Bibliographically approved
Söderström, K., Nilsson, P., Laurell, G., Zackrisson, B. & Jaghagen, E. L. (2017). Dysphagia - Results from multivariable predictive modelling on aspiration from a subset of the ARTSCAN trial. Radiotherapy and Oncology, 122(2), 192-199.
Open this publication in new window or tab >>Dysphagia - Results from multivariable predictive modelling on aspiration from a subset of the ARTSCAN trial
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2017 (English)In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 122, no 2, 192-199 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: To establish predictive models for late objective aspiration and late patient-reported choking based on dose-volume parameters and baseline patient and treatment characteristics, for patients with head and neck cancer undergoing definitive radiotherapy (RT). The impact of electively treated volume on late aspiration was also investigated. Methods and material: This prospective cohort is a subsample of 124 survivors from the ARTSCAN study. Late aspiration was identified with videofluoroscopy, at a minimum of 25 months after the start of RT. Patient-reported choking was analysed at 12 and 60 months post RT using the EORTC Quality of Life Module for Head and Neck Cancer 35. Univariable and multivariable analyses were performed to describe the association between clinical factors and dose-volume descriptors for organs at risk (OARs) and late dysphagia. Results: Aspiration was found in 47% of the eligible patients. Mean dose to the middle pharyngeal constrictor (MPC), neck dissection post RT and age at randomisation in ARTSCAN were associated to late aspiration. Mean dose to the superior pharyngeal constrictor (SPC) and swallowing complaints at baseline were associated to patient reported choking at both time-points. Conclusions: Three separate risk groups for late aspiration, and two risk groups for late patient-reported choking were identified based on number of risk factors. The size of the electively treated volume could be used as a surrogate for individual OARs predicting late aspiration.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2017
Keyword
Head and neck cancer, Radiotherapy, Dysphagia, Normal tissue complication probability
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-320781 (URN)10.1016/j.radonc.2016.09.001 (DOI)000395607300004 ()27687824 (PubMedID)
Funder
Swedish Cancer SocietyCancer and Allergy Foundation
Available from: 2017-04-25 Created: 2017-04-25 Last updated: 2017-04-25Bibliographically approved
Assadian, F., Kamel, W., Laurell, G., Svensson, C., Punga, T. & Akusjärvi, G. (2017). Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes. PLoS ONE, 12(5), Article ID e0177275.
Open this publication in new window or tab >>Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, e0177275Article in journal (Refereed) Published
Abstract [en]

We have used high-throughput small RNA sequencing to characterize viral small RNA expression in purified tonsillar B and T lymphocytes isolated from patients tested positive for Epstein-Barr virus (EBV) or human adenovirus (HAdV) infections, respectively. In the small set of patients analyzed, the expression profile of EBV and HAdV miRNAs could not distinguish between patients diagnosed with tonsillar hypertrophy or chronic/recurrent tonsillitis. The EBV miR-BART expression profile among the patients diagnosed with tonsillar diseases resembles most closely the pattern seen in EBV+ tumors (Latency II/I). The miRBARTs that appear to be absent in normal EBV infected cells are essentially all detectable in the diseased tonsillar B lymphocytes. In the EBV+ B cells we detected 44 EBV miRBARTs derived from the proposed BART precursor hairpins whereof five are not annotated in miRBase v21. One previously undetected miRNA, BART16b-5p, originates from the miR-BART16 precursor hairpin as an alternative 5 A miR-BART16 located precisely upstream of the annotated miR-BART16-5p. Further, our analysis revealed an extensive sequence variation among the EBV miRNAs with isomiRs having a constant 5 A end but alternative 3 A ends. A range of small RNAs was also detected from the terminal stem of the EBER RNAs and the 3 A part of v-snoRNA1. During a lytic HAdV infection in established cell lines the terminal stem of the viral non-coding VA RNAs are processed to highly abundant viral miRNAs (mivaRNAs). In contrast, mivaRNA expression in HAdV positive tonsillar T lymphocytes was very low. The small RNA profile further showed that the 5 A mivaRNA from VA RNAI and the 3 A mivaRNA from VA RNAII were as predicted, whereas the 3 A mivaRNA from VA RNAI showed an aberrant processing upstream of the expected Dicer cleavage site.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326234 (URN)10.1371/journal.pone.0177275 (DOI)000402062800013 ()28542273 (PubMedID)
Funder
Swedish Cancer Society, 120678, 130469
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2017-11-29Bibliographically approved
Boldrup, L., Gu, X., Coates, P. J., Norberg-Spaak, L., Fahraeus, R., Laurell, G., . . . Nylander, K. (2017). Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma. OncoTarget, 8(12), 19389-19402.
Open this publication in new window or tab >>Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 12, 19389-19402 p.Article in journal (Refereed) Published
Abstract [en]

Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keyword
tongue cancer, RNA expression, field cancerization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-319866 (URN)10.18632/oncotarget.14288 (DOI)000396879200062 ()
Funder
Swedish Cancer Society, 15 06 37
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2017-11-29Bibliographically approved
Fransson, A. E., Kisiel, M., Pirttilä, K., Pettersson, C., Videhult Pierre, P. & Laurell, G. (2017). Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig. Frontiers in Cellular Neuroscience, 11, Article ID 280.
Open this publication in new window or tab >>Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig
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2017 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 11, 280Article in journal (Refereed) Published
Abstract [en]

Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.

Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.

Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.

Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.

Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

Keyword
ABR, inner hair cells, outer hair cells, synaptophysin, organic cation transporter 2, copper transporter 1, perilymph metabolomics, in vivo
National Category
Otorhinolaryngology Analytical Chemistry Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-330897 (URN)10.3389/fncel.2017.00280 (DOI)000410583900001 ()28955207 (PubMedID)
Available from: 2017-10-06 Created: 2017-10-06 Last updated: 2018-01-13Bibliographically approved
Jonsson, E. L., Nylander, K., Hallén, L. & Laurell, G. (2017). Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0. Acta Oto-Laryngologica, 137(8), 877-882.
Open this publication in new window or tab >>Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0
2017 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 137, no 8, 877-882 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate whether the extent of expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the mobile tongue can predict the risk of cervical metastasis and survival. Study design: Retrospective histopathologic study. Methods: Surgical specimens from 64 patients who had undergone surgery for squamous cell carcinoma of the mobile tongue were assessed using immunohistochemistry to investigate the expression of HA and EGFR in the primary tumours, and the data were then correlated to cervical metastasis and survival. Results: There was a significant correlation between the intensity of HA staining and patient survival (p .024), and a weak correlation between the staining proportion of EGFR and the risk for regional recurrence (AUC 66). Conclusions: This study indicates that immunoscoring using HA could be used to provide prognostic tools for tongue cancer, and that it might be of interest to study the prognostic properties of EGFR further concerning the risk for regional recurrence after the primary treatment.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
Keyword
Epidermal growth factor receptor expression, immunoscoring, oral tongue squamous cell carcinoma, prognostic factors, biomarkers
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-316243 (URN)10.1080/00016489.2017.1292049 (DOI)000404684100016 ()28355940 (PubMedID)
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-10-19Bibliographically approved
Ward, H. A., Wark, P. A., Muller, D. C., Steffen, A., Johansson, M., Norat, T., . . . Riboli, E. (2017). Measured Adiposity in Relation to Head and Neck Cancer Risk in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiology, Biomarkers and Prevention, 26(6), 895-904.
Open this publication in new window or tab >>Measured Adiposity in Relation to Head and Neck Cancer Risk in the European Prospective Investigation into Cancer and Nutrition
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2017 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 6, 895-904 p.Article in journal (Refereed) Published
Abstract [en]

Background: Emerging evidence from cohort studies indicates that adiposity is associated with greater incidence of head and neck cancer. However, most studies have used self-reported anthropometry which is prone to error. Methods: Among 363,094 participants in the European Prospective Investigation into Cancer and Nutrition study (EPIC) with measured anthropometry, there were 837 incident cases of head and neck cancer. Head and neck cancer risk was examined in relation to body mass index (BMI) [lean: <22.5 kg/m(2), normal weight (reference): 22.5-24.9 kg/m(2), overweight 25-29.9 kg/m(2), obese: >= 30 kg/m(2)], waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) using Cox proportional hazards models. Results: Among men, a BMI <22.5 kg/m(2) was associated with higher head and neck cancer risk [HR 1.62; 95% confidence interval (CI), 1.23-2.12)]; BMI was not associated with head and neck cancer among women. WC and WHR were associated with greater risk of head and neck cancer among women (WC per 5 cm: HR, 1.08; 95% CI, 1.02-1.15; WHR per 0.1 unit: HR, 1.64; 95% CI, 1.38-1.93). After stratification by smoking status, the association for WHR was present only among smokers (P-interaction = 0.004). Among men, WC and WHR were associated with head and neck cancer only upon additional adjustment for BMI (WC per 5 cm: HR 1.16; 95% CI, 1.07-1.26; WHR per 0.1 unit: HR, 1.42; 95% CI, 1.21-1.65). Conclusions: Central adiposity, particularly among women, may have a stronger association with head and neck cancer risk than previously estimated.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-327232 (URN)10.1158/1055-9965.EPI-16-0886 (DOI)000402765600011 ()28183827 (PubMedID)
Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2017-08-25Bibliographically approved
Counter, S. A., Buchanan, L. H., Ortega, F., Jacobs, A. B. & Laurell, G. (2017). Middle Ear Function and Pathophysiology in Andean Children Living at High Altitudes. High Altitude Medicine & Biology, 18(2), 163-170.
Open this publication in new window or tab >>Middle Ear Function and Pathophysiology in Andean Children Living at High Altitudes
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2017 (English)In: High Altitude Medicine & Biology, ISSN 1527-0297, E-ISSN 1557-8682, Vol. 18, no 2, 163-170 p.Article in journal (Refereed) Published
Abstract [en]

The extent of altitude-related middle ear disorders in children native to high altitudes is unclear. This study examined middle ear pathophysiology in two groups of children living in high-altitude Ecuadorian Andean communities by investigating middle ear pressure (MEP), tympanic membrane compliance (TMC), and ear canal volume (ECV) using tympanometry, and by otological examination. Altitude I Group lived at 2850m, and Altitude II Group resided at around 4000m. The two high-altitude groups were compared with a reference group of children residing at sea level. Mean MEP was -3.6daPa (SD: 39.2), 3.5daPa (SD: 28.7), and 1.3daPa (SD: 13.6) for Altitude I Group, Altitude II Group, and the Sea Level Group, respectively. The MEP was not significantly different among the three groups. Mean TMC was 0.63cm3 (SD: 0.51), 0.60cm3 (SD: 0.43), and 0.60cm3 (SD: 0.24) for Altitude I Group, Altitude II Group, and the Sea Level Group, respectively. The TMC was not significantly different among the three groups. Mean ECV was 1.1 (SD: 0.26), 1.2 (SD: 0.26), and 1.0 (SD: 0.23) for Altitude I Group, Altitude II Group, and the Sea Level Group, respectively. The difference in ECV between Altitude I Group and Altitude II Group was significant (p=0.043), as was the difference between Altitude II Group and the Sea Level Group (p=0.001). ECV did not differ significantly between Altitude I Group and the Sea Level Group. Otological examination revealed a low incidence of ear canal and middle ear pathology. In conclusion, tympanometric and otological findings did not reveal a high incidence of middle ear pathophysiology in children living at altitudes as high as around 4000m.

Keyword
altitude, Andean, hypoxia, impedance, middle ear disorders, tympanometry
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-329702 (URN)10.1089/ham.2016.0160 (DOI)000403937500010 ()28530447 (PubMedID)
Available from: 2017-10-09 Created: 2017-10-09 Last updated: 2017-10-09Bibliographically approved
Counter, S. A., Nikkhou-Aski, S., Damberg, P., Berglin, C. E. & Laurell, G. (2017). Ultra-high-field (9.4 T) MRI Analysis of Contrast Agent Transport Across the Blood-Perilymph Barrier and Intrastrial Fluid-Blood Barrier in the Mouse Inner Ear. Otology and Neurotology, 38(7), 1052-1059.
Open this publication in new window or tab >>Ultra-high-field (9.4 T) MRI Analysis of Contrast Agent Transport Across the Blood-Perilymph Barrier and Intrastrial Fluid-Blood Barrier in the Mouse Inner Ear
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2017 (English)In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 38, no 7, 1052-1059 p.Article in journal (Refereed) Published
Abstract [en]

Hypothesis: Effective paramagnetic contrast agent for the penetration of the perilymphatic spaces of the scala tympani, scala vestibuli, and scala media of the mouse inner ear can be determined using intravenous injection of various gadolinium (Gd) complexes and ultra-high-field magnetic resonance imaging (MRI) at 9.4 Tesla.

Background: A number of contrast agents have been explored in experimental high-field MRI to determine the most effective Gd complex for ideal signal-to-noise ratio and maximal visualization of the in vivo mammalian inner ear in analyzing the temporal and spatial parameters involved in drug penetration of the blood-perilymph barrier and intrastrial fluid-blood barrier in the mouse model using MRI.

Methods: Gadoteric acid (Dotarem), Gadobutrol (Gadovist), Gadodiamide (Omniscan), Gadopent acid (Magnevist), and Mangafodipir (Teslascan) were administered intravenously using the tail vein of 60 Balb/C mice. High-resolution T1 images of drug penetration were acquired with a horizontal 9.4 T Agilent magnet after intravenously injection. Signal intensity was used as a metric of temporal and spatial parameters of drug delivery and penetration of the perilymphatic and endolymphatic spaces.

Results: ANOVA analysis of the area under the curve of intensity enhancement in perilymph revealed a significant difference (p < 0.05) in the scalae uptake using different contrast agents (F (3,25) = 3.54, p = 0.029). The Gadoteric acid complex Dotarem was found to be the most effective Gd compound in terms of rapid, morphological enhancement for analysis of the temporal, and spatial distribution in the perilymphatic space of the inner ear.

Conclusion: Gadoteric acid (Dotarem) demonstrated efficacy as a contrast agent for enhanced visualization of the perilymphatic spaces of the inner ear labyrinthine in the mouse, including the scala tympani and scala vestibuli of the cochlea, and the semicircular canals of the vestibular apparatus. These findings may inform the clinical application of Gd compounds in patients with inner ear fluid disorders and vertigo.

Keyword
Cochlea, Contrast agents, Gadolinium, Magnetic resonance imaging
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-332937 (URN)10.1097/MAO.0000000000001458 (DOI)000405393400023 ()28570419 (PubMedID)
Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2017-11-02Bibliographically approved
Farnebo, L., Laurell, G. & Makitie, A. (2016). A Nordic survey on the management of head and neck CUP. Acta Oto-Laryngologica, 136(11), 1159-1163.
Open this publication in new window or tab >>A Nordic survey on the management of head and neck CUP
2016 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 136, no 11, 1159-1163 p.Article in journal (Refereed) Published
Abstract [en]

Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a continuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries.Results: Four of the five Nordic countries use either national guidelines or specific protocols when handling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or chemoradiotherapy to treat N+ HNCUP patients. Robotic surgery for biopsy of the tongue base is beginning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.

Keyword
Cancer of unknown origin, follow up, multidisciplinary tumour board meeting, PET-CT
National Category
Cancer and Oncology Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-308622 (URN)10.1080/00016489.2016.1193894 (DOI)000386069300014 ()27310467 (PubMedID)
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2017-11-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-7760-246x

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