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  • 1. Ahlberg, Alexander
    et al.
    al-Abany, Massoud
    Alevronta, Eleftheria
    Friesland, Signe
    Hellborg, Henrik
    Mavroidis, Panayiotis
    Lind, Bengt K
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Esophageal stricture after radiotherapy in patients with head and neck cancer: experience of a single institution over 2 treatment periods2010In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 32, no 4, p. 452-461Article in journal (Refereed)
    Abstract [en]

    Enteral feeding during EBRT is strongly associated with the development of stricture of the esophagus, as is a mean dose of >45 Gy to the upper esophagus. Treatment of the stricture with Savary-Gilliard bougienage or through scope balloon dilatation is safe and successful but often has to be repeated.

  • 2. Ahlberg, Alexander
    et al.
    Engström, Therese
    Nikolaidis, Polymnia
    Gunnarsson, Karin
    Johansson, Hemming
    Sharp, Lena
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Early self-care rehabilitation of head and neck cancer patients2011In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 131, no 5, p. 552-61Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS: No positive effects of early preventive rehabilitation could be identified. The results do not contradict the proposition that rehabilitation based on self-care can be effective but it is important to establish evidence-based training programs and identify proper instruments for selection of patients and evaluation of intervention.

    OBJECTIVES: Patients with head and neck cancer suffer from functional impairments due to intense treatment. In this study, we investigated the effectiveness of an experimental early preventive rehabilitation using hard, objective end points in a nonselective, longitudinal, prospective cohort study.

    METHODS: In all, 190 patients were included in the program and received instructions for training before the start of treatment with the aim of reducing swallowing problems and reducing mouth opening and stiffness in the neck. A control group of 184 patients was recruited.

    RESULTS: There was no difference in weight loss and 2-year survival between the two groups. No positive effects concerning functional impairments were found in patient-reported outcome measures.

  • 3. Ahlberg, Alexander
    et al.
    Nikolaidis, Polymnia
    Engström, Therese
    Gunnarsson, Karin
    Johansson, Hemming
    Sharp, Lena
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Morbidity of supraomohyoidal and modified radical neck dissection combined with radiotherapy for head and neck cancer: a prospective longitudinal study2012In: Head and Neck, ISSN 1043-3074, E-ISSN 1097-0347, Vol. 34, no 1, p. 66-72Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of this study was to show the investigated impact of supraomohyoidal neck dissection and modified radical neck dissection, both combined with radiotherapy, on cervical range of motion (CROM), mouth opening, swallowing, lymphedema, and shoulder function.

    METHODS: One hundred eight patients who had neck dissections and 98 patients who had non-neck dissections were evaluated in a prospective, nonselective, longitudinal cohort study by a physiotherapist and a speech-language pathologist (SLP) before the start of radiotherapy and up to 12 months after treatment.

    RESULTS: The incidence of shoulder disability after neck dissection was 18%. Supraomohyoidal neck dissection had no significant effect on the evaluated parameters at any time point. Modified radical neck dissection significantly reduced CROM and mouth opening 2 months after treatment, but after 12 months only cervical rotation was still significantly reduced.

    CONCLUSION: In patients treated with external beam radiation (EBRT), modified radical neck dissection induced additional morbidity regarding CROM but not regarding mouth opening, swallowing, and lymphedema 1 year after treatment. Both modified radical neck dissection and supraomohyoidal neck dissection induced shoulder disability.

  • 4.
    Alevronta, Eleftheria
    et al.
    Department of Oncology-Pathology, Division of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden.
    Ahlberg, Alexander
    Department of Otolaryngology, Karolinska University Hospital, Stockholm, Sweden.
    Mavroidis, Panayiotis
    Department of Oncology-Pathology, Division of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden.
    al-Abany, Massoud
    Department of Oncology-Pathology, Division of Clinical Cancer Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Friesland, Signe
    Department of Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
    Tilikidis, Aris
    Department of Medical Physics, Karolinska University Hospital, Stockholm, Sweden.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lind, Bengt K
    Department of Oncology-Pathology, Division of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden.
    Dose-response relations for stricture in the proximal oesophagus from head and neck radiotherapy2010In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 97, no 1, p. 54-59Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Determination of the dose-response relations for oesophageal stricture after radiotherapy of the head and neck.

    MATERIAL AND METHODS: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992-2000 and 2001-2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model.

    RESULTS: For the treatment period 1992-2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992-2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001-2005 were 49.8 and 21.4 Gy. For the period 2001-2005 the best estimates of the dose-response parameters are D(50)=61.5 Gy (52.9-84.9 Gy), γ=1.4 (0.8-2.6) and s=0.1 (0.01-0.3).

    CONCLUSIONS: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001-2005. However, no dose response relation was found for the complete material.

  • 5. Berglin, Cecilia Engmer
    et al.
    Pierre, Pernilla Videhult
    Bramer, Tobias
    Edsman, Katarina
    Ehrsson, Hans
    Eksborg, Staffan
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Prevention of cisplatin-induced hearing loss by administration of a thiosulfate-containing gel to the middle ear in a guinea pig model2011In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, no 6, p. 1547-1556Article in journal (Refereed)
    Abstract [en]

    Thiosulfate may reduce cisplatin-induced ototoxicity, most likely by relieving oxidative stress and by forming inactive platinum complexes. This study aimed to determine the concentration and protective effect of thiosulfate in the cochlea after application of a thiosulfate-containing high viscosity formulation of sodium hyaluronan (HYA gel) to the middle ear prior to i.v. injection of cisplatin in a guinea pig model. The release of thiosulfate (0.1 M) from HYA gel (0.5% w/w) was explored in vitro. Thiosulfate in the scala tympani perilymph of the cochlea 1 and 3 h after application of thiosulfate in HYA gel to the middle ear was quantified with HPLC and fluorescence detection. Thiosulfate in blood and CSF was also explored. The potential otoprotective effect was evaluated by hair cell count after treatment with thiosulfate in HYA gel applied to the middle ear 3 h prior to cisplatin injection (8 mg/kg b.w.). HYA did not impede the release of thiosulfate. Middle ear administration of thiosulfate in HYA gel gave high concentrations in the scala tympani perilymph while maintaining low levels in blood, and it protected against cisplatin-induced hair cell loss. HYA gel is an effective vehicle for administration of thiosulfate to the middle ear. Local application of a thiosulfate-containing HYA gel reduces the ototoxicity of cisplatin most likely without compromising its antineoplastic effect. This provides a minimally invasive protective treatment that can easily be repeated if necessary.

  • 6.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Differences in p63 expression in SCCHN tumours of different sub-sites within the oral cavity2011In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 47, no 9, p. 861-865Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck, SCCHN, the sixth most common cancer in the world, comprises tumours of differentanatomical sites. The overall survival is low, and there are no good prognostic or predictive markers available. The p53 homologue, p63, plays an important role in development of epithelial structures and has also been suggested to be involved in development of SCCHN. However, most studies on p63 in SCCHN have not taken into account the fact that this group of tumours is heterogeneous in terms of the particular site of origin of the cancer. Mapping and comparing p63 expression levels in tumours and corresponding clinically normal tissue in SCCHN from gingiva, tongue and tongue/floor of the mouth revealed clear differences between these regions. In normal samples from tongue and gingiva, tongue samples showed 2.5-fold higher median p63 expression and also more widespread expression compared to gingival samples. These results emphasise the importance of taking sub-site within the oral cavity into consideration in analyses of SCCHN.

  • 7.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    p63 transcriptionally regulates BNC1, a Pol I and Pol II transcription factor that regulates ribosomal biogenesis and epithelial differentiation2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no 9, p. 1401-1406Article in journal (Refereed)
    Abstract [en]

    The p53-family member, p63 is a transcription factor that influences cellular adhesion, motility, proliferation, survival and apoptosis, and has a major role in regulating epithelial stem cells. Expression of p63 is often dysregulated in squamous cell carcinomas of the head and neck. In this study we show that p63 induces the expression of the basal epithelial transcription factor, Basonuclin 1. Basonuclin 1 is an unusual transcription factor that interacts with a subset of promoters of genes that are transcribed by both RNA polymerase-I and -II and has roles in maintaining ribosomal biogenesis and the proliferative potential of immature epithelial cells. Chromatin immunoprecipitation and reporter assays demonstrate that Basonuclin 1 is a direct transcriptional target of p63 and we also show that up-regulation of Basonuclin 1 is a common event in squamous cell carcinomas of the head and neck. These data identify a new transcriptional programme mediated by p63 regulation of the Basonuclin 1 transcription factor in squamous cell carcinomas and provide a novel link of p63 with the regulation of ribosomal biogenesis in epithelial cancer.

  • 8.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Tayside Tissue Bank Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
    Wahlgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins.2012In: Journal of Carcinogenesis, ISSN 0974-6773, E-ISSN 1477-3163, Vol. 11, p. 18-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools.

    MATERIALS AND METHODS: In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity.

    RESULTS: We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b.

    CONCLUSION: The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.

  • 9.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gu, Xiaolian
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010 Paris, France.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences/ENT, Uppsala University, 752 36 Uppsala, Sweden.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 12, p. 19389-19402Article in journal (Refereed)
    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.

  • 10.
    Duan, Maoli
    et al.
    Center for Hearing and Communication Research, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Bjelke, Börje
    Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Fridberger, Anders
    Center for Hearing and Communication Research, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Counter, S Allen
    Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Klason, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Skjönsberg, Åsa
    Center for Hearing and Communication Research, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Herrlin, Petra
    Center for Hearing and Communication Research, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Borg, Erik
    Ahlsen Research Institute, Örebro University Hospital, 701 85 Örebro, Sweden.
    Laurell, Göran
    Center for Hearing and Communication Research, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Imaging of the guinea pig cochlea following round window gadolinium application2004In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, Vol. 15, no 12, p. 1927-1930Article in journal (Refereed)
    Abstract [en]

    Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.

  • 11. Duan, Maoli
    et al.
    Chen, Zhiqiang
    Qiu, Jianxin
    Ulfendahl, Mats
    Laurell, Göran
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Borg, Erik
    Ruan, Runsheng
    Low-dose, long-term caroverine administration attenuates impulse noise-induced hearing loss in the rat2006In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Acta Otolaryngol, Vol. 126, no 11, p. 1140-7Article in journal (Refereed)
  • 12. Duan, Maoli
    et al.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Qiu, Jianxin
    Borg, Erik
    Susceptibility to impulse noise trauma in different species: guinea pig, rat and mouse.2007In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 128, no 3, p. 277-283Article in journal (Refereed)
  • 13.
    Ehrsson, Ylva Tiblom
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Hellström, Per M
    Department of Medical Science, Uppsala University Hospital, 751 85 Uppsala, Sweden.
    Brismar, Kerstin
    Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Sharp, Lena
    Department of Oncology, Karolinska University Hospital, 118 83 Stockholm, Sweden.
    Langius-Eklöf, Ann
    School of Medical and Health Sciences, Örebro University, 701 82 Örebro, Sweden.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Explorative study on the predictive value of systematic inflammatory and metabolic markers on weight loss in head and neck cancer patients undergoing radiotherapy2010In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 18, no 11, p. 1385-1391Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study aimed to explore the predictive value of systematic inflammatory and metabolic markers in head and neck (H&N) cancer patients during radiotherapy (RT).

    METHODS: Twenty-seven patients were evaluated. The protocol included serial blood tests [highly sensitive C-reactive protein (hsCRP), albumin, insulin-like growth factor 1 (IGF-1), IGF binding protein 1 (IGFBP-1) and ghrelin], measurements of body weight and assessment of oral mucositis.

    RESULTS: The mean nadir of weight loss was observed at the end of RT. At the time of diagnosis, mean hsCRP was 5.2 ± 1.0 mg/L. HsCRP significantly increased during RT and decreased during the post-RT period. Mean maximum hsCRP was 35.8 ± 8.5 mg/L, with seven patients reaching >40 mg/L. A numerical decrease of albumin (by 18.2%) and only small changes in IGF-1, IGFBP-1 and ghrelin levels were observed. None of the metabolic parameters was significantly associated with weight loss.

    CONCLUSIONS: HsCRP increased in response to RT for H&N cancer as a sign of irradiation-induced inflammation. Weight loss was not preceded by changes of the metabolic parameters, indicating that assessment of the blood markers used in this study is of little value. Regular body weight measurement and assessment of oral mucositis are feasible, cheap and important procedures to control the metabolic homeostasis during RT.

  • 14. Ehrsson, Ylva Tiblom
    et al.
    Langius-Eklöf, Ann
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nutritional surveillance and weight loss in head and neck cancer patients2012In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 20, no 4, p. 757-765Article in journal (Refereed)
    Abstract [en]

    This retrospective single-institution cohort study aims to evaluate if therapeutic approach, tumour site, tumour stage, BMI, gender, age and civil status predict body weight loss and to establish the association between weight loss on postoperative infections and mortality. Consecutive patients with head and neck cancer were seen for nutritional control at a nurse-led outpatient clinic and followed-up for 2 years after radiotherapy. Demographic, disease-specific and nutrition data were collected from case records. The primary outcome measure was maximum body weight loss during the whole study period. The nadir of body weight loss was observed 6 months after radiotherapy. In total, 92 patients of 157 (59%) with no evidence of residual tumour after treatment received enteral nutrition. The mean maximum weight loss for patients receiving enteral nutrition and per oral feeding was 13% and 6%, respectively (p < 0.001). Using multivariate analysis, tumour stage (p < 0.001) was the only independent factor of maximum weight loss. Weight loss was not significantly related to risk for postoperative infection. Weight loss is frequently noted among head and neck cancer patients during and after treatment. Weight loss was not found to be associated with postoperative infections and mortality. Nutritional surveillance is important in all patients, but special attention should be given to those on enteral nutrition and those with more advanced disease.

  • 15.
    Ekborn, Andreas
    et al.
    Departments of Otolaryngology—Head and Neck Surgery, Stockholm, Sweden.
    Hansson, Johan
    Oncology-Radiology, Stockholm, Sweden.
    Ehrsson, Hans
    Oncology-Pathology, Stockholm, Sweden.
    Eksborg, Staffan
    Woman and Child Health, Stockholm, Sweden.
    Wallin, Inger
    Karolinska Institute, and Karolinska Pharmacy, Stockholm, Sweden.
    Wagenius, Gunnar
    Department of Oncology, Uppsala University Hospital (Akademiska Sjukhuset), Uppsala, Sweden.
    Laurell, Göran
    Departments of Otolaryngology—Head and Neck Surgery, Stockholm, Sweden.
    High-dose cisplatin with amifostine: ototoxicity and pharmacokinetics2004In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 114, no 9, p. 1660-1667Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES/HYPOTHESIS: Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin.

    STUDY DESIGN: Prospective study of 15 patients with stage IV malignant melanoma.

    METHODS: Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry.

    RESULTS: Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis.

    CONCLUSION: Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment.

  • 16. Engmér, Cecilia
    et al.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Bagger-Sjöbäck, Dan
    Rask-Andersen, Helge
    Immunodefense of the round window2008In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 118, no 6, p. 1057-1062Article in journal (Refereed)
    Abstract [en]

    A systematic analysis using serial sectioning of the round window membrane (RWM) in the cynomolgus monkey was performed. Light and transmission electron microscopy (LM and TEM) revealed that the RWM rim may be endowed with gland-like structures with glyco-protein material secernated into the window niche. This was detected in one third of the specimens. The secreted material displayed waste material and scavenger cells. There was also a rich network of capillaries, lymph channels, and sinusoidal veins containing leukocytes. Their abluminal surfaces displayed mature plasma cells and monocytes. These findings suggest that in certain primates the middle ear may have developed specific immunoprotective means for disposal of foreign and noxious substances before they reach the inner ear.

  • 17. Hellberg, Victoria
    et al.
    Wallin, Inger
    Eriksson, Sofi
    Hernlund, Emma
    Jerremalm, Elin
    Berndtsson, Maria
    Eksborg, Staffan
    Arnér, Elias SJ
    Shoshan, Maria
    Ehrsson, Hans
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity2009In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 101, no 1, p. 37-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.

    METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.

    RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.

    CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

  • 18.
    Isaksson, Joakim
    et al.
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Salander, Pär
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Granström, Brith
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Uppsala universitet, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Critical incidents reveal how patients with head and neck cancer construct their 'secure base' as a 'helping system'2014In: Journal of psychosocial oncology, ISSN 0734-7332, E-ISSN 1540-7586, Vol. 32, no 3, p. 322-341Article in journal (Refereed)
    Abstract [en]

    Most studies of the psychosocial needs of patients with head and neck cancers' (HNC) use predefined categories and explicitly ask for specified needs. These studies are important but should be complemented with inductive studies based on patients' own descriptions of experiences. The present qualitative study is such a contribution. In repeated interviews positive and negative incidents were collected from 137 patients with HNC, and these experiences were categorized in dimensions expressing needs. A core category - 'being included - neglected by a helping system' - emerged from the narrated incidents and it was based on the dimensions 'engagement', 'competence' and 'information'. The findings are easily related to attachment theory by stressing the significance of establishing trustful relationships with the health care staff, as attachment figures, who respond flexibly and sensitively to the patient's needs. In the constitution of health care as a helping system, all encounters between the patient and health care staff matters. Further research should preferably focus on the creation of guidelines for the constitution of health care as a helping system, i.e. how the found factors of a helping system can be operationalized in clinical practice.

  • 19.
    Jonsson, Eva Lindell
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallen, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck2012In: ONCOL LETT, ISSN 1792-1074, Vol. 4, no 6, p. 1177-1182Article in journal (Refereed)
    Abstract [en]

    Head and neck squamous cell carcinoma is a common form of cancer, and despite improvements in treatment during the last decades, survival rates have not significantly increased. There is therefore a need to better understand how these tumours and the adjacent tissues react to radiotherapy, the most common type of treatment for this group of tumours. In order to improve this understanding, the expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) and the presence of mast cells were mapped before and after radiotherapy using immunohistochemistry. The results showed HA and EGFR to have similar expression patterns in tumour tissue and histologically normal squamous epithelium prior to radiotherapy. Following radiotherapy, EGFR increased in histologically normal epithelium. An increased number of mast cells were also observed as a result of radiotherapy. No expression of EGFR was observed in the connective tissue either prior to or following radiotherapy.

  • 20. Kreimer, Aimée R
    et al.
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Waterboer, Tim
    Kaaks, Rudolf
    Chang-Claude, Jenny
    Drogen, Dagmar
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    González, Carlos A
    Sánchez, Maria José
    Larrañaga, Nerea
    Navarro, Carmen
    Barricarte, Aurelio
    Travis, Ruth C
    Khaw, Kay-Tee
    Wareham, Nick
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H M
    Panico, Salvatore
    Masala, Giovanna
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Manjer, Jonas
    Ekström, Johanna
    Skeie, Guri
    Lund, Eiliv
    Weiderpass, Elisabete
    Ferrari, Pietro
    Byrnes, Graham
    Romieu, Isabelle
    Riboli, Elio
    Hildesheim, Allan
    Boeing, Heiner
    Pawlita, Michael
    Brennan, Paul
    Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer2013In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, no 21, p. 2708-2715Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera.

    METHODS: We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression.

    RESULTS: HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative.

    CONCLUSION: HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

  • 21.
    Laurell, Göran
    et al.
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Ekborn, Andreas
    Viberg, Agneta
    Canlon, Barbara
    Effects of a single high dose of cisplatin on the melanocytes of the stria vascularis in the guinea pig2007In: Audiol Neurootol, ISSN 1421-9700, Vol. 12, no 3, p. 170-178Article in journal (Refereed)
  • 22.
    Laurell, Göran
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Institut National de la Santé et de la Recherche Médicale, Department of Physiology, Faculté Xavier Bichat, Université Paris, Center for Hearing and Communication.
    Teixeira, Marie
    Duan, Maoli
    Sterkers, Olivier
    Ferrary, Evelyne
    Intact blood-perilymph barrier in the rat after impulse noise trauma2008In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 128, no 6, p. 608-612Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: The permeability of the blood-labyrinth barrier for radioactive mannitol was unchanged after impulse noise trauma. The present findings are contradictory to the theory of an increased permeability in the blood-labyrinth barrier as a result of extensive noise exposure.

    OBJECTIVE: Noise trauma is reported to cause multiple effects on the cochlea including mechanical and metabolic damage. The aim of the study was to observe the effects of impulse noise on cochlear homeostasis.

    MATERIALS AND METHODS: A well-established rat model was used for evaluation of the early effects of impulse noise trauma on the integrity of the blood-perilymph barrier. To evaluate whether a blood-perilymph barrier disruption contributes to cochlear injury after impulse noise, the paracellular transport of radioactive mannitol into scala vestibuli perilymph (PLV) and electrolyte concentration in perilymph were estimated. Thirteen animals exposed to synthesized impulses of 160 dB SPL peak value, at a rate of 100 pulses, were designed as the study group and 15 rats not exposed to noise were designed as the control group. After mannitol infusion each ear of the animal in the study group was separately exposed to impulse noise and PLV samples were taken during 2 h post-infusion. In the control group, corresponding PLV samples were taken after mannitol injection.

    RESULTS: At 2 h after mannitol infusion there was no difference in PLV mannitol concentration in the study group and control group (21.5%+/-2.2 and 20.5%+/-2.1, respectively). Impulse noise had no effect on the electrochemical composition of PLV.

  • 23. Lindblom, Ulrika
    et al.
    Nilsson, Per
    Gärskog, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Kjellen, Elisabeth
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wahlberg, Peter
    Zackrisson, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Levring Jäghagen, Eva
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aspiration as a late complication after accelerated versus conventional radiotherapy in patients with head and neck cancer2016In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 136, no 3, p. 304-311Article in journal (Refereed)
    Abstract [en]

    Conclusion Neck dissection after radiotherapy increased the risk of aspiration as a late effect in a sub-sample of patients treated for head and neck cancer in the ARTSCAN study. Patients treated with accelerated fractionation (AF) developed aspiration, with or without coughing, more frequently than patients treated with conventional fractionation (CF). Objectives A long-term follow-up study was conducted to determine the frequency of aspiration as a late effect in patients with head and neck cancer treated with AF or CF. Method One-hundred and eight patients were recruited from two centres of the Swedish multi-centre study, ARTSCAN, where AF and CF were compared. Patients with positive lymph nodes were treated with neck dissection after completing radiotherapy. The follow-up was performed at a median of 65 months after initiation of radiotherapy and included an ENT and a videofluoroscopic examination. Results Aspiration was found in 51/108 (47%) and silent aspiration in 34/96 (35%) patients. Neck dissection (n = 47 patients) was significantly associated with both aspiration and silent aspiration. Aspiration was more common among patients treated with AF (34/61; 56%) compared to CF (17/47; 36%; p = 0.053). Silent aspiration was also more common after AF (24/54; 44%) than after CF (10/42; 24%; p = 0.052).

  • 24.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Arvidsson, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Recurrent respiratory papillomatosis in northern Sweden: Clinical characteristics and practical guidance2015In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 135, no 10, p. 1058-1064Article in journal (Refereed)
    Abstract [en]

    Conclusion: Recurrent respiratory papillomatosis (RRP) patients with high surgical treatment frequency (>= 1/year, HF) were significantly younger and had a more widespread laryngeal disease compared to a low frequency treated group (< 1 treatment/year, LF). This study confirms the existence of a clinical RRP group, not primarily related to HPV sub-type, but more care-intensive and in need of more vigilant follow-up. Objectives: RRP is associated with high morbidity due to its influence on breathing and voice. The purpose of this study was to characterize RRP patients in northern Sweden and investigate possible predictor factors affecting therapeutic needs. Method: Patients from the regional referral area (northern Sweden) were categorized for age, disease duration, juvenile or adult onset, profile of disease development, number of surgical sessions in relation to disease duration, laryngeal deposition of papilloma, gender, and HPV sub-types, in order to identify patients with increased need for frequent surgical treatment. Results: The median age of the RRP patients (n = 48) was 44.5 years; 34 (71%) were males and 14 (29%) females, most were infected with HPV 6. Patients with high surgical treatment frequency/year were significantly younger and showed more widespread papillomatous vegetation in the larynx, compared to the low frequency treated group.

  • 25.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Voice and quality of life in patients with recurrent respiratory papillomatosis in a northern Sweden cohort2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, ISSN 1651-2251 (online), Vol. 134, no 4, p. 401-406Article in journal (Refereed)
    Abstract [en]

    Abstract Conclusion:

    The frequency of operations, age at onset, gender and subtype of the human papilloma virus (HPV) may be used as factors to predict voice disability.

    Objectives:

    Patients with recurrent respiratory papillomatosis (RRP) are characterized by morbid consequences due to a lifelong repetitive influence on voice and breathing ability and the need for recurrent surgical treatments. The aim of the study was to measure the quality of voice and life using evaluated and validated questionnaires in a northern Sweden RRP population.

    Methods:

    A total of 27 consecutive patients with RRP (age 21-71 years, median 47 years) were evaluated 3 months postoperatively (CO2 laser treatment) using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in an RRP population. The values were compared to historical normative data, VHI ≤ 20.

    Results:

    Patients that underwent more than one operation per year were younger (p = 0.028) than those treated less frequently. The mean VHItotal score in patients with RRP was 39.3, indicating a statistically significant impairment of voice quality (p < 0.001) as compared with normal subjects. Voice dysfunction was observed in 21 patients (78%). Significantly lower values than the normal population regarding the quality of life in patients with RRP were obtained in the domain of social functioning (p = 0.029). Females, patients with frequent surgical treatment sessions and patients with the high-risk HPV types scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. The results should be interpreted with caution due to the limited number of subjects.

  • 26.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus2015In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, no 6, p. 3565-3572Article in journal (Refereed)
    Abstract [en]

    The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

  • 27.
    Loljung, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Nekulova, Marta
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wahlgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Widlöf, Mikael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hansel, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of p63 is correlated to poor prognosis in squamous cell carcinoma of the tongue2014In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 43, no 1, p. 14-19Article in journal (Refereed)
    Abstract [en]

    Backgroundp63 proteins are important in formation of the oral mucosa. Normal oral mucosa shows a balance between the six protein isoforms, whereas an imbalance between them is seen in squamous cell carcinomas (SCC). There is controversy over the clinical impact of p63 in SCC, which may relate to different expression in different areas. In addition, p63 isoforms can act as p53-like molecules (TAp63) or can inhibit p53 functions (Np63) and expression of these isoforms varies in different tumours. Here, we chose to concentrate on the most common intra-oral sub-site, SCC of the mobile tongue. MethodsTotal p63, Np63 and TAp63 were analysed separately using immunohistochemistry. The percentage of cells and intensity of expression of different isoforms of p63 was evaluated using a quick score method and correlated with clinical data in a group of 87 patients with tongue SCC. ResultsAll tumours expressed p63 in at least 60% of the cells when using two different antibodies detecting all 6 isoforms. p63 expression correlated significantly with 2-year survival (P=0.018), with fewer patients surviving 2years if their tumours expressed p63 with strong intensity in at least 80% of the cells (quick score 18). Looking at 5-year survival, this was even more emphasized. Np63 was expressed in all tumours, whereas expression of TAp63 was seen only in 59/87 patients, usually at very low levels. ConclusionsBased on the present data, we recommend using expression of p63 as an additional factor contributing prognostic information in analysis of SCC in the tongue.

  • 28. Lorito, Guiscardo
    et al.
    Hatzopoulos, Stavros
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Campbell, Kathleen C. M.
    Petruccelli, Joseph
    Giordano, Pietro
    Kochanek, Krzysztof
    Sliwa, Lech
    Martini, Alessandro
    Skarzynski, Henryk
    Dose-dependent protection on cisplatin-induced ototoxicity: an electrophysiological study on the effect of three antioxidants in the Sprague-Dawley rat animal model2011In: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 17, no 8, p. BR179-BR186Article in journal (Refereed)
    Abstract [en]

    Background: Sprague-Dawley rats were used as an acute cisplatin ototoxicity model to compare the chemo-protective efficacy of 2 sulphur-containing antioxidants (D-methionine, N-L-acetylcysteine) and 1 seleno-organic compound (ebselen). Each putative chemo-protective agent was tested at 3 different dosages in order to assess the influence of dose on auditory preservation.

    Material/Methods: A total of 40 Sprague-Dawley albino male rats were used in the study. Animals were divided into 10 groups, 3 groups of different doses for each protective agent and a cisplatin-treated control group. The animals were weight-matched before drug exposure to ensure similar weights in all groups. Auditory function was assessed with auditory brainstem responses and distortion product otoacoustic emissions at time zero and at 96 hours post-treatment.

    Results: At the post-treatment follow-up no significant threshold change at 8 kHz was found in the D-Met- and NAC-treated groups. All ebselen-treated animals presented significant threshold elevations. At 12 and 16 kHz, only the groups treated with 300, 450 mg/kg of D-Met and 475 mg/kg of NAC presented thresholds comparable to the pre-treatment ABR data. The ebselen-treated animals presented significant threshold shifts and showed the highest threshold elevations. The DPOAE data analysis showed that only the animals from the 350 mg/kg D-met group presented lack of statistical differences between the pre and post recordings.

    Conclusions: Considering the outcome from the ABR and DPOAE analyses together, only the 350 mg/kg D-met group presented a complete auditory preservation against the 14 mg/kg cisplatin administered i.v. Data from ebselen pre-treated Sprague-Dawley albino male rats demonstrate that ebselen dosages up to 12 mg/kg given by i.p. administration lack auditory preservation in this species.

  • 29.
    Lundqvist, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The importance of stromal inflammation in squamous cell carcinoma of the tongue2012In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, no 5, p. 379-383Article in journal (Refereed)
    Abstract [en]

    Background: Histological risk assessment evaluating worst pattern of tumour invasion (WPOI), and lymphocytic response (LR), has previously been shown to be of prognostic significance in squamous cell carcinomas of the head and neck (SCCHN). SCCHN is a heterogeneous group of tumours including tumours located in the oral cavity, of which the majority is located in the tongue.

    Methods: Haematoxylin/eosin-stained slides from diagnostic biopsies from 94 cases of SCC on the tongue were evaluated for WPOI and LR. Within the inflammatory infiltrate, the percentage of eosinophilic granulocytes was also estimated. Results were correlated with clinical data such as response to treatment and recurrence.

    Results: For WPOI the majority of patients, 84%, showed small invasive tumours islands with a size <15 cells (grade 4). No correlation with survival, response to treatment or recurrence was seen for WPOI. More than half of the patients showed a dense lymphocytic infiltrate, a factor that was significantly correlated with complete response to radio therapy. Of the patients with dense lymphoid infiltrate, the majority, 63%, did not either have a recurrence. No significant correlation with recurrence, response to treatment or any other factor was seen for presence of eosinophils.

    Conclusions:  Data clearly showed that tongue tumours have a split invasive growth pattern and an intense inflammatory response at the tumour interface. Results also indicated that evaluation of the intensity of the inflammatory infiltrate at the tumour interface in tongue SCC could provide information of potential importance for choice of treatment and prognosis.

  • 30.
    Mavroidis, Panayiotis
    et al.
    Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden .
    Lind, Bengt K
    Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden .
    Theodorou, Kyriaki
    Department of Medical Physics, Larissa University Hospital, Larissa, Greece .
    Laurell, Göran
    Department of Otolaryngology, Head and Neck Surgery, Karolinska Hospital, Stockholm, Sweden .
    Fernberg, Jan-Olof
    Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden .
    Lefkopoulos, Dimitrios
    Department of Radiation Physics, Tenon Hospital, Paris, France .
    Kappas, Constantin
    Department of Medical Physics, Larissa University Hospital, Larissa, Greece .
    Brahme, Anders
    Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Sweden .
    Statistical methods for clinical verification of dose-response parameters related to esophageal stricture and AVM obliteration from radiotherapy2004In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 49, no 16, p. 3797-3816Article in journal (Refereed)
    Abstract [en]

    The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and chi2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.

  • 31. Norling, Rikke
    et al.
    Grau, Cai
    Nielsen, Michael B
    Homøe, Preben
    Sørensen, Jens A
    Lambertsen, Karin
    Bundgaard, Troels
    Mäkitie, Antti
    Grénman, Reidar
    Larenne, Jussi
    Koivunen, Petri
    Virtaniemi, Jukka
    Gudjonsson, Arnar
    Jetlund, Olav
    Abendstein, Helmut
    Rikardsen, Oddveig
    Lybak, Stein
    Wennerberg, Johan
    Högmo, Anders
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Westerborn, Anders
    Hammerlid, Eva
    Tytor, Wieslaw
    Cederblad, Lena
    von Buchwald, Christian
    Radiological imaging of the neck for initial decision-making in oral squamous cell carcinomas-A questionnaire survey in the Nordic countries2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 3, p. 355-361Article in journal (Refereed)
    Abstract [en]

    Background. Fast and accurate work-up is crucial to ensure the best possible treatment and prognosis for patients with head and neck cancer. The presence or absence of neck lymph node metastases is important for the prognosis and the choice of treatment. Clinical lymph node (N)-staging is done by palpation and diagnostic imaging of the neck. We investigated the current practice of the initial radiological work-up of patients with oral squamous cell carcinomas (OSCC) in the Nordic countries. Methods. A questionnaire regarding the availability and use of guidelines and imaging modalities for radiological N-staging in OSCC was distributed to 21 Head and Neck centres in Denmark (n = 4), Finland (n = 5), Iceland (n = 1), Norway (n = 4) and Sweden (n = 7). We also asked for a description of the radiological criteria for determining the lymph nodes as clinical positive (cN+) or negative (cN0). Results. All 21 Head and Neck centres responded to the questionnaire. Denmark and Finland have national guidelines, while Norway and Sweden have local or regional guidelines. Seventeen of the 19 centres with available guidelines recommended computed tomography (CT) of the cN0 neck. The waiting time may influence the imaging modalities used. Lymph node size was the most commonly used criteria for radiological cN+, but the cut-off measures vary from 0.8 to 2.0 cm. Conclusion. Overall, CT is the most commonly recommended and used imaging modality for OSCC. Despite availability of national guidelines the type and number of radiological examinations vary between centres within a country, but the implementation of a fast-track programme may facilitate fast access to imaging. The absence of uniform criteria for determining the lymph nodes of the neck as cN+ complicates the comparison of the accuracy of the imaging modalities. Well-defined radiological strategies and criteria are needed to optimise the radiological work-up in OSCC.

  • 32.
    Nyqvist, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Otolaryngology and Head and Neck Surgery, Skåne University Hospital, Lund.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Nursing.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Otolaryngology and Head and Neck Surgery, Uppsala University Hospital.
    Hammerlid, Eva
    Kjellén, Elisabeth
    Franzén, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Söderström, Karin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wickart-Johansson, Gun
    Friesland, Signe
    Sjödin, Helena
    Brun, Eva
    Ask, Anders
    Nilsson, Per
    Ekberg, Lars
    Björk-Eriksson, Thomas
    Nyman, Jan
    Lödén, Britta
    Lewin, Freddi
    Reizenstein, Johan
    Lundin, Erik
    Zackrisson, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer: A five year follow up2016In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 118, no 2, p. 335-341Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer.

    Material and methods: 750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1-2, NO glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2 Gy/day, 5 days/week in 49 days, total dose 68 Gy) or accelerated fractionation (1.1 + 2.0 Gy/day, 5 days/week in 35 days, total dose 68 Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6 months and 1, 2 and 5 years after start of treatment.

    Results: The AF group reported HRQoL was significantly lower at eRT and at 3 months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6 months and 5 years. Scores related to functional oral intake never reached baseline.

    Conclusion: In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.

  • 33.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Studie av larynxpapillom i norra Sverige: två fall av onkogena HPV bland 26 patienter2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 21, p. 1187-1189Article in journal (Refereed)
    Abstract [en]

    Laryngeal papilloma is associated with human papillomavirus (HPV) 6, 11, 16, 18 and 31. The variation in the frequency of surgical treatment between patients for the same subtypes of HPV is inconsistent and poorly understood. Comparisons of the female laryngeal papilloma group (n?=?8, median age 46 yrs) with the male (n= 18, median age 32 yrs) with respect to gender, age, time of disease, period of life for diagnosis, disease progression profile, frequency of surgery (CO2 laser) during time of disease, localisation of papilloma in the upper airway and HPV subtype did not reach significance. In contrast the comparison between the high frequency (Ž 1 treatment/yr, n?=?11, median age 31 yrs) and low frequency (<1 treatment/yr, n?=?15 median age 45 yrs) treatment groups with regard to the same parameters as the female-male comparison, showed a clear-cut higher median age in the low frequency group (P?=?0,01).

  • 34.
    Ottosson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Olsson, Cecilia
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    The experience of food, eating and meals following radiotherapy for head and neck cancer: a qualitative study2013In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 22, no 7-8, p. 1034-1043Article in journal (Refereed)
    Abstract [en]

    Aims and objectives. To describe the experience of food, eating and meals following radiotherapy in patients with head and neck cancer.

    Background. Eating problems are common in patients with head and neck cancer and may remain for a long period of time after treatment.

    Design. A qualitative study design using in-depth semi-structured interviews.

    Methods. Interviews were conducted nine months after the termination of radiotherapy. A purposive sample of thirteen patients with head and neck cancer participated in the study. The interviews were tape-recorded, transcribed verbatim and analysed using content analysis.

    Results. The experience of food, eating and meals up to nine months after radiotherapy was captured in six categories: ‘Along journey – taking small steps to an uncertain future’, ‘A new way of eating’, ‘Eating without satisfaction’, ‘Challenging meals outside the family’, ‘Support and information – the key to a successful journey’ and ‘The creation and acceptance of a new normal’.

    Conclusion. This study provides new information on the long-term aspects of food, eating and meals in patients with head and neck cancer. Head and neck cancer signifies a long journey with problems affecting physical, psychological and social aspects of food. Information and support and the use of strategies are important for patients with head and neck cancer to adapt to new possibilities for living after cancer treatment. Relevance to clinical practice. All members of the multiprofessional team need to be aware of the struggles with food and eating experienced by patients with head and neck cancer during the convalescent period. It is therefore important that the follow-up focuses on all aspects of food, eating and meals as a part of a holistic approach.

  • 35.
    Ottosson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Zackrisson, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kjellén, Elisabeth
    Lunds Universitet, Klinisk vetenskap.
    Nilsson, Per
    Lunds Universitet, Klinisk vetenskap.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Weight loss in patients with head and neck cancer during and after conventional and accelerated radiotherapy2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 4, p. 711-718Article in journal (Refereed)
    Abstract [en]

    Background. Weight loss is common among patients with squamous cell carcinoma of the head and neck (SCCHN) and is mainly due to tumor and treatment related factors. The aim of the present study was to evaluate weight loss in patients with SCCHN undergoing two different radiotherapy (RT) schedules.

    Material and methods. Nutritional data were analyzed from the ARTSCAN study, a controlled randomized prospective Swedish multicenter study conducted with the aim of comparing conventional fractionation (2.0 Gy per day, total 68 Gy during 7 weeks) and accelerated fractionation (1.1 + 2.0 Gy per day, total 68 Gy during 4.5 weeks). Seven hundred and fifty patients were randomized and 712 patients were followed from the start of RT in the present nutritional study.

    Results. The patients had a weight loss of 11.3% (± 8.6%) during the acute phase (start of RT up to five months after the termination of RT). No difference in weight loss was seen between the two RT fractionation schedules (p = 0.839). Three factors were significantly predictive for weight loss during the acute phase, i.e. tumor site, overweight/obesity or lack of tube feeding at the start of RT. Moreover, the nadir point of weight loss occurred at five months after the termination of RT.

    Conclusion. The results of the present study showed no difference in weight loss between the two RT fractionation schedules and also highlight that weight loss in SCCHN is a multifactorial problem. Moreover, the nadir of weight loss occurred at five months after the termination of treatment which calls for more intense nutritional interventions during the period after treatment.

  • 36. Qiu, Jian-xin
    et al.
    Fang, Xian-zhao
    Tong, Bu-shen
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Duan, Mao-li
    [Study of sensitivity to impulse noise in guinea pig, rat and mouse]2004In: Zhonghua er bi yan hou ke za zhi, ISSN 0412-3948, Vol. 39, no 8, p. 472-475Article in journal (Refereed)
    Abstract [zh]

    OBJECTIVE: To study sensitivity to impulse noise in guinea pig, rat and mice. METHODS: Six groups were divided. Group I: Guinea pigs (n = 5) were exposed to 50 impulses of 160 dB SPL; Group II: Guinea pigs (n = 5) were exposed to 100 impulses of 160 dB SPL; Group III: Guinea pigs (n = 5) were exposed to 200 impulses of 160 dB SPL; Group IV: Guinea pigs (n = 6) were exposed 400 impulses of 160 dB SPL; Group V: Rats (n = 10) were exposed to 50 impulses of 160 dB SPL; Group VI: Mice (n = 10) were exposed to 50 impulses of 160 dB SPL. ABR thresholds were determined prior to, immediately, one day, one week, two weeks and four weeks after impulse noise exposure. RESULTS: The rat and mice were shown temporary threshold shift (TTS) and permanent threshold shift (PTS) after 50 times impulse noise (160), while no TTS and PTS in the guinea pigs but it was shown TTS and PTS after 400 times impulse noise (160). CONCLUSIONS: Sensitivity to impulse noise is different among guinea pig, rat and mouse. Guinea pig has less sensitivity to impulse noise while rat and mouse have higher sensitivity to impulse noise. In addition, rat has higher sensitivity to impulse noise than mouse.

  • 37.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip John
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Transcriptional profiling of formalin fixed paraffin embedded tissue: pitfalls and recommendations for identifying biologically relevant changes2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35276-Article in journal (Refereed)
    Abstract [en]

    Expression profiling techniques have been used to study the biology of many types of cancer but have been limited to some extent by the requirement for collection of fresh tissue. In contrast, formalin fixed paraffin embedded (FFPE) samples are widely available and represent a vast resource of potential material. The techniques used to handle the degraded and modified RNA from these samples are relatively new and all the pitfalls and limitations of this material for whole genome expression profiling are not yet clarified. Here, we analyzed 70 FFPE tongue carcinoma samples and 17 controls using the whole genome DASL array covering nearly 21000 genes. We identified that sample age is related to quality of extracted RNA and that sample quality influences apparent expression levels in a non-random manner related to gene probe sequence, leading to spurious results. However, by removing sub-standard samples and analysing only those 28 cancers and 15 controls that had similar quality we were able to generate a list of 934 genes significantly altered in tongue cancer compared to control samples of tongue. This list contained previously identified changes and was enriched for genes involved in many cancer-related processes such as tissue remodelling, inflammation, differentiation and apoptosis. Four novel genes of potential importance in tongue cancer development and maintenance, SH3BGL2, SLC2A6, SLC16A3 and CXCL10, were independently confirmed, validating our data. Hence, gene expression profiling can be performed usefully on archival material if appropriate quality assurance steps are taken to ensure sample consistency and we present some recommendations for the use of FFPE material based on our findings.

  • 38.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip John
    Univ Dundee, Ninewells Hosp & Med Sch, Tayside Tissue Bank, Med Res Inst, Dundee DD1 9SY, Scotland.
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Univ Uppsala Hosp, Dept Surg Sci ENT, S-75185 Uppsala, Sweden.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 5, p. 4191-4198Article in journal (Refereed)
    Abstract [en]

    Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81% for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42% to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue.

  • 39.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fahlén, Jessica
    Umeå University, Faculty of Social Sciences, Department of Statistics.
    Coates, PJ
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    miRNA analysis of formalin-fixed squamous cell carcinomas of the tongue is affected by age of the samples2011In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 1, p. 61-69Article in journal (Refereed)
    Abstract [en]

    Global miRNA expression arrays were used for analysis of 836 miRNAs in formalin-fixed paraffin-embedded samples from 21 tongue cancer patients and 8 controls. Samples had been stored for one to eleven years. Results separated tumour samples from controls, however, the largest variation was correlated to sample storage time, detectable already after one year. With the use of a linear regression model we could adjust for the storage-dependent effect, leading to the identification of 54 differentially expressed miRNAs in tongue cancer, compared to 16 when using standard normalization, including up-regulation of a novel miRNA, miR-424.

  • 40.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultin, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tubulin-α-6-chain is a stably expressed reference gene in archival samples of normal oral tissue and squamous cell carcinoma of the head and neck2010In: Experimental and Therapeutic Medicine, ISSN 1792-0981, Vol. 1, no 3, p. 419-423Article in journal (Refereed)
    Abstract [en]

    One of the most critical factors in gene expression studies using quantitative real-time PCR is the choice of reference gene. Many of the commonly used reference genes have been shown to vary during a number of biological processes as well as between tissues. It is therefore important to always verify the stability of the gene of choice for all new tissues and experimental conditions. Here, we used two publicly available computer software packages (GeNorm and NormFinder) to investigate the stability of eight potential reference genes in formalin-fixed paraffin-embedded (FFPE) samples from normal oral tissue of different origin as well as from oral squamous cell carcinomas. Both programs found the tubulin α-6 chain (TUBA6) and ribosomal protein S13 (RPS13) to have the most stable expression between malignant and non-malignant tissue. NormFinder also found TUBA6 to be the most stable gene when samples were grouped according to tissue origin. FFPE samples constitute a large research resource, which considerably increases the number of samples available for analysis, leading to more reliable conclusions. Verification of a proper reference gene in oral FFPE tissue is therefore of great importance for future studies.

  • 41.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johnsson, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Goran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Coates, Philip J.
    Nylander, Karin
    RNA expression profiling of archival tongue carcinoma samples2011Conference paper (Refereed)
  • 42.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Coates, Philip J
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Comments on "Transcriptional profiling of oral squamous cell carcinoma using formalin-fixed paraffin-embedded samples" by Saleh et al., Oral Oncol 46 (2010) 379-386.2010In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 46, no 12, p. 891-892Article in journal (Other academic)
  • 43.
    Rentoft, Matilda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Coates, Philip John
    Sjöström, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gene expression profiling of archival tongue squamous cell carcinomas provides sub-classification based on DNA repair genes2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 35, no 6, p. 1321-1330Article in journal (Refereed)
    Abstract [en]

    A subgroup of patients with squamous cell carcinoma of the head and neck (SCCHN) comprise young persons under the age of 40, who have not been heavily exposed to the classical risk factors, smoking and alcohol. The number of SCCHN in young adults, particularly tongue tumours, is increasing in several parts of the world. Here we employed a novel gene expression array methodology specifically developed for analysis of degraded RNA and investigated the expression of 502 cancer-related genes in archival paraffin-embedded SCCHN of the tongue from young (< or =40) and elderly patients (> or =50). Genes detected as de-regulated in tumours compared to non-malignant controls were in concordance with results from earlier studies of fresh frozen material. No genes were detected as significantly differentially expressed between young and old patients suggesting that the overall pathobiology of SCCHN is similar in young and old. Unsupervised clustering divided tumours into three groups, irrespective of age, where several differentially expressed DNA repair genes were a prominent separation factor. High levels of DNA repair genes associated with impaired therapeutic response to radiation, suggesting that DNA repair genes play a role in clinical outcome after radiotherapy.

  • 44. Saber, Amanj
    et al.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Bramer, Tobias
    Edsman, Katarina
    Engmér, Cecilia
    Ulfendahl, Mats
    Middle ear application of a sodium hyaluronate gel loaded with neomycin in a Guinea pig model.2009In: Ear and Hearing, ISSN 0196-0202, E-ISSN 1538-4667, Vol. 30, no 1, p. 81-89Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Establishing methods for topical administration of drugs to the inner ear have great clinical relevance and potential even in a relatively short perspective. To evaluate the efficacy of sodium hyaluronate (HYA) as a vehicle for drugs that could be used for treatment of inner ear disorders. METHODS: The cochlear hair cell loss and round window membrane (RWM) morphology were investigated after topical application of neomycin and HYA into the middle ear. Sixty-five albino guinea pigs were used and divided into groups depending on the type of the treatment. Neomycin was chosen as tracer for drug release and pharmacodynamic effect. HYA loaded with 3 different concentrations of neomycin was injected to the middle ear cavity of guinea pigs. Phalloidin stained surface preparations of the organ of Corti were used to estimate hair cell loss induced by neomycin. The thickness of the midportion of the RWM was measured and compared with that of controls using light and electron microscopy. All animal procedures were pe rformed in accordance with the ethical standards of Karolinska Institutet. RESULT: Neomycin induced a considerable hair cell loss in guinea pigs receiving a middle ear injection of HYA loaded with the drug, demonstrating that neomycin was released from the gel and delivered to the inner ear. The resulting hair cell loss showed a clear dose-dependence. Only small differences in hair cell loss were noted between animals receiving neomycin solution and animals exposed to neomycin in HYA suggesting that the vehicle neither facilitated nor hindered drug transport between the middle ear cavity and the inner ear. One week after topical application, the thickness of the RWM had increased and was dependent upon the concentration of neomycin administered to the middle ear. At 4 weeks the thickness of the RWM had returned to normal. CONCLUSION: HYA is a safe vehicle for drugs aimed to pass into the inner ear through the RWM. Neomycin was released from HYA and transported into the inner ear as evidenced by hair cell loss.

  • 45.
    Salander, Pär
    et al.
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Isaksson, Joakim
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Granström, Brith
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Uppsala Universitet, Department of Surgical Sciences - Otolaryngology and Head & Neck Surgery.
    Motives that head and neck cancer patients have for contacting a specialist nurse: an empirical study2016In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 25, no 21-22, p. 3160-3166Article in journal (Refereed)
    Abstract [en]

    Aims and objectives: The purpose of this study is to systematically explore the motives for patients with head and neck cancer to contact a speciaist nurse during two years postdiagnosis.

    Background: Research focusing on the role of specialist nurses in cancer care almost exclusively concern cancers other than head and neck cancer

    Design: Qualitative, descriptive study based on the contacts between patients with head and neck cancer and a specialist nurse.

    Methods: Patients were invited to contact a specialist nurse by telephone. The specialist nurse took systematic field notes, that is, she registered who contacted her, the nature of the call and the outcome. Sixty patients were included.

    Results: In descending order, the motives for contact were questions about practical and uncomplicated matters, consultations about medical troubles/worries, presenting a report of the patient's situation, requests for additional information about the treatment plan and requests for medical information. The pattern of the patients' motivations for calling was not related to medical or social factors, suggesting that the initiative to make a contact is very much a question of the complexity of individual life circumstances. Very few referrals were sent from the specialist nurse to other professionals.

    Conclusions: The specialist nurse turned out to be more than just a coordinator of health-care resources. The findings bring up questions about the potential of the nurse's function as a coordinator, but also as a potential attachment figure, and questions about the nurse's relationships to other professionals.

    Relevance to clinical practice: When implementing a specialist nurse function, it is important to decide whether the function should be inspired by a broader relational perspectice. In addition to the indispensible competence and experience in the clinical field of head and neck cancer, training in counselling and acquaintance with object-relational psychology will then be desirable.

  • 46.
    Sgaramella, Nicola
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Second University of Naples, Multidisciplinary Department of Medical, Surgical and Dental Specialties, Naples, Italy; Department of Neuroscience Reproductive and Dentistry Sciences, University of Naples Federico II, Naples, Italy.
    Lindell Jonsson, Eva
    Uppsala university.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Califano, Luigi
    University of Naples, Italy.
    Coates, Philip J
    University of Dundee, UK.
    Tartaro, Gianpaolo
    Second University of Naples, Italy.
    Lo Muzio, Lorenzo
    University of Foggia, Italy.
    Fåhraeus, Robin
    University Paris Diderot, INSERM UMRS1162, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    Colella, Giuseppe
    Second University of Naples, Italy.
    Dell'Aversana Orabona, Giovanni
    University of Naples, Italy.
    Loljung, Lotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Santagata, Mario
    Second University of Naples, Italy.
    Rossiello, Riccardo
    Seconda Universita’ Degli Studi di Napoli, Italy.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Danielsson, Karin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Laurell, Göran
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients ≤ 40 years but does not correlate with tumour spread2016In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p 50.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies.

  • 47. Skjönsberg, Åsa
    et al.
    Bucinskaite, Violeta
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Ulfendahl, Mats
    Augmented ototoxic effect of cisplatin in heterozygotes of the German waltzing guinea pig2008In: Audiology & neuro-otology, ISSN 1420-3030, E-ISSN 1421-9700, Vol. 13, no 2, p. 97-104Article in journal (Refereed)
    Abstract [en]

    It has previously been demonstrated that the carriers of the German waltzing guinea pig are less susceptible to noise trauma. To explore whether this represents a general resistance to inner ear trauma, carriers of the German waltzing guinea pig were exposed to the ototoxic agent cisplatin. Two doses of cisplatin were injected intravenously into anesthetized carriers and weight-matched control animals. Prior to and 96 h after the injections hearing thresholds were established by recording the auditory brainstem responses at 3.5, 7, 14, and 28 kHz. The cochleae were harvested to estimate hair cell loss and to analyze total platinum content. The carriers of the German waltzing guinea pig strain suffered from a more pronounced cisplatin-induced hearing loss compared to the control animals. The results suggest that mechanisms responsible for the protection against acoustic stress do not provide any protection against cisplatin in carriers of the German waltzing guinea pig.

  • 48. Videhult, Pernilla
    et al.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Clinical Sciences, Otorhinolaryngology.
    Wallin, Inger
    Ehrsson, Hans
    Kinetics of Cisplatin and its monohydrated complex with sulfur-containing compounds designed for local otoprotective administration2006In: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 231, no 10, p. 1638-45Article in journal (Refereed)
  • 49. Videhult Pierre, Pernilla
    et al.
    Engmér, Cecilia
    Wallin, Inger
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Ehrsson, Hans
    High concentrations of thiosulfate in scala tympani perilymph after systemic administration in the guinea pig2009In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 129, no 2, p. 132-137Article in journal (Refereed)
    Abstract [en]

    CONCLUSION: High concentrations of the antioxidant thiosulfate reach scala tympani perilymph after i.v. administration in the guinea pig. Thiosulfate concentrations in perilymph remain elevated longer than in blood. This warrants further studies on the possibility of obtaining otoprotection by thiosulfate administration several hours before that of cisplatin without compromising the anticancer effect caused by cisplatin inactivation in the blood compartment.

    OBJECTIVE: Thiosulfate may reduce cisplatin-induced ototoxicity, presumably by oxidative stress relief and formation of inactivate platinum complexes. This study aimed to explore to what extent thiosulfate reaches scala tympani perilymph after systemic administration in the guinea pig.

    MATERIALS AND METHODS: Scala tympani perilymph (1 microl) was aspirated from the basal turn of each cochlea up to 3 h after thiosulfate administration (103 mg/kg b.w., i.v.). Blood samples were also taken. Thiosulfate was quantified by HPLC and fluorescence detection.

    RESULTS: Substantial thiosulfate concentrations were found in perilymph. The area under the concentration-time curve for thiosulfate in perilymph and blood was 3100 microMxmin and 6300 microMxmin, respectively. The highest thiosulfate concentrations in perilymph were found at the first sampling at about 10 min. Due to a more rapid elimination from blood, perilymph concentrations exceeded those of blood towards the end of the experiment.

  • 50.
    Wagner, Niels
    et al.
    Departments of Otorhinolaryngology, Head and Neck Surgery, Gentofte University Hospital of Copenhagen, Hellerup, Denmark.
    Cayé-Thomasen, Per
    Departments of Otorhinolaryngology, Head and Neck Surgery, Gentofte University Hospital of Copenhagen, Hellerup, Denmark.
    Laurell, Göran
    Departments of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Bagger-Sjöbäck, Dan
    Departments of Otorhinolaryngology, Head and Neck Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Thomsen, Jens
    Departments of Otorhinolaryngology, Head and Neck Surgery, Gentofte University Hospital of Copenhagen, Hellerup, Denmark.
    Cochlear hair cell loss in single-dose versus continuous round window administration of gentamicin2005In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 125, no 4, p. 340-345Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS: Gentamicin-induced cochlear hair cell loss depends on local middle ear administration kinetics and the total drug dose. Single-dose gentamicin instillation in the middle ear is associated with a high variation in hair cell loss.

    OBJECTIVE: To compare the effects of single-dose and continuous round window administration of gentamicin on cochlear hair cell loss in a guinea pig model.

    MATERIAL AND METHODS: Two methods for drug administration to the inner ear were used. In groups of five animals, a total dose of 0.8 or 3.2 mg of gentamicin was either instilled as a single dose directly into the round window niche or administered continuously over a 1-week period using a pump-catheter system. Continuous administration was achieved by means of a posterior tympanotomy and subcutaneous placement of an osmotic pump fitted with a catheter. The tip of the catheter was fixed in the round window niche. One group of five animals served as controls and received a saline infusion. The animals were sacrificed after 1 week and hair cell loss was determined microscopically after dissection and phalloidin labelling of the basilar membrane and organ of Corti.

    RESULTS: Quantitation of cochlear hair cell loss revealed a dose-dependent effect of gentamicin. With both treatment modalities the higher dose induced a higher percentage of hair cell loss. There was inner and outer hair cell loss in all four groups that received gentamicin. With the single-dose instillation, hair cell loss was distributed irregularly from the round window membrane towards the cochlear apex, whereas continuous administration induced hair cell loss close to the round window membrane. Single-dose instillation induced greater hair cell loss than continuous administration at the same dose. The inter-individual variation in hair cell loss was highest following single-dose instillation.

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