Elisabeth Kjellén

Skåne University Hospital, Malmö, Skåne, Sweden

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Publications (93)225.19 Total impact

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    ABSTRACT: Objectives Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth. Materials and methods We investigated the effect of the EGFR ligand transforming growth factor alpha (TGF-α) and cetuximab, alone and in combination, on HNSCC cell lines, measuring proliferation and the activity of intracellular signalling pathways. Results In line with previous reports we found the majority of the cell lines to be growth-inhibited by TGF-α. Surprisingly, two of the cell lines, which were more thoroughly investigated, were either growth-inhibited or stimulated by both cetuximab and TGF-α, depending on the presence or absence of the other substance. We also present data indicating the existence of two different receptor activities emanating from the EGFR protein. Conclusion We therefore show that TGF-α can have both growth-stimulating and growth-inhibiting effects in the same cell line and that EGFR-targeting drugs can be similarly double-edged. The implication for such drugs is that the micro-environment within a tumour, and possibly within portions of a tumour, may influence the growth-inhibiting effect of the drug. There may also be important implications for our understanding of EGFR signalling and its influence on growth and development.
    Oral Oncology. 09/2014;
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    ABSTRACT: Several studies on the use of erythropoietin (Epo) to treat anaemia in patients undergoing cancer treatment have shown adverse effects on tumour control and survival. Experimental studies indicate that this could be linked to an interaction with wound healing processes and not an effect on tumour cells per se. We have previously shown that erythropoietin in combination with surgical trauma stimulates tumour growth. In the present study, we investigated the effect of surgery and Epo on gene expression.
    BMC Cancer 09/2014; 14(1):648. · 3.33 Impact Factor
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    ABSTRACT: Weight loss is a common problem in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) treated with radiotherapy (RT). The aims of the present study were to determine if treated volume (TV), as a measure of the radiation dose burden, can predict weight loss in patients with oropharyngeal cancer and to analyze weight loss and body mass index (BMI) in the same patient group in relation to 5-year overall survival.
    Radiation oncology (London, England). 07/2014; 9(1):160.
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    ABSTRACT: To analyse late morbidity and mortality in pre and post-menopausal breast cancer patients treated with postmastectomy radiotherapy, with emphasis on side-effects from the heart, cerebrovascular and respiratory systems.
    European journal of cancer (Oxford, England: 1990) 06/2014; · 4.12 Impact Factor
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    ABSTRACT: Abstract Conclusion: PET-CT scans seem to be sufficient to rule out residual tumour at the primary site. Patients with positive or equivocal PET findings should be scheduled for endoscopy with biopsy or a second PET-CT scan. Objectives: Assessment of remission at the primary site, in patients treated with organ preservation therapy with curative intent, is important to identify residual tumours requiring treatment with salvage surgery. The aim of this study was to evaluate the diagnostic accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) after radiotherapy with or without chemotherapy in assessing primary site response in patients with head and neck cancer. Methods: A total of 82 patients, with a positive baseline PET-CT scan before start of treatment, were evaluated with a PET-CT scan 6-7 weeks post-radiotherapy and with a clinical examination/endoscopy with or without biopsy 1-2 weeks later. The majority of patients had p16-positive oropharyngeal tumours. Results: Post-treatment, 77% of the patients had no visible hypermetabolism. If equivocal PET scans are regarded as positive, the sensitivity, specificity, negative (NPV) and positive predictive value (PPV) and accuracy were 100%, 78%, 100%, 6% and 78%, respectively. Eight patients suffered from relapses involving the primary site during the 9-month follow-up.
    Acta oto-laryngologica 04/2014; · 0.98 Impact Factor
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    ABSTRACT: Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment. Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures. Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up. Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction.
    Supportive Care in Cancer 04/2014; · 2.09 Impact Factor
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    ABSTRACT: Trismus, a well-known sequelae after treatment of head and neck cancer, decreases a patient's oral function and quality of life. The main objectives of this study were to: 1) investigate the long-term prevalence of radiation-induced trismus in patients treated for head and neck cancer according to two different fractionation schedules; and 2) model a dose-response relationship for trismus. Material and methods. Patients were recruited from the Swedish ARTSCAN trial, a prospective randomised multicentre study comparing conventional and accelerated fractionation. A total of 124 patients agreed to a clinical ENT examination 21-127 months (median 66 months) after beginning radiation therapy. Trismus-related scores were assessed using the EORTC H&N35 Quality of Life questionnaire. The TheraBite(®) range of motion scale was used to measure maximal interincisal distance. The dose-response relationship for structures important for mastication and the temporomandibular joints was investigated by normal tissue complication probability modelling. Results. No significant differences in patient-reported trismus or maximal interincisal distance were found between the two trial arms. Patient-reported moderate to high scores regarding trismus increased from 3% at the start of radiation therapy to 25% at the long-term follow-up. Maximal interincisal distance correlated significantly with patient-reported scores of trismus. The best dose-response fit to the endpoint data was found for the dose to the ipsilateral masseter. Conclusions. Trismus is a persistent complication after radiotherapy with 3D-conformal radiation therapy. We found no difference between the severity and prevalence of trismus between conventional and accelerated fractionation, but a significant correlation between the absorbed dose to the mastication structures and opening of the mouth. Further prospective studies may determine whether a reduced dose to structures important for mastication using intensity-modulated radiation therapy will reduce problems with trismus.
    Acta oncologica (Stockholm, Sweden) 03/2014; · 2.27 Impact Factor
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    ABSTRACT: Hypo-fractionated external beam radiotherapy with narrow CTV-PTV margins is increasingly applied for prostate cancer. This demands a precise target definition and knowledge on target location and extension during treatment. It is unclear how increase in fraction size affects changes in prostate volume during treatment. Our aim was to study prostate volume changes during extreme hypo-fractionation (7 x 6.1Gy) by using sequential MRIs. Twenty patients treated with extreme hypo-fractionation were recruited from an on-going prospective randomized phase III trial. An MRI scan was done before start of treatment, at mid treatment and at the end of radiotherapy. The prostate was delineated at each MRI and the volume and maximum extension in left-right, anterior-posterior and cranial-caudal directions were measured. There was a significant increase in mean prostate volume (14%) at mid treatment as compared to baseline. The prostate volume remained enlarged (9%) at the end of radiotherapy. Prostate swelling was most pronounced in the anterior-posterior and cranial-caudal directions. Extreme hypo-fractionation induced a significant prostate swelling during treatment that was still present at the time of last treatment fraction. Our results indicate that prostate swelling is an important factor to take into account when applying treatment margins during short extreme hypo-fractionation, and that tight margins should be applied with caution.
    Radiation Oncology 01/2014; 9(1):22. · 2.11 Impact Factor
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    ABSTRACT: Background and purpose The purpose of this study was to investigate the correlation between the haematological toxicity observed in patients treated with craniospinal irradiation, and the dose distribution in normal tissue, specifically the occurrence of large volumes exposed to low dose. Materials and methods Twenty adult male patients were included in this study; eight treated with helical tomotherapy (HT), and twelve with three-dimensional conformal radiation therapy. The relative volume of red bone marrow and body that was exposed to low dose (i.e. the so-called dose bath) was evaluated and correlated with nadir blood values during treatment, i.e. the severity of anaemia, leukopaenia, and thrombocytopaenia. The correlation was tested for different dose levels representing the dose bath using the Pearson product-moment correlation method. Results We found a significant correlation between the volume of red bone marrow exposed to low dose and the severity of thrombocytopaenia during treatment. Furthermore, for the HT patients, a significant correlation was found between the relative volume of the body exposed to low dose and the severity of anaemia and leukopenia. Conclusions The severity of haematological toxicity correlated with the fraction of red bone marrow or body that was exposed to low dose.
    Radiotherapy and Oncology 01/2014; · 4.52 Impact Factor
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    ABSTRACT: Aim of the study To analyse late morbidity and mortality in pre and post-menopausal breast cancer patients treated with postmastectomy radiotherapy, with emphasis on side-effects from the heart, cerebrovascular and respiratory systems. Methods Long term follow-up of two randomised, clinical trials with 1100 patients was carried out. Pre-menopausal women were allocated to radiotherapy (RT), RT + oral cyclophosphamide (RT + C) or cyclophosphamide only (C). Post-menopausal women were allocated to RT, RT + Tamoxifen for one year (RT + Tam) or tamoxifen only (Tam). Information on admission to hospital, mortality and causes of death was obtained from national registers. Results After 25 years, adding RT to cyclophosphamide in pre-menopausal women raised the mortality from heart disease from zero to 0.8% (p = 0.04). In post-menopausal women, adding RT to Tam raised the mortality from heart disease from 10.5% to 18.4% (p = 0.005). In post-menopausal women mortality due to cerebrovascular disease increased from 3.4% to 8.7% by adding RT to Tam (p = 0.015). The differences were not evident until in the second decade of follow-up. In spite of differences in specific causes of death, there were no significant differences between the treatment arms concerning morbidity or overall mortality. Conclusion Postmastectomy radiotherapy to the chest wall and loco-regional lymph nodes including the parasternal lymph nodes as delivered in the end of the seventies did not reduce overall mortality, but gave a significantly increased risk of death from heart and cerebrovascular disease, which appeared during the second decade after radiotherapy.
    European Journal of Cancer. 01/2014;
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    ABSTRACT: The aim of the present study was to evaluate the prevalence and severity of lower limb lymphedema after pelvic lymphadenectomy and radiotherapy to the pelvic lymph nodes in patients with prostate cancer. Twenty-six patients underwent combined treatment for high-risk node-positive prostate cancer at Skane University Hospital between April 2008 and March 2011. The treatment consisted of extended pelvic lymphadenectomy followed by androgen deprivation therapy and radiotherapy. The pelvic lymphnodes, prostate and seminal vesicles were treated with external beam radiotherapy (EBRT) to an absorbed dose of 50 Gy followed by a brachytherapy (BT) boost of 2x10 Gy to the prostate only. Twenty-two patients accepted an invitation to a clinical examination with focus on lower limb swelling. The median time between the end of radiotherapy and examination was 2.2 years (range 1.2-4.1). Six patients (27%) experienced grade 1 lymphedema and two patients (9%) grade 2 while none had grade 3 or 4 according to the CTC Common Toxicity Criteria scale 4.0. Three patients required treatment with compression stockings. Brachytherapy and pelvic EBRT have a low incidence of lymphedema (at median 2.2 y after treatment) in patients with high-risk node-positive prostate cancer that have undergone pelvic lymph node dissection.
    Radiation Oncology 11/2013; 8(1):271. · 2.11 Impact Factor
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    ABSTRACT: BACKGROUND: Local recurrence is a major factor affecting survival after treatment for head and neck squamous cell carcinoma (HNSCC). It is possible that the normal processes involved in wound healing after surgical removal of a primary tumor can boost the regrowth of residual cancer cells, thereby contributing to the recurrent growth. In this work, we collected human wound fluids and used them to investigate the effect of wound healing factors on HNSCC cell lines in vitro. METHODS: Wound fluids were collected from thyroidectomized patients diagnosed with benign disease and were included in assays of cell proliferation, migration, cell scattering, and invasion. The involvement of intracellular signaling pathways and membrane receptors were investigated by western blotting and the inclusion of specific inhibitors. RESULTS: One out of four cell lines was greatly stimulated in proliferation, migration, cell scattering, and invasion by the addition of wound fluid as compared with addition of fetal bovine or human serum. These effects were accompanied by a sharp increase in activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 activation abolished the wound fluid response, showing that STAT3 plays an important role in the wound healing response. Several of the observed phenotypic changes were epithelial-to-mesenchymal transition (EMT)-like, but the appropriate changes were not seen in any of the EMT markers investigated. The involvement of c-Met or epidermal growth factor receptor family members was excluded, while the interleukin-6 receptor was found to be partly responsible for the activation of STAT3. CONCLUSIONS: In conclusion, we found cell-line-specific effects of wound healing factors on HNSCC, setting the stage for therapy development and predictive opportunities.
    BMC Cancer 01/2013; 13(1):33. · 3.33 Impact Factor
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    ABSTRACT: 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.
    Acta oncologica (Stockholm, Sweden) 10/2012; · 2.27 Impact Factor
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    ABSTRACT: Abstract Conclusion: The study showed the value of using intravital microscopy (IVM) analysis for the study of neoangiogenesis. It demonstrated that the model and the analytical methodology could be used to evaluate in detail the effects of treatment strategies for solid tumours. Objectives: Neoangiogenesis is a key component of tumour progression, invasion and metastasis. In clinical trials monoclonal antibodies specific for vascular endothelial growth factor - VEGF (bevacizumab) - have been shown to significantly affect tumour progression when given in combination with standard chemotherapy, and also to improve the overall survival of patients. For squamous cell carcinoma of the head and neck (HNSCC), we still await definitive evidence of the effect of such treatment. The present study was designed to investigate the anti-angiogenesis effect of beviacizumab in green fluorescent protein (GFP)-labelled HNSCC xenografts using IVM technology. Methods: We performed IVM and used image analysis for quantification of angiogenesis and of effects of bevacizumab on cell viability, combined with histochemical and immunohistochemical analysis to standardize the digital analysis of changes in tumour vascularization and cell viability. Results: We found significant effects of bevacizumab on angiogenesis and cancer cell survival in HNSCC. Repeated injections of bevacizumab were found to provide the greatest effects.
    Acta oto-laryngologica 10/2012; · 0.98 Impact Factor
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    ABSTRACT: Predictive strategies for the treatment efficacy of cetuximab are currently not available for head and neck cancer. We investigated the correlation between the expression of epidermal growth factor receptor (EGFR) ligands and EGFR expression, and the growth inhibitory activity of cetuximab in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. The growth inhibiting effect of cetuximab was measured for eight HNSCC cell lines and correlated with the autocrine production of five EGFR ligands as measured by ELISA, and the mRNA expression of two ligands, as measured by quantitative RT-PCR. EGFR expression was assessed by western blot analysis. There was a good correlation between the expression of four of the EGFR ligands (TGF-α, amphiregulin, epiregulin and epigen) and the growth inhibiting effect of cetuximab. TGF-α had the highest predictive potential but had to be combined with epigen for full prediction. EGFR expression also correlated with cetuximab sensitivity but less clearly. The results indicate that the expression of several EGFR ligands has to be used to predict sensitivity to cetuximab in HNSCC. This has to be further evaluated in clinical samples.
    Journal of Cancer Research and Clinical Oncology 12/2011; 138(3):491-9. · 2.91 Impact Factor
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    ABSTRACT: The role of chemotherapy (CHX) in squamous cell carcinoma of the head and neck (SCCHN) has been expanding. Although combination chemotherapy regimens regularly produce significantly high response rates, meta-analyses show little benefit regarding final outcome. One way to improve induction CHX is to improve drug combinations and schedules for CHX. Cisplatin (CDDP) is one of the most active drugs in the treatment of patients with SCCHN, and it is used in most combinations. Ifosfamide (IFO) is another agent that has shown activity in the treatment of patients with SCCHN. A poorly differentiated squamous cell carcinoma xenografted to nude mice was used. CDDP (2.5 mg/kg) and IFO (100 mg/kg) as single bolus doses induced significant retardation of tumour growth. Single drug administration was compared with CDDP given before IFO and IFO given before CDDP. Mean specific growth delay (SGD) for untreated controls was 0. For CDDP as single drug it was 1.50, for IFO as single drug it was 0.79, for CDDP given 4 h before IFO it was 1.79, and for IFO given 4 h before CDDP it was 2.90. Maximum toxicity, calculated as change in median weight at day 7, was less than 10%. The efficacy and toxicity of CDDP and IFO is schedule-dependent, with IFO given before CDDP being more effective than CDDP given before IFO. This is in contrast to most schedules used clinically. The toxicities were comparable. The number of combinations of drugs with respect to order and time interval is of a magnitude that would not be possible to test clinically. In the pursuit of more efficient combinations, the importance of order and schedule of drugs and also the potential of xenografted SSCHN are underestimated.
    Oral Oncology 09/2011; 48(1):61-6. · 2.70 Impact Factor
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    ABSTRACT: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF. Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment. The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects. Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated.
    Radiotherapy and Oncology 02/2011; 100(1):41-8. · 4.52 Impact Factor
  • Clinical Nutrition Supplements 01/2011; 6(1):146-146.
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    ABSTRACT: PURPOSE: Early metabolic response with a decrease in glucose demand after cytotoxic treatment has been reported to precede tumor volume shrinkage. However, preclinical studies report of a very early rise in metabolism, a flare, following treatment. To elucidate these observations, we performed an experimental study on early metabolic response with sequential analysis of metabolic changes. METHODS: Three squamous cell carcinoma cell lines and one nontumorigenic cell line were exposed to cisplatin. The uptake of the fluorescent glucose analogue 2-NBDG was examined at days 1-6 using fluorescence microscopy. The relation between 2-NBDG-uptake and cell survival was evaluated. RESULTS: The tumor cells exhibited a high uptake of 2-NBDG, whereas the uptake in the nonmalignant cells was low. The more cisplatin sensitive cell lines exhibited a more pronounced metabolic flare than the less sensitive cell line. CONCLUSION: A metabolic flare was a very early sign of treatment response and potentially it could be used as an early marker of treatment sensitivity.
    Nuclear Medicine and Molecular Imaging 09/2010; 44(3):165-169.
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    ABSTRACT: We have performed extensive investigations of laser-induced fluorescence in animal and human tissue aimed at instant tissue characterization. Autofluorescence, as well as specific fluorescence from HPD/DHE and other photosensitizers, has been utilized. The studies have been focused on the demarcation of malignant tumours and atheroscleortic plaques. A nitrogen laser or an excimer-pumped dye laser was used to induce fluorescence, which was analysed with an intensified optical multichannel system. A fibre-optic sensor system was developed for the clinical work. Multi-colour fluorescence imaging has also been demonstrated along a line and equipment for two-dimensional imaging is being constructed. Dimensionless spectroscopic functions, which are not affected by factors that are clinically uncontrollable have been employed for optimum tissue discrimination. The investigations have so far been performed in a time-integrated mode, but time-resolved studies are now being initiated to fully exploit the diagnostic power of tissue laser-induced fluorescence. In addition to a presentation of our own work a brief review of tissue fluorescence studies performed by other groups is also given.
    Berichte der Bunsengesellschaft für physikalische Chemie. 05/2010; 93(3):335 - 342.

Publication Stats

992 Citations
225.19 Total Impact Points

Institutions

  • 2011–2014
    • Skåne University Hospital
      Malmö, Skåne, Sweden
  • 1982–2014
    • Lund University
      • • Department of Oncology
      • • Department of Otorhinolaryngology, Head and Neck Surgery
      • • Department of Otolaryngology
      Lund, Skåne, Sweden
  • 2011–2012
    • Hamamatsu University School of Medicine
      • Division of Otorhinolaryngology/Head and Neck Surgery (School of Medicine)
      Hamamatu, Shizuoka, Japan
  • 2008–2012
    • Umeå University
      • • Department of Clinical Sciences
      • • Department of Radiation Sciences
      Umeå, Vaesterbotten, Sweden
  • 2007–2009
    • Malmö University
      Malmö, Skåne, Sweden
  • 1990
    • The Hillingdon Hospitals NHS Foundation Trust
      अक्सब्रिज, England, United Kingdom