| 1. |
- Loizou, Christos, 1980-
(författare)
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Human papillomavirus in recurrent respiratory papillomatosis, tonsillar and mobile tongue cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the effects of the human papillomavirus (HPV) in tonsillar cancer, mobile tongue cancer, and recurrent respiratory papillomatosis (RRP). The purpose was to characterize patients with RRP in northern Sweden in order to identify more care-intensive RRP patients and to describe the voice and quality of life aspects that follow RRP. Further aims were to confirm the expected increase of HPV-positive tonsillar cancer cases in northern Sweden, and to study the correlation between HPV, its surrogate marker p16 and HPV receptor syndecan-1 in both tonsillar cancer and mobile tongue cancer.A total of 27 consecutive patients with RRP were evaluated at 3 months postoperatively using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in a RRP population. The values were compared to normative data. This report was further extended by examining consecutive data from 21 new patients in order to characterize RRP patients in northern Sweden. In order to study HPV DNA in tonsillar (n= 65) and mobile tongue cancer (n=109), HPV DNA was extracted from paraffin-embedded biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of HPV surrogate marker p16 and the HPV receptor syndecan-1 was analysed by immunohistochemistry.Patients that underwent more than one RRP surgery per year were younger than those treated less frequently and they had significantly impaired voice quality as compared to normal subjects. Females, patients with frequent surgical treatment sessions, and patients with the high-risk HPV subtypes scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. Forty-eight RRP patients had a median age of 44.5 years; 71% were men and 29% females, preferentially infected with HPV6. Patients with high surgical treatment frequency/year showed more widespread RRP in the larynx compared to the patients treated less frequently.A total of 214 tonsillar cancer cases were identified. The vast majority were men. They had a median age of 58 years at diagnosis and expressed HPV as well as p16. The incidence of tonsillar cancer revealed a 2,7-fold increase in men between the years 1990 and 2013. The study demonstrates a strong association between p16 and HPV infection in tonsillar malignancies. These findings are in contrast to the mobile tongue cancer cases, where no evidence of HPV DNA could be detected although one-third showed p16 staining. This demonstrated a poor correlation between HPV and p16 in mobile tongue cancer. There was no difference in the expression of the primary HPV receptor, syndecan-1, between tonsillar and mobile tongue cancer.In conclusion, the frequency of RRP operations, age at onset, gender and subtype of the HPV may be used as factors to predict voice disability. RRP patients with high surgical treatment frequency were significantly younger and had a more widespread laryngeal disease compared to the low-frequency treated group. This study confirms the existence of a clinical RRP group, not primarily related to HPV subtype, but to a more care-intensive RRP population. Our findings identify a 2,7-fold increase in the incidence of tonsillar cancer, HPV and p16 in men between 1990-2013. We can use p16 to detect HPV in tonsillar cancer but not in tongue cancer.The introduction of vaccination against HPV may have a role in the prevention of specific HPV-subtype positive head and neck malignancies and recurrent respiratory papillomatosis since the current vaccine protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58. Males will definitely benefit indirectly from vaccination of females, though males will still remain at risk of cancers associated with HPV. This highlights the need for sex-neutral vaccination strategy. Our intention is that this thesis will provide scientific data to support a gender-neutral vaccination and to develop simple tools to detect HPV in tonsillar cancer.
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| 2. |
- Haylock, Anna-Karin, 1972-
(författare)
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Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules.
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| 3. |
- Jensson, David
(författare)
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Sequelae after Facial Palsy : Clinical, Anatomical and Electrophysiological Studies
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Sequelae after peripheral facial palsy, which among others include synkinesis, non-functional smile and/or lower lip asymmetry, may be devastating for the patient. Bell’s palsy is the most common form of peripheral facial palsy. Aim: The aim was to study a) frequency and potential predictive factors of synkinesis in Bell’s palsy b) new surgical treatment options after facial nerve injury c) coactivation between muscles innervated by the facial nerve and the most common donor nerves in smile reanimation d) anatomical features of the lower lip depressors. Methods: I: Frequency, severity and early predictors of synkinesis development were studied in 829 Bell’s palsy patients. II and IV: Anatomical technical feasibility of intra-facial nerve transfers was analyzed. V: Anatomical features of lower lip depressor muscles were studied and a literature review for lower lip depressor myectomies was performed. III: Coactivation of muscles innervated by cranial nerves during voluntary facial movements was measured with electromyography. Results: I: In Bell’s palsy, synkinesis frequency was 21.3% at 12-months and Sunnybrook composite score at one month was found to be a good predictor for synkinesis. II and IV: A tension-free oculo-zygomatic and platysma-marginal mandibular nerve transfer was anatomically feasible. Full recovery of the lower lip after platsysma-marginal mandibular nerve transfer was found in a clinical case. III: The masseter muscle had a narrower coactivation pattern compared to the tongue. Bite induced a strong coactivation in the zygomaticus major muscle. V: The width of the depressor labii inferioris was 20 ± 4 mm and the distance from the midline to the lateral muscle border was 32 ± 4 mm. For the depressor anguli oris muscle, the corresponding measurements were 14 ± 3 mm and 54 ± 4 mm. The mean recurrence rate after lower lip myectomy reported in the literature is 21%. Conclusion: I: Synkinesis in Bell’s palsy was 21%. Sunnybrook composite score at one month is a good predictor for synkinesis. II: Oculo-zygomatic nerve transfer may be a suitable technique to reduce eye synkinesis and achieve a stronger smile. III: The narrow coactivation pattern in the masseter muscle may be advantageous for spontaneous smile development. IV: The platysma motor nerve transfer is a feasible procedure and can lead to full recovery in lower lip paralysis. V: Knowledge of the width of the depressor muscles is of importance to ensure complete resection in lower lip myectomy.
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| 4. |
- Ottosson, Sandra, 1981-
(författare)
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Impact of disease and treatment on body weight and eating in patients with head and neck cancer : experiences from a multicenter study
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Nutritional deterioration in patients with head and neck cancer (HNC) has a multifactorial etiology mainly associated with tumor and treatment related factors. The objective of the present thesis was to investigate the impact of the disease and treatment on body weight and eating in patients with HNC treated with radiation therapy (RT) as the single modality treatment or as preoperative RT by analyzing body weight and body mass index (BMI) over time, predictive factors for weight loss and BMI, weight loss and BMI as prognostic factors for survival, and by studying the patients’ own experience of food and eating.Methods ARTSCAN is a randomized prospective multicenter trial conducted between the years of 1998 - 2006. Data were collected during and after RT with a total follow-up time of five years. Nutritional data from the whole study cohort (n = 712), from patients with oropharyngeal cancer (n = 232) and from two of the participating treatment centers (n = 101) were retrospectively analyzed in the present thesis. In addition, interviews (n = 13) were conducted nine months after the termination of RT as part of a care development project.Results On a group level, the patients lost weight during and after RT with a nadir at five months after the termination of RT. Factors related to a higher weight loss were oropharyngeal cancer, a high BMI at the start of RT, post-treatment aspiration, no tube feeding at the start of RT, and larger treated volumes. Furthermore, a high BMI at the start of RT was shown to be significantly related to a better five-year overall survival in patients with oropharyngeal cancer, whereas weight loss was not. The patients’ own narratives showed that all aspects of food, eating and meals were affected by the remaining sequelae, and that the patients found ways to accept and cope with the changes that had to be done to facilitate eating.Conclusions and clinical implications The disease and treatment gave persistent effects on the HNC patients’ weight and BMI which calls for a prolonged nutritional follow-up. The predictive factors found for weight loss can be used during patient history to find patients at risk for nutritional deterioration. In oropharyngeal cancer, patients with a high BMI at the start of RT had the best survival. This finding indicates that patients with a low BMI should be encouraged to gain weight before RT start. All aspects of food, eating and meals were affected during and after RT, and therefore the nutritional treatment should be given with a holistic approach to meet the multifaceted need patients with HNC experience.
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| 5. |
- Cederblad, Lena, 1959-
(författare)
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Aspects on Head and neck Cancer with special reference to Salivary Gland Tumours and Single Nucleotide Polymorphism
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A thesis on Head and neck cancer focusing on dose planning, salivary gland carcinoma and Single nucleotide polymorphism.For dose planning PET/CT (Positron emissions tomography/computed tomography) with tracer gave more precise information in comparison dose planning with CT. More primary tumours and metastases were found with the acetate tracer than with glucose tracer. Acetate PET/CT also showed larger volume of tumours attributed to lipid metabolism.In a retrospective study salivary gland cancer 5-year overall survival (OS) was 53 %. Salivary gland carcinoma consists of many histopathological groups, the two largest groups being mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ASCC). For ACC, having the best 5-year OS, it was 70 percent. Facial palsy, advanced stage disease, lymph node metastases worsened prognosis. ACC and polymorphous low grade carcinoma (PLGA) expressed c-myc and cyclin D1 to a larger extent than MEC.In squamous cell carcinoma of the head and neck we examined the occurrence of Single Nucleotide polymorphism, SNP. We found that the SNPs in male and female patients differed from each other. In male patients the SNPs were associated with immune response while in female patients the association was to SNPs concerning inflammation. This means that different pathways were engaged in cancer development for men and women. We also found that the SNPs in patients were different from those expressed in the healthy controls.
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| 6. |
- Holm, Anna M., 1989-
(författare)
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Human papillomavirus in sinonasal inverted papilloma, recurrent respiratory papilloma and non-malignant tonsils
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Human papillomavirus (HPV) is known to cause recurrent respiratory papilloma (RRP) and certain types of oropharyngeal cancer. HPV has also been associated with sinonasal inverted papilloma (SIP). HPV transmission routes are under investigation and the conviction is that the infection occurs sexually at an adult stage, however, vertical transmission at birth with a dormant viral condition until disease eruption/co-activation has been stated as a possibility.Purpose: The purpose of this work was to contribute to the understanding of HPV related chronic diseases in the airway. Specific aims were: 1. To increase understanding regarding changes in the immune system as well as of the glycosaminoglycan hyaluronan in patients with RRP. 2. To evaluate prevalence of HPV and its surrogate marker p16 in SIP as well as HPV, p16 and Epstein-Barr virus (EBV) in benign tonsillar disease. HPV and EBV in non-malignant tonsillar disease were studied due to the fact that incidence of HPV positive tonsillar cancer is increasing and the time of viral infection is unknown.Methods: A phenotypic characterization of peripheral blood from 16 RRP patients and 12 age-matched controls, using immunoflow cytometry, and monoclonal antibodies against differentiation and activation markers, was performed. The cytokine mRNA profile of monocytes, T helper-, T cytotoxic-, and NK cells was assessed using RT-qPCR. 54 SIP samples were studied of which 53 were available for analyzation with PCR. Genotype screening for 18 high risk and six low risk HPV types was performed using the PapilloCheck® HPV-screening test (a PCR method). 54 samples were immunohistochemically (IHC) stained for p16. Biopsies from vocal folds (VFs) and false vocal folds (FVFs) were collected from 24 patients with RRP, 12 were randomly selected to histochemistry for Hyaluronan (HA) and IHC staining for CD44 in the epithelium, stroma and RRP lesions. The remaining 12 patients were analyzed for HA molecular mass distribution with a gas-phase electrophoretic molecular mobility analyzer (GEMMA). Eight VF samples and four FVF samples were successfully analyzed. Biopsies from 40 non-malignant tonsils were analyzed using Papillocheck® for HPV, IHC for p16 and EBER analysis for EBV.Results: We found a dominance of cytotoxic T cells, activated NK cells, and high numbers of stressed MIC A/B (MHC class I chain-related molecule A/B) expressing lymphocytes. The HPV analysis was successful for 38 SIP samples and two (5%) were positive for HPV 11. Notably, p16 was present in the epithelia of all samples and in the papilloma portions in 37 of 38 samples. We found extensive HA staining in the stroma of both VFs and FVFs. CD44 was expressed throughout the epithelium, stroma, and RRP lesions in both FVFs and VFs, it did however, not concur with the expression of HA. Very high mass HA was found in both VFs and FVFs, though more variation regarding amounts of HA was seen in the VFs compared to FVFs. No HPV was found in non-malignant tonsils, the p16 levels were low and the counted EBER positive cells showed great variation in numbers.Conclusions: Our findings demonstrate an immune dysregulation with inverted CD4+/CD8+ ratio and aberrant cytokine mRNA production in RRP patients, compared to healthy controls. We concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP and that HPV incidence was low (5%). CD44 does not seem to bind to HA, which might explain the noninflammatory response previously described in RRP. Very high mass HA possibly crosslinked was seen in both VFs and FVFs. A possibility to counteract inflammatory crosslinking of HA may be found for medical treatment options in RRP.
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| 7. |
- Kämpfe Nordström, Charlotta
(författare)
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The Human Vestibular Aqueduct, Endolymphatic Duct and Sac : A Morphological Study Using Micro-CT, Super Resolution Immunohistochemistry and Synchrotron Phase Contrast Imaging
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The inner ear lies sheltered in the temporal bone and consists of basically three parts: the cochlea (the hearing organ), the vestibular (the balance organ), and the endolymphatic duct (ED) and endolymphatic sac (ES). The ES and ED are located in a bony canal, the vestibular aqueduct (VA), located on the medial side of the vestibule. While the functions of the cochlea and the vestibular part of the inner ear are rather well studied, our knowledge of the function/s of the ES and ED remains limited and has intrigued scientists for centuries. Earlier studies have supported several theories, such as being an immune mediator, an aid in pressure regulation, related to the absorption of endolymph, and the production of endolymph. Otologic disorders, which affect both hearing and balance, such as Meniere’s disease (MD) and large vestibular aqueduct syndrome (LVAS), have been linked to dysfunction of the ES/ED. Studies of the human inner ear are fairly sparse. Research on the ES and ED have mainly been performed on animals, although both the anatomy and function may differ among various species.This thesis aims to further investigate the anatomy and function of the human ES and ED with the two otologic disorders MD and LVAS in mind. To achieve this, we have used novel imaging techniques, such as super-resolution structured illumination microscopy (SR-SIM), micro-computerized tomography (micro-CT), and synchrotron radiation phase-contrast imaging (SR-PCI). The material used for imaging comes from different sources: human archival temporal bones from the Uppsala temporal bone collection; human fresh-frozen cadaveric bones from our collaborators at Western University, in London, Ontario, Canada; and fresh-frozen human ES harvested during vestibular schwannoma surgery after securing ethical permission.The results of these studies describe the micro-anatomy of the VA, ED and ES down to a nanoscopic level. The discussion is based on the findings, relating them to earlier research with clinical implications regarding MD and LVAS.
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| 8. |
- Sandström, Karl, 1973-
(författare)
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Radioimmunodiagnosis of Head and Neck Squamous Cell Carcinomas : Preclinical Studies
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model. Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’. Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate. To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.
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| 9. |
- Granström, Brith, 1962-
(författare)
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Life after treatment for head and neck cancer
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Treatment for head and neck cancer (HNC) is often multimodal, including surgery, radiotherapy, and chemotherapy. The anatomic location of HNC and its treatments often affect vital functions such as swallowing and speech, but also physical appearance, leading to a risk for social withdrawal and nutritional difficulties that can affect the patient’s quality of life.Aims: The general aims of this thesis were to describe the physical and social consequences for patients treated for HNC and to identify supportive needs in regaining a new everyday life including intimate relationships, return to work, and nutritional recovery.Methods: Paper I (n = 131), objectives: to determine how patients with HNC experience changes in intimate relationships and to identify factors interfering with such relations. A semi-structured interview study was carried out on patients after treatment, and the analysis was inspired by the guidelines in constructive Grounded Theory. Paper II (n = 295), objective: to describe the frequency of patients’ returning to work after treatment for oropharyngeal cancer and to identify predictors and physical barriers (with a focus on pain, swallowing and speech difficulties, and physical appearance), that might interfere with the return-to-work process. A cross-sectional study using questionnaires was carried out 15 months after the diagnosis. Data were obtained from the Swedish Head and Neck Cancer Register. Paper III (n = 197), objective: to assess nutritional aspects and body weight in patients with HNC. A nutrition impact symptom-specific questionnaire for HNC was used to assess symptoms interfering with oral intake as well as interfering with body weight during the first year post-treatment. Paper IV (n = 21), objective: to examine how patients with HNC perceive life one year after treatment and how they experience health care. A semi-structured interview study was performed with an interview guide developed using concepts from the literature and clinical experience, and a thematic analysis approach was used.Results: In Paper I most patients reported no major changes in intimate relationships at the end of treatment. In resuming intimate relationships, facilitating factors were stable relationships before treatment, engagement from others, and being open regarding the cancer, while detrimental factors were patronization and dis-engagement. This was summarised as “being open versus not sharing the cancer journey”. In Paper II, 15 months after diagnosis 84% of the patients who were working at the time for diagnosis had returned to work. Factors negatively associated with return to work were swallowing difficulties, problems talking on the telephone, and changed physical appearance. In Paper III, the post-treatment weight loss was related to the degree of symptoms and interference with oral intake, which also increased the risk for a body weight loss of ≥10% at 12 months after the end of treatment. In Paper IV, the patients were still suffering from side effects one year after treatment and from fear of recurrence, but they tried to live as they did before the cancer diagnosis. Even if most contacts with health care were experienced positively, patients lacked regular follow-ups regarding rehabilitation and contact with their contact nurse.Conclusions: In Paper I, when resuming intimate relationships, the challenges were related to whether the patients were open or not about the disease. In Paper II, some remaining physical barriers were identified. A positive result from the study that can be reported to future patients is the high number of patients returning to work after treatment. In Paper III, both nutritional and clinical factors were shown to affect body weight, and a holistic approach is needed when addressing the patients’ nutritional needs. In Paper IV, despite the sequelae from treatment, the patients sought to live as they did before the diagnosis. This may disguise continuing needs, and by meeting the patients with engagement, the contact nurse-patient relation may uncover these needs and proper individualized support and rehabilitation can be offered.
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| 10. |
- von Beckerath, Mathias, 1966-
(författare)
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Photodynamic therapy in the head and neck
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Photodynamic therapy, PDT, is a method to diagnose and treat cancer. In PDT a sensitizer is administered to the patient and this sensitizer is accumulated in tumors. If the sensitizer-containing tumor is subjected to a laser of a specific wavelength the tumor is fluorescing allowing diagnostics. If other wavelengths are used a process involving reactive oxygen species and singlet oxygen is started and the tumor cells are killed. This process thus requires oxygen as well.This thesis investigates how UV-induced damage of the skin and different physiological factors of the skin influences the uptake of 5- aminolevulinic acid, ALA, and its conversion to the active sensitizer protoporphyrin IX, PpIX. It shows that UV-induced damage affects both the uptake and production of PpIX. UV-induced damage lowers the PpIX produced after ALA application both if the damage is acute and in chronically UV-affected skin.The PpIX production differs inter and intra individually. When looking how different physiological factors affect the PpIX production after topically applied ALA the thesis shows that an increase of temperature increases the production. No correlation between the formation of PpIX and the density of hair follicles was found and a weak correlation was seen comparing the epidermal and total dermal thickness and PpIX productionThe thesis also shows how PDT is used in treating laryngeal malignancies. It shows that it is possible to cure laryngeal tumors (both squamous cell carcinomas and sarcomas) using PDT primarily, and that the cure rate as well as outcome of voice and patient safety is comparable to the conventional treatment modalities.PDT can also be used as a function and organ sparing treatment for recurring laryngeal cancers, both squamous cell carcinomas and sarcomas.
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| 11. |
- Ölander, Christine, 1976-
(författare)
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Vestibular schwannoma : Clinical, Epidemiological and Biochemical perspectives
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Vestibular schwannoma (VS) is a slow growing benign tumour originating in the Schwann cells surrounding the vestibulocochlear nerve. Over recent decades, the incidence rate for VS has steadily increased, with greater numbers of patients with smaller tumours being diagnosed. Today, it is estimated that around 1 in 500 people will suffer from VS in their lifetime. The most common symptom of VS is unilateral hearing loss, tinnitus or dizziness. The growth rate of the tumour is unpredictable and not related to degree of symptoms. The overall aim of this thesis was to provide new knowledge that could be used to improve routines for treatment and clinical guidelines for future patients with sporadic VS.A local clinical quality database was used to identify patients with VS treated at Uppsala University hospital. The information in the database of patients with VS was used to analyze postoperative complications after translabyrinthine surgery, hearing outcomes after hearing preservation middle cranial fossa surgery, both postoperative and after more than 10 years of follow up, and the risk of enduing a fall-related injury. The proteome of the human endolymphatic sac endolymph in six patients with VS was described. 13% of the translabyrinthine operated patients (93 of 700) suffered from one or more complications postoperatively. Increasing age and tumour size were both risk factors for postoperative facial nerve dysfunction. Greater tumour size increased the risk for intracranial hemorrhage. 60 out of 84 patients with VS operated on through middle fossa surgery had preserved hearing after surgery. After 10 years, the hearing had deteriorated symmetrically in the tumour ear and the contralateral ear. There was no increased risk for fall-related injuries among patient with VS compared to VS-free controls. Studying subgroups, an increased risk of fall-related injury was displayed among middle-aged patients before being diagnosed with VS and postoperatively in patients treated with middle fossa surgery. A total of 1,211 proteins were detected in the ES endolymph, of which 110 were unique for the endolymph. To further improve the knowledge regarding patients with VS, a joint national guideline program would be desirable.
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| 12. |
- Edvardsson Rasmussen, Jesper, 1984-
(författare)
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Inner ear proteomics and barriers : Clinical and experimental findings
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hearing is important in many aspects of life, including communication, assessing one’s surroundings, entertainment and social interaction. Hearing loss is common and according to the Global Burden of Disease Study, 5% of the global population require hearing rehabilitation (1). Pharmacological treatment options are limited, so understanding cellular mechanisms in the damaged inner ear is crucial for developing novel therapies.In this thesis, the human inner ear proteome in patients with sporadic vestibular schwannoma (VS) and its association with hearing loss were investigated. Ototoxic effects induced by furosemide were also examined, focusing on inner ear barrier function, furosemide sensitive Na-K-Cl co-transporter 1 (NKCC1), Fetuin-A, linked to tumour-associated hearing loss, and Pigment epithelium-derived factor (PEDF), potentially important for blood-endolymph barrier integrity.Translabyrinthine surgery on 35 patients, 32 with VS and three with meningioma, provided samples from perilymph, endolymph, endolymphatic sac tissue, VS biopsies and cerebrospinal fluid (CSF) for proteome analysis. Effects of furosemide on the inner ear barriers were studied in mice using 9.4Tesla MRI, and in guinea pigs using immunohistochemistry and mRNA in situ hybridisation focusing on NKCC1, Fetuin-A, and PEDF.Proteomic analysis revealed consistent sets of proteins in perilymph (91/315) and endolymph (545/1211). The proteomes of perilymph and CSF exhibited specific differences, with proteins unique to each fluid, thereby emphasizing the distinct origin of perilymph separate from CSF. Fetuin-A was inversely related to tumour-associated hearing loss, while patients with severe to profound hearing loss exhibited upregulation of complement factor H-related protein 2 (CFHR2).Furosemide compromised the blood-endolymph barrier, allowing gadolinium contrast into scala media. It affected NKCC1 of type II fibrocytes coinciding with the onset of hearing loss following high-dose furosemide, suggesting early disruption in potassium ion recirculation. Fetuin-A and PEDF were identified in the cochlea at protein and mRNA level. Their staining intensity increased in various cochlear subsites 120 minutes after furosemide administration, indicating their involvement in the cochlear response to the effects of furosemide.In summary, this thesis uncovered significant inter-individual variability in both the perilymph and endolymph proteome, alongside a consistent subset of proteins. Further, associations between hearing loss and proteome changes suggest inflammation as a potential mechanism for hearing degradation caused by vestibular schwannomas. Experimentally, impact of furosemide on blood-inner ear barriers were visualised in vivo and type II fibrocytes were identified as potential initial targets for NKCC1 blockade. Fetuin-A and PEDF were confirmed in several cell types in the cochlea and may increase in response to very high furosemide doses.
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| 13. |
- Jonsson, Eva Lindell, 1982-
(författare)
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Biomolecular markers in head and neck cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Head and neck cancer is a heterogeneous group of tumours, of which certain subgroups such as cancer of the mobile tongue frequently are associated with a relatively poor prognosis due to the high risk of regional failure and mortality rates that haven’t improved in a significant way over the last 3 decades, despite advancements in both diagnostics and treatment.Today we lack means to assess the biological aggressiveness of each individual tumour, which varies largely. Treatment comprises of surgery with additional radiotherapy and medical therapies in more advanced tumours.The focus in this thesis is on molecular biomarker expression in head and neck cancer and especially in association with radiotherapy. Increased knowledge paves the way to a more individualized cancer treatment aiming for better outcome and less overtreatment and sequelae.The aims of this thesis was:To map the effects of radiotherapy in both tumour and adjacent tissue for the possible markers hyaluronan, EGFR and mast cells.To investigate whether the expression of hyaluronan in the epithelium and connective tissue stroma and EGFR in the tumour correlates with the risk for developing cervical metastasis in N0 patients, and to find out whether the 3-year tumour-specific survival rates correlates with the expression of HA in the epithelium and EGFR in the tumour.To establish an animal model for radiation-induced mucositis and to use that model to examine the pattern of invading inflammatory cells.To investigate whether the expression of podoplanin in tongue cancer correlates with the risk for cervical metastasis and to determine whether the total amount of lymph vessels in the diagnostic biopsy has any impact on the clinical outcome.To investigate the differences in the metabolome of tongue cancer cell lines with different radiosensitivity.The most important findings of this thesis were:The expression of EGFR and hyaluronan hade the same pattern of expression in both tumour and adjacent tissues before radiotherapy. The expression of EGFR was increased in the epithelium of the adjacent tissue close to the tumour after radiotherapy.The intensity of the staining of hyaluronan was correlated to the 3-year survival rates in patients with tongue cancer.An experimental model for radiation-induced oral mucositis in rat was established and in this model a temporal pattern of macrophage invasion with two different subtypes of macrophages was found.There were no correlation between the expression of podoplanin in the tumour tissue and the cervical metastasis rate in patients with tongue cancer, but the younger patients were more likely to have a higher expression of podoplanin in their tumour than elder patients.Tongue cancer cell lines with different radiosensitivity respond to irradiation with different patterns of metabolic expressions.
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| 14. |
- Langegård, Ulrica, et al.
(författare)
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Internet-based support for informal caregivers to individuals with head and neck cancer (Carer eSupport) : a study protocol for the development and feasibility testing of a complex online intervention
- 2022
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- It is strongly recommended that randomised controlled trials are preceded with an exploration of the needs of the target population and feasibility testing of the intervention. The present study protocol is set out to describe these steps in the development of a complex intervention.The past decades’ transition of care from inpatient to outpatient settings has increased the complexity of caregivers’ responsibilities, which they may not be prepared for. There is a need to support informal caregivers (ICs) to prepare them for caregiving and decrease the caregiver burden. The main aim of this study is to describe the development of an internet-based intervention (Carer eSupport) to improve ICs’ ability to support individuals with head and neck cancer and to describe the testing of the feasibility and acceptability of Carer eSupport.Methods and analysisThis is a multicentre study involving the ear, nose and throat clinics and the oncology and radiotherapy clinics at three university hospitals. The study protocol comprises two phases, development and feasibility testing, using the Medical Research Council framework for developing a complex intervention. Carer eSupport will be based on the results from focus group discussions with ICs and healthcare professionals (planned for n=6–8 in respective groups) and scientific evidence, the Social Cognitive Theory and the Theory of Acceptance and Use of Technology. The feasibility testing will include 30 ICs who will have access to Carer eSupport for 1 month. The feasibility testing will be evaluated with a mixed-method design.Ethics and disseminationAll procedures have been approved by the Ethics Committee at Uppsala University (Dnr: 2020-04650). Informed consent will be obtained before enrolment of patients, their ICs and healthcare staff. The feasibility testing is registered at Clinicaltrials.gov (Identifier: NCT05028452). Findings will be disseminated in peer-reviewed journal publications.
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| 15. |
- Morén, Staffan
(författare)
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Unilateral Cleft Lip and Palate : Speech, Voice and Nasal Function in Adults
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cleft lip and palate (CLP) is the most common craniofacial malformation. Even after repair of the cleft there may be persistent symptoms affecting speech, voice, nasal breathing, dentition, appearance and quality of life. The aims of the thesis were to: (I) investigate subjective nasal function and nasal airway at clinical examination, (II) evaluate speech by perceptual evaluation, (III) assess voice quality by perceptual evaluation and acoustic analysis and (IV) compare ratings of speech by naïve listeners, speech-language pathologists (SLPs) and patients.All consecutive patients with complete unilateral CLP, born 1960-1987, and treated at Uppsala University Hospital were invited. A total of 83 (76%) (I) and 73 (67%) (II, III, IV) of the 109 eligible patients and non-cleft controls (n=63) participated. Patients had been treated in childhood with one- or two-stage palate closure. The participants underwent clinical examination, recording of speech and filled in questionnaires.The results showed that: (I) Patients earlier treated for UCLP suffer from more nasal symptoms than controls. However, nasal symptoms were not associated with clinical findings or method of palate closure. (II) Seven patients (10%) presented with hypernasality, 12 (16%) had audible nasal emission and/or nasal turbulence, five (7%) had consonant production errors, one (2%) had glottal reinforcements/substitutions, and one had reduced intelligibility. Controls had no quantifiable problems with speech. (III) Among patients, the mean values for the 12 perceptual voice variables on a visual analogue scale (0 = no abnormality, 100 = maximal abnormality) ranged between 1 and 22 and the mean for all was 6 mm. Voice variables were similar between patients and controls except “vocal fry”; this and total mean of all the perceptual voice variables were slightly lower among patients (p = 0.009 and p = 0.018 ). No clear association was found between velopharyngeal insufficiency and dysphonia. (IV). There were positive correlations between speech ratings by naïve listeners and SLPs (r =0.44 to 0.69, p always < 0.001, Spearman). The correlations between ratings of any of these groups and the patients’ self-ratings were weaker (r < 0.40). The patients were less satisfied with their speech and rated themselves to have more speech abnormalities than controls (p < 0.001). There were no statistically significant differences in any of the variables regarding speech, voice or nose between patients treated with one-stage and two-stage palate closure in any of the studies.This thesis shows that adults treated for unilateral CLP have more nasal symptoms and cleft related speech abnormalities compared to the controls, however the prevalence of speech abnormalities are relatively low. Voice quality is not affected. Speech quality is rated differently by naïve listeners, SLPs and patients.
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