Despite advances in therapeutic options for head and neck cancer (HNC), treatment-associated toxicities and overall clinical outcomes have remained disappointing. Even with radiation therapy (RT), which remains the primary curative modality for HNC, the most effective regimens achieve local control rates of 45-55%, with disease-free survival rates of only 30-40%. Thus, the development of novel strategies to enhance tumor cell killing, while minimizing damage to the surrounding normal tissues, is critical for improving cure rates with RT. Accordingly, we sought to identify novel radiosensitizing therapies for HNC, exploiting a high-throughput screening (HTS) approach. Initially, a cell-based phenotype-driven HTS of ~2,000 commercially available natural products was conducted, utilizing the short-term MTS cell viability assay. Cetrimonium bromide (CTAB) was identified as a novel anti-cancer agent, exhibiting in vitro and in vivo efficacy against several HNC models, with minimal effects on normal fibroblasts. Two major limitations of our findings, however, were that CTAB did not synergize with radiation, nor was its precise cellular target(s) elucidated. Consequently, an alternative strategy was proposed involving a target-driven RNAi-based HTS. Since the colony formation assay (CFA) is the gold standard for measuring cellular effects of radiation in vitro, an automated high-throughput colony-formation read-out was developed as a more appropriate end-point for radiosensitivity. Although successful as a tool for the discovery of potent anti-cancer cytotoxics, a technical drawback was its limited dynamic range. Thus, the BrdU incorporation assay, which measures replicative DNA synthesis and is a viable CFA alternative, was employed. From an RNAi-based screen of ~7000 human genes, uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified as a novel tumor-selective radiosensitizing target against HNC in vitro and in vivo. Radiosensitization appeared to be mediated via tumor-selective enhancement of oxidative stress from perturbation of iron homeostasis and increased ROS production. UROD was significantly over-expressed in HNC patient biopsies, wherein lower pre-RT UROD levels correlated with improved disease-free survival, suggesting that UROD expression could also be a potential predictor for radiation response. Thus, employing a HTS approach, this thesis identified two novel therapeutic strategies with clinical potential in the management of HNC.

Treatment of head and neck cancer with radiation therapy is associated with adverse side effects to the oral cavity and surrounding areas. These complications include mucositis, mucosal fibrosis and atrophy, salivary gland dysfunction, increased risk of dental caries, increased susceptibility to infections, tissue necrosis, taste dysfunction, and muscular and/or cutaneous fibrosis. The often permanent nature of the radiation-induced damage necessitates the maintenance of a strict oral care program, involving frequent flossing and brushing in addition to daily fluoride applications, for the rest of the patient's life. An additional concern among patients with head and neck cancer is the use of tobacco and alcohol. Both are known risk factors in the development of head and neck cancers and failure to abstain from either after diagnosis increases the risk for relapse and development of secondary cancers. The present study was a longitudinal investigation of several factors that may influence patients' consistency in following their prescribed oral care program and abstaining from alcohol and tobacco use, including, but not limited to, patient satisfaction with the doctor-patient communication, patient coping, and patient illness perceptions. The study examined an integrative model seeking to explain patient adherence to the oral care regimen as well as tobacco and alcohol use. While results were inconclusive with respect to the model, there were several interesting findings, which were consistent with previous literature examining doctor-patient communication and illness perceptions among other cancer populations. Results from this study suggested that both satisfaction with doctor-patient communication and coping play an important role in forming patients’ illness perceptions. Furthermore beliefs about the severity of oral complications emerged as a predictor of oral care at follow-up. / text

published_or_final_version / Surgery / Master / Master of Philosophy

No description available.

Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease. We chose to address this challenge by studying the role of micro-RNAs (miRNAs), and iron in HNSCC. We performed global profiling on 51 primary HNSCC compared to 4 normal laryngeal epithelial tissues, and identified 38 differentially expressed miRNAs between cancer vs. normal patient tissues. Functional validation confirmed a tumour promoting phenotype for miR-106b and miR-375. Integrating these findings with global miR profiling of HNSCC revealed two significantly over expressed miRNAs in HNSCC cell lines and patient samples: miR-193b and miR-205. Knockdown of miR-205 and miR-193b in HNSCC cell lines significantly decreased cell proliferation and colony formation. Moreover, NF1 was identified as a target of miR-193b. Downstream targets of NF1 including active-RAS and p-ERK were also suppressed after miR-193b knockdown. Finally, HNSCC patients with high levels of miR-193b experienced a lower disease-free survival than patients with low miR-193b expression. The second approach we took to better understand the biology of HNSCC was to examine the involvement of iron in the disease. In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. Knockdown of HFE in HNSCC cell lines significantly decreased intracellular iron levels, resulting in a significant decrease in HNSCC cell proliferation, DNA synthesis, and Wnt signalling. When iron was re-introduced back into the cell after HFE knockdown, these cellular changes were reversed, indicating that iron was mediating this phenotype. Concordantly, HNSCC cells treated with an iron chelator ciclopirox olamine (CPX) significantly reduced proliferation and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression, corroborating the oncogenic role of HFE in HNSCC. In summary, using two independent methods, we have identified two potential prognostic biomarkers for HNSCC, namely miR-193b and HFE. Characterization of these two molecules, exposed critically dysregulated pathways driving disease progression. Specifically, the miR-193b~NF1 axis uncovered a novel mechanism of RAS and p-ERK activation in HNSCC; similarly, HFE exposed a novel tumour promotion role of iron in this disease.

Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), clinical outcome has remained disappointing, with 5-year overall survival rates hovering around 40-50%, underscoring an urgent need to better understand the biological bases of this disease. We chose to address this challenge by studying the role of micro-RNAs (miRNAs), and iron in HNSCC. We performed global profiling on 51 primary HNSCC compared to 4 normal laryngeal epithelial tissues, and identified 38 differentially expressed miRNAs between cancer vs. normal patient tissues. Functional validation confirmed a tumour promoting phenotype for miR-106b and miR-375. Integrating these findings with global miR profiling of HNSCC revealed two significantly over expressed miRNAs in HNSCC cell lines and patient samples: miR-193b and miR-205. Knockdown of miR-205 and miR-193b in HNSCC cell lines significantly decreased cell proliferation and colony formation. Moreover, NF1 was identified as a target of miR-193b. Downstream targets of NF1 including active-RAS and p-ERK were also suppressed after miR-193b knockdown. Finally, HNSCC patients with high levels of miR-193b experienced a lower disease-free survival than patients with low miR-193b expression. The second approach we took to better understand the biology of HNSCC was to examine the involvement of iron in the disease. In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. Knockdown of HFE in HNSCC cell lines significantly decreased intracellular iron levels, resulting in a significant decrease in HNSCC cell proliferation, DNA synthesis, and Wnt signalling. When iron was re-introduced back into the cell after HFE knockdown, these cellular changes were reversed, indicating that iron was mediating this phenotype. Concordantly, HNSCC cells treated with an iron chelator ciclopirox olamine (CPX) significantly reduced proliferation and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression, corroborating the oncogenic role of HFE in HNSCC. In summary, using two independent methods, we have identified two potential prognostic biomarkers for HNSCC, namely miR-193b and HFE. Characterization of these two molecules, exposed critically dysregulated pathways driving disease progression. Specifically, the miR-193b~NF1 axis uncovered a novel mechanism of RAS and p-ERK activation in HNSCC; similarly, HFE exposed a novel tumour promotion role of iron in this disease.

Die vorliegende retrospektive Studie zur postoperativen Radiochemothera-pie bei fortgeschrittenen Kopf-Hals-Tumoren sollte die eigenen Ergebnisse mit den prospektiv-randomisierten Studien vergleichend darlegen und dabei den Nutzen einer Radiochemotherapie überprüfen. Insgesamt wurden 155 Patienten in der retrospektiven Analyse eingeschlossen. Die Überlebens- und Rezidivraten des Patientengutes konnten anlehnend zu den publizier-ten Studien reproduziert werden. Ein Vorteil der Radiochemotherapie in Bezug nehmend auf den posttherapeutischen Verlauf konnte hierbei nicht festgestellt werden. Es traten signifikant vermehrt höhergradige Akutne-benwirkungen nach Applizierung der simultanen, systemischen Therapie auf. Die Arbeit konnte zeigen, dass sich durch die Reduzierung der Gesamt-behandungszeit als auch des Intervalls zwischen Operation und Beginn der adjuvanten Therapie das Gesamtüberleben sowie die lokoregionäre Rezidiv-rate signifikant verbessern ließen. Insgesamt scheinen die Fernmetastasie-rungen und die lokoregionären Rezidive maßgebend für die immer noch un-befriedigenden Überlebensraten zu sein. Gegenstand weiterer Untersu-chungen sollte daher die Optimierung der prätherapeutischen Diagnostik sowie der adjuvanten Therapie sein.

Bakgrund: Cancer i huvud- och halsområdet är den sjätte vanligaste cancerdiagnosen i världen. Begreppet huvud- och halscancer innefattar läppcancer, cancer i näsa och bihålor, i munhåla och svalg, struphuvud, på stämbanden och i spottkörtlarna. De vanligaste behandlingsformerna är kirurgi, strålbehandling och cytostatikabehandling. Sjukdomen och behandlingen innebär ofta svåra fysiska, psykiska och sociala biverkningar för patienten. Detta ställer stora krav på sjuksköterskans kunskaper och färdigheter inom området och i omvårdnaden av dessa patienter. Syfte: Syftet är att beskriva hur patienter med huvud- och halscancer kan uppleva behandlingsrelaterade biverkningar och hur dessa kan hanteras. Metod: En litteraturöversikt där tio kvalitativa artiklar granskades. Resultat: Resultatet presenteras i tre övergripande teman som även innehåller underteman. De tre huvudteman är; Lidande och upplevelsen av behandlingsrelaterade biverkningar, Omvårdnadsrelaterade upplevelser samt Hopp och mening. Slutsats: Patienter med huvud- och halscancer upplever sin sjukdom och behandling på många olika sätt. Sjukdomen i sig innebär en mångfacetterad problematik med både fysiska, psykiska och sociala aspekter. Oavsett behandlingsform drabbas patienten av biverkningar av varierande grad. För att hantera dessa biverkningar använder sig patienter av olika strategier och vissa gynnsamma aspekter av sjukdom som exempelvis ny positiv livsåskådning kan påvisas. Klinisk betydelse: Genom att belysa vilka problemområden som upplevs som mest betungande kan sjuksköterskor lättare söka lindra dessa. De positiva strategier som beskrivs kan av sjuksköterskan användas för att stärka patientens möjlighet till egenvård. / Background: Head and neck cancer is the worlds´ sixth most common malignancy. Head and neck cancer includes cancer in the lip, nasal cavity and the paranasal sinuses, the oral cavity, in the pharynx and larynx, in the glottis and in the salivary glands. The most common used treatments are surgery, radiotherapy and chemotherapy. The disease and it´s treatment often result in severe physical, psychological and social side effects. Aim: The aim is to describe how patients with head and neck cancer can experience the treatment related side effects and how they are managed. Method: A literature review of ten qualitative articles. Results: Three primary themes were identified; Suffering and the experience of treatment related side effects, Experiences related to nursing and Hope and meaning. Conclusion: Patients with head and neck cancer experience their disease and treatment in many different ways. The cancer alone can bring multifaceted problems including physical, psychological and social aspects. The patient will experience side effects of varying degree irrespective of which treatment being used. Different coping strategies are being used to cope with these side effects and some patients even report positive aspects of the disease. Clinical importance: By highlighting which areas that are the most burdensome for patients the nurses can more easily alleviate these areas. The positive strategies that are described can be used by the nurse to improve the patients´ ability for self care.

Purpose: At the Wellington Blood and Cancer Centre (WBCC), Volumetric Modulated Arc Therapy (VMAT) is used to treat a variety of head and neck (H&N) cancers. Presently, the complexity of plans is limited to ensure the accuracy of patient treatment within the range of the departmental experience. The complexity limitation is applied through use of a monitor unit (MU) constraint during plan optimisation. Plans of higher complexity can be obtained by loosening the MU constraint, and setting more stringent optimisation objectives on organs at risk (OAR) and target volumes (PTV). This could potentially yield higher quality treatment plans but may also degrade the accuracy of the TPS calculation or the plan delivery at the treatment machine. The aim of this study is to investigate the level of plan complexity that results in accurate treatment plan calculation and delivery, and quantify the corresponding gain in plan quality. Methods: Five previously treated H&N patients were selected for the study. Each patient’s clinical plan was used as the lowest complexity level and labelled C1. Subsequently, an approximate pareto-optimal plan (C3) was created that focused equally on sparing spinal cord, brain stem and parotid gland while maintaining, or improving on, the previously obtained target coverage. Next, a C2 plan was created such that the plan quality was in between C1 and C3. Plan quality of each complexity level was assessed in terms of OAR sparing and PTV coverage. The average leaf pair opening (LPO), critical leaf pair opening (%LPO<1cm) and mean leaf travel were used as plan complexity metrics. The calculation and delivery accuracy of each complexity level using Varian TrueBeam LINAC/Eclipse TPS was verified using time resolved point dose measurements (TRPD), EBT film measurements (Ashland Inc.) and ArcCheck measurements (Sun Nuclear Corp.). A comprehensive uncertainty analysis was carried out including a quantification of the measurement and delivery reproducibility. Results: Increasing plan complexity from C1 to C3 reduced the Spinal Cord D1cc, Brain Stem D1 and Parotid Gland Dmean up to 14.7 Gy, 7.1 Gy and 7.8 Gy, respectively. In addition, C3 plans improved the target coverage compared to C1 plans, with the PTV66 and PTV54 D98 increasing up to 1.0 Gy and 0.6 Gy, respectively. The verification measurements showed that the plan calculation and delivery for all complexity levels was well within clinical acceptance levels (Table 1). TRPD showed that VMAT dose delivery itself was repeatable within 0.1% (1 S.D.) over 10 consecutive deliveries for both C1 and C3 complexity levels. Discussion & Conclusions: This study has shown that increasing the plan complexity can provide significant dosimetric advantages for the treatment of H&N cancer. Verification measurement results indicated that this did not noticeably degrade the calculation and delivery accuracy of VMAT using a Varian TrueBeam LINAC and our Eclipse TPS beam model. H&N VMAT at the WBCC can now be developed further with greater confidence in the dosimetric accuracy of higher complexity plans.

Introduction: Each year 1200-1300 patients are diagnosed with head neck cancer. Treatment that involves radiotherapy can cause severe side effects for example trismus that affects quality of life. Purpose: To study health-related quality of life in patients who have undergone radiation treatment for head and neck cancer and participated in a intervention group who received training intended to prevent trismus or in a control group who received standard treatment. Method: This is a prospective study in which data is collected from 66 patients participating in a randomized study aiming to evaluate a training program to prevent trismus. Thirty three participated in the intervention group and thirty three in the control group. Both patient groups assessed health related quality of life (HRQOL) with EORTC QLQ C30 and QLQ-H&amp;N35, at start and end of the radiation treatment, and at 3 and 6-months after completing radiation treatment. Results: There is no difference between the intervention and control groups regarding symptoms, functional status and global health, except for intake of nutritional supplements.  For both groups almost all scales measuring HRQOL deteriorated under the radiation treatment. However, 3 and 6 months after end of radiotherapy HRQOL had improved and had returned to the baseline values. The only exceptions were dry mouth, sticky saliva, problems with social eating, senses and physical ability. Conclusion: Radiation therapy for head and neck cancer affects patients HRQOL both in the short and long term. Medical staff needs strategies to manage patients ' functional and symptomatic deterioration throughout the treatment period and try to prevent or relieve the symptoms that may still remain several months after radiotherapy.