Head and neck squamous cell carcinomas (HNSCCs) most commonly develop in older patients (≥60 years of age) with a history of tobacco and alcohol use. However, young individuals (≤45 years of age) can also develop HNSCC, often without common risk factors. Increasing evidence shows that Human Papillomavirus (HPV) infection is associated with particular HNSCC sites (e.g. oropharynx). We assessed the Roche Linear Array HPV Genotyping Test in several lesions and then examined the prevalence of HPV in HNSCCs from young and older patients. HPV infection was most prevalent in oropharyngeal cancers (16/22, 73%), rarely found in oral cavity cancers (2/53, 4%), and other head and neck sites (1/17, 6%). HPV positive tumors were associated with patients that were >40 and <60 years old (p=0.02). The absence or shortened time of carcinogen exposure from common risk factors and the development of oral squamous cell carcinoma (OSCC) at an early age suggest aberrant genetic events that are different than those in OSSCs from older patients. We used Affymetrix SNP 6.0 arrays to genomically profile oral tumors from young and older patients. Tumors from young patients showed different regions/genes of copy number alterations than those from older patient tumors. An increase of regions of loss of heterozygosity (LOH) in tumors from older patients was observed, and there was a high prevalence of copy number neutral LOH on chromosome 9 in tumors from young and older patients. These data suggest different genetic mechanisms in these patient groups. We have previously shown that HNSCCs from younger patients exhibited a high incidence of microsatellite instability (MSI), a marker of defective mismatch repair (MMR). Deregulated mRNA levels of hPMS1, hPMS2 and hMLH1 were observed and absent/low expression of hPMS1, hPMS2 and hMLH1 protein levels were observed in >50% of OSCCs. No mutations were observed in hPMS1 and hPMS2 and no significant differences of MSI or LOH were observed across genomic loci between tumors of young and older patients. The role of these genetic mechanisms in oral cancer appears complex; studies such as ours should further improve our knowledge of the molecular mechanisms leading to early-onset oral carcinomas.

Objective: Evaluate a patient-reported-oral mucositis scale (PROMS) on its own and in relation to existing measures of mucositis. Methods: 50 patients with head and neck cancer receiving radiotherapy were examined before cancer treatment, twice weekly during 6-7 weeks of therapy and post-therapy. Oral mucositis (OM) signs were evaluated clinically using NCI-CTCAE v.3, OMAS criteria and Total VAS-OMAS score. OM symptoms were recorded on PROMS-VAS questionnaires. Albumin and polymorphonuclear neutrophils were measured in saline rinses. The PROMS data were subjected to Spearman rank correlations versus the other clinical and biomarker data. Results: 33 participants completed the study. Significant correlations (p<.001) were seen between PROMS scores and other clinical and biomarker indicators of OM at a group level. Significant variations were seen between individuals. Conclusion: The PROMS tool demonstrates good correlation with other clinical indicators of OM and adds novel dimensions to currently available methods of assessments used for quantification of OM.

Objective: Evaluate a patient-reported-oral mucositis scale (PROMS) on its own and in relation to existing measures of mucositis. Methods: 50 patients with head and neck cancer receiving radiotherapy were examined before cancer treatment, twice weekly during 6-7 weeks of therapy and post-therapy. Oral mucositis (OM) signs were evaluated clinically using NCI-CTCAE v.3, OMAS criteria and Total VAS-OMAS score. OM symptoms were recorded on PROMS-VAS questionnaires. Albumin and polymorphonuclear neutrophils were measured in saline rinses. The PROMS data were subjected to Spearman rank correlations versus the other clinical and biomarker data. Results: 33 participants completed the study. Significant correlations (p<.001) were seen between PROMS scores and other clinical and biomarker indicators of OM at a group level. Significant variations were seen between individuals. Conclusion: The PROMS tool demonstrates good correlation with other clinical indicators of OM and adds novel dimensions to currently available methods of assessments used for quantification of OM.

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.

Head and neck squamous cell carcinomas (HNSCCs) most commonly develop in older patients (≥60 years of age) with a history of tobacco and alcohol use. However, young individuals (≤45 years of age) can also develop HNSCC, often without common risk factors. Increasing evidence shows that Human Papillomavirus (HPV) infection is associated with particular HNSCC sites (e.g. oropharynx). We assessed the Roche Linear Array HPV Genotyping Test in several lesions and then examined the prevalence of HPV in HNSCCs from young and older patients. HPV infection was most prevalent in oropharyngeal cancers (16/22, 73%), rarely found in oral cavity cancers (2/53, 4%), and other head and neck sites (1/17, 6%). HPV positive tumors were associated with patients that were >40 and <60 years old (p=0.02). The absence or shortened time of carcinogen exposure from common risk factors and the development of oral squamous cell carcinoma (OSCC) at an early age suggest aberrant genetic events that are different than those in OSSCs from older patients. We used Affymetrix SNP 6.0 arrays to genomically profile oral tumors from young and older patients. Tumors from young patients showed different regions/genes of copy number alterations than those from older patient tumors. An increase of regions of loss of heterozygosity (LOH) in tumors from older patients was observed, and there was a high prevalence of copy number neutral LOH on chromosome 9 in tumors from young and older patients. These data suggest different genetic mechanisms in these patient groups. We have previously shown that HNSCCs from younger patients exhibited a high incidence of microsatellite instability (MSI), a marker of defective mismatch repair (MMR). Deregulated mRNA levels of hPMS1, hPMS2 and hMLH1 were observed and absent/low expression of hPMS1, hPMS2 and hMLH1 protein levels were observed in >50% of OSCCs. No mutations were observed in hPMS1 and hPMS2 and no significant differences of MSI or LOH were observed across genomic loci between tumors of young and older patients. The role of these genetic mechanisms in oral cancer appears complex; studies such as ours should further improve our knowledge of the molecular mechanisms leading to early-onset oral carcinomas.

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.

Syftet med denna studie var att beskriva sjuksköterskors erfarenheter av kommunikation med huvud-halscancerpatienter som har talsvårigheter.   Metod: Forskningsdesignen var kvalitativ och metoden var att spela in semistrukturerade intervjuer med åtta sjuksköterskor på en öron-, näs- och halsavdelning på ett universitetssjukhus i Sverige.     Resultat: De mer erfarna sjuksköterskorna uttryckte inte några speciella känslor eller svårigheter att bedöma de omvårdnadsbehov som huvud-halscancerpatienter med talsvårigheter har, medan de mindre erfarna sjuksköterskorna uttryckte mer känsla av osäkerhet och frustration när de inte kunde förstå vad patienten försökte säga. Alla sjuksköterskorna uppgav att patienterna ofta uttryckte frustration när de inte blev förstådda. De strategierna sjuksköterskorna använde mest var att tolka kroppsspråket och att ställa ja och nej frågor. Det mest använda hjälpmedlet var papper och penna. Alla sjuksköterskorna uppgav att kommunikation med dessa patienter krävde mer tid och att tidsbrist var en stressfaktor. Trots att huvud-halscancerpatienter var en vanlig patientgrupp på avdelningen talades det sällan om dessa kommunikationssvårigheter. Slutsats: Det framträdde en motsägelsefull bild av kommunikationsmönstret på avdelningen / The purpose of this study was to explore nurses' experiences of communication with patients suffering from head&amp; neck cancer, resulting in speech loss or impaired speech.         The methodology was qualitative and the method used to collect data was audio-taped, semistructured interviews with eight nurses on an ear, nose and throat hospital ward in a university hospital in Sweden.         Results: More experienced nurses did not express any special feelings or difficulties in assessing the head-neck cancer patients' needs, whereas less experienced nurses expressed more feelings of insecurity and frustration when they were not able to understand what the patients tried to say. All of the nurses stated that the patients often expressed frustration when they were not understood. The most usual strategy for communication was to interpret the patients' body language and ask yes or no questions. The most frequently used device was paper and pencil. All of the nurses stated that communication with these patients required more time and that lack of time was a stress factor. Despite the fact that these patients were a common group of patients, communication problems were not discussed in the department.         Conclusion: There emerged a contradictory picture of the pattern of communication within the hospital ward.

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

Modern image-guided surgery aids minimally-invasive, high-precision procedures that increase efficacy of treatment. This thesis investigates two research aims to improve precision and integration of intraoperative cone-beam CT (CBCT) imaging in guidance of head and neck (H&N) surgery. First, marker configurations were examined to identify arrangements that minimize target registration error (TRE). Best arrangements minimized the distance between the configuration centroid and surgical target while maximizing marker separation. Configurations of few markers could minimized TRE with more markers providing improved uniformity. Second, an algorithm for automatic registration of image and world reference frames was pursued to streamline integration of CBCT with real-time tracking and provide automatic updates per scan. Markers visible to the tracking and imaging systems are automatically co-localized and registered with equivalent accuracy and superior reproducibility compared to conventional registration. Such work helps the implementation of CBCT in H&N surgery to maximize surgical precision and exploit intraoperative image guidance.

Modern image-guided surgery aids minimally-invasive, high-precision procedures that increase efficacy of treatment. This thesis investigates two research aims to improve precision and integration of intraoperative cone-beam CT (CBCT) imaging in guidance of head and neck (H&N) surgery. First, marker configurations were examined to identify arrangements that minimize target registration error (TRE). Best arrangements minimized the distance between the configuration centroid and surgical target while maximizing marker separation. Configurations of few markers could minimized TRE with more markers providing improved uniformity. Second, an algorithm for automatic registration of image and world reference frames was pursued to streamline integration of CBCT with real-time tracking and provide automatic updates per scan. Markers visible to the tracking and imaging systems are automatically co-localized and registered with equivalent accuracy and superior reproducibility compared to conventional registration. Such work helps the implementation of CBCT in H&N surgery to maximize surgical precision and exploit intraoperative image guidance.