Cancer cells are believed to exist in a condition of metabolic oxidative stress compared to normal cells because of inherent mitochondrial dysfunction. Cancer cells up regulate antioxidant defense mechanisms to combat the toxic effect of reactive oxygen species (ROS). Many anticancer agents block ROS detoxification mechanisms and utilize oxidative stress to cause cytotoxicity to cancer cells. However, ROS also up-regulate many pro-survival signaling pathways that may mediate resistance to chemotherapy. I hypothesize that ROS induces both cytotoxicity and pro-survival mechanisms in cells treated with chemotherapeutic agents such as the EGFR inhibitor erlotinib. This thesis explores how oxidative stress may induce both pro-survival and pro-death mechanisms in HNSCC cells and how this can be exploited to increase the cytotoxicity of erlotinib. The combined use of buthionine-[S,R]-sulfoximine, an inhibitor of glutathione and auranofin, an inhibitor of thioredoxin metabolism enhanced human head and neck cancer cell killing by a mechanism involving oxidative stress both in vitro and in vivo and sensitized cells to erlotinib in vitro. However, in other studies erlotinib as a single agent induced oxidative stress and this was mediated by NADPH oxidase 4 (NOX4). NOX4 mediated oxidative stress activated a process called autophagy which protected cancer cells from cytotoxic effect of erlotinib and inhibition of autophagy sensitized cells to erlotinib in vitro. These studies show that oxidative stress may have a dual role in cancer chemotherapy. ROS generated from various drug treatments can cause oxidative damage of cells culminating in cell death. However, it may also activate autophagy protecting cells against the stress and leading to decreased efficacy of the treatment. Hence inhibiting autophagy and hydroperoxide metabolism can be effective treatment modalities to enhance the cytotoxicity of erlotinib and achieve maximum therapeutic efficacy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22038号 / 医博第4523号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 松村 由美, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

No description available.

Necrotizing fasciitis (NF) is a critical and rapidly progressive infection of the skin and soft tissue, and it is associated with a high mortality rate. NF of the cervicofacial region is uncommon due to the rich vascular supply of the head and neck, which promotes an efficient immune response to infection. Patients who are immunocompromised or have comorbidities affecting the vasculature, such as diabetes mellitus or peripheral vascular disease, are at an increased risk of more severe disease and outcome. Cervicofacial necrotizing fasciitis (CNF) is most frequently attributed to mucosal damage, such as those related to dental infections or local trauma including medical procedures. Due to its ability to quickly spread to the neck and mediastinum, CNF must be diagnosed and treated expeditiously. In this report, we present a case of a 28-year-old female with a past medical history significant for obesity and tobacco abuse who presented to the emergency department (ED) with fever, left-sided facial pain, cervical pain, and swelling. She had worsening symptoms despite current treatment with clindamycin for a dental abscess. A CT scan of the head and neck revealed an odontogenic abscess complicated by CNF. Intravenous antibiotics were initiated and she underwent prompt surgical intervention. She remained nasally intubated following her surgery due to concern for postoperative edema leading to airway compromise. Following extubation, she experienced an uncomplicated recovery. This case demonstrates that NF is a complication of dental infection that may occur even in young and relatively healthy patients. Additionally, due to the swiftly destructive nature and high mortality rate of CNF, early diagnosis and aggressive medical and surgical therapy are essential to reduce morbidity and mortality.

Cancer is a major cause of morbidity and mortality with increasing incidence worldwide. Early detection of cancers and better treatments would improve the outcome for patients. The overall 5-year survival rates of head and neck squamous cell carcinoma have not improved in the past several decades due to diagnosis at advanced stages and recurrent disease. Early detection and improved chemotherapy drugs are two key areas that are required to help to improve the prognosis for this disease. This thesis focuses on the enzyme telomerase which is known to contribute to one of the hallmarks of cancer (immortality). Elevated telomerase activity has been observed in the majority of cancer cells but not in most normal human cells so there is an opportunity to use telomerase as a biomarker for disease. This first part of this study assessed telomerase activity in saliva and tissues of head and neck squamous cell cancer patients. The Telomerase PCR-ELISA kit was used to assess telomerase activity in the saliva of patients with confirmed oral carcinomas and its expression was analysed in paraffin embedded tissue using immunohistochemistry (IHC). Whilst telomerase was detected in cell lines, no telomerase activity was detected in saliva samples from patients but was detectable in IHC specimens. The second part of the study focused on the pharmacological evaluation of a series of small molecule G–quadruplex DNA binding agents as potential telomerase inhibitors. A total of 19 telomerase inhibitors were identified but of these, only 4 were specific inhibitors of telomerase. These compounds also caused toxicity to cell lines following a 2 hour drug exposure at doses that also inhibit telomerase activity. Further studies are required to explore these compounds further. In conclusion, the results of this study have demonstrated that detection of telomerase activity I the saliva of patients with oral cancers is unlikely to be useful in terms of detecting oral cancers before symptoms of the disease are clinically manifest. A series of novel and specific inhibitors of telomerase have been identified and further studies are required to develop these compounds further.

No description available.

Head and neck cancer (HNC) is one of the top ten cancers in the world, and is caused by tobacco use, alcohol consumption and Human Papillomavirus (HPV). HPV associated HNC patients have improved survival rates compared to non -HPV associated HNC patients. This improved survival is due to HPV- positive tumors favorable response to chemotherapy and radiation. The literature has shown that there is a racial disparity in survival rates between Caucasians and African Americans, with African Americans having poorer survival rates. The aim of this study is to determine if the racial disparity among HNC patients is due to a difference in HPV prevalence between races. HPV prevalence in HNC was assessed by a meta-analysis of published articles (30/247) that reported race specific HPV prevalence. We also conducted a pooled analysis in which authors that assessed HPV in HNC were invited to submit their datasets. Meta-pooled prevalence estimates revealed that 20% of African American HNC patients had HPV-positive tumors, compared to 44% in Caucasians. However for both African American HNC patients and Caucasian HNC patients there was low to moderate heterogeneity between the studies (Q-test p-value = p < 0.001, I2 = 18.87%, and p= 0.008. I2 =65.47% respectively). The prevalence of HPV in African Americans was 60% and in Caucasians it was 39%. African Americans had a risk of oropharyngeal cancer that was no different from Caucasians (OR: 1.38, 95% CI: 0.53-3.62) but had an increased risk of death from oropharyngeal cancer (HR: 2.39, 95% CI 1.03-5.55) compared to Caucasians. The results of the pooled analysis does not support the concept that African Americans HNC patients have a lower prevalence of HPV, but substantiates the notion that African Americans have worse survival than Caucasians. However, these are preliminary results as the pooled analysis is still being conducted, the inclusion of more datasets in the analysis could alter these preliminary findings. / Public Health

Objective: Existing patient-reported outcome measures (PROM)s for patients with facial differences lack content validity, as few items address appearance and function issues. The FACE-Q is a new PROM developed to measure outcomes important to patients aged 8-29 years with craniofacial conditions. A process was needed to determine if the FACE-Q content is relevant to patients with head and neck cancer (HNC). Methods: Cognitive interviews with patients with HNC aged 8 to 29 years (n=15) were conducted and feedback from experts in pediatric oncology (n=21) was obtained. Input was sought on all aspects of the FACE-Q content. Results: A total of 1573 codes were developed from patient comments and 234 codes were developed from expert feedback that related to the COSMIN criteria for judging content validity. A total of 12 items were flagged for review from qualitative interviews and 4 comments were coded from expert feedback among the core scales for comprehensibility. Instructions, time frame, and response options were found to be comprehensible and appropriate by almost all patient and expert participants. Participants identified a total of 10 missing items identified across the core scales, while no additional items were identified by experts for the core scales. However, 4 experts identified swallowing/dysphagia as an important item missing from the mouth function scale. Discussion: Content validity of the FACE-Q for patients with HNC was evaluated through cognitive interviews with patients and feedback from pediatric oncology experts. The core scales were answered by all participants and demonstrate overall content validity from feedback offered by both patients and experts. Conclusion: The FACE-Q showed evidence of content validity for its core scales along with limited evidence that the remaining scales covered issues relevant to specific HNC patients. Assessment of the psychometric properties of the new measure is forthcoming as part of an international FACE-Q field-test study. / Thesis / Master of Science (MSc) / The FACE-Q is a patient-reported outcome measure developed to assess outcomes important to patients aged 8-29 years with craniofacial conditions. The current study aimed to determine its content validity for use in patients with head and neck cancer (HNC). Cognitive interviews with patients with HNC aged 8-29 years (n=15) were conducted and feedback from experts in pediatric oncology (n=21) was obtained. A total of 1573 codes from patient comments and 234 codes from expert feedback were developed. A total of 12 items were flagged for review from qualitative interviews along with 4 items from expert feedback among the core scales for comprehensibility. Instructions and response options were found to be comprehensible and appropriate. A total of 10 missing items were identified across the core scales by patient participants while experts identified 1 missing item. The FACE-Q evidenced content validity for core scales along with limited evidence for remaining scales.