Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.

IMPORTANCE: Advanced stage head and neck cancers are often deemed unresectable due to the aggressive nature of the cancer. In evaluating survival patterns of patients with stage IVb tumors, it is valuable to determine whether patients who undergo oncological surgery have favorable outcomes in order to deem surgery as a viable treatment option and demonstrate that these patients can survive with adequate treatment. OBJECTIVE: To determine whether patients with stage IVb cancers who undergo oncological surgery have favorable survival outcomes. MATERIALS AND METHODS: Of 320 cases reviewed of patients treated for head and neck cancer at Boston Medical Center between June 2009 and October 2014, 18 patients with stage IVb tumors were identified. Information regarding date of initial diagnosis, date and type of treatment, and date of death were extrapolated from medical records. Mean survival rates were calculated to compare survival outcomes of those who received and those who did not receive surgical intervention. RESULTS: The mean survival rate for patients who underwent surgical intervention was found to be 29.5 months while those who did not receive surgical intervention had a mean survival of 20.83 months. CONCLUSION: Cancers of the head and neck are associated with poor prognoses and are often deemed unresectable. Patients should be offered definitive treatment despite recommended palliative treatment, as, with adequate treatment, favorable survival outcomes are attainable.

Head and neck cancer (HNC) accounts for 3-5% of all malignancies in the United States and is the sixth most common cancer worldwide. Over the past two decades, radiation therapy (RT) has become a frequent therapeutic strategy, however one of its side effects, dysphagia has had a huge impact on patients’ quality of life. The value of determining the true prevalence of dysphagia is remarkable, which is what prompted us to carry out a study to determine the prevalence, trends, and risk factors for dysphagia following completion of RT over one year in patients diagnosed with HNC at Boston Medical Center over a 7-year period. A retrospective cohort study was conducted that involved a chart review of the medical records of all patients who completed RT for HNC cancer from January 1, 2003 to December 31, 2009 at Boston University Medical Center. 113 eligible patients were who had comprehensive treatment and follow up data at 3, 6, 9 or 12 months post RT were analyzed. Outcome variables of interest included feeding tube status, diet status, subjective swallow status, and percent weight loss from end of RT. 113 patients were identified for this study, of which 31% (n=35) were female and 69% (n=78) were male. Average age was 58.6 years old (35 to 88). The most common cancer sites were oropharynx and nasopharynx (38.9%) as well as hypopharynx and larynx (31%). 71.7% of the cohort had chemotherapy (CT) in addition to RT, and about half the patients had some degree of surgery. Altogether, the most “clinically meaningful” indicator of dysphagia (diet level of moderate/severe diet restriction) showed that the prevalence or probability of dysphagia to be 49% at 3 months, 56% at 6 months, 45% at 9 months, and 31% at 12 months. Our results suggest that about half the patients who undergo RT may be expected to develop a significant swallowing dysfunction in the first year following RT. This is extremely useful data for a health care provider to present to a patient after diagnosis of HNC and should complement counseling provided to them at the time of creating a treatment plan. Interestingly most of the patients who developed moderate/severe dysphagia did so within the first 6 months of completion of RT. Only oral cavity as cancer site was associated with moderate/severe dysphagia in our cohort of patients.

The goal of this thesis was to evaluate the cost-effectiveness of implantable Doppler technology (IDT) used to monitor free tissue transfer (FTT) procedures in the treatment of cancer of the upper aerodigestive tract (UADT). First, a systematic review of the literature on the effectiveness of traditional and IDT monitoring techniques was performed. Second, a utility survey using a time trade-off technique was created and administered. The results from this survey were used to establish utility values for health states common in patients undergoing FTT procedures. Third, a cost study using the microcosting data available through the Ottawa Hospital was performed. Finally, a decision analytic model was created and an economic evaluation from the payer perspective was completed. A probabilistic sensitivity analysis (PSA) and a value of information analysis (VOI) were performed. The thesis found that the currently available evidence supports IDT as a cost-effective intervention. Further research should be directed towards determining the effectiveness of both traditional and IDT monitoring.

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

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Yes / Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700. / The authors would like to thank Bradford Institute for Health Research for funding a PhD studentship to DP through a competitive scheme and Yorkshire Cancer Research programme Grant (B381PA) for supporting our cytochrome P450-focused drug discovery research.

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