A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Radiation Oncology Johannesburg, 2016 / Purpose: To assess the improvement in swallowing status, overall survival and treatment related complications in patients with Carcinoma of the Oesophagus treated with palliative radiotherapy. Methods: A retrospective analysis of patients with advanced squamous cell carcinoma of the oesophagus who were treated for palliation from May 2007 to June 2012 at the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) was done. Ninety- nine patients received palliative radiation therapy during this period, 63% were male and 37% female with a mean age of 60, 6 years. The predominant site of lesion was middle 3rd (56%) and 86, 9% of patients had lesions more than 5cm in length. Patients received palliative External beam irradiation (EBRT) with or without High dose rate brachytherapy (HDRBT) as per the CMJAH, Department of Radiation Oncology protocol. Results: There was an overall significant improvement in swallowing status (p<0,001). Eighty –four patients (85%) had an improvement in swallowing score after treatment. The effect of treatment was not significant in the relationship between the change in swallowing status and treatment group. Overall mean time to progression was 3, 7 months. The median overall survival was 7, 7 months. The type of treatment did not affect survival significantly, unadjusted (p=0, 31) or adjusted for prognostic parameters (age, sex, length of lesion, site of lesion, and pre-treatment swallowing status) (p=0.29). There were treatment related complications in 32% of cases, consisting of ulcerations (24%), tracheo- oesophageal fistula (5%) and strictures (3%). Conclusion: In patients with advanced squamous cell oesophageal carcinoma, palliative radiotherapy is an effective modality in improving a patient’s dysphagia and thus quality of life. / MT2016

<p>Esophageal carcinoma is a malignancy with a poor prognosis and is the sixth cause of cancer related death worldwide. In Sweden approximately 400 new cases are diagnosed every year. The aim of this present thesis was to investigate predictive factors for esophageal carcinoma patients.126 esophageal carcinoma patients admitted to the department of Oncology at the University Hospital in Uppsala between 1990-2000 were investigated with focus on known and potential prognostic factors. Performance status and stage of the disease were the only independent prognostic factors (p-values <0.001). </p><p>Angiogenic factors VEGF and bFGF were correlated to platelet and leukocyte counts and VEGF was correlated to tumor volume (p=0.04) whereas bFGF was not (p=0.08) in pre-treatment serum samples from 42 esophageal carcinoma patients. The use of the angiogenic factors as prognostic factors, prior to therapy in patients with esophageal carcinoma, according to the results from the present study, seems limited. </p><p>HER-2 overexpression was seen in 17% of 97 investigated esophageal tumor samples. In squamous cell carcinoma patients, HER-2 overexpression correlated with poorer survival (p=0.035), whereas in adenocarcinoma patients, HER-2 status did not. HER-2 overexpression seems to be associated with poorer survival in esophageal carcinomas, especially in patients with squamous cell esophageal carcinoma. </p><p>Telomerase activity was detected in all esophageal cell lines, with a broad range of activity levels. No correlation was found between telomerase activity levels and sensitivity to investigated cytotoxic drugs. We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines. </p><p>The virus HPV-16 was detected in 16 % of the patients; no other type HPV was detected. HPV-16 infection had no significant effect on survival (p=0.72). Our results did not show that HPV-16 increases survival or improve therapy response in patients with esophageal carcinoma.</p>

Esophageal carcinoma is a malignancy with a poor prognosis and is the sixth cause of cancer related death worldwide. In Sweden approximately 400 new cases are diagnosed every year. The aim of this present thesis was to investigate predictive factors for esophageal carcinoma patients.126 esophageal carcinoma patients admitted to the department of Oncology at the University Hospital in Uppsala between 1990-2000 were investigated with focus on known and potential prognostic factors. Performance status and stage of the disease were the only independent prognostic factors (p-values &lt;0.001). Angiogenic factors VEGF and bFGF were correlated to platelet and leukocyte counts and VEGF was correlated to tumor volume (p=0.04) whereas bFGF was not (p=0.08) in pre-treatment serum samples from 42 esophageal carcinoma patients. The use of the angiogenic factors as prognostic factors, prior to therapy in patients with esophageal carcinoma, according to the results from the present study, seems limited. HER-2 overexpression was seen in 17% of 97 investigated esophageal tumor samples. In squamous cell carcinoma patients, HER-2 overexpression correlated with poorer survival (p=0.035), whereas in adenocarcinoma patients, HER-2 status did not. HER-2 overexpression seems to be associated with poorer survival in esophageal carcinomas, especially in patients with squamous cell esophageal carcinoma. Telomerase activity was detected in all esophageal cell lines, with a broad range of activity levels. No correlation was found between telomerase activity levels and sensitivity to investigated cytotoxic drugs. We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines. The virus HPV-16 was detected in 16 % of the patients; no other type HPV was detected. HPV-16 infection had no significant effect on survival (p=0.72). Our results did not show that HPV-16 increases survival or improve therapy response in patients with esophageal carcinoma.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22146号 / 医博第4537号 / 新制||医||1039(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 富樫 かおり, 教授 武田 俊一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Störung des G1-Restriktionspunkts des Zellzyklus und Verlust der Wachstumskontrolle in Folge der Inaktivierung des Rb-Signalwegs ist ein häufiges Ereignis in malignen Tumoren. Gemeinsam mit der Hemmung von Apoptose-Signalwegen sind solche genetischen Ereignisse zentrale pathogenetische Faktoren der Tumorentstehung. Diese Veränderungen prägen aber auch entscheidend die Tumorbiologie und bestimmen somit intrinische und erworbene Therapieresistenz und konsequenterweise auch die klinische Prognose der Tumorerkrankung. In der vorliegenden Arbeit wurden Veränderungen im Rb- und im p53-Signalweg in Plattenepithelkarzinomen des Ösophagus untersucht. Diese retrospektive Studie wurde an Tumorproben von 53 mit kurativer Intention R0-resezierten Patienten durchgeführt. Proteinexpression wurde mittels Immunhistochemie und Mutationen mittels SSCP-PCR analysiert. Aktivierende Punktmutationen des K-ras Onkogens wurden mittels mutationsselektiver genomischer PCR und eines sequenzspezifischen Festphasen-Hybridisierungstests nachgewiesen. Die Analyse der individuellen Gene zeigte, dass Expressionsverlust der Rb-Signalwegskomponenten p16INK4a, p21CIP/WAF-1, p27KIP1 und von Rb selbst, sowie die Überexpression von Cyclin D1 bzw. Verlust des pro-apoptotischen Bcl-2 Homologs Bax mit schlechter Prognose, d.h. kürzerem Überleben korrelierte. Überexpression von Cyclin E, p53 oder Bcl-2, sowie Mutation von p53 bzw. K-ras zeigten hingegen keinen Einfluss auf die Prognose. Das längste Überleben wurde in einer Subgruppe von Patienten beobachtet deren Tumore eine Kombination günstiger Genotypen zeigte, und zwar niedrige Cyclin D1 Expression, sowie hohe Expression von Rb, p21CIP/WAF-1, p16INK4a und Bax. Diese Ergebnisse zeigen, dass eine Multigen- oder "Multimarker"-Analyse von Genen, die konsekutiv oder synergistisch in Zellzyklus- und Apoptose-Signalwegen agieren, zur Prognoseabschätzung der Analyse individueller Gene deutlich überlegen ist. Die Identifikation solcher genetischer Markerprofile sollte sich auch zukünftig als nützlich für die klinische Entscheidungsfindung in der Therapie maligner Tumore erweisen und wird konventionelle klinische und pathologische Faktoren komplementieren, die bisher keine ausreichende Prognoseabschätzung erlauben. / Malignant tumors frequently show inactivation of the Rb pathway and, as a result, deregulation of the G1 restriction point of the cell cycle and loss of growth control. Together with the inhibition of apoptosis signaling pathways, such events are key pathogenetic factors in tumor development. Moreover, these aberrations are decisive in determining tumor biology and characteristics such as intrinisic or acquired resistance to therapy and, consequently, the clinical prognosis of the malignant disease. In the present work, aberrations in the Rb and the p53 pathway were analysed. This retrospective study was undertaken in a cohort of 53 patients with esophageal squamous cell carcinoma who underwent R0 resection with a curative intent. Protein expression in tumor samples was analysed by means of immunohistochemistry and mutations were investigated by the use of genomic SSCP-PCR. Activating point mutations of the K-ras oncogene were detected by the use of mutation-selective genomic PCR and a sequence specific solid phase hybridization assay. The analysis of individual genes showed a correlation between poor prognosis, i.e. short overall survival, and loss of the Rb pathway components p16INK4a, p21CIP/WAF-1, p27KIP1, and Rb itself, or overexpression of cyclin D1 or loss of the pro-apoptotic Bcl-2 homolog Bax. In contrast, overexpression of cyclin E, p53 or Bcl-2 and mutation of p53 or K-ras had no influence on disease prognosis. The longest survival was found in a subgroup of patients whose tumors exhibited a combination of favorable genotypes, i.e. low expression of cyclin D1, and high expression of Rb, p21CIP/WAF-1, p16INK4a and Bax. These results demonstrate that a multigene or "multimarker"-analysis of genes that act consecutively or synergistically in cell cycle and apoptosis signaling pathways is far superior to determine disease prognosis when compared to the analysis of individual genes. The identification of such genetic marker profiles should proove beneficial in clinical decision making in the therapy of malignant tumors. In the future, such diagnostic tools may be useful to complement conventional clinical and pathologic factors which in most instances do not allow prediction of disease prognosis.