(<特集>悪性脳腫瘍の病態と治療) (<SPECIAL ISSUE>Pathology and Treatment of Malignant Brain Tumors)

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Malignant melanoma is a common type of solid tumor that causes high cancer-related mortality in young adults of Northern Europe. The incidence of melanoma increases rapidly which renders us a special responsibility to investigate this disease in depth. One recent promising approach to treat malignant melanoma is adoptive cell therapy with tumor-directed autologous T cells. This thesis aims to improve this therapy in four different studies. We first sought to establish a protocol for the assessment of melanoma-specific T-cell cultures in order to screen for optimal specificity and reactivity in a robust, reliable and simple manner. The conclusion was that reactive cells could be found in a majority of patients and could be screened for specificity by stimulation with melanoma cell lines. In the next study, 28 melanoma patients with advanced disease were treated with autologous tumor-infiltrating T cells. Objective responses (18%) including one sustained complete response were observed. This is the first study in cancer patients with autologous T cell transfer combined with low-dose s.c. IL-2 as supportive cytokine. In the following two studies we wanted to improve management and culture conditions of the T cells. When investigating methods for improved handling and preservation of large numbers of T cells, we observed that freeze-thawing of T cells could impair the metabolic activity of the T cells. Another conclusion was that rapid expansion of T cells could lead to loss of antigenic specificity and apoptosis. These adverse effects could be prevented with short time recovery. In order to improve expansion methods, mass expansion of T cells in an automated bioreactor was evaluated. We concluded that the bioreactor is suitable for this task and allows for higher cell densities and absolute cell numbers compared to traditional culturing conditions without influencing cell phenotype or reactivity. Taken together, my current studies present guiding principles and encouragement for the further development of immunotherapies for treatment of patients with malignant melanoma.

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Magister Public Health - MPH / The availability of information on profile and trends of cancer in South African populations is important for the development of appropriate cancer control strategies, as well as monitoring the efficacy of the existing cancer control programmes. Yet, generally there is a scarcity of systematically analysed reports on hospital cancer cases in South Africa, even for urban hospitals. The aim of this study was to describe the cancer profile of patients diagnosed at Frere Hospital‟s Oncology and Radiation Department and estimate the incidence of cancer among Buffalo City (BFC) urban area residents, for the 19-year period 01 January 1991 to 31 December 2009 based on the clinical administrative data system maintained by the department. The study was a descriptive case series study based on a retrospective review of Frere Hospital‟s Oncology and Radiation Department patient records from 1991 to 2009. Permission was obtained to retrieve records of cancer cases for the 19-year period from the database. Data were extracted from the customized administrative system to an excel spread sheet. Variables for each case retrieved included: socio-demographic details; age at diagnosis, sex, race, place of residence and medical aid information, tumor information; site and date of diagnosis. Data cleaning incorporated techniques such as checking of completeness and accuracy of patient information details. Dates were formatted into month-day-year sequence and checked so that the date of birth precedes the date of diagnosis of the patient and the date last seen. Age less than zero and greater than ninety nine was replaced as missing. Geographical areas were coded according to the South African Population Census. Duplicates and cases with missing diagnosis were excluded.

Class of 2006 Abstract / Objectives: To create, deliver, and evaluate a malignant melanoma continuing education (CE) seminar for pharmacists. Methods: A CE program was developed and presented to educate pharmacists about skin cancer prevention, specifically malignant melanoma, and their role in prevention through patient counseling. All practicing pharmacists who attended the CE program were asked to fill out a knowledge indicator and assess their comfort level in counseling patients about sun safety before and after the program. The participants also answered questions addressing how often they counsel patients on sunscreen use, their personal experience with skin cancer, preferred CE format, previous CE attendance, sex, age, practice site, hours worked per week, and years since graduation from pharmacy school. Results: The survey instrument was completed by 84 pharmacists. The average score on the pre-test knowledge indicator was 4.95 ± 0.39 and the average score on the post-test knowledge indicator was 7.81 ± 0.39. This was a significant improvement (p < 0.01). There was a significant increase in participant comfort level when counseling patients about sun safety after attending the CE program (p < 0.01). Personal experience with skin cancer did not have a significant effect on the pre-test knowledge indicator scores, however it was associated with the knowledge indicator change score (p < 0.01). Completion of previous skin cancer CE programs did not have a significant effect on the pre-test knowledge indicator score or the change score. Conclusions: Pharmacists who attended the CE program improved their knowledge indicator scores when tested about malignant melanoma and sun safety. Many participants felt more comfortable counseling patients about sun safety and felt their counseling on sun safety would change as a result of attending this CE program.

There is limited data on mortality, health service use and costs following treatment of malignant pleural effusions (MPE) in the real-world setting. We performed a retrospective population-based study using health administrative data of adults with indwelling pleural catheter (IPC) insertion (n=4,574) or pleurodesis (n=1,235) for MPE between 2015 to 2019. Inverse probability of treatment weighting using the propensity score was performed to adjust for baseline characteristic imbalances. After weighting to balance on baseline characteristics, there was no significant difference in post-procedure mortality between individuals receiving IPCs and pleurodesis, with IPCs inserted significantly later after an initial cancer diagnosis. IPCs with home nursing drainage were associated with reduced subsequent health resource use and healthcare costs compared to pleurodesis. A protocol was developed for a future economic evaluation to compare the cost-effectiveness of the procedures. This thesis provides the foundation for further research to help optimize the treatment of individuals with MPEs.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13480号 / 論医博第2255号 / 新制||医||1059(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 小川 誠司, 教授 羽賀 博典, 教授 伊藤 貴浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Malignant melanoma is a neoplasm of melanocytes. It typically originates in skin, but may metastasize to other body systems. It is a relatively common neoplasm in both humans and horses, with striking similarities across both species. Heritable genetic factors associated with melanoma have been identified in both human malignant melanoma (HMM) and equine malignant melanoma (EMM). This work investigates similarities and differences of EMM and HMM through comparative protein expression using immunohistochemical staining. Nestin, Pax-3/7, B-Raf, and SOX-10 are commonly expressed in HMM tissues. Expression of these proteins is not noted in normal human melanocytes, is associated with decreased melanocytic differentiation, and with increased proliferation leading to tumorigenesis. My findings demonstrate similar expression of these proteins in EMM. Aberrant protein expression patterns may signal underlying genetic mutations. Similar abnormal expression patterns suggest that EMM and HMM may share common genetic abnormalities. Treatment of malignant melanoma presents similar challenges in both horses and humans. In general, early stages of the disease can be successfully treated with surgical excision; however, advanced stages of EMM and HMM are often refractory. Therefore, development of novel therapies for advanced stages of melanoma is essential in both species, with the horse representing a useful model for this process. One novel therapy, frankincense oil (FO) is a resin distillate from trees of the genus Boswellia. Studies have demonstrated cytostatic and apoptotic-modulating properties of FO in various human cancer cell lines. No studies have evaluated FO as a therapy for skin neoplasms. In my work, the apoptotic properties of FO from Boswellia frereana were verified in a HMM cell line (SK-Mel-5). The cytotoxicity and therapeutic efficacy of FO were also studied by evaluating the effects of FO in cases of perianal EMM. FO was found to be consistently cytotoxic when injected directly into EMM tumors, but largely inconsequential when applied topically. FO was found to substantially decrease the size of injected masses. These findings suggest that FO could be useful for debulking large masses in late stage dermal EMM. The combined results of these studies support further investigation of EMM as a translational model for HMM. / Ph. D.

Ovine herpesvirus 2 (OvHV-2) is the causative agent of sheep-associated malignant catarrhal fever (MCF) in susceptible ruminants. Through an unknown mechanism, presence of the virus leads to proliferation of NK-like T cells that are not targetrestricted by the MHC class molecules. These host cells cause the symptoms found in MCF; fever, swollen lymph nodes, and necrotic lesions of the nasal, conjunctival, and oral mucosa, which usually leads to death of the host. MicroRNAs (miRNAs) are ~22 nt RNA molecules expressed by eukaryotes and viruses that regulate genes post-transcriptionally. Viral miRNAs have been found to regulate cellular genes to control the cell cycle and have a role in pathogenesis. It was hypothesised that OvHV-2 expresses miRNAs and these play a role in MCF pathogenesis. The aim of this project was to determine if OvHV-2 encodes miRNAs. Bioinformatic analysis was conducted on deep sequencing data from RNA of OvHV-2- immortalised T cells. Candidate miRNAs were selected if they adhered to miRNA secondary structure. 46 candidate miRNAs were found, with three clusters on the minus strand; one at the 5’ end and the other two in a 9.3 kb region that contains no predicted open reading frames. The 8 most abundant candidates were successfully validated by northern hybridisation for small RNAs. The majority of the predicted targets for the 8 validated OvHV-2 miRNAs were from the OvHV-2 genome. This study adds OvHV-2 to the list of herpesviruses that encode miRNAs and provides another tool for studying the pathogenesis of MCF.