BACKGROUND: Advanced stage epithelial ovarian cancer (EOC) presents with an extremely poor prognosis. While some patients respond well to standard treatments of chemotherapy and cytoreductive surgery, the recurrence rate is high and five-year survival is low. The importance of nutritional eating and a healthy lifestyle has been recognized as a protective factor against the development of many cancers. There may be a role for dietary and lifestyle interventions on reducing the recurrence of EOC, thereby prolonging survival. LITERATURE REVIEW FINDINGS: A review of the literature was performed, focusing on dietary and lifestyle patterns and their effects on the development and recurrence of epithelial ovarian cancers. In general, carotenoids, flavonoids, cruciferous vegetables, and flaxseed rich diets have all been proposed to reduce the risk of developing ovarian cancer. Conversely, red and processed meats, and foods with high glycemic index have been associated with an increased risk of ovarian cancer development. Additionally, obesity and high Body Mass Index (BMI) have been linked to increased cancer risk as well as increased mortality rates from cancer. PROPOSE METHODS: Given the broad spectrum of dietary and lifestyle recommendations for prevention of EOC, many providers are not aware of what information they can give to their patients regarding this topic. A Continuing Medical Education (CME) lecture summarizing the most up-to-date literature on the topic of lifestyle interventions to increase EOC survival would be beneficial. A one hour long course will be offered for CME credit to expand the knowledge base of providers and equip them with the resources necessary to educate patients on healthy lifestyle modifications in order to minimize ovarian cancer recurrence. CONCLUSIONS: With a lack of definitive cure and poor overall prognosis for women diagnosed with advanced stage epithelial ovarian cancer, there is a need for alternative treatment options when traditional methods fail. There is promising evidence that a diet high in carotenoids, cruciferous vegetables, flaxseed, and several other nutritional components is beneficial in preventing development of ovarian cancer. A diet containing processed foods, red meats, dairy, and high sugar content has been associated with increased ovarian cancer risk. It is possible that these dietary recommendations may apply to prevention of recurrence of EOC as well. The CME lecture will present the most up-to-date knowledge in the area of lifestyle interventions for the prevention of EOC. A curriculum for primary care and oncology health care providers will provide them with the tools necessary to provide their patients with nutrition and lifestyle recommendations that may prevent cancer recurrence.

Melanoma is the most lethal type of skin cancer with over 132,000 cases occurring globally each year and continually rising incidence. BRAFV600E inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance. Evidence from human melanoma indicates that the melanocyte lineage is critical for melanoma survival and contributes to therapeutic resistance. MITF is a highly conserved “master melanocyte transcription factor” with a complex role in melanoma. Our lab has previously developed a temperature sensitive BRAFV600E mitfavc7 zebrafish melanoma model carrying a human oncogene and mitfavc7 splice site mutation that enables the conditional control of its endogenous activity by changes to water temperature. As part of my PhD project, I characterized and compared two new models developed since then: a very aggressive BRAFV600E mitfavc7p53M214K melanoma model with three driving mutations and a slower developing BRAF-independent mitfavc7p53M214K. I showed that the MITF activity is crucial for melanocyte survival in both models and that both mutated BRAF and p53 deficiency are oncogenic with low levels of MITF, and result in fish nevi and melanoma resembling the pathology of human disease. Both models are also relevant to a low-MITF subclass of human melanomas that emerged from a recent classification by The Cancer Genome Atlas Network. In addition, I established that, similarly to the BRAFV600Emitfavc7, complete inhibition of MITF activity leads to rapid tumour regression, but once its activity is restored the melanomas recur at the same site as the original tumour. I used histopathology studies and melanocyte lineage transgenes to identify and visualize subpopulations of cells remaining at the site of regression in these new zebrafish melanoma models. I hypothesised that these are the cells of origin for tumour recurrence (melanoma stem or progenitor cells), showed that some of them express a cancer stem cell marker aldehyde dehydrogenase, and attempted to target these subpopulations using 5-nitrofurans (a prodrug NFN1, shown previously by our lab to target ALDHhigh subpopulations in context of melanoma) in fish after melanoma regression. Finally, I also developed and described a new primary zebrafish melanoma cell line that I derived from one of these zebrafish tumours. This study is still in progress, but the cell line will be a useful tool for further investigation of these proposed melanoma progenitor cells in vitro, with potential applications for lineage tracing and transplantations.

Orientador: Marcelo Marotta Araujo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-15T10:49:15Z (GMT). No. of bitstreams: 1 Santos_SauloEllery_M.pdf: 1737074 bytes, checksum: 8ed6ac21f702ecbc6b2ad93be3ecf662 (MD5) Previous issue date: 2010 / Resumo: A deficiência vertical de maxila verdadeira é uma característica da Síndrome de Face Curta (SFC), neste padrão de pacientes o reposicionamento inferior desta base óssea é realizado com o objetivo de proporcionar uma melhor estética e função. Porém este movimento cirúrgico tem sido descrito como o movimento de maior instabilidade cirúrgica pós-operatória, sendo muitas vezes associados ao uso de enxerto na região do "gap" ósseo. O objetivo deste trabalho foi avaliar a estabilidade em longo prazo do reposicionamento inferior da maxila onde foram utilizadas quatro placas em forma de "L" (duas no pilar canino e duas no pilar zigomático) do sistema 2,0mm sem a utilização de qualquer forma de enxerto, através da realização de um estudo cefalométrico retrospectivo utilizando medidas lineares dos pontos I, A, ENA, CMV, ENP as linhas de referências horizontal (S-N rotacionado 7° inferiormente) e vertical (perpendicular a S-N 7° passando pelo ponto S) onde foram utilizadas telerradiografias em três tempos: pré - operatória, pós imediata e tardia (mínimo 6 meses) em uma amostra de 10 pacientes adultos jovens. Como resultado encontrou-se uma média de movimento inferior nos pontos anteriores: incisivo de 5,13mm e uma recidiva de 2,36mm (43,39%), no ponto ENA de 5,82 e 2,87mm (48,44%) respectivamente e para o ponto A os valores de 5,34 e 2,80mm (51,41%). Uma forte correlação foi encontrada entre quantidade de movimento e quantidade de recidiva para todo os pontos analisados com um coeficiente de Pearson r>0,500. Pode-se concluir que somente a utilização de 4 placas em "L" do sistema 2,0mm utilizado não foram suficientes para alcançar uma estabilidade adequada em longo prazo e que existe uma forte correlação positiva entre a quantidade de movimento inferior e a quantidade de recidiva / Abstract: The true vertical maxillary deficiency is a characteristic of Short Face Syndrome (CFS), in these patients, the inferior repositioning of the maxilla is indicated in order to provide a better facial esthetics and improved function. But this surgical movement has been described as the most instable movement, and interpositional autogenous bone graft usually is used to increase post-surgical stability. The objective from this study was to evaluate long term post surgical stability of the inferior repositioning of the maxilla, fixed with four 2.0mm "L" shaped miniplate, positioned at canine and zygomatic-maxillary buttresses, without any type of graft. A cephalometric study was performed, analyzing linear measures the I, A, ANS, CMV and PNS points until horizontal reference line (S-N drawing 7° inferiorly) and vertical reference line (perpendicular the S-N 7° crossing S point) traced at 3 different times: immediate pre operative, immediate post operative and a long time post operative with least 6 months. A total sample of 10 young adult patients who underwent an inferior repositioning of the maxilla was achieved. As result of this study, it was found an average surgical movement of 5.13 mm at I point, 5.82mm at SNA point and 5.34mm at A point. A relapse of 2.36 mm (43.39%), 2.87 mm (48.44%) and2.80 mm (51.41%) was found respectively. A strong statistical positive correlation was found between the amount of movement and amount of relapse for all points analyzed with a Pearson coefficient r> 0.5000. It was concluded, in this sample, that the inferior repositioning of the maxilla using this type of internal rigid fixation without any type of graft is not stable and that one strong positive correlation exist enters the amount of inferior movement and amount relapse / Mestrado / Cirurgia e Traumatologia Buco-Maxilo-Faciais / Mestre em Clínica Odontológica

Objective/Hypothesis: This study aimed to determine the clinical and cost-effectiveness of endoscopes during cholesteatoma surgery. More specifically, this study hypothesized that endoscope use would reduce cholesteatoma recurrence rates and cost. Study Design: Case series involving the prospective enrollment of 110 consecutive cholesteatoma patients over a 2-year period. Methods: Patients underwent cholesteatoma surgery with microscopy. During dissection, the location of the cholesteatoma was assessed. At the end of dissection and before reconstruction, the same subunits were visualized with straight and angled endoscopes for residual cholesteatoma. Hearing was analyzed before surgery and at the last possible examination. Costs were analyzed using Medicare reimbursement rates from the Centers for Medicare and Medicaid Services. Results: Intraoperative endoscopic surveillance was able to detect residual cholesteatoma in 18 patients. With a 0° endoscope, residual cholesteatoma was noted in the epitympanum (two patients), sinus tympani (one patient), and the supratubal air cells (one patient). With a 45° endoscope, residual cholesteatoma was noted in the epitympanum (three patients), sinus tympani (nine patients), the supratubal air cells (two patients), and the mesotympanum (two patients). From a cost analysis, endoscopic surveillance ($6110.36 per patient) are less expensive than second look surgeries ($11,829.83 per patient), observation ($7097.20 per patient), and observation with annual magnetic resonance imaging studies ($9891.95 per patient). The patients hearing improved after surgery, consistent with previous studies. No complications were noted from the use of endoscopes. Conclusions: Intraoperative endoscopic surveillance reduced recurrence in our series of 110 patients. Endoscopes are particularly useful in evaluating the epitympanum, mesotympanum, sinus tympani, and supratubal air cells. Moreover, endoscopic surveillance is cost-effective. Level of Evidence: 4 Laryngoscope, 128:2867–2871, 2018.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21014号 / 医博第4360号 / 新制||医||1028(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 武藤 学, 教授 木原 正博, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21621号 / 医博第4427号 / 新制||医||1033(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 湊谷 謙司, 教授 佐藤 俊哉, 教授 横出 正之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Medulloblastoma (MB) is the most common malignant pediatric brain tumour. Of its four distinct molecular subgroups (WNT, SHH, Group 3, and Group 4), Group 3 MB patients hold the worst clinical prognosis due to their high incidence of tumour recurrence and metastasis to the spinal leptomeninges. Relapsed Group 3 MB patients, particularly those with MYC amplification (known as Group 3𝛾), carry a mortality rate of nearly 100%, given the paucity of effective therapeutic options currently available. The most common cause of mortality amongst these patients is leptomeningeal metastasis, yet this metastatic disease is poorly characterized. Our understanding of MB tumour recurrence and leptomeningeal metastasis is further encumbered by the rare clinical opportunities at which specimens may be collected from relapsed patients. We were able to circumvent this obstacle by establishing a patient-derived xenograft mouse-adapted therapy model, which mimics the treatments administered in the clinic and in turn, recapitulates both local and metastatic human MB recurrence. This model system enabled the collection of valuable, patient-derived Group 3𝛾 MB tumour cells from the spinal leptomeninges at relapse. It provides an opportunity for chemical screening, with the aim of identifying small molecule inhibitors capable of eradicating these cells. Existing studies on MB leptomeningeal dissemination at diagnosis suggest that effective treatments may target signalling proteins, such as phosphatidylinositol 3-kinases and histone deacetylases (HDACs). Therefore, I hypothesized that selective kinase and HDAC inhibitors would pose as effective therapies against Group 3𝛾 MB metastatic recurrences. In this thesis, I conducted a high-throughput screen of 640 kinase inhibitors and robust testing of novel HDAC6-selective inhibitors against these treatment-refractory, metastatic cells. Here, I showed that metastatic recurrences of Group 3𝛾 MB are therapeutically vulnerable to selective inhibitors of checkpoint kinase 1 (CHK1), platelet-derived growth factor receptor beta (PDGFRβ), and HDAC6. Functional studies demonstrated that these inhibitors selectively target the aggressive, migratory Group 3𝛾 MB cells, while sparing healthy neural stem cells. They also showed effective blood-brain-barrier penetration in silico and in vitro, while significantly reducing MB tumour cell properties that are often associated with treatment failure. Taken together, my thesis highlights specific inhibitors of CHK1, PDGFRβ, and HDAC6 that effectively target MB tumour cells that fuel treatment-refractory leptomeningeal metastases. With additional preclinical validation, these compounds may serve as potent therapeutic options to extend survival and improve the quality of life for patients that are ostensibly limited to palliation. / Thesis / Master of Science (MSc) / Medulloblastoma is an aggressive brain cancer in children. While current standard treatment improves patient survival, 30-40% of all medulloblastoma patients relapse at local (brain) or metastatic (spine) sites. Medulloblastoma metastatic recurrences remain poorly understood, yet they result in an alarmingly high mortality rate amongst patients due to inadequate treatment options currently available. Specific molecular targets are common in both medulloblastoma and metastatic cancer research. These targets are particularly important in governing cell signalling pathways that regulate tumour growth and migration. Therefore, treatment against these targets may be effective at preventing medulloblastoma metastatic recurrences. As the collection of local and metastatic tumour samples at patient relapse are rare, the Singh lab developed an animal model that mimics human medulloblastoma recurrence. In this thesis, recurrent medulloblastoma metastases were isolated from our established animal model and tested against compounds that inhibit the specific molecular targets previously implicated in medulloblastoma and other metastatic tumours. We identified potent compounds that effectively target these metastatic cells. Next, we determined which compounds spared healthy cells and were able to penetrate the brain, given our future objective of targeting these MB cells from their source to ultimately prevent metastasis. The identified compounds substantially reduced the ability of these cells to divide. With further investigation, these compounds may pose as effective therapeutic agents to treat human medulloblastoma patients with metastatic recurrences.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Overall survival is about 70% and in cases where current treatment fails, the disease recurs and most often is fatal. At the molecular level, MB can be divided into four defined subgroups: WNT, SHH, Group 3 and Group 4. Amplification of MYC family genes is common in MB and correlates with poor prognosis and tumor relapse. In this thesis we showed how MYCN initiates brain tumors when transduced in neural stem cells (NSCs). Prior to transduction, NSCs were isolated from different brain regions and at various time points. While overexpression of wild-type MYCN did not generate any tumors, orthotopic transplantation of MYCNT58A-expressing forebrain, brain stem and cerebellar NSCs induced diffuse malignant glioma, PNET-like tumors and MB, respectively. Interestingly, MYCNT58A-expressing cerebellar NSCs induced SHH-dependent MB from embryonic cells but SHH-independent MB from postnatal cells. We further showed that cerebellar NSCs transduced with both MYCNT58A and transcription factor SOX9 developed tumors faster and promoted distant migration into the forebrain. The function and regulation of SOX9 in MB cells is poorly understood. We identified SOX9 protein as target of FBW7 ubiquitin ligase and demonstrated the effects of SOX9 on MB cells migration, metastasis and drug resistance. We further blocked PI3K pathway to destabilize SOX9 which sensitized cells to cytostatic treatment. We used a (TetOFF) transgenic mouse model of MYCN-induced MB (GTML) and crossed it with a (TetON) transgene which allowed us to specifically target rare SOX9-positive cells in the tumor. In this system, MB develops spontaneously and SOX9-negative tumor cells can be killed off by doxycycline. The few remaining SOX9-positive cancer cells were able to promote distant MB recurrences. Such a pattern of relapse was recently shown for Group 3 and 4 human MB where about 90% of the recurrences were distant. In summary, this thesis demonstrates that MYCN can generate various types of brain tumors depending on the timing and location of its expression. It further defines the existence of a rare population of SOX9-expressing MB cells that are involved in causing distant MB recurrences. Finally, it describes how SOX9 is stabilized in MB cells and increases MB migration and therapy resistance.

Background: New prognostic grade groupings were recently proposed for prostate cancer. They are based on Gleason grading of either biopsy or prostatectomy specimen. Former Gleason 6 corresponds to group 1, Gleason 7=3+4 corresponds to group 2, Gleason 7=4+3 corresponds to group 3, Gleason 8 corresponds to group 4, and Gleason 9-10 correspond to group 5. Objective: To assess the prognostic value of Gleason grade groups in men with prostate cancer from a nationwide population‑based cohort. Design, Setting and Participants: From the National Prostate Cancer Register of Sweden, we identified 5,880 men diagnosed with prostate cancer from 2005 to 2007, including 4,325 who had radical prostatectomy and 1,555 treated by radiotherapy.  Outcome Measurements and Statistical Analysis: Kaplan-Meier survival analysis was used to calculate the cumulative 4-year biochemical recurrence-free survival. Cox proportional hazards regression models were used to examine the relationship between prognostic Gleason grade groups and biochemical recurrence after radical prostatectomy and radiotherapy. The 4-year biochemical progression-free survival was compared for groups based on biopsy and prostatectomy Gleason grade groups. Results and Limitations: Among men undergoing surgery, the 4‑year biochemical progression-free survival was 89%, 82%, 74%, 77%, and 49% for prognostic Gleason grade groups 1-5 on biopsy. The corresponding 4-year biochemical progression-free survival based on prostatectomy prognostic Gleason grade groups was 92%, 85%, 73%, 63%, and 51% for prognostic Gleason grade groups 1-5. For men undergoing radiotherapy, biopsy prognostic Gleason grade groups 1-5 had 4-year biochemical progression-free survival of 95%, 91%, 85%, 78%, and 70%. After adjusting for preoperative serum prostate specific antigen and clinical stage, biopsy prognostic Gleason grade groups were significant independent predictors of biochemical progression after radical prostatectomy and radiotherapy. There was no central review of pathology. Conclusions: These results confirm the prognostic value of the newly proposed prognostic Gleason grade groups in men undergoing radical prostatectomy and radiotherapy in a population-based setting.