Class of 2017 Abstract / Objectives: The specific aims of this project were to evaluate the incidence of carboplatin HSR in patients with the BRCA1 or BRCA2 mutations compared to those without these mutations. Secondary objectives were to identify carboplatin cycles where reactions occurred, grade of reaction, and treatment outcomes. Methods: This retrospective chart review included 167 ovarian, fallopian tube, and primary peritoneal cancer patients at the University of Arizona Cancer Center who underwent a regimen with carboplatin from 2013-2015. Results: 126 out of 167 patients were analyzed. HSR occurred in 4 patients with BRCA mutations, and in 9 patients without mutations, though incidence was not significant with respect to the groups (3.1% versus 17.4%, P=0.5291). Overall, there were 11 grade 1 reactions, 14 grade 2 reactions, and 16 grade 3 reactions to carboplatin. Conclusions: Presence of a BRCA1/2 mutation was not associated with a higher incidence of HSR in carboplatin. More studies are needed to clarify the impact of BRCA mutations on developing carboplatin HSR.

The clinical management of cancer has principally relied upon surgery, radiation therapy, and chemotherapy for many decades. Despite recent advances in molecularly-targeted diagnostic and therapeutic agents, the long-term survival rates in patients with solid malignancies including ovarian cancer have improved only incrementally. Nanotechnologies designed to locally interrogate and modulate the tumor microenvironment offer a promising opportunity to enhance existing treatment modalities and establish new therapeutic paradigms. By virtue of their elemental composition, geometry, and surface chemistry, nanomaterials can be engineered with optical and pharmacokinetic properties which permit these agents to localize, fluoresce, and deposit energy within tumors. Nanomaterials therefore provide a clear route towards future approaches for sensitive diagnosis and imaging of tumors and targeted therapeutic delivery.

The aim of this study was to define the ovarian follicular reserve of wild African elephants in terms of its type of small follicles (SF), its establishment and distribution throughout the ovaries, and the change in numbers of SF in the embryo and fetus as well as throughout prepubertal and adult life. The large elephant population in Zimbabwe provided the opportunity to collect ovaries from elephants culled for management reasons and hunted professionally. In total, gross morphological and histological studies were done on the gonadal ridges from 5 embryos (76–96 days post conception) and ovaries from 11 fetuses (4.8–22.2 months), 29 prepubertal females (2 months–10 years), 24 adult females (11–55 years) and 7 aged females (56–70 years). Specimens were fixed in 4% buffered formalin before a series of 25 ìm thick sections were cut and examined using stereological protocols to count SF numbers in each section and thereby calculate the follicle reserve of the whole ovary. Prior to counting SF numbers, their distribution throughout the ovary was studied and the repeatability of counts was validated. Numbers of SF were highest in mid-term fetuses, lower in fetuses during the second half of gestation, even lower in calves younger than 4½ years, whereas the numbers in calves aged 4½–9 years were significantly higher than those in younger calves, and similar to what they were in late-term fetuses. The numbers of SF were substantially and highly significantly lower in elephant 10–15 years in age compared to calves aged 4½9 years, suggesting a reduction around puberty. Thereafter the ovarian reserve fell steadily until depletion around the age of 70 years. During adult life the ovarian reserve was composed of early-primary (EP) and true-primary (TP) follicles. By 45 years of age only TP follicles remained although these enabled oestrous cyclical activity for many more years; of 7 sets of ovaries recovered from females aged 57–70 years, 6 showed evidence of cyclical activity or pregnancy within the preceding 6 years. The study shows that EP and TP form the follicular reserve from before birth until 45 years, with TP forming the reserve thereafter, which depletes in some old elephants and persists to maximum life span in others. / Thesis (PhD)--University of Pretoria, 2012. / Production Animal Studies / unrestricted

AimsParticipant drop out is a major barrier to high-quality patient-reported outcome (PRO) data analysis in cancer research as patients with worsening health are more likely to dropout. To test the hypothesis that ovarian cancer patients with worse PROs would drop out earlier, we examined how patients differed by time of dropout on health-related quality of life (HRQOL), anxiety, depression, optimism and insomnia. MethodsThis analysis included 619 participants, stratified by time of dropout, from the Australian Ovarian Cancer Study - Quality of Life substudy, in which participants completed PRO questionnaires at three-monthly intervals for 21 months. Trends in PROs over time were examined. Pearson correlations examined the relationship between time of dropout and baseline PROs. Multiple linear regression models including age, disease stage and time since diagnosis examined relationships between baseline and final PRO scores, and final PRO scores and dropout group. ResultsParticipants who dropped out earlier had significantly worse baseline HRQOL (p<0.0001) and higher depression (p<0.0001). For all five PROs, final scores were significantly associated with baseline scores (p<0.0001). Time of dropout was significantly associated with final HRQOL (p=0.003), anxiety (p=0.05), depression (p=0.02) and optimism (p=0.02) scores. Depression, HRQOL and anxiety worsened at a faster rate overtime in dropouts than study completers. ConclusionsPoorer HRQOL and higher depression at baseline, and final HRQOL, anxiety, depression and optimism scores were predictive of time of dropout. These results highlight the importance of collecting auxiliary data to inform careful and considered handling of missing PRO data during analysis, interpretation and reporting.

Cancer develops in many organs and tissues in the body through genetic and environmental modifications to acquire the hallmarks of cancer. The hallmarks of cancer allow the cells to become malignant and progress to a tumorigenic state. It has previously been shown in various carcinomas that HIF-2a, a key component in hypoxia adaptation, has a role in autonomous growth, the first hallmark of cancer. Ovarian cancer is the most lethal of the gynecological malignancies and accounts for 3% of new cases in women annually but is the fifth most common cause of death due to cancer. Here, it is shown in two ovarian carcinoma cell lines that HIF-2a is involved in in vitro and in vivo growth. It is also shown that the effect of HIF-2a is due to its role in autonomous growth and not vascularization with the use of in vitro spheroids. From recent findings in the laboratory the oxygen-stimulated translation initiation complex was discovered and HIF-2a is one of its components. In the absence of HIF-2a there is a downregulation in translation in hypoxia in ovarian carcinoma. This is also seen in a HIF-2a translational target, IGF1R and its downstream signaling pathway, which may be involved in autonomous growth as well as other hallmarks of cancer. Taken together, the data in this thesis presents the importance of HIF-2a in autonomous growth and cancer progression in ovarian carcinoma, as well as verifying its role in translation.

Follicular growth and maturation are tightly regulated processes, which involve the participation of endocrine, autocrineparacrine factors and intracellular molecules. Due to the numerous research efforts, a large number of regulators and their mechanisms of regulation of follicular growth and differentiation have been established. Although the abnormal expression and activities of some of these regulators are believed to be associated with ovarian dysfunction diseases, such as polycystic ovarian syndrome (PCOS), the etiology and pathogenesis of this syndrome are not completely understood. In this thesis, we have identified two novel regulators of follicular growth and differentiation and examined the cellular and molecular mechanisms that contribute to the folliculogenesis. We present here that chemerin reduces FSH-induced steroidogenic enzyme expression and steroid hormone production in follicles and granulosa cells. Prohibitin expression is upregulated by chemerin and knockdown of prohibitin attenuates the suppressive role of chemerin on steroidogenesis, an action regulated by Akt. Using an androgenized rodent model, we also present the dysregulation of chemerin and prohibitin and their association with dysregulated follicular steroidogenesis. Our data and preliminary clinical studies demonstrate the potential involvement of chemerin and prohibitin in the etiology of PCOS. These studies significantly improve the knowledge of ovarian functions and the pathophysiology of PCOS, and provide important clues for the development of novel diagnosis biomarkers and new treatment strategies for this complex syndrome.

Orientadores: Sophie Françoise Mauricette Derchain, Luis Otavio Zanatta Sarian / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T14:37:04Z (GMT). No. of bitstreams: 1 Campos_CamiladeMelo_M.pdf: 1462137 bytes, checksum: faa2f41f3fb8975de5506f358d8e374d (MD5) Previous issue date: 2014 / Resumo: A discriminação de tumores malignos entre mulheres com diagnóstico de massas anexiais pode ser difícil devido a limitações na acurácia do exame ultrassonográfico e à disponibilidade de pessoal especializado para realizá-lo. O índice de risco de malignidade visa a simplificar e padronizar a rotina ultrassonográfica para fornecer uma avaliação rápida e direta da massa anexial. Neste estudo foi examinado o desempenho de quatro variações deste índice (IRM 1 a 4) em um centro terciário de assistência e pesquisa em câncer ginecológico com a realização de exame ultrassonográfico por pessoal inserido em programa de treinamento supervisionado. Método: 158 mulheres com diagnóstico de massa anexial foram avaliadas antes da cirurgia utilizando-se as quatro variações do IRM. O exame foi realizado por ultrassonografistas com níveis variados de experiência e incluídos em programa de treinamento. Indicadores de desempenho para os diferentes tipos de IRM foram calculados utilizando-se de metodologia conhecida e o padrão-ouro para diagnóstico foi a análise anatomopatológica. Resultados: A prevalência de tumores malignos foi de 32%. Pacientes com tumores malignos eram mais idosas quando comparadas às pacientes com diagnóstico de tumores benignos (idade média 45,9+15,0 anos versus 55,7+16,2; p<0,001). A maioria (77%) dos tumores malignos era epitelial, embora 7/51 (13%) eram originados do estroma. Aproximadamente metade dos tumores primários ovarianos era estágio I. Endometriomas foram as mais frequentes (11%) massas vii anexiais não neoplásicas. Mulheres com tumores malignos apresentaram níveis de CA125, escores de ultrassom e número de tumores com diâmetro >7 cm significativamente maiores que mulheres com tumores benignos. Quando se comparou o desempenho das variantes do IRM no melhor ponto de corte determinado pela análise da curva ROC (receiver operator characteristic), percebeu-se que as variantes do IRM apresentam desempenho semelhante na população geral (pré e pós-menopausa). Entre as mulheres na pré-menopausa, a melhor sensibilidade é obtida com o IRM2 (90%; 95% IC 83-97%) e com o IRM4 (89%; 95% IC 81-97%). A especificidade entre as diferentes variantes do IRM não apresentou diferença significativa. O mesmo desempenho foi obtido entre as variantes do IRM nas mulheres na pré e pós-menopausa. Foram também analisados os indicadores de desempenho nas diferentes variantes do IRM nos pontos de corte progressivos na população geral (pré e pós-menopausa). Os pontos de corte recomendados pela literatura para os IRM1 a 3 é 200 e para o IRM4 é 450. Nesses pontos de corte recomendados, a sensibilidade entre os diferentes IRM variou entre 68% e 78% e a especificidade variou entre 82% e 87%. A pior correspondência entre valores do IRM e o resultado final anatomopatologico foi obtido entre os tumores borderline, em que os tumores foram classificados incorretamente em 50% dos casos utilizando o IRM1 e 3 e em 37% dos casos utilizando o IRM2 e 4. Proporções similares de tumores classificados corretamente e incorretamente foram obtidos com as quatro variantes do IRM. Os tumores epiteliais são mais bem classificados pelo IRM que os não epiteliais. A taxa de falso negativo é maior entre os tumores do estroma: 5/7 tumores de células da granulosa foram incorretamente classificados como viii benignos entre as quatro variantes do IRM. Tumores borderlines foram incorretamente classificados como benignos em 37% a 50% dos casos, dependendo do IRM utilizado. Falsos negativos entre as quatro variantes do IRM são maiores em mulheres com tumores de estágio 1 quando comparados com mulheres em estágio mais avançado (p com valor significativo entre as quatro variantes). Os IRM 1 e 3 classificaram incorretamente a maioria dos tumores estágio 1 como benigno; IRM 2 classifica melhor tumores de estágio 1. É importante ressaltar que 7 tumores de células da granulosa eram estágio 1. Analisou-se a curva ROC para os diferentes IRM na discriminação das mulheres entre tumores malignos e benignos. Os testes que compararam a área sobre a curva de todas as curvas revelaram superioridade discreta do IRM4 sobre o IRM2 (p=0.06). Todos os outros testes realizados entre as curvas não obtiveram resultado significativo. Conclusão: o IRM apresentou desempenho aceitável em um centro terciário de assistência e pesquisa em câncer ginecológico, com ultrassonografistas de conhecimento moderado e em treinamento. O equilíbrio entre o desempenho e a viabilidade, devido à baixa complexidade da realização do exame ultrassonográfico, favorece o IRM quando comparado a outros modelos de triagem para avaliação de massas anexiais / Abstract: Discriminating women with ovarian malignancies among those with adnexal masses may be difficult in medium resource settings due to limitations in ultrasound accuracy and availability of specialized personnel. The Risk of Malignancy Index (RMI) aims at simplifying and standardizing the ultrasound routine in order to provide a fast and straightforward evaluation of the adnexal mass. We examined the performance of four RMI variants (RMI 1 to 4) in a middle-resources gynecologic cancer center, with ultrasound performed by personnel under a training program. Methods: 158 referred due to an adnexal mass were evaluated before surgery using the four RMI variants. Ultrasound was performed by sonographers with variable expertise levels and enduring a training program. Performance indicators for the RMI variants were calculated using standard methodology and the gold standard was pathology of the adnexal mass. Results: The prevalence of malignant tumor was 32%. Patients with malignant tumors were significantly more aged than their counterparts with benign adnexal masses (mean age 45.9+15.0 years versus 55.7+16.2; p<0.001). Most (77%) malignant tumors were epithelial, although 7/51 (13%) were originated in the stroma. Approximately half of the malignant primary ovarian tumors were stage I. Endometriomas were the most frequent (11%) non-neoplasic adnexal masses. Women with malignant tumors had significantly higher CA125 levels, US Scores and tumors of >7cm in diameter than women with benign masses. When comparing the performance of x the RMI variants using the optimal cutoff points as determined with ROC analyses, we notivce than in the general population (pre and postmenopausal women), RMI variants yielded similar performance indicators. In the subset of premenopausal women, the best sensitivity was obtained with RMI 2 (90%; 95%CI 83-97%) and RMI4 (89%; 95%CI 81-97%). Specificity for the RMI variants did not differ significantly. Similar performance was obtained for the RMI variants in pre and post-menopausal women. We then analysed the performance indicators of RMI variants at progressive cutoff points in the general (pre- and postmenopausal) population. The standard (literature recommended) cutoff points for RMI 1 to 3 is 200 and for RMI 4 is 450. At these recommend cutoff points, the sensitivity of the different RMI1 vary from 68% to 78% and specificity vary from 82% to 87%. The worst correspondence between RMI values and final pathology was obtained for borderline tumors, which were incorrectly classified in 50% of the cases using RMI 1 and 3 and 37% of the cases using RMI 2 and 4. Similar proportions of correctly and incorrectly classified benign and malignant tumors were obtained with the four RMI variants. Clearly, RMI classified epithelial tumors much better than it did with non-epithelial tumors. The false negative rate was higher for stromal tumors: 5/7 granulosa cell tumors were incorrectly classified as benign by the four RMI variants. Borderline tumors were also incorrectly classified as benign in 37-50% of the cases depending on the RMI variant used. False negatives of for the RMI variants are higher in women with stage 1 tumors compared to women with more advanced stages (significant p values for all variants). RMI 1 and 3 incorrectly classified the majority of stage 1 tumors as benign; RMI 2 was the variant that best classified stage 1 tumors. It is worth noting that all 7 granulosa cell tumors were xi stage 1. We analysed the receiver¿operating characteristics curve analysis of RMI variants for the discrimination of women with malignant tumors from those with benign tumors. The pairwise permutation tests comparing the AUC for the curves revealed marginally significant superiority of RMI4 over RMI2 (p=0.06). All other pairwise comparisons between the curves returned nonsignificant results. Conclusions: RMI performed acceptably in a medium-resource setting where sonographers had moderate expertise and/or were under training. The tradeoff between performance and feasibility, due to lower ultrasound complexity, favors RMI over other adnexal mass ultrasound-based triaging models / Mestrado / Oncologia Ginecológica e Mamária / Mestra em Ciências da Saúde

Little research has examined the effect of non-cancer life stressors on psychological well-being and recurrence in patients with cancer, and results have been mixed. Furthermore, no studies have examined specific types of stress, including loss, danger, and entrapment in patients with cancer, utilizing data obtained from the Life Events and Difficulties Schedule. Given that specifics stressors have been associated with certain psychological responses, this study sought to obtain a more nuanced understanding of the relationship between life stress and psychological well-being. This was examined in a sample of 135 women with ovarian cancer prior to surgery and during the year after diagnosis using latent growth curve analyses. Models of protective psychosocial resources examining social support, mastery, self-acceptance, and purpose in life as potential moderators and mediators of the relationship between life stress and psychosocial outcomes were also evaluated. Results indicated that cancer-related losses were most closely associated with psychological well-being across several analyses, and non-cancer losses had the greatest impact on psychological outcomes when cancer-related loss was low. Non-cancer losses were significantly related to greater fatigue prior to surgery. Additionally, major non-cancer danger stressors were associated with greater distress prior to surgery. In this sample, no stressors were significantly related to cancer recurrence. Social support was the most consistent moderator of life stress on psychological well-being, and its effects on distress and depression at baseline were mediated through self-acceptance. These findings highlight the importance of both cancer- and non-cancer-related stressors on psychological wellbeing among cancer patients in their first year following surgery and furthers our understanding of the role of protective psychosocial factors. This study has significant implications for distress screenings in patients with cancer, psychological interventions, and future research.

Thesis (M. Sc. (Animal Production)) -- University of Limpopo, 2015 / The objectives of this study were: 1) To determine the effect of oocyte retrieval techniques (slicing and aspiration) on the quality and quantity of cattle oocytes, 2) To evaluate the effect of different concentrations of hormones on the maturational rate of cattle oocytes selected by brilliant cresyl blue staining, 3) To evaluate fertilization rate and cleavage/embryonic development of oocytes with or without cumulus cells, and 4) To compare the effect of fresh and frozen thawed semen on the fertilization rate of cattle oocytes. In Experiment 1: oocytes were recovered from abattoir derived ovaries using slicing and aspiration. The recovered oocytes were exposed for 90 minutes to 26μM of brilliant cresyl blue (BCB) stain and classified according to the colour of their cytoplasm: BCB+ (oocytes with blue cytoplasm) and BCB- (unstained oocytes). There was no difference (P>0.05) in the quality of oocytes recovered using slicing (60.7 %) or aspiration (53.7 %) techniques. In experiment 2: The BCB selected and the non-selected immature oocytes were randomly allocated into medium 199 + 10 % fetal bovine serum (FBS) maturation media. The media was supplemented with three different concentrations of hormones as treatments (T). The T1 (0.5 μg/ml of follicle stimulating hormone (FSH), 5mg/ml of luteinizing hormone (LH) and 2 μg/ml of estradiol (E2) as the control group. Then, T2 (1 μg/ml of FSH, 6 mg/ml of LH and 2.5 μg/ml of E2) and T3 (1.5 μg/ml of FSH, 7 mg/ml of LH and 4.5 μg/ml of E2). Maturation rate of oocytes was determined by the protrusion of the first polar bodies 24 hours following in vitro maturation. Treatment 2 yielded higher (P<0.05) maturation rate for both BCB+ (65.6 %) and without BCB (60.3 %) oocytes with T1 giving lower (P<0.05) maturation rate for BCB+ (22 %) and without BCB (16 %) oocytes. However, BCB- oocytes had lower (P<0.05) polar body extrusion (3.03 %, 8.1 % and 2.2 %) for T1, T2 and T3, respectively. In Experiment 3: one group of the presumptive zygotes was denuded of cumulus cells and the other group was cultured with cumulus cells. The presumptive zygotes were in vitro cultured in SOF-BSA and changed to SOF-FBS after 48 hours. High fertilization/cleavage rate was observed in oocytes cultured with cumulus cells (29.0 %) compared to the denuded oocytes (20.0 %) for 2-4 cells stage. Day 7 blastocysts were more (P<0.05) on oocytes cultured with cumulus cells (32 %) compared to denuded oocytes (13 %). In experiment 4: The matured oocytes were fertilized using fresh and frozen thawed semen. The oocytes fertilized with frozen thawed semen obtained a better number of 2-4 cell cleavage (23 %) when compared to fresh semen (19 %). Oocytes that were fertilized with frozen thawed semen also obtained higher morula (13 %) and blastocyst (8 %) compared to fresh semen with morula (3.4 %) and blastocyst (2 %). In conclusion, immature oocytes that were exposed to BCB+ and cultured in M199 supplemented with 10 % FBS, 0.5 μg/ml of FSH, 5 mg/ml of LH and 2 μg/ml of E2 had a higher (P<0.05) number of matured oocytes (extrusion of first polar body) compared to those that were not exposed to BCB (no BCB). Oocytes that were cultured with cumulus cells yielded a higher (P<0.05) number of cleaved embryos compared to the denuded oocytes. Slicing yielded a higher (P<0.05) number of oocytes, however the quality of oocytes recovered was similar compared to those recovered by the aspiration technique (P>0.05). Oocytes fertilized with frozen thawed semen yielded higher (P<0.05) number of 2-4 cell, morula and blastocyst when compared with oocytes that were fertilized using fresh semen. Keywords: ovaries, oocytes, slicing, aspiration, COCs, BCB, polar body and cattle

La chimiothérapie induit une baisse de la fertilité en exerçant une toxicité directe sur les ovaires entrainant une diminution du stock ovocytaire. Couramment utilisé dans le traitement du cancer du sein, le cyclophosphamide (Cy) est une des drogues reconnue comme la plus gonadotoxique. Récemment, il a été proposé que le Cy provoquait une déplétion folliculaire par une entrée en croissance massive des follicules au repos. L’Hormone Anti-Müllérienne (AMH) étant un des facteurs régulant la sortie des follicules primordiaux de la réserve ovarienne, nous avons émis l’hypothèse que cette hormone pourrait limiter la gonadotoxicité du Cy. Nous avons montré qu’un traitement par AMH recombinante chez des souris pubères traitées par Cy, permettait effectivement de limiter la déplétion folliculaire. Sur le plan fondamental, nous avons mis en évidence que l’autophagie pouvait être un des mécanismes impliqués dans l’inhibition du recrutement folliculaire exercée par l’AMH. Enfin, la méthode de référence consistant à évaluer la réserve ovarienne chez la souris étant particulièrement longue et fastidieuse, nous avons développé une technique de comptage folliculaire automatisé en utilisant des méthodes d’intelligence artificielle, et plus particulièrement une approche de « deep learning». / Chemotherapy induces infertility by exerting a direct toxicity on the ovaries, resulting in a depletion of the follicular stockpile. Cyclophosphamide (Cy), widely used for breast cancer, is recognized as one of the most gonadotoxic agent. Recently, it has been proposed that Cy gives rise to follicular depletion by a massive growth of resting follicles which are then destroyed. Since Anti-Müllerian Hormone (AMH) is one of the factors regulating primordial follicles activation, we hypothesized that this hormone might limited Cy-induced gonadotoxicity. We have shown in pubertal mice that recombinant AMH injections are able to preserve primordial follicle loss Cy-induced and might improve fertility outcome after treatment. In addition, we provide evidence that autophagy could be one of the mechanisms involved in the inhibition of follicular recruitment by AMH. At least, nowadays, the “gold standard” method of evaluating ovarian reserve in mouse is a process particularly time-consuming and tedious. We developed a new methodology of automatic primordial follicles detection and counting within mouse ovaries, using modern artificial intelligence methods, especially deep learning approach.