This study examines the risk of cancer in children of pesticide applicators from the Agricultural Health Study. The study includes 36,537 children of Iowa participants who were evaluated for cancer incidence during 1975 through 2013 from birth through the age of seventeen. Standard incidence rates for any cancer and specific groups of cancers classified using the International Classification of Childhood Cancer was calculated using rates from the general population of Iowa controlling for year of follow, age, sex, and race. Hazard ratios for Group I-III cancers and paternal exposure to specific pesticides were calculated using exposure information collected on 50 pesticides during phase 1 and 2 of the Agricultural Health Study. The exposure information allowed for calculation of intensity-weighted days of exposure to pesticides using the Agricultural Health Study exposure algorithm. Additionally, maternal ever exposure to specific pesticides was used to evaluate risk of childhood cancer. There were 118 cancers identified in children of Agricultural Health Study participants. The all-cancer standardized incidence ratio was significantly elevated (SIR = 1.27 95% CI: 1.04-1.50). The most common groups of cancers were Group I leukemia, myeloproliferative disease, and myelodysplastic disease (n=34) followed by Group III central nervous system (CNS) and miscellaneous intracranial and intraspinal neoplasms (n=25). For paternal intensity-weighted days of exposure, there were 31 of 50 specific pesticides that had sufficient cases of cancer to investigate using Cox proportional hazard models. The herbicide trifluralin significantly increased the risk for Group I childhood cancers for any parental pesticide exposure 2 years before birth through birth when compared to children with no paternal exposure (HR = 2.72 95% CI: 1.15, 6.44). This was consistent with results found from analyzing exposure split into two quantiles based on median exposure of exposed children with a Group I cancer. Parental use of the herbicide S-Ethyl-dipropylthiocarbamate (EPTC) did not result in a sufficient number of Group III cancer cases to look at levels of exposure to EPTC, but ever exposure showed an increased hazard ratio when compared to children with unexposed fathers (HR = 2.56 95% CI: 1.06, 6.20). Other pesticides (dicamba, cyanazine, and terbufos) showed mixed evidence of an association with specific childhood cancers, but were either under powered to evaluate with sensitivity analysis or showed inconsistent risk across exposure levels. Less extensive exposure information was available for mothers of children of the Agricultural Health Study, so analysis was restricted to ever or never exposure to pesticides during a mother’s lifetime. Additionally, there were a limited number of cases of cancer for which maternal exposure to specific pesticides was reported resulting in only 4 pesticides being evaluated for childhood cancer risk (glyphosate, 2,4-dichlorophenoxyacetic acid (2,4-D), carbaryl, and malathion). For these four pesticides, this study did not detect any increased risk of childhood cancer from maternal exposure. In summary, this study provides the first epidemiological evidence of an increased risk of childhood cancer for trifluralin and EPTC. Since this study provides the first evidence of this increased risk, additional analysis is needed to validate the results. This study demonstrates how pesticide exposure information from participants of the AHS can be used in the evaluation of their children’s cancer risk. Additional follow-up and analysis of this cohort beyond the age of 17 would provide further insight into cancer risk during early adulthood from early life pesticide exposure.

Indiana University-Purdue University Indianapolis (IUPUI) / Post-craniotomy brain tumor patients often experience pain in the post-surgical period which can negatively affect recovery and surgical outcomes. Research with this population has focused on pharmacological treatments of post-craniotomy pain and measurement of pain intensity. Little is known about how these patients experience the quality of their pain and how this pain is managed. The purpose of this dissertation was to provide an in-depth description of the experience of post-craniotomy pain during the post-surgical period. The information gained about how post-craniotomy patients experience pain and pain management will contribute the development of effective, tailored interventions to enhance patient satisfaction and outcomes. This dissertation project was composed of two components. The first component was an integrative review of literature examining the evidence of pain and associated symptoms in adult (aged 21 and older), post-craniotomy brain tumor patients. The review examined studies from the past fourteen years that focused on the incidence and treatment of postcraniotomy pain. It revealed that the majority of post-craniotomy patients experience moderate to severe pain after surgery. This pain is associated with nausea, vomiting, changes in blood pressure, and increased length of hospital stay. The second component was a qualitative descriptive study of a sample of 28 adult (aged 21 and older) post-craniotomy patients hospitalized on an inpatient neurosurgical stepdown unit at a Midwestern urban teaching hospital. During semi-structured interviews, participants described their experiences of post-craniotomy pain and of their experiences of postcraniotomy pain management. Data generated from the qualitative descriptive study were analyzed and resulted in two qualitatively derived products. The first was a description of participants’ experiences of the quality of their post-craniotomy pain during the post-surgical period. The six types of pain quality described were pain as pressure, pain as tender or sore, pain as stabbing, pain as throbbing, pain as jarring, and pain as itching. The second was a description of how post-craniotomy patients experience the management of their pain during the post-surgical period. The four groups of types of pain management experiences described were pain-as-non-salient, routine pain management; pain-as-non-salient, complex pain management; pain-as-salient, routine pain management; and pain-as-salient, complex pain management.

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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.

The Wilms' tumor 1 gene is overexpressed in many types of cancer and is associated with poor prognosis and resistance to anti-cancer therapies. In vitro studies in non-glioma cells types have demonstrated that WTl plays a role in increased proliferation, resistance to apoptosis, and increased cellular invasion. We aimed to thoroughly characterize the expression pattern of Wilms' tumor 1 in human malignant glioma and discern its function in this complex disease process. We screened a large sample of established human malignant glioma cell lines and glioma tissue specimens of all grades for WT1 expression. The majority of cell lines and 80% of all glioma tissue expressed WTI mRNA, all of which expressed WTl(+KTS) isoforms. Further screening of the glioblastoma specimens for p53 mutation followed by logistic regression analysis demonstrated a positive correlation between WTl expression and wild-type p53 (p = 0.04). To determine if WTl and p53 functionally interacted, we generated LN-229 glioblastoma cells that stably expressed WTl. As LN-229 cells harbor a p53 mutation, transient transfection with wild-type p53 induced apoptosis. However, stable WTI expression did not protect cells from p53-mediated cell death. We then generated U87MG cells (p53 wild-type) that stably expressed WT1 to model an endogenous p53 response. It is well known that after treatment with ionizing radiation, U87MG cells readily undergo p53-mediated apoptosis. Again, WTI expression did not protect against ionizing radiation induced p53-mediated cell death. We next examined the effect of transient WTI silencing on ionizing radiation induced cell death in T98G and LN-18 cells which express endogenous WTl. Combination treatment with ionizing radiation and silencing of WTI using short interfering RNA caused a decrease in viability and clonogenic survival relative to radiation alone in both cell lines. Lastly, we studied the effect of stable WTl silencing using short hairpin RNA on glioblastoma cell tumorigenicity. Stable transduction of U25 1MG and LN-18 cells with WTI short hairpin RNA resulted in a marked decrease in proliferation. WTI silencing in U251MG cells also caused a decrease in in vitro invasion. WTl silencing in U251MG cells caused an increase in tumor latency and a decrease in tumor growth rate when cells were used to subcutaneously inoculate nude mice. Not only do these studies support an oncogenic role for WTI in glioma biology, they provide encouraging evidence that WTl may be a therapeutic target for molecular treatment of glioblastoma.

Glioblastomas are an incurable type of brain tumor with a mean survival time of 9-12 months following diagnosis. One of the reasons for this poor prognosis is the ability of tumor cells to invade the surrounding normal brain tissue. Enzymes responsible for this invasive nature include the matrix metalloproteinase family. MMP-1 is a member of this family which has been well studied in many types of invasive tumors, with gliomas being an exception. We studied a single nucleotide polymorphism (SNP) in the MMP-1 promoter that may influence glioma biology. This SNP consists of the presence (2G) or absence (1G) of a guanine nucleotide at position -1607. The additional guanine nucleotide creates a binding site for ETS transcription factors and combined with the AP-1 binding site at position -1602 creates a Ras Responsive Element. We determined that the distribution of the MMP-1 genotype differed significantly between the healthy population and the glioblastoma patient population, with the 2G/2G genotype more prevalent in the glioblastoma patients. In addition, MMP-1 mRNA and protein examined in a select group of patient tissue had significantly higher levels when compared to normal brain controls, however, there was no correlation with genotype. Promoter reporter assays indicated that the 2G promoter was approximately three times more active than the 1G promoter in three different glioma cell lines.We investigated potential signaling mechanisms responsible for increases in MMP-1 transcription due to the presence of the RAS responsive element. Treatment of glioma cell lines with hepatocyte growth factor/scatter factor (HGF/SF) led to significant increases in MMP-1 transcription, via the MAP kinase ERK pathway. AP-1 transcription factor proteins, cJun and cFos were increased in response to HGF treatment but not Ets-1 and ETV-1. HGF/SF treatment of glioma cell lines differing in their MMP-1 genotype affected binding of ETS and AP-1 proteins to the endogenous MMP-1 distal promoter. Using chromatin immunoprecipitation assays, we identified these differentially DNA-bound AP-1 and ETS proteins. The data presented indicate that the MMP-1 SNP (-1607) is important in glioma biology and may contribute to tumor function and future investigations into its role in glioma biology is warranted.

Meningiomas petroclivais são tumores da base do crânio desafiadores para ressecção cirúrgica devido a sua localização profunda e relação com estruturas neurovasculares vitais. Geralmente são lesões benignas, mas podem envolver ou infiltrar o osso da base do crânio, dura-máter, tronco encefálico e todas as estruturas neurovasculares desta região, tornando a remoção total difícil sem causar déficits neurológicos. O objetivo deste estudo é revisar uma série de casos de meningiomas petroclivais tratados cirurgicamente em centro de referência de base de crânio, considerando os fatores determinantes para a escolha da abordagem. A casuística foi analisada com coleta retrospectiva dos dados. Devido à dificuldade de acesso, essas lesões geralmente requerem diferentes abordagens cirúrgicas e apresentam dificuldades cirúrgicas distintas. Embora as abordagens fronto-órbito-zigomática, petrosas, incluindo présigmoide retrolabiríntica, translabiríntica e petrosectomia total, e a retrossigmoide sejam as mais utilizadas para ressecção destes tumores, não foi realizado até o presente momento estudo comparativo que determine qual abordagem apresenta maior grau de ressecção cirúrgica associada a menor taxa de morbidade. / Petroclival meningiomas are challenging skull base tumors for surgical resection because of its deep location and their relationship to vital neurovascular structures. They are usually benign, but may involve or infiltrate the bone of the skull base, dura, brain stem and all neurovascular structures in this region, making it difficult to completely remove without causing neurological deficits. The aim of this study is to review a surgical series of petroclival meningioma treated in a referral center for skull base tumors, considering the determining factors to the choice of approach. The casuistry was analyzed with retrospective data collection. Due to difficult access, these injuries usually require different surgical approaches and have different surgical difficulties. Although the fronto-orbital-zygomatic, petrous, including retrolabyrinthine pre-sigmoid, translabyrinthine and total petrosectomy, and retrosigmoid are frequently used for resection of these tumors, it has not been realized to date comparative study to determine which approach has greater degree of surgical resection associated with lower morbidity rate.