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. / Background: Great strides have been made in childhood cancer treatment efficacy over the past two decades leading to improved survival rates, and now attention is being directed toward identifying and understanding complications that affect many of these patients as they reach adulthood. Obesity is a well‐recognized late effect that has many potential long‐term consequences some of which include cardiovascular disease, type II diabetes mellitus, dyslipidemia and even death. Materials/Methods: We conducted a retrospective chart review to determine the prevalence of obesity among survivors of pediatric brain tumors 5 years after the completion of therapy and compare this to the general pediatric population of the same age. We also sought to identify potential risk factors for the development of obesity among survivors of childhood brain tumors. Obesity was defined as a body mass index (BMI) greater than the 95th percentile for age and gender as defined by the most recent Center for Disease Control growth curves. Results: We identified 96 patients who met our inclusion criteria, however only 43 had follow‐up data at 5 years after the completion of therapy to be included in final analysis. Of 43 patients, 5 (11.63%) were obese 5 years after completion of therapy. The CDC sites general population obesity rates in three age groups: 2‐5 years (8.4% obesity rate), 6‐ 11 years (18% obesity rate), 12‐19 years (21% obesity rate). Using CDC guidelines, we found no significant difference between the obesity rate among the brain tumor survivor population for each age group and the general population, p‐values of 0.865, 0.865, and 0.249 respectively. Conclusion: Our small sample size was likely not adequate to find a significant difference between the two groups or identify risk factors associated with the development of obesity. Larger studies are needed to further examine the risk of obesity among pediatric brain tumor survivors and to identify risk factors associated with this late effect.

In the early 1920s, Otto Warburg demonstrated that tumor cells have a capacity to convert glucose and other substrates into lactic acid instead of CO2 and water, even under aerobic conditions. Consequently, Warburg assumed that the intracellular pH (pHi) of tumor was acidic. However, later studies have shown that maintenance of pHi within a pH range of 7.0-7.2 is necessary for normal cellular proliferation and that the extracellular pH (pHe) is partially acidic in solid tumors. A low pHe may be an important factor inducing invasive behavior in tumor cells. Research into causes and consequences of this acid pH of tumors are highly dependent on accurate, precise and reproducible measurements. Techniques for measuring tissue pHi and pHe have undergone great changes since 1950s. From microelectrode and dye distribution studies, measurement of pH underwent a revolution with the advent of pH-sensitive dyes that could be loaded into the cytosol. Further significant advances have come from the measurement of cell and tissue pH in whole organisms by magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and pH-sensitive Positron Emission Tomography (PET) radiotracers.

Objective: To report experience with borderline ovarian tumors (BOTs) in a developing country like Pakistan with limited resources and weak database of health system. Methods: Patients with BOTs managed at Shaukat Khanum Cancer hospital, Lahore, Pakistan from 2004 to 2014 were included and reviewed retrospectively. Data was recorded on histopathological types, age, CA-125, stage of disease, treatment modalities and outcomes. Results: Eighty-six patients with BOT were included with a median age of 35 years. Forty-two (49%) patients had serous BOTs and 43 (50%) had mucinous BOTs, while one (1%) had mixed type. Using FIGO staging, 80 patients had stage I; two patients had IIA, IIB and stage III each. Median follow-up time was 31.5 months. All patients had primary surgery. Seventy (81%) patients underwent complete surgical resection of tumor. Forty-three (50%) patients had fertility preserving surgery. Seventy-three (85%) patients remained in remission. Recurrent disease was observed in 13 (15%) patients. Median time to recurrence was 22 months. On further analysis, age above forty years, late stage at diagnosis and incomplete surgery were significantly associated with invasive recurrence. Conclusion: Despite a low malignant potential, relapses may occur in patients above forty years of age, incomplete surgery and staging information and advanced stage at presentation. Fertility sparing surgery should be considered in young patients. Complete excision of tumor and prolonged follow-up are advised because recurrence and transformation to invasive carcinoma may occur.

Purpose: In oncological orthopedics, navigation systems are limited to use in specialized centers, because specific, expensive, software is necessary. To resolve this problem, we present a technique using general spine navigation software to resect tumors located in different segments. Materials and Methods: This technique requires a primary surgery during which screws are inserted in the segment where the bone tumor is; next, a CT scan of the entire segment is used as a guide in a second surgery where a resection is performed under navigation control. We applied this technique in four selected cases. To evaluate the procedure, we considered resolution obtained, quality of the margin and its control. Results: In all cases, 1 mm resolution was obtained; navigation allowed perfect control of the osteotomies, reaching the minimum wide margin when desired. No complications were reported and all patients were free of disease at follow-up (average 25.5 months). Conclusions: This technique allows any bone segment to be recognized by the navigation system thanks to the introduction of screws as landmarks. The minimum number of screws required is four, but the higher the number of screws, the greater the accuracy and resolution. In our experience, five landmarks, placed distant from one another, is a good compromise. Possible disadvantages include the necessity to perform two surgeries and the need of a major surgical exposure; nevertheless, in our opinion, the advantages of better margin control justify the application of this technique in centers where an intraoperative CT scanner, synchronized with a navigation system or a dedicated software for bone tumor removal were not available.

by Chung-Pui Cheng. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1987. / Bibliography: leaves 142-163.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

As immunotherapy grows in popularity as a cancer treatment option, we need to further understand how immune cells interact with the tumor microenvironment and influence tumor progression. The goal of this thesis was to characterize the different immune, cellular, and structural components within the breast tumor tissues of two orthotopic (MCaP0008 and M3C) and one spontaneous (MMTV-PyVT) murine models of immunogenic breast cancer. Identification of the tumor components in question, including CD3+ lymphocytes, CD11b+ myeloid cells, CD31+ endothelial cells, αSMA+ cancer associated fibroblasts, Ki67+ cells, cleaved caspase-3+ cells, collagen-1, and hyaluronan, were done by immunohistochemistry (IHC)-immunofluorescence (IF) staining of frozen tumor tissues with appropriate antibodies and imaging with multispectral confocal microscopy. Quantification and further data analysis were performed using a custom MATLAB program designed by Dr. Mei Rosa Ng. Gaining understanding of these stromal compositions will allow for better utilization of these breast cancer mouse models in future experiments. / 2019-10-31

Pyruvate carboxylase (PC), converting pyruvate to oxaloacetate (OAA), is a critical contributor to anaplerosis in pancreatic β-cell, the process that can replenish the intermediates in Krebs cycle. The level of PC is markedly high in pancreatic β-cell, about 7-fold higher than that in α-cell. PC activity is reduced in the islets of animals with type 2 diabetes. Moreover, the rate of pyruvate carboxylation catalyzed by PC is well correlated with glucose-stimulated insulin secretion (GSIS), further supporting the important role of PC in insulin secretion. Tumor protein p53 or p53, best known for its role as a tumor suppressor, has been studied extensively for its broad influence and complex regulation. p53 suppresses tumor progression by responding to a wide variety of intrinsic and extrinsic cellular stress signals. Recent studies have revealed novel roles of p53 in response to metabolic stress, such as oxidative or nutrient stress. MDM2 is the major E3 ubiquitin ligases to control p53 activity negatively. p53 and MDM2 form a negative-feedback loop, where p53 stimulates the expression of MDM2, in turn MDM2 inhibits not only the stability but also the transcriptional activity of p53. In the previous study, mice lacking Mdm2 specifically in pancreatic β-cells have been generated, and display impaired insulin secretion and glucose metabolism. Further study has suggested that the impaired insulin secretion is caused by downregulation of pyruvate carboxylase (PC). To explore the interaction of PC with MDM2-p53 pathway in regulating insulin secretion, we inserted human PC DNA into a shuttle vector pShuttle-CMV to generate a recombinant adenovirus containing human PC gene, that is then used to restore the level of PC in Mdm2 KO islet. The recovery of insulin secretion confirmed that the downregulation of PC leads to β-cell dysfunction. Given that MDM2 is the main E3 ubiquitin protein ligase to restrain p53 activity, abnormal high level of p53 is suggested to suppress the activity of PC in Mdm2 β-cell KO mice. The putative p53 response element is found in a sequence of PC intron gene, indicating that PC can be a downstream target of p53. Using pGL3 Luciferase Reporter Vector, it is verified that p53 suppresses the activity of PC by directly targeting PC. / published_or_final_version / Medicine / Master / Master of Medical Sciences

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