Browsing by Subject "Neoplasms"
Now showing 1 - 20 of 131
- Results Per Page
- Sort Options
Item Adrenal incidentalomas for the internist(2013-03-08) Ghayee, Hans K.Item Anemia of malignancy: the role of the internist in the clinical approach to this paraneoplastic lesion(1996-02-08) Frenkel, Eugene P.Item Angiogenesis and cancer(1995-04-27) Minna, John D.Item Anti-Angiogenic Therapy in Non-Small Cell Lung Cancer: Characterizing a New Therapy and Investigating Potential Mechanisms of Resistance(2012-07-20) Sullivan, Laura Anne; Brekken, Rolf A.Angiogenesis is the development of blood vessels from a pre-existing vascular network. This process is essential during growth, development and wound healing and plays a critical role in the growth and progression of cancer. Initial tumor size is restricted by the diffusion capacity of oxygen and nutrients from surrounding blood vessels. Therefore, to progress beyond a volume of several millimeters, a tumor must stimulate angiogenesis to generate a vascular network that will supply the tumor with the necessary blood, oxygen and nutrients that will allow for continued growth, invasion and metastasis. Over forty years ago, Judah Folkman hypothesized that targeting tumor angiogenesis would be beneficial for cancer patients. One of the first targets for this new class of drugs was vascular endothelial growth factor (VEGF) a predominant mediator of physiological and pathological angiogenesis. Bevacizumab (Avastin®, Genentech/Roche), a humanized monoclonal antibody that recognizes human VEGF and blocks VEGF from binding to VEGF receptor (VEGFR) 1 and 2, was the first anti-angiogenic drug approved by the United States Food and Drug Administration for the treatment of cancer and remains the gold standard for this class of therapeutics. The Brekken laboratory, in collaborations with Peregrine Pharmaceuticals and Affitech A/S has generated a fully human monoclonal antibody, r84 that recognizes mouse and human VEGF and blocks VEGF binding only to VEGFR2. The data presented in the first half of this dissertation demonstrate the specificity of r84 for VEGF in vitro and in vivo, the efficacy of r84 to control tumor growth and the superior safety profile of r84 as compared to bevacizumab. Although anti-angiogenic therapy was highly anticipated to have great success in patients, overall results have been somewhat disappointing with modest improvements in patient progression free survival and few improvements to overall survival. In addition, with the expanding use of anti-angiogenic drugs such as bevacizumab and a host of receptor tyrosine kinase inhibitors in the clinic, it is becoming increasingly apparent that not all tumors respond or maintain sensitivity to treatment. Therefore, it is increasingly important to identify mechanisms of resistance to anti-angiogenic therapy so that new drug targets can be identified and/or patients can be appropriately screened for markers that can predict for resistance or sensitivity to anti-angiogenic therapy de novo. Non-small cell lung cancer (NSCLC), the most common form of lung cancer, claims the most new diagnoses and cancer-related deaths than any other cancer worldwide and the therapeutic options currently available for this disease, including bevacizumab have done little to change this statistic. The latter half of this thesis focuses on the in vivo screening of human NSCLC cell lines to identify mechanisms of resistance to the anti-angiogenic monoclonal antibodies bevacizumab and r84 in non-small cell lung cancer.Item Assessing the Relationship Between Electronic Medical Record (EMR) Generated QTc Alerts and Cancer Patient Mortality(2020-05-01T05:00:00.000Z) Bleiberg, Benjamin Aaron; Khan, Saad A.; Gerber, David E.; Terauchi, StephanieBACKGROUND: EMR generated drug associated QTc alerts are generated frequently in cancer patient populations and in the last few years their annual frequency has outgrown the number of unique patient visits at our institution. Anecdotally, they are largely ignored by providers, contributing to provider cognitive burnout and alert fatigue. While they may be considered nuisance alerts, the EMR collects rich data on the circumstances underlying the alert, the patients impacted, and their outcomes. By querying the EMR, we aimed to risk stratify patients by cancer site and demographic factors and provide meaning to these alerts allowing providers to incorporate the information we have provided in clinical decision making regarding the care of cancer patients. Our project is the first large-scale analysis of EMR generated QTc prolongation alerts at a tertiary referral center in the United States. OBJECTIVE: Acute mortality of cancer patients varies significantly by cancer site and demographic factors following EMR generated drug associated QTc interval prolongation alerts. METHODS: UT-Southwestern's EMR was queried to identify all patients between 10/04/2005 (the date of the 1st recorded alert) and 08/13/2019 over 18-years of age with a diagnosis of cancer and EMR generated drug associated QTc interval prolongation alerts yielding a sample of 19,223 patients. We collected the alert triggering medications, patient demographics, cancer site, and mortality data to identify the time between a patient's 1st alert and recorded death date. Rates of death by age, ethnicity, gender, race, number of alerts, and primary cancer site were identified in the following intervals: within 10 days, 11-180 days, and 181-365 days. Kaplan-Meier Overall Survival Analysis with Cox regression and multinomial multivariable analysis controlling for age, race, ethnicity, and gender, and median survival data analytic methods were used to identify if there were statistically significant differences in mortality at the pre-specified time points based on the above listed variables. Head and neck cancer patients were used as our reference group for comparison when analyzing mortality by primary cancer site. This group was chosen as their rates of within 10-day mortality closely aligned with those predicted by the null hypothesis that there would be no difference in mortality rates within 10-days across primary cancer sites used in our preliminary chi-squared goodness of fit model. Additionally, for patients with EKG's recorded within 10 days of their 1st alert, QTc intervals utilizing Bazett's correction algorithm were collected and the recorded interval of patients with deaths within 10 days was compared to those who were alive after 10 days, with participants separated by gender. RESULTS: Analysis of mortality from a patient's 1st QTc alert demonstrated statistically significant (p<0.05) higher risk of ≤10-day mortality in: patients with increasing number of QTc alerts, particularly patients with 6-10, HR=1.67 or >11 HR=1.88 alerts. Additionally, increased ≤10-day mortality was demonstrated in cancer patients with male gender, (female patients demonstrated a HR=0.83, compared to a male reference group), African American, HR=1.26, or other/unknown race, HR=1.29, and age >70, hazard ratio (HR)=2.32. Chi-squared goodness of fit testing identified head and neck cancer patients had a ratio of expected (by chance) to observed mortality of 0.98 and given the close concordance with our null model, were used as our reference group in multivariable analysis. Compared to a head and neck cancer patient baseline, significantly increased ≤10-day mortality was seen in: GI, HR=2.16; lung, HR=1.94; blood, HR=1.46; soft tissue, HR=2.26; and female genital, HR=1.55 cancers. Male genital, HR=0.39; breast, HR=0.57; and endocrine, HR=0.48 cancers had significantly decreased ≤10-day mortality. Of patients with EKG's, male patients who died ≤10-days of their 1st alert had significantly longer QTc intervals than males who survived to day 11 (469 vs 450 milliseconds, p<0.0001). In patients with any cancer and a QTC alert, 0.01 (male genital)-2.50% (GI) died ≤10 days of their 1st alert. The majority of deaths recorded <1 year after a patient's 1st alert occurred between 11-180 days during which 2.93 (male genital)-23.8% (GI) of the total sample with that primary cancer site diagnosis died. 63.2 (GI)-95.9% (endocrine) of cancer patients were alive >1 year after their 1st alert. CONCLUSION: Our research supports the anecdotal suggestion that very few patients die within 10 days of their initial QTc alert, suggesting that in many cases they function as distractions, especially in male genital, breast, and endocrine cancer patients and females or individuals <50 years of age. However, they may also identify patients at imminent risk of death, particularly those with lung, soft tissue, GI, blood, and female genital cancers, or males, African Americans, and individuals >70 years of age. Further, our analysis shows that QTc alerts may be a negative prognostic factor as the patients with more alerts (>5) have greater ≤10-day mortality rates. Additionally, of the patients who die within 365 days of their first alert the vast majority across cancer sites die between 11-180 days.Item Attachment Influences within a Gynecologic Cancer Population(2012-08-31) Adams, Cassandra Leigh; Evans, Harry M.Despite significant levels of distress and demonstrated benefits of psychosocial intervention, few women diagnosed with gynecologic cancers utilize psychosocial resources. Research indicates adult attachment style and perception of social support impact distress. However, relationships between these variables are poorly understood. Participants completed measures of distress, adult attachment style, and perception of social support and provided information regarding self-reported openness to psychosocial services and barriers to using those services. Our analyses identified significant relationships between adult attachment dimensions, distress, perceived social support, and openness to and use of psychosocial services. Distress was significantly associated with openness to and use of psychiatric medication. Perceived social support demonstrated significant mediation effects between attachment anxiety and distress. Similarly, perceived social support demonstrated significant mediation effects in the relationship of elevated depression and high attachment avoidance to use of psychiatric medication. However, significant study limitations may be assumed to have negatively impacted the ability to draw meaningful conclusions from the data. Future research would benefit from further examination of the relationships among adult attachment, distress, perceived social support, and openness to and use of psychosocial services. Clearer understanding the nature of these relationships could guide care providers in being able to more effectively provide services to women who are experiencing significant distress but fail to access services. More effective provision of services and subsequent reduction in distress would likely improve health outcomes.Item Autologous bone marrow transplantation: climbing the dose-response curve(1989-03-30) Fleischman, Roger A.Item Biosimilars in oncology(2020-01-24) Unni, NishaItem Brain metastases: finally a light at the end of this long dark tunnel(2014-06-13) Maher, ElizabethItem Brain tumor(1961-01-19) Eliasson, Sven G.Item Cancer from an unknown primary site(2002-06-13) Dowell, Jonathan E.Item Cancer genetics 2013: seeking meaning in our patients' genomes(2013-03-01) Ross,Theodora S.Item Cancer in children part I: modern medical therapy(1981-07-29) Harrell, AnnItem Cancer in children part II: play therapy(1981-07-29) Harrell, AnnItem The Cancer Specific Ubiquitin Ligase MAGE-A3/6-TRIM28 Drives Tumorigenesis by Ubiquitination and Proteasomal Degradation of AMPK(2015-08-27) Pineda, Carlos Tyler; Yu, Hongtao; Levine, Beth; White, Michael A.; Potts, Patrick RyanThe genes MAGE-A3 and MAGE-A6 (MAGE-A3/6) have a unique expression pattern in which they are normally expressed in the adult testis but are aberrantly expressed in cancer. It is known that when expressed in cancer, MAGE-A3/6 is a negative prognostic indicator and cancer cells are dependent on it for survival. Using the knowledge that MAGE-A3/6 binds and regulates the E3 ubiquitin ligase TRIM28, I investigated its biochemical role in cancer. I used unbiased methods to identify 19 novel substrates of MAGE-A3/6-TRIM28, including the known tumor suppressor AMPK. Ubiquitination of AMPK by MAGE-A3/6-TRIM28 induces its proteasomal degradation, thereby enhancing mTOR signaling and inhibiting autophagy within cells. Through this modulation of AMPK, MAGE-A3/6 is also able to act as an oncogene, inducing anchorage independent growth and the growth of tumors in vivo. Understanding the mechanism by which MAGE-A3/6 acts as an oncogene has revealed potential avenues of therapeutic intervention. Treatment of MAGE-A3/6 expressing cells with AMPK agonists reverses oncogenic properties in vitro. Ultimately, these studies have revealed how a germline protein functions in cancer and the potential points for therapeutic intervention.Item Cancer survivorship care: instructions not included!(2019-08-09) Sadeghi, NavidItem Cancer: the missing gene hypothesis(1988-02-18) Brown, Michael S.Item Congruence of Parent-Report, Self-Report, and Performance-Based Neuropsychological Functioning in Pediatric Acute Lymphoblastic Leukemia Survivors(2017-07-28) Clem, Matthew Alan; Holland, Alice A.; Stavinoha, Peter L.; Cullum, C. Munro; Holm, Suzanne; Lampson, ErinAcute Lymphoblastic Leukemia (ALL) is thought to have long-term cognitive effects, and clinicians often rely on parent report to screen for cognitive impairment during survivorship, despite limited congruence with neuropsychological performance and susceptibility to parental factors such as stress. This study was the first to investigate the moderating effect of parental stress on the congruence between reported child functioning and neuropsychological performance in pediatric ALL. Based on prior literature, performance-based, parent-report, and self-report measures were expected to show significantly worse child functioning compared to norms, with parents expected to report elevated stress compared to norms. Parental stress was expected to moderate the congruence between parent report and neuropsychological performance or self-report, with more stressed parents overestimating child impairment. A relatively large (N=107) sample of pediatric ALL survivors treated on chemotherapy-only protocols completed neuropsychological screening and standardized questionnaires on cognitive, behavioral, and emotional functioning at an annual follow-up visit (minimum six months post-treatment completion). Parents completed standardized questionnaires on child cognitive, behavioral, and emotional functioning; and parental stress and mood. Independent t-tests showed average overall cognitive functioning compared with normative data, but higher-than-expected frequencies of impairment (≤ 2nd percentile) in attention and executive functioning. ANOVA/ANCOVA analyses showed greater methotrexate exposure and younger age of diagnosis are associated with worse attention and processing speed performances. Parental stress and depression were lower than expected, likely indicating good parental adjustment. Correlation analyses revealed low to moderate (r = .21 - .41) congruence between parent report and neuropsychological performance; parent- and self-reported behavioral/emotional functioning were weakly associated. Moderation analyses indicated ratings of parents reporting mild stress were more congruent with neuropsychological performance than ratings of parents reporting no stress (ΔR2 = .05, p < .05), suggesting parents reporting at least some stress are more attuned to subtle aspects of child functioning. Contemporary treatment protocols show generally intact child cognitive functioning, though some are vulnerable to late effects. Parental psychological factors may steer clinicians toward performance-based methods of child assessment. Longitudinal studies with healthy and matched controls are necessary to fully understand the variable course and expression of late cognitive effects in pediatric leukemia survivors.Item A Cytokine Receptor Masked IL-2 Prodrug Selectively Activates Tumor-Infiltrating Lymphocytes for Potent Antitumor Therapy(August 2021) Hsu, Eric Jonathan; Zhang, Chengcheng "Alec"; Farrar, J. David; Malladi, Srinivas; Yan, Nan; Fu, Yang-XinCancers are very difficult to treat, and many cancer patients fail to respond to numerous standard of care therapies. Many of these tumors have been observed to lack functional CD8 T cells, which have been observed to be correlated with improved patient prognosis. One of the main strategies to combat the lack of functional tumor infiltrating immune cells is to treat patients with immune stimulating cytokines such as interleukin-2 (IL-2). As a potent lymphocyte activator, IL-2 is an FDA approved treatment for multiple metastatic cancers. However, its clinical use is limited by short half-life, low potency, and severe in vivo toxicity. Current IL-2 engineering strategies exhibit evidence of peripheral cytotoxicity. Here, limitations of both recombinant IL-2 and these next generation IL-2 variants are addressed through the engineering of a novel IL-2 prodrug (ProIL2). Numerous designs of ProIL2 were designed, engineered, and tested until a final optimal construct was synthesized. The activity of a CD8 T cell-preferential IL-2 mutein/Fc fusion protein is masked with IL2 receptor beta linked to a tumor-associated protease substrate. ProIL2 restores activity after cleavage by tumor-associated enzymes, and preferentially activates inside tumors, where it expands antigen-specific CD8 T cells. This significantly reduces IL-2 toxicity and mortality without compromising antitumor efficacy. ProIL2 also overcomes resistance of cancers to immune checkpoint blockade. Furthermore, neoadjuvant ProIL2 treatment can eliminate metastatic cancer through an abscopal effect. Lastly, ProIL2 can also synergize with radiation therapy to more effectively control both primary and metastatic cancer. Further protein engineering strategies are being implemented to overcome potential limitations of ProIL2. Taken together, this approach presents an effective tumor targeting therapy with reduced toxicity.Item Deciphering AXL-Driven Molecular Mechanisms of EMT(December 2021) Arner, Emily Nicole; Raj, Ganesh V.; Brekken, Rolf A.; Cobb, Melanie H.; Kim, JamesCellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasis and poor outcome. AXL, a receptor tyrosine kinase (RTK), drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer (PDA) and breast cancer. We investigated the contribution of TANK-binding kinase 1 (TBK1) to PDA progression and report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. We identified that the receptor tyrosine kinase AXL induces TBK1 activity in a Ras-RalB-dependent manner. Furthermore, we report that AXL activation stimulates TBK1 binding and phosphorylation of the specific AKT isoform, AKT3 at S472. Activation of AKT3 drives the binding of AKT3 to slug/snail, where the complex is translocated into the nucleus. The binding of AKT3 to slug/snail protects the EMT-TFs from proteasomal degradation thus leading to an increase in EMT. These data suggest that the translocation of AKT3 to the nucleus is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast. These results suggest that selective AKT3 targeting represents a novel therapeutic avenue for treating aggressive cancer that may avoid toxicity associated with pan-AKT inhibition. Additionally, our findings suggest that interruption of the AXL-TBK1-AKT3 cascade, has potential therapeutic efficacy in AXL positive metastatic cancer.