Class of 2013 Abstract / Specific Aims: To describe the outcomes of olanzapine in the treatment of refractory chemotherapy-induced nausea and vomiting (CINV). Methods: Data were collected regarding demographic information, chemotherapy regimen, CINV prophylaxis, rescue antiemetics, and olanzapine usage for subjects, age 18-79, who were admitted to the University of Arizona Medical Center for chemotherapy and received at least one dose of olanzapine for CINV between January 2008 and January 2012. The primary outcome measure was the number of rescue antiemetics required following the first dose of olanzapine (greater than 10 doses was considered treatment failure). Comparisons using chi square to determine if differences existed with respect to the level of chemotherapy emetogenicity and demographic information were conducted. Main Results: No statistical difference between chemotherapy regimens of high versus low-to-moderate emetogenicity was seen (P=0.79). However, 7 of 10 (70%) subjects receiving highly emetogenic chemotherapy achieved success and 15 of 23 (65%) subjects receiving low-to-moderately emetogenic chemotherapy achieved success. No statistical differences appeared when evaluating usage of 1 versus 2 or more prophylactic antiemetics (P=0.77), men versus women (P=0.08), and age over 50 versus 50 years or younger (P<0.99). Conclusion: This study demonstrated a trend towards greater emetic control with the addition of olanzapine in patients failing first-line antiemetic pharmacotherapy. Additionally, a trend towards greater emetic control was seen in women. The rates of success among all groups may suggest benefit to adding olanzapine to subjects experiencing refractory CINV. Due to the limited sample size and retrospective methodology of the study, the use of olanzapine in refractory CINV merits further research with large, prospective studies directly comparing addition of olanzapine to other appropriate antiemetics.

Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters. Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The Xc⁻ amino acid transporter (Xc⁻) mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the Xc⁻ has been regulates the growth of various cancer cell types, and Xc⁻ is expressed in the pancreas, I postulated that the Xc⁻ may be involved in growth and drug resistance in PC. The Xc⁻ transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. Using PC cell lines, I found that cystine uptake via the Xc⁻ was required for growth and survival in response to oxidative stress, and that expression of the Xc⁻ correlated with gemcitabine resistance. Accordingly, inhibition of Xc⁻ expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the Xc⁻, which acts to inhibit cell proliferation via reducing Xc⁻ activity and not by reducing NFKB activity. My findings thus indicate that the Xc⁻ plays a role in PC growth in partby contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate

The stability constants for the ligand 1-hydroxyl-3-aminopropilydene diphosphonic acid (APD) or Pamidronate with metal ions CdII, PbII and ZnII were established in this work by sampled direct current polarography (DCTAST). Due to precipitation of the metal-ligand complexes in the pH range about 4.0 to 5.0 at typical glass electrode potentiometric conditions, these systems could not be studied by glass electrode potentiometry (GEP). The concept of Virtual Potentiometry (VP) was used in the modelling of the metal-ligand system and refinement of stability constants to evaluate further the metal-ligand models derived from DCTAST. Virtual potentiometry uses virtual potentials to refine polarographic data by employing dedicated potentiometric software, ESTA. The structure of the metal complexes determined in this work is also proposed and compared to the reported crystal structures of the metal complexes of the ligand APD. The Linear Free Energy Relationship, LFER (log KML′ vs. log KM(OH) ) for the ligand APD is derived here for the first time using the log KML′ values from literature as well as the values for CdII, PbII and ZnII determined in this work. The log KML′ values of 153SmIII–APD and 166HoIII–APD, which cannot be determined by these two techniques (GEP and DCTAST), were predicted in this work using the LFER methodology. / Dissertation (MSc (Chemistry))--University of Pretoria, 2006. / Chemistry / MSc / Unrestricted

Background: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. Methods: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998–2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. Results: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20–74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Background. Clear cell sarcoma of the kidney (CCSK) is known for its propensity to metastasize to bone, but it also spreads to other sites including the brain. This study was undertaken to describe the treatment and outcomes of patients with recurrent CCSK involving the brain. Methods. A retrospective records review was conducted on eight patients with CCSK who developed brain metastases after complete responses to initial therapy. Results. The recurrences occurred at a median of 24.5 months after initial diagnosis (range, 12-53 months). At the time of recurrence, patients were treated with multimodal therapy including biopsy or resection, radiation therapy, and chemotherapy. All patients received a variable number of courses of ifosfamide, carboplatin, and etoposide (ICE), with or without other agents. Four patients received high-dose chemotherapy with autologous stem cell rescue. One patient died from complications of bacteremia 8 weeks after starting chemotherapy. The other seven patients achieved a complete response after either surgery or ICE chemotherapy. Of these, six patients were alive without disease with a median follow-up of 30 months from the time of recurrence (range, 24 to 71 months). All six survivors received radiation therapy and four had gross total resections. Three survivors received high-dose chemotherapy with stem cell rescue. Conclusion. Patients with recurrent CCSK involving the brain can have durable survival after recurrence. ICE chemotherapy, together with radiation therapy and surgery, provides a reasonable salvage regimen for recurrent CCSK. It is unclear whether high-dose chemotherapy confers a benefit compared to conventional-dose chemotherapy.

Student Number : 9411363J - PhD thesis - School of Medicine - Faculty of Health Sciences / This study on non-compliance with chemotherapy in the oncology patient with a good prognosis was done in the Johannesburg Hospital in South Africa. 114 compliant and 33 non compliant oncology patients with a good prognosis showed significant differences (at the 5% level) on the MCMI2 on the following scales: Disclosure, Debasement, Avoidance, Passive Aggressive, Self-defeating, Schizotypal, Anxiety, Dysthymia, Alcohol Dependence and Major Depression. In a Linear Discriminant Function Analysis . two variables, Debasement and Schizotypal were selected that linearly affected compliance significantly. A linear discriminant model was constructed from the two variables which could predict non compliance in these patients 72.5% of the time. The next step was to construct a treatment model , an intervention which would have some impact on improving compliance. After trial and error with various methods, a Medical Trauma Debriefing Model was worked out and used, based on the Wits Trauma Intervention Model, which up to this time had been used for trauma debriefing of people who had experienced trauma due to violence and abuse on a criminal or political level. This is in accordance with recent studies which are beginning to show the link between PTSD and medical non-compliance. It is suggested that Medical Trauma Debriefing, as a preventative measure, be incorporated automatically and routinely into the treatment of certain medical and surgical conditions, especially in Oncology.

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The aim of this study was to investigate the mechanisms of action of and development of cellular resistance to various anticancer agents in human (HeLa) cells using a combined genetic and biochemical approach. The agents employed for this purpose included: the purine nucleoside analogues, toyocamycin, tubercidin, and 6-methyl-mercaptopurine riboside (6-MeMPR); the protein synthesis inhibitor, puromycin; and the microtubule stabilizer, taxol. To investigate the mechanisms of action and cellular resistance to the purine nucleoside analogues, stable first-step toyocamycin, tubercidin and 6-MeMPR resistant HeLa mutants were isolated. These mutants exhibited high degrees of resistance and cross-resistance to various adenosine kinase-activated nucleoside analogues, possessed <2% of the adenosine kinase activity of parental HeLa cell extracts and exhibited severely reduced cellular uptake and macromolecular incorporation of adenosine in vivo. These results indicate that in human cells the cytotoxic effects of toyocamycin, tubercidin and 6-MeMPR are dependent upon adenosine kinase-catalyzed phosphorylation of these drugs to their respective monophosphates and that resistance to these agents results from a deficiency in adenosine kinase activity in vivo. Further insight into the nature of the genetic and biochemical alteration(s) affecting adenosine kinase in these mutants was achieved using SDS-polyacryamide gel electrophoretic and immunoblot analysis. Immunoblots -revealed that each toyocamycin, tubercidin and 6-MeMPR resistant mutant contained similar amounts of cross-reacting material that had the same electrophoretic mobility as adenosine kinase in parental HeLa cells. Therefore, the lesion in these mutants must be a missense type of alteration in the structural gene for adenosine kinase. The utility of the 6-MeMPR resistant mutant selection system for quantitative mutagenesis studies was also investigated. Numerous favourable attributes appropriate to mutagenesis studies were found using this selection system. These included: the obtainment of highly resistant mutants which were stable in the absence of drug, the absence of cell density or cross-feeding effects in the selection system, maximum phenotypic expression required a relatively short time period and mutagen treatment increased the mutant frequency in a linear dose-dependent manner. Thus, selection for genetic alterations at the adenosine kinase locus appears to provide a valuable system for quantitative mutagenesis studies in human cells. The combined genetic and biochemical approach was also used to investigate the development of resistance to puromycin and taxol. Therefore, first-and second-step mutants resistant to each of these drugs were selected and characterized. Cross-resistance and uptake studies with the puromycin resistant mutants suggest that the most common -mechanism for the development of cellular resistance to puromycin in human (HeLa) cells involves an alteration in membrane permeability that reduces drug uptake/transport. Similar studies with the taxol resistant mutants suggest the existence of two possible mechanisms for the development of resistant to this agent in human (HeLa) cells. One mechanism involves a biochemical lesion that specifically affects a microtubule-related cellular component. The second mechanism, however, nonspecifically affects cellular membrane permeability and results in reduced drug uptake/transport. / Thesis / Master of Science (MS)