Palliative radiotherapy (PRT) is proven to be effective in palliation of symptoms for end-stage cancer patients. However, little is known about its utilization at the end of life. This research aims to examine the utilization and the practice patterns of PRT at the end of life for cancer patients in British Columbia using population-based data. The pattern observed for PRT1Y dose-fractionation practice in BC are in line with published clinical guidelines and evidence from the literature, which advises “proper” use of PRT in BC as delivered to cancer patients at the end of life. However, after controlling for age, primary cancer site, and survival time, geographic access is found to be significantly associated with PRT1Y utilization. Variations found in PRT1Y rates by geographic access, which is operationalized by the Health Services Delivery Area (HSDA) and travel time, suggests potential underutilization of PRT1Y for patients with suboptimal access. / Graduate / 0992 / 0769 / 0574 / jinhuang@uvic.ca

APLF (Aprataxin and Polynucleotide kinase-Like Factor), a novel protein with a forkhead-associated (FHA) domain and two poly(ADP-ribose)-binding zinc fingers (PBZ), interacts with core non-homologous end-joining (NHEJ) repair factors, Ku and XRCC4-DNA ligase IV, and facilitates NHEJ. However, how APLF functions in NHEJ is undefined. This thesis demonstrates that the Ku-binding domain on APLF is mapped to amino acid residues 180-200, where conserved amino acid residue W189 strongly contributes to the APLF-Ku interaction. Remarkably, the APLF-Ku interaction is involved in the nuclear localization of APLF. Furthermore, we demonstrate that the N-terminal region (amino acids 1-200), containing the XRCC4-Ligase IV and Ku binding domains, is required for APLF- dependent NHEJ. Collectively, these findings suggest that Ku contributes to APLF nuclear localization, and that once APLF is retained in the nucleus, the N-terminal portion of APLF, which facilitates interactions with the core NHEJ proteins Ku and XRCC4-DNA ligase IV, is required for efficient NHEJ.

APLF (Aprataxin and Polynucleotide kinase-Like Factor), a novel protein with a forkhead-associated (FHA) domain and two poly(ADP-ribose)-binding zinc fingers (PBZ), interacts with core non-homologous end-joining (NHEJ) repair factors, Ku and XRCC4-DNA ligase IV, and facilitates NHEJ. However, how APLF functions in NHEJ is undefined. This thesis demonstrates that the Ku-binding domain on APLF is mapped to amino acid residues 180-200, where conserved amino acid residue W189 strongly contributes to the APLF-Ku interaction. Remarkably, the APLF-Ku interaction is involved in the nuclear localization of APLF. Furthermore, we demonstrate that the N-terminal region (amino acids 1-200), containing the XRCC4-Ligase IV and Ku binding domains, is required for APLF- dependent NHEJ. Collectively, these findings suggest that Ku contributes to APLF nuclear localization, and that once APLF is retained in the nucleus, the N-terminal portion of APLF, which facilitates interactions with the core NHEJ proteins Ku and XRCC4-DNA ligase IV, is required for efficient NHEJ.

This thesis demonstrates relations among health, social network, ADL and patterns of care in the oldest old guided by a resource theoretical model. The analyzed data are based on two studies: the Nona study, a longitudinal study of 157 individuals aged 86 to 94 years, and the H70 study, a longitudinal study of 964 individuals aged 70 at baseline. Data were collected by interviews and to some extent in the H70 study, medical exams and medical records. The results demonstrate that perceived resources seem to affect patterns of care to a higher extent than the more objective resources in the sample of the oldest old. On the other hand, sociodemographic variables such as gender, marital status and SES, in addition to the more objective resources of having children nearby and the number of symptoms of illness predicted institutionalization during a subsequent 30-year period from the age of 70. The proportion of elderly persons’ institutionalization was further significantly higher than that generally found in cross-sectional studies. ADL was one of the strongest predictors for both use of formal care and institutionalization in both samples, indicating an effective targeting of the formal care system in Sweden. The care at end of life in the oldest old is challenged by the problems with progressive declines in ADL and health, which makes it hard to fit in the dying oldest old in the palliative care system. There is a need to increase the knowledge and the possibility for care staff to support and encourage social network factors and for decision-making staff to consider factors beyond ADL.

PhD / Introduction Kidney transplantation confers both survival and quality of life advantages over dialysis for most people with end-stage kidney disease (ESKD). The mortality rate on dialysis is 10-15% per year, compared with 2-4% per year post-transplantation. Short-term graft survival is related to control of the acute rejection process, requiring on-going immunosuppression. Most current immunosuppressive algorithms include one of the calcineurin inhibitors (CNI: cyclosporin or tacrolimus), an anti-metabolite (azathioprine or mycophenolate) and corticosteroids, with or without antibody induction agents (Ab) given briefly peri-transplantation. Despite this approach, between 15-35% of recipients undergo treatment for an episode of acute rejection (AR) within one year of transplantation. Transplantation is not without risk, and relative mortality rates for kidney recipients after the first post-transplant year remain 4-6 times that of the general population. Longer-term transplant and recipient survival are related to control of chronic allograft nephropathy (rooted in the interplay of AR, non-immunological factors, and the chronic nephrotoxicity of CNI) and limitation of the complications of chronic ESKD and long-term immunosuppression: cardiovascular disease, cancer and infection, which are responsible for 22%, 39% and 21% of deaths respectively. This thesis is presented as published works on the theme of immunosuppression and cancer after kidney transplantation. The work presented in the first chapters of this thesis has striven to identify, evaluate, synthesise and distil the entirety of evidence available of new and established immunosuppressive drug agents through systematic review of randomised trial data, with particular emphasis on quantifying harms of treatment. The final chapters use inception cohort data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which is first validated then used to explore the risk of cancer in more detail than was possible from trial data alone. Interleukin 2 receptor antagonists Interleukin-2 receptor antagonists (IL2Ra, commercially available as basiliximab and daclizumab) are humanised or chimeric IgG monoclonal antibodies to the alpha subunit of the IL2 receptor present only on activated T lymphocytes, and the rationale for their use has been as induction agents peri-transplantation. Introduced in the mid-1990s, IL2Ra use has increased globally, and by 2003 38% of new kidney transplant recipients in the United States and 25% in Australasia received an IL2Ra. This study aimed to systematically identify and synthesise the evidence of effects of IL2Ra as an addition to standard therapy, or as an alternative to other induction agents. We identified 117 reports from 38 randomised trials involving 4893 participants. Where IL2Ra were compared with placebo (17 trials; 2786 patients), graft loss was not different at one (Relative Risk -RR 0.84; 0.64 to 1.10) or 3 years (RR 1.08; 0.71 to1.64). AR was reduced at 6 months (RR 0.66; 0.59 to 0.74) and at 1 year (RR 0.66; 0.59 to 0.74) but cytomegalovirus (CMV) disease (RR 0.82; CI 0.65 to 1.03) and malignancy (RR 0.67; 0.33 to1.36) were not different. Where IL2Ra were compared with other antibody therapy no significant differences in treatment effects were demonstrated, but IL2Ra had significantly fewer side effects. Given a 40% risk of rejection, 7 patients would need treatment with IL2Ra in addition to standard therapy, to prevent 1 patient having rejection, with no definite improvement in graft or patient survival. There was no apparent difference between basiliximab and daclizumab. Tacrolimus versus cyclosporin for primary immunosuppression There are pronounced global differences in CNI use; 63% of new kidney transplant recipients in the USA but only 22% in Australia receive tacrolimus as part of the initial immunosuppressive regimen. The side effects of CNI differ: tacrolimus is associated more with diabetes and neurotoxicity, but less with hypertension and dyslipidaemia than cyclosporin, with uncertainty about equivalence of nephrotoxicity or how these relate to patient and graft survival, or impact on patient compliance and quality of life. This study aimed to systematically review and synthesise the positive and negative effects of tacrolimus and cyclosporin as initial therapy for renal transplant recipients. We identified 123 reports from 30 randomised trials involving 4102 participants. At 6 months graft loss was reduced in tacrolimus-treated recipients (RR 0•56; 0•36 to 0•86), and this effect persisted for 3 years. The relative reduction in graft loss with tacrolimus diminished with higher levels of tacrolimus (P=0.04), but did not vary with cyclosporin formulation (P=0.97) or cyclosporin level (P=0.38). At 1 year, tacrolimus patients suffered less AR (RR 0•69; 0•60 to 0•79), and less steroid-resistant AR (RR 0•49; 0•37 to 0•64), but more insulin-requiring diabetes (RR 1•86; 1•11 to 3•09), tremor, headache, diarrhoea, dyspepsia and vomiting. The relative excess in diabetes increased with higher levels of tacrolimus (P=0.003). Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Treating 100 recipients with tacrolimus instead of cyclosporin for the 1st year post-transplantation avoids 12 suffering acute rejection and 2 losing their graft but causes an extra 5 to become insulin dependent diabetics, thus optimal drug choice may vary among patients. Target of rapamycin inhibitors for primary immunosuppression Target of rapamycin inhibitors (TOR-I) are among the newest immunosuppressive agents and have a novel mode of action but uncertain clinical role. Sirolimus is a macrocyclic lactone antibiotic and everolimus is a derivative of sirolimus. Both prevent DNA synthesis resulting in arrest of the cell cycle. Animal models suggested TOR-I would provide synergistic immunosuppression when combined with CNI, but early clinical studies demonstrated synergistic nephrotoxicity. Since then diverse trials have explored strategies that avoid this interaction and investigated other potential benefits. The aim of this study was to systematically identify and synthesise available evidence of sirolimus and everolimus when used in initial immunosuppressive regimens for kidney recipients. We identified 142 reports from 33 randomised trials involving 7114 participants, with TOR-I evaluated in four different primary immunosuppressive algorithms: as replacement for CNI, as replacement for antimetabolites, in combination with CNI at low and high dose, and with variable dose of CNI. When TOR-I replaced CNI (8 trials, 750 participants), there was no difference in AR (RR 1.03; 0.74 to 1.44), but creatinine was lower (WMD -18.31 umol/l; -30.96 to -5.67), and bone marrow more suppressed (leucopoenia RR 2.02; 1.12 to 3.66, thrombocytopenia RR 6.97; 2.97 to 16.36, anaemia RR 1.67; 1.27 to 2.20). When TOR-I replaced antimetabolites (11 trials, 3966 participants), AR and CMV were reduced (RR 0.84; 0.71 to 0.99 and RR 0.49; 0.37 to 0.65) but hypercholesterolaemia was increased (RR 1.65; 1.32 to 2.06). When low was compared to high-dose TOR-I, with equal CNI dose (10 trials, 3175 participants), AR was increased (RR 1.23; 1.06 to 1.43) but GFR higher (WMD 4.27 ml/min; 1.12 to 7.41). When low-dose TOR-I and standard-dose CNI were compared to higher-dose TOR-I and reduced CNI AR was reduced (RR 0.67; 0.52 to 0.88), but GFR also reduced (WMD -9.46 ml/min; -12.16 to -6.76). There was no significant difference in mortality, graft loss or malignancy risk demonstrated for TOR-I in any comparison. Generally surrogate endpoints for graft survival favoured TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes were worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust randomised trials are still needed. Monoclonal and polyclonal antibody therapy for treating acute rejection Strategies for treating AR include pulsed steroids, an antibody (Ab) preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the USA 61.4% of patients with AR received steroids, 20.4% received Ab and 18.2% received both. The Ab available for AR are not new: horse and rabbit derived polyclonal antibodies (ATG and ALG) have been used for 35 years, and a mouse monoclonal antibody (muromonab-CD3) became available in the late 1980s. These preparations remove the functional T-cell population from circulation, producing powerful saturation immunosuppression which is useful for AR but which may be complicated by immediate toxicity and higher rates of infection and malignancy. The aim of this study was to systematically evaluate and synthesise all evidence available to clinicians for treating AR in kidney recipients. We identified 49 reports from 21 randomised trials involving 1394 participants. Outcome measures were inconsistent and incompletely defined across trials. Fourteen trials (965 patients) compared therapies for 1st AR episodes (8 Ab versus steroid, 2 Ab versus another Ab, 4 other comparisons). In treating first rejection, Ab was better than steroid in reversing AR (RR 0.57; CI 0.38 to 0.87) and preventing graft loss (RR 0.74; CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection (RR 0.67; CI 0.43 to 1.04) or death (RR 1.16; CI 0.57 to 2.33) at 1 year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection (4 Ab vs another Ab, 1 different doses Ab, 1 different formulation Ab, 2 other comparisons). There was no benefit of muromonab-CD3 over ATG or ALG in reversing rejection (RR 1.32; CI 0.33 to 5.28), preventing subsequent rejection (RR 0.99; CI 0.61 to 1.59), graft loss (RR 1.80; CI 0.29 to 11.23) or death (RR 0.39; CI 0.09 to 1.65). Given the clinical problem caused by AR, comparable data are sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed. Validity of cancer data in an end stage kidney disease registry Registries vary in whether the data they collect are given voluntarily or as a requirement of law, the completeness of population coverage, the breadth of data collected and whether data are assembled directly or indirectly through linkage to other databases. Data quality is crucial but difficult to measure objectively. Formal audit of ANZDATA cancer records has not previously taken place. The aim of this study was to assess agreement of records of incident cancer diagnoses held in ANZDATA (voluntary reporting system) with those reported under statute to the New South Wales (NSW) state Central Cancer Registry (CCR), to explore the strengths and weaknesses of both reporting systems, and to measure the impact of any disagreement on results of cancer analyses. From 1980-2001, 9453 residents received dialysis or transplantation in NSW. Records from ANZDATA registrants were linked to CCR using probabilistic matching and agreement between registries for patients with 1 or more cancers, all cancers and site-specific cancer was estimated using the kappa-statistic (κ). ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%), with κ =0.76. ANZDATA had sensitivity 77.3% (CI 74.2 to 80.2), specificity 98.1% (CI 97.7 to 98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses whilst receiving dialysis (κ =0.78) or after transplantation (κ =0.79), but varied by cancer type. Melanoma (κ =0.61) and myeloma (κ =0.47) were less good; lymphoma (κ =0.80), leukaemia (κ =0.86) and breast cancer (κ =0.85) were very good. Artefact accounted for 20.8% non-concordance but error and misclassification did occur in both registries. Cancer risk did not differ in any important way whether estimated using ANZDATA or CCR records. Quality of cancer records in ANZDATA are high, differences largely explicable, and seem unlikely to alter results of analyses. Risk of cancer after kidney transplantation Existing data on the magnitude of excess risk of cancer across different kidney recipient groups are sparse. Quantifying an individual transplant candidate’s cancer risk informs both pre-transplant counselling, treatment decisions and has implications for monitoring, screening and follow-up after transplantation. The aims of this study were firstly to establish the risk of cancer in the post-transplant population compared to that experienced by the general population, and secondly to quantify how excess risk varied within the transplanted population, seeking to establish meaningful absolute risk estimates for post-transplant cancer based on unalterable recipient characteristics known a priori at the time of transplantation. 15,183 residents of Australia and New Zealand had a transplant between 1963 and 2004, and were followed for a median of 7.2 years (130,186 person-years), with 1642 (10.8%) developing cancer. Overall, kidney recipients had 3 times the cancer risk, with risk inversely related to age (Standardised Incidence Ratio of 15 to 30 in children reducing to 2 in people > 65 years). Female recipients aged 25 -29 had rates of cancer (779.2/100,000) equivalent to women aged 55 - 59 from the general population. The risk pattern of lymphoma, colorectal and breast cancer was similar to the overall age trend, melanoma showed less variability across ages and prostate cancer showed no risk increase. Within the transplanted population cancer risk was affected by age differently for each sex (P=0.007), and was elevated for recipients with prior non-skin malignancy (Hazard Ratio: HR 1.40; 1.03 to 1.89), of white race (HR 1.36; 1.12 to 1.89), but reduced for those with diabetic ESKD (HR 0.67; 0.50 to 0.89) Rates of cancer in kidney recipients were similar to non-transplanted people 20 -30 years older, but risk differed across patient groups. Men aged 45 - 54 at transplantation with graft function at 10 years had a risk of cancer that varied from 1 in 13 (non-white, diabetic ESKD, no prior cancer) to 1 in 5 (white, prior cancer, ESKD from other causes).

Over the last few decades, the importance of inflammation in the initiation and perpetuation of cardiovascular (CV) disease has become increasingly recognized. Patients with Rheumatoid Arthritis (RA) have been shown to have an increased risk of premature death, occurring predominantly due to an increased rate of premature CV disease. The presence of an adverse risk factor profile in RA is well established, but does not fully explain the excess risk. It is clear that chronic inflammation is a major pathogenic mechanism in atherosclerosis, and this is likely to explain at least some of the increased risk of CV disease in subjects with RA. Carotid intima-media thickness (cIMT) measured by ultrasound, is a good non-invasive approach to measurement of atherosclerotic burden, and is increased in preclinical atherosclerotic disease. cIMT is significantly higher in patients with RA than age and sex matched controls. The Receptor for Advanced Glycation End Products (RAGE) may be important for the perpetuation of chronic inflammation. This cell surface receptor molecule is upregulated at sites of chronic vascular inflammation, and can be signalled by a range of proinflammatory ligands as well as advanced glycation end-products. The gene has a number of polymorphisms, and the Glycine 82 Serine polymorphism has a prevalence of about 10% in Caucasians. Patients with RA are more likely to have this polymorphism than control subjects, as the gene is in linkage disequilibrium with DRB1*0401, one of the RA susceptibility alleles. There is evidence that ligation of RAGE in monocytes derived from donors with the Ser 82 allele signals an enhanced NF-kB and p38 MAP Kinase cellular response, associated with production of pro-inflammatory cytokines. In this study, I hypothesized an association between the RAGE 82 Ser polymorphism of this receptor, which is enriched in RA, and the risk of CV disease in subjects with RA. To investigate whether RAGE 82Ser is associated with CV disease in RA, I examined events, risk factors, features of RA and RAGE 82Ser, in 232 patients with RA attending a tertiary referral hospital. Carotid intima-media thickness was measured using carotid duplex scanning in 137 of those patients. CV events, duration and severity of RA, and CV disease risk factors were determined using patient questionnaires, chart review, laboratory analysis, and radiographs. DNA was typed for HLA-DRB1 genes and the RAGE 82Ser polymorphism. Twenty percent of patients carried the RAGE 82Ser allele. More than 20% of the cohort had suffered a vascular event. Increasing age, elevated fasting glucose, a history of hypercholesterolemia, and a shorter duration of RA were significantly associated with events. RAGE 82Ser was protective against CV events in this cohort. RA patients with RAGE 82Ser had lower LDL levels and LDL/HDL ratio. cIMT was independently and significantly associated with increasing age, male sex, hypertension, low BMI, and the number of pack years of smoking, but not RAGE genotype. Multiple factors, both CV and RA disease-related, contribute to atherosclerosis in established RA. These data suggest RAGE genotype may contribute to the risk of CV events in RA. The role of RAGE genotype requires further study in inception cohorts examining CV events to better understand its contribution to RA-associated CV disease.

Thesis (Ph. D.)--Computing, Georgia Institute of Technology, 2007. / Committee Chair: Dovrolis, Constantine; Committee Member: Ammar, Mostafa; Committee Member: Schwan, Karsten; Committee Member: Steenkiste, Peter; Committee Member: Zegura, Ellen.

Zugl.: München, Univ., Diss., 2006

Thesis (Ph.D.)--Drexel University, 2009. / Includes abstract and vita. Includes bibliographical references (leaves 108-114).

Thesis (M.Dev.Stud.)--Victoria University of Wellington, 2009. / Includes bibliographical references.