Investigating the breast cancer screening-treatment-mortality pathway of women diagnosed with invasive breast cancer: Results from linked health data.

OBJECTIVE: To examine the screening-treatment-mortality pathway among women with invasive breast cancer in 2006-2014 using linked data. METHODS: BreastScreen histories of South Australian women diagnosed with breast cancer (n = 8453) were investigated. Treatments recorded within 12 months from diagnosis were obtained from linked registry and administrative data. Associations of screening history with treatment were investigated using logistic regression and with cancer mortality outcomes using competing risk analyses, adjusting for socio-demographic, cancer and comorbidity characteristics. RESULTS AND CONCLUSION: For screening ages of 50-69 years, 70% had participated in BreastScreen SA ≤ 5 years and 53% ≤ 2 years of diagnosis. Five-year disease-specific survival post-diagnosis was 90%. Compared with those not screened ≤5 years, women screened ≤2 years had higher odds, adjusted for socio-demographic, cancer and comorbidity characteristics, and diagnostic period, of breast-conserving surgery (aOR 2.5, 95% CI 1.9-3.2) and radiotherapy (aOR 1.2, 95% CI 1.1-1.3). These women had a lower unadjusted risk of post-diagnostic cancer mortality (SHR 0.33, 95% CI 0.27-0.41), partly mediated by stage (aSHR 0.65, 95% CI 0.51-0.81), and less breast surgery (aSHR 0.78, 95% CI 0.62-0.99). Screening ≤2 years and conserving surgery appeared to have a greater than additive association with lower post-diagnostic mortality (interaction term SHR 0.42, 95% CI 0.23-0.78). The screening-treatment-mortality pathway was investigated using linked data.

Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice.

Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice. Herein we report that the tolerance defect is revealed by TLR7 and TLR9 as well as TLR4 ligands, with additive effect, and is partially reversed by Mek inhibition. Gene expression analysis reveals significant differences in transcription of multiple TLR pathway genes and ptpn22 in stimulated NZB compared to B6 B cells. Additionally, the defect is detected in Ig transgenic NZB F1 hybrid strains (NZBxNZW)F1 and (B6xNZB)F1. These results implicate an inherited defect wherein NZB anergic B cells maintain coordinated TLR/BCR signaling that permits autoantibody production. Agents targeting these pathways may have therapeutic benefit in the subset of lupus patients that manifest similar defects in B-cell regulation.

Comparison of the clinical effectiveness of different off-loading devices for the treatment of neuropathic foot ulcers in patients with diabetes: a systematic review and meta-analysis.

Effective off-loading is considered to be an important part of the successful clinical management of diabetic foot ulcers. The aim of this systematic review is to investigate the safety and effectiveness of different off-loading devices for the treatment of diabetic foot ulcers. The medical literature was extensively searched from January 1966 to May 2012. Systematic reviews and controlled studies that compared the use of different off-loading devices formed the evidence base. Studies were critically appraised to determine their risk of methodological bias, and data were extracted. Results were pooled using random effects meta-analysis and tested for heterogeneity. When compared with removable devices, non-removable off-loading devices were found, on average, to be more effective at promoting the healing of diabetic foot ulcers (RRp = 1.43; 95% CI 1.11, 1.84; I(2) = 66.9%; p = 0.001; k = 10). Analysis, stratified by type of removable device, did not detect a statistically significant difference between non-removable off-loading devices and removable cast walkers; however, on average non-removable off-loading devices performed better than therapeutic shoes at promoting the healing of diabetic foot ulcers (RRp = 1.68; 95% CI 1.09, 2.58; I(2) = 71.5%; p = 0.004; k = 6). The two types of non-removable off-loading devices i.e. total contact casts and instant total contact casts (removable cast walker rendered irremovable by securing with bandage or lace), were found to be equally effective (RRp = 1.06; 95% CI 0.88, 1.27; I(2) = 3.3%; p = 0.31; k = 2). In conclusion, non-removable off-loading devices regardless of type, are more likely to result in ulcer healing than removable off-loading devices, presumably because patient compliance with off-loading is facilitated.

Carcinosarcomas of the Uterus: Prognostic Factors and Impact of Adjuvant Treatment.

BACKGROUND: Uncertainties remain about the most effective treatment for uterine carcinosarcoma (UCS), a rare but aggressive uterine cancer, due to the limited scope for randomized trials. This study investigates whether nodal excision or adjuvant therapies after hysterectomy offer a survival benefit, using multi-institutional clinical registry data from South Australia. METHODS: Data for all consecutive cases of UCS from 1980 to 2019 were extracted from the Clinical Cancer Registry. Clinical and treatment-related factors associated with disease-specific mortality (DSM) and all-cause mortality (ACM) were determined using multivariable Cox proportional hazards regression, with subgroup analyses by stage. RESULTS: Median follow-up for the 140 eligible cases was 21 months. 94% underwent hysterectomy, and 72% had an additional pelvic lymph node dissection (PLND). Furthermore, 16% received adjuvant chemotherapy; 11% adjuvant radiotherapy and 16% multimodal chemoradiotherapy, with an increase in the latter two modalities over time. DSM was reduced among those who underwent PLND (HR: 0.41; 95%CI: 0.23-0.74), adjuvant chemotherapy (HR: 0.39; 95%CI: 0.18-0.84) or multimodality treatment (HR: 0.11; 95%CI: 0.06-0.30) compared with hysterectomy alone for the whole cohort and for late stage disease (FIGO III/IV) but not for earlier stage disease, except for reduced DSM with multimodal therapy. Findings were similar for ACM. CONCLUSION: Our findings indicate better survival among those who received PLND, chemotherapy and multimodal adjuvant therapy, with the latter applying to early and late stage disease. However, cautious interpretation is warranted, due to potential "indication bias" and limited power. Further research into effective treatment modalities, ideally using prospective study designs, is needed.

Associations between markers of health and playing golf in an Australian population.

OBJECTIVE: To investigate associations between markers of health and playing golf in an Australian population. METHODS: Secondary analysis of data from the Australian National Nutrition and Physical Activity Survey to compare selected health outcomes between golfers (n=128) and non-golfers (n=4999). RESULTS: Golfers were older than non-golfers (mean±SD 57.7±14.2 years, 48.5±17.6 years, p<0.05). A higher proportion of golfers were overweight or obese compared with non-golfers (76% vs 64%, p<0.05), and golfers were more likely to have been diagnosed with ischaemic heart disease (IHD) at some time in their life (OR 2.8, 95% CI 1.0 to 7.8). However, neither the risk of being overweight or obese (OR 1.4, 95% CI 0.9 to 2.2) or having been diagnosed with IHD (OR 2.1, 95% CI 0.8 to 5.8), were significant after controlling for age. Golfers were more physically active than non-golfers (8870±3810 steps/day vs 7320±3640 steps/day, p<0.05) and more likely to report high health-related quality of life (HRQoL) than non-golfers (OR 1.8; 95% CI 1.0 to 3.3), but not after adjusting for physical activity (OR 1.4, 95% CI 0.9 to 2.2). CONCLUSION: Compared with non-golfers, golfers were more likely to be overweight or obese and to have been diagnosed with IHD, but not after adjusting for golfers being older. Golfers were more likely to report a higher HRQoL, but not after adjusting for golfers being more physically active. There may be an association between golfers being more physically active than non-golfers and reporting a higher HRQoL.

Lutein Intake and Blood Lutein Concentration Are Positively Associated with Physical Activity in Adults: A Systematic Review.

Lutein is a carotenoid that reduces the risk of some chronic diseases, possibly by altering physical activity behavior. The objective of this study was to conduct a systematic review of studies examining the relationship between lutein status (dietary intake/blood concentration) and physical activity. Peer-reviewed studies published in Medline, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Embase were included if they reported a measure of association between lutein status and physical activity. Seventeen studies met the inclusion criteria. Eleven reported positive associations, three reported mixed results, and three reported no association. Two studies used objective measures of lutein status (blood concentration) and physical activity (accelerometry) and reported positive associations, with correlations of ≥0.36 and differences of ≥57% in physical activity between upper and lower tertiles. Studies using self-report measures reported weaker correlations (r = 0.06 to 0.25), but still more physical activity (18% to ≥600% higher) in those with the highest compared with the lowest lutein status. Higher lutein status may be associated with higher levels of physical activity, which may contribute to a reduced risk of chronic disease.

Uncommon structural motifs dominate the antigen binding site in human autoantibodies reactive with basement membrane collagen.

Autoantibodies mediate organ destruction in multiple autoimmune diseases, yet their origins in patients remain poorly understood. To probe the genetic origins and structure of disease-associated autoantibodies, we engrafted immunodeficient mice with human CD34+ hematopoietic stem cells and immunized with the non-collagenous-1 (NC1) domain of the alpha3 chain of type IV collagen. This antigen is expressed in lungs and kidneys and is targeted by autoantibodies in anti-glomerular basement membrane (GBM) nephritis and Goodpasture syndrome (GPS), prototypic human organ-specific autoimmune diseases. Using Epstein Barr virus transformation and cell fusion, six human anti-alpha3(IV)NC1 collagen monoclonal autoantibodies (mAb) were recovered, including subsets reactive with human kidney and with epitopes recognized by patients' IgG. Sequence analysis reveals a long to exceptionally long heavy chain complementarity determining region3 (HCDR3), the major site of antigen binding, in all six mAb. Mean HCDR3 length is 25.5 amino acids (range 20-36), generated from inherently long DH and JH genes and extended regions of non-templated N-nucleotides. Long HCDR3 are suited to forming noncontiguous antigen contacts and to binding recessed, immunologically silent epitopes hidden from conventional antibodies, as seen with self-antigen crossreactive broadly neutralizing anti-HIV Ig (bnAb). The anti-alpha3(IV)NC1 collagen mAb also show preferential use of unmutated variable region genes that are enriched among human chronic lymphocytic leukemia antibodies that share features with natural polyreactive Ig. Our findings suggest unexpected relationships between pathogenic anti-collagen Ig, bnAb, and autoreactive Ig associated with malignancy, all of which arise from B cells expressing unconventional structural elements that may require transient escape from tolerance for successful expansion.

The utility of linked cancer registry and health administration data for describing system-wide outcomes and research: a BreastScreen example.

RATIONALE, AIMS AND OBJECTIVES: Stratification of women with screen-detected ductal carcinoma in situ (DCIS) by risk of subsequent invasive breast cancer (IBC) could assist treatment planning and selection of surveillance protocols that accord with risk. We assessed the utility of routinely collected administrative data for stratifying by IBC risk following DCIS detection in a population-based screening programme to inform ongoing surveillance protocols. METHODS: A retrospective cohort design was used, employing linked data from the South Australian breast screening programme and cancer registry. Women entered the study at screening commencement and were followed until IBC diagnosis, death or end of the study period (1 December 2010), whichever came first. Routinely collected administrative data were analyzed to identify predictors of invasive breast cancer. RESULTS: Proportional hazards regression confirmed that the DCIS cohort had an elevated risk of IBC after adjustment for relevant confounders (HR = 4.0 (95% CL 3.4, 4.8)), which accorded with previous study results. Within the DCIS cohort, conservative breast surgery and earlier year of screening commencement were both predictive of an elevated invasive breast cancer risk. CONCLUSIONS: These linked cancer registry and administrative data gave plausible estimates of IBC risk following DCIS diagnosis, but were limited in coverage of key items for further risk stratification. It is important that the research utility of administrative datasets is maximized in their design phase in collaboration with researchers.