Emerging treatments for recurrent prostate cancer

Despite radical treatment, many men with prostate cancer will develop recurrence of their disease. In an exciting era of new therapies for prostate cancer in general, we focus on how these will specifically benefit those men with recurrent disease. We consider salvage treatments aimed at those with local recurrence confined to the prostate gland, therapies for those presenting with metastatic recurrence and the approach to men presenting with a rising prostate-specific antigen but no demonstrable disease (M0). In general, men with recurrent disease are often under-represented in randomized clinical trials. Consequently, evidence to guide treatment for these men is often lacking and this needs to be addressed in order to improve and better define our approach to this problem in the future

Rapid Evolution of Sperm Chromatin Remodeling Proteins in Primates

Spermatogenesis requires both the remodeling and condensation of chromatin, a process facilitated by the sequential replacement of histones with sperm-specific DNA binding proteins. First, the transition nuclear proteins 1 and 2 (TNP1, TNP2) act to replace the sperm-specific histones, then they are themselves replaced by protamine 1 (PRM1) and, in some species, protamine 2 (PRM2). It has been theorized that changes to these chromatin-remodeling proteins may affect an organism’s sperm formation, and thus reproductive success. While studies have found that PRM1 evolves rapidly, with evidence of positive selection on the human lineage, and that PRM2 has also evolved rapidly in some groups, the evolutionary rates of the TNPs have not been reported. Our research therefore compares the rates and patterns of evolution of the genes that encode the proteins in the protamine locus (Prm1, Prm2, Prm3, and Tnp2) and Tnp1, which is on a different chromosome. To do this, we have utilized NCBI databases and their BLAST tools to retrieve sequences of these five genes from diverse mammalian species, with an emphasis on the primates. We have obtained gene sequences of 25 primate species of known phylogenetic relationship, and aligned them against each other using the molecular analysis software package MEGA7. From these alignments, we were able to both characterize the overall consensus sequence for each protein and analyze interspecies differences. We also produced expanded alignments including other mammalian sequences, so that we may compare them to the primates. Our analyses suggest a few patterns of evolution within the genes that encode our proteins of interest. In general, the genes in the protamine locus appear to have experienced more rapid evolution than Tnp1, which appears to be highly conserved in most species studied, with the notable exception of the gorilla, where it appears to be an expressed pseudogene. Surprisingly, Tnp2 has evolved so rapidly that its sequences were difficult to align across some species, even within the primates. This rapid evolution appears to be due primarily to repeat sequence expansion and contraction, rather than to simple point mutations. Prm1 and Prm2, though also experiencing relatively rapid evolution (mostly at a point mutational level), exhibit conservation of certain positions, including characteristic cysteine residues and arginine stretches. Similar to Tnp2, Prm3 shows dramatic evolution due to repeat expansions. In rodents and primates, there is a 12-nucleotide expansion that encodes a 4-amino acid repeat near the Nterminus; in addition, all mammals show a simple repeat region that encodes a stretch of glutamate residues. We note that proteins encoded at the protamine locus have evolved more rapidly in the hominoids than in the Old World monkeys. Our study of these sequences using the alignments and sequence analysis tools has led us to theorize that the evolution of the protamine locus is not only in rapid in nature, but characterized by several repeat expansion areas, indicative of non-B DNA motifs that are known to be mutagenic. We believe that the possibility of non-B DNA mutagenesis driving the rapid evolution of the protamine locus merits further study, because this implies that these proteins evolved quickly due to mutational drive, rather than to positive selection, as previously suggested by several authors. If true, this has broad implications for the study of molecular evolution, in general

Factors Related to Financial Stress among College Students

Concerns that debt loads and other financial worries negatively affect student wellness are a top priority for many university administrators. Factors related to financial stress among college students were explored using the Roy Adaptation Model, a conceptual framework used in health care applications. Responses from the 2010 Ohio Student Financial Wellness Survey were analyzed using proportion tests and multivariate logistic regressions. The results show that financial stress is widespread among students – 71% of the sample reported feeling stress from personal finances. The results of the proportion tests and logistic regressions show that this study successfully identified important financial stressors among college students. Two of the most important financial stressors were not having enough money to participate in the same activities as peers and expecting to have higher amounts of student loan debt at graduation. The results also indicate that students with higher financial self-efficacy and greater financial optimism about the future are significantly less likely to report financial stress. Implications for student life administrators, policymakers, financial counselors, and financial therapists are discussed

The capital accumulation ratio as an indicator of retirement adequacy

The relationship between meeting the Capital Accumulation Ratio Guideline and retirement adequacy was investigated. About 63% of the households had a consistent relationship between meeting the 25% ratio guideline and being adequately prepared for retirement, with 46% of households both meeting the 25% ratio guideline and being prepared for retirement and 17% not meeting the guideline and not being adequately prepared for retirement. However, 37% of households did not have a consistent relationship. Meeting the 25% ratio guideline does not appear to be an accurate indicator of retirement adequacy. The 25% guideline was a better indicator than the 50% guideline.Includes bibliographical references

Factors related to meeting the capital accumulation ratio guideline

The capital accumulation ratio, investment assets divided by net worth, has been proposed as a useful indicator of financial health. Various experts recommend a minimum value of 25% to 50% for the ratio. When certificates of deposit are not counted as investment assets, 56% of U.S. households meet the 25% guideline and only 40% meet the 50% guideline. In a multivariate logistic regression, education, income, number of years until retirement, overspending, and financial risk tolerance are positively related to meeting the guidelines.Includes bibliographical references

Haemolytic anaemia complicating the concurrent use of allopurinol & azathioprine after kidney transplantation

Gout is a common problem in renal transplant recipients but often difficult to treat. Allopurinol can be combined with azathioprine but clinicians should be aware of the need for dose reduction, the potential to measure azathioprine breakdown products and the possible side effects of this combination. Leucopenia is a known side effect but this case report shows that haemolytic anaemia can also occur

Very unusual case of a primary sinonasal germ cell tumour

Sinonasal malignancies are a very rare diagnosis. We present a unique case of a 32-year-old man who presented with symptoms of worsening sinusitis and periorbital cellulitis. Investigation found a sinonasal malignancy and pathology confirmed this to be a primary germ cell tumour. The patient was managed with chemotherapy, surgery and consolidation radiotherapy and has remained well to date. This case report outlines an unusual presentation and diagnostic challenge for the primary care physician, ear, nose and throat surgeon, pathologist and oncologist with review of the surrounding literature

Health Economic Studies of Colorectal Cancer and the Contribution of a National Administrative Data Repository: a Systematic Review

Introduction: Several forces are contributing to an increase in the number of people living with and surviving colorectal cancer (CRC). However, due to the lack of available data, little is known about the implications of these forces. In recent years, the use of administrative records to inform research has been increasing. The aim of this paper is to investigate the potential contribution that administrative data could have on the health economic research of CRC. Methods: To achieve this aim, we conducted a systematic review of the health economic CRC literature published in the United Kingdom and Europe within the last decade (2009–2019). Results: Thirty-seven relevant studies were identified and divided into economic evaluations, cost of illness studies and cost consequence analyses. Conclusions: The use of administrative data, including cancer registry, screening and hospital records, within the health economic research of CRC is commonplace. However, we found that this data often come from regional databases, which reduces the generalisability of results. Further, administrative data appear less able to contribute towards understanding the wider and indirect costs associated with the disease. We explore several ways in which various sources of administrative data could enhance future research in this area

Cancer clinical trials: identifying & testing approaches to impact evaluation

Most cancer research is performed with the aim of generating new knowledge that leads to benefits such as improved treatments, higher cure rates, and better cancer prevention. Evaluating these downstream effects of research, often referred to as research impact, is of increasing importance to all cancer research stakeholders. There is currently no consensus surrounding the optimal way to approach this evaluation. The work in this thesis aimed to address this gap by first identifying which approaches to impact assessment have been applied previously for cancer research, and in particular for cancer clinical trials, and secondly to test a number of these approaches within the context of a case study of one cancer clinical trial. The Short Course Oncology Treatment (SCOT) trial was chosen for the purposes of the case study. SCOT was a phase III randomised controlled trial (RCT) which tested the non-inferiority of shortening adjuvant treatment for patients with colorectal cancer (CRC) from the standard of 6 months to 3 months of doublet chemotherapy. The trial met its pre-specified non-inferiority end-point but showed unexpected differences in outcome based on the treatment regimen used and stage of disease. Specifically, for patients receiving CAPOX (capecitabine and oxaliplatin), non-inferiority for 3 months versus 6 months of treatment was met, but this was not the case for those treated with FOLFOX (5-fluorouracil and oxaliplatin). Similarly, non-inferiority was met for patients with small tumours with a small nodal burden (low-risk stage III), but not for those with more extensive disease and/or a higher nodal burden (high-risk stage III disease). SCOT was the largest contributor to a collaboration of six trials addressing the same research question, called the International Duration Evaluation of Adjuvant therapy (IDEA). A systematic literature review was used to identify methods, frameworks, and categories of impact frequently used to perform research impact assessment (Chapter 3). This review was also used to identify previous impact assessments specific to cancer research. Fourteen empirical examples were identified, published between the years 1996 to 2015. These included assessment of research at the cancer project, programme and research centre level. One example specifically assessed the impact of a phase III cancer RCT. The methods for impact analysis included across these examples included surveys, interviews, bibliometric searching of journals and clinical guidelines, economic approaches and documentary analysis. The categories of impact most commonly used were policy, clinical practice, health and economic impact. The Payback framework and the Canadian Academy of Health Sciences (CAHS) framework were utilised to collect data and communicate the results of impact assessment in two of these examples. A second approach was adopted to identify ways that have previously been used to assess the impact of cancer clinical trials in particular (Chapter 4). The research impact case studies submitted to the United Kingdom government’s research performance exercise for universities in 2014 were screened to find examples of assessments of the impact of cancer clinical trials. In total, 46 case studies describing 110 clinical trials were identified. Many of these trials were phase III trials that met their primary endpoint, but earlier phase trials and those with negative findings were also impactful. Policy impact was the most commonly described downstream effect. There was a gap within these case studies in the use of real world evidence to demonstrate the impact of cancer trials on clinical practices and health. A number of the approaches to impact assessment identified in the literature review and in the analysis of the REF 2014 case studies were then tested to evaluate the impact of the SCOT Trial. The methods used for this assessment included surveys of clinician prescribing practices (Chapter 5), economic evaluation of the budget impact of trial results implementation (Chapter 6), and interrogation of real world data to explore the clinical practice and potential health benefits attributable to the SCOT trial at both a local (Chapter 7) and national (Chapter 8) level. A clinician survey performed in April 2019 demonstrated a high level of awareness of SCOT trial results (Chapter 5), with 98% of those who were aware of the trial indicating they had changed their clinical practice based on the trial results. This impact on practice was driven mainly by shortening of treatment to 3 months for patients with low-risk stage III CRC (SCOT non-inferiority met), whereas most clinicians reported they still used 6 months of doublet chemotherapy for patients with high-risk stage III disease (SCOT non-inferiority not met). This finding aligned with the post-hoc subgroup analysis performed for both the SCOT trial and IDEA collaboration. When shortening treatment for this subgroup of patients, clinicians mainly used CAPOX, whereas there was a more even split between using CAPOX and FOLFOX when 6 months of treatment was still used. A follow up survey in August 2020 was performed using a subset of respondents to the first survey and showed an increase in the use of shorter (3 months) treatment for patients with stage III disease with one high-risk feature, compared to responses in April 2019. The results of the first clinician survey were applied within a budget impact analysis (Chapter 6) to estimate the economic impact of implementing SCOT trial results in the six countries that recruited to the trial. It was estimated that implementation of SCOT trial findings could translate to over $150 million USD savings over five years for those 6 healthcare systems (Australia, Denmark, New Zealand, Spain, Sweden, UK). Adopting a societal perspective by including money lost because patients did not work when receiving longer treatment, as well as travel costs to hospital, increased this impact to$340 million USD. Adding the monetised quality adjusted life-year (QALY) gains from implementation to this calculation ($456 million USD) meant that the gains from implementation of SCOT were vastly in excess of the original investment to conduct the SCOT trial ($8.8 million USD). The final analysis conducted as part of the SCOT case study involved examination of individual patient level chemotherapy prescribing data. Using local (one health board in Scotland) level data, five different approaches were tested to evaluate the impact of the SCOT trial. In this instance, the change in practice was obvious even using simple descriptive statistics. Out of the other methods tested, interrupted time series analysis (ITSA) was the additional method that added the most value; the strengths of the ITSA were the ability to visualise the trends in prescribing pre and post-SCOT, as well as the counterfactual situation. Focusing on patients prescribed doublet chemotherapy (as per the SCOT trial), there was a significant decrease (85% to 31%) in the proportion of patients receiving over 3 months of treatment after the SCOT trial results were published (ꭓ2 p<0.001) compared to before this time-point. There was no significant change in a comparator group of patients who received monotherapy (76% pre-SCOT versus 77% post-SCOT (ꭓ2 p=0.774)). In order to evaluate this impact at a national level, it was first necessary to establish, for the first time, linkage of chemotherapy prescribing data at a pan-Scottish level. This process presented several challenges relating to data access, resource and infrastructure. Analysis of this data demonstrated a reduction in the proportion of patients receiving over 3 months of treatment across cancer networks in Scotland, although this change was less marked for patients treated in the Northern cancer network because 3 months of treatment was used proportionally more in the pre-SCOT period, compared to in the West or South-East of the country. The change in practice across the country was driven by changes for patients receiving CAPOX specifically, rather than FOLFOX or monotherapy, again fitting with the SCOT and IDEA subgroup analyses. Change was also greater for patients with low-risk rather than high-risk stage III disease, mirroring the clinician survey results. Following these in-depth analyses across Chapters 5-8, results from the survey, economic evaluation and administrative data interrogation were combined and summarised using a number of different impact frameworks that had been identified in Chapter 3, including the Payback framework. This study has demonstrated how cancer research impact has been assessed in the past and has tested how impact analysis can be performed specifically for a cancer clinical trial. Evaluating the impact of the SCOT trial demonstrated its rapid and significant effects on new knowledge, future research, policy, clinical practice, and monetary savings for the health service. This assessment also allowed reflection on the pathway to these impacts occurring, as well as on how future trials could be designed to maximise impact. The study has highlighted challenges that currently exist to accessing real world data to investigate cancer trial impact. Further research to understand which impacts from clinical trials are meaningful to patients and trialists would be useful. More investment by funders and governments to support access to healthcare datasets that can be used to assess clinical practice change in response to trials would make impact assessments more straightforward in future

Workshop synopses : Pathways for public health education

The Commonwealth introduced the Public Health Education and Research Program (PHERP) initiative to support capacity building within the public health workforce, primarily through investment in Master of Public Health programs. Following the 2005 review of PHERP, a national \u27Quality Agenda\u27 was proposed to establish minimum standards in public health competencies of graduates; and Master of Public Health (MPH) graduates in particular. This \u27agenda\u27 has triggered renewed discussion on public health workforce needs, public health graduate competencies, and the capacity of the tertiary education sector to deliver these.The Australian Network of Academic Public Health Institutions (ANAPHI) has worked with the Department of Health and Ageing on the \u27Quality Agenda\u27. In 2008, ANAPHI convened a working group to further open up discussion among academic institutions on the public health education context to the Quality Agenda. The group held a lunchtime workshop at the 2008 Population Health Congress in Brisbane, as one of a themed pair of sessions entitled \u27Public Health Professionals - Shaping our Future\u27. A further aim of the workshop was to identify key themes to shape the next ANAPHI Teaching and Learning Forum (September 23rd to 24th 2008, Canberra, www.anaphi.org.au).<br /