Medical Student Perspectives on Undergraduate Oncology Education in the UK.

AIMS: The British Oncology Network for Undergraduate Societies (BONUS) surveyed students who attended an oncology revision day to determine their views on the current quantity, quality and type of curriculum-based oncology teaching they have experienced. MATERIALS AND METHODS: Students attending two BONUS revision days received a questionnaire assessing their experience of oncology teaching within the medical curriculum and interest in pursuing a future career in oncology using a 10-point Likert scale. Data were collected with informed consent to be anonymised and used for research. Student demographics and qualitative and quantitative data about experiences of oncology education were analysed. RESULTS: In total, 451 students registered to attend the revision days. After removal of duplicates, non-responders and non-UK participants, responses from 153 students studying across years 1-6 at 22 UK medical schools were analysed. The mean quantity of oncology lectures students reported receiving was 8.9 hours and the mean quantity of clinic/ward-based oncology teaching was 7.5 hours. Ninety (62.1%) of the 145 students who responded to the relevant question reported that they had received dedicated teaching in oncology. Students who had received dedicated oncology teaching reported a statistically significantly higher mean quality 6.1 (95% confidence interval 5.6-6.5) versus 5.0 (95% confidence interval 4.3-5.5; P = 0.003) and quantity 5.2 (95% confidence interval 4.7-5.6) versus 4.3 (95% confidence interval 3.7-4.9; P = 0.03) of oncology teaching compared with those who had not received this. CONCLUSION: Appropriate oncology education is essential for all medical students due to the high prevalence of cancer. All future doctors need the appropriate knowledge and communication skills to care for cancer patients. Our analysis provides quantitative evidence to support the value of specialist oncology teaching within the medical school curriculum in improving student-reported experience. National student-led revision days and events may widen interest in a future career in oncology and aid collaboration between oncology societies. It is important for the general undergraduate medical curriculum to integrate specialty content. An integrated curriculum should facilitate a holistic approach that spans prevention, screening, treatment and palliation rather than being split by subspeciality.

Building on existing tools to improve chronic disease prevention and screening in public health: a cluster randomized trial.

BACKGROUND: The BETTER (Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care) intervention was designed to integrate the approach to chronic disease prevention and screening in primary care and demonstrated effective in a previous randomized trial. METHODS: We tested the effectiveness of the BETTER HEALTH intervention, a public health adaptation of BETTER, at improving participation in chronic disease prevention and screening actions for residents of low-income neighbourhoods in a cluster randomized trial, with ten low-income neighbourhoods in Durham Region Ontario randomized to immediate intervention vs. wait-list. The unit of analysis was the individual, and eligible participants were adults age 40-64 years residing in the neighbourhoods. Public health nurses trained as "prevention practitioners" held one prevention-focused visit with each participant. They provided participants with a tailored prevention prescription and supported them to set health-related goals. The primary outcome was a composite index: the number of evidence-based actions achieved at six months as a proportion of those for which participants were eligible at baseline. RESULTS: Of 126 participants (60 in immediate arm; 66 in wait-list arm), 125 were included in analyses (1 participant withdrew consent). In both arms, participants were eligible for a mean of 8.6 actions at baseline. At follow-up, participants in the immediate intervention arm met 64.5% of actions for which they were eligible versus 42.1% in the wait-list arm (rate ratio 1.53 [95% confidence interval 1.22-1.84]). CONCLUSION: Public health nurses using the BETTER HEALTH intervention led to a higher proportion of identified evidence-based prevention and screening actions achieved at six months for people living with socioeconomic disadvantage. TRIAL REGISTRATION: NCT03052959 , registered February 10, 2017.

The Selby-Russell Dispute Regarding the Nonreporting of Critical Data in the Mega-Mouse Experiments of Drs William and Liane Russell That Spanned Many Decades: What Happened, Current Status, and Some Ramifications.

The Russells began their studies of the hereditary effects of radiation in the late 1940s, and their experiments contributed much to what is known about the induction of gene mutations in mice. I had a close association with them for about 26 years, and they relied on me considerably for database management and statistical support. In 1994, I was shocked to discover that, in experiments on males, they had failed to report numerous spontaneous mutations that arose during the perigametic interval and were detected as clusters of mutations. I realized that their nondisclosure of this information meant that the decades-long application of their data to estimate hereditary risks of radiation to humans using the doubling-dose approach had resulted in a several-fold overestimation of risk. I accordingly reported the situation to funding agencies. The resulting complicated situation is referred to here as the Selby-Russell Dispute. Highlights of the resulting investigation, as well as what occurred afterward, are described, and reasons will be provided to show why, in my opinion, the hereditary risk from radiation in humans was likely overestimated by at least 10-fold because the Russells decided not to report critical information from their massive experiments.

Predisposing and protective factors influencing suicide ideation, attempt, and death in patients accessing substance use treatment: a systematic review and meta-analysis protocol.

BACKGROUND: The lifetime risk of suicide in patients with substance use disorder is five to ten times the risk in the general population. Critically, up to 19% of patients continue to think about and attempt suicide even after accessing treatment. Therefore, suicidality represents a significant clinical concern in patients struggling with substance use that warrants careful investigation of the factors involved. While most previous research has relied on limited cross-sectional designs, a growing number of prospective studies are improving our understanding of the factors involved. However, a systematic study of these factors has not yet been conducted. METHODS: The primary objective of this review and possible meta-analysis will be to identify key risk and protective factors for suicide ideation, attempt, and death in patients accessing substance use treatment, guided by current models of suicide. Secondary and tertiary objectives will be to obtain pooled effect sizes for the factors identified and to disaggregate factors for suicidality before and after treatment, and for suicidal thought versus action. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we will conduct an electronic search of the literature using the databases Embase, Medline, PsycINFO, and Web of Science. Two authors will independently screen studies based on pre-specified inclusion and exclusion criteria, extract relevant data, and assess study quality. Observational and randomized-controlled studies will be included, whereas case-studies and reviews will be excluded. We will extract data on risk and protective factors associated with suicide ideation, attempt (odds or risk ratios), and death (hazard ratio). Given sufficient data (> 5 studies), we will calculate pooled effects using comprehensive meta-analysis. DISCUSSION: This systematic review will contribute to our knowledge of risk and protective factors for suicidality in patients before and after treatment. Understanding these factors will help define areas of research for further investigation to ultimately inform risk assessment and prevention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (reference number: CRD42018076260).

Ceftazidime stability and pyridine toxicity during continuous i.v. infusion.

PURPOSE: This article reviews the literature concerning ceftazidime stability and potential for toxicity from pyridine (a degradation product) in the light of decades of apparent safe use of this antibiotic when given by continuous i.v. infusion but recent changes in regulatory body/manufacturer advise a need to change infusion devices more frequently. SUMMARY: In the outpatient setting, ceftazidime is ideally administered by continuous i.v. infusion because of its short half-life and lack of post-antibiotic effect. While continuous i.v. infusion provides the optimal pharmacokinetic/pharmacodynamic profile, the frequency with which infusion devices need to be changed is critical to the practicality in the outpatient setting, especially where trained staff are required to visit the patient in their home to change the device. The rate of ceftazidime degradation (and pyridine formation) is temperature, concentration, and solvent dependent. By using the lowest effective dose (guided by pathogen minimum inhibitory concentration [MIC] so as to achieve a blood concentration ≥ 4 × MIC over the whole dosage interval), keeping ceftazidime concentration ≤ 3%, using 0.9% sodium chloride injection as diluent and maintaining temperature between 15-25°C when connected to the patient, the amount of pyridine formed over a 24-hour period can be minimized and toxicity prevented. When pathogen MIC dictates that > 6 g ceftazidime/day is required, alternative antibiotics should be considered and/or greater attention paid to temperature and concentration of the infusion solution. CONCLUSION: Ceftazidime can be used safely and effectively via continuous i.v. infusion in the outpatient setting with once-daily changes of infusion device provided the concentration and temperature of the infusion solution is controlled. In this way, more frequent changes of infusion device (that increase the risk of blood-borne infection and reduce the practicality of continuous i.v. infusion in the home) can be avoided.

Lessons learned implementing a province-wide smoking cessation initiative in Ontario's cancer centres.

PURPOSE: A large body of evidence clearly shows that cancer patients experience significant health benefits with smoking cessation. Cancer Care Ontario, the provincial agency responsible for the quality of cancer services in Ontario, has undertaken a province-wide smoking cessation initiative. The strategies used, the results achieved, and the lessons learned are the subject of the present article. METHODS: Evidence related to the health benefits of smoking cessation in cancer patients was reviewed. A steering committee developed a vision statement for the initiative, created a framework for implementation, and made recommendations for the key elements of the initiative and for smoking cessation best practices. RESULTS: New ambulatory cancer patients are being screened for their smoking status in each of Ontario's 14 regional cancer centres. Current or recent smokers are advised of the benefits of cessation and are directed to smoking cessation resources as appropriate. Performance metrics are captured and used to drive improvement through quarterly performance reviews and provincial rankings of the regional cancer centres. CONCLUSIONS: Regional smoking cessation champions, commitment from Cancer Care Ontario senior leadership, a provincial secretariat, and guidance from smoking cessation experts have been important enablers of early success. Data capture has been difficult because of the variety of information systems in use and non-standardized administrative and clinical processes. Numerous challenges remain, including increasing physician engagement; obtaining funding for key program elements, including in-house resources to support smoking cessation; and overcoming financial barriers to access nicotine replacement therapy. Future efforts will focus on standardizing processes to the extent possible, while tailoring the approaches to the populations served and the resources available within the individual regional cancer programs.

UK clinical guideline for the prevention and treatment of osteoporosis.

INTRODUCTION: In 2008, the UK National Osteoporosis Guideline Group (NOGG) produced a guideline on the prevention and treatment of osteoporosis, with an update in 2013. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over. METHODS: Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS: Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment, lifestyle measures and pharmacological interventions, duration and monitoring of bisphosphonate therapy, glucocorticoid-induced osteoporosis, osteoporosis in men, postfracture care and intervention thresholds. CONCLUSION: The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management.

Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy.

The anti-tumour effects associated with oncolytic virus therapy are mediated significantly through immune-mediated mechanisms, which depend both on the type of virus and the route of delivery. Here, we show that intra-tumoral oncolysis by Reovirus induced the priming of a CD8+, Th1-type anti-tumour response. By contrast, systemically delivered Vesicular Stomatitis Virus expressing a cDNA library of melanoma antigens (VSV-ASMEL) promoted a potent anti-tumour CD4+ Th17 response. Therefore, we hypothesised that combining the Reovirus-induced CD8+ T cell response, with the VSV-ASMEL CD4+ Th17 helper response, would produce enhanced anti-tumour activity. Consistent with this, priming with intra-tumoral Reovirus, followed by an intra-venous VSV-ASMEL Th17 boost, significantly improved survival of mice bearing established subcutaneous B16 melanoma tumours. We also show that combination of either therapy alone with anti-PD-1 immune checkpoint blockade augmented both the Th1 response induced by systemically delivered Reovirus in combination with GM-CSF, and also the Th17 response induced by VSV-ASMEL. Significantly, anti-PD-1 also uncovered an anti-tumour Th1 response following VSV-ASMEL treatment that was not seen in the absence of checkpoint blockade. Finally, the combination of all three treatments (priming with systemically delivered Reovirus, followed by double boosting with systemic VSV-ASMEL and anti-PD-1) significantly enhanced survival, with long-term cures, compared to any individual, or double, combination therapies, associated with strong Th1 and Th17 responses to tumour antigens. Our data show that it is possible to generate fully systemic, highly effective anti-tumour immunovirotherapy by combining oncolytic viruses, along with immune checkpoint blockade, to induce complementary mechanisms of anti-tumour immune responses.

FRAX-based assessment and intervention thresholds--an exploration of thresholds in women aged 50 years and older in the UK.

UNLABELLED: Under current guidelines, based on prior fracture probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold (a fixed threshold from the age of 70 years) reduces this disparity, increases treatment access and decreases the need for bone densitometry. INTRODUCTION: Several international guidelines set age-specific intervention thresholds at the 10-year probability of fracture equivalent to a woman of average BMI with a prior fracture. At older ages (≥70 years), women with prior fracture selected for treatment are at lower average absolute risk than those selected for treatment in the absence of prior fracture, prompting consideration of alternative thresholds in this age group. METHODS: Using a simulated population of 50,633 women aged 50-90 years in the UK, with a distribution of risk factors similar to that in the European FRAX derivation cohorts and a UK-matched age distribution, the current NOGG intervention and assessment thresholds were compared to one where the thresholds remained constant from 70 years upwards. RESULTS: Under current thresholds, 45.1% of women aged ≥70 years would be eligible for therapy, comprising 37.5% with prior fracture, 2.2% with high risk but no prior fracture and 5.4% selected for treatment after bone mineral density (BMD) measurement. Mean hip fracture probability was 11.3, 23.3 and 17.6%, respectively, in these groups. Under the alternative thresholds, the overall proportion of women treated increased from 45.1 to 52.9%, with 8.4% at high risk but no prior fracture and 7.0% selected for treatment after BMD measurement. In the latter group, the mean probability of hip fracture was identical to that observed in women with prior fracture (11.3%). The alternative threshold also reduced the need for BMD measurement, particularly at older ages (>80 years). CONCLUSIONS: The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages.

Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia.

The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication-competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-α (IFNα)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL.

The prevalence and outcomes of frailty in older cancer patients: a systematic review.

BACKGROUND: Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or cancer surgery. Better knowledge of the epidemiology of frailty could help drive a global cancer care strategy for older people. The aim of this review was to establish the prevalence and outcomes of frailty and pre-frailty in older cancer patients. METHODS: Observational studies that reported data on the prevalence and/or outcomes of frailty in older cancer patients with any stage of solid or haematological malignancy were considered. We searched Medline, CINAHL, Cochrane Library, EMBASE, Web of Science, Allied and Complementary medicine, Psychinfo and ProQuest (1 January 1996 to 30 June 2013). The primary outcomes were prevalence of frailty, treatment-related side-effects, unplanned hospitalization and mortality. Risk of bias was assessed using the Newcastle-Ottawa checklist. RESULTS: Data from 20 studies evaluating 2916 participants are included. The median reported prevalence of frailty and pre-frailty was 42% (range 6%-86%) and 43% (range 13%-79%), respectively. A median of 32% (range 11%-78%) of patients were classified as fit. Frailty was independently associated with increased all-cause mortality [adjusted 5-year hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.36-2.57]. There was evidence of increased risk of postoperative mortality for both frailty (adjusted 30-day HR 2.67, 95% CI 1.08-6.62) and pre-frailty (adjusted HR 2.33, 95% CI 1.20-4.52). Treatment complications were more frequent in those with frailty, including intolerance to cancer treatment (adjusted odds ratio 4.86, 95% CI 2.19-10.78) and postoperative complications (adjusted 30-day HR 3.19, 95% CI 1.68-6.04). CONCLUSIONS: More than half of older cancer patients have pre-frailty or frailty and these patients are at increased risk of chemotherapy intolerance, postoperative complications and mortality. The findings of this review support routine assessment of frailty in older cancer patients to guide treatment decisions, and the development of multidisciplinary geriatric oncology services.

The PRIMARA study: a prospective, descriptive, observational study to review cinacalcet use in patients with primary hyperparathyroidism in clinical practice.

OBJECTIVE: Medical management of primary hyperparathyroidism (PHPT) is important in patients for whom surgery is inappropriate. We aimed to describe clinical profiles of adults with PHPT receiving cinacalcet. DESIGN: A descriptive, prospective, observational study in hospital and specialist care centres. METHODS: For patients with PHPT, aged 23-92 years, starting cinacalcet treatment for the first time, information was collected on dosing pattern, biochemistry and adverse drug reactions (ADRs). Initial cinacalcet dosage and subsequent dose changes were at the investigator's discretion. RESULTS: Of 303 evaluable patients with PHPT, 134 (44%) had symptoms at diagnosis (mostly bone pain (58) or renal stones (50)). Mean albumin-corrected serum calcium (ACSC) at baseline was 11.4 mg/dl (2.9 mmol/l). The reasons for prescribing cinacalcet included: surgery deemed inappropriate (35%), patient declined surgery (28%) and surgery failed or contraindicated (22%). Mean cinacalcet dose was 43.9 mg/day (s.d., 15.8) at treatment start and 51.3 mg/day (31.8) at month 12; 219 (72%) patients completed 12 months treatment. The main reason for cinacalcet discontinuation was parathyroidectomy (40; 13%). At 3, 6 and 12 months from the start of treatment, 63, 69 and 71% of patients, respectively, had an ACSC of ≤10.3 mg/dl vs 9.9% at baseline. Reductions from baseline in ACSC of ≥1 mg/dl were seen in 56, 63 and 60% of patients respectively. ADRs were reported in 81 patients (27%), most commonly nausea. A total of 7.6% of patients discontinued cinacalcet due to ADRs. CONCLUSIONS: Reductions in calcium levels of ≥1 mg/dl was observed in 60% of patients 12 months after initiation of cinacalcet, without notable safety concerns.

Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.

Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNÉ£, IL-12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing.

Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013.

Since the launch in 2008 by the National Osteoporosis Guideline Group (NOGG), of guidance for the diagnosis and management of osteoporosis in postmenopausal women and older men in the UK there have been significant advances in risk assessment and treatment. These have been incorporated into an updated version of the guideline, with an additional focus on the management of glucocorticoid-induced osteoporosis, the role of calcium and vitamin D therapy and the benefits and risks of long-term bisphosphonate therapy. The updated guideline is summarised below. The recommendations in the guideline are intended to aid management decisions but do not replace the need for clinical judgement in the care of individuals in clinical practice.

miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis.

BACKGROUND: Clear cell renal cancer frequently harbours von Hippel-Lindau (VHL) gene mutations, leading to stabilisation of the hypoxia-inducible factors (HIFs) and expression of their target genes. We investigated HIF-1 and HIF-2 in the regulation of microRNA-210 (miR-210), and its clinical relevance in renal tumours. METHODS: RCC4 and 786-O renal cancer cell lines transfected with either an empty vector or functional VHL and incubated in normoxia or hypoxia were examined for miR-210 expression. Hypoxia-inducible factor siRNAs were used to examine their regulation of miR-210. Seventy-one clear cell renal tumours were sequenced for VHL mutations. Expression of miR-210, VHL, CA9, ISCU and Ki-67 were determined by immunohistochemistry and qRT-PCR. RESULTS: In addition to HIF-1 regulating miR-210 in renal cancer, HIF-2 can regulate this microRNA in the absence of HIF-1. MicroRNA-210 is upregulated in renal cancer compared with normal renal cortex tissue. MicroRNA-210 correlates negatively with its gene target ISCU at the protein and mRNA level. MicroRNA-210 correlated with positive outcome variables and negatively with Ki-67. CONCLUSION: We provide further evidence of miR-210 activity in vivo, and show that high miR-210 expression is associated with better clinico-pathological prognostic factors.

Measles virus causes immunogenic cell death in human melanoma.

Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.