Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs.

PURPOSE OF REVIEW: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. RECENT FINDINGS: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with "target" trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

Effectiveness of weight loss interventions in breast cancer survivors: a systematic review of reviews.

BACKGROUND: Elevated body mass index (BMI) in breast cancer survivors (BCS) is associated with cancer recurrence and poorer treatment response. Guidelines recommend 5%-10% weight loss for overweight or obese BCS. OBJECTIVES: To assess effectiveness of lifestyle interventions for female BCS on weight loss, BMI, body composition, health-related quality of life (HRQoL), physical functioning, psychosocial measures, biomarkers. DESIGN: Systematic review of reviews and meta-analyses. SETTING: All clinical settings. PARTICIPANTS: Adult female BCS (active treatment or post-treatment). METHODS: Medline, Embase, CINAHL, PsycINFO, Cochrane Library (including Database of Abstracts of Reviews of Effects) were searched for systematic reviews published in English between 1990 and 2022, with weight, BMI or body fat as primary outcome. Narrative reviews, editorials, letters, conference abstracts were excluded. Review quality was assessed using the Joanna Briggs Institute quality assessment tool. RESULTS: 17 reviews were included. Twelve reported significant reductions in one or more anthropometric outcomes: weight -1.36 kg (95% CI:-2.51 to -0.21) to -3.8 kg (95% CI: -5.6 to -1.9); BMI -0.89 kg/m2 (95% CI: -0.15 to -0.28) to -3.59 kg/m2 (95% CI: -6.29 to 0.89) or body fat -1.6% (95% CI: -2.31 to -0.88) to -2.6% (95% CI not reported). Significant reductions in two or more anthropometric outcomes were reported in 7/12 reviews, with effective interventions comprising aerobic exercise/aerobic exercise plus resistance training (n=5), or diet and exercise with or without counselling (n=2). Significant improvements were also reported for HRQoL (8/11 reviews), mental health (4/7) and physical functioning (2/3). Group interventions comprising aerobic exercise or aerobic exercise plus resistance training were most likely to improve outcomes. CONCLUSIONS: Lifestyle interventions can significantly improve outcomes for BCS. Multimodal interventions are likely to have the greatest impact in reducing weight, BMI and body fat. Further research must define the optimal combination, intensity and duration of effective interventions. PROSPERO REGISTRATION NUMBER: CRD42021283481.

Cardiac safety profile for Random Complex Waveforms.

INTRODUCTION: A rigorous method for assessing the Ventricular Fibrillation (VF) risk of a Random Complex Waveform (RCW) has not been previously available. Real-life hazardous events motivated us to develop such method. An RCW is observable and recordable. It consists of multiple different components randomly added one to the other. Assessment for VF risk exists for non-random waveforms, particularly VF thresholds for 50/60 Hz alternating currents, but not for RCWs. METHODS: We developed a method which considers exposure to a segment of an RCW. It transforms complex segment exposure to values which can be compared with AC root-mean-square (rms) magnitude/duration curves, for determination of VF risk. Human contact could occur for any given time duration within the segment. The current of most risk is the greatest found for all possible instances of that duration. This is termed the "Probable Current" (PC) for that duration. All possible exposure durations in the waveform segment are considered, giving a set of PCs, thus allowing the plotting of a PC curve. The PC set is compared with a criterion for VF risk, termed the Justified Current (JC) curve. RESULTS: The theory is presented. Demonstrations and examples are given. Code is shown for generating the PC curve. CONCLUSION: VF risk can be found for an RCW using the rigorous algorithm presented. SIGNIFICANCE: The VF for RCWs has not been considered previously. A rigorous statement of a method for VF risk assessment allows extension from regular waveforms to RCWs.

Surgical assessment clinic - One stop emergency out-patient clinic for rapid assessment, reduced admissions and improved acute surgical service: A quality improvement study.

BACKGROUND: There is increasing pressure on emergency services within the NHS requiring efficient, rapid assessment and management of patients. A subsequent reduction in hospital admissions reduces overall costs with an aim to improve quality of care. At the Royal Shrewsbury Hospital we run a one stop emergency surgical clinic. With strict criteria for admission to this clinic we have established a care pathway for those patients requiring urgent surgical review but not necessarily hospital admission. MATERIALS AND METHODS: We reviewed our initial referral pathway to the emergency surgical assessment clinic. New guidelines were distributed to the local Care Coordination Centre (CCC) through which GP referrals to the clinic were made. A re-audit carried out 6 weeks later assessed change in clinical practice. RESULTS: With the introduction of guidelines for referral we significantly increased the percentage of appropriate referrals to the one stop emergency surgical clinic (42.9%-79.4%, p = 0.000017). The majority (75.8%) of appropriate referrals can be successfully managed on an urgent outpatient basis. Appropriate referrals unsuitable for discharge from clinic had genuine reasons for admission such as abnormal results on assessment, or a need for surgery. 97.8% of referrals not deemed appropriate for the clinic were admitted for inpatient management. CONCLUSION: By providing suitable guidance for referring practitioners we have optimised our clinic use significantly and improved our acute ambulatory surgical care. We have reduced admissions, provided rapid treatment and have established a service that helps address the ever increasing demand on acute services within the NHS.

Poor awareness of symptoms of oesophageal cancer.

Oesophageal cancer presents as advanced disease; in the majority of patients the symptoms are present for many months prior to diagnosis. Dysphagia has been described as the key to an early diagnosis of oesophageal cancer. This study aims to assess the public perception of the importance of this symptom. Ninety-six patients completed a questionnaire. This evaluated patient understanding of symptoms of dysphagia compared to the finding of a breast lump, haemoptysis, chest pain and loss of weight concerning urgency, probable cause of symptoms and treatment required. Sixty-five patients (71%) would visit their GP within 24 h of finding a breast lump or suffering from haemoptysis (82%) or having chest pain (82%). Forty-seven patients (51%) who experienced dysphagia would seek medical advice after one week and further 18 (19%) after one month (P<0.0001). Only eight patients (10%) associated dysphagia with cancer compared to 53 patients (57%) with the finding of a breast lump (P<0.031). This study concludes that there is poor understanding of the main symptoms of oesophageal cancer. New health campaigns are needed if the cancer is to be detected at an earlier and potentially curable stage.