A mixed-methods landscape assessment of supportive care for heart failure.

Aim: Understanding factors that shape leading health systems' (LHS) perspectives around heart failure (HF) treatment. Patients & methods: First of its kind study using a cross-sectional, descriptive, mixed-method design (from executives and frontline healthcare providers) with quantitative survey (n = 35) and qualitative interview (n = 12) data from 47 participants (41 different LHS). Results: 97% of LHS had dedicated HF programs, but variations in maturity highlights opportunities for care standardization. Treatment innovations continue, though practitioners may struggle to keep pace amid provider/patient barriers. HF programs strive to co-locate supportive care services to optimize treatment, but access can prove challenging. Conclusion: Opportunities exist, with external partner support, for LHS to become more comprehensive HF care providers, increasing standardization of care across LHS and improved HF treatment.

What is this summary about? We interviewed frontline healthcare workers (such as doctors and nurses) as well as executives at large US health systems to understand how they treat people with heart failure. What were the results? We learned that healthcare workers as well as executives would like to provide many different services to help people with heart failure. However, many health systems do not have all of these services available and can only provide a few basic services. We also learned healthcare workers sometimes struggle to keep up to date with new scientific discoveries and heart failure treatments. What do the results mean? With support from external healthcare partners, health systems can improve their ability to treat people with heart failure.

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

BACKGROUND: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. METHODS: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. PERSPECTIVE: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05546476.

Arterial desaturation rate does not influence self-selected knee extension force but alters ventilatory response to progressive hypoxia: A pilot study.

The absolute magnitude and rate of arterial desaturation each independently impair whole-body aerobic exercise. This study examined potential mechanisms underlying the rate-dependent relationship. Utilizing an exercise protocol involving unilateral, intermittent, isometric knee extensions (UIIKE), we provided sufficient reperfusion time between contractions to reduce the accumulation of intramuscular metabolic by-products that typically stimulate muscle afferents. The objective was to create a milieu conducive to accentuating any influence of arterial desaturation rate on muscular fatigue. Eight participants completed four UIIKE sessions, performing one 3 s contraction every 30s at a perceived intensity of 50% MVC for 25 min. Participants voluntarily adjusted their force generation to maintain perceptual effort at 50% MVC without feedback. Reductions in inspired oxygen fraction (FI O2 ) decreased arterial saturation from >98% to 70% with varying rates in three trials: FAST (5.3 ± 1.3 min), MED (11.8 ± 2.7 min), and SLOW (19.9 ± 3.7 min). FI O2 remained at 0.21 during the control trial. Force generation and muscle activation remained at baseline levels throughout UIIKE trials, unaffected by the magnitude or rate of desaturation. Minute ventilation increased with hypoxia (p < 0.05), and faster desaturation rates magnified this response. These findings demonstrate that arterial desaturation magnitude and rate independently affect ventilation, but do not influence fatigue development during UIIKE.

Indirect Calorimetry to Measure Metabolic Rate and Energy Expenditure in Psychiatric Populations: A Systematic Review.

Psychiatric and metabolic disorders are highly comorbid and the relationship between these disorders is bidirectional. The mechanisms underlying the association between psychiatric and metabolic disorders are presently unclear, which warrants investigation into the dynamics of the interplay between metabolism, substrate utilization, and energy expenditure in psychiatric populations, and how these constructs compare to those in healthy controls. Indirect calorimetry (IC) methods are a reliable, minimally invasive means for assessing metabolic rate and substrate utilization in humans. This review synthesizes the extant literature on the use of IC on resting metabolism in psychiatric populations to investigate the interaction between psychiatric and metabolic functioning. Consistently, resting energy expenditures and/or substrate utilization values were significantly different between psychiatric and healthy populations in the studies contained in this review. Furthermore, resting energy expenditure values were systematically overestimated when derived from predictive equations, compared to when measured by IC, in psychiatric populations. High heterogeneity between study populations (e.g., differing diagnoses and drug regimens) and methodologies (e.g., differing posture, time of day, and fasting status at measurement) impeded the synthesis of results. Standardized IC protocols would benefit this line of research by enabling meta-analyses, revealing trends within and between different psychiatric disorders.

Dietary Intakes From Ad Libitum Consumption of Canadian Armed Forces Field Rations Compared With Usual Home Dietary Intakes and Military Dietary Reference Intakes.

INTRODUCTION: Diet has an impact on weight status, health, and physical performance. Assessing the usual at-home dietary intakes of military personnel can help ascertain their nutritional status before field training or operations. Preference for foods consumed on a routine basis can also impact the military's preference for and consumption of field rations. Military personnel are limited by the inherent nature of the field rations and availability of calories and food types; and despite previous studies indicating a high acceptability of the field rations, it is unknown whether military personnel self-select the same number of calories when faced with a restricted list of field ration options as they would from their usual foods. Although field rations are intended to be nutritionally sufficient for standard military operations, there are limited data on the ad libitum intake of nutrients of Canadian Armed Forces (CAF) personnel from field rations in comparison to the military dietary reference intake (MDRI) recommendations, which establishes standards intended to meet the nutritional requirements of military personnel on duty. Thus, assessing the adequacy of their usual diets at home and longer-term sustenance on field rations in relation to MDRIs can provide insight on CAF personnel's operational readiness. The objectives of this study were to describe and compare, in a convenience sample of CAF, their ad libitum nutrient intakes from the consumption of self-selected field rations at home with their usual home intakes and to compare both with MDRI recommendations. MATERIALS AND METHODS: Eighteen CAF participants weighed and recorded their dietary intake from the ad libitum consumption of field rations at home and their usual at-home diets. Both MDRIs and the Institute of Medicine's dietary reference intake recommendations were used to assess the adequacy of intakes for each individual. Paired Student's t-test or Wilcoxon-matched paired tests were used to compare nutrient intake levels between usual at-home diets and field rations consumed at home. RESULTS: Mean daily energy intakes were similar between ad libitum intakes from field rations (2,688 ± 619 kcal) and usual home diets (2,657 ± 580 kcal), although participants had significantly higher intakes of protein and fat from their home diets and higher intakes of carbohydrates from the field rations (P ≤ 0.05). Participants had less than the recommended intakes of some micronutrients (vitamins A and D, folate, calcium, magnesium, and potassium), from both their home diets and field rations, but adequate intakes of vitamin C and iron. CONCLUSIONS: The results of this study showed no difference in energy intake between the consumption of field rations and home diets, with levels consistent with recommendations for individuals with average physical activity levels. The results also demonstrated less than the recommended intakes (in comparison with MDRIs) of some nutrients from both home diets and self-selected consumption of field rations, warranting further research into nutritional adequacy for operational readiness.

Potential physiological responses contributing to the ergogenic effects of acute ischemic preconditioning during exercise: A narrative review.

Ischemic preconditioning (IPC) has been reported to augment exercise performance, but there is considerable heterogeneity in the magnitude and frequency of performance improvements. Despite a burgeoning interest in IPC as an ergogenic aid, much is still unknown about the physiological mechanisms that mediate the observed performance enhancing effects. This narrative review collates those physiological responses to IPC reported in the IPC literature and discusses how these responses may contribute to the ergogenic effects of IPC. Specifically, this review discusses documented central and peripheral cardiovascular responses, as well as selected metabolic, neurological, and perceptual effects of IPC that have been reported in the literature.

Accelerating Virtual Health Implementation Following the COVID-19 Pandemic: Questionnaire Study.

BACKGROUND: The COVID-19 pandemic accelerated drivers for virtual health adoption and triggered the US federal government to implement regulatory changes to reduce barriers to virtual health implementation. Consequently, virtual health solutions have been increasingly adopted, and health systems in the United States have been reorganizing their care delivery process with unprecedented speed. OBJECTIVE: This study aimed to assess and make recommendations on the strategy, business model, implementation, and future considerations for scaling and sustaining virtual health solutions based on the views of executives from the largest health systems in the United States. METHODS: In September 2020 and October 2020, the Health Management Academy conducted 29 quantitative surveys and 23 qualitative interviews involving 58 executives from 41 of the largest health systems in the United States. Participating health systems were approximately equally distributed across size categories (small, medium, and large, defined as annual total operating revenue US $2-3 billion, $3-6 billion, and >$6 billion, respectively) and US Census Bureau regions (Northeast, Midwest, South, and West). RESULTS: Based on the Health Management Academy's assessment of approaches to governance, financing, data infrastructure, and clinical integration of virtual health, most participating health systems (13/24, 54%) had a mid-stage level of maturity in virtual health implementation. Executives reported the pandemic is forcing health systems to re-examine strategic priorities; the most commonly raised key impacts were increased access (15/21, 71%) and flexibility (10/21, 48%) as well as lower costs of care delivery (9/21, 43%). Most executives (16/28, 57%) reported their organization had a defined budget for virtual health, and many noted that virtual health is best supported through value-based payment models. Irrespective of health system maturity, reimbursement was consistently rated as a key challenge to virtual health scaling, along with patient access to and understanding of virtual health technology. The success of virtual health implementation was most commonly measured by patient satisfaction, health care provider engagement, and proportion of health care providers using virtual health solutions (reported by 7/8, 88%; 6/8, 75%; and 7/8, 75% of information technology executives, respectively). Almost all health systems (27/29, 93%) expect to continue growing their virtual health offerings for the foreseeable future, with user-friendliness and ease of integration into the electronic medical record as key factors in making go-forward decisions on virtual health solutions (each selected by 9/10, 90% executives). CONCLUSIONS: The increased demand for virtual health solutions during the COVID-19 pandemic is expected to continue postpandemic. Consequently, health systems are re-evaluating their current platforms, processes, and strategy to develop a sustainable, long-term approach to virtual health. To ensure future success, health system leaders need to proactively build on their virtual health solutions; advocate for payment, site flexibility, and reimbursement parity for virtual health; and demonstrate continued engagement and boldness to evolve care beyond established models.

The Effects of L-Citrulline on Blood-Lactate Removal Kinetics Following Maximal-Effort Exercise.

The accumulation of lactate in muscle and blood during high-intensity exercise is negatively correlated with the duration exercise can be sustained. Removal of lactate is a key component of acute recovery between consecutive bouts of such exercise. Low-intensity exercise enhances recovery by accelerating lactate turnover in metabolically active tissues, largely mediated by blood flow to these tissues. Therefore, the purpose of this research was to clarify if L-citrulline, a nutritional supplement purported to promote vasodilation via enhanced nitric oxide availability, would augment the removal of blood lactate during active recovery (AR). L-citrulline ingestion will augment the rate of blood lactate concentration decrease during AR, reduce the oxygen-cost of submaximal exercise, and increase time-to-exhaustion and peak oxygen uptake (V̇O2peak) during a test of maximal aerobic power. Healthy university students (five males & five females) participated in this double-blind, randomized, placebo-controlled study. Participants exercised on a cycle ergometer at submaximal steady-state intensities followed by progressively increasing intensity to exhaustion, 10 min of AR, and then supramaximal intensity exercise to exhaustion. Oxygen uptake was measured throughout the trial and blood lactate was sampled repeatedly during AR. The protocol elicited very high peak blood lactate concentrations after exercise (11.3 + 1.3 mmol/L). L-citrulline supplementation did not significantly alter blood lactate kinetics during AR, the oxygen cost of exercise, V̇O2peak, or time-to-exhaustion. Despite a strong theoretical basis by which L-citrulline could augment lactate removal from the blood, L-citrulline supplementation showed no effect as an exercise-recovery supplement.

Association of Tumor Mutational Burden and Immune Gene Expression with Response to PD-1 Blockade by Sasanlimab Across Tumor Types and Routes of Administration.

BACKGROUND: Sasanlimab is a monoclonal antibody that binds to the programmed cell death receptor 1 (PD-1). Anti-PD-1 monoclonal antibodies have improved patient clinical outcomes; however, not all treated patients derive clinical benefit. Further insights on potential biomarkers beyond PD-L1 expression levels would help to identify the patients most likely to respond to treatment. OBJECTIVE: This study evaluated tumor biopsies from patients treated with intravenous or subcutaneous sasanlimab to identify biomarkers of response and characterize pharmacodynamic activity. METHODS: Anti-PD-1/PD-ligand 1 (PD-L1)-naive patients with advanced solid tumors received sasanlimab intravenously at 1, 3, or 10 mg/kg every 3 weeks (n = 23) or subcutaneously at 300 mg every 4 weeks (n = 15). Best tumor percentage change from baseline was determined by RECIST. Whole-exome DNA and RNA sequencing were performed in tumor samples collected from treated patients at protocol-defined timepoints. PD-L1 and CD8 protein expression were evaluated in tumor biopsies by immunohistochemistry. Associations with response were assessed by linear regression analysis. RESULTS: Baseline tumor mutational burden (TMB), as well as PD-L1 and CD8 expression, were significantly associated with response to sasanlimab across the multiple dose levels, routes of administration, and range of tumor types evaluated. TMB is an independent biomarker from the various tumor inflammatory genes and signatures evaluated. Gene set enrichment analysis showed that higher baseline expression levels of genes related to the interferon-γ and PD-1 signaling pathways and the cell cycle were significantly associated with response to sasanlimab across tumor types. No differences were observed between routes of administration with regard to response to sasanlimab for the biomarkers of interest (TMB, PD-L1, CD8, and interferon-γ signature). Evaluation of pharmacodynamic changes showed increased tumor expression of genes enriched in adaptive immune response pathways. CONCLUSIONS: Our findings indicate an active, immunomodulatory mechanism for the anti-PD-1 antibody sasanlimab across different tumor types and routes of administration. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02573259; registered October 2015.

Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.

Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.

In the last few decades, great progress has been made in developing new treatments for adult cancers. However, development of new treatments for childhood cancers has been much slower. To encourage drug companies (sponsors) to develop effective treatments for childhood cancer, authorities in the United States (US) and Europe have made new rules for drug development. Under these new rules, sponsors developing drugs for specific cancers in adults have to consider whether the target of that drug also causes cancers in children. If this is the case, sponsors have to carry out clinical studies of their drug in children who have cancer that is caused by the same drug target. In this article, we describe some reasons for why drug development for childhood cancers has been slow and the rules created to address this problem in the US and Europe. We share some recommendations to help sponsors maximize their chances of developing an effective drug in children while satisfying the new rules. Specifically, sponsors need to be aware of the differences between studying drugs in adults versus children and how these influence the way the drug is tested. We make several recommendations for each stage of the development process, beginning with what is needed even before human studies begin. Finally, we highlight some issues that sponsors need to think about during drug development, from the preclinical stage (testing drugs in cells and animals) through to clinical testing in adults and pediatric patients with cancer.

Methodological Variations Contributing to Heterogenous Ergogenic Responses to Ischemic Preconditioning.

Ischemic preconditioning (IPC) has been repeatedly reported to augment maximal exercise performance over a range of exercise durations and modalities. However, an examination of the relevant literature indicates that the reproducibility and robustness of ergogenic responses to this technique are variable, confounding expectations about the magnitude of its effects. Considerable variability among study methodologies may contribute to the equivocal responses to IPC. This review focuses on the wide range of methodologies used in IPC research, and how such variability likely confounds interpretation of the interactions of IPC and exercise. Several avenues are recommended to improve IPC methodological consistency, which should facilitate a future consensus about optimizing the IPC protocol, including due consideration of factors such as: location of the stimulus, the time between treatment and exercise, individualized tourniquet pressures and standardized tourniquet physical characteristics, and the incorporation of proper placebo treatments into future study designs.

Race and ethnicity representation in clinical trials: findings from a literature review of Phase I oncology trials.

Aim: To provide an assessment of published literature on the demographic representation in Phase I trials of biopharmaceutical oncology agents. Materials & methods: We conducted a rapid evidence assessment to identify demographic representation reported in Phase I clinical trials for biopharmaceutical oncology agents published in 2019. Results: Globally, the population was predominantly White/Caucasian (62.2%). In the USA, the distribution was heavily skewed toward White/Caucasian (84.2%), with minimal representation of Blacks/African-Americans (7.3%), Asians (3.4%), Hispanics/Latinos (2.8%) or other race/ethnicity groups. Conclusion: Our data highlight that Phase I oncology trials do not reflect the population at large, which may perpetuate health disparities. Further research is needed to understand and address barriers to participation, particularly among under-represented groups.

Lay abstract A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2020-1262.

The Use of Patient-Reported Outcome Measures in Phase I Oncology Clinical Trials.

OBJECTIVE: To investigate patient-reported outcome (PRO) usage in phase I oncology clinical trials, including types of PRO measures and changes over time. METHODS: We analyzed ClinicalTrials.gov records of phase I oncology clinical trials completed by December 2019. RESULTS: Of all eligible trials, 2.3% (129/5,515) reported ≥1 PRO, totaling 181 instances of PRO usage. PRO usage increased over time, from 0.6% (trials initiated before 2000) to 3.4% (trials starting between 2015 and 2019). The most common PRO measures were unspecified (29%), tumor-specific (24%), and generic cancer (19%). CONCLUSION: Although uncommon in phase I oncology clinical trials, PRO usage is increasing over time. PRO measures were often unspecified on ClinicalTrials.gov, suggesting that more precise reporting and standardization are needed.

Menthol Mouth Rinsing and Cycling Performance in Females Under Heat Stress.

PURPOSE: The effects of menthol (MEN) mouth rinse (MR) on performance, physiological, and perceptual variables in female cyclists during a 30-km independent time trial (ITT) were tested. METHODS: The participants (n = 9) cycled for 30 km in hot conditions (30°C [0.6°C], 70% [1%] relative humidity, 12 [1] km/h wind speed) on 2 test occasions: with a placebo MR and with MEN MR. Handgrip and a 5-second sprint were measured before, following the first MR, and after the ITT. Ratings of perceived exertion Borg 6 to 20, thermal sensation, and thermal pleasantness were recorded every 5 km. Core temperature and heart rate were recorded throughout. RESULTS: The ITT performance significantly improved with MEN MR by 2.3% (2.7%) relative to the placebo (62.6 [5.7] vs 64.0 [4.9] min P = .034; d = 0.85; 95% confidence interval, 0.14 to 2.8 min). The average power output was significantly higher in the MEN trial (P = .031; d = 0.87; 95% confidence interval, 0.9 to 15.0 W). No significant interaction of time and MR for handgrip (P = .581, η2 = .04) or sprint was observed (P = .365, η2 = .103). Core temperature, heart rate, ratings of perceived exertion, and thermal sensation did not significantly differ between trials at set distances (P > .05). Pleasantness significantly differed between the placebo and MEN only at 5 km, with no differences at other TT distances. CONCLUSION: These results suggest that a nonthermal cooling agent can improve 30-km ITT performance in female cyclists, although the improved performance with MEN MR is not due to altered thermal perception.

Addressing resistance to immune checkpoint inhibitor therapy: an urgent unmet need.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop resistance. ICI resistance mechanisms can be tumor-intrinsic, related to the tumor microenvironment or patient-specific factors. Multiple resistance mechanisms may be present within one tumor subtype, or heterogeneity exists among patients with the same tumor type. Consequently, designing effective combination treatment strategies is challenging. This review will discuss ICI resistance mechanisms, and summarize findings from key preclinical and clinical trials of ICIs, to identify potential treatment strategies or pathways to overcome ICI resistance.

Ovarian cancer: new strategies and emerging targets for the treatment of patients with advanced disease.

Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.

Application of Real-World Data to External Control Groups in Oncology Clinical Trial Drug Development.

Randomized controlled trials (RCTs) that assess overall survival are considered the "gold standard" when evaluating the efficacy and safety of a new oncology intervention. However, single-arm trials that use surrogate endpoints (e.g., objective response rate or duration of response) to evaluate clinical benefit have become the basis for accelerated or breakthrough regulatory approval of precision oncology drugs for cases where the target and research populations are relatively small. Interpretation of efficacy in single-arm trials can be challenging because such studies lack a standard-of-care comparator arm. Although an external control group can be based on data from other clinical trials, using an external control group based on data collected outside of a trial may not only offer an alternative to both RCTs and uncontrolled single-arm trials, but it may also help improve decision-making by study sponsors or regulatory authorities. Hence, leveraging real-world data (RWD) to construct external control arms in clinical trials that investigate the efficacy and safety of drug interventions in oncology has become a topic of interest. Herein, we review the benefits and challenges associated with the use of RWD to construct external control groups, and the relevance of RWD to early oncology drug development.

Humanistic and Economic Burden of Non-Muscle Invasive Bladder Cancer: Results of Two Systematic Literature Reviews.

PURPOSE: Non-muscle invasive bladder cancer (NMIBC) is a malignancy restricted to the inner lining of the bladder. Intravesical Bacillus Calmette-Guerin (BCG) following transurethral resection of the bladder tumor is the mainstay first-line treatment for high-risk NMIBC patients. Two systematic literature reviews (SLRs) were conducted to further assess the current evidence on BCG use in NMIBC and the humanistic and economic burden of disease. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, Embase® and MEDLINE® were searched using the Ovid platform to identify interventional or real-world evidence studies on the health-related quality of life (HRQoL) and economic burden in NMIBC. Limited evidence was found from initial economic SLR searches in NMIBC, so additional targeted searches for bladder cancer were conducted to expand findings. RESULTS: Fifty-nine publications were included in the HRQoL SLR, of which 23 reported HRQoL and symptoms in NMIBC. At diagnosis, HRQoL was comparable with population norms but worsened considerably 2 years following diagnosis. Maintenance therapy with intravesical BCG was associated with reduced HRQoL, and treatment-related adverse events (AEs) resembled typical NMIBC symptoms. Twenty-two studies reported decreasing BCG compliance over time. Common AEs with BCG were frequent urination, lower urinary tract symptoms, pain, and hematuria. Forty-two publications were included in the economic SLR, of which nine assessed healthcare costs and resource use in NMIBC or bladder cancer. High-risk disease and high-intensity treatment were associated with increased healthcare costs. CONCLUSION: NMIBC has a considerable symptomatic, HRQoL, and economic burden. Symptoms persisted and HRQoL worsened despite intravesical BCG treatment. NMIBC is a costly disease, with higher healthcare costs associated with increased risk of disease progression and recurrence. There is a high unmet need for safe and effective treatments that reduce the risk of disease progression and recurrence, provide symptomatic relief, and improve HRQoL for patients.

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.

Energy Balance of Canadian Armed Forces Personnel during an Arctic-Like Field Training Exercise.

Operating in temperature extremes frequently leads to a discrepancy in energy balance. Investigating the effects of operating in extreme cold temperatures on metabolic requirements has not been well described in Canadian Armed Forces (CAF) personnel. The objective was to accurately assess energy deficits using the "gold standard" methodology for measuring energy intake (EI) and energy expenditure (EE). Nutritional intake of a convenience sample of 10 CAF Class A Reservists, completing a basic military qualification (land) course under winter weather conditions, was assessed using the daily measured food intake/food waste collections. EE was measured by the doubly-labelled water method. Average EI was 2377 ± 1144 kcal/day, which was below the EE (4917 ± 693 kcal/day), despite having ~5685 kcal available in the field rations. A significant body weight loss of 2.7% was associated with the average daily energy deficit of 2539 ± 1396 kcal. As a result, participants demonstrated voluntary anorexia. Such results may have important implications for the impairment of performance and health under longer duration operations.