On the Design of Combination Cancer Therapy.

Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug interactions rarely translate clinically and that the results of combination therapies in mouse models or human clinical trials, even if successful, are best explained by the independent activities of the individually administered drugs.

KIDS SAVE LIVES: Basic Life Support Education for Schoolchildren: A Narrative Review and Scientific Statement From the International Liaison Committee on Resuscitation.

BACKGROUND: Basic life support education for schoolchildren has become a key initiative to increase bystander cardiopulmonary resuscitation rates. Our objective was to review the existing literature on teaching schoolchildren basic life support to identify the best practices to provide basic life support training in schoolchildren. METHODS: After topics and subgroups were defined, a comprehensive literature search was conducted. Systematic reviews and controlled and uncontrolled prospective and retrospective studies containing data on students <20 years of age were included. RESULTS: Schoolchildren are highly motivated to learn basic life support. The CHECK-CALL-COMPRESS algorithm is recommended for all schoolchildren. Regular training in basic life support regardless of age consolidates long-term skills. Young children from 4 years of age are able to assess the first links in the chain of survival. By 10 to 12 years of age, effective chest compression depths and ventilation volumes can be achieved on training manikins. A combination of theoretical and practical training is recommended. Schoolteachers serve as effective basic life support instructors. Schoolchildren also serve as multipliers by passing on basic life support skills to others. The use of age-appropriate social media tools for teaching is a promising approach for schoolchildren of all ages. CONCLUSIONS: Schoolchildren basic life support training has the potential to educate whole generations to respond to cardiac arrest and to increase survival after out-of-hospital cardiac arrest. Comprehensive legislation, curricula, and scientific assessment are crucial to further develop the education of schoolchildren in basic life support.

Microengineering 3D Collagen Matrices with Tumor-Mimetic Gradients in Fiber Alignment.

Collagen fibers in the 3D tumor microenvironment (TME) exhibit complex alignment landscapes that are critical in directing cell migration through a process called contact guidance. Previous in vitro work studying this phenomenon has focused on quantifying cell responses in uniformly aligned environments. However, the TME also features short-range gradients in fiber alignment that result from cell-induced traction forces. Although the influence of graded biophysical taxis cues is well established, cell responses to physiological alignment gradients remain largely unexplored. In this work, fiber alignment gradients in biopsy samples are characterized and recreated using a new microfluidic biofabrication technique to achieve tunable sub-millimeter to millimeter scale gradients. This study represents the first successful engineering of continuous alignment gradients in soft, natural biomaterials. Migration experiments on graded alignment show that HUVECs exhibit increased directionality, persistence, and speed compared to uniform and unaligned fiber architectures. Similarly, patterned MDA-MB-231 aggregates exhibit biased migration toward increasing fiber alignment, suggesting a role for alignment gradients as a taxis cue. This user-friendly approach, requiring no specialized equipment, is anticipated to offer new insights into the biophysical cues that cells interpret as they traverse the extracellular matrix, with broad applicability in healthy and diseased tissue environments.

Comparing Simulation Training of Bronchoscopy-Guided Percutaneous Dilatational Tracheostomy Using Conventional Versus 3D Printed Simulators (TRAC-Sim Study).

Background: Individual implementation rate of bronchoscopy-guided percutaneous dilatational tracheostomy (PDT) varies among intensivists. Simulation training (ST) can increase the safety of medical procedures by reducing stress levels of the performing team. The aim of this study was to evaluate the benefit of ST in PDT regarding procedural time, quality of performance, and percepted feelings of safety of the proceduralist and to compare conventional simulators (CSIM) with simulators generated from 3D printers (3DSIM). Methods: We conducted a prospective, single-center, randomized, blinded cross-over study comparing the benefit of CSIM versus 3DSIM for ST of PDT. Participants underwent a standardized theoretical training and were randomized to ST with CSIM (group A) or 3DSIM (group B). After ST, participants' performance was assessed by two blinded examiners on a porcine trachea regarding time required for successful completion of PDT and correct performance (assessed by a performance score). Percepted feelings of safety were assessed before and after ST. This was followed by a second training and second assessment of the same aspects with crossed groups. Results: 44 participants were included: 24 initially trained with CSIM (group A) and 20 with 3DSIM (group B). Correctness of the PDT performance increased significantly in group B (p < .01) and not significantly in group A (p = .14). Mean procedural time required for performing a PDT after their second ST compared to the first assessment (p < .01) was lower with no difference between group A and group B and irrespective of the participants' previous experience regarding PDT, age, and sex. Moreover, percepted feelings of safety increased after the first ST in both groups (p < .001). Conclusions: ST can improve procedural skills, procedural time, and percepted feelings of safety of the proceduralist in simulated PDT.

Resource selection by New York City deer reveals the effective interface between wildlife, zoonotic hazards and humans.

Although the role of host movement in shaping infectious disease dynamics is widely acknowledged, methodological separation between animal movement and disease ecology has prevented researchers from leveraging empirical insights from movement data to advance landscape scale understanding of infectious disease risk. To address this knowledge gap, we examine how movement behaviour and resource utilization by white-tailed deer (Odocoileus virginianus) determines blacklegged tick (Ixodes scapularis) distribution, which depend on deer for dispersal in a highly fragmented New York City borough. Multi-scale hierarchical resource selection analysis and movement modelling provide insight into how deer's movements contribute to the risk landscape for human exposure to the Lyme disease vector-I. scapularis. We find deer select highly vegetated and accessible residential properties which support blacklegged tick survival. We conclude the distribution of tick-borne disease risk results from the individual resource selection by deer across spatial scales in response to habitat fragmentation and anthropogenic disturbances.

Association of Insurance Type With Inpatient Surgery 30-Day Complications and Costs.

INTRODUCTION: Safety-net hospitals (SNHs) have higher postoperative complications and costs versus low-burden hospitals. Do low socioeconomic status/vulnerable patients receive care at lower-quality hospitals or are there factors beyond providers' control? We studied the association of private, Medicare, and vulnerable insurance type with complications/costs in a high-burden SNH. METHODS: Retrospective inpatient cohort study using National Surgical Quality Improvement Program (NSQIP) data (2013-2019) with cost data risk-adjusted by frailty, preoperative serious acute conditions (PASC), case status, and expanded operative stress score (OSS) to evaluate 30-day unplanned reoperations, any complication, Clavien-Dindo IV (CDIV) complications, and hospitalization variable costs. RESULTS: Cases (Private 1517; Medicare 1224; Vulnerable 3648) with patient mean age 52.3 y [standard deviation = 14.7] and 47.3% male. Adjusting for frailty and OSS, vulnerable patients had higher odds of PASC (aOR = 1.71, CI = 1.39-2.10, P < 0.001) versus private. Adjusting for frailty, PASC and OSS, Medicare (aOR = 1.27, CI = 1.06-1.53, P = 0.009), and vulnerable (aOR = 2.44, CI = 2.13-2.79, P < 0.001) patients were more likely to undergo urgent/emergent surgeries. Vulnerable patients had increased odds of reoperation and any complications versus private. Variable cost percentage change was similar between private and vulnerable after adjusting for case status. Urgent/emergent case status increased percentage change costs by 32.31%. We simulated "switching" numbers of private (3648) versus vulnerable (1517) cases resulting in an estimated variable cost of $49.275 million, a 25.2% decrease from the original $65.859 million. CONCLUSIONS: Increased presentation acuity (PASC and urgent/emergent surgeries) in vulnerable patients drive increased odds of complications and costs versus private, suggesting factors beyond providers' control. The greatest impact on outcomes may be from decreasing the incidence of urgent/emergent surgeries by improving access to care.

Education of schoolchildren in cardiopulmonary resuscitation - overview of the current literature.

PURPOSE OF REVIEW: Recognition of cardiac arrest and initiation of cardiopulmonary resuscitation (CPR) can be learned and adequately replicated by schoolchildren. Regular instruction of schoolchildren in CPR is therefore a core element to increase low bystander CPR rates. Thereby, schoolchildren CPR training evolved as own scientific field within the last decade. Aim was to describe current evidence in terms of epidemiology, teaching approaches and political aspects. RECENT FINDINGS: Schoolchildren demonstrate a high motivation to be trained in CPR. Teaching approaches that combine theoretical and practical learning sessions guarantee a sustainable learning effect. Schoolchildren can adequately perform chest compressions and mouth-to-mouth ventilation from the age of 12 years. Use of digital media is a highly promising teaching approach. CPR training conducted by teachers from the own school is effective and guarantees continuous development of CPR skills. Integration of schoolchildren CPR training into school curricula is the foundation for a sustainable increase of lay resuscitation rates in the population. Scientific and political promotion of schoolchildren CPR training is needed to sensitize the population and move bystander CPR in the social focus. SUMMARY: While bystander CPR rates are low in Europe comprehensive establishment of schoolchildren CPR training may sustainably increase survival after cardiac arrest.

[Medical emergencies during running events]. / Notfallmedizinische Aspekte bei Laufveranstaltungen.

Background: The number of short- and long-distance running events in Germany is increasing. Running as a popular sport is practiced by a large number of people of different ages, risk groups, and degrees of professionalism, which results in a wide range of medical emergencies. Objective: The present article elucidates incidence, pathophysiology and therapy of relevant emergencies during running events. Aim was the optimization of work processes of emergency personnel. Materials and methods: A literature search was conducted in PubMed. Results: Exercise-associated muscle cramps, gastrointestinal symptoms, collapse, compartment syndrome, and tendinopathy are common clinical manifestations. Cardiac arrest and sudden cardiac death are rare events. Consciousness and seizures are major complications. Disseminated intravascular coagulation, exercise-associated hyponatremia, heat stroke, rhabdomyolysis, and thromboembolism are associated with high morbidity and mortality. Substances increasing pain resilience as well as performance-enhancing substances are popular among amateur and professional runners and are associated with a high incidence of side effects. Conclusion: General symptoms including vomiting, fever, collapse, muscle-pain, nausea and weakness are the leading symptoms during running events. A careful anamnesis is important for targeted clinical therapy. Symptom control is the main task. Fluid management the most challenging task for healthcare providers in the prehospital setting.

Acute kidney injury in cystic fibrosis patients treated with intravenous colistimethate sodium or tobramycin.

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Comparing suction rates of novel DuCanto catheter against Yankauer and standard suction catheter using liquids of different viscosity-a technical simulation.

PURPOSE: Aspiration is a feared complication that may occur during airway management, and can significantly contribute to morbidity and mortality. Availability of a suctioning device with a suction catheter capable of clearing the airway is mandatory for airway management. However, suction performance may be significantly different amongst different suction catheters. The aim of this study was to compare suction rates of a standard 14 Ch suction catheter (SC), a Yankauer catheter (Y) and a DuCanto catheter (DC) using 4 fluids with different viscosity. METHODS: In this simulation trial, 4 preparations with standardized viscosity were prepared using a Xanthane-based medical fluid thickener. Lowest viscosity was achieved using tap water without thickener, syrup-like viscosity was achieved by adding 10 g per liter tap water, honey-like viscosity was achieved by adding 20 g per liter, and a pudding-like viscosity was achieved by adding 30 g of thickening powder per liter tap water. Each preparation was suctioned for 15 s with the three different suctioning devices. Measurements were repeated four times. The amount of removed preparation by suctioning was measured using a tared scale. RESULTS: Suction rates for water were 580 ± 34 mg for SC, 888 ± 5 mg for Y and 1087 ± 15 for DC; for syrup-like viscosity it was 383 ± 34(SC) vs. 661 ± 64(Y) vs. 935 ± 42(DC); for honey-like viscosity it was 191 ± 21(SC) vs. 426 ± 34(Y) vs. 590 ± 68(DC); and for pudding-like viscosity 74 ± 13(SC) vs. 164 ± 6(Y) vs. 211 ± 8(DC). CONCLUSION: Suctioning liquids of different viscosity, the new DuCanto catheter was more effective than the Yankauer catheter that was more effective than a standard suctioning catheter. The relative superiority of the DuCanto was highest in fluids with high viscosity.

Maintenance tobramycin primarily affects untargeted bacteria in the CF sputum microbiome.

RATIONALE: The most common antibiotic used to treat people with cystic fibrosis (PWCF) is inhaled tobramycin, administered as maintenance therapy for chronic Pseudomonas aeruginosa lung infections. While the effects of inhaled tobramycin on P. aeruginosa abundance and lung function diminish with continued therapy, this maintenance treatment is known to improve long-term outcomes, underscoring how little is known about why antibiotics work in CF infections, what their effects are on complex CF sputum microbiomes and how to improve these treatments. OBJECTIVES: To rigorously define the effect of maintenance tobramycin on CF sputum microbiome characteristics. METHODS AND MEASUREMENTS: We collected sputum from 30 PWCF at standardised times before, during and after a single month-long course of maintenance inhaled tobramycin. We used traditional culture, quantitative PCR and metagenomic sequencing to define the dynamic effects of this treatment on sputum microbiomes, including abundance changes in both clinically targeted and untargeted bacteria, as well as functional gene categories. MAIN RESULTS: CF sputum microbiota changed most markedly by 1 week of antibiotic therapy and plateaued thereafter, and this shift was largely driven by changes in non-dominant taxa. The genetically conferred functional capacities (ie, metagenomes) of subjects' sputum communities changed little with antibiotic perturbation, despite taxonomic shifts, suggesting functional redundancy within the CF sputum microbiome. CONCLUSIONS: Maintenance treatment with inhaled tobramycin, an antibiotic with demonstrated long-term mortality benefit, primarily impacted clinically untargeted bacteria in CF sputum, highlighting the importance of monitoring the non-canonical effects of antibiotics and other treatments to accurately define and improve their clinical impact.

Apneic laryngeal oxygenation during elective fiberoptic intubation - a technical simulation.

BACKGROUND: Sedation during elective fiberoptic intubation for difficult airway can cause respiratory depression, apnea and periods of desaturation. During apneic episodes, hypoxemia can be prevented by insufflation of oxygen in the deep laryngeal space. The aim of this study was to evaluate an oropharyngeal oxygenation device (OOD) designed for deep laryngeal insufflation during fiberoptic intubation. METHODS: The OOD is split in the front to form a path for the bronchoscope. An external lumen delivers oxygen in the deep laryngeal space. In this experimental study, air application (as control group), oxygen application via nasal prongs, oxygen application via the OOD, and oxygen application via the working channel of a bronchoscope were compared in a technical simulation. In a preoxygenated test lung of a manikin, decrease of the oxygen saturation was measured over 20 min for each method. RESULTS: Oxygen saturation in the test lung dropped from 97 ± 1% (baseline in all groups) to 58 ± 3% in the control-group (p < 0.001 compared to all other groups) and to 78 ± 1% in the nasal prong group (p < 0.001 compared to all other groups). Oxygen saturation remained at 95 ± 2% in both the OOD group and the bronchoscopy group (p = 0.451 between those two groups). CONCLUSION: Simulating apneic laryngeal oxygenation in a preoxygenated manikin, both oxygen insufflation via the OOD and the bronchoscope kept oxygen saturation in the test lung at 95% over 20 min. Both methods significantly were more effective than oxygen insufflation via nasal prongs.

Using Bayesian modeling in frequentist adaptive enrichment designs.

Our increased understanding of the mechanistic heterogeneity of diseases has pushed the development of targeted therapeutics. We do not expect all patients with a given disease to benefit from a targeted drug; only those in the target population. That is, those with sufficient dysregulation in the biomolecular pathway targeted by treatment. However, due to complexity of the pathway, and/or technical issues with our characterizing assay, it is often hard to characterize the target population until well into large-scale clinical trials. This has stimulated the development of adaptive enrichment trials; clinical trials in which the target population is adaptively learned; and enrollment criteria are adaptively updated to reflect this growing understanding. This paper proposes a framework for group-sequential adaptive enrichment trials. Building on the work of Simon & Simon (2013). Adaptive enrichment designs for clinical trials. Biostatistics 14(4), 613-625), it includes a frequentist hypothesis test at the end of the trial. However, it uses Bayesian methods to optimize the decisions required during the trial (regarding how to restrict enrollment) and Bayesian methods to estimate effect size, and characterize the target population at the end of the trial. This joint frequentist/Bayesian design combines the power of Bayesian methods for decision making with the use of a formal hypothesis test at the end of the trial to preserve the studywise probability of a type I error.

OpenGeneMed: a portable, flexible and customizable informatics hub for the coordination of next-generation sequencing studies in support of precision medicine trials.

Trials involving genomic-driven treatment selection require the coordination of many teams interacting with a great variety of information. The need of better informatics support to manage this complex set of operations motivated the creation of OpenGeneMed. OpenGeneMed is a stand-alone and customizable version of GeneMed (Zhao et al. GeneMed: an informatics hub for the coordination of next-generation sequencing studies that support precision oncology clinical trials. Cancer Inform 2015;14(Suppl 2):45), a web-based interface developed for the National Cancer Institute Molecular Profiling-based Assignment of Cancer Therapy (NCI-MPACT) clinical trial coordinated by the NIH. OpenGeneMed streamlines clinical trial management and it can be used by clinicians, lab personnel, statisticians and researchers as a communication hub. It automates the annotation of genomic variants identified by sequencing tumor DNA, classifies the actionable mutations according to customizable rules and facilitates quality control in reviewing variants. The system generates summarized reports with detected genomic alterations that a treatment review team can use for treatment assignment. OpenGeneMed allows collaboration to happen seamlessly along the clinical pipeline; it helps reduce errors made transferring data between groups and facilitates clear documentation along the pipeline. OpenGeneMed is distributed as a stand-alone virtual machine, ready for deployment and use from a web browser; its code is customizable to address specific needs of different clinical trials and research teams. Examples on how to change the code are provided in the technical documentation distributed with the virtual machine. In summary, OpenGeneMed offers an initial set of features inspired by our experience with GeneMed, a system that has been proven to be efficient and successful for coordinating the application of next-generation sequencing in the NCI-MPACT trial.

Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment.

BACKGROUND: The APOBEC gene family of cytidine deaminases plays important roles in DNA repair and mRNA editing. In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature. Some studies also suggested a possible involvement of APOBEC3A, REV1, UNG, and FHIT in molecular processes affecting APOBEC mutagenesis. It is important to understand how mutagenic processes linked to the activity of these genes may affect sensitivity of cancer cells to treatment. RESULTS: We used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs. Among the five genes, APOBEC3B expression levels were bimodally distributed, whereas expression of APOBEC3A, REV1, UNG, and FHIT was unimodally distributed. The majority of the cell lines had low levels of APOBEC3A expression. The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A. Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types. CONCLUSIONS: We observed correlations of expression levels of the five candidate genes in cell line models with sensitivity to cancer drug treatment. We also noted suggestive correlations between measures of abundance of APOBEC-like sequence motifs with drug sensitivity in small samples of cell lines from individual cancer categories, which require further validation in larger datasets. Molecular mechanisms underlying the links between the activities of the products of each of the five genes, the resulting mutagenic processes, and sensitivity to each category of antitumor agents require further investigation.

Criteria for the use of omics-based predictors in clinical trials.

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

Intravascular Cooling Device Versus Esophageal Heat Exchanger for Mild Therapeutic Hypothermia in an Experimental Setting.

BACKGROUND: Targeted temperature management is a standard therapy for unconscious survivors of cardiac arrest. To date, multiple cooling methods are available including invasive intravascular cooling devices (IVDs), which are widely used in the clinical setting. Recently, esophageal heat exchangers (EHEs) have been developed providing cooling via the esophagus that is located close to the aorta and inferior vena cava. The objective was to compare mean cooling rates, as well as differences, to target temperature during maintenance and the rewarming period of IVD and EHE. METHODS: The study was conducted in 16 female domestic pigs. After randomization to either IVD or EHE (n = 8/group), core body temperature was reduced to 33°C. After 24 hours of maintenance (33°C), animals were rewarmed using a target rate of 0.25°C/h for 10 hours. All cooling phases were steered by a closed-loop feedback system between the internal jugular vein and the chiller. After euthanasia, laryngeal and esophageal tissue was harvested for histopathological examination. RESULTS: Mean cooling rates (4.0°C/h ± 0.4°C/h for IVD and 2.4°C/h ± 0.3°C/h for EHE; P < .0008) and time to target temperature (85.1 ± 9.2 minutes for IVD and 142.0 ± 21.2 minutes for EHE; P = .0008) were different. Mean difference to target temperature during maintenance (0.07°C ± 0.05°C for IVD and 0.08°C ± 0.10°C for EHE; P = .496) and mean rewarming rates (0.2°C/h ± 0.1°C/h for IVD and 0.3°C/h ± 0.2°C/h for EHE; P = .226) were similar. Relevant laryngeal or esophageal tissue damage could not be detected. There were no significant differences in undesired side effects (eg, bradycardia or tachycardia, hypokalemia or hyperkalemia, hypoglycemia or hyperglycemia, hypotension, overcooling, or shivering). CONCLUSIONS: After insertion, target temperatures could be reached faster by IVD compared to EHE. Cooling performance of IVD and EHE did not significantly differ in maintaining target temperature during a targeted temperature management process and in active rewarming protocols according to intensive care unit guidelines in this experimental setting.

Finding the intended use population for a new treatment.

Genomic tools are demonstrating that many human diseases are molecularly heterogeneous and likely to respond differently to molecularly targeted therapeutics. For many widely used treatments, the number of patients needed to treat (NNT) for each patient who benefits is large indicating that many patients are being exposed to the risks of serious adverse effects although they do not benefit from the drug. Consequently, more accurately determining the intended use population for new therapeutics is of increased importance. In this paper, we describe a new paradigm for identifying and internally validating an estimate of the intended use population in randomized phase III clinical trials. The approach preserves the type I error of the trial and approaches determination of the intended use population as a classification problem, not a multiple hypothesis testing problems.

New designs for basket clinical trials in oncology.

The established molecular heterogeneity of human cancers has had profound effects on the design of cancer therapeutics. Most cancer drugs are today targeted to molecular alterations present in cancer cells. Tumors of the same primary site, however, often differ with regard to the alterations that they harbor. Consequently, this heterogeneity has required the development of new paradigms for clinical development. In this paper, we review some clinical trial designs finding active use in co-development of therapeutics and predictive biomarkers to inform their use in oncology.

Estimation of tumour regression and growth rates during treatment in patients with advanced prostate cancer: a retrospective analysis.

BACKGROUND: We applied mathematical models to clinical trial data available at Project Data Sphere LLC (Cary, NC, USA), a non-profit universal access data-sharing warehouse. Our aim was to assess the rates of cancer growth and regression using the comparator groups of eight randomised clinical trials that enrolled patients with metastatic castration-resistant prostate cancer. METHODS: In this retrospective analysis, we used data from eight randomised clinical trials with metastatic castration-resistant prostate cancer to estimate the growth (g) and regression (d) rates of disease burden over time. Rates were obtained by applying mathematical models to prostate-specific antigen levels as the representation of tumour quantity. Rates were compared between study interventions (prednisone, mitoxantrone, and docetaxel) and off-treatment data when on-study treatment had been discontinued to understand disease behaviour during treatment and after discontinuation. Growth (g) was examined for association with a traditional endpoint (overall survival) and for its potential use as an endpoint to reduce sample size in clinical trials. FINDINGS: Estimates for g, d, or both were obtained in 2353 (88%) of 2678 patients with data available for analysis; g differentiated docetaxel (a US Food and Drug Administration-approved therapy) from prednisone and mitoxantrone and was predictive of overall survival in a landmark analysis at 8 months. A simulated sample size analysis, in which g was used as the endpoint, compared docetaxel data with mitoxantrone data and showed that small sample sizes were sufficient to achieve 80% power (16, 47, and 25 patients, respectively, in the three docetaxel comparator groups). Similar results were found when the mitoxantrone data were compared with the prednisone data (41, 39, and 41 patients in the three mitoxantrone comparator groups). Finally, after discontinuation of docetaxel therapy, median tumour growth (g) increased by nearly five times. INTERPRETATION: The application of mathematical models to existing clinical data allowed estimation of rates of growth and regression that provided new insights in metastatic castration-resistant prostate cancer. The availability of clinical data through initiatives such as Project Data Sphere, when combined with innovative modelling techniques, could greatly enhance our understanding of how cancer responds to treatment, and accelerate the productivity of clinical development programmes. FUNDING: None.