A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

Predictors of parent's knowledge of hospital-based pediatric falls.

PURPOSE: This study aimed to validate and to determine the individual characteristics and demographic factors associated with parents' knowledge of hospital-based pediatric falls and to identify parent populations more likely to report low levels of falls-related knowledge. DESIGN: Validation of a questionnaire and a cross-sectional survey design. METHODS: Parents (n = 200) of hospitalized children admitted to a tertiary specialist pediatric hospital in Australia completed an online questionnaire. Parents were asked to rate their hospital-based falls knowledge using a Likert scale (1-5). The questionnaire was administered to parents across six hospital wards, 1 day a week, from May to August 2019. Validation of the questionnaire involved factor analyses and reliability tests. Finally, descriptive analysis measured parents' knowledge, and a multivariate logistic regression analysis reported factors associated with parents' falls knowledge. All data were analyzed in Statistical Package for the Social Sciences (V27). Ethical approval was received for all stages. RESULTS: The final version of the parent knowledge of falls (PKOF) questionnaire consisted of 23 questions across five domains (Cronbach α = .929-.70). Parents' knowledge of hospital-based falls ranged from 2.5 to 4.5, while knowledge that children may fall during parental presence rated the lowest score. Knowledge of inpatient falls was higher if their child had a high risk of falls (odds ratio [OR]: 2.1, p = .04) and they were Australian-born parents (OR: 1.9, p = .05). PRACTICE IMPLICATIONS: The PKOF questionnaire is an evidence-based instrument developed for a pediatric hospital setting. Findings highlight knowledge gaps and parent groups with the highest risk of having inadequate hospital-based falls knowledge. The questionnaire enables pediatric nurses and educators to measure parents' knowledge of hospital-based falls accurately and consistently, and so to identify gaps and, subsequently, develop, implement, and evaluate falls education using an evidence-based approach.

Discordant attitudes and beliefs about cancer clinical trial participation between physicians, research staff, and cancer patients.

BACKGROUND/AIMS: Essential to bringing innovative cancer treatments to patients is voluntary participation in clinical trials but approximately 8% of American cancer patients are enrolled onto a trial. We used a domain-oriented framework to assess barriers to cancer clinical trial enrollment. METHODS: Physicians (MD, DO, fellows, residents) and research staff (physician assistants, nurse practitioners, staff and research nurses, clinical assistants, and program coordinators) involved in clinical research at a comprehensive cancer center completed an online survey in 2017; adult cancer patients not currently enrolled in a trial were interviewed in 2018. To inform the construct of our physician/staff and patient surveys and to assess barriers to clinical trial enrollment, we first conducted in-depth interviews among 14 key informants representing medical, hematologic, gynecologic, neurologic, radiation oncology, as well as members of the clinical research team (one clinical research coordinator, one research nurse practitioner). Perceived structural, provider- and patient-level barriers to clinical trial enrollment were assessed. Differences in perceptions, attitudes, and beliefs toward clinical trial enrollment between (1) physicians and staff, (2) patients by ethnicity, and (3) physicians/staff and patients were examined. RESULTS: In total, 120 physicians/staff involved in clinical research (39.2% physicians, 60.8% staff; 48.0% overall response rate) and 150 cancer patients completed surveys. Nearly three-quarters of physician/staff respondents reported difficulty in keeping track of the eligibility criteria for open studies but was more often cited by physicians than staff (84.4% vs 64.3%, p = 0.02). Physicians more often reported lack of time to present clinical trial information than did staff(p < 0.001); 44.0% of staff versus 18.2% of physicians reported patient family interaction as a clinical trial enrollment barrier (p = 0.007). Hispanic patients more often stated they would join a trial, even if standard therapy was an option compared to non-Hispanic patients (47.7% vs 20.8%, p = 0.002). Comparing the beliefs and perceptions of physicians/staff to those of patients, patients more often reported negative beliefs about clinical trial enrollment (e.g. being in a trial does not help patients personally, 32.9% vs 1.8%, p < 0.001) but less often felt they had no other options when agreeing to join (38.1% vs 85.6%, p < 0.001), and less often refused clinical trial enrollment due to lack of understanding (9.1% vs 63.3%, p = 0.001) than reported by physicians/staff. CONCLUSION: Our findings indicate a wide gap between physician/staff and patient attitudes and beliefs about clinical trial enrollment and highlight the importance of focusing future initiatives to raise awareness of this incongruency. Reconciling these differences will require tailored education to reduce implicit biases and dispel misperceptions. Strategies to improve the quality of patient-provider communication and address infrastructure and resource issues are also needed to improve patient enrollment onto cancer clinical trials.

Readability of Cancer Clinical Trials Websites.

Clinical trials are critically important for the development of new cancer treatments. According to recent estimates, however, clinical trial enrollment is only about 8%. Lack of patient understanding or awareness of clinical trials is one reason for the low rate of participation. The purpose of this observational study was to evaluate the readability of cancer clinical trial websites designed to educate the general public and patients about clinical trials. Nearly 90% of Americans use Google to search for health-related information. We conducted a Google Chrome Incognito search in 2018 using the keywords "cancer clinical trial" and "cancer clinical trials." Content of the 100 cancer clinical trial websites was analyzed using an online readability panel consisting of Flesch-Kincaid Grade Level, Flesch Reading Ease, Gunning-Fog Index, Coleman-Liau Index, and Simple Measure of Gobbledygook scales. Reading level difficulty was assessed and compared between commercial versus non-commercial URL extensions. Content readability was found to be "difficult" (10.7 grade level). No significant difference in readability, overall, and between commercial and non-commercial URL extensions was found using 4/5 measures of readability; 90.9% of commercial versus 49.4% of non-commercial websites were written at a >10th grade (P = .013) using Gunning-Fog Index. Written cancer clinical trials content on the Internet is written at a reading level beyond the literacy capabilities of the average American reader. Improving readability to accommodate readers with basic literacy skills will provide an opportunity for greater comprehension that could potentially result in higher rates of clinical trial enrollment.

Exploring Australian parents' knowledge and awareness of pediatric inpatient falls: A qualitative study.

PURPOSE: While there has been extensive published research into adult inpatient falls, less is known about pediatric falls in Australia. Falls pose a safety risk to pediatric patients potentially causing harm, increased length of stay, and death. Parents play a central role in reducing falls-related incidents given that, as parents, they provide care and/or oversee care delivered to their child at the bedside. Developing a better understanding of what parents and carers know about falls and associated risks, particularly those hospital-naïve, is central to developing family centered strategies and targeted education to meet the needs of parents. Our study aimed to explore Australian parents' knowledge and awareness of pediatric inpatient falls. DESIGN: Qualitative methods utilizing descriptive thematic analysis. METHODS: Parents of children and/or young people hospitalized during the last 6 months were eligible to participate. Potential participants attending the outpatient clinics of two tertiary pediatric outpatient clinics hospitals in Sydney, Australia were invited to participate in the study. Willing participants consented to complete a face to face in-depth interview. Open-ended questions sought to explore participants' knowledge, knowledge acquisition, and awareness of inpatient falls. Interviews were digitally recorded and transcribed verbatim. Data familiarization and open coding were completed by researchers independently. Researchers explored and discussed emerging categories until patterns emerged and a consensus of dominant themes were agreed upon. RESULTS: Interviews were conducted with mothers (n = 17), fathers ( n = 4), or both parents together (n = 2) of a child or a young person who had been recently hospitalized. Four dominant themes emerged from the data namely: Supervision: falls won't happen, unexpected, parent priorities, and ways of learning about inpatient falls and risks. Despite parents' awareness of falls risk, parents were unaware that falls occur within a hospital setting and did not prioritize "falls prevention" during admission. PRACTICE IMPLICATIONS: Findings have implications for nursing practice, particularly in the delivery, content, and timing of falls prevention education.

YouTube Videos as a Source of Information About Clinical Trials: Observational Study.

BACKGROUND: Clinical trials are essential to the advancement of cancer treatment but fewer than 5% of adult cancer patients enroll in a trial. A commonly cited barrier to participation is the lack of understanding about clinical trials. OBJECTIVE: Since the internet is a popular source of health-related information and YouTube is the second most visited website in the world, we examined the content of the top 115 YouTube videos about clinical trials to evaluate clinical trial information available through this medium. METHODS: YouTube videos posted prior to March 2017 were searched using selected keywords. A snowballing technique was used to identify videos wherein sequential screening of the autofill search results for each set of keywords was conducted. Video characteristics (eg, number of views and video length) were recorded. The content was broadly grouped as related to purpose, phases, design, safety and ethics, and participant considerations. Stepwise multivariable logistic regression analysis was conducted to assess associations between video type (cancer vs noncancer) and video characteristics and content. RESULTS: In total, 115 videos were reviewed. Of these, 46/115 (40.0%) were cancer clinical trials videos and 69/115 (60.0%) were noncancer/general clinical trial videos. Most videos were created by health care organizations/cancer centers (34/115, 29.6%), were oriented toward patients (67/115, 58.3%) and the general public (68/115, 59.1%), and were informational (79/115, 68.7%); altruism was a common theme (31/115, 27.0%). Compared with noncancer videos, cancer clinical trials videos more frequently used an affective communication style and mentioned the benefits of participation. Cancer clinical trial videos were also much more likely to raise the issue of costs associated with participation (odds ratio [OR] 5.93, 95% CI 1.15-29.46) and advise patients to communicate with their physician about cancer clinical trials (OR 4.94, 95% CI 1.39-17.56). CONCLUSIONS: Collectively, YouTube clinical trial videos provided information on many aspects of trials; however, individual videos tended to focus on selected topics with varying levels of detail. Cancer clinical trial videos were more emotional in style and positive in tone and provided information on the important topics of cost and communication. Patients are encouraged to verify and supplement YouTube video information in consultations with their health care professionals to obtain a full and accurate picture of cancer clinical trials to make an adequately informed decision about participation.

Gemcitabine-induced pulmonary toxicity.

BACKGROUND: Gemcitabine is the only approved cytotoxic agent for the treatment of pancreatic cancer by the Food and Drug Administration. In addition, gemcitabine is also commonly used for the management of breast, ovarian, and non-small cell lung cancer. Myelosuppression is the most common toxicity of gemcitabine therapy. Pulmonary toxicities due to gemcitabine have, however, been reported. Dyspnea occurs in approximately 25% of patients treated with gemcitabine, whereas serious pulmonary toxicities are much less common, approximately 0.3%. Here, we present a case of gemcitabine-induced pneumonitis, encountered during treatment of pancreatic cancer, and review the literature of this rare, but dangerous complication. CASE REPORT: A 56-year old male being treated for stage IV pancreatic cancer developed progressive dyspnea on exertion, chest tightness, and palpitations. Oxygen saturation was 82-84%. Computerized-tomography (CT) angiography of the chest demonstrated new diffuse groundglass opacities in the bilateral lower lobes when compared to the CT of the chest without intravenous contrast, 5 weeks prior. Mild to moderate emphysema was also seen, but no pulmonary emboli were detected. Myocardial infraction was ruled-out by normal electrocardiogram and normal cardiac biomarkers. CONCLUSION: We report another case of gemcitabine-induced pneumonitis. Physicians seeing such patients should be aware of this rare but real pulmonary toxicity. A delay in diagnosis and treatment can lead to potentially fatal outcomes.

Sildenafil for chronic obstructive pulmonary disease: a randomized crossover trial.

RATIONALE: Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema. METHODS: We performed a randomized, double-blind, placebo-controlled 2-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan without pulmonary hypertension. We randomized study participants to 4 weeks of sildenafil (or placebo) followed by a 1-week washout and then 4 weeks of placebo (or sildenafil). The 2 primary outcomes were the 6-minute walk distance and oxygen consumption at peak exercise. RESULTS: Sildenafil had no effect on 6-minute walk distance (placebo-corrected difference = -7.8 m, 95% confidence interval, -23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = -0.1 ml/kg/min, 95% confidence interval -2.1 to 1.8 ml/kg/min, p = 0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p = 0.02), worsened symptoms (p = 0.04), and decreased quality-of-life (p = 0.03). Adverse events were more frequent while receiving sildenafil (p = 0.005). CONCLUSIONS: Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema without pulmonary hypertension. Sildenafil significantly worsened gas exchange at rest and quality of life. (clinicaltrials.gov NCT00104637).

NETT coordinators: researchers, caregivers, or both?

The National Emphysema Treatment Trial (NETT) required the coordinated evaluation and treatment of thousands of patients with emphysema simultaneous with data collection to evaluate the safety and efficacy of surgery versus medical treatment for emphysema. These tasks were performed by a multidisciplinary team led by the clinic coordinator at each NETT center. The clinic coordinators functioned as members of the research team as well as communicators, managers, and members of the patient care team. The clinic coordinators' ability to balance these roles was instrumental to the successful completion of NETT, as evidenced by randomization of 1,218 subjects with only 10 subjects being lost to follow-up. Striving to achieve recruitment goals and working to retain study subjects was very labor intensive. The coordinator role was complicated by the study population's severity of illness combined with the complexity of the NETT protocol. Management of the study subjects' medical condition had to be balanced with the management of a multicenter, randomized clinical trial to ensure quality data collection and protocol adherence.

Multidisciplinary care of the patient with chronic obstructive pulmonary disease.

The National Emphysema Treatment Trial used a multidisciplinary team approach to implement the maximum medical care protocol, including adjustment of medications and outpatient pulmonary rehabilitation for all patients and nutritional and psychological counseling as needed. This article discusses the benefits of such an approach in the care of the patient with chronic obstructive pulmonary disease. Team member roles complement each other and contribute to the goal of providing the highest-quality medical care. The primary focus of the team is to reinforce the medical plan and to provide patient education and support. This article reviews the elements of the initial patient assessment and the functional and nutritional assessment. Patient education focuses on medication use, recognition and management of chronic obstructive pulmonary disease exacerbation symptoms, smoking cessation, advance directives, and travel.

Lung-volume reduction surgery for pulmonary emphysema: Improvement in body mass index, airflow obstruction, dyspnea, and exercise capacity index after 1 year.

OBJECTIVES: We hypothesized that lung-volume reduction surgery for pulmonary emphysema would improve body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index, a multidimensional predictor of survival in chronic obstructive pulmonary disease. We also aimed to identify preoperative predictors of improvement in the BODE index. METHODS: In a prospective cohort study of patients undergoing lung-volume reduction surgery at our center, with the methodology of the National Emphysema Treatment Trial, we compared clinical characteristics before and 1 year after surgery with the Wilcoxon signed rank test. Changes in the BODE index were correlated with preoperative variables with the Spearman correlation coefficient. RESULTS: Twenty-three patients with predominantly upper-lobe pulmonary emphysema underwent lung-volume reduction surgery (14 by video-assisted thoracoscopic surgery, 9 by median sternotomy). There were no postoperative or follow-up deaths. The BODE index improved from a median of 5 (interquartile range 4-5) before surgery to 3 (interquartile range 2-4) 1 year after surgery (P < .0001). Improvements were seen in the lung function and dyspnea components of the BODE index. Lower preoperative 6-minute walk distance and lower postwalk Borg fatigue scores were each associated with greater improvement in the BODE index after 1 year. CONCLUSION: Lung-volume reduction surgery for pulmonary emphysema improved the BODE index in patients with predominantly upper-lobe disease. Lower preoperative 6-minute walk distance correlated with greater improvement in the BODE index.