NCI intramural program approach to rare tumors: Natural history study of rare solid tumors in children and adults: A longitudinal, comprehensive data and biospecimen collection protocol.

Rare tumors across the world are lacking adequate knowledge, resources, and community. Through partnership with patients, advocacy organizations, researchers, and clinicians, we have developed a comprehensive, longitudinal, prospective, and retrospective natural history protocol to collect, analyze, and share data on patients with rare tumors. A strong collaborative effort is vital to ensure success of enrollment, patient engagement, data collection, and analysis to ultimately develop clinical trials to improve outcomes for patients with rare cancers.

The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor.

BACKGROUND: Chordomas are rare tumors arising from the skull base and spine, with approximately 20 pediatric chordoma cases in the Unitedn States per year. The natural history and optimal treatment of pediatric chordomas, especially poorly differentiated and dedifferentiated subtypes, is incompletely understood. Herein, we present findings from our first National Cancer Institute (NCI) chordoma clinic and a retrospective analysis of published cases of pediatric poorly differentiated chordomas (PDC) and dedifferentiated chordomas (DC). METHODS: Patients less than 40 years old with chordoma were enrolled on the NCI Natural History and Biospecimens Acquisitions Study for Children and Adults with Rare Solid Tumors protocol (NCT03739827). Chordoma experts reviewed patient records, evaluated patients, and provided treatment recommendations. Patient-reported outcomes, biospecimens, and volumetric tumor analyses were collected. A literature review for pediatric PDC and DC was conducted. RESULTS: Twelve patients (median age: 14 years) attended the clinic, including four patients with active disease and three patients with PDC responsive to systemic therapy. Consensus treatment, management, and recommendations were provided to patients. Literature review returned 45 pediatric cases of PDC or DC with variable treatments and outcomes. CONCLUSIONS: A multidisciplinary expert clinic was feasible and successful in improving understanding of pediatric chordoma. While multimodal approaches have all been employed, treatment for PDC has been inconsistent and a recommended standardized treatment approach has not been defined. Centralized efforts, inclusive of specialized chordoma-focused clinics, natural history studies, and prospective analyses will help in the standardization of care for this challenging disease.

Mercapturate pathway metabolites of sotorasib, a covalent inhibitor of KRASG12C, are associated with renal toxicity in the Sprague Dawley rat.

Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. In the nonclinical toxicology studies of sotorasib, the kidney was identified as a target organ of toxicity in the rat but not the dog. Renal toxicity was characterized by degeneration and necrosis of the proximal tubular epithelium localized to the outer stripe of the outer medulla (OSOM), which suggested that renal metabolism was involved. Here, we describe an in vivo mechanistic rat study designed to investigate the time course of the renal toxicity and sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted to the OSOM, and the morphologic features progressed from vacuolation and necrosis to regeneration of tubular epithelium. The renal toxicity correlated with increases in renal biomarkers of tubular injury. Using mass spectrometry and matrix-assisted laser desorption/ionization, a strong temporal and spatial association between renal toxicity and mercapturate pathway metabolites was observed. The rat is reported to be particularly susceptible to the formation of nephrotoxic metabolites via this pathway. Taken together, the data presented here and the literature support the hypothesis that sotorasib-related renal toxicity is mediated by a toxic metabolite derived from the mercapturate and ß-lyase pathway. Our understanding of the etiology of the rat specific renal toxicity informs the translational risk assessment for patients.

Nonclinical Safety Profile of Sotorasib, a KRASG12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer.

Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors.

Barriers to identifying and obtaining CME: a national survey of physicians, nurse practitioners and physician assistants.

BACKGROUND: CPD educators and CME providers would benefit from further insight regarding barriers and supports in obtaining CME, including sources of information about CME. To address this gap, we sought to explore challenges that clinicians encounter as they seek CME, and time and monetary support allotted for CME. METHODS: In August 2018, we surveyed licensed US clinicians (physicians, nurse practitioners, and physician assistants), sampling 100 respondents each of family medicine physicians, internal medicine and hospitalist physicians, medicine specialist physicians, nurse practitioners, and physician assistants (1895 invited, 500 [26.3%] responded). The Internet-based questionnaire addressed barriers to obtaining CME, sources of CME information, and time and monetary support for CME. RESULTS: The most often-selected barriers were expense (338/500 [68%]) and travel time (N = 286 [57%]). The source of information about CME activities most commonly selected was online search (N = 348 [70%]). Direct email, professional associations, direct mail, and journals were also each selected by > 50% of respondents. Most respondents reported receiving 1-6 days (N = 301 [60%]) and $1000-$5000 (n = 263 [53%]) per year to use in CME activities. Most (> 70%) also reported no change in time or monetary support over the past 24 months. We found few significant differences in responses across clinician type or age group. In open-ended responses, respondents suggested eight ways to enhance CME: optimize location, reduce cost, publicize effectively, offer more courses and content, allow flexibility, ensure accessibility, make content clinically relevant, and encourage application. CONCLUSIONS: Clinicians report that expense and travel time are the biggest barriers to CME. Time and money support is limited, and not increasing. Online search and email are the most frequently-used sources of information about CME. Those who organize and market CME should explore options that reduce barriers of time and money, and creatively use online tools to publicize new offerings.

Mitosis in neurons: Roughex and APC/C maintain cell cycle exit to prevent cytokinetic and axonal defects in Drosophila photoreceptor neurons.

The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.

Costs and Economic Impacts of Physician Continuous Professional Development: A Systematic Scoping Review.

PURPOSE: Nearly all health care professionals engage in continuous professional development (CPD), yet little is known about the cost and cost-effectiveness of physician CPD. Clarification of key concepts, comprehensive identification of published work, and determination of research gaps would facilitate application of existing evidence and planning for future investigations. The authors sought to systematically map study themes, methods, and outcomes in peer-reviewed literature on the cost and value of physician CPD. METHOD: The authors conducted a scoping review, systematically searching MEDLINE, Embase, PsycInfo, and Cochrane Library databases for comparative economic evaluations of CPD for practicing physicians through April 2020. Two reviewers, working independently, screened all articles for inclusion. Three reviewers iteratively reviewed all included articles to inductively identify key features including participants, educational interventions, study designs, cost ingredients, and cost analyses. Two reviewers then independently reexamined all included articles to code these features. RESULTS: Of 3,338 potentially eligible studies, 111 were included. Physician specialties included internal, family, or general medicine (80 studies [72%]), surgery (14 studies [13%]), and medicine subspecialties (7 studies [6%]). Topics most often addressed general medicine (45 studies [41%]) or appropriate drug use (37 studies [33%]). Eighty-seven studies (78%) compared CPD with no intervention. Sixty-three studies (57%) reported the cost of training, and 79 (71%) evaluated the economic impact (money saved/lost following CPD). Training cost ingredients (median 3 itemized per study) and economic impact ingredients (median 1 per study) were infrequently and incompletely identified, quantified, or priced. Twenty-seven studies (24%) reported cost-impact expressions such as cost-effectiveness ratio or net value. Nineteen studies (17%) reported sensitivity analyses. CONCLUSIONS: Studies evaluating the costs and economic impact of physician CPD are few. Gaps exist in identification, quantification, pricing, and analysis of cost outcomes. The authors propose a comprehensive framework for appraising ingredients and a preliminary reference case for economic evaluations.

Fracture Risk in Pediatric Patients With MEN2B.

CONTEXT: The skeletal phenotype of patients with MEN2B has been described but fracture risk in these patients has not yet been evaluated. OBJECTIVE: This work aims to better delineate fracture risk in patients with multiple endocrine neoplasia type 2B (MEN2B). METHODS: This case series with chart review was conducted at the National Institutes of Health, Pediatric Oncology Branch. A total of 48 patients with MEN2B were identified, with an age range of 5 to 36 years, median of 19; 24 of 48 (50%) patients were female. Medical records, demographic information, available imaging, and laboratory results were reviewed. History up to age 19 was included in the statistical analyses. RESULTS: Of the 48 patients with MEN2B, 20 patients experienced at least one fracture. The majority (n = 18) experienced their first fracture at or before age 19. The observed frequency of fracture occurrence throughout childhood (0-19 years) was 38%, with very little difference between males and females. This frequency is higher than the 9.47 to 36.1 fractures per 1000 persons per year that has been reported in healthy pediatric cohorts in the United States. Less common sites of fracture including vertebral compression fracture and pelvic fractures were observed in patients with MEN2B. CONCLUSION: In this group of patients with MEN2B, there was an increased overall risk of fracture compared to general pediatric cohorts in the United States. Less common sites of fracture were also observed. This suggests a possible effect of an activating RET mutation on bone physiology and warrants further investigation.

Update on Targeted Therapy in Medullary Thyroid Cancer.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor that accounts for 2-4% of all thyroid cancers. All inherited MTC and approximately 50% of sporadic cases are driven by mutations in the REarranged during Transfection (RET) proto-oncogene. The recent expansion of the armamentarium of RET-targeting tyrosine kinase inhibitors (TKIs) has provided effective options for systemic therapy for patients with metastatic and progressive disease. However, patients that develop resistant disease as well as those with other molecular drivers such as RAS have limited options. An improved understanding of mechanisms of resistance to TKIs as well as identification of novel therapeutic targets is needed to improve outcomes for patients with MTC.

What Influences Choice of Continuing Medical Education Modalities and Providers? A National Survey of U.S. Physicians, Nurse Practitioners, and Physician Assistants.

PURPOSE: To explore what influences clinicians in selecting continuing medical education (CME) activities in the United States. METHOD: In August 2018, the authors conducted an Internet-based national survey, sampling 100 respondents from each of 5 groups: family medicine physicians, internal medicine and hospitalist physicians, medicine specialist physicians, nurse practitioners, and physician assistants. In total, 1,895 clinicians were invited and 500 (26%) responded. Questions addressed the selection and anticipated use of CME delivery modalities and perceived characteristics of specific CME providers. Response formats used best-worst scaling or 5-point ordinal response options. RESULTS: The factors identified as most important in selecting CME activities were topic (best-worst scaling net positivity 0.54), quality of content (0.51), availability of CME credit (0.43), and clinical practice focus (0.41), while referral frequency (-0.57) ranked lowest. The activities that the respondents anticipated using most in the future were live (mean 3.8 [1 = not likely, 5 = very likely]), online (mean 3.5), point-of-care (mean 3.5), and print-based (mean 3.5) activities. For online CME, the features of greatest appeal were that learning could be done when clinicians had time (mean 4.4), at their own pace (mean 4.2), and at lower cost (mean 4.2). For live CME, the features of greatest appeal were that the subject was best taught using this modality (mean 4.0), or the activity was located in a destination spot (mean 4.0) or a regional location (mean 3.9). When rating specific CME providers, most academic institutions received relatively high ratings for research focus and clinical practice focus, whereas commercial providers had slightly higher ratings for ease of access. Responses were generally similar across clinician types and age groups. CONCLUSIONS: Physicians, nurse practitioners, and physician assistants are interested in using a variety of CME delivery modalities. Appealing features of online and live CME were different.

Cell-cycle control during development: taking it up a notch.

The signals that coordinate cellular proliferation with G1 arrest and differentiation have long been of interest. Two papers in this issue of Developmental Cell show that the conserved Hedgehog and Notch signaling pathways regulate cell division during development of the Drosophila compound eye.

Impact of comorbid cannabis use on outcome in first episode psychosis.

AIM: Comorbid cannabis abuse is common in patients with early psychosis. Little is known about the effect of stopping cannabis use on positive, negative and depressive symptoms. Few studies have controlled for multiple substance use that may mask the specific role that cannabis plays in symptom outcomes. The aim of this study was to investigate whether course and level of cannabis use negatively impacted early psychosis patient symptom profiles (positive, negative and depressive symptoms) over 24 months. METHODS: One hundred and ninety-two patients admitted to an early psychosis intervention programme in a naturalistic setting were followed across three time periods: initial presentation, 12 and 24 months. Patients' clinical characteristics (substance use, positive/negative symptoms and depressive symptoms) were assessed at each time period. RESULTS: There were no significant associations found between cannabis abuse and positive and negative symptoms. Continuation and discontinuation of cannabis use were not significant for cannabis or any other substance when compared to positive and negative symptoms. There was a significant interaction between cannabis and alcohol for depressive symptoms, where depressive symptoms were significantly higher in patients who abused cannabis without co-occurring alcohol abuse when compared to non-cannabis using patients. CONCLUSION: The current study findings indicate a complex interaction between cannabis and alcohol use in a sample of early psychosis patients across 24 months. More research is needed into the association between ceasing cannabis use and long-term outcome for early psychosis patients. Of particular importance is the interaction between level of cannabis and alcohol use as it is related to symptom outcome in early psychosis patients.

Educational Technologies for Physician Continuous Professional Development: A National Survey.

PURPOSE: To determine the past experiences with, current use of, and anticipated use of online learning and simulation-based education among practicing U.S. physicians, and how findings vary by age. METHOD: The authors surveyed 4,648 randomly sampled board-certified U.S. physicians, September 2015 to April 2016, using Internet-based and paper questionnaires. Survey items (some optional) addressed past and current technology usage, perceived technology effectiveness, and anticipated future use of specific technology innovations. RESULTS: Of 988 respondents, 444 completed optional items. Of these, 429/442 (97.1%) had used online learning and 372/442 (84.2%) had used simulation-based education in the past five years. Desire for more online learning was modest (mean [standard deviation], 4.6 [1.5]; 1 = strongly disagree, 7 = strongly agree), as was desire for more simulation-based education (4.2 [1.7]). Both online learning and simulation-based education were perceived as effective (5.2 [1.4]; 5.0 [1.4]). Physicians believed they possess adequate skills for online learning (5.8 [1.2]) and that point-of-care learning is vital to effective patient care (5.3 [1.3]). Only 39.0% used objective performance data to guide their learning choices, although 64.6% agreed that such information would be useful. The highest-rated innovations included a central repository for listing educational opportunities and tracking continuing education credits, an app to award credit for answering patient-focused questions, 5-minute and 20-minute clinical updates, and an e-mailed "question of the week." Responses to most survey items were similar across age groups. CONCLUSIONS: Practicing physicians generally seem receptive and prepared to use a variety of educational technologies, regardless of age.

A heart for change.

The effectiveness of change management is driven by six factors: A clear and consistent message from the top. A palpable connection between leaders and clinicians. Departments that perform their functions well, but also work in sync with other departments. A healthy level of resistance in the change process. Effective communication. A model for monitoring the change process and responding early to variances.

Visual art and breast health promotion: artists' perspectives.

Unique methodologies to promote health are important to meet the needs of various populations. This paper presents a collaborative approach among nursing, visual arts, and women's studies to promote breast health using visual art. The purpose of this paper is to describe the project from the perspectives of the artists, gain insight into breast health, and understand the use of visual art as a health promotion tool. A structured interview format was employed and data were thematically analyzed. The three main themes that emerged were a strong personal connection to and fear of breast cancer, the need and desire to promote health within the community, and the uni-dimensional nature of breast cancer and breast health. The interviews demonstrated that visual art is an innovative and adaptive methodology to promote breast health.

A national survey of Canadian women: breast health practices, influences, and satisfaction.

In an earlier survey of over 900 women in the local automobile industry, several influences and preferences for breast screening were identified. The purpose of the current study was to extend the survey population to women across Canada, as well as to ascertain women's satisfaction with organized (governmental) screening programs within their geographic areas. Using random-digit-dialing, 1,224 women 25 years and older were interviewed in French or English and their responses entered in a CATI system. The interviewers used a modified version of Health Care Practices: A Worksite Survey. Results were analyzed by age and geographic region. Results indicated support for earlier local findings, as well as high satisfaction, but low knowledge and usage of organized breast screening clinics.

Breast health educational interventions. Changes in beliefs and practices of working women.

Health education programs supported by women's groups or workplaces have been successful in reaching large populations and changing intentions to perform breast health behaviors. This study examined the responses women working in the automotive industry had to two health education interventions, mailed pamphlets, and a combination of mailed material and classes at the worksite compared to a control group. A quasi-experimental design was used. Of the 948 women completing the pre-test, 437 also completed the post-test and were highly representative of the initial sample. The findings suggest that although the mailed information produced some change in practices and intentions, the classes in combination with the mailed pamphlets produced greater change. In addition, confidence in breast self examination as a method of detecting an existing breast lump increased from pre-test to post-test across all age groups. The reported influences on the women's decisions related to breast health varied across the life span. The results of this study can be used to support the development of effective health promotion programs for use at workplaces to increase the likelihood of women engaging in healthy breast practices.

Piloting a nationally disseminated, interactive human subjects protection program for community partners: design, content, and evaluation.

Funders, institutions, and research organizations are increasingly recognizing the need for human subjects protections training programs for those engaged in academic research. Current programs tend to be online and directed toward an audience of academic researchers. Research teams now include many nonacademic members, such as community partners, who are less likely to respond to either the method or the content of current online trainings. A team at the CTSA-supported Michigan Institute for Clinical and Health Research at the University of Michigan developed a pilot human subjects protection training program for community partners that is both locally implemented and adaptable to local contexts, yet nationally consistent and deliverable from a central administrative source. Here, the developers and the analysts of this program discuss its development, its content, and the results of its evaluation.

Delirium secondary to pregabalin.

Fibromyalgia is a common and disabling disease, and treatment can be challenging. More recently, pregabalin has been approved to treat pain associated with fibromyalgia. However, it can have serious neuropsychiatric sequelae. Several case reports have documented delirium secondary to pregabalin, usually in older patients with multiple medical comorbidities and concurrent medications. We describe a case of delirium in a young patient without significant medical problems and in the absence of other potentially causal medications. In this case, pregabalin appears to be the single causal etiology for delirium. We recommend clinicians to consider the causal role it may play in any patient who presents with delirium.

Endo-epicardial ablation of ventricular arrhythmias in the left ventricle with the Remote Magnetic Navigation System and the 3.5-mm open irrigated magnetic catheter: results from a large single-center case-control series.

BACKGROUND: Remote magnetic navigation (RMN) has been reported as a feasible and safe mapping and ablation system for treatment of ventricular arrhythmias (VAs). However, the reported success rates have been limited with the 4- and 8-mm catheter tips. OBJECTIVE: This study sought to report the results in a large series of consecutive patients undergoing radiofrequency (RF) catheter ablation of VAs using the RMN with the 3.5-mm magnetic open-irrigated-tip catheter (OIC). METHODS: A total of 110 consecutive patients with a clinical history of left VA were included in the study. In all cases, an OIC was utilized for mapping and ablation. When ablation with the RMN catheters failed, a manual OIC was used to eliminate the VA. Postablation pacing maneuvers and isoproterenol were used to verify the inducibility of the VAs. Outcomes were compared with those of a group of 92 consecutive patients undergoing manual ablation by the same operator. RESULTS: Mapping and ablation with the magnetic OIC were performed in all 110 patients with VA. Ischemic cardiomyopathy was present in 33 (30%), nonischemic in 14 (13%), and in 63 (57%) patients no structural heart disease was present. Endocardial mapping was performed in all patients, whereas both endocardial and epicardial mapping were performed in 36 (33%) patients. Compared with manual ablation, RMN was associated with a longer procedural time (2.9 +/- 1.2 hours vs. 3.3 +/- 1.1 hours, P = 0.004) and RF time (24 +/- 12 minutes vs. 33 +/- 18 minutes, P = 0.005), whereas fluoroscopic time was significantly shorter (35 +/- 22 minutes vs. 26 +/- 14 minutes, P = 0.033). During the procedures, crossover to manual ablation was required in 15 patients (14%). At 11.7 +/- 2.1 months of follow-up in the study group and 18.7 +/- 3.7 months in the manual ablation group, 85% and 86% (P = 0.817) of patients, respectively, were free of VA. CONCLUSION: This large series of consecutive patients demonstrates that OIC ablation using RMN is effective for the treatment of left VAs.