The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

PURPOSE: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. EXPERIMENTAL DESIGN: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. RESULTS: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. CONCLUSION: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. IMPLICATIONS FOR PRACTICE: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.

Prevalence of and Risk Factors for Low Bone Mineral Density in Children With Celiac Disease.

BACKGROUND & AIMS: Celiac disease can reduce bone mineral density. We sought to determine the prevalence and risk factors for low areal bone mineral density (aBMD) in children with celiac disease. METHODS: We performed a retrospective cohort study of 673 children with celiac disease (63% female; median age at diagnosis, 10.6 y; interquartile range, 7.8-13.9) who underwent dual x-ray absorptiometry (DXA) from 2009 through 2016 at the Children's Hospital of Philadelphia. We collected demographic, clinical, and laboratory data from medical records. We performed logistic regression analysis to identify factors associated with low (Z less than -2) lumbar spine aBMD Z (aBMD-Z) scores at initial and subsequent tests. RESULTS: The time between diagnosis of celiac disease and first DXA was 0 days (interquartile range, -11 to 31 d). The mean aBMD-Z score at the children's initial scan was -0.4 ± 1.2; 46 children had aBMD-Z scores less than -2 (6.8%; 95% CI, 5.2%-9.0%). Those who had a second DXA analysis (n = 108; 16.0%) had a significant increase in aBMD-Z score (mean change, 0.29; P = .0005). Higher body mass index (BMI) was associated with lower odds of a low aBMD-Z score at the initial DXA analysis (odds ratio, 0.46, 95% CI, 0.35-0.50). BMI-Z scores greater than -0.4 identified children with a low aBMD-Z at their initial DXA analysis with a 95% negative predictive value. CONCLUSIONS: Approximately 7% of subjects with celiac disease had a low aBMD-Z score, determined by DXA, at the time of diagnosis; this value was nearly 3-fold higher than expected from a population of children of this age and sex distribution. BMI-Z scores could be used to identify children with celiac disease at risk for low BMD who should receive DXA screening.

Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.

By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.

Characterization of early non-responders within behavioral weight loss treatment.

Objective: Given that low early (4 weeks) weight loss (WL) predicts longer-term WL, the purpose of this study was to identify factors associated with poor early WL. Methods: 438 adults with overweight/obesity participating in an Internet-delivered behavioral WL program provided weights at baseline and 4 weeks. Participants were stratified by percent WL at 4 weeks: LOW: <2% WL, MEDIUM: 2 to <4% WL, HIGH: ≥4% WL and groups were compared on baseline variables (demographics, physical activity, and psychosocial measures) and 4-week intervention adherence. Results: 37.4%, 40.9%, and 21.7% of participants had LOW, MEDIUM, and HIGH early WL respectively. LOW was more likely to be female compared to HIGH and less likely to be non-Hispanic White compared to MEDIUM and HIGH (p's<0.05). After controlling for demographic differences, LOW had lower baseline physical activity compared to HIGH and watched fewer video lessons, self-monitored calorie intake and weight on fewer days, and were less likely to achieve the exercise goal compared to MEDIUM and HIGH (p's<0.05). Conclusion: Findings can inform future adaptive interventions which tailor treatment based upon early WL to improve WL outcomes for more individuals.

Associations of daily weight management-focused social support with weight loss, activity behaviors, and eating regulation in the context of metabolic and bariatric surgery.

Objective: Greater perceived social support (PSS) is associated with more favorable changes in weight loss, activity behaviors, and eating regulation after metabolic and bariatric surgery (MBS). However, studies have relied on generic, retrospective PSS measures, and stability of PSS levels and relations with weight loss and weight-related behaviors over time is unknown. Using smartphone-based Ecological Momentary Assessment, this study evaluated pre-to 1-year post-MBS changes in daily weight management-focused PSS and associations with weight loss, device-measured activity behaviors, and eating regulation before and during the initial year after MBS. Method: Adult MBS patients (n = 71) received (1) an accelerometer to measure daily moderate-to-vigorous intensity physical activity (MVPA) and sedentary time (ST) minutes/day, and (2) a smartphone to complete morning weight-focused PSS ratings and eating regulation (dietary restraint/disinhibition) ratings at four semi-random times daily for 10 days at pre- and 3, 6, and 12-month postoperative. Generalized linear mixed models analyzed the associations of PSS with total weight loss (%TWL) and activity/eating outcomes. Results: Participants on average reported relatively stable moderate-to-high PSS (3.98 on one to five scale) across assessments. Perceived social support was not related to %TWL, MVPA, or ST. Participants with higher PSS reported lower disinhibition and higher restraint than those with lower PSS (ps < 0.05); however, participants reported higher restraint on days that PSS was lower than their usual levels (p = 0.009). Conclusions: MBS patients on average had stable PSS levels across time. Higher PSS levels were associated with greater resistance to overeating cues (disinhibition) and cognitive control to restrict food intake (restraint) over time. Additionally, participants reported higher restraint when PSS levels were lower than usual. Overall, weight-focused PSS appeared to hold greater importance in relation to regulating eating behavior than engaging in activity behaviors or weight loss among MBS patients during the initial postoperative year. Clinical Trial Registration: NCT02777177.

An Adaptive Telephone Coaching Intervention for Patients in an Online Weight Loss Program: A Randomized Clinical Trial.

Importance: Weight loss (WL) during the first month of a behavioral program is associated with longer-term WL. Testing of translatable and adaptive obesity programs is needed. Objective: To compare brief, extended, and no telephone coaching for individuals with suboptimal response (ie, 1-month WL <4%) within an online WL program. Design, Setting, and Participants: This randomized clinical trial with enrollment between March 2019 and April 2022 (data collection completed May 2023) was conducted at an academic research center in the US. Eligible participants included adults aged 18 to 70 years with daily access to internet and a body mass index between 25 and 45. Interventions: All participants received an automated online WL program (4 months) and WL maintenance program (8 months), consisting of video lessons, self-monitoring, and personalized feedback. Participants were randomized, such that individuals with suboptimal response received either brief telephone coaching (3 calls during weeks 5-8), extended telephone coaching (12 calls during weeks 5-16), or no coaching (control). Coaching included education, problem solving, and goal setting, and promoted engagement with the online program. Main Outcomes and Measures: The primary outcomes were percent weight change and proportion of participants achieving 5% or greater WL at 4 and 12 months. A priori hypotheses for WL were that WL for extended coaching would be greater than for brief coaching, and both extended and brief coaching would be greater than no coaching (control). A longitudinal mixed-effects model with participant-specific intercept was used to examine intervention effects on percent WL at 4 and 12 months. Secondary analyses focused on program engagement and cost/kilogram of WL. Results: The study included a total of 437 participants who reported WL at 1 month (mean [SD] age, 50.8 [11.4] years; mean [SD] BMI, 34.6 [5.0]; 305 female [69.8%] and 132 male [30.2%]) with 148 randomized to extended coaching, 143 assigned to brief coaching, and 146 assigned to the control group. Of all participants, 346 (79.2%) were considered to have a suboptimal response. WL at 4 months was significantly greater in the extended coaching group (mean [SD] WL, -7.0% [5.1%]) and brief coaching group (mean [SD] WL, -6.2% [4.7%]) vs the control group (mean [SD] WL, -4.5% [4.7%]) (P < .001). Similarly, the proportion of participants achieving 5% or greater WL at 4 months was greater in the extended coaching group (89 participants [65.9%]) and brief coaching group (77 participants [58.5%]) vs control group (46 participants [36.5%]) (P < .001). At 12 months, a similar pattern was observed for achievement of 5% WL or greater (extended coaching, 63 participants [48.1%]; brief coaching, 58 participants [45.9%]; control, 38 participants [32.8%]; P = .03). Percent WL at 12 months was significantly higher in extended coaching vs control (mean [SD] WL for extended coaching, -5.5% [6.7%]; mean [SD] WL for control, -3.9% [7.4%]; P = .03) but not for brief coaching (mean [SD] WL, -4.9% [6.1%]).Both the brief and extended coaching groups watched more lessons and self-monitored on more days compared with the control group. The cost per additional kilogram of WL, beyond that of the control group, was $50.09 for brief coaching and $92.65 for extended coaching. Conclusions and Relevance: In this randomized clinical trial testing an adaptive intervention, the provision of coaching for individuals with suboptimal response improved WL and was cost-effective; further testing in clinical settings (eg, health care systems) is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03867981.

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies.

PURPOSE: The aim of this study was to develop, operationalize, and pilot test a transparent, reproducible, and evidence-informed method to determine when to report incidental findings from next-generation sequencing technologies. METHODS: Using evidence-based principles, we proposed a three-stage process. Stage I "rules out" incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (stage III). We used expert opinion to determine the face validity of stages II and III using three case studies. We evaluated the time and effort for stages I and II. RESULTS: For stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-antitrypsin deficiency were all recommended for routine reporting as incidental findings. The method requires <3 days per topic. CONCLUSION: We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.

Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer.

PURPOSE: The aim of this study was to examine Lynch syndrome screening of patients with metastatic colorectal cancer in integrated health-care-delivery organizations. METHODS: We determined the availability of Lynch syndrome screening criteria and actual Lynch syndrome screening in the medical records of 1,188 patients diagnosed with metastatic colorectal cancer between 2004 and 2009 at seven institutions in the Cancer Research Network. RESULTS: We found infrequent use of Lynch syndrome screening (41/1,188). Family history was available for 937 of the 1,188 patients (79%). There was sufficient information to assess Lynch syndrome risk using family history-based criteria in 719 of the 937 patients (77%) with family history documentation. In 391 individuals with a family history of a Lynch syndrome-associated cancer, 107 (27%) could not be evaluated due to missing information such as age of cancer onset. Eleven percent of patients who met the Bethesda criteria and 25% of individuals who met the Amsterdam II criteria were screened for Lynch syndrome. Recommended guidelines were adhered to during screening, but no testing method was preferred. CONCLUSION: The information required for Lynch syndrome screening decisions is routinely collected but seldom used. There is a critical gap between collection of family history and its use to guide Lynch syndrome screening, which may support a case for implementation of universal screening guidelines.

The prognostic value of Eastern Cooperative Oncology Group performance status on overall survival among patients with metastatic prostate cancer: a systematic review and meta-analysis.

Background: There is heterogeneity in the literature regarding the strength of association between Eastern Cooperative Oncology Group performance status (ECOG PS) and mortality. We conducted a systematic review and meta-analysis of studies reporting the prognostic value of ECOG PS on overall survival (OS) in metastatic prostate cancer (mPC). Methods: PubMed was searched from inception to March 21, 2022. A meta-analysis pooling the effect of ECOG PS categories (≥2 vs. <2, 2 vs. <2, and ≥1 vs. <1) on OS was performed separately for studies including patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC) using a random-effects model. Analyses were stratified by prior chemotherapy and study type. Results: Overall, 75 studies, comprising 32,298 patients, were included. Most studies (72/75) included patients with mCRPC. Higher ECOG PS was associated with a significant increase in mortality risk, with the highest estimate observed among patients with mCRPC with an ECOG PS of ≥2 versus <2 (hazard ratio [HR]: 2.10, 95% confidence interval [CI]: 1.87-2.37). When stratifying by study type, there was a higher risk estimate of mortality among patients with mCRPC with an ECOG PS of ≥1 versus <1 in real-world data studies (HR: 1.98, 95% CI: 1.72-2.26) compared with clinical trials (HR: 1.32, 95% CI: 1.13-1.54; p < 0.001). There were no significant differences in the HR of OS stratified by previous chemotherapy. Conclusion: ECOG PS was a significant predictor of OS regardless of category, previous chemotherapy, and mPC population. Additional studies are needed to better characterize the effect of ECOG PS on OS in mCSPC.

The NOAA NCEI marine microplastics database.

Microplastics (<5 mm) pollution is a growing problem affecting coastal communities, marine ecosystems, aquatic life, and human health. The widespread occurrence of marine microplastics, and the need to curb its threats, require expansive, and continuous monitoring. While microplastic research has increased in recent years and generated significant volumes of data, there is a lack of a robust, open access, and long-term aggregation of this data. The National Oceanic and Atmospheric Administration (NOAA) National Centers for Environmental Information (NCEI) now provides a global open access to marine microplastics data on an easily discoverable and accessible GIS web map and data portal ( https://www.ncei.noaa.gov/products/microplastics ). The objective of this data portal is to develop a repository where microplastics data are aggregated, archived, and served in a user friendly, consistent, and reliable manner. This work contributes to NCEI's efforts towards data standardization, integration, harmonization, and interoperability among national and international collaborators for monitoring global marine microplastics. This paper describes the NOAA NCEI global marine microplastics database, its creation, quality control procedures, and future directions.

Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.

Hearing loss is the most common form of sensory impairment in humans and is frequently progressive in nature. Here we link a previously uncharacterized gene to hearing impairment in mice and humans. We show that hearing loss in the ethylnitrosourea (ENU)-induced samba mouse line is caused by a mutation in Loxhd1. LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains and is expressed along the membrane of mature hair cell stereocilia. Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate. Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). LOXHD1, MYO3a, and PJVK are the only human genes to date linked to progressive ARNSHL. These three genes are required for hair cell function, suggesting that age-dependent hair cell failure is a common mechanism for progressive ARNSHL.

Genetic control of human brain transcript expression in Alzheimer disease.

We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

Implementation of a Clinical Decision Support (CDS) Tool for the Management of Functional Constipation in Pediatric Primary Care.

Constipation is common in general pediatrics and often results in potentially unnecessary referrals to pediatric gastroenterology. We hypothesized that a clinical decision-making tool would support primary care providers to manage pediatric constipation, improve workflow, and prevent unnecessary subspecialty care. In this pilot quality improvement initiative, a multidisciplinary team completed a root cause analysis related to challenges with the care of pediatric constipation. The results informed the development of interventions including a Clinical Decision Support tool and patient educational materials embedded within an existing order-set in the electronic health record, which we implemented in our primary care network. The use of the updated order-set continues to increase monthly, and there is reported improved workflow and increased confidence by providers. These interventions demonstrated that it is feasible to implement tools to support primary care clinicians in their management of pediatric patients with constipation.

Associations of physical activity and sedentary behavior with appetite sensations and eating regulation behaviors before and during the initial year following bariatric surgery.

Background: Bariatric surgery produces weight loss in part by impacting appetite and eating behavior. Research suggests physical activity (PA) assists with regulation of appetite and eating during non-surgical weight loss, although whether PA carries similar benefits in the context of bariatric surgery is unknown. Objective: Evaluate associations of moderate-to-vigorous intensity PA (MVPA) and sedentary time (ST) with appetite sensations (hunger [homeostatic/hedonic], satiety) and eating regulation behaviors (restraint, disinhibition) before and during the initial year following bariatric surgery. Method: Adult bariatric patients received an accelerometer to measure MVPA/ST and a smartphone to complete appetite/eating ratings at four semi-random times daily for 10 days at pre- and 3-, 6-, and 12-months post-surgery. Data were analyzed using generalized linear mixed models. Results: Higher MVPA levels related to more satiety across time (p = 0.045) and more restraint at 3-months post-surgery (p < 0.001). At pre-surgery, higher MVPA levels also related to more disinhibition (p's < 0.01), although participants reported more disinhibition on days they performed less MVPA than usual (p = 0.017). MVPA did not relate to hunger. Lower ST levels related to more hedonic hunger (p = 0.003), especially at 12-months post-surgery (p < 0.001), and participants reported more homeostatic hunger on days they accumulated more ST than usual (p = 0.044). Additionally, higher ST levels related to more disinhibition at 3-months post-surgery (p's < 0.01) and lower restraint at pre-surgery (p's < 0.05). ST did not relate to satiety. Conclusions: This study is the first to show that MVPA and ST each associate with appetite and eating regulation in daily life before and during post-surgical weight loss. Results, while preliminary and requiring experimental confirmation, highlight potential for targeting bariatric patients' activity behaviors to enhance modulation of appetite, control of food intake, and resistance to overeating.

GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

Acupuncture and chiropractic care for chronic pain in an integrated health plan: a mixed methods study.

BACKGROUND: Substantial recent research examines the efficacy of many types of complementary and alternative (CAM) therapies. However, outcomes associated with the "real-world" use of CAM has been largely overlooked, despite calls for CAM therapies to be studied in the manner in which they are practiced. Americans seek CAM treatments far more often for chronic musculoskeletal pain (CMP) than for any other condition. Among CAM treatments for CMP, acupuncture and chiropractic (A/C) care are among those with the highest acceptance by physician groups and the best evidence to support their use. Further, recent alarming increases in delivery of opioid treatment and surgical interventions for chronic pain--despite their high costs, potential adverse effects, and modest efficacy--suggests the need to evaluate real world outcomes associated with promising non-pharmacological/non-surgical CAM treatments for CMP, which are often well accepted by patients and increasingly used in the community. METHODS/DESIGN: This multi-phase, mixed methods study will: (1) conduct a retrospective study using information from electronic medical records (EMRs) of a large HMO to identify unique clusters of patients with CMP (e.g., those with differing demographics, histories of pain condition, use of allopathic and CAM health services, and comorbidity profiles) that may be associated with different propensities for A/C utilization and/or differential outcomes associated with such care; (2) use qualitative interviews to explore allopathic providers' recommendations for A/C and patients' decisions to pursue and retain CAM care; and (3) prospectively evaluate health services/costs and broader clinical and functional outcomes associated with the receipt of A/C relative to carefully matched comparison participants receiving traditional CMP services. Sensitivity analyses will compare methods relying solely on EMR-derived data versus analyses supplementing EMR data with conventionally collected patient and clinician data. DISCUSSION: Successful completion of these aggregate aims will provide an evaluation of outcomes associated with the real-world use of A/C services. The trio of retrospective, qualitative, and prospective study will also provide a clearer understanding of the decision-making processes behind the use of A/C for CMP and a transportable methodology that can be applied to other health care settings, CAM treatments, and clinical populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01345409.

Tumor Lysis Syndrome: Implications for Oncology Nursing Practice.

OBJECTIVES: To provide an overview of tumor lysis syndrome, which is one of the metabolic oncologic emergencies. DATA SOURCES: A review and synthesis of empirical articles. CONCLUSION: One of the metabolic oncologic emergencies identified by the Oncology Nursing Society is tumor lysis syndrome. This condition is life-threatening and is characterized by metabolic derangements that can lead to acute kidney injury and multiple organ dysfunction. Normal intracellular components (potassium, phosphorus, and nucleic acids) spill into the bloodstream when cancer cells die. If the tumor is large and highly responsive to chemotherapy, the resulting cascade of dead tumor cells may overwhelm normal homeostatic mechanisms. The cells enter the bloodstream faster than they can be cleared by the kidneys. This results in hyperkalemia and hyperphosphatemia. Nucleic acids convert to uric acid in the liver with a resultant hyperuricemia. Excess uric acid in the kidneys can lead to uric acid nephropathy and renal insufficiency. Phosphorus binds with calcium, leading to hypocalcemia from the formation of calcium phosphate precipitate or crystals. These crystals can also lead to renal insufficiency or acute kidney injury, which can lead to a metabolic acidosis and exacerbation of the hyperkalemic state. These metabolic derangements define presence of tumor lysis syndrome. IMPLICATIONS FOR NURSING PRACTICE: Multidisciplinary collaboration and communication is essential to identifying patients at risk prior to treatment. Meticulous nursing care in terms of prevention and treatment is critical to patient survival.

Relationship between stress and weight management behaviors during the COVID-19 pandemic among those enrolled in an internet program.

BACKGROUND: The COVID-19 pandemic resulted in mandated stay-at-home orders, potentially resulting in changes in mental health (e.g., stress, anxiety) and challenges maintaining healthy dietary and physical activity behaviors. OBJECTIVE: This study examined how stress was associated with mental well-being and weight loss behaviors during the COVID-19 pandemic among adults enrolled in an internet-based weight loss program. METHODS: Participants enrolled in a weight-loss program residing in Rhode Island or Massachusetts, USA, completed a brief survey on their mental health and current weight-loss behaviors during the COVID-19 pandemic. Surveys were completed between 14 April 2020 and 21 April 2020, approximately one month after stay-at-home orders were mandated. Linear regression was used to examine associations between stress, mental health, and weight-loss behaviors. RESULTS: A total of 99 participants completed the survey (79% female, 91% white, 52.2 ± 9.8 years, 34.0 ± 5.2 kg/m2, 77% reported moderate to extreme stress). Greater stress was associated with higher BMI (p = 0.04), higher education (p = 0.04), working more hours (p = 0.003), and having school-age children at home (p = 0.002). Greater stress was also associated with higher levels of anxiety, worry, and concern regarding COVID-19 (p's < 0.001) and having less time to spend on weight-loss efforts (p < 0.001), after controlling for BMI and education. CONCLUSIONS: Many individuals enrolled in a weight-loss program experienced more stress during COVID-19 compared to before the pandemic. This stress was related to more mental health challenges as well as more difficulties finding time for weight management efforts.

Ecological momentary assessment of gastrointestinal symptoms and risky eating behaviors in Roux-en-Y gastric bypass and sleeve gastrectomy patients.

BACKGROUND: Gastrointestinal symptoms (GIS) are common after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). However, little is known about frequencies of GIS and their co-occurrence with risky eating behaviors. OBJECTIVES: Compare RYGB and SG on GIS and risky eating behaviors, and test associations between GIS and behaviors. SETTING: Two university hospitals in Northeastern United States. METHODS: RYGB (n = 18) and SG (n = 53) patients completed smartphone-based ecological momentary assessment of GIS and risky eating behaviors at 4 semi-random times daily for 10 days preoperatively and at 3, 6, and 12 months postoperatively. Study objectives were evaluated using generalized linear mixed-effects models. RESULTS: All available data from each assessment were included in the analysis: participant attrition was 18%, 30%, and 38% at 3, 6, and 12 months. All GIS were reduced at 12 months postoperative. Bloating decreased consistently whereas cramping, dehydration, and dumping first increased at 3 to 6 months then decreased to 12 months. Diarrhea, nausea, reflux, and vomiting decreased to 12 months for RYGB, but first increased at 3 to 6 months then decreased to 12 months for SG. Consumption of carbonated and sugar-sweetened beverages, fatty meats, and sweets decreased to 6 months then rebounded at 12 months. Eating past the first sign of fullness, drinking liquids with meals, not starting meals with protein, and fried foods consumption decreased to 6 months and then rebounded for RYGB only at 12 months. Alcohol consumption did not change. Sweets consumption and eating past the first sign of fullness were most consistently associated with GIS for both RYGB and SG patients. CONCLUSION: GIS and risky eating behaviors improved postoperatively, although patterns of change were variable and occasionally differed between RYGB and SG. Pending replication, patients may benefit from intervention to limit risky behaviors that are tailored to their surgery type.

Comprehensive Genomic Profiling of Adult Renal Sarcomas Provides Insight into Disease Biology and Opportunities for Targeted Therapies.

BACKGROUND: Primary adult renal sarcomas (RSs) are rare aggressive neoplasms. Clinical outcomes are extremely poor, and optimal treatment remains challenging. OBJECTIVE: To identify genomic alterations (GAs) in patients with RSs. DESIGN, SETTING, AND PARTICIPANTS: Comprehensive genomic profiling (CGP) was conducted on DNA/RNA extracted from formalin-fixed paraffin-embedded tissue using the FoundationOne Heme/Sarcoma assay in 13 adult, locally advanced or metastatic RSs of various histologic types. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All classes of GAs, including base substitutions, small indels, rearrangements, copy number alterations, tumor mutational burden (TMB), and microsatellite instability (MSI), were analyzed. RESULTS AND LIMITATIONS: CGP revealed 55 GAs (4.2 per tumor), 29 of which were clinically relevant genomic alterations (CRGAs; 2.2 per tumor). At least one CRGA was detected in nine (69%) cases. High-level amplifications (more than six copies) involving 4q12 amplicon of the KIT and PDGFRA genes were identified in four (31%) cases (two undifferentiated pleomorphic sarcomas [UPSs], one sarcomatoid renal cell carcinoma, and one myxofibrosarcoma). Both UPSs also had KDR gene amplification in addition to KIT and PDGFRA. Additional CRGAs were found in CDKN2A/B (23%), NF1 (23%), and MET (8%). All RSs were MSI stable, the mean TMB was 3.5 mutations/megabase (Mb), and none (0%) featured TMB >10 mutations/Mb. Limitations include the small sample size. CONCLUSIONS: RSs are characterized by diverse histology and genomic profiles including 31% of cases with 4q12 amplification harboring the KIT/PDGFRA/KDR genes. Of the tumors, 69% carry CRGAs, which could lead to potential benefit from targeted therapies; however, a low TMB also suggests that these cases are unlikely to respond to checkpoint inhibitors. PATIENT SUMMARY: This study provides insights into molecular biology of renal sarcoma, a rare aggressive subtype of kidney tumors. We demonstrated that renal sarcomas harbor unique, recurrent, clinically relevant molecular abnormalities that provide new opportunities for targeted therapies.