Risk Prediction Models for Atherosclerotic Cardiovascular Disease in Patients with Chronic Kidney Disease: The CRIC Study.

BACKGROUND: Individuals with CKD may be at high risk for atherosclerotic cardiovascular disease (ASCVD). However, there are no ASCVD risk prediction models developed in CKD populations to inform clinical care and prevention. METHODS: We developed and validated 10-year ASCVD risk prediction models in patients with CKD that included participants without self-reported cardiovascular disease from the Chronic Renal Insufficiency Cohort (CRIC) study. ASCVD was defined as the first occurrence of adjudicated fatal and nonfatal stroke or myocardial infarction. Our models used clinically available variables and novel biomarkers. Model performance was evaluated based on discrimination, calibration, and net reclassification improvement. RESULTS: Of 2604 participants (mean age 55.8 years; 52.0% male) included in the analyses, 252 had incident ASCVD within 10 years of baseline. Compared with the American College of Cardiology/American Heart Association pooled cohort equations (area under the receiver operating characteristic curve [AUC]=0.730), a model with coefficients estimated within the CRIC sample had higher discrimination (P=0.03), achieving an AUC of 0.736 (95% confidence interval [CI], 0.649 to 0.826). The CRIC model developed using clinically available variables had an AUC of 0.760 (95% CI, 0.678 to 0.851). The CRIC biomarker-enriched model had an AUC of 0.771 (95% CI, 0.674 to 0.853), which was significantly higher than the clinical model (P=0.001). Both the clinical and biomarker-enriched models were well-calibrated and improved reclassification of nonevents compared with the pooled cohort equations (6.6%; 95% CI, 3.7% to 9.6% and 10.0%; 95% CI, 6.8% to 13.3%, respectively). CONCLUSIONS: The 10-year ASCVD risk prediction models developed in patients with CKD, including novel kidney and cardiac biomarkers, performed better than equations developed for the general population using only traditional risk factors.

Progress toward liquid biopsies in pediatric solid tumors.

Pediatric solid tumors have long been known to shed tumor cells, DNA, RNA, and proteins into the blood. Recent technological advances have allowed for improved capture and analysis of these typically scant circulating materials. Efforts are ongoing to develop "liquid biopsy" assays as minimally invasive tools to address diagnostic, prognostic, and disease monitoring needs in childhood cancer care. Applying these highly sensitive technologies to serial liquid biopsies is expected to advance understanding of tumor biology, heterogeneity, and evolution over the course of therapy, thus opening new avenues for personalized therapy. In this review, we outline the latest technologies available for liquid biopsies and describe the methods, pitfalls, and benefits of the assays that are being developed for children with extracranial solid tumors. We discuss what has been learned in several of the most common pediatric solid tumors including neuroblastoma, sarcoma, Wilms tumor, and hepatoblastoma and highlight promising future directions for the field.

Twist1 activity thresholds define multiple functions in limb development.

The basic helix-loop-helix transcription factor Twist1 is essential for normal limb development. Twist1(-/-) embryos die at midgestation. However, studies on early limb buds found that Twist1(-/-) mutant limb mesenchyme has an impaired response to FGF signaling from the apical ectodermal ridge, which disrupts the feedback loop between the mesenchyme and AER, and reduces and shifts anteriorly Shh expression in the zone of polarizing activity. We have combined Twist1 null, hypomorph and conditional alleles to generate a Twist1 allelic series that survives to birth. As Twist1 activity is reduced, limb skeletal defects progress from preaxial polydactyly to girdle reduction combined with hypoplasia, aplasia or mirror symmetry of all limb segments. With reduced Twist1 activity there is striking and progressive upregulation of ectopic Shh expression in the anterior of the limb, combined with an anterior shift in the posterior Shh domain, which is expressed at normal intensity, and loss of the posterior AER. Consequently limb outgrowth is initially impaired, before an ectopic anterior Shh domain expands the AER, promoting additional growth and repatterning. Reducing the dosage of FGF targets of the Etv gene family, which are known repressors of Shh expression in anterior limb mesenchyme, strongly enhances the anterior skeletal phenotype. Conversely this and other phenotypes are suppressed by reducing the dosage of the Twist1 antagonist Hand2. Our data support a model whereby multiple Twist1 activity thresholds contribute to early limb bud patterning, and suggest how particular combinations of skeletal defects result from differing amounts of Twist1 activity.

Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. The late stage of MPM diagnosis and the long latency that exist between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. METHODS: This manuscript is a review of current literature about the pathogenesis of malignant mesothelioma. In this overview, current published studies concerning pathogenesis of malignant mesothelioma are reviewed, with insights into its etiology and pathogenesis. We searched pubmed using the following subjects: mesothelioma, radiation, genetics, pediatric malignant mesothelioma, SV40 virus, and growth factors. We selected 350 valuable articles of which 152 sources were used to complete this review. CONCLUSION: Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. In this review, we discuss the current molecular and genetic contributors to MPM pathogenesis and the risk factors associated with these carcinogenic processes.

Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors.

Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes.

Detection of circulating tumor DNA in patients with osteosarcoma.

Identification and quantification of somatic alterations in plasma-derived, circulating tumor DNA (ctDNA) is gaining traction as a non-invasive and cost effective method of disease monitoring in cancer patients, particularly to evaluate response to treatment and monitor for disease recurrence. To our knowledge, genetic analysis of ctDNA in osteosarcoma has not yet been studied. To determine whether somatic alterations can be detected in ctDNA and perhaps applied to patient management in this disease, we collected germline, tumor, and serial plasma samples from pediatric, adolescent, and young adult patients with osteosarcoma and used targeted Next Generation Sequencing (NGS) to identify somatic single nucleotide variants (SNV), insertions and deletions (INDELS), and structural variants (SV) in 7 genes commonly mutated in osteosarcoma. We demonstrate that patient-specific somatic alterations identified through comparison of tumor-germline pairs can be detected and quantified in cell-free DNA of osteosarcoma patients.

Telemedicine to Promote Patient Safety: Use of Phone-Based Interactive Voice-Response System to Reduce Adverse Safety Events in Pre-dialysis CKD.

CKD patients have several features conferring on them a high risk of adverse safety events, which are defined as incidents with unintended harm related to processes of care or medications. These characteristics include impaired kidney function, polypharmacy, and frequent health system encounters. The consequences of such events in CKD can include new or prolonged hospitalization, accelerated kidney function loss, acute kidney injury, ESRD, and death. Health information technology administered via telemedicine presents opportunities for CKD patients to remotely communicate safety-related findings to providers for the purpose of improving their care. However, many CKD patients have limitations that hinder their use of telemedicine and access to the broad capabilities of health information technology. In this review, we summarize previous assessments of the pre-dialysis CKD populations' proficiency in using telemedicine modalities and describe the use of interactive voice-response system to gauge the safety phenotype of the CKD patient. We discuss the potential for expanded interactive voice-response system use in CKD to address the safety threats inherent to this population.

Incidence of atrial fibrillation after extrapleural pneumonectomy vs. pleurectomy in patients with malignant pleural mesothelioma.

Extrapleural pneumonectomy (EPP) and pleurectomy are the surgical procedures for the treatment of pleural mesothelioma. However, EPP increases the risk for postoperative atrial fibrillation (AF). We conducted a retrospective chart review of 130 patients who underwent EPP or pleurectomy. Seventy patients (excluding three patients with a prior history of AF) underwent EPP and 57 patients underwent pleurectomy. The mean ages were 60+/-11 and 63+/-13 years, and the male to female ratios were 50/20 and 44/13, respectively. Postoperative AF was observed in 45 patients with 36 (51%) of these cases occurring after EPP and 9 (17%) after pleurectomy (P<0.0001). There were no significant differences between the two treatment groups for gender, age, side of affected lung, preoperative heart rate, history of beta-blocker use, coronary heart disease, and chronic obstructive pulmonary disease. Through logistic regression, EPP (OR=7.1, 95% CI: 2.9, 17.8) and age over 65 years (OR=2.9, 95% CI: 1.2, 6.8) were found to be risk factors for AF. We conclude that EPP vs. pleurectomy and age over 65 years are risk factors for postoperative AF. The increased odds of having AF after EPP could be due to right heart stress caused by pneumonectomy.