Plasma Circulating Tumor DNA to Assist in the Diagnose of Unknown Primary Malignancy Underlying Choroidal Metastases.

PURPOSE: Management of suspected choroidal metastases requires diagnostic imaging and an invasive, sometimes intraocular, biopsy to determine the primary malignancy. This multistep process takes time which may impact morbidity and mortality. METHODS: Retrospective review of one case. RESULTS: A 56-year-old woman presented with bilateral amelanotic choroidal masses suspicious for metastases of unknown origin. Plasma circulating tumor DNA revealed EGFR, PTEN, SMAD4, a profile consistent with non-small cell lung cancer. Subsequent radiographic imaging and scapular biopsy revealed lung adenocarcinoma and genetic profile concordant with the liquid biopsy. Patient was started on EGFR-inhibitor, Osimertinib1, with measurable systemic and ocular response. CONCLUSION: Plasma circulating tumor DNA revealed the genetic profile of the primary malignancy underlying choroidal metastases of unknown origin; aiding in the prompt diagnosis and detecting the driver mutation which guided management with targeted therapy.

Hemodynamic and Echocardiographic Predictors of Mortality in Pediatric Patients on Venoarterial Extracorporeal Membrane Oxygenation: A Multicenter Investigation.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (ECMO) supports patients with advanced cardiac dysfunction; however, mortality occurs in a significant subset of patients. The authors performed a multicenter, prospective study to determine hemodynamic and echocardiographic predictors of mortality in children placed on ECMO for cardiac support. METHODS: Over 8 years, six heart centers prospectively assessed echocardiographic and hemodynamic variables on full and minimum ECMO flow. Sixty-three patients were enrolled, ranging in age from 1 day to 16 years. Hemodynamic measurements included heart rate, vasoactive inotropic score, arteriovenous oxygen difference, pulse pressure, and lactate. Echocardiographic variables included shortening fraction, ejection fraction (EF), right ventricular fractional area change, outflow tract Doppler-derived stroke distance (velocity-time integral [VTI]), and degree of atrioventricular valve regurgitation. Patients were stratified into two groups: those who were able to wean within 48 hours of assessment and survived without ventricular assist devices or orthotopic heart transplantation (successful wean group) and those with unsuccessful weaning. For each patient, variables were compared between full and minimum ECMO flow for each group. RESULTS: Thirty-eight patients (60%) formed the unsuccessful group (two with ventricular assist devices, four with orthotopic heart transplantation, 24 deaths), and 25 constituted the successful wean group. At minimum flow, higher EF (53 ± 16% vs 40 ± 20%, P = .0094), less mitral regurgitation (0.8 ± 0.9 vs 1.4 ± 0.9, P = .0329), and lower central venous pressure (12.0 ± 3.9 vs 14.7 ± 5.4 mm Hg), along with higher VTI (9.0 ± 2.9 vs 6.8 ± 3.7 cm, P = .0154), correlated successful weaning. A longer duration of ECMO (8 vs 5 days, P < .0002) was associated with unsuccessful weaning. Multivariate logistic regression predicted minimum-flow EF and VTI to independently predict successful weaning with cutoff values by receiver operating characteristic analysis of EF > 41% (area under the curve, 0.712; P = .0005) and VTI > 7.9 cm (area under the curve, 0.729; P = .0010). CONCLUSIONS: Diminished VTI or EF during ECMO weaning predicts the need for orthotopic heart transplantation or ventricular assist device support or death in children on ECMO for cardiac dysfunction. Increased postwean central venous pressure or mitral regurgitation along with a prolonged ECMO course also predicted these adverse outcomes. These measurements should be used to help discriminate which patients will require alternative methods of circulatory support for survival.

Detectability of Plasma-Derived Circulating Tumor DNA Panel in Patients Undergoing Primary Treatment for Uveal Melanoma.

Purpose: To investigate the presence of plasma circulating tumor DNA (ctDNA) in patients with uveal melanoma during and after primary tumor treatment. Methods: Detectability and variant allele frequency of ctDNA were assessed using a 129-oncogene panel using next-generation deep sequencing and hybridization capture in 69 patients with uveal melanoma undergoing primary treatment with enucleation (n = 8, during surgery) or plaque brachytherapy (n = 61; postoperative day 0, 1, 2, or 3). Follow-up assessments were performed in 39 patients over a median of 21 months (range, 3.2-31.9 months) of follow-up. Correlations between genomic data and disease parameters were performed. Results: Overall, ctDNA was detectable in 20 of 69 patients with uveal melanoma (28.9%) during the perioperative period. On the day of enucleation, ctDNA was detected in two of eight patients (25%). In patients undergoing brachytherapy, ctDNA was significantly more detectable on postoperative days 2 or 3 compared with postoperative day 0 or 1 (32.4% vs 0.0%; P = 0.0015). Patients with follow-up ctDNA that became detectable or had an increased variant allele frequency were significantly more likely to develop metastasis compared with patients with follow-up ctDNA that became undetectable or decreased variant allele frequency (P = 0.04). In patients with detectable vs. undetectable ctDNA, there was no significant difference in tumor size, stage or location. Conclusions: ctDNA is significantly more detectable at 48 to 72 hours after plaque brachytherapy compared with less than 48 hours. ctDNA can be detected during enucleation. Relative increases in ctDNA levels may herald the development of clinically apparent metastases.

Demographics and Outcomes of Patients With Eating Disorders Treated in Residential Care.

The use of residential eating disorder (ED) treatment has grown dramatically in the United States, yet there has been minimal evaluation of treatment outcomes. Thus, outcome data on weight restoration, purging behaviors, and/or Global Assessment of Functioning (GAF) for 1,421 patients treated over an 8-year period in residential ED programs are described. Results suggest that, (1) for patients who needed weight restoration upon admission, adolescent and adult patients gained 2.0 and 2.1 lb/week, respectively; (2) of patients who reported purge behavior the month before admission, 89.1% were able to completely cease purging while in treatment; (3) although improvement of approximately 10 mean GAF points was made during treatment, patients were still quite impaired at discharge; and (4) mean length of stay was 12 days longer for adolescents than adults, and 10-15 days longer for patients diagnosed with anorexia compared to bulimia or ED Not Otherwise Specified (EDNOS), respectively. Other demographic statistics and additional analyses are presented. Limitations include the high variance of purging data and reliance on self- and parent-report for admission data. The data on the 1,421 patients, which represents 96% of all patients treated during the study period, more than doubles the number of residential ED patients with outcome in the literature.

Predictors of mortality in pediatric patients on venoarterial extracorporeal membrane oxygenation.

OBJECTIVES: Currently, there are no established echocardiographic or hemodynamic predictors of mortality after weaning venoarterial extracorporeal membrane oxygenation in children. We wished to determine which measurements predict mortality. DESIGN: Over 3 years, we prospectively assessed six echo and six hemodynamic variables at 3-5 circuit rates while weaning extracorporeal membrane oxygenation flow. Hemodynamic measurements were heart rate, inotropic score, arteriovenous oxygen difference, pulse pressure, oxygenation index, and lactate. Echo variables included shortening/ejection fraction, outflow tract Doppler-derived stroke distance (velocity-time integral), degree of atrioventricular valve regurgitation, longitudinal strain (global longitudinal strain), and circumferential strain (global circumferential strain). SETTING: Cardiovascular ICU at Lucille Packard Children's Hospital Stanford, CA. SUBJECTS: Patients were stratified into those who died or required heart transplant (Gr1) and those who did not (Gr2). For each patient, we compared the change for each variable between full versus minimum extracorporeal membrane oxygenation flow for each group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 21 patients ranging in age from 0.02 to 15 years. Five had dilated cardiomyopathy, and 16 had structural heart disease with severe ventricular dysfunction. Thirteen of 21 patients (62%) comprised Gr1, including two patients with heart transplants. Eight patients constituted Gr2. Gr1 patients had a significantly greater increase in oxygenation index (35% mean increase; p < 0.01) off extracorporeal membrane oxygenation compared to full flow, but no change in velocity-time integral or arteriovenous oxygen difference. In Gr2, velocity-time integral increased (31% mean increase; p < 0.01), with no change in arteriovenous oxygen difference or oxygenation index. Pulse pressure increased modestly with flow reduction only in Gr1 (p < 0.01). CONCLUSION: Failure to augment velocity-time integral or an increase in oxygenation index during the extracorporeal membrane oxygenation weaning is associated with poor outcomes in children. We propose that these measurements should be performed during extracorporeal membrane oxygenation wean, as they may discriminate who will require alternative methods of circulatory support for survival.

Initial experience using aminophylline to improve renal dysfunction in the pediatric cardiovascular ICU.

OBJECTIVE: To determine if aminophylline administration is associated with improved creatinine clearance and greater urine output in children with acute kidney injury in the cardiovascular ICU. DESIGN: Single-center retrospective cohort study. SETTING: Pediatric cardiovascular ICU, university-affiliated children's hospital. PATIENTS: Children with congenital or acquired heart disease in the cardiovascular ICU who received aminophylline to treat oliguric acute kidney injury and fluid overload. INTERVENTIONS: Patients received aminophylline after consultation with a pediatric nephrologist. Data were collected retrospectively over 7 days to assess if aminophylline was associated with improvement in creatinine clearance, urine output, and fluid overload. MEASUREMENTS AND MAIN RESULTS: Thirty-one patients received 52 aminophylline courses. Over the 7-day study period, serum creatinine decreased from a mean of 1.13 ± 0.91 to 0.87 ± 0.83 mg/dL (-0.05 mg/dL/d, p < 0.001). A concomitant increase was seen in estimated glomerular filtration rate from a mean of 50.0 ± 30.0 to 70.6 ± 58.1 mL/min/1.73 m (+3.66 mL/min/1.73 m/d, p < 0.001). Average daily urine output increased by 0.22 mL/kg/hr (p < 0.001), and fluid overload decreased on average by 0.42% per day in the 7-day study period (p = 0.005). Although mean furosemide dose increased slightly (0.12 mg/kg/d, p = 0.01), hydrochlorothiazide dosing did not significantly change over the study period. There were no complications related to aminophylline administration. CONCLUSIONS: Our study suggests that aminophylline therapy may be associated with significantly improved renal excretory function and may augment urine output in children who experience oliguric acute kidney injury in the cardiovascular ICU. Additionally, we did not identify any aminophylline-related side effects in this high-risk cardiac population. Future prospective studies are necessary to confirm the safety profile and to ensure that the beneficial effects are independent of other clinical interventions.

Delivering adolescent preventive services in an office setting.

Adolescence has long been recognized as a vulnerable period. Although several major medical professional organizations have published adolescent preventive care guidelines, regional and national surveys of youth, providers, and medical records all suggest many gaps exist in the delivery of recommended preventive services. In this article, we review the development of adolescent preventive health guidelines, describe current rates of preventive health screening and counseling, and explore barriers to delivery of preventive care for this age group. We present resources and practical suggestions to help the reader create an adolescent-friendly environment and to facilitate preventive health care delivery in your practice.

Nonmedical use of prescription medications: an emerging risk behavior among rural adolescents.

Little is known about prescription medication abuse by rural youth. We surveyed 849 rural high school students and found that 34% reported lifetime nonmedical use of prescription medication higher than the 12% reported nationally. Boys and marijuana users had higher odds of nonmedical use of prescription medication than did girls or marijuana nonusers (odds ratio 1.9 and 3.8, respectively).

Oral baclofen increases maximal voluntary neuromuscular activation of ankle plantar flexors in children with spasticity due to cerebral palsy.

Although spasticity is a common symptom in children with cerebral palsy, weakness may be a much greater contributor to disability. We explore whether a treatment that reduces spasticity may also have potential benefit for improving strength. Ten children with cerebral palsy and spasticity in the ankle plantar flexor muscles were treated with oral baclofen for 4 weeks. We tested voluntary ability to activate ankle plantar flexor muscles using the ratio of the surface electromyographic signal during isometric maximal voluntary contraction to the M-wave during supramaximal electrical stimulation of the tibial nerve and tested muscle strength using maximal isometric plantar flexion torque. Mean maximal voluntary neuromuscular activation increased from 1.13 +/- 1.02 to 1.60 +/- 1.30 ( P < .05) after treatment, corresponding to an increase in 9 of 10 subjects. Mean maximal plantar flexion torque did not change. We conjecture that antispasticity agents could facilitate strength training by increasing the ability to voluntarily activate muscle.

Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy.

Although trihexyphenidyl is used clinically to treat both primary and secondary dystonia in children, limited evidence exists to support its effectiveness, particularly in dystonia secondary to disorders such as cerebral palsy. A prospective, open-label, multicenter pilot trial of high-dose trihexyphenidyl was conducted in 23 children aged 4 to 15 years with cerebral palsy judged to have secondary dystonia impairing function in the dominant upper extremity. All children were given trihexyphenidyl at increasing doses over a 9-week period up to a maximum of 0.75 mg/kg/d. Trihexyphenidyl was subsequently tapered off over the next 5 weeks. Objective motor assessments were performed at baseline, 9 weeks, and 15 weeks. The primary outcome measure was the Melbourne Assessment of Unilateral Upper Limb Function, tested in the dominant arm. Tolerability and safety were monitored closely throughout the trial. Of the 31 children who agreed to participate in the study, 5 failed to meet entry criteria and 3 withdrew due to nonserious adverse events (chorea, drug rash, and hyperactivity). Three children required a dosage reduction because of nonserious adverse events but continued to participate. The 23 children who completed the study showed a significant improvement in arm function at 15 weeks (P = .045) but not at 9 weeks (P = .985). Post hoc analysis showed that a subgroup (n = 10) with hyperkinetic dystonia (excess involuntary movements) worsened at 9 weeks (P = .04) but subsequently returned to baseline following taper of the medicine. The authors conclude that scientific evidence for the clinical use of trihexyphenidyl in cerebral palsy remains equivocal. Trihexyphenidyl may be a safe and effective for treatment for arm dystonia in some children with cerebral palsy if given sufficient time to respond to the medication. Post hoc analyses based on the type of movement disorder suggested that children with hyperkinetic forms of dystonia may worsen. A larger, randomized prospective trial stratified by the presence or absence of hyperkinetic movements is needed to confirm these results.

Botulinum toxin type B improves the speed of reaching in children with cerebral palsy and arm dystonia: an open-label, dose-escalation pilot study.

Seven children between 2 and 15 years of age with cerebral palsy and upper extremity dystonia were enrolled in an open-label, dose-escalation pilot clinical trial of botulinum toxin type B (Myobloc), injected into the biceps and brachioradialis muscles of I or both arms. The primary outcome measure was the change in maximum speed of hand movement during attempted forward reaching. Escalating doses of 12.5, 25, and 50 U/kg per muscle were injected at each of 3 visits. Reaching speed improved in response to injection, and dystonia scores on the Burke-Fahn-Marsden dystonia scale, the Unified Dystonia Rating Scale, and the Unified Parkinson's Disease Rating Scale improved. There was not a dose-related effect on efficacy. There were no serious adverse events. Two children reported transient weakness. These results support the use of botulinum toxin type B as a safe and effective treatment for upper extremity dystonia in children with cerebral palsy. Larger controlled trials are needed to confirm these results.

Adolescent substance use, sexual behavior, and metropolitan status: is "urban" a risk factor?

PURPOSE: To determine if urban youth ("metropolitan" status) are at greater risk of engaging in risk behaviors than suburban or rural youth. METHODS: We analyzed data on substance use and sexual risk behaviors from the national school-based Youth Risk Behavior Survey (YRBS) conducted in 1999, an anonymous questionnaire self-administered by students in grades 9 through 12. The national survey employs a multistage cluster sample to produce a nationally representative sample of high school students. Data were analyzed using SUDAAN software to take into account the sampling model. RESULTS: In 1999, metropolitan status was not a significant determining factor for involvement in risk behaviors. Of the specific risk factors examined in this analysis, there were no significant differences between rural and suburban youth, and these two groups were combined as "nonurban." In subsequent analysis of urban vs. nonurban youth, no significant differences in risk behaviors were found on bivariate or multivariate analyses. CONCLUSIONS: This analysis suggests that metropolitan status has little if any association with youth engaging in substance use and sexual risk behaviors. In addition, it appears that urban youth are engaging in these risk behaviors no more frequently than their nonurban counterparts.