GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients.

There is a need for biomarkers to predict and measure the severity of immune effector cell-associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well-validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS and that increases in GFAP and NfL levels during treatment reflect ICANS severity. We measured cerebrospinal fluid GFAP (cGFAP) and NfL (cNfL) along with serum NfL (sNfL) levels at pretreatment and day 7 to 10 after chimeric antigen receptor (CAR) T-cell infusion in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL levels increased during grade ≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. The sNfL levels did not increase during ICANS. Prelymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline cGFAP levels were associated with a history of transplantation. Patients with prior central nervous system (CNS) radiation had higher cNfL levels, and elevated baseline sNfL levels were associated with a history of peripheral neuropathy. Thus, cGFAP and cNfL may be useful biomarkers for measuring the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL, and sNfL likely reflect the cumulative injury to the central and peripheral nervous systems from prior treatment. However, levels of any of the 3 biomarkers before CAR T-cell infusion did not predict the risk of ICANS.

Perceptions of risk of infertility among male survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The objective of the current study was to characterize and identify factors associated with perceptions of risk of infertility among adult male survivors of childhood cancer. METHODS: A total of 1233 adult male survivors from the Childhood Cancer Survivor Study who were without a history of disease recurrence or subsequent malignancy reported their perceptions of their risk of infertility compared with men never diagnosed with cancer. Survivors were a median age of 37.8 years (range, 22.0-58.7 years) and were 28.4 years from their diagnosis (range, 21.4-39.2 years). Multivariable logistic regression evaluated factors associated with perceptions of risk. RESULTS: Overall, 35.9% of the survivors (443 of 1233 survivors) reported perceptions of their risk of infertility that were discordant with their actual risk based on previous cancer treatment exposures. Discordant perceptions were equally common among men exposed to gonadotoxic therapies (36.3%; 311 of 857 men) and those with no history of gonadotoxic exposure (35.1%; 132 of 376 men). Survivors who fathered children (odds ratio [OR], 4.14; 95% confidence interval [95% CI], 2.74-6.24), had no survivor-focused health care (OR, 3.07; 95% CI, 1.57-5.99), were nonwhite (OR, 2.28; 95% CI, 1.10-4.75), and were of lower income were more likely to report no increased risk of infertility after gonadotoxic treatment. Perceptions of increased risk of infertility among men with no history of gonadotoxic treatment were predicted by never having fathered a child (OR, 1.88; 95% CI, 1.17-3.03), recent participation in survivor-focused health care (OR, 2.11; 95% CI, 1.01-4.42), and higher educational achievement. CONCLUSIONS: Many male survivors of childhood cancer are unaware of how their cancer treatments could impact their reproductive health, underscoring the need for all patients to receive education regarding their risk of infertility throughout the continuum of cancer care. Cancer 2018;124:2447-55. © 2018 American Cancer Society.

Erectile Dysfunction in Male Survivors of Childhood Cancer-A Report From the Childhood Cancer Survivor Study.

INTRODUCTION: With survival rates higher than 80%, the number of survivors from pediatric cancer continues to increase. Late effects resulting from cancer and cancer therapy are being characterized, but little information exists on sexual health for men who have survived childhood cancer. AIM: To assess erectile dysfunction (ED) in men who survived childhood and adolescent cancers and to identify potential risk factors for ED. METHODS: In total, 1,622 men and 271 eligible brothers in the Childhood Cancer Survivor Study cohort completed the Male Health Questionnaire, which provided information on sexual practices and sexual function. Combined with demographic, cancer, and treatment information from medical record abstraction, results of the Male Health Questionnaire were analyzed using multivariable modeling. The International Index of Erectile Function was used to identify ED in subjects. MAIN OUTCOME MEASURE: International Index of Erectile Function. RESULTS: Survivors (mean age = 37.4 years, SD = 7.3 years) reported significantly lower sexual activity in the year before the survey than the brothers (mean age = 38.8 years, SD = 8.5 years) without cancer. ED was reported by 12.3% (95% CI = 10.4-14.3) of survivors and 4.2% (95% CI = 2.0-7.9) of brothers. Survivors showed significantly higher relative risk (RR) for ED (RR = 2.63, 95% CI = 1.40-4.97). In addition to older age, survivors who were exposed to higher-dose (≥10 Gy) testicular radiation (RR = 3.55, 95% CI = 1.53-8.24), had surgery on the spinal cord or nerves (RR = 2.87, 95% CI = 1.36-6.05), prostate surgery (RR = 6.56, 95% CI = 3.84-11.20), or pelvic surgery (RR = 2.28, 95% CI = 1.04-4.98) were at higher risk for ED. CONCLUSION: Men who have survived childhood cancer have a greater than 2.6-fold increased risk for ED and certain cancer-specific treatments are associated with increased risk. Attention to sexual health, with its physical and emotional implications, and opportunities for early detection and intervention in these individuals could be important.

Inactive disease in polyarticular juvenile idiopathic arthritis: current patterns and associations.

OBJECTIVES: To describe the achievement of inactive disease (ID) and remission in polyarticular juvenile idiopathic arthritis (JIA) and to measure the associations among patient characteristics, imaging results and these outcomes. METHODS: We performed a retrospective cohort study of children with polyarticular JIA diagnosed and treated at Seattle Children's Hospital between 1 January 2000 and 31 December 2006. Each patient's disease status (active disease vs ID) was determined for every clinic visit. Adjusted relative risk estimates were obtained using Mantel-Haenszel methods. RESULTS: One hundred and four children were included. Patients were followed up for an average of 30 months. Patients achieved 138 episodes of ID. Fifty-one patients achieved 69 episodes of clinical remission on medication. When duration of active disease was summed over each patient's follow-up, patients spent a mean of 66.3% of their follow-up with active disease. Patients with evidence of joint damage on imaging studies obtained within 6 months of their first clinic visit spent a mean of 79% of their follow-up with active disease. Patients without these findings spent a mean of 58.5% of their follow-up with active disease (P < 0.001). Children who were RF(+) and children with early evidence of joint damage tended to have a higher prevalence of active disease during the follow-up period. CONCLUSIONS: In this cohort, children with polyarticular JIA spent the majority of their follow-up with active disease. Because children with early radiographic evidence of joint damage and children who were RF(+) tended to have the most active disease, improving outcomes for these subgroups may be an important goal for prospective study.

Cytomegalovirus and Epstein-Barr virus in breast milk are associated with HIV-1 shedding but not with mastitis.

BACKGROUND: Breast milk HIV-1 load is associated with clinical and subclinical mastitis, and both milk viral load and mastitis are associated with increased mother-to-child-transmission of HIV-1 through breastfeeding. Bacterial infections may cause clinical mastitis, but whether other copathogens common in HIV-1 infection are associated with subclinical mastitis or HIV-1 shedding is unknown. DESIGN: A cross-sectional study of HIV-1-infected breastfeeding women in Zimbabwe was performed to examine the relationship between a wide range of breast coinfections, mastitis, and HIV-1 shedding. METHODS: Breast milk was cultured for bacteria and fungi and tested by PCR for mycobacteria, mycoplasmas, human herpesvirus (HHV)-6, HHV-7, HHV-8, cytomegalovirus, Epstein-Barr virus, and HIV-1 RNA and DNA. Symptoms of clinical mastitis were documented and subclinical mastitis was identified by breast milk sodium concentration (Na) and leukocyte counts. RESULTS: Coinfections of milk were not associated with clinical or subclinical mastitis in the 217 women studied. Detection of HIV-1 RNA, but not DNA, in breast milk was associated with cytomegalovirus concentration (odds ratio = 1.8, P = 0.002) and detection of Epstein-Barr virus (odds ratio = 3.8, P = 0.0003) but not other coinfections in multivariate analysis. CONCLUSION: Coinfection of breast milk with bacteria, fungi, or herpes viruses was not associated with mastitis. The associations between shedding of cytomegalovirus and Epstein-Barr virus with HIV-1 in milk suggest a local interaction between herpes virus infection and HIV-1 independent of mastitis. Cytomegalovirus and Epstein-Barr virus infections may impact HIV-1 shedding in breast milk and the risk of MTCT.

Laboratory indicators of mastitis are not associated with elevated HIV-1 DNA loads or predictive of HIV-1 RNA loads in breast milk.

BACKGROUND: Mother-to-child transmission (MTCT) of HIV-1 has been associated with symptomatic and asymptomatic mastitis and with the quantity of HIV-1 RNA and DNA in maternal milk. An improved understanding of the relationship between indicators of inflammation and HIV-1 loads in breast milk could improve MTCT prevention strategies. METHODS: In a cross-sectional study, laboratory indicators of mastitis (breast milk sodium [Na(+)] concentration, sodium : potassium ratio [Na(+) : K(+)], and leukocyte count) were related to breast milk HIV-1 RNA and DNA loads and were evaluated for predicting viral loads in milk. RESULTS: Mastitis was present in 63 (15%) of 407, 60 (15%) of 407, and 76 (18%) of 412 milk specimens, as defined by Na(+) concentration >12 mmol/L, Na(+) : K(+) >1, and total leukocyte counts > or =10(6) cells/mL, respectively. Each indicator was associated with an increased milk HIV-1 RNA load (P<.05) but not with HIV-1 DNA load. Neutrophils correlated better with milk HIV-1 RNA load than total leukocytes. However, neither neutrophil count, Na(+) concentration, nor Na(+) : K(+) displayed a threshold that was both sensitive and specific for the detection of HIV-1 RNA in milk at thresholds of > or =50 or > or =10(4) copies/mL. CONCLUSIONS: HIV-1 DNA loads in breast milk were not increased during mastitis. Neither milk cell counts nor electrolyte concentrations were useful predictors of milk HIV-1 RNA or DNA loads for individual women.

Tanning device usage: what are parents thinking?

Tanning device usage is prevalent among adolescents. Few studies have assessed the role of parental influence on children's use of indoor tanning facilities. Our objective was to determine if children's tanning device usage is affected by parental knowledge of risks of indoor tanning or by parental tanning practices. A survey was administered to 160 parents of 328 children at a general pediatrics clinic and 204 parents of 367 children at a pediatric dermatology clinic (parents n=364, children n=695). Over half of all parents and 17% of all teenagers queried had previously used tanning devices. The level of parental knowledge did not predict tanning device usage by their children. However, parental tanning device usage was associated with increased usage by children (p<0.05). Children began using tanning devices on average more than 4 years earlier than their parents. Most parents (69%) never wanted their children to use tanning devices, but only 15% of parents had discussed them with their children. Therefore, health providers can provide an important service by initiating discussions about tanning devices. Additional measures, including legislation requiring parental consent for indoor tanning, are needed to reduce tanning device usage by minors.

Do antireflux operations decrease the rate of reflux-related hospitalizations in children?

OBJECTIVE: Gastroesophageal reflux disease is extremely common in the pediatric population, and antireflux procedures are performed with increasing frequency. The objective of this study was to determine whether pediatric antireflux procedures are associated with a decreased rate of reflux-related hospitalizations. METHODS: A study was conducted of pediatric patients who were undergoing antireflux procedures using data that were derived from the Washington State Comprehensive Hospital Abstract Reporting System and Vital Records. Patients were identified by a search of all records (1987-2001) for procedure codes that pertained to antireflux procedures in patients who were younger than 19 years. The number of hospitalizations for and rates of reflux-related events per patient-year before and after an antireflux procedure was calculated, and factors that were associated with higher antireflux procedure rates were examined. RESULTS: A total of 1142 patients underwent antireflux procedures. The rate of reflux-related events declined sharply with age both before and after an antireflux procedure. The cohort was divided into 3 groups on the basis of age at first antireflux procedure (<1 year, 1-3 years, or 4-19 years), and the calculations of incidence rate ratios before to after an antireflux procedure were done within the same age strata. Results suggest an overall benefit of antireflux procedures in young children. For antireflux procedures that were performed in children who were older than 4 years, the benefit is less clear. Developmental delay was significantly associated with higher rates of reflux-related events among patients who underwent an antireflux procedure after age 4. CONCLUSIONS: The rate of reflux-related events was lower after an antireflux operation for children who underwent an antireflux procedure before age 4. Older children, however, were hospitalized at equal rates before and after an antireflux procedure, and older children with developmental delay were hospitalized at greater rates after an antireflux procedure. These findings highlight the need to clarify the subjective and objective indications for antireflux procedures in infants and children.

A comparison of a needle-free injection system for local anesthesia versus EMLA for intravenous catheter insertion in the pediatric patient.

Placement of IV catheters is a painful and stressful procedure for children. J-Tip is a needle-less Food and Drug Administration approved injection system that can be used for delivery of local anesthetic before IV cannulation. In this study, we compared the effectiveness of J-Tip versus eutectic mixture of local anesthetics (EMLA) to facilitate IV cannulation and provide adequate analgesia before IV placement. Children 7-19 years of age (n = 116) were randomized to receive 0.25 mL of 1% buffered lidocaine with J-Tip (n = 57) or 2.5 g of EMLA (n = 59) before IV cannulation. Measurements of success of cannulation (number of attempts for IV placement) and pain (0-10 visual analog scale) at application of local anesthetic and at cannulation were performed. There was a significant (P = 0.0001) difference in pain ratings during IV cannulation between EMLA (median = 3) and the J-Tip (median = 0). Eighty-four percent of patients reported no pain at the time of J-Tip lidocaine application compared to 61% in the EMLA group at the time of dressing removal (P = 0.004). We did not find differences in the number of attempts for IV cannulation. J-Tip application of 1% buffered lidocaine before IV cannulation is not painful and has better anesthetic effectiveness compared with EMLA.

Liver histology and alanine aminotransferase levels in children and adults with chronic hepatitis C infection.

BACKGROUND: Chronic hepatitis C is often a mild disease in children, but whether this is related to younger age or shorter duration of infection is unclear. Histologic severity has been shown to correlate with duration of infection regardless of age. OBJECTIVES: We compared histologic findings in children and adults with chronic hepatitis C while controlling for sex, duration of infection, hepatitis C virus (HCV)-RNA level, and genotype. METHODS: Twenty-one children and 52 adults whose infection was less than 20 years in duration and who had undergone a liver biopsy were included. Two blinded liver pathologists reviewed the liver biopsies and scored inflammatory activity and fibrosis using the modified Knodell scoring system. RESULTS: The groups were the same with respect to HCV-RNA level (P=0.8), and genotype (P=0.6) but differed in duration of disease (P=0.01) and sex composition (P=0.005). Covariate analysis showed no influence of genotype, duration of infection, or HCV-RNA level on outcome. In controlling for sex, children had significantly milder liver disease and alanine aminotransferase (ALT) elevations. CONCLUSIONS: With equal duration of infection, HCV-RNA level, and genotype, children have lower serum ALT levels and less severe liver disease than adults infected with HCV.

Detection and quantification of human immunodeficiency virus type 1 p24 antigen in dried whole blood and plasma on filter paper stored under various conditions.

The quantification of human immunodeficiency virus type 1 (HIV-1) by an assay measuring heat-dissociated (HD) p24 antigen (Ag) in specimens of whole blood and plasma stored on filter paper, and of plasma stored in tubes, was compared to HIV-1 RNA plasma levels determined by real-time reverse transcription (RT)-PCR. The stability of p24 Ag on filter paper under conditions simulating specimen transport was also evaluated. The HD p24 Ag in both plasma and whole-blood specimens stored on filter paper correlated with plasma HIV-1 RNA levels (Spearman rank rho = 0.74 [P < 0.0001] and rho = 0.56 [P = 0.0001], respectively). The sensitivity of the HD p24 Ag assay was similar when plasma and whole blood on filter paper were contrasted to the real-time RT-PCR assay (80% versus 82.5% and 78.6% versus 83.3%, respectively). However, while the specificity of the HD p24 Ag assay of plasma on filter paper was 100%, the specificity was diminished in whole-blood specimens. The storage of specimens on filter paper for 2 weeks at 37 degrees C, 24 degrees C, or 0 degrees C did not alter the detection or quantification of HD p24 Ag. These results suggest that transport and storage of plasma on filter paper and quantification of HD p24 Ag may be a reliable method for HIV-1 load monitoring.

Persistence of human immunodeficiency virus type 1 subtype B DNA in dried-blood samples on FTA filter paper.

The stability of human immunodeficiency virus type 1 (HIV-1) DNA in whole blood collected on filter paper (FTA Card) was evaluated. After >4 years of storage at room temperature in the dark our qualitative assay detected virus at a rate similar to that of our initial test (58 of 60, 97%; P = 0.16), suggesting long-term HIV-1 DNA stability.

Cranial suture simulator for ultrasound diagnosis of craniosynostosis.

BACKGROUND: In evaluating the effectiveness of ultrasound as a screening tool for craniosynostosis it was discovered that sonologists and sonographers needed more experience scanning and visualizing cranial sutures on ultrasound. OBJECTIVE: To create an ultrasound simulator to train radiologists and technologists to locate and recognize patent and fused cranial sutures in children. MATERIALS AND METHODS: The hypoechoic appearance of patent sutures was simulated by cutting lines into life-sized plastic doll heads and filling them with a commercial hypoechogenic material. Fused hyperechoic sutures were simulated by not cutting into the hard plastic region of a suture. The simulator's teaching value was evaluated on three radiology residents and three fellows. Subjects performed pre-training scans on unknown simulators, received feedback and an opportunity to scan a training simulator, and then performed post-training scans on random unknown simulators. Accuracy was recorded as percentage of correctly demonstrated sutures. RESULTS: The suture simulator reproduces the sonographic appearance of patent and fused cranial sutures. Accuracy of acquisition, interpretation, and overall diagnosis increased from 64 to 91%, 79 to 91%, 61 to 97%, respectively, between pre and post training scans. CONCLUSION: An ultrasound simulator can reproduce the appearance of patent and fused cranial sutures in children and can be used to train radiologists and technologists in the performance of a screening protocol.

Rapid computed tomography technique to measure ventricular volumes in the child with suspected ventriculoperitoneal shunt failure I. Validation of technique with a dynamic phantom.

OBJECTIVES: Assessment of ventricular volume change is critical and can be difficult in the child with suspected shunt failure. Objective techniques described to measure ventricular volumes have used limited anatomic sampling or have been computationally intensive. Phantoms used to evaluate these techniques have used static volumes. The purpose of this study was to construct a computed tomography (CT) phantom to simulate changing ventricular volumes and to evaluate a new program to measure volumes. METHODS: The phantom is 5 Foley catheters embedded in gelatin. The balloons were filled and then scanned at 15-mL increments from 0-300 mL. The program measures the voxels of specified density within a larger volume created by applying a region of interest to a stacked volume. Calculated volumes and percent changes were compared with actual volumes and percent changes. RESULTS: Calculated volumes were consistently 7%-9% (mean: -7.8%) less than actual injected volumes across the entire 0- to 300-mL range. For true changes between -50% and +50%, all calculated changes were within +/-2.5% points of true percent change; for true changes between +50% and +100%, all calculated changes were within +/-5% points of true percent change. CONCLUSIONS: A dynamic CT phantom simulating changing ventricular volumes can be constructed from readily available materials. A new volumetric program accurately measures ventricular volumes and percent change from baseline across a wide range of volumes.

Rapid computed tomography technique to measure ventricular volumes in the child with suspected ventriculoperitoneal shunt failure II. Clinical application.

OBJECTIVES: Assessment of ventricular volume change is critical in the child with suspected shunt failure. Minimal increases may represent high pressures in the child with reduced ventricular compliance but are difficult to detect subjectively. Objective techniques described limit anatomic sampling and are time intensive. The purpose of this study was to develop a rapid technique to measure ventricular volumes in children with suspected shunt failure. METHODS: Ventricular volumes were calculated in 12 children with baseline and emergent computed tomography scans performed for suspected shunt failure. Volumes and percent interval changes were correlated with clinical course. Two observers performed the volume analysis blinded to the clinical information; 1 observer performed the analysis twice. Time to perform the analysis was recorded for 5 studies. RESULTS: The intraobserver and interobserver correlation coefficients were 0.99 and 0.96/0.97, respectively. The mean time to perform the analysis was 2 minutes 42 seconds. Median percent change in patients with and without shunt obstruction was +50% (range: +24%-+367%) and +2% (range: -22%-+36%), respectively. Among patients subjectively read as having stable ventricular sizes, volume changes of -11% to +32% were calculated. CONCLUSIONS: The technique has excellent intra- and interobserver correlation and is rapidly performed. The range of percent volume changes between patients with and without shunt malfunction overlaps. Subjective assessment of ventricular changes is significantly less sensitive than the volume calculation technique. The technique may be most useful in patients with decreased ventricular compliance in whom small interval changes may represent large pressure increases.

Ultrasound screening of the lambdoid suture in the child with posterior plagiocephaly.

BACKGROUND: The child with posterior plagiocephaly may have positional molding or unilateral lambdoid synostosis. Molding responds to conservative treatment, lambdoid synostosis requires surgical reconstruction. CT is diagnostic, but uses ionizing radiation, may need sedation, and the incidence of lambdoid fusion is only 2-3%. OBJECTIVE: The purpose of this prospective study was to evaluate ultrasound as a screening test of lambdoid sutural patency using CT as the reference standard. MATERIALS AND METHODS: In total, 41 children having head CT examinations were enrolled over 6 months. Of those, 29 were referred for abnormal head shape and suspected synostosis, of whom two had lambdoid fusion; 12 were referred for indications not related to head shape and found to have a normal study. Ultrasound scanning and interpretation of the lambdoid sutures was performed blinded to the CT reference standard. The lambdoid suture was read as patent or fused if a hypoechoic gap could or could not be seen between the hyperechoic calvarial bones, respectively. RESULTS: The mean sensitivity and specificity of ultrasound in distinguishing a patent from fused lambdoid suture by three blinded pediatric radiologists was 100% and 89%, respectively. CONCLUSIONS: Sonography of the lambdoid sutures shows excellent preliminary promise as a screening test of lambdoid sutural patency.

A randomized, clinical trial of oral midazolam plus placebo versus oral midazolam plus oral transmucosal fentanyl for sedation during laceration repair.

OBJECTIVE: To determine whether a combination of oral transmucosal fentanyl (Fentanyl Oralet, Abbott Laboratories, North Chicago, IL) plus oral midazolam has an acceptable safety profile and is more effective than oral midazolam alone for sedation during laceration repair in a pediatric emergency department (ED). METHODS: Randomized, double-blind, placebo-controlled, clinical trial. Patients between 2 and 8 years of age who weighed >10 kg and presented to the ED with a laceration in need of repair under sedation were eligible for inclusion. All patients received oral midazolam (0.5 mg/kg; maximum dose 10 mg) and either fentanyl (5-10 microg/kg) or placebo in oralet form. Data collected every 5 minutes included the following: heart rate, oxygen saturation, respiratory rate, pain as measured on a Children's Hospital of Eastern Ontario Pain Score (CHEOPS) scale (range: 4-13), and an activity scale (range: 1-5). Effectiveness of sedation was measured by CHEOPS and activity scores compared between the treatment groups. RESULTS: Fifty-one patients were randomized to receive oral midazolam plus fentanyl (N = 28) or oral midazolam plus placebo (N = 23). Age, weight, gender, or baseline pain and activity scores did not differ between the 2 groups. Seven patients in the fentanyl group vomited compared with 0 patients in the placebo group. Three patients in the fentanyl group and no patients in the placebo group had brief oxygen saturation below 93% on room air. The mean pain score within 5 minutes of the start of the procedure did not differ between the 2 groups (fentanyl group, 9.4 versus placebo group, 8.8). Mean activity scores within 5 minutes of the start of the procedure were also similar (fentanyl group, 4.3 versus placebo group, 4.3). CONCLUSIONS: The addition of oral transmucosal fentanyl to oral midazolam did not improve pain or activity scores in pediatric patients given sedation for laceration repair. Patients who received Fentanyl Oralet suffered significantly more side effects despite the relatively low doses administered in this study. Oral transmucosal fentanyl should not be used for procedural sedation in the ED.