Clinical Utility of Repeat Magnetic Resonance Imaging Studies Among Children With Acute Hematogenous Osteomyelitis.

BACKGROUND AND OBJECTIVES: There is limited guidance for whether repeat magnetic resonance imaging (MRI) studies are clinically impactful among children with acute hematogenous osteomyelitis (AHO) who fail to improve as expected. This study aimed to determine whether repeat MRIs changed management among children with AHO and identify clinical characteristics predictive of which patients benefit from repeat MRIs. METHODS: Children admitted to a quaternary care pediatric hospital with AHO were identified during a 9-year period. Patients with chronic symptoms, non-hematogenous infections, or significant contributing comorbidities were excluded. Medical records were retrospectively reviewed for all MRIs performed 3 weeks before admission to 24 months after discharge. An MRI was considered clinically impactful if it identified a new infectious process (eg, abscess not seen on the initial MRI) or if it resulted in surgical intervention within 24 hours. Bivariable comparisons of categorical variables were performed, and multivariable logistic regression was used to assess the clinical factors of impactful repeat MRIs. RESULTS: Among the 239 included patients, 41 (17%) had more than 1 MRI performed during their clinical course, the majority of whom (53.7%) had a repeat MRI that impacted care. Patients who underwent repeat MRIs had longer hospitalizations (7 vs. 5 d, P <0.01), were more likely to have C-reactive protein (CRP) levels >20 mg/dL (41% vs. 10%, P <0.01), and were more likely to have a delayed transition to oral antimicrobials (8.4 vs. 3.3 d, P <0.01). Peak CRP >20 mg/dL and prolonged bacteremia were found to be associated with increased odds of having an impactful repeat MRI, with adjusted odds ratios of 3.9 ( P =0.007) and 3.4 ( P =0.03), respectively. CONCLUSIONS: When used judiciously among ill children with complicated AHO, repeat MRI can be clinically impactful. Prospective studies are needed to better define which children with AHO benefit from repeat MRI. LEVEL OF EVIDENCE: Level II evidence-this is a retrospective cohort study interested in determining the clinical utility of repeat magnetic resonance imaging studies for children with osteomyelitis.

Clinical Pathway Adherence and Missed Diagnostic Opportunities Among Children with Musculoskeletal Infections.

INTRODUCTION: Clinical care pathways (CPs) integrate best evidence into the local care delivery context to promote efficiency and patient safety. However, the impact of CPs on diagnostic performance remains poorly understood. The objectives of this study were to evaluate adherence to a musculoskeletal infection (MSKI) diagnostic CP and identify recurrent failure points leading to missed diagnostic opportunities (MDOs). METHODS: Retrospective chart review was performed from January 2018 to February 2022 for children 6 months to 18 years of age who had an unplanned admission for MSKI after being evaluated and discharged from the pediatric emergency department (PED) for related complaints within the previous 10 days. MDOs were identified using the Revised Safer Dx. Demographic and clinical characteristics of children with and without MDOs were compared using bivariate descriptive statistics. An improvement team reviewed the diagnostic trajectories of MDOs for deviations from the MSKI CP and developed a fishbone diagram to describe contributing factors to CP deviations. RESULTS: The study identified 21 children with and 13 children without MSKI-associated MDOs. Children with MDOs were more likely to have an initial C-reactive protein value > 2 mg/dL (90.0% vs. 0%, p = 0.01) and returned to care earlier than children without MDOs (median 2.8 days vs. 6.7 days, p = 0.004). Factors contributing to MDOs included failure to obtain screening laboratory tests, misinterpretation of laboratory values, failure to obtain orthopedic consultation, and failure to obtain definitive imaging. CONCLUSION: Several recurrent deviations from an MSKI diagnostic CP were found to be associated with MDOs. Future quality improvement efforts to improve adherence to this MSKI CP may prevent MDOs.

Prediction of quadriceps tendon-patellar bone autograft diameter in adolescents with 2-dimensional magnetic resonance imaging and anthropometric measures.

OBJECTIVES: This study evaluates the correlation between the bone end and soft tissue end of the quadriceps tendon-patellar bone autograft (QPA) size and pre-operative MRI measurements of the quadriceps tendon along sections to be included in the graft harvest in adolescents. We also assessed association between graft diameter and anthropometric measures (height, weight, and BMI), age, and sex. METHODS: Patients (10-18 years) who underwent QPA ACL reconstruction and had a pre-operative MRI were considered for inclusion. Age, height, and weight, tibial and femoral side graft diameter, and patellar bone block dimensions were collected. Using a pre-operative 2D sagittal plane MRI, we measured the quadriceps at 10-mm increments above the patella, up to 40 mm. We assessed correlation between the bone-end graft diameter and the AP measure at 10 mm above the patella, and correlation between the soft-tissue end graft diameter and the most proximal AP measure. RESULTS: A total of 103 patients were included. A significant correlation between the soft-tissue side graft diameter and most proximal AP measurement was observed (rs = 0.51; p < 0.001). However, measurements significantly underestimated the soft-tissue end graft diameter (9.6 ± 0.8 vs. 7.4 ± 1.1; p < 0.001). There was no correlation between the bone-end graft diameter and AP measurement 10 mm above the patella. Anthropometric measures were not associated with graft size. Skeletal maturity was associated with smaller graft size (p = 0.08). CONCLUSION: Soft-tissue end graft diameter is associated with the AP measure of the quadriceps at 20-40 mm above the superior pole of the patella.

Safety of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease.

BACKGROUND: Patients with pre-existing autoimmune disease (AD) have been largely excluded from clinical trials of immune checkpoint inhibitors (ICI), so data on safety of ICIs among patients with pre-existing AD are relatively limited. There is a need for deeper understanding of the type and management of complications from ICI in patients with pre-existing AD. We sought to investigate the safety of ICIs in patients with pre-existing ADs as well as factors associated with AD flare. METHODS: Consecutive patients with pre-existing AD who received monotherapy as well as combination of ICI therapies at our institution from September 2015 through September 1st, 2018 were identified. Clinical information was abstracted via manual chart review. Clinical factors associated with AD flare were determined using multivariable logistic regression. RESULTS: A total of 42 patients were identified of whom 12 developed AD flare. All flares were treated with oral or topical corticosteroids, while a patient with flare of rheumatoid arthritis was treated with tofacitinib and another patient with Crohn's flare was treated with infliximab. Female sex, smoking status, higher age at the start of ICI therapy, cancer type, such as melanoma and lung cancer as compared to other cancers, were not significantly associated with AD flare, however, patients with underlying rheumatologic AD were noted to have a five times greater likelihood of flare as compared to other non-rheumatologic AD. Nine patients developed new immune related adverse events (IRAEs) unrelated to underlying AD, such as inflammatory poly-arthropathy, neuropathy, hypothyroidism, diarrhea, lichenoid drug eruptions, which were managed with oral and/or topical corticosteroids. ICI was stopped in six patients due to AD flare, in four patients due to IRAE flare (out of which one resumed ICI after resolution of IRAE). CONCLUSIONS: In patients with pre-existing AD treated with ICI, AD flare occurred in 28% of patients and were managed successfully with corticosteroids alone or with additional disease-modifying therapies. ICI could be considered in patients with AD, but with very close monitoring and preemptive multidisciplinary collaboration.

Evaluation of Checkpoint Inhibitors in Cancer Patients With End-stage Renal Disease on Hemodialysis: Case Series and Review of the Literature.

Checkpoint inhibitors (CPIs) have become standard of care for multiple types of malignancies and while end-stage renal disease is not a contraindication, these patients are frequently excluded from clinical trials. As a result, there is limited data regarding the safety and efficacy of CPI use in this patient population. In this case series, we report outcomes and adverse events in 8 patients on hemodialysis treated with CPIs. Treatment was overall well-tolerated with adverse events in 3 of 8 (37.5%) patients, with 1 (12.5%) having a grade 4 adverse event, which is comparable to the rate reported in literature for the overall population receiving CPI. No treatment related deaths were seen. Because of small sample size, efficacy data is limited. Further studies are needed in this patient population to elucidate the true incidence of adverse events and antitumor activity.

Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study.

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years ("early prophylaxis"); 18 initially randomized to episodic treatment, starting "delayed prophylaxis" at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

Clinical outcomes and toxicities of pazopanib administered orally in crushed form: Case reports and review of the literature.

Cancer treatment has changed dramatically with the development of oral targeted therapies. Pazopanib, an oral VEGF tyrosine kinase inhibitor, is currently approved for advanced renal cell carcinoma, advanced soft tissue sarcoma, and is being studied for various tumor types. Due to the potential of increased exposure to pazopanib when crushed, pazopanib should be given as an intact whole tablet. Thus, in patients with difficulty swallowing medications or feeding tubes, pazopanib is usually not considered to be an option. Here, we describe two cases which show the administration of crushed pazopanib was feasible and had apparent clinical activity.

Pulmonary Embolism in Children.

Pulmonary embolism is an uncommon but potentially life-threatening event in children. There has been increasing awareness of pulmonary embolism in children with improved survival in children with systemic disease and advancements in diagnostic modalities. However, literature regarding pulmonary embolism in children is sparse, and thus current guidelines for management of pulmonary embolism in children are extrapolated from adult literature and remain controversial. This article reviews the background and pathophysiology of venous thromboembolism, as well as current diagnostic approach and recommended management of pulmonary embolism in children.

Quantitative CT scans of lung parenchymal pathology in premature infants ages 0-6 years.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common, heterogeneous disease in premature infants. We hypothesized that quantitative CT techniques could assess lung parenchymal heterogeneity in BPD patients across a broad age range and demonstrate how pathologies change over time. METHODS: A cross-sectional, retrospective study of children age 0-6 years with non-contrast chest CT scans was conducted. BPD subjects met NICHD/NHLBI diagnostic criteria for BPD and were excluded for congenital lung/airway abnormalities or other known/suspected pulmonary diagnoses; control subjects were not premature and had normal CT scan findings. Radiologic opacities, lucencies, and spatial heterogeneity were quantified via: 1) thresholding using CT-attenuation (HU); 2) manual segmentation; and 3) Ochiai reader-scoring system. Clinical outcomes included BPD severity by NICHD/NHLBI criteria, respiratory support at NICU discharge, wheezing, and respiratory exacerbations. RESULTS: Heterogeneity (standard deviation) of lung attenuation in BPD was significantly greater than in controls (difference 36.4 HU [26.1-46.7 HU], P < 0.001); the difference between the groups decreased 0.58 HU per month of age (0.08-1.07 HU per month, P = 0.02). BPD patients had greater amounts of opacities and lucencies than controls except with automated quantification of lucencies. Cross-sectionally, lucencies per Ochiai score and opacities per manual segmentation decreased with time. No approach measured a statistically significant relationship to BPD clinical severity. CONCLUSIONS: Opacities, lucencies, and overall heterogeneity of lungs via quantitative CT can distinguish BPD patients from healthy controls, and these abnormalities decrease with age across BPD patients. Defining BPD severity by clinical outcomes such as respiratory support at several time points (vs a single time point, per current guidelines) may be meaningful.

The Effect of Scapular Position on Magnetic Resonance Imaging Measurements of Glenohumeral Dysplasia Caused by Neonatal Brachial Plexus Palsy.

PURPOSE: Neonatal brachial plexus palsy (NBPP) frequently causes glenohumeral dysplasia. Quantification of this dysplasia on magnetic resonance imaging can determine the need for and the success of nonsurgical or surgical intervention. However, we hypothesize that the variable position of the scapula on the thorax between affected and unaffected shoulders affects dysplasia measurements. METHODS: Magnetic resonance imaging studies were analyzed from 19 NBPP patients (ages 0.8-18 years; median, 2.4 years) without prior shoulder surgery. Three reviewers measured the glenoid version angle (GVA) and percentage of humeral head anterior to the midscapular line (PHHA) on standard axial images ("thoracic axial") and on reformatted axial images aligned perpendicular to the scapular plane ("scapular axial"), which corrects for scapulothoracic position. Scapular tilt and protraction were measured to assess their impact on the difference between thoracic and scapular GVA and PHHA measurements. Intra- and interrater reliability were calculated for GVA and PHHA on both views. RESULTS: The GVA of the affected shoulder was significantly greater on thoracic than on scapular images, by an average of 5° and as much as 34°. The PHHA was significantly less in the affected shoulders on thoracic than on scapular images, by an average of 5% and as much as 33% of humeral head width. The difference in GVA, but not PHHA, between thoracic and scapular axial images in the affected shoulder correlated with scapular tilt. Unaffected shoulders showed no significant difference in GVA or PHHA between thoracic and scapular axial images. Interrater reliability ranged from fair to substantial and did not differ between thoracic and scapular images. CONCLUSIONS: Thoracic axial images overestimate the severity of glenohumeral dysplasia in NBPP, owing at least in part to the variable position of the scapula on the thorax. This confounding effect must be considered in interpretation of axial quantitative measures of glenohumeral dysplasia in NBPP. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Acute traumatic intraosseous fluid sign predisposes to dynamic fracture mobility.

The intraosseous fluid sign (IFS) in chronic osteoporotic vertebral fractures is attributed to fluid accumulation within non-healing intervertebral clefts. IFS can also be seen in acute traumatic fractures, not previously described. We hypothesize a pathophysiological mechanism for the acute traumatic intraosseous fluid sign (ATIFS) and its predisposition to dynamic fracture mobility with axial loading on upright radiographs. Retrospective analysis was performed of 41 acute thoracic and lumbar compression or stable burst fractures with both supine CT and upright plain films completed within 1 week of each other. The presence of an intravertebral cleft with fluid attenuation and vertebral body height loss was assessed on CT scans. Changes in the fractured vertebral body height and angulation were measured on upright radiographs. The ATIFS was identified in 18 (44%) of the 41 acute fractures. Mean kyphotic angle increase was significantly greater (p = 0.000) for ATIFS fractures (8.2°, SD ±4.2) than fractures without ATIFS (1.6°, SD ±3.4). There was significantly greater mean anterior (p = 0.0009) and central (p = 0.026) height loss in ATIFS fractures (4.3 mm, SD ±3.76 and 1.89 mm, SD ±4.44, respectively) compared to fractures without ATIFS (0.59 mm, SD ±2.24 and -0.52 mm, SD ±2.01, respectively). The IFS can be seen in acute traumatic vertebral fractures and show dynamic mobility. These ATIFS fractures show statistically significant greater mean height loss ratio differences and have significantly greater changes in kyphotic angulation on upright imaging when compared to fractures without ATIFS.

Quantitative CT characterization of pediatric lung development using routine clinical imaging.

BACKGROUND: The use of quantitative CT analysis in children is limited by lack of normal values of lung parenchymal attenuation. These characteristics are important because normal lung development yields significant parenchymal attenuation changes as children age. OBJECTIVE: To perform quantitative characterization of normal pediatric lung parenchymal X-ray CT attenuation under routine clinical conditions in order to establish a baseline comparison to that seen in pathological lung conditions. MATERIALS AND METHODS: We conducted a retrospective query of normal CT chest examinations in children ages 0-7 years from 2004 to 2014 using standard clinical protocol. During these examinations semi-automated lung parenchymal segmentation was performed to measure lung volume and mean lung attenuation. RESULTS: We analyzed 42 CT examinations in 39 children, ages 3 days to 83 months (mean ± standard deviation [SD] = 42 ± 27 months). Lung volume ranged 0.10-1.72 liters (L). Mean lung attenuation was much higher in children younger than 12 months, with values as high as -380 Hounsfield units (HU) in neonates (lung volume 0.10 L). Lung volume decreased to approximately -650 HU by age 2 years (lung volume 0.47 L), with subsequently slower exponential decrease toward a relatively constant value of -860 HU as age and lung volume increased. CONCLUSION: Normal lung parenchymal X-ray CT attenuation decreases with increasing lung volume and age; lung attenuation decreases rapidly in the first 2 years of age and more slowly thereafter. This change in normal lung attenuation should be taken into account as quantitative CT methods are translated to pediatric pulmonary imaging.

Specialty pharmacy services for patients receiving oral medications for solid tumors.

PURPOSE: Currently available oral oncology therapies are reviewed, and specialty pharmacy services for patients receiving these drugs are described. SUMMARY: Market introductions of new oral oncology drugs have increased substantially over the past decade, and 25-30% of all oncology agents in development are oral medications. Oral agents for treatment of breast cancer include capecitabine, lafatinib, and palbociclib. Several oral agents are used in treating patients with lung cancer driven by mutations of genes coding for anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR); currently available agents include the ALK inhibitors certinib and crizotinib and the EGFR inhibitors afatinib, erlotinib, and gefitinib. Four oral targeted therapies are used in the treatment of melanoma associated with the B-Raf proto-oncogene, BRAF: cobimetinib, dabrafenib, trametinib, and vemurafenib. Oral agents for treatment of prostate cancer include abiraterone acetate and enzalutamide. Oral agents for treatment of renal cell carcinoma include axitinib, everolimus, pazopanib, sorafenib, and sunitinib. Specialty pharmacy services for patients receiving oral oncology agents can include (1) providing patient counseling and education on adverse effects and self-management strategies, (2) processing prior-authorization requests and helping patients navigate copayment assistance programs, and (3) monitoring for medication toxicities and recommending dose adjustments as appropriate. CONCLUSION: Many oral oncology medications have been introduced over the past 10-15 years, with many others in clinical development. Due to the complexity of initiating and monitoring patients receiving these oral therapies, specialty pharmacy services are an essential component of many patients' cancer care.

In harm's way: toxic threats to child development.

Developmental disabilities result from complex interactions of genetic, toxicologic (chemical), and social factors. Among these various causes, toxicologic exposures deserve special scrutiny because they are readily preventable. This article provides an introduction to some of the literature addressing the effects of these toxicologic exposures on the developing brain. This body of research demonstrates cause for serious concern that commonly encountered household and environmental chemicals contribute to developmental disabilities. The developing brain is uniquely susceptible to permanent impairment by exposure to environmental substances during time windows of vulnerability. Lead, mercury, and polychlorinated biphenyls (PCBs) have been extensively studied and found to impair development at levels of exposure currently experienced by significant portions of the general population. High-dose exposures to each of these chemicals cause catastrophic developmental effects. More recent research has revealed toxicity at progressively lower exposures, illustrating a "declining threshold of harm" commonly observed with improved understanding of developmental toxicants. For lead, mercury, and PCBs, recent studies reveal that background-population exposures contribute to a wide variety of problems, including impairments in attention, memory, learning, social behavior, and IQ. Unfortunately, for most chemicals there is little data with which to evaluate potential risks to neurodevelopment. Among the 3000 chemicals produced in highest volume (over 1 million lbs/yr), only 12 have been adequately tested for their effects on the developing brain. This is a matter of concern because the fetus and child are exposed to untold numbers, quantities, and combinations of substances whose safety has not been established. Child development can be better protected by more precautionary regulation of household and environmental chemicals. Meanwhile, health care providers and parents can play an important role in reducing exposures to a wide variety of known and suspected neurodevelopmental toxicants that are widely present in consumer products, food, the home, and wider community.