Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement.

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Hepatic steatosis modeling and MRI signal simulations for comparison of single- and dual-R2* models and estimation of fat fraction at 1.5T and 3T.

BACKGROUND AND OBJECTIVE: Magnetic resonance imaging (MRI) has emerged as a noninvasive clinical tool for assessment of hepatic steatosis. Multi-spectral fat-water MRI models, incorporating single or dual transverse relaxation decay rate(s) (R2*) have been proposed for accurate fat fraction (FF) estimation. However, it is still unclear whether single- or dual-R2* model accurately mimics in vivo signal decay for precise FF estimation and the impact of signal-to-noise ratio (SNR) on each model performance. Hence, this study aims to construct virtual steatosis models and synthesize MRI signals with different SNRs to systematically evaluate the accuracy of single- and dual-R2* models for FF and R2* estimations at 1.5T and 3.0T. METHODS: Realistic hepatic steatosis models encompassing clinical FF range (0-60 %) were created using morphological features of fat droplets (FDs) extracted from human liver biopsy samples. MRI signals were synthesized using Monte Carlo simulations for noise-free (SNRideal) and varying SNR conditions (5-100). Fat-water phantoms were scanned with different SNRs to validate simulation results. Fat water toolbox was used to calculate R2* and FF for both single- and dual-R2* models. The model accuracies in R2* and FF estimates were analyzed using linear regression, bias plot and heatmap analysis. RESULTS: The virtual steatosis model closely mimicked in vivo fat morphology and Monte Carlo simulation produced realistic MRI signals. For SNRideal and moderate-high SNRs, water R2* (R2*W) by dual-R2* and common R2* (R2*com) by single-R2* model showed an excellent agreement with slope close to unity (0.95-1.01) and R2 > 0.98 at both 1.5T and 3.0T. In simulations, the R2*com-FF and R2*W-FF relationships exhibited slopes similar to in vivo calibrations, confirming the accuracy of our virtual models. For SNRideal, fat R2* (R2*F) was similar to R2*W and dual-R2* model showed slightly higher accuracy in FF estimation. However, in the presence of noise, dual-R2* produced higher FF bias with decreasing SNR, while leading to only marginal improvement for high SNRs and in regions dominated by fat and water. In contrast, single-R2* model was robust and produced accurate FF estimations in simulations and phantom scans with clinical SNRs. CONCLUSION: Our study demonstrates the feasibility of creating virtual steatosis models and generating MRI signals that mimic in vivo morphology and signal behavior. The single-R2* model consistently produced lower FF bias for clinical SNRs across entire FF range compared to dual-R2* model, hence signifying that single-R2* model is optimal for assessing hepatic steatosis.

Virtual reality applications in pediatric surgery.

Virtual reality modeling (VRM) is a 3-dimensional (3D) simulation. It is a powerful tool and has multiple uses and applications in pediatric surgery. Patient-specific 2-dimensional imaging can be used to generate a virtual reality model, which can improve anatomical perception and understanding, and can aid in preoperative planning for complex operations. VRM can also be used for realistic training and simulation. It has also proven effective in distraction for pediatric patients experiencing pain and/or anxiety. We detail the technical requirements and process required for VRM generation, the applications, and future directions.

Progressive metastatic infantile fibrosarcoma with multiple acquired mutations.

Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes.

Computed Tomographic Analysis of the Sagittal Orbit-globe Relationship.

Identifying the normal relationship of the orbital rims to the globes is critical in planning surgical correction of craniofacial deformities affecting the orbit. This article illustrates a technical proof of principle and mathematical basis for a computed tomography-based measurement of the sagittal orbit-globe relationship. The technique does not require subject cooperation and is, therefore, optimal for pediatric craniofacial surgical treatment planning and outcome evaluation.

Productivity in Pediatric Palliative Care: Measuring and Monitoring an Elusive Metric.

CONTEXT: Workforce productivity is poorly defined in health care. Particularly in the field of pediatric palliative care (PPC), the absence of consensus metrics impedes aggregation and analysis of data to track workforce efficiency and effectiveness. Lack of uniformly measured data also compromises the development of innovative strategies to improve productivity and hinders investigation of the link between productivity and quality of care, which are interrelated but not interchangeable. OBJECTIVES: To review the literature regarding the definition and measurement of productivity in PPC; to identify barriers to productivity within traditional PPC models; and to recommend novel metrics to study productivity as a component of quality care in PPC. METHODS: PubMed® and Cochrane Database of Systematic Reviews searches for scholarly literature were performed using key words (pediatric palliative care, palliative care, team, workforce, workflow, productivity, algorithm, quality care, quality improvement, quality metric, inpatient, hospital, consultation, model) for articles published between 2000 and 2016. Organizational searches of Center to Advance Palliative Care, National Hospice and Palliative Care Organization, National Association for Home Care & Hospice, American Academy of Hospice and Palliative Medicine, Hospice and Palliative Nurses Association, National Quality Forum, and National Consensus Project for Quality Palliative Care were also performed. Additional semistructured interviews were conducted with directors from seven prominent PPC programs across the U.S. to review standard operating procedures for PPC team workflow and productivity. RESULTS: Little consensus exists in the PPC field regarding optimal ways to define, measure, and analyze provider and program productivity. Barriers to accurate monitoring of productivity include difficulties with identification, measurement, and interpretation of metrics applicable to an interdisciplinary care paradigm. In the context of inefficiencies inherent to traditional consultation models, novel productivity metrics are proposed. CONCLUSIONS: Further research is needed to determine optimal metrics for monitoring productivity within PPC teams. Innovative approaches should be studied with the goal of improving efficiency of care without compromising value.

Radiology of Cleft Lip and Palate: Imaging for the Prenatal Period and throughout Life.

Recent advances in prenatal imaging have made possible the in utero diagnosis of cleft lip and palate and associated deformities. Postnatal diagnosis of cleft lip is made clinically, but imaging still plays a role in detection of associated abnormalities, surgical treatment planning, and screening for or surveillance of secondary deformities. This article describes the clinical entities of cleft lip with or without cleft palate (CLP) and isolated cleft palate and documents their prenatal and postnatal appearances at radiography, ultrasonography (US), magnetic resonance (MR) imaging, and computed tomography (CT). Imaging protocols and findings for prenatal screening, detection of associated anomalies, and evaluation of secondary deformities throughout life are described and illustrated. CLP and isolated cleft palate are distinct entities with shared radiologic appearances. Prenatal US and MR imaging can depict clefting of the lip or palate and associated anomalies. While two- and three-dimensional US often can depict cleft lip, visualization of cleft palate is more difficult, and repeat US or fetal MR imaging should be performed if cleft palate is suspected. Postnatal imaging can assist in identifying associated abnormalities and dentofacial deformities. Dentofacial sequelae of cleft lip and palate include missing and supernumerary teeth, oronasal fistulas, velopharyngeal insufficiency, hearing loss, maxillary growth restriction, and airway abnormalities. Secondary deformities can often be found incidentally at imaging performed for other purposes, but detection is necessary because they may have considerable implications for the patient.

Geometry of anterior open bite correction.

Correction of anterior open bite is a frequently encountered and challenging problem for the craniomaxillofacial surgeon and orthodontist. Accurate clinical evaluation, including cephalometric assessment, is paramount for establishing the diagnosis and appropriate treatment plan. The purposes of this technical note were to discuss the basic geometric principles involved in the surgical correction of skeletal anterior open bites and to offer a simple mathematical model for predicting the amount of posterior maxillary impaction with concomitant mandibular rotation required to establish an adequate overbite. Using standard geometric principles, a mathematical model was created to demonstrate the relationship between the magnitude of the open bite and the magnitude of the rotational movements required for correction. This model was then validated using a clinical case. In summary, the amount of open bite closure for a given amount of posterior maxillary impaction depends on anatomic variables, which can be obtained from a lateral cephalogram. The clinical implication of this relationship is as follows: patients with small mandibles and steep mandibular occlusal planes will require greater amounts of posterior impaction.

Effects of mandibular distraction osteogenesis on three-dimensional airway anatomy in children with congenital micrognathia.

PURPOSE: To assess the 3-dimensional (3D) computed tomography (CT) changes in airway size and shape in children with congenital micrognathia treated by mandibular distraction osteogenesis (DO). PATIENTS AND METHODS: This was a retrospective study of patients with congenital micrognathia, treated by mandibular DO, who had pre- and postoperative 3D maxillofacial CT scans from the hard palate to the hyoid bone. Digital 3D-CT reconstructions were made before and after distraction. Demographic (age, gender, and diagnosis) and anatomic (airway size and shape) variables were recorded and analyzed. The pre-distraction measures of size and shape were compared with the post-distraction measures. P≤.05 was considered significant. RESULTS: During the study period (1999 to 2010), 17 children with congenital micrognathia underwent mandibular DO. Of these patients, 11 (3 females) met the inclusion criteria. The mean age was 6.8 years (range 1.3 to 20.6). All subjects had first and second pharyngeal arch deformities. Nine were tracheostomy dependent before distraction. Postdistraction increases in the anteroposterior diameter (153%), lateral airway diameter (70%), airway volume (76%), minimal retroglossal (162%) and retropalatal (77%), and minimal cross-sectional areas (282%) were obtained. The mean airway length decreased after distraction by 4 mm DO also affected the airway shape: the airway surface area and airway compactness increased after distraction. Six subjects were decannulated or had their tracheostomies capped. Three subjects remained tracheostomy dependent after distraction. The reasons for continued tracheostomy included copious secretions, muscle hypotonia, hypopharnygeal stenosis, and mandibular hypomobility. CONCLUSIONS: DO for congenital micrognathia increases airway size, decreases airway length, and alters the shape as measured using 3D-CT.

Upper airway length decreases after maxillomandibular advancement in patients with obstructive sleep apnea.

PURPOSE: Most reports on airway anatomy after maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) have focused on changes in airway diameter, ie, posterior airway space (PAS), rather than airway length. The purpose of this study was to evaluate changes in cephalometrically measured upper airway length (UAL) after MMA. MATERIALS AND METHODS: This was a retrospective cohort study. The sample was composed of subjects who underwent MMA for OSA. The primary outcome measurement was change in UAL measured on lateral cephalograms. Predictor variables included patient demographic and cephalometric characteristics. Secondary outcome measurements were changes in sleep disturbance. Descriptive, bivariate, and regression statistics were computed. For all analyses, P ≤ .05 was considered statistically significant. RESULTS: The sample included 23 adult subjects (mean age, 39.3 ± 12.1 years; 6 women). Subjects had average maxillary and mandibular advancements of 9.8 ± 2.0 and 10.8 ± 2.2 mm, respectively. Mean pre- and postoperative UALs were 75.8 ± 7.0 and 67.0 ± 5.7 mm, respectively (P < .001). Mean pre- and postoperative respiratory disturbance indexes were 53.2 ± 22.4 and 19.0 ± 12.0 events/hour, respectively (P = .003). All patients had improvement in OSA symptoms, but 3 (13%) required continuous positive airway pressure. CONCLUSION: The results of this study suggest that UAL decreases as a result of MMA. In addition, these results support the observation that MMA is associated with objective and subjective improvements in patients with OSA.

Cephalometric measurement of upper airway length correlates with the presence and severity of obstructive sleep apnea.

PURPOSE: The purpose of this study was to measure upper airway length (UAL) on lateral cephalograms and to assess its relationship with the presence and severity of obstructive sleep apnea (OSA). MATERIALS AND METHODS: Using a case-control study design, the investigators enrolled a sample of cases defined as adult subjects with OSA and controls who were adult patients with skeletal Class II malocclusions. The primary predictor variable was UAL. Other variables were demographic and cephalometric parameters. The respiratory disturbance index (RDI) was used to measure disease severity in cases. Bivariate analyses were computed to evaluate the associations between predictor and outcome variables. Multiple regression analyses were used to provide adjusted measures of association, controlling for the effects of confounders/effect modifiers. Diagnostic test characteristics were computed for threshold airway lengths. P ≤ .05 was considered statistically significant. RESULTS: The sample consisted of 96 cases with OSA (76 males) and 56 controls without OSA (36 males). OSA subjects were older, were predominately male, and had higher body mass indexes and longer and narrower airways (P < .05). After controlling for confounding variables, UALs ≥ 72 mm for males and ≥ 62 mm for females were significantly associated with the presence of OSA (P = .03). The sensitivity and specificity of UAL as a diagnostic test for OSA were ≥ 0.8. UAL was strongly correlated with RDI (disease severity) in males (r = 0.72, P < .01) and moderately correlated with RDI in females (r = 0.52, P < .01). CONCLUSION: Increased upper airway length was correlated with the presence and severity of OSA in this sample of adult patients.

Three-dimensional computed tomographic analysis of airway anatomy.

PURPOSE: To test the reliability of a 3-dimensional computed tomographic (3D-CT) analysis of airway size and shape and to correlate the 3D-CT findings with lateral cephalometric measurements. MATERIALS AND METHODS: Fifteen pairs of preoperative maxillofacial 3D-CT scans and digital lateral cephalograms of patients treated for obstructive sleep apnea were used in the present study. Digital 3D-CT reconstructions were created and 12 measurements of airway size and 4 of shape were analyzed. The posterior airway space (PAS), middle airway space, and hyoid to mandibular plane distances were measured on the cephalograms. We then randomly selected 5 CT scans and 5 cephalograms which were analyzed blindly on 5 separate occasions by 2 investigators (Z.A., J.T.) to establish the intraclass correlation coefficients for inter- and intraexaminer reliability. All 15 pairs of images were used to compute the Pearson correlation coefficients to establish the relationship between the CT and cephalometric measurements. RESULTS: The intra- and interexaminer reliabilities were high for all CT (0.86 to 1.0 and 0.89 to 1.0, respectively; P < .001) and cephalometric measurements (0.84 to 1.0 and 0.91 to 0.99, respectively; P < .001). The CT measurements retroglossal anteroposterior dimension and distance between the genial tubercle and hyoid exhibited a positive correlation with the PAS (r = .60, P = 02 and r = .54, P = .04, respectively), and the lateral/anteroposterior dimension demonstrated an inverse correlation (r = -.68, P = .01) with the PAS. CONCLUSION: The results of the present study indicate that the 3D-CT and lateral cephalometric measurements we selected are reliable and reproducible. The only cephalometric measurement that exhibited any correlation with the CT parameters was PAS.

Use of (99m)Tc-MDP SPECT for assessment of mandibular growth: development of normal values.

PURPOSE: Planar scintigraphy using (99m)Tc-labeled methylene diphosphonate ((99m)Tc-MDP) has been established as a method for evaluating mandibular growth and asymmetry. However, (99m)Tc-MDP single photon emission computed tomography (SPECT) provides improved image contrast and quantitative capability potentially allowing the clinician to make a more accurate assessment of the stage of activity of normal and asymmetric mandibular growth. The purpose of this study was to utilize (99m)Tc-MDP SPECT in normal subjects to develop a standardized approach to imaging the mandible that could subsequently be used to evaluate patients with potential for mandibular growth abnormalities. METHODS: Thirty-two patients (22 females, 10 males, 8-25 years of age, mean of 14 years) having (99m)Tc-MDP bone scans (7.4 MBq/kg, maximum of 518 MBq) for indications not involving the head were asked to have an additional SPECT that included the mandibular condyles. Internal (clivus) and external (source of known activity included within the field of view) standards were both investigated. Two- and three-dimensional (2-D and 3-D) regions of interest (ROI) were drawn over each condyle and the clivus in a single slice containing the maximum pixel value within the structure. A 3-D ROI was also drawn about the external standard. Maximum and average pixel values within the 2-D and 3-D ROIs were recorded. RESULTS: Correlation analysis indicated that essentially the same information was obtained whether the maximum or average pixel value within a 2-D or 3-D ROI was used. The right to left ratio provided a parameter that can be used to assess the magnitude of mandibular metabolic asymmetry. Use of an external standard provides the potential for quantifying condylar uptake for assessment of the activity of mandibular growth. Normal ranges for different age groups were determined for condylar uptake using both internal and external standards. CONCLUSION: (99m)Tc-MDP SPECT provides a quantitative method for assessing mandibular condylar uptake as a reflection of the activity of mandibular growth. The maximum pixel value of a 2-D ROI using external standardization and the right to left ratio of the condylar uptake provide the potential for quantitative evaluation of patients with mandibular asymmetry. These parameters will be further evaluated in an upcoming clinical investigation.

Three-dimensional micro-computed tomographic imaging of alveolar bone in experimental bone loss or repair.

BACKGROUND: Micro-computed tomography (micro-CT) offers significant potential for identifying mineralized structures. However, three-dimensional (3-D) micro-CT of alveolar bone has not been adapted readily for quantification. Moreover, conventional methods are not highly sensitive for analyzing bone loss or bone gain following periodontal disease or reconstructive therapy. The objective of this investigation was to develop a micro-CT methodology for quantifying tooth-supporting alveolar bone in 3-D following experimental preclinical situations of periodontitis or reconstructive therapy. METHODS: Experimental in vivo bone loss or regeneration situations were developed to validate the micro-CT imaging techniques. Twenty mature Sprague-Dawley rats were divided into two groups: bone loss (Porphyromonas gingivalis lipopolysaccharide-mediated bone resorption) and regenerative therapy. Micro-CT and software digitized specimens were reconstructed three-dimensionally for linear and volumetric parameter assessment of alveolar bone (linear bone height, bone volume, bone volume fraction, bone mineral content, and bone mineral density). Intra- and interexaminer reproducibility and reliability were compared for methodology validation. RESULTS: The results demonstrated high examiner reproducibility for linear and volumetric parameters with high intraclass correlation coefficient (ICC) and coefficient of variation (CV). The ICC showed that the methodology was highly reliable and reproducible (ICC >0.99; 95% confidence interval, 0.937 to 1.000; CV <1.5%), suggesting that 3-D measurements may provide better alveolar bone analysis than conventional 2-D methods. CONCLUSIONS: The developed methods allow for highly accurate and reproducible static measurements of tooth-supporting alveolar bone following preclinical situations of bone destruction or regeneration. Future investigations should focus on using in vivo micro-CT imaging for real-time assessments of alveolar bone changes.