Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Case report: Magnetic resonance imaging-based three-dimensional printing for reconstruction of complex cloacal malformations.

Background: Surgical reconstruction of the urinary tract, anus, and vagina is the definitive treatment for cloacal malformation. However, this procedure may be technically challenging in patients with a long common channel (>3 cm), because further reconstructive procedures, such as vaginal replacement or vaginal switch maneuver, may be required. Thus, accurate determination of spatial anatomy is essential during surgical planning. Three-dimensional (3D) reconstruction using rotational fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI) has recently been reported to help in determining the relationship between the rectum, vagina, and bladder, and provides a more accurate measurement of the channel length compared to conventional cloacography. MRI-based 3D reconstruction provides substantial information regarding soft tissue structures around the cloaca, including the pelvic floor musculature and anus. Case: A 2-year-old girl with cloacal malformation required reconstructive surgery. Colostomy and cystostomy had been performed on the first day of her life. Preoperative loopogram revealed a cloaca with a long common channel (35 mm) and short urethra (9 mm), single vaginal opening in the bladder neck, and the colon anterior to the vagina with a fistula at the vaginal neck. Because the vagina was too short to be pulled through, 3D printing based on MRI was performed to visualize structural relationships prior to surgical correction. Saline was used for cloacal visualization. Furthermore, endoscopy-assisted urogenital mobilization was performed, and vaginal substitution was performed using the rectum. No postoperative complications were observed. Conclusions: We believe this is the first report of the use of MRI-based 3D imaging and printing, with saline as a contrast agent during surgical planning for correction of cloacal malformation. MRI-based 3D printing is a potentially promising technique for surgical planning of cloacal malformation correction in patients with a long common channel, as it provides detailed information about the surrounding soft tissue structures without exposure to radiation or contrasting agents.

Application of the postnatal urinary tract dilation classification system to predict the need for surgical intervention among neonates and young infants.

PURPOSE: The aim of this study was to validate the postnatal urinary tract dilation (UTD) classification system by correlating it with the need for surgical intervention. METHODS: Young infants who underwent ultrasound (US) examinations for prenatal hydronephrosis were retrospectively identified. The kidney units (KUs; right, left, or bilateral) were graded from UTD P0 (very low risk) to P3 (high risk) based on seven US criteria from the UTD system. Surgery-free survival curves were constructed using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards regression analysis clustered by patients was performed. Interobserver agreement was analyzed using the weighted kappa coefficient. RESULTS: In total, 504 KUs from 336 patients (mean age, 18.3±15.9 days; range, 1 to 94 days; males, n=276) were included, with a median follow-up of 24.2 months. Fifty-eight KUs underwent surgical intervention. Significant differences were observed among the Kaplan-Meier curves stratified into UTD groups (P<0.001). The presence of anterior-posterior renal pelvic diameter ≥15 mm (hazard ratio [HR], 8.602; 95% confidence interval [CI], 1.558 to 43.065), peripheral calyceal dilation (HR, 8.190; 95% CI, 1.558 to 43.065), ureteral dilation (HR, 2.619; 95% CI, 1.274 to 5.380), parenchymal thickness abnormality (HR, 3.371; 95% CI, 1.574 to 7.223), bladder abnormality (HR, 12.209; 95% CI, 3.616 to 41.225) were significantly associated with the occurrence of surgery. The interobserver agreement was moderate to almost perfect agreement for US features (κ=0.564-0.898) and substantial for final UTD grades (κ=0.716). CONCLUSION: The UTD classification system is reliable and appropriately stratifies the risk of surgical intervention.

Diagnostic performance of the 2021 Korean thyroid imaging reporting and data system in pediatric thyroid nodules.

OBJECTIVES: To evaluate the diagnostic performance of 2021 K-TIRADS biopsy criteria for detecting malignant thyroid nodules in a pediatric population, making comparisons with 2016 K-TIRADS. METHODS: This retrospective study included pediatric patients with histopathologically confirmed diagnoses. The diagnostic performance of 2021 K-TIRADS was compared with that of 2016 K-TIRADS. Simulation studies were performed by changing biopsy cut-off sizes for K-TIRADS 5 to 1.0 cm (K-TIRADS5-1.0cm) and 0.5 cm (K-TIRADS5-0.5cm), and for K-TIRADS 4 to 1.0 cm (K-TIRADS4-1.0cm) and 1.0-1.5 cm (K-TIRADS4-1.0~1.5cm). Subgroup analysis was performed in small (< 1.5 cm) and large nodules (≥ 1.5 cm). RESULTS: Two hundred seventy-seven thyroid nodules (54.9% malignant) from 221 pediatric patients were analyzed. All simulated 2021 K-TIRADS showed higher accuracy than 2016 K-TIRADS. Compared with 2021 K-TIRADS5-1.0cm, 2021 K-TIRADS5-0.5cm showed lower specificity (51.6% vs. 47.9%; p = 0.004) but higher sensitivity (77.2% vs. 90.3%; p < 0.001) and accuracy (62.7% vs. 68.9%; p < 0.001). Compared with 2021 K-TIRADS4-1.0cm, 2021 K-TIRADS4-1.0~1.5cm showed higher specificity (44.9% vs. 47.9%; p = 0.018) without significant difference in other diagnostic measures. Compared with 2016 K-TIRADS, 2021 K-TIRADS (biopsy cut-offs, 0.5 cm for K-TIRADS 5; 1.0-1.5 cm for K-TIRADS 4) showed higher sensitivity (34.0% vs. 67.3%; p < 0.001) while maintaining specificity (89.4% vs. 88.2%; p = 0.790) in small nodules, and higher specificity (5.9% vs. 25.4%; p < 0.001) while maintaining sensitivity (100% vs. 98.7%; p = 0.132) in large nodules. CONCLUSIONS: In pediatric patients, 2021 K-TIRADS showed superior diagnostic accuracy to 2016 K-TIRADS, especially with a biopsy cut-off of 0.5 cm for K-TIRADS 5 and 1.0-1.5 cm for K-TIRADS 4. KEY POINTS: • All simulated 2021 K-TIRADS showed higher accuracy than 2016 K-TIRADS. • 2021 K-TIRADS with cut-off size for K-TIRADS 5 of 0.5 cm showed lower specificity but higher sensitivity and accuracy than that of 1.0 cm. • Compared with 2016 K-TIRADS, 2021 K-TIRADS (biopsy cut-offs, 0.5 cm for K-TIRADS 5; 1.0-1.5 cm for K-TIRADS 4) showed higher sensitivity while maintaining specificity in small nodules, and higher specificity while maintaining sensitivity in large nodules.

Diagnostic Performance of Five Adult-based US Risk Stratification Systems in Pediatric Thyroid Nodules.

Background The validation of adult-based US risk stratification systems (RSSs) in the discrimination of malignant thyroid nodules in a pediatric population remains lacking. Purpose To estimate and compare the diagnostic performance of pediatric US RSSs based on five adult-based RSSs in the discrimination of malignant thyroid nodules in a pediatric sample. Materials and methods Pediatric patients (age ≤18 years) with histopathologically confirmed US-detected thyroid nodules at a tertiary referral hospital between January 2000 and April 2020 were analyzed retrospectively. The diagnostic performance of US-based fine-needle aspiration biopsy (FNAB) criteria in thyroid cancer detection was estimated. The following sensitivity analyses were performed: (a) scenario 1: nodules smaller than 1 cm, with the highest category additionally biopsied; (b) scenario 2, application of American College of Radiology Thyroid Imaging Reporting and Data System nodule size cutoffs to other RSSs; (c) scenario 3, scenarios 1 and 2 together. Generalized estimating equations (GEEs) were used for estimation. Results A total of 277 thyroid nodules in 221 pediatric patients (median age, 16 years [interquartile range {IQR}, 13-17]; 172 female; 152 of 277 patients [55%] malignant) were analyzed. The GEE-estimated sensitivity and specificity ranged from 70% to 78% (104 to 119 of 152 patients, based on each reader's interpretation) and from 42% to 78% (49 of 124 patients to 103 of 125 patients). In scenario 1, the missed malignancy rate was reduced from 32%-38% (41 of 134 patients to 34 of 83 patients) to 15%-21% (eight of 59 patients to 28 of 127 patients). In scenario 2, the unnecessary biopsy rate was reduced from 35%-39% (60 of 176 patients to 68 of 175 patients) to 20%-34% (18 of 109 patients to 62 of 179 patients). The highest accuracy was noted in scenario 3 (range, 71%-81%; 199 of 277 patients to 216 of 262 patients). Conclusion The diagnostic performances of the fine-needle aspiration biopsy criteria of five adult-based risk stratification systems were acceptable in the pediatric population and were improved by applying the American College of Radiology Thyroid Imaging Reporting and Data System size cutoff for nodules 1 cm or larger and allowing biopsy of the highest category nodules smaller than 1 cm. © RSNA, 2022 Online supplemental material is available for this article.

Efficacy and Safety of Selumetinib in Pediatric Patients With Neurofibromatosis Type 1: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Although the recent approval of selumetinib is expected to transform the management of children with neurofibromatosis type 1 (NF1), particularly those with symptomatic and inoperable plexiform neurofibromas, no systematic review has summarized its efficacy and safety based on the latest studies. This study was conducted to systematically evaluate the efficacy and safety of selumetinib in children with NF1. METHODS: Original articles reporting the efficacy and safety of selumetinib in patients with NF1 were identified in PubMed and EMBASE up to January 28, 2021. The pooled objective response rates (ORRs) and disease control rates (DCRs) were calculated using the DerSimonian-Laird method based on random-effects modeling. The pooled proportion of adverse events (AEs) was also calculated. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system. RESULTS: Five studies involving 126 patients were included in our analysis. The studies had a very low to moderate quality of the evidence. The pooled ORR was 73.8% (95% CI 57.3%-85.5%) and the DCR was 92.5% (95% CI 66.5%-98.7%). The 2 most common AEs were diarrhea, which had a pooled rate of 63.8% (95% CI 52.9%-73.4%), and an increase in creatine kinase levels, which had a pooled rate of 63.3% (95% CI 35.6%-84.3%). DISCUSSION: Our results indicate that selumetinib is an effective and safe treatment for pediatric patients with symptomatic, inoperable plexiform neurofibromas. Further larger-scale randomized controlled studies are needed to confirm the long-term outcome of patients treated with this drug.

Whole-body MRI evaluation in neurofibromatosis type 1 patients younger than 3 years old and the genetic contribution to disease progression.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common human genetic disease with age-dependent phenotype progression. The overview of clinical and radiological findings evaluated by whole-body magnetic resonance imaging (WBMRI) in NF1 patients < 3 years old assessed with a genetic contribution to disease progression is presented herein. METHODS: This study included 70 clinically or genetically diagnosed NF1 patients who received WBMRI before 3 years old. Clinical, genetic, and radiologic features were collected by retrospective chart review. In NF1+, widely spread diffuse cutaneous neurofibromas, developmental delay, autism, seizure, cardiac abnormalities, hearing defect, optic pathway glioma, severe plexiform neurofibromas (> 3 cm in diameter, disfigurement, accompanying pain, bony destruction, or located para-aortic area), brain tumors, nerve root tumors, malignant peripheral nerve sheath tumors, moyamoya disease, and bony dysplasia were included. RESULTS: The age at WBMRI was 1.6 ± 0.7 years old, and NF1 mutations were found in 66 patients (94.3%). Focal areas of signal intensity (FASI) were the most common WBMRI finding (66.1%), followed by optic pathway glioma (15.7%), spine dural ectasia (12.9%), and plexiform neurofibromas (10.0%). Plexiform neurofibromas and NF1+ were more prevalent in familial case (28.7% vs 5.7%, p = 0.030; 71.4% vs 30.2%, p = 0.011). Follow-up WBMRI was conducted in 42 patients (23 girls and 19 boys) after 1.21 ± 0.50 years. FASI and radiologic progression were more frequent in patients with mutations involving GTPase activating protein-related domain (77.8% vs 52.4%, p = 0.047; 46.2% vs 7.7%, p = 0.029). CONCLUSIONS: WBMRI provides important information for the clinical care for young pediatric NF1 patients. As NF1 progresses in even these young patients, and is related to family history and the affected NF1 domains, serial evaluation with WBMRI should be assessed based on the clinical and genetic features for the patients' best care.

Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) System for Pediatric Patients with Hepatoblastoma: A Retrospective, Hospital-Based Cohort Study in South Korea.

PURPOSE: In 2017, the Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system was introduced. We aimed to evaluate the accuracy of CHIC-HS System for the prediction of event-free survival (EFS) in Korean pediatric patients with hepatoblastoma. MATERIALS AND METHODS: This two-center retrospective study included consecutive Korean pediatric patients with histopathologically confirmed hepatoblastoma from March 1988 through September 2019. We compared EFS among four risk groups according to the CHIC-HS system. Discriminatory ability of CHIC-HS system was also evaluated using optimism-corrected C-statistics. Factors associated with EFS were explored using multivariable Cox regression analysis. RESULTS: We included 129 patients (mean age, 2.6±3.3 years; female:male, 63:66). The 5-year EFS rates in the very low, low, intermediate, and high-risk groups, according to the CHIC-HS system were 90.0%, 82.8%, 73.5%, and 51.3%, respectively. The CHIC-HS system aligned significantly well with EFS outcomes (p=0.004). The optimism-corrected C index of CHIC-HS was 0.644 (95% confidence interval [CI], 0.561 to 0.727). Age ≥ 8 (vs. age ≤ 2; hazard ratio [HR], 2.781; 95% CI, 1.187 to 6.512; p=0.018), PRE-Treatment EXTent of tumor (PRETEXT) stage IV (vs. PRETEXT I or II; HR, 2.774; 95% CI, 1.228 to 5.974; p=0.009), and presence of metastasis (HR, 2.886; 95% CI, 1.457 to 5.719; p=0.002), which are incorporated as the first three nodes in the CHIC-HS system, were independently associated with EFS. CONCLUSION: The CHIC-HS system aligned significantly well with EFS outcomes in Korean pediatric patients with hepatoblastoma. Age group, PRETEXT stage, and presence of metastasis were independently associated with EFS.

Neoplastic Etiology and Natural Course of Pituitary Stalk Thickening.

CONTEXT: Pituitary stalk thickening (PST) is often identified on magnetic resonance imaging (MRI), either incidentally or during diagnostic workup of hypopituitarism. However, the neoplastic etiology and natural course of PST are not fully understood, although this knowledge is required to establish diagnostic and surveillance strategies. OBJECTIVE: This work aimed to investigate the neoplastic etiology and natural course of PST. METHODS: MEDLINE/PubMed and EMBASE databases were searched up to February 2021 to identify original research investigating the etiologies of PST. The proportion of neoplastic etiology in patients with PST was meta-analytically pooled. Supplementary analysis exploring factors suggesting neoplasm was also performed. For initially indeterminate cases without confirmed diagnosis, the proportion of patients showing progression of PST during follow-up was evaluated. RESULTS: Eighteen studies covering 1368 patients with PST were included. The pooled proportion of neoplasm was 45.2% (95% CI, 33.3%-57.8%), with substantial heterogeneity across studies (I2 = 93%). The most common neoplasm was germ cell tumor (14.0% of study population), followed by Langerhans cell histiocytosis (10.2%) and metastasis (4.7%). The studies on pediatric populations and those with more than 50% of patients having at least one pituitary hormone deficiency tended to show a higher proportion of neoplasm. The pituitary stalk was thicker in neoplasms, but the difference was not significant (pooled mean difference, 2.08 mm; P = .08). In initially indeterminate cases, 18.5% (95% CI, 7.6%-38.3%) showed progression of PST during follow-up. CONCLUSION: PST was commonly confirmed to be neoplastic, especially in pediatric populations. As isolated PST frequently progresses, follow-up imaging is essential in initially indeterminate cases.

The association of lung function changes with outcomes in children with bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a life-threatening respiratory complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although pulmonary function testing is crucial for monitoring BOS, little information exists on the association of these test results with outcomes in children with BOS. OBJECTIVES: The purpose of this study was to determine the correlation between changes in lung function after BOS diagnosis and long-term outcomes. METHODS: A total of 428 children underwent allogeneic HSCT from January 2006 to December 2017 at Asan Medical Center. Twenty-three (5.4%) were diagnosed with BOS after allogeneic HSCT, and their clinical data were reviewed. Twenty-one subjects underwent regular pulmonary function testing for 24 months after BOS diagnosis. RESULTS: Among the 21 children with BOS, 8 died, 5 underwent lung transplantation (TPL), and 15 required oxygen (O2 ) therapy. The FEV1 % predicted (pred), FVC% pred, and FEF25%-75% pred were 37.8 ± 12.7% (mean ± SD), 62.2 ± 16.2%, and 16.4 ± 9.6%, respectively, at the time of BOS diagnosis. Changes in the FEV1 % pred were greater in the death and lung TPL groups (-24.8 ± 22.3%) than in the survival without lung TPL group (5.7 ± 21.8%) and greater in the O2 therapy (-19.4 ± 23.4%) group than in the group without O2 therapy (14.2 ± 20.0%) during the first 3 months after BOS diagnosis. CONCLUSION: The change in FEV1 during the first 3 months after BOS diagnosis correlated with outcomes including survival, lung TPL, and O2 therapy. These results suggest that more active intervention in the first 3 months after BOS diagnosis may be needed to improve prognosis.

Outcome of staging chest CT and identification of factors associated with lung metastasis in children with hepatoblastoma.

OBJECTIVES: To evaluate the outcome of staging chest CT and to identify clinicoradiological factors predictive of lung metastasis in patients with hepatoblastoma based on the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system. METHODS: This bi-center study retrospectively identified patients diagnosed with hepatoblastoma between January 1998 and September 2019 in two tertiary hospitals. The primary outcome was the proportion of the patients who had lung metastasis at staging chest CT. The diagnostic accuracy of staging chest CT was calculated based on the 2017 PRETEXT criteria. The secondary outcome was the identification of factors predictive of lung metastasis using multivariable logistic regression. RESULTS: In total, 123 patients (median age, 1 year; interquartile range, 0-4 years; 59 female) were included. Among those, 28% (35/123; 95% confidence interval [CI], 21-37%) had lung metastasis at staging chest CT. The overall accuracy of staging chest CT was 96.8%. The proportion of lung metastasis in patients with stage I, II, III, and IV was 0%, 24% (12 of 49; 95% CI, 14-38%), 23% (9 of 40; 95% CI, 12-38%), and 56% (14 of 25; 95% CI, 37-73%), respectively. Multifocality (adjusted odds ratio, 6.7; 95% CI, 2.7-17.5; p < .001) and male sex (adjusted odds ratio, 3.1; 95% CI, 1.2-8.6; p = .02) were associated with the presence of lung metastasis. CONCLUSIONS: Twenty-eight percent of the patients with hepatoblastoma had lung metastasis at staging chest CT. Multifocality and male sex were predictive factors for lung metastasis on staging chest CT. KEY POINTS: • The proportion of lung metastasis in patients with hepatoblastoma was 28%. • The overall accuracy of staging chest CT was 97% based on the 2017 PRETEXT system. • Hepatic tumor multifocality and male sex were predictors of lung metastasis.

Recent improvement in survival outcomes and reappraisal of prognostic factors in hepatoblastoma.

BACKGROUND: Prognostic factors in hepatoblastoma need to be reevaluated considering the advances in treatment modalities. The study aimed to evaluate current outcomes of hepatoblastoma and reappraise the association of prognostic factors, including pre-treatment extent of tumor (PRETEXT) stage with annotation factors and Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system, with survival outcomes. METHODS: We evaluated 103 consecutive patients with hepatoblastoma retrospectively according to the treatment period based on the introduction of a liver transplantation program. RESULTS: The 5-year overall survival (OS), event-free survival (EFS), and transplant-free survival rates were 80.2%, 74.2%, and 61.8%, respectively. EFS and OS were improved significantly from 58.6% to 81.6% (P = 0.024) and from 58.6% to 90.8% (P < 0.001), respectively, in the late period (N = 74) compared with the early period (N = 29). The PRETEXT stage was significant or marginally significant for EFS and OS in the early period but not in the late period. The P, F, R, and C factors were significant for OS and EFS in the early period. However, in the late period, only the P factor was significant for OS, and the F and M factors were significant for EFS. The CHIC-HS system was significant or marginally significant for EFS in both the early and late periods; however, it was significant for OS only in the early period. CONCLUSION: Survival rates were significantly improved in children with hepatoblastoma, especially in those with advanced PRETEXT stages with positive annotation factors and in a high-risk CHIC-HS group. Prognostic factors had different clinical implications with evolved treatment modalities.

Diagnostic performance of adult-based ATA and ACR-TIRADS ultrasound risk stratification systems in pediatric thyroid nodules: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the diagnostic performance of adult-based "American College of Radiology- Thyroid Imaging Reporting And Data System" (ACR-TIRADS) and "American Thyroid Association" (ATA) in the pediatric population. METHODS: MEDLINE/PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for articles investigating the diagnostic performance of each stratification system (ACR-TIRADS or ATA) and evaluated them according to three aspects: (a) the risk of malignancy in each category; (b) diagnostic performance using the classic indicators (sensitivity, specificity); and (c) diagnostic performance regarding fine needle aspiration/biopsy recommendation. In addition to pathologic diagnosis, we allowed imaging follow-up as the reference standard for benign nodules. RESULTS: Eight articles (1036 thyroid nodules) were included. For ACR-TIRADS, the pooled risk of malignancy in category was as follows: category 5 (59.3%); 4 (20.7%); 3 (11.0%); 2 (6.0%), and 1 (5.5%). For nodules of high suspicion of malignancy (category 4 or 5), the pooled sensitivity and specificity were 0.84 and 0.64. For ATA, the pooled risk of malignancy was as follows: category 5 (55.4%); 4 (34.2%); 3 (12.2%); and 2 (7.5%). For nodules of high suspicion of malignancy (category 4 or 5), the pooled sensitivity and specificity were 0.90 and 0.50. For category 5 nodules, the pooled specificity was significantly higher in ACR-TIRADS (p = 0.02). For ACR-TIRADS, the missed malignancy rate was 21.7% and the unnecessary biopsy rate was 62.7%. Information was not sufficient for this calculation with ATA. CONCLUSIONS: The diagnostic performance of ACR-TIRADS and ATA in the pediatric population was somewhat modest. Large studies are mandatory for further validation and future amendments. KEY POINTS: • The pooled sensitivity and specificity for highly suspicious nodules (category 4 or 5) for ACR-TIRADS were 0.84 and 0.64, and for ATA were 0.90 and 0.50, respectively. • When applying ACR-TIRADS for children, the pooled missed malignancy rate (21.7%) and unnecessary biopsy rates (62.7%) are still reasonably high. Insufficient information was available to perform these calculations for the ATA system. • Current risk stratification systems, especially ACR-TIRADS, require modification by focusing more on increasing the sensitivity and decreasing the missed malignancy rate. Lowering size cut-off for biopsy would be a reasonable option.

Technical Performance of Acoustic Radiation Force Impulse Imaging for Measuring Renal Parenchymal Stiffness: A Systematic Review and Meta-Analysis.

OBJECTIVES: To estimate the technical performance of acoustic radiation force impulse (ARFI) imaging (two-dimensional shear wave elastography [2D-SWE] and point shear wave elastography [p-SWE]) for measuring renal parenchymal stiffness. METHODS: EMBASE and PubMed databases were searched for studies reporting technical performance of ARFI imaging in terms of technical failure, interobserver agreement, and/or intraobserver agreement. The proportion of technical failure and intraclass correlation coefficients (ICCs) for interobserver and intraobserver agreement was pooled. The pooled estimates of native and transplanted kidneys were obtained separately. Meta-regression and subgroup analyses were conducted to explore heterogeneity. RESULTS: Twenty-four studies (2993 patients) were included. The pooled proportions of technical failure were 4.3% (95% confidence interval [CI] 2.2-8.5%) and 6.6% (95% CI 4.0-10.7%) in native and transplanted kidneys, respectively. The pooled ICCs of interobserver agreement were 0.70 (95% CI 0.68-0.83) and 0.81 (95% CI 0.68-0.89), indicating moderate and good agreement in native and transplanted kidneys, respectively. The pooled ICC showed good (0.77; 95% CI 0.49-0.91) intraobserver agreement in native kidneys. Regarding interobserver agreement in transplanted kidneys, ROI location (mid pole only versus others) was a significant factor of heterogeneity (P = .04). CONCLUSIONS: The ARFI-based SWE techniques show good technical performance for measuring renal parenchymal stiffness. The wide range of SWE protocols necessitates development of standardized guidelines on the use of renal ARFI imaging.

Ability of Pelvic Magnetic Resonance Imaging to Predict Clinical Course of Perianal Fistula in Paediatric Crohn's Disease Patients.

BACKGROUND AND AIMS: Evidence is limited regarding clinical course and magnetic resonance imaging [MRI] features of perianal fistula [PAF] in Korean children with Crohn's disease [CD]. We investigated MRI features of PAF and associations with long-term outcomes. METHODS: We retrospectively analysed 243 patients with pelvic MRI for diagnosis of CD. Incidence of clinically evident PAF at diagnosis was determined, as were the proportions of patients with clinical failure [failure to achieve fistula healing within 1 year] and recurrence [new/recurrent PAF after fistula healing within 1 year]. Associations between outcomes and MRI features, specified in modified Van Assche index and MAGNIFI-CD, were evaluated. Associations between later development of clinically evident PAF and subclinical PAF detected on MRI at diagnosis were evaluated. RESULTS: Among 243 included patients, 108 [44.4%] and 76 [31.3%] had clinically evident and subclinical PAF at diagnosis, respectively; 66.4% of the patients with clinically evident PAF achieved fistula healing within 1 year, and 32.7% of those patients developed recurrence. Fistula length and dominant features of the tracts were associated with clinical failure, and fistula length was associated with recurrence. Clinically evident PAF developed in 17.0% of the patients without clinically evident PAF at diagnosis. We did not find statistically significant association between subclinical PAF and later development of clinically evident PAF [adjusted hazard ratio, 2.438; p = 0.15]. CONCLUSIONS: A considerable proportion of Korean paediatric CD patients had clinically evident and subclinical PAF. Fistula length and dominant feature of the tract on MRI are useful predictors of outcomes.

Neurofibromatosis type I: points to be considered by general pediatricians.

Neurofibromatosis type 1 (NF1), a prevalent genetic disease that is transmitted in an autosomal dominant manner, is characterized by multiple cutaneous café-au-lait spots and neurofibromas as well as various degrees of neurological, skeletal, and neoplastic manifestations. The clinical features of NF1 increase in frequency with age, while the clinical diagnosis can remain undetermined in some pediatric patients. Importantly, affected patients are at risk for developing tumors of the central and peripheral nervous system. Therefore, adequate counseling for genetic testing, age-appropriate surveillance, and management are important. This review suggests several issues that should be considered to help general pediatricians provide adequate clinical care and genetic counseling to patients with NF1 and their families.

Assessment of native liver fibrosis using ultrasound elastography and serological fibrosis indices in children with biliary atresia after the Kasai procedure.

BACKGROUND: Validated non-invasive examinations are necessary to monitor liver fibrosis in children with biliary atresia (BA) after the Kasai procedure. PURPOSE: To evaluate the diagnostic accuracy of two-dimensional shear wave elastography (2D-SWE), transient elastography (TE), and the serologic biomarkers of aspartate transaminase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4) score for evaluating native liver fibrosis in children with BA. MATERIAL AND METHODS: We retrospectively reviewed same-day 2D-SWE and TE liver stiffness (LS) measurements of 63 patients with BA who underwent the Kasai procedure. The APRI and FIB-4 score were computed. Hepatic fibrosis was categorized into three clinical categories based on the ultrasound (US) hepatic morphology and clinical manifestations of liver cirrhosis: I, pre-cirrhotic liver state (n = 15); II, US and/or clinical signs of liver cirrhosis with compensated liver function (n = 27); and III, liver cirrhosis with decompensated liver function (n = 21). We compared area under the receiver operating characteristic curve (AUC) data among 2D-SWE, TE, APRI, and FIB-4 score. Combined evaluation of serologic fibrosis indices and US elastography was conducted and AUCs of combinations were analyzed. RESULTS: 2D-SWE, TE, APRI, and FIB-4 score showed good to excellent diagnostic accuracy for differentiating clinical categories (AUCs 0.779-0.955). AUC values were significantly increased after adding TE to FIB-4 score for detecting liver cirrhosis (P = 0.02). CONCLUSION: 2D-SWE, TE, APRI, and FIB-4 score are accurate non-invasive markers for monitoring native liver fibrosis in patients with BA. Combined use of serologic markers and US elastography could yield more accurate diagnoses of liver fibrosis than serologic markers alone.

Incidence of Occult Spinal Dysraphism Among Infants With Cutaneous Stigmata and Proportion Managed With Neurosurgery: A Systematic Review and Meta-analysis.

Importance: Occult spinal dysraphism (OSD) is the most common congenital spinal anomaly. Cutaneous anomalies such as skin dimples or deviated gluteal folds are well known as stigmata of OSD and are indicators for further evaluation; however, the association between cutaneous anomalies and OSD has not been systemically evaluated. Objective: To evaluate the incidence of OSD and the proportion of OSD cases managed with a neurosurgical intervention among neonates or infants with various cutaneous stigmata. Data Sources: PubMed and Embase databases were searched for studies published up to July 25, 2018, that evaluated the proportion of OSD cases in neonates or infants with cutaneous stigmata. Search terms included ultrasound, dysraphism, dimple, and infant or neonate. The search was limited to English-language publications. Study Selection: Two reviewers selected the studies evaluating the incidence of OSD among neonates or infants with cutaneous stigmata. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for data extraction were followed. Pooled proportions of OSD cases and OSD cases that were managed with a neurosurgical intervention were obtained using the generalized linear mixed model and maximum likelihood method. Main Outcome and Measures: The pooled incidence of OSD and OSD cases managed with neurological surgery among patients with cutaneous stigmata was the primary outcome. This outcome was also evaluated in each subgroup, and heterogeneity was explored using subgroup analysis. Results: A total of 15 studies, involving 6558 neonate or infant patients with various cutaneous stigmata, were included. The pooled proportion of OSD cases among the patients with cutaneous stigmata was 2.8% (95% CI, 2.1%-3.8%; I2 = 51.6%), and the proportion managed with neurological surgery was 0.6% (95% CI, 0.3%-1.3%; I2 = 66.4%). Cases with combined stigmata showed a significantly higher association with OSD than those with a single stigma (10.5% [95% CI, 6.9%-15.8%] vs 2.3% [%, 95% CI, 1.5%-3.5%]; P < .001). The pooled proportion of OSD cases among patients with an atypical dimple was significantly higher than among those with simple dimple (8.8% [95% CI, 4.5%-16.6%] vs 0.6% [95% CI of 1.4%-2.1%]; P = .001). Conclusions and Relevance: The proportion of OSD in healthy, asymptomatic patients with midline cutaneous stigmata was low, and the proportion of patients who underwent a neurosurgical intervention was even lower. However, a careful evaluation as well as potential spinal magnetic resonance imaging is recommended for neonates or infants with combined stigmata or an atypical dimple for possible high-risk lesions.

Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype-phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+ and mutation types. NF1+ was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+ was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

Prognostic Factors for Event-Free Survival in Pediatric Patients with Hepatoblastoma Based on the 2017 PRETEXT and CHIC-HS Systems.

This study aimed to evaluate the prognostic value of variables used in the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system and the Children's Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system in pediatric patients with hepatoblastoma. A retrospective analysis of data from the pediatric hepatoblastoma registry of a tertiary referral center was conducted to evaluate the clinical and imaging variables (annotation factors) of the PRETEXT staging system. The primary outcome was event-free survival (EFS). Data from 84 patients (mean age: 2.9 ± 3.5 years) identified between 1998 and 2017 were included. Univariable Cox proportional hazards analysis revealed that PRETEXT annotation factors P (portal vein involvement), F (multifocality of tumor), and M (distant metastasis) showed a significant negative association with EFS. Multivariable Cox proportional hazard analysis showed that factor F was the strongest predictor (HR (hazard ratio), 2.908; 95% CI (confidence interval), 1.061-7.972; p = 0.038), whereas factor M showed borderline significance (HR, 2.416; 95% CI, 0.918-6.354; p = 0.074). The prediction model based on F and M (F + M) showed good performance to predict EFS (C-statistic, 0.734; 95% CI, 0.612-0.854). In conclusion, the PRETEXT annotation factor F was the strongest predictor of EFS, and the F + M model showed good performance to predict EFS in pediatric patients with hepatoblastoma.