Cancer Therapy-related Hepatic Injury in Children: Imaging Review from the Pediatric LI-RADS Working Group.

The liver is the primary organ for the metabolism of many chemotherapeutic agents. Treatment-induced liver injury is common in children undergoing cancer therapy. Hepatic injury occurs due to various mechanisms, including biochemical cytotoxicity, hepatic vascular injury, radiation-induced cytotoxicity, and direct hepatic injury through minimally invasive and invasive surgical treatments. Treatment-induced liver injury can be seen contemporaneous with therapy and months to years after therapy is complete. Patients can develop a combination of hepatic injuries manifesting during and after treatment. Acute toxic effects of cancer therapy in children include hepatitis, steatosis, steatohepatitis, cholestasis, hemosiderosis, and vascular injury. Longer-term effects of cancer therapy include hepatic fibrosis, chronic liver failure, and development of focal liver lesions. Quantitative imaging techniques can provide useful metrics for disease diagnosis and monitoring, especially in treatment-related diffuse liver injury such as hepatic steatosis and steatohepatitis, hepatic iron deposition, and hepatic fibrosis. Focal liver lesions, including those developing as a result of treatment-related vascular injury such as focal nodular hyperplasia-like lesions and hepatic perfusion anomalies, as well as hepatic infections occurring as a consequence of immune suppression, can be anxiety provoking and confused with recurrent malignancy or hepatic metastases, although there often are imaging features that help elucidate the correct diagnosis. Radiologic evaluation, in conjunction with clinical and biochemical screening, is integral to diagnosing and monitoring hepatic complications of cancer therapy in pediatric patients during therapy and after therapy completion for long-term surveillance. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material See the invited commentary by Ferraciolli and Gee in this issue.

Introduction to the COG Diagnostic Imaging Committee/SPR Oncology Committee White Papers: Rationale and methods.

Pediatric cancer is a rare disease. Because of this, many sites do not have experience providing imaging for specific tumor types. The Children's Oncology Group Diagnostic Imaging Committee and the Society for Pediatric Radiology Oncology Committee are comprised of radiologists with expertise in pediatric cancer imaging. Recently, this group endeavored to create a series of 23 White Papers designed to provide evidence-based imaging recommendations and minimum achievable imaging protocols. The purpose of this manuscript is to describe the methods employed in authoring the White Paper series.

Imaging of pediatric abdominal soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

This paper provides imaging recommendations for pediatric abdominal tumors that arise outside of the solid viscera. These tumors are rare in children and have been categorized in two groups: abdominal wall and peritoneal tumors (desmoid tumor and desmoplastic small round cell tumor) and tumors that arise from the gastrointestinal tract (gastrointestinal stromal tumor and gastrointestinal neuroendocrine tumor). Authors offer consensus recommendations for imaging assessment of these tumors at diagnosis, during follow-up, and when off-therapy.

Imaging of pediatric liver tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Primary hepatic malignancies are relatively rare in the pediatric population, accounting for approximately 1%-2% of all pediatric tumors. Hepatoblastoma and hepatocellular carcinoma are the most common primary liver malignancies in children under the age of 5 years and over the age of 10 years, respectively. This paper provides consensus-based imaging recommendations for evaluation of patients with primary hepatic malignancies at diagnosis and follow-up during and after therapy.

Optimizing Imaging of Pediatric Liver Lesions: Guidelines from the Pediatric LI-RADS Working Group.

A differential diagnosis based on a patient's age, clinical presentation, and serum α-fetoprotein level will help guide the initial imaging workup in children with a liver lesion. Children vary significantly in size, the ability to stay still, and the ability to breath hold for imaging examinations. Choosing and tailoring imaging techniques and protocols for each indication and age group is important for optimal care with minimal invasiveness. The need for sedation or anesthesia can be obviated by using techniques like feed and bundle, distraction, contrast-enhanced US, and motion-insensitive sequences for MRI. US is often the first imaging modality used in children with a suspected abdominal mass. Once a hepatic lesion is confirmed, multiphasic contrast-enhanced MRI is recommended for most lesions as the next imaging modality allowing full characterization of the lesion and assessment of the liver parenchyma. Contrast-enhanced CT can also be performed for assessment of pediatric focal liver lesions, especially in patients who have a contraindication to MRI. Contrast-enhanced US has shown promise to decrease the need for MRI or CT in some lesions such as hemangioma and focal nodular hyperplasia. Children with a history of malignancy can develop multiple types of hepatic lesions at various stages, including infections during an immunocompromised state, manifesting as focal liver lesions. Based on available limited data in the literature and the collective experiences of the Liver Imaging and Reporting Data System Pediatric Working Group, the authors provide guidelines for the imaging workup of pediatric focal liver lesions with an indication- and age-based approach and discuss the selection and performance of various imaging techniques and modalities. ©RSNA, 2022 See the invited commentary by Chojniak and Boaventura in this issue.

Imaging of pediatric cardiac tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.

Contrast-enhanced voiding urosonography (CEVUS) as a safe alternate means of assessing vesicoureteral reflux in pediatric kidney transplant patients.

BACKGROUND: Although voiding cystourethrogram (VCUG) is currently the gold standard in VUR evaluation, there is ionizing radiation exposure. Contrast-enhanced voiding urosonography (CEVUS) uses ultrasound contrast agents to visualize the urinary tract and has been reported to be safe and effective in VUR evaluation in children. CEVUS application has yet to be specifically described in VUR evaluation in the pediatric kidney transplant population. The purpose of this study was to report the use of CEVUS and VCUG in evaluating and managing VUR in pediatric renal transplant patients. METHODS: Retrospective review was conducted for pediatric kidney transplant patients (18 years and younger) who underwent VCUG or CEVUS to assess for transplant VUR from July 2019 through June 2021. Demographic information, reason for VUR evaluation, fluoroscopy time, and postimaging complications were evaluated. Costs of imaging modalities were also considered. RESULTS: Eight patients were evaluated for transplant VUR during the study period. Of the 3 patients who underwent VCUG, all 3 had VUR (median grade 3). Median fluoroscopy time was 18 s and dose-area product was 18.7 uGy*m2 . Of the 5 patients who underwent CEVUS, 4 had VUR (median grade 4). There were no complications for either modality. Based on clinical and radiographic findings, patients were recommended no intervention, behavioral modification, or ureteral reimplantation. The total cost of CEVUS was $800 less than that of VCUG. CONCLUSION: CEVUS can provide an alternate means of safely evaluating VUR in kidney transplant patients with similar outcomes, potentially lower costs, and no exposure to ionizing radiation.

Pathogenesis of Tobacco-Associated Lung Adenocarcinoma Is Closely Coupled with Changes in the Gut and Lung Microbiomes.

Microbial dysbiosis has emerged as a modulator of oncogenesis and response to therapy, particularly in lung cancer. Here, we investigate the evolution of the gut and lung microbiomes following exposure to a tobacco carcinogen. We performed 16S rRNA-Seq of fecal and lung samples collected prior to and at several timepoints following (nicotine-specific nitrosamine ketone/NNK) exposure in Gprc5a-/- mice that were previously shown to exhibit accelerated lung adenocarcinoma (LUAD) development following NNK exposure. We found significant progressive changes in human-relevant gut and lung microbiome members (e.g., Odoribacter, Alistipes, Akkermansia, and Ruminococus) that are closely associated with the phenotypic development of LUAD and immunotherapeutic response in human lung cancer patients. These changes were associated with decreased short-chain fatty acids (propionic acid and butyric acid) following exposure to NNK. We next sought to study the impact of Lcn2 expression, a bacterial growth inhibitor, given our previous findings on its protective role in LUAD development. Indeed, we found that the loss of Lcn2 was associated with widespread gut and lung microbiome changes at all timepoints, distinct from those observed in our Gprc5a-/- mouse model, including a decrease in abundance and diversity. Our overall findings apprise novel cues implicating microbial phenotypes in the development of tobacco-associated LUAD.

MARK2 and MARK4 Regulate Sertoli Cell BTB Dynamics Through Microtubule and Actin Cytoskeletons.

Microtubule affinity-regulating kinases (MARKs) are nonreceptor Ser/Thr protein kinases known to regulate cell polarity and microtubule dynamics in Caenorhabditis elegans, Drosophila, invertebrates, vertebrates, and mammals. An earlier study has shown that MARK4 is present at the ectoplasmic specialization and blood-testis barrier (BTB) in the seminiferous epithelium of adult rat testes. Here, we report the function of MARK4 and another isoform MARK2 in Sertoli cells at the BTB. Knockdown of MARK2, MARK4, or MARK2 and MARK4 by RNAi using the corresponding siRNA duplexes without apparent off-target effects was shown to impair tight junction (TJ)-permeability barrier at the Sertoli cell BTB. It also disrupted microtubule (MT)- and actin-based cytoskeletal organization within Sertoli cells. Although MARK2 and MARK4 were shown to share sequence homology, they likely regulated the Sertoli cell BTB and MT cytoskeleton differently. Disruption of the TJ-permeability barrier following knockdown of MARK4 was considerably more severe than loss of MARK2, though both perturbed the barrier. Similarly, loss of MARK2 affected MT organization in a different manner than the loss of MARK4. Knockdown of MARK2 caused MT bundles to be arranged around the cell periphery, whereas knockdown of MARK4 caused MTs to retract from the cell edge. These differences in effects on the TJ-permeability barrier are likely from the unique roles of MARK2 and MARK4 in regulating the MT cytoskeleton of the Sertoli cell.

Pediatric radiologic manifestations of COVID-19.

PURPOSE: While full description of pediatric COVID-19 manifestations is evolving, children appear to present less frequently, and often display a less severe disease phenotype. There is correspondingly less data regarding pediatric radiologic findings. To describe the imaging findings of pediatric COVID-19, we evaluated the radiologic imaging of the initial patient cohort identified at our institution. METHODS: In this IRB approved study, all patients at our institution aged 0-21 with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on PCR or immunoglobulin testing were identified. Imaging was reviewed by the co-authors and presence of abnormalities determined by consensus. Pre-existing comorbidities and alternative diagnoses were recorded. Rates of each finding were calculated. Findings were compared to published data following review of the available literature. RESULTS: Out of 130 Covid-19 positive patients, 24 patients underwent imaging, including 21 chest radiographs and 4 chest CT scans. Chest x-rays were normal in 33%. Patchy or streaky opacities were the most common radiographic abnormality, each seen in 38% of patients. CT findings included ill-defined or geographic ground glass opacities, dense opacities, septal thickening and crazy paving, and small pleural effusions. Results are similar to those reported in adults. Multiple COVID-19 positive children presented for symptoms due to an additional acute illness, including appendicitis and urinary infection. CONCLUSIONS: Radiologic findings of COVID-19 in pediatric patients range from normal to severe ARDS type appearance. During this ongoing pandemic, these radiographic signs can be useful for the evaluation of disease status and guiding care, particularly in those with comorbidities. PRECIS: Radiologic findings of COVID-19 in pediatric patients are similar to those seen in adults, and may range from normal to severe ARDS type appearance.

An In Vitro Assay to Monitor Sertoli Cell Blood-Testis Barrier (BTB) Integrity.

In this chapter, we detail a reliable, effective, and easy to perform assay to monitor the Sertoli cell blood-testis barrier (BTB) integrity. While the BTB in the testis is composed of the tight junction (TJ) barrier and basal ES (ectoplasmic specialization, a testis-specific actin-rich adherens junction (AJ) type), this method is applicable to all other blood-tissue barrier in vitro, including endothelial TJ-barrier of the blood-brain barrier (BBB). Furthermore, this method does not require expensive set up, and can be rapidly performed by any standard biochemistry/cell biology/molecular biology laboratory. The basic idea is built on the concept that a functional blood-tissue barrier, such as the BTB conferred by Sertoli cells in the testis, is capable of blocking the diffusion of a small membrane impermeable biotin (e.g., EZ-Link Sulfo-NHS-LC-biotin, Mr. 556.59) across the barrier. However, when this barrier is compromised, such as following treatment with a toxicant or knockdown of a relevant gene necessary to confer the TJ-barrier function, the biotin will permeate the barrier, reaching the Sertoli cell cytosol. Biotin can be subsequently visualized by using streptavidin conjugated to a fluorescence tag such as Alexa Fluor 488 (green fluorescence) which can be easily visualized by a standard fluorescence microscope.

Transjugular intrahepatic portosystemic shunt creation may be associated with hyperplastic hepatic nodular lesions in the long term: an analysis of 18 pediatric and young adult patients.

BACKGROUND: Retrospective studies have demonstrated the efficacy and safety of pediatric and adolescent transjugular intrahepatic portosystemic shunt (TIPS), but long-term outcomes warrant further investigation. OBJECTIVE: To report on the development of hyperplastic hepatic nodular lesion development in children and young adults (<21 years) with TIPS patency >3 years. MATERIALS AND METHODS: Eighteen children and young adults, including 10 (55.6%) females and 8 (44.4%) males, underwent TIPS creation with >3 years' patency and follow-up evaluation at a tertiary children's hospital. The mean age at the time of TIPS creation was 12.5±5.1 years (range: 1.5-20.0 years). The mean model for end-stage liver disease (MELD) at the time of TIPS creation was 8.1±1.6 (range: 6-11). Indications for TIPS creation included acute variceal bleeding (8/18, 44.4%), primary (1/18, 5.6%) or secondary (7/18, 38.9%) prevention of varices, portal vein thrombosis (1/18, 5.6%), and splenic sequestration (1/18, 5.6%). Technical successes, intra-procedural parameters, hemodynamic and clinical successes, TIPS patencies, adverse events, imaging evaluations, and follow-ups were recorded. RESULTS: All (100%) TIPS placements were successful; however, a direct intrahepatic portosystemic shunt was created in one (5.6%) patient. Mean reduction of the portosystemic shunt gradient was 9.1±3.3 mmHg (range: 4-16 mmHg). Seventeen (94.4%) patients demonstrated clinical success with resolution of their initial clinical indication for TIPS placement. The 3-year TIPS primary, primary-assisted, and secondary patencies were 83.3% (15/18), 94.4% (17/18), and 100% (18/18), respectively. Two (11.1%) patients developed mild, medically controlled hepatic encephalopathy. One (5.6%) patient developed hepatopulmonary syndrome. Nine (50%) patients developed single or multiple hepatic nodules at a mean imaging surveillance time after TIPS of 4.4±3.0 years (range: 1.5-10.2 years). Six (33.3%) patients developed nodules >1 cm with imaging features most consistent with focal nodular hyperplasia or focal nodular hyperplasia-like nodules. The mean follow-up duration was 5.7±2.9 years (range: 3.0-13.1 years). CONCLUSION: Long-term (>3 years) portosystemic shunting via TIPS is associated with the development of hepatic nodular lesions in children. Consequently, children with TIPS may need gray-scale assessment of hepatic parenchyma as part of routine ultrasound exams and extended imaging surveillance until more is understood regarding the natural history of induced nodularity.

Ultrasound Evaluation of Pediatric Slow-Flow Vascular Malformations: Practical Diagnostic Reporting to Guide Interventional Management.

OBJECTIVE. This article reviews the ultrasound characteristics of pediatric slow-flow vascular malformations and underscores findings that significantly impact diagnosis and treatment. Key imaging features are discussed including lesion size, malformation location, morphology, and mimics. CONCLUSION. Ultrasound findings affect the management of slow-flow vascular malformations and should be emphasized in lesion diagnosis. Superficial, focal lesions with well-defined margins are ideal for ultrasound evaluation.

Mesenteric Plexiform Neurofibroma as a Cause of Weight Loss and Chronic Diarrhea in a Patient with YPEL3 Variant.

Mesenteric plexiform neurofibroma is a subtype of plexiform neurofibroma that involves the mesentery and causes a variety of gastrointestinal complaints. Plexiform neurofibroma is classically found in patients with neurofibromatosis type 1, although genetic contributions to plexiform neurofibroma pathogenesis are heterogeneous. We report the first case of mesenteric plexiform neurofibroma in a patient with a YPEL3 pathogenic variant. This patient presented with growth failure, generalized abdominal pain and chronic diarrhea. She was confirmed to have mesenteric plexiform neurofibroma on histopathology and targeted sequencing on affected tissue confirmed that there were no neurofibromatosis type 1 variants present. Given that this patient's mesenteric plexiform neurofibroma is associated with YPEL3 dysfunction, she is unlikely to benefit from MEK inhibitors, which are the newly approved treatment for inoperable plexiform neurofibroma in patients with neurofibromatosis type 1.

Combined endolymphatic and surgical treatment of a leaking central conducting lymphatic malformation in a neonate.

Lymphatic malformations are congenital alterations of normal embryonic lymphatic development. We present a case of a premature 7-week-old male with a large central conducting lymphatic malformation and significant abdominal chylorrhea. He was successfully treated with combined endolymphatic and surgical approaches. To the authors' knowledge, this is the first case to be described.

Optimization of Pediatric Body CT Angiography: What Radiologists Need to Know.

OBJECTIVE. Pediatric CT angiography (CTA) presents unique challenges compared with adult CTA. Because of the ionizing radiation exposure, CTA should be used judiciously in children. The pearls offered here are observations gleaned from the authors' experience in the use of pediatric CTA. We also present some potential follies to be avoided. CONCLUSION. Understanding the underlying principles and paying meticulous attention to detail can substantially optimize dose and improve the diagnostic quality of pediatric CTA.

Applications of Pediatric Body CT Angiography: What Radiologists Need to Know.

OBJECTIVE. Pediatric CT angiography (CTA) can be useful for assessing numerous congenital and acquired disorders. This article discusses common pediatric applications of thoracoabdominal CTA, including for congenital pulmonary airway malformation, sequestration, vascular rings, aortic coarctation, pulmonary embolism, nontraumatic hemorrhage, abdominal transplant evaluation, and several vascular disorders, and highlights key clinical and imaging features. CONCLUSION. With appropriate use, CTA can play a fundamental role in diagnostic and preprocedural assessment in a variety of pediatric conditions.