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.

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 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.

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.

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.

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.

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.

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.

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.

Cell polarity and cytoskeletons-Lesson from the testis.

Cell polarity in the adult mammalian testis refers to the polarized alignment of developing spermatids during spermiogenesis and the polarized organization of organelles (e.g., phagosomes, endocytic vesicles, Sertoli cell nuclei, Golgi apparatus) in Sertoli cells and germ cells to support spermatogenesis. Without these distinctive features of cell polarity in the seminiferous epithelium, it is not possible to support the daily production of millions of sperm in the limited space provided by the seminiferous tubules in either rodent or human males through the adulthood. In short, cell polarity provides a novel mean to align spermatids and the supporting organelles (e.g., phagosomes, Golgi apparatus, endocytic vesicles) in a highly organized fashion spatially in the seminiferous epithelium during the epithelial cycle of spermatogenesis. This is analogous to different assembling units in a manufacturing plant such that as developing spermatids move along the "assembly line" conferred by Sertoli cells, different structural/functional components can be added to (or removed from) the developing spermatids during spermiogenesis, so that functional spermatozoa are produced at the end of the assembly line. Herein, we briefly review findings regarding the regulation of cell polarity in the testis with specific emphasis on developing spermatids, supported by an intriguing network of regulatory proteins along a local functional axis. Emerging evidence has suggested that cell cytoskeletons provide the tracks which in turn confer the unique assembly lines in the seminiferous epithelium. We also provide some thought-provoking concepts based on which functional experiments can be designed in future studies.

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.

Regulation of microtubule (MT)-based cytoskeleton in the seminiferous epithelium during spermatogenesis.

In rodents and humans, testicular cells, similar to other mammalian cells, are supported by actin-, microtubule (MT)- and intermediate filament-based cytoskeletons. Although the cytoskeletal network of the testis serves an important role in regulating spermatogenesis during the epithelial cycle, most of the published findings in the literature are limited to studies that only visualize these cytoskeletons in the seminiferous epithelium. Few focus on the underlying molecular mechanism that regulates their organization in the epithelium in response to changes in the stages of the epithelial cycle. Functional studies in the last decade have begun to focus on the role of binding proteins that regulate these cytoskeletons, with some interesting findings rapidly emerging in the field. Since the actin- and intermediate filament-based cytoskeletons have been recently reviewed, herein we focus on the MT-based cytoskeleton for two reasons. First, besides serving as a structural support cytoskeleton, MTs are known to serve as the track to support and facilitate the transport of germ cells, such as preleptotene spermatocytes connected in clones and elongating/elongated spermatids during spermiogenesis, across the blood-testis barrier (BTB) and the adluminal compartment, respectively, during spermatogenesis. While these cellular events are crucial to the completion of spermatogenesis, they have been largely ignored in the past. Second, MT-based cytoskeleton is working in concert with the actin-based cytoskeleton to provide structural support for the transport of intracellular organelles across the cell cytosol, such as endosome-based vesicles, and phagosomes, which contain residual bodies detached from spermatids, to maintain the cellular homeostasis in the seminiferous epithelium. We critically evaluate some recent published findings herein to support a hypothesis regarding the role of MT in conferring germ cell transport in the seminiferous epithelium.

Dynein 1 supports spermatid transport and spermiation during spermatogenesis in the rat testis.

In the mammalian testis, spermatogenesis is dependent on the microtubule (MT)-specific motor proteins, such as dynein 1, that serve as the engine to support germ cell and organelle transport across the seminiferous epithelium at different stages of the epithelial cycle. Yet the underlying molecular mechanism(s) that support this series of cellular events remain unknown. Herein, we used RNAi to knockdown cytoplasmic dynein 1 heavy chain (Dync1h1) and an inhibitor ciliobrevin D to inactivate dynein in Sertoli cells in vitro and the testis in vivo, thereby probing the role of dynein 1 in spermatogenesis. Both treatments were shown to extensively induce disruption of MT organization across Sertoli cells in vitro and the testis in vivo. These changes also perturbed the transport of spermatids and other organelles (such as phagosomes) across the epithelium. These changes thus led to disruption of spermatogenesis. Interestingly, the knockdown of dynein 1 or its inactivation by ciliobrevin D also perturbed gross disruption of F-actin across the Sertoli cells in vitro and the seminiferous epithelium in vivo, illustrating there are cross talks between the two cytoskeletons in the testis. In summary, these findings confirm the role of cytoplasmic dynein 1 to support the transport of spermatids and organelles across the seminiferous epithelium during the epithelial cycle of spermatogenesis.

Signaling pathways regulating blood-tissue barriers - Lesson from the testis.

Signaling pathways that regulate blood-tissue barriers are important for studying the biology of various blood-tissue barriers. This information, if deciphered and better understood, will provide better therapeutic management of diseases particularly in organs that are sealed by the corresponding blood-tissue barriers from systemic circulation, such as the brain and the testis. These barriers block the access of antibiotics and/or chemotherapeutical agents across the corresponding barriers. Studies in the last decade using the blood-testis barrier (BTB) in rats have demonstrated the presence of several signaling pathways that are crucial to modulate BTB function. Herein, we critically evaluate these findings and provide hypothetical models regarding the underlying mechanisms by which these signaling molecules/pathways modulate BTB dynamics. This information should be carefully evaluated to examine their applicability in other tissue barriers which shall benefit future functional studies in the field. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

N-wasp is required for structural integrity of the blood-testis barrier.

During spermatogenesis, the blood-testis barrier (BTB) segregates the adluminal (apical) and basal compartments in the seminiferous epithelium, thereby creating a privileged adluminal environment that allows post-meiotic spermatid development to proceed without interference of the host immune system. A key feature of the BTB is its continuous remodeling within the Sertoli cells, the major somatic component of the seminiferous epithelium. This remodeling is necessary to allow the transport of germ cells towards the seminiferous tubule interior, while maintaining intact barrier properties. Here we demonstrate that the actin nucleation promoting factor Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP) provides an essential function necessary for BTB restructuring, and for maintaining spermatogenesis. Our data suggests that the N-WASP-Arp2/3 actin polymerization machinery generates branched-actin arrays at an advanced stage of BTB remodeling. These arrays are proposed to mediate the restructuring process through endocytic recycling of BTB components. Disruption of N-WASP in Sertoli cells results in major structural abnormalities to the BTB, including mis-localization of critical junctional and cytoskeletal elements, and leads to disruption of barrier function. These impairments result in a complete arrest of spermatogenesis, underscoring the critical involvement of the somatic compartment of the seminiferous tubules in germ cell maturation.

Role of non-receptor protein tyrosine kinases in spermatid transport during spermatogenesis.

Non-receptor protein tyrosine kinases are cytoplasmic kinases that activate proteins by phosphorylating tyrosine residues, which in turn affect multiple functions in eukaryotic cells. Herein, we focus on the role of non-receptor protein tyrosine kinases, most notably, FAK, c-Yes and c-Src, in the transport of spermatids across the seminiferous epithelium during spermatogenesis. Since spermatids, which are formed from spermatocytes via meiosis, are immotile haploid cells, they must be transported by Sertoli cells across the seminiferous epithelium during the epithelial cycle of spermatogenesis. Without the timely transport of spermatids across the epithelium, the release of sperms at spermiation fails to occur, leading to infertility. Thus, the molecular event pertinent to spermatid transport is crucial to spermatogenesis. We provide a critical discussion based on recent findings in this review. We also provide a hypothetical model on spermatid transport, and the role of non-receptor protein tyrosine kinases in this event. We also highlight areas of research that deserve attention by investigators in the field.