Mediastinal Masses in Children: Radiologic-Pathologic Correlation.

Most pediatric masses in the chest are located in the mediastinum. These masses are often initially detected incidentally on chest radiographs in asymptomatic children, although some patients may present with respiratory symptoms. At chest radiography, the mediastinum has been anatomically divided into anterior, middle, and posterior compartments. However, with the International Thymic Malignancy Interest Group classification scheme, which is based on cross-sectional imaging findings, the mediastinum is divided into prevascular, visceral, and paravertebral compartments. In the prevascular compartment, tumors of thymic origin, lymphomas, germ cell tumors, and vascular tumors are encountered. In the visceral compartment, lymphadenopathy and masses related to the foregut are seen. In the paravertebral compartment, neurogenic tumors are most common. Using the anatomic location in combination with knowledge of the imaging and pathologic features of pediatric mediastinal masses aids in accurate diagnosis of these masses to guide treatment and management decisions. An invited commentary by Lee and Winant is available online. ©RSNA, 2021.

Primary Lung Tumors in Children: Radiologic-Pathologic Correlation From the Radiologic Pathology Archives.

Primary lung tumors in children are rare, with a narrow range of diagnostic considerations. However, the overlapping imaging appearances of these tumors necessitate attention to key discriminating imaging and pathologic features. In the neonate and infant, the important considerations include pleuropulmonary blastoma (PPB), infantile fibrosarcoma, and fetal lung interstitial tumor. Among these tumors, imaging findings such as air-filled cysts in type 1 PPB and homogeneously low attenuation of fetal lung interstitial tumors are relatively specific. Key pathologic and genetic discriminators among this group of tumors include the DICER1 germline mutation found in PPB and the t(12,15)(p13;q25) translocation and ETV6-NTRK3 fusion gene seen in infantile fibrosarcoma. Primary lung tumors in older children include inflammatory myofibroblastic tumors (IMTs), carcinoid salivary gland-type tumors of the lung, recurrent respiratory papillomatosis, and other rare entities. IMT, a spindle-cell proliferation with inflammatory elements, is the most common lung tumor in children. Anaplastic lymphoma kinase, a receptor-type protein tyrosine kinase, is present in 50% of these tumors, and this finding may support an imaging diagnosis of IMT. Carcinoid tumors account for a substantial portion of childhood lung tumors, and their characteristic avid enhancement on images corresponds to the compressed fibrovascular stroma histologically. Furthermore, novel imaging agents used with somatostatin receptor analogs have an emerging role in the evaluation of carcinoid tumors. Although less common than mucoepidermoid carcinoma, adenoid cystic carcinoma tends to recur given the perineural spread seen histologically. Integrating radiologic and pathologic knowledge is critical to accurate diagnosis, treatment planning, and surveillance of primary lung tumors in children.

Renal Tumors of Childhood: Radiologic-Pathologic Correlation Part 2. The 2nd Decade: From the Radiologic Pathology Archives.

Malignant renal tumors account for 7% of childhood cancers, and Wilms tumors are by far the most common-but not in older children and adolescents. Among individuals in the latter half of their 2nd decade of life, renal cell carcinoma (RCC) is more common than Wilms tumor. The histopathologic spectrum of RCCs in children differs from that in adults. The most common subtype of RCC in children and adolescents is Xp11.2 translocation RCC, which is distinguished by hyperattenuation at nonenhanced computed tomography, a defined capsule, and associated retroperitoneal lymphadenopathy. Papillary RCC is the second most common histologic subtype. It enhances less intensely compared with the adjacent renal parenchyma and has a propensity for calcification. Clear cell RCC is seen in patients with von Hippel-Lindau disease and is distinguished by its relatively hypervascular nature. Medullary carcinoma affects adolescents with the sickle cell trait and is characterized by an infiltrative growth pattern and extensive metastasis at presentation. Angiomyolipoma is seen in children with tuberous sclerosis complex and is often multifocal and hypervascular, with macroscopic fat. Metanephric tumors are central, circumscribed, and typically calcified. Lymphoma usually manifests as multifocal masses, but it may involve a solitary mass or infiltrative pattern. Extensive adenopathy and involvement of the gastrointestinal tract or other organs also may be seen. Primitive neuroectodermal tumor is an aggressive neoplasm that is typically quite large at diagnosis. Knowledge of the clinical, biologic, and histopathologic features of renal tumors in older children and adolescents and their effects on the imaging appearance can help the radiologist offer a useful preoperative differential diagnosis.

Imaging of the Pediatric Urinary System.

Recent advances in pediatric urinary tract imaging include development of alternative imaging methods without use of ionizing radiation; evolving understanding of the relationship of urinary tract infection, vesicoureteral reflux, and renal scarring, including the important role of dysfunctional voiding; development of a consensus nomenclature and risk-based classification for fetal and antenatal urinary tract dilation; advances in the understanding of sporadic and inherited renal cystic disease; and a proposed modification of the Bosniak criteria for distinguishing complex renal cysts from cystic renal tumors in children.

CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects.

Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and Cmin decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination.

Pediatric Extranodal Lymphoma.

Lymphoma is the third most common pediatric neoplasm. Non-Hodgkin lymphoma (NHL) accounts for nearly half of cases and commonly involves extranodal sites. Compared with adults, this histologic spectrum of pediatric NHL is very narrow and consists of aggressive tumors. Patients typically present with widespread disease. Generally, NHL occurring in children includes Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma. Staging and assessment of therapeutic response are usually based on FDG-PET/CT. Due to the increased susceptibility of young patients to the effects of ionizing radiation, alternative methods of imaging are being explored.

Renal Tumors of Childhood: Radiologic-Pathologic Correlation Part 1. The 1st Decade: From the Radiologic Pathology Archives.

Wilms tumor is the second most common pediatric solid tumor and by far the most common renal tumor of infants and young children. As most tumors are large at presentation and are treated with nephrectomy, the role of imaging is primarily in preoperative planning and evaluation for metastatic disease. However, with treatment protocols increasingly involving use of preoperative (neoadjuvant) chemotherapy (the standard in Europe) and consideration of nephron-sparing surgery, the role of imaging is evolving to include providing initial disease staging information and a presumptive diagnosis to guide therapy. Differential diagnostic considerations include lesions that are clinically benign and others that require more intensive therapy than is used to treat Wilms tumor. In part 1 of this article, the unique histologic spectrum of renal neoplasms of infants and young children is reviewed with emphasis on radiologic-pathologic correlation. Part 2 will focus on renal tumors of older children and adolescents.

White Paper on P4 Concepts for Pediatric Imaging.

Over the past decade, innovations in the field of pediatric imaging have been based largely on single-center and retrospective studies, which provided limited advances for the benefit of pediatric patients. To identify opportunities for potential "quantum-leap" progress in the field of pediatric imaging, the ACR-Pediatric Imaging Research (PIR) Committee has identified high-impact research directions related to the P4 concept of predictive, preventive, personalized, and participatory diagnosis and intervention. Input from 237 members of the Society for Pediatric Radiology was clustered around 10 priority areas, which are discussed in this article. Needs within each priority area have been analyzed in detail by ACR-PIR experts on these topics. By facilitating work in these priority areas, we hope to revolutionize the care of children by shifting our efforts from unilateral reaction to clinical symptoms, to interactive maintenance of child health.

Solid tumors of the peritoneum, omentum, and mesentery in children: radiologic-pathologic correlation: from the radiologic pathology archives.

Intraperitoneal solid tumors are far less common in children than in adults, and the histologic spectrum of neoplasms of the peritoneum and its specialized folds in young patients differs from that in older patients. Localized masses may be caused by inflammatory myofibroblastic tumor, Castleman disease, mesenteric fibromatosis, or other mesenchymal masses. Inflammatory myofibroblastic tumor is a mesenchymal tumor of borderline biologic potential that appears as a solitary circumscribed mass, possibly with central calcification. Castleman disease is an idiopathic lymphoproliferative disorder that appears as a circumscribed, intensely enhancing mass in the mesentery. Mesenteric fibromatosis, or intra-abdominal desmoid tumor, is a benign tumor of mesenchymal origin associated with familial adenomatous polyposis. Mesenteric fibromatosis appears as a mildly enhancing, circumscribed solitary mass without metastases. Diffuse peritoneal disease may be due to desmoplastic small round cell tumor (DSRCT), non-Hodgkin lymphoma, or rhabdomyosarcoma. DSRCT is a rare member of the small round blue cell tumor family that causes diffuse peritoneal masses without a visible primary tumor. A dominant mass is typically found in the retrovesical space. Burkitt lymphoma is a pediatric tumor that manifests with extensive disease because of its short doubling time. The bowel and adjacent mesentery are commonly involved. Rhabdomyosarcoma may arise as a primary tumor of the omentum or may spread from a primary tumor in the bladder, prostate, or scrotum. Knowledge of this spectrum of disease allows the radiologist to provide an appropriate differential diagnosis and suggest proper patient management.

From the radiologic pathology archives imaging of osteonecrosis: radiologic-pathologic correlation.

Osteonecrosis is common and represents loss of blood supply to a region of bone. Common sites affected include the femoral head, humeral head, knee, femoral/tibial metadiaphysis, scaphoid, lunate, and talus. Symptomatic femoral head osteonecrosis accounts for 10,000-20,000 new cases annually in the United States. In contradistinction, metadiaphyseal osteonecrosis is often occult and asymptomatic. There are numerous causes of osteonecrosis most commonly related to trauma, corticosteroids, and idiopathic. Imaging of osteonecrosis is frequently diagnostic with a serpentine rim of sclerosis on radiographs, photopenia in early disease at bone scintigraphy, and maintained yellow marrow at MR imaging with a serpentine rim of high signal intensity (double-line sign) on images obtained with long repetition time sequences. These radiologic features correspond to the underlying pathology of osseous response to wall off the osteonecrotic process and attempts at repair with vascularized granulation tissue at the reactive interface. The long-term clinical importance of epiphyseal osteonecrosis is almost exclusively based on the likelihood of overlying articular collapse. MR imaging is generally considered the most sensitive and specific imaging modality both for early diagnosis and identifying features that increase the possibility of this complication. Treatment subsequent to articular collapse and development of secondary osteoarthritis typically requires reconstructive surgery. Malignant transformation of osteonecrosis is rare and almost exclusively associated with metadiaphyseal lesions. Imaging features of this dire sequela include aggressive bone destruction about the lesion margin, cortical involvement, and an associated soft-tissue mass. Recognizing the appearance of osteonecrosis, which reflects the underlying pathology, improves radiologic assessment and is important to guide optimal patient management.

From the radiologic pathology archives: pediatric polycystic kidney disease and other ciliopathies: radiologic-pathologic correlation.

Genetic defects of cilia cause a wide range of diseases, collectively known as ciliopathies. Primary, or nonmotile, cilia function as sensory organelles involved in the regulation of cell growth, differentiation, and homeostasis. Cilia are present in nearly every cell in the body and mutations of genes encoding ciliary proteins affect multiple organs, including the kidneys, liver, pancreas, retina, central nervous system (CNS), and skeletal system. Genetic mutations causing ciliary dysfunction result in a large number of heterogeneous phenotypes that can manifest with a variety of overlapping abnormalities in multiple organ systems. Renal manifestations of ciliopathies are the most common abnormalities and include collecting duct dilatation and cyst formation in autosomal recessive polycystic kidney disease (ARPKD), cyst formation anywhere in the nephron in autosomal dominant polycystic kidney disease (ADPKD), and tubulointerstitial fibrosis in nephronophthisis, as well as in several CNS and skeletal malformation syndromes. Hepatic disease is another common manifestation of ciliopathies, ranging from duct dilatation and cyst formation in ARPKD and ADPKD to periportal fibrosis in ARPKD and several malformation syndromes. The unifying molecular pathogenesis of this emerging class of disorders explains the overlap of abnormalities in disparate organ systems and links diseases of widely varied clinical features. It is important for radiologists to be able to recognize the multisystem manifestations of these syndromes, as imaging plays an important role in diagnosis and follow-up of affected patients.

Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.

BACKGROUND & AIMS: The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. METHODS: We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). RESULTS: In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. CONCLUSIONS: In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

MR findings in the arthropathy of relapsing polychondritis.

We report a case of relapsing polychondritis involving three synovial joints in a child. Initial presentation was at 5 years of age with periorbital edema and chemosis of the conjunctiva with a definite diagnosis established at 9 years of age following an acute monoarticular arthropathy of the knee. The role of MRI in suggesting the diagnosis of relapsing polychondritis is emphasized by demonstrating a unique pattern of inflammation and enhancement that preferentially involves the perichondrium and chondroepiphysis.

Pharmacokinetics and pharmacodynamics of atazanavir-containing antiretroviral regimens, with or without ritonavir, in patients who are HIV-positive and treatment-naïve.

STUDY OBJECTIVE: To investigate the pharmacokinetic and pharmacodynamic relationships of the human immunodeficiency virus (HIV)-protease inhibitor atazanavir (ATV) in the presence and absence of the pharmacokinetic booster ritonavir, utilizing ATV plasma trough concentrations (Ctrough ) and clinical biomarkers of antiviral efficacy and safety over 48 weeks. DESIGN: Randomized, open-label, multicenter, study designed to compare the efficacy and safety of ATV 300 mg plus ritonavir 100 mg (ATV300/r) with that of ATV 400 mg (ATV400). SETTING: Thirty clinic sites across 10 countries in Africa, Europe, North America, and South America. PATIENTS: Patients who were HIV-positive and treatment-naïve. INTERVENTIONS: Randomized to once-daily ATV400 (105 patients) or ATV300/r (95 patients) plus lamivudine and extended-release stavudine. MEASUREMENTS AND MAIN RESULTS: The Ctrough approximately 24 hours after the prior unobserved dose was measured through week 48. Composite Ctrough (i.e., the geometric mean of all trough concentrations over the 48 weeks), population inhibitory quotient ([IQ], i.e., Ctrough divided population estimated protein binding adjusted effective concentration at 90% [EC90 , 14 ng/ml]), composite population IQ (i.e., ATV composite trough divided by population estimated protein binding adjusted EC90 ), HIV RNA, CD4 cell counts, and metabolic and safety parameters were also assessed. For ATV400 and ATV300/r, respectively, geometric mean composite Ctrough (CV%) were 127 (106) ng/ml and 670 (63) ng/ml, geometric mean composite population IQ were 9 and 48, and composite Ctrough values of HIV EC90 or more were achieved in 98% and 100% of patients. High ATV Ctrough was associated with low HIV RNA at week 48; however, 88% of patients had HIV RNA less than 400 copies/ml in the lowest composite Ctrough quartile. There was no clear relationship between ATV Ctrough and changes in CD4 cell count. Increases in total bilirubin or jaundice were associated with higher Ctrough . Modest increases in triglycerides and cholesterol were associated with the addition of ritonavir. CONCLUSION: ATV-containing regimens with or without ritonavir achieved ATV exposures that provide robust antiretroviral efficacy and acceptable tolerability in treatment-naïve patients.

From the radiologic pathology archives: precocious puberty: radiologic-pathologic correlation.

Precocious puberty represents a unique diagnostic problem in which imaging plays an important role. Development of secondary sex characteristics may result from inappropriate activation of the hypothalamic-pituitary axis with release of gonadotropin, or from gonadotropin-independent secretion of sex steroids by the adrenal glands or gonads. A variety of lesions can manifest with precocious puberty, including various central nervous system (CNS) lesions, adrenal lesions, and sex cord-stromal tumors of the testis or ovary. CNS lesions causing precocious puberty are much more common in boys than in girls and are well evaluated with brain magnetic resonance imaging. Neoplastic (hypothalamic-chiasmatic astrocytoma, suprasellar germinoma) and nonneoplastic (hypothalamic hamartoma, hydrocephalus, trauma, empty sella, infection, congenital midline anomalies) conditions may affect the function of the hypothalamic-pituitary axis. The adrenal cortex may produce sex hormones. Some adrenal cortical neoplasms (ACNs) in patients under 5 years of age are related to a mutation of the tumor suppressor gene p53 and represent a disease that is distinct from ACNs in older children and adults. Adrenal cortical hyperplasia secondary to an enzymatic defect in steroid biosynthesis causes virilization and salt wasting, which usually manifest in the neonatal period; however, milder forms of the disease may manifest in childhood. Female precocious puberty may be caused by an autonomously functioning ovarian cyst or a juvenile granulosa cell tumor of the ovary. Male precocious puberty may be caused by a sex steroid-producing Leydig or Sertoli cell tumor of the testis. Ultrasonography is the primary modality for evaluating the sex organs and may also be used to evaluate for adrenal abnormalities.

Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1.

UNLABELLED: The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log(10) IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. CONCLUSION: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1.

Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients.

Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H(2)-receptor antagonist, reduces exposures of atazanavir by 4-28% at doses of 20-40 mg twice daily. This study evaluated the effect of famotidine 20-40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26-63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (C(min)). In the presence of TDF, administration of famotidine 20-40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19-25%. However, all individual atazanavir C(min) values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC(90)) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H(2)-receptor antagonist with atazanavir/ritonavir.