Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders.

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Neonatal vascular anomalies manifesting as soft-tissue masses.

The broad and heterogeneous spectrum of vascular anomalies ranges from an innocuous localized cutaneous discoloration to complex, extensive and life-threatening diagnoses. While many of these lesions are present at birth, smaller and deeper lesions might be clinically occult for months or years. Certain vascular anomalies commonly manifest in the prenatal or neonatal period and often have suggestive clinical and imaging features that can aid the radiologist in making a correct diagnosis. The characteristics of such lesions presenting very early in life, particularly those manifesting as soft-tissue masses, are the focus of this review.

Congenital hemangioma of the face-Value of fetal MRI with prenatal ultrasound.

We report the presentation, workup, and pre/perinatal management of a fetus with a large congenital hemangioma of the face. Hemangiomas are benign vascular neoplasms frequently encountered in neonates and infants. The less common congenital variant develops in utero and can present on prenatal ultrasound with diagnostic uncertainty as well as clinical implications for delivery. The differential diagnosis for these solid vascular masses when located in the head and neck includes myofibroma, kaposiform hemangioendothelioma, teratoma, and encephalocele. Potential clinical issues relate to size and location of the mass and include airway obstruction, disruption in development or compression of the globe, invasion into the cranial vault, bleeding and ulceration, and high output heart failure. Prenatal ultrasound and MRI play an important role in the diagnosis of congenital hemangiomas and planning for delivery and immediate postnatal cares.

Spaced radiology: encouraging durable memory using spaced testing in pediatric radiology.

Applied memory research in the field of cognitive and educational psychology has generated a large body of data to support the use of spacing and testing to promote long-term or durable memory. Despite the consensus of this scientific community, most learners, including radiology residents, do not utilize these tools for learning new information. We present a discussion of these parallel and synergistic learning techniques and their incorporation into a software platform, called Spaced Radiology, which we created for teaching radiology residents. Specifically, this software uses these evidence-based strategies to teach pediatric radiology through a flashcard deck system.

Non-contrast three-dimensional gradient recalled echo Dixon-based magnetic resonance angiography/venography in children.

Magnetic resonance imaging (MRI) has been considered a valuable diagnostic tool for noninvasive imaging of the vasculature in children and adults for more than two decades. While a variety of non-contrast MRI methods have been described for imaging of both arteries and veins (e.g., time-of-flight, phase contrast, and balanced steady-state free precession imaging), contrast-enhanced magnetic resonance angiography/venography are the most commonly employed vascular imaging techniques due to their high spatial and contrast resolutions and general reliability. In this technical innovation article, we describe a novel 3-D respiratory-triggered gradient recalled echo Dixon-based MR angiography/MR venography technique that provides high-resolution anatomical imaging of the vasculature of the neck, body and extremities without the need for intravenous contrast material or breath-holding.

Decreased rectal meconium signal on MRI in fetuses with open spinal dysraphism.

OBJECTIVE: To evaluate rectal meconium signal in fetuses with open spinal dysraphism and correlate findings with postnatal exam. METHODS: This is a single-institution Institutional Review Board-approved Health Insurance Portability and Accountability Act (HIPAA) compliant retrospective analysis of fetal MRIs of open spinal dysraphism from 2004 to 2016. Fetuses with diagnostic T1-weighted images and postnatal follow-up at our institution were included. RESULTS: A total of 115 fetuses (average gestational age 23.9 ± 3.6 weeks) met inclusion criteria. Of these, 80% (92/115) had T1 hyperintense rectal meconium signal. Average height of the meconium column, measured from the base of the bladder to its most inferior extent, was 9.2 ± 4.3 mm in fetuses ≥20-week gestational age and 11.1 ± 4.4 mm in fetuses ≥23-week gestational age (n = 110) . None had bowel dilation. One of 115 fetuses had a simple form of anorectal malformation allowing complete repair in the neonatal period, but this fetus had a normal meconium column height on fetal MRI of 22 mm. The remaining 23/115 fetuses with lack of normal rectal meconium signal were born without evidence of anorectal malformation. CONCLUSION: Decreased or absent T1-hyperintense rectal meconium signal in fetuses with open spinal dysraphism does not correlate with imperforate anus postnatal and may be a reflection of neurogenic bowel in this patient population.

Fowler syndrome and fetal MRI findings: a genetic disorder mimicking hydranencephaly/hydrocephalus.

Fetal ventriculomegaly is a common referral for prenatal MRI, with possible etiologies being hydrocephalus and hydranencephaly. The underlying cause of hydranencephaly is unknown, but many have suggested that the characteristic supratentorial injury is related to idiopathic bilateral occlusions of the internal carotid arteries from an acquired or destructive event. Fowler syndrome is a rare genetic disorder that causes fetal akinesia and a proliferative vasculopathy that can result in an apparent hydranencephaly-hydrocephaly complex. On prenatal imaging, the presence of significant parenchymal loss in the supratentorial and infratentorial brain is a clue to the diagnosis, which should prompt early genetic testing.

Imaging of Pediatric Growth Plate Disturbances.

The growth plates, or physes, are visible on virtually all images obtained in skeletally immature children. The proper function of these growth plates depends on an intricate balance between chondrocyte proliferation, which requires nourishment from the epiphyseal vessels, and chondrocyte death, which requires the integrity of the metaphyseal vessels. Therefore, injury to the growth plate (ie, direct insult) or vascular compromise on either side of the growth plate (ie, indirect insult) can cause growth plate dysfunction. Direct growth plate insults occur most commonly with Salter-Harris fractures, and injuries that allow the transphyseal communication of vessels are at a higher risk for subsequent transphyseal bone bridge formation. Indirect insults lead to different sequelae that are based on whether the epiphyseal blood supply or metaphyseal blood supply is compromised. Epiphyseal osteonecrosis can result in slowed longitudinal bone growth, with possible growth plate closure, and is often accompanied by an abnormal secondary ossification center. In contrast, the disruption of metaphyseal blood supply alters endochondral ossification and allows the persistence of chondrocytes within the metaphysis, which appear as focal or diffuse growth plate widening. Imaging remains critical for detecting acute injuries and identifying subsequent growth disturbances. Depending on the imaging findings and patient factors, these growth disturbances may be amenable to conservative or surgical treatment. Therefore, an understanding of the anatomy and physiologic features of the normal growth plate and the associated pathophysiologic conditions can increase diagnostic accuracy, enable radiologists to anticipate future growth disturbances, and ensure optimal imaging, with the ultimate goal of timely and appropriate intervention. ©RSNA, 2017.

Four cases of pediatric deep-seated/subcutaneous pyogenic granuloma: Review of literature and differential diagnosis.

BACKGROUND: Pyogenic granulomas are benign, reactive, typically superficial vascular lesions that can be idiopathic or arise secondary to trauma, underlying vascular malformations, infections, physiologic or pathologic endocrine changes, and hormone therapy. Deep-seated/subcutaneous pyogenic granulomas (DSPG) are rarely seen in any age group. Pediatric DSPGs can be a clinical and pathologic challenge because these lesions mimic other vascular lesions, including kaposiform hemangioendothelioma, infantile hemangiomas and vascular malformations. METHODS: Retrospective search of DSPG excised at Cincinnati Children's Hospital Medical center between June 2010 and June 2011 was conducted. Clinical information was obtained from patient charts and histologic slides were retrieved and reviewed. RESULTS: Of the 106 cases of pyogenic granuloma, 4 (3.8%) were diagnosed as DSPG. We report the details of those 4 cases and compare them with the other pediatric DSPG cases reported in the literature. We also review the histologic differential diagnosis of DSPG in pediatric population. CONCLUSION: Our results suggest that these lesions may not be as rare as inferred by literature, but, rather, underdiagnosed.

Diffuse phalangeal signal abnormality on magnetic resonance imaging: phalangeal microgeodic disease.

BACKGROUND: Phalangeal microgeodic disease is a rare and benign self-limited condition involving the phalanges, often in the setting of cold exposure, with characteristic MR imaging abnormalities. Radiographic case descriptions are predominantly from Asia and Europe, with only seven cases using MR to characterize phalangeal microgeodic disease. OBJECTIVE: In this study we describe the MR imaging appearance of unusual and striking phalangeal signal abnormality compatible with phalangeal microgeodic disease at our institution in North America. MATERIALS AND METHODS: We retrospectively reviewed cases presenting at our institution with unusual or unexplained phalangeal signal abnormalities between 2001 and 2014. We reviewed the MR imaging appearances in conjunction with radiographs and any other available imaging investigations. RESULTS: Of 189 examinations reviewed during the study period, 8 imaging studies in 6 patients met the study inclusion criteria. Signal abnormality was present in 57 of 112 phalanges (51%), frequently involving the distal phalanges (70%, 28 of 40), followed by the middle phalanges (56%, 18 of 32) and the proximal phalanges (28%, 11 of 40). The pattern of involvement was most commonly diaphysis (38%), followed by metaphysis (32%) and epiphysis (30%). The extent of MR signal abnormality was greater than that suspected based on clinical presentation or on radiographs. CONCLUSION: The presence of unexplained diffuse characteristic marrow involvement of multiple painful phalanges on MR images, often in the setting of cold exposure, should raise the possibility of phalangeal microgeodic disease. Consideration of this diagnosis based on MR findings would lead to a more conservative management and avoid unnecessary invasive diagnostic procedures.

Peer Feedback, Learning, and Improvement: Answering the Call of the Institute of Medicine Report on Diagnostic Error.

In September 2015, the Institute of Medicine (IOM) published a report titled "Improving Diagnosis in Health Care," in which it was recommended that "health care organizations should adopt policies and practices that promote a nonpunitive culture that values open discussion and feedback on diagnostic performance." It may seem counterintuitive that a report addressing a highly technical skill such as medical diagnosis would be focused on organizational culture. The wisdom becomes clearer, however, when examined in the light of recent advances in the understanding of human error and individual and organizational performance. The current dominant model for radiologist performance improvement is scoring-based peer review, which reflects a traditional quality assurance approach, derived from manufacturing in the mid-1900s. Far from achieving the goals of the IOM, which are celebrating success, recognizing mistakes as an opportunity to learn, and fostering openness and trust, we have found that scoring-based peer review tends to drive radiologists inward, against each other, and against practice leaders. Modern approaches to quality improvement focus on using and enhancing interpersonal professional relationships to achieve and maintain high levels of individual and organizational performance. In this article, the authors review the recommendations set forth by the recent IOM report, discuss the science and theory that underlie several of those recommendations, and assess how well they fit with the current dominant approach to radiology peer review. The authors also offer an alternative approach to peer review: peer feedback, learning, and improvement (or more succinctly, "peer learning"), which they believe is better aligned with the principles promoted by the IOM. © RSNA, 2016.

Long-term outcome for kaposiform hemangioendothelioma: A report of two cases.

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular tumor of skin and deep soft tissues that typically presents in infancy and may be associated with a potentially life-threatening coagulopathy known as Kasabach-Merrit phenomenon (KMP). Recent advances in medical therapy have successfully treated many patients. However, our knowledge regarding the natural history of these lesions and optimum surveillance strategies remains rudimentary. We report two young women who had KHE with KMP treated in infancy and presented in adolescence with comorbidities related to their KHE tumor. This presentation supports the need for long-term surveillance in these patients.

Clinical validation of synthetic brain MRI in children: initial experience.

INTRODUCTION: The purpose of this study was to determine the diagnostic accuracy of synthetic MR sequences generated through post-acquisition processing of a single sequence measuring inherent R1, R2, and PD tissue properties compared with sequences acquired conventionally as part of a routine clinical pediatric brain MR exam. METHODS: Thirty-two patients underwent routine clinical brain MRI with conventional and synthetic sequences acquired (22 abnormal). Synthetic axial T1, T2, and T2 fluid attenuation inversion recovery or proton density-weighted sequences were made to match the comparable clinical sequences. Two exams for each patient were de-identified. Four blinded reviewers reviewed eight patients and were asked to generate clinical reports on each exam (synthetic or conventional) at two different time points separated by a mean of 33 days. Exams were rated for overall and specific finding agreement (synthetic/conventional and compared to gold standard consensus review by two senior reviewers with knowledge of clinical report), quality, and diagnostic confidence. RESULTS: Overall agreement between conventional and synthetic exams was 97%. Agreement with consensus readings was 84% (conventional) and 81% (synthetic), p = 0.61. There were no significant differences in sensitivity, specificity, or accuracy for specific imaging findings involving the ventricles, CSF, brain parenchyma, or vasculature between synthetic or conventional exams (p > 0.05). No significant difference in exam quality, diagnostic confidence, or noise/artifacts was noted comparing studies with synthetic or conventional sequences. CONCLUSIONS: Diagnostic accuracy and quality of synthetically generated sequences are comparable to conventionally acquired sequences as part of a standard pediatric brain exam. Further confirmation in a larger study is warranted.

2014 Revised Classification of Vascular Lesions from the International Society for the Study of Vascular Anomalies: Radiologic-Pathologic Update.

Since the publication of the seminal work on the histology-based classification of vascular anomalies by Mulliken and Glowacki in 1982 and the subsequent adoption of an expanded and modified version in 1996 by the International Society for the Study of Vascular Anomalies, an increasing number of vascular lesions have been recognized as histologically distinct entities. Furthermore, there have been significant advances in detailing the behavior and underlying genetics of previously identified lesions. These developments have required restructuring and expansion of the classification scheme so that appropriate therapies may be studied and implemented in affected patients. The new classification retains the broad categories of neoplasms and malformations but now divides the tumor group into benign, locally aggressive or borderline, and malignant, with the malformation group being divided into simple, combined, those of major named vessels, and those associated with other anomalies. Additionally, a category has been created for lesions in which the histology and behavior do not yet allow clear separation into neoplasm or malformation (thus named "provisionally unclassified vascular anomalies"). The known clinical courses and imaging, histologic, and genetic findings of the most common and/or clinically relevant lesions in the newly adopted revised system are reviewed in this article. (©)RSNA, 2016.

Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment.

BACKGROUND: Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon-α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports. PROCEDURE: We performed a single-institution retrospective review of four children with BRBNS, who received sirolimus as part of their treatment regimens. A diagnosis of BRBNS was based on clinical, radiologic, and pathologic criteria. RESULTS: Median age was 6.5 years (range: 2-16 years). Pathologic evaluations revealed a combined malformation with venous and lymphatic components. The novel finding of a lymphatic component was confirmed with PROX-1 immunostaining. Patients received oral sirolimus with target drug levels between 10 and 13 ng/ml. Responses to treatment were defined as stabilization/decrease in size of lesions; resolution of transfusion requirements; reduction in pain, and improvement in quality of life (QOL). Median time to response was 1.5 months (SD ± 0.96 month, range: 1-3 months). Median follow-up was 21 months (range: 18-26 months). Lesion size and characteristics improved in all patients. All patients reported decrease in pain and improvement in QOL. All three patients requiring transfusions became transfusion-independent. One patient had resolution of coagulopathy. Adverse effects of sirolimus consisted of mucositis in three patients and neutropenia in one patient. CONCLUSIONS: Sirolimus is safe and efficient for the treatment of BRBNS. Further prospective studies are needed to evaluate the long-term effectiveness of this drug. This is the first report that identifies a lymphatic component as part of BRBNS.

Case 4: an adolescent girl with left lower quadrant pain.

The imaging management of an adolescent girl with pelvic pain and ovarian pathology is discussed through the details of a specific case.

Gorham-Stout Disease Successfully Treated With Sirolimus and Zoledronic Acid Therapy.

Gorham-Stout disease is a life-threatening disorder often manifested by lymphatic malformation and osteolysis. Unfortunately, available therapies are not uniformly effective and often carry substantial morbidity. We report an 18-year-old male with Gorham-Stout disease manifested by lytic rib lesions and an intractable pleural effusion that responded dramatically to the combination of the mammalian target of rapamycin (mTOR) inhibitor sirolimus and the aminobisphosphonate zoledronic acid after failing interferon therapy. This tolerable therapeutic combination has demonstrated synergism in preclinical cancer models and merits further study in vascular anomalies.

Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m(2) per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.