Paritosh C. Khanna

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model

The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.

Image-guided cerebrospinal fluid shunting in children: catheter accuracy and shunt survival.

OBJECT Cerebrospinal fluid shunt placement has a high failure rate, especially in patients with small ventricles. Frameless stereotactic electromagnetic image guidance can assist ventricular catheter placement. The authors studied the effects of image guidance on catheter accuracy and shunt survival in children. METHODS Pediatric patients who underwent placement or revision of a frontal ventricular CSF shunt were retrospectively evaluated. Catheters were placed using either anatomical landmarks or image guidance. Preoperative ventricular size and postoperative catheter accuracy were quantified. Outcomes of standard and image-guided groups were compared. RESULTS Eighty-nine patients underwent 102 shunt surgeries (58 initial, 44 revision). Image guidance was used in the placement of 56 shunts and the standard technique in 46. Shunt failure rates were not significantly different between the standard (22%) and image-guided (25%) techniques (p = 0.21, log-rank test). Ventricular size was significantly smaller in patients in the image-guided group (p < 0.02, Student t-test) and in the surgery revision group (p < 0.01). Small ventricular size did not affect shunt failure rate, even when controlling for shunt insertion technique. Despite smaller average ventricular size, the accuracy of catheter placement was significantly improved with image guidance (p < 0.01). Shunt accuracy did not affect shunt survival. CONCLUSIONS The use of image guidance improved catheter tip accuracy compared with a standard technique, despite smaller ventricular size. Failure rates were not dependent on shunt insertion technique, but an observed selection bias toward using image guidance for more at-risk catheter placements showed failure rates similar to initial surgeries.

Pediatric Bone Imaging: Imaging Elbow Trauma in Children???A Review of Acute and Chronic Injuries

OBJECTIVE Pediatric elbow trauma is challenging because of the complex nature of the growing skeleton. The objectives of this article are to review the anatomy and radiographic landmarks and to discuss common acute and chronic injuries sustained. CONCLUSION Radiographic evaluation of elbow trauma in the acute setting requires a firm understanding of developmental anatomy, radiographic landmarks, and the common injury patterns. Both radiography and MRI are vital tools for diagnosing chronic elbow overuse injuries in adolescent athletes.

Making the Diagnosis: Metopic Ridge Versus Metopic Craniosynostosis

Introduction The metopic suture is the only calvarial suture which normally closes during infancy. Upon closure, a palpable and visible ridge often forms which can be confused with metopic craniosynostosis. Metopic ridging (MR) is treated nonsurgically while metopic craniosynostosis (MCS) is treated surgically. Differentiating between the two is paramount; however, consensus is lacking about where a clear diagnostic threshold lies. The goal of this study is to describe the physical examination and CT scan characteristics which may help to differentiate between physiological closure of the metopic suture with ridging (MR) and MCS. Methods A retrospective chart review of all patients seen at Seattle Children’s Hospital between 2004 and 2009 with the diagnosis of either MCS or MR (n = 282) was performed. Physical examination characteristics described by diagnosing practitioners were analyzed. Clinical photos were assessed by 3 expert raters to determine the importance of these characteristics. CT scan findings were abstracted and compared between the two diagnoses. Results The “classic” triad of narrow forehead, biparietal widening, and hypotelorism was present in only 14% of patients with MCS. Ninety-eight percent of patients in both groups had a palpable metopic ridge. The photographic finding of narrow forehead and pterional constriction was present in all patients with MCS, but only in 11.2% and 2.8% of patients with MR. On CT scan, the presence of 3 or more MCS findings was diagnostic of MCS in 96% of patients. Patients with MCS were more likely to present before 6 months of age (66% vs. 32%). Conclusions Patients with MCS tend to present earlier than those with MR. Upon physical examination, the relationship between the lateral frontal bone and the lateral orbit is important in distinguishing between the two diagnoses. A CT scan can be helpful in making the diagnosis not to confirm a closed suture but to identify 3 or more MCS characteristics.

Craniosynostosis: imaging review and primer on computed tomography

Craniosynostosis is encountered in the pediatric population in isolated or syndromic forms. The resulting deformity depends on the number and type of sutures involved and, in multi-sutural synostosis, the order of suture fusion. Primary craniosynostosis needs to be differentiated from the secondary variety and positional or deformational mimics. Syndromic craniosynostoses are associated with other craniofacial deformities. Evaluation with 3-D CT plays an important role in accurate diagnosis and management; however, implementation of appropriate CT techniques is essential to limit the radiation burden in these children. In this article, the authors briefly review the classification, embryopathogenesis and epidemiology and describe in detail the radiologic appearance and differential diagnoses of craniosynostosis.

FDG PET of the Brain in Pediatric Patients: Imaging Spectrum with MR Imaging Correlation

Positron emission tomography (PET) of the brain is an important problem-solving tool in pediatric neuroimaging, neurology, and neurosurgery. Fluorine 18 fluorodeoxyglucose (FDG) PET or dual-modality PET and computed tomographic (CT) imaging (PET/CT), with magnetic resonance (MR) imaging correlation, can be used to evaluate childhood epilepsy and pediatric brain tumors, areas in which PET adds value in patient management. FDG PET has been widely used in pediatric temporal lobe epilepsy, most commonly manifesting as mesial temporal sclerosis, which demonstrates hypometabolism at interictal PET and hypermetabolism during seizures. Recently, FDG PET has shown added value for patients with extratemporal epilepsy, in whom FDG PET can help identify cortical foci of interictal hypometabolism that are undetectable or difficult to detect with MR imaging. These findings can then guide additional investigations and surgery. FDG PET also enhances medical decision making in children with brain tumors, in whom FDG PET can be used to (a) improve the diagnostic yield of stereotactic biopsies by detecting metabolically active areas of tumor, (b) help guide the surgeon in achieving total tumor resection, and (c) increase detection of residual or recurrent tumor. Technologic advances in the past decade have allowed fusion of PET and MR images, combining the high resolution of MR imaging with the low-resolution functional capability of PET. As dual-modality integrated PET/MR imaging systems become available, CT coregistration for PET can be eliminated, thus reducing patient radiation exposure. Increasing familiarity with normal and abnormal appearances of FDG PET brain images correlated with MR images can enhance diagnostic yield and improve the care of children with epilepsy and brain tumors.

Pictorial essay: The many faces of craniosynostosis.

Craniosynostosis is a common condition in the pediatric age group, which may either be isolated or may present as part of a craniofacial syndrome. This pictorial review illustrates the underlying mechanisms and pathophysiology of craniosynostosis, the various types of craniosynostoses, common craniofacial syndromes and the role of imaging in their diagnosis and management.

The Growing Skeleton: MR Imaging Appearances of Developing Cartilage

Developing hyaline cartilage at ends of long bones consists of the epiphyseal, physeal, and articular cartilage components, each of which has specific imaging characteristics that reflect biochemical and macromolecular composition. Standard MR imaging protocols used in adults do not provide sufficient information when used for children, and MR imaging techniques need to be tailored to the developmental stage of the child. This article presents the biochemical and histologic features of normal hyaline cartilage and its MR imaging characteristics, followed by a practical approach to optimizing imaging protocols for cartilage imaging. Finally, common abnormalities and advanced hyaline cartilage imaging techniques are described.

MRI of Pediatric Patients: Part 2, Normal Variants and Abnormalities of the Knee

OBJECTIVE The purpose of this article is to discuss MRI of the pediatric knee and familiarize the reader with conditions encountered in the pediatric population. Clinical scenarios are included to convey important concepts and to orient the learner to normal variants and abnormalities of the pediatric knee. The conditions discussed include, but are not limited to, distal femoral metaphysial irregularity, isolated popliteus tendon avulsion, juvenile idiopathic arthritis, and discoid meniscus. CONCLUSION The knee is the joint that is most commonly imaged by MRI in children. Injury patterns and signs of other pathologic processes seen in skeletally immature patients are different from those seen in adults. Interpreting pediatric knee MRI studies may be a challenge for those unfamiliar with the evolving patterns of normal development and of the signs of conditions that are more prevalent in children. Through case scenarios, this article describes and provides images that depict conditions commonly encountered in the pediatric knee. Most of the described normal findings and abnormalities are more prevalent in the pediatric population than in adults, and a few of the conditions are, in fact, unique to pediatric patients.

Oculoauriculofrontonasal syndrome: case series revealing new bony nasal anomalies in an old syndrome.

Frontonasal Dysplasia (FND) and Oculo‐auriculo‐vertebral spectrum (OAVS) are two well‐recognized clinical entities. With features of both FND and OAVS, the term oculoauriculofrontonasal syndrome (OAFNS) was coined in 1981. The OAFNS phenotype combines elements of abnormal morphogenesis of the frontonasal and maxillary process (derived from forebrain neural crest) with abnormal development of the first and second branchial arches (derived from hindbrain neural crest). We present a case series of 33 children with OAFNS ascertained from a comprehensive review of the literature and report an additional retrospective series of eight patients displaying features consistent with OAFNS. Notably, in a subset of our cases, we have observed abnormalities in nasal ossification and bony structures of the maxilla that have not previously described in OAFNS and are not seen in either FND or OAVS. We present the phenotype and novel naso‐maxillary findings and explore potential etiologic and developmental pathways for OAFNS. We highlight the differences in phenotypic characteristics of OAFNS compared to OAVS and FND. These observations support the classification of OAFNS as a discrete syndrome. Further phenotypic refinements of OAFNS are needed to understand pathogenesis of this syndrome and the newly described nasal malformation may help identify the etiology.