Advantages of CT Versus MRI for Preoperative Assessment of Osteochondritis Dissecans of the Capitellum.

BACKGROUND: Magnetic resonance imaging (MRI) is considered to be the gold standard for imaging of osteochondritis dissecans (OCD). PURPOSE/HYPOTHESIS: The purpose was to determine the additional value of a preoperative computed tomography (CT) scan in adolescent patients with capitellar OCD of the elbow. Consistent with the fact that OCD is a lesion involving the subchondral bone, the hypothesis was that CT would be superior to MRI for imaging OCD of the capitellum. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: All patients being treated surgically for an OCD of the capitellum between 2006 and 2016 at one institution were reviewed for preoperative imaging. A total of 28 patients met the inclusion criteria. Corresponding MRI and CT scans were compared retrospectively. Multiple parameters were recorded, with special emphasis on OCD lesion size, fragmentation, and tilt as well as joint surface integrity, loose bodies, and osteophytes. RESULTS: The OCD lesions were best seen on CT scans, whereas MRI T1-weighted images overestimated and T2-weighted images underestimated the size of defects. A subchondral fracture nonunion was found on CT scans in 18 patients, whereas this was seen on MRI T1-weighted images in only 2 patients (P < .001) and MRI T2-weighted images in 4 patients (P < .001). Fragmentation of the OCD fragment was found on CT scans in 17 patients but on MRI scans in only 9 patients (P = .05). Osteophytes as a sign of secondary degenerative changes were seen on CT scans in 24 patients and were seen on MRI scans in 15 patients (P = .02). Altogether, only 51 of 89 secondary changes including loose bodies, effects on the radial head and ulnohumeral joint, and osteophytes that were seen on CT scans were also seen on MRI scans (P = .002). CONCLUSION: OCD fragmentation and secondary changes were more often diagnosed on CT. These factors indicate OCD instability or advanced OCD stages, which are indications for surgery. In an adolescent who is considered at risk for OCD (baseball, gymnastics, weightlifting, tennis) and who has lateral elbow joint pain with axial or valgus load bearing, CT is our imaging modality of choice for diagnosing and staging OCD of the capitellum.

An app-enhanced cognitive fitness training program for athletes: The rationale and validation protocol.

The core dimensions of cognitive fitness, such as attention and cognitive control, are emerging through a transdisciplinary expert consensus on what has been termed the Cognitive Fitness Framework (CF2). These dimensions represent key drivers of cognitive performance under pressure across many occupations, from first responders to sport, performing arts and the military. The constructs forming the building blocks of CF2 come from the RDoC framework, an initiative of the US National Institute of Mental Health (NIMH) aimed at identifying the cognitive processes underlying normal and abnormal behavior. Similar to physical conditioning, cognitive fitness can be improved with deliberate practice. This paper reports the development of a prototype cognitive fitness training program for competitive athletes and the protocol for its evaluation. The program is focused on primary cognitive capacities and subtending skills for adjusting training rhythms and enhancing readiness for competition. The project is driven by the Australian Psychological Society's College of Sport & Exercise Psychology and includes the development of a Cognitive Gym program for a smartphone app-enhanced implementation. Its key building blocks are training protocols (drills) connected by a periodized training plan. A website with background supporting resources has also been developed as part of the project. National-level training squads will participate in a three-week pilot evaluation protocol, assessing the program's efficacy and usability through gamified cognitive assessment of participants' training gains and coaching staff evaluations, respectively. Both near and far transfer of training effects will be examined.

Building a transdisciplinary expert consensus on the cognitive drivers of performance under pressure: An international multi-panel Delphi study.

Introduction: The ability to perform optimally under pressure is critical across many occupations, including the military, first responders, and competitive sport. Despite recognition that such performance depends on a range of cognitive factors, how common these factors are across performance domains remains unclear. The current study sought to integrate existing knowledge in the performance field in the form of a transdisciplinary expert consensus on the cognitive mechanisms that underlie performance under pressure. Methods: International experts were recruited from four performance domains [(i) Defense; (ii) Competitive Sport; (iii) Civilian High-stakes; and (iv) Performance Neuroscience]. Experts rated constructs from the Research Domain Criteria (RDoC) framework (and several expert-suggested constructs) across successive rounds, until all constructs reached consensus for inclusion or were eliminated. Finally, included constructs were ranked for their relative importance. Results: Sixty-eight experts completed the first Delphi round, with 94% of experts retained by the end of the Delphi process. The following 10 constructs reached consensus across all four panels (in order of overall ranking): (1) Attention; (2) Cognitive Control-Performance Monitoring; (3) Arousal and Regulatory Systems-Arousal; (4) Cognitive Control-Goal Selection, Updating, Representation, and Maintenance; (5) Cognitive Control-Response Selection and Inhibition/Suppression; (6) Working memory-Flexible Updating; (7) Working memory-Active Maintenance; (8) Perception and Understanding of Self-Self-knowledge; (9) Working memory-Interference Control, and (10) Expert-suggested-Shifting. Discussion: Our results identify a set of transdisciplinary neuroscience-informed constructs, validated through expert consensus. This expert consensus is critical to standardizing cognitive assessment and informing mechanism-targeted interventions in the broader field of human performance optimization.

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra-Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma. METHODS: Two p53 wild-type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host. RESULTS: The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death. CONCLUSION: This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.

Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients.

Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV+ CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV+ CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV+ CTCs nor MycN amplification. Of note, the low number of CSV+ CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV+ CTCs (every 6 mL) are present in the blood samples compared to >3 CSV+ CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV+ CTC data in any study in a long-term longitudinal manner.

Maintenance DFMO Increases Survival in High Risk Neuroblastoma.

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

Molecular Guided Therapy Provides Sustained Clinical Response in Refractory Choroid Plexus Carcinoma.

Choroid plexus carcinomas (CPCs) are rare, aggressive pediatric brain tumors with no established curative therapy for relapsed disease, and poor survival rates. TP53 Mutation or dysfunction correlates with poor or no survival outcome in CPCs. Here, we report the case of a 4 month-old female who presented with disseminated CPC. After initial response to tumor resection and adjuvant-chemotherapy, the tumor recurred and metastasized with no response to aggressive relapse therapy suggesting genetic predisposition. This patient was then enrolled to a Molecular Guided Therapy Clinical Trial. Genomic profiling of patient tumor and normal sample identified a TP53 germline mutation with loss of heterozygosity, somatic mutations including IDH2, and aberrant activation of biological pathways. The mutations were not targetable for therapy. However, targeting the altered biological pathways (mTOR, PDGFRB, FGF2, HDAC) guided identification of possibly beneficial treatment with a combination of sirolimus, thalidomide, sunitinib, and vorinostat. This therapy led to 92% reduction in tumor size with no serious adverse events, excellent quality of life and long term survival.

The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns.

T lymphocyte homeostatic proliferation, driven by the engagement of T cell antigen receptor with self-peptide/major histocompatibility complexes, and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by the Fas death receptor (Fas, CD95). In the absence of Fas, Fas-deficient lymphoproliferation spontaneous mutation (lpr) mice accumulate homeostatically expanded T cells. The functional consequences of sequential rounds of homeostatic expansion are not well defined. We thus examined the gene expression profiles of murine wild-type and Fas-deficient lpr CD8+ T cell subsets that have undergone different amounts of homeostatic proliferation as defined by their level of CD44 expression, and the CD4-CD8-TCRαß+ T cell subset that results from extensive homeostatic expansion of CD8+ T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as programmed cell death protein 1 (PD-1) and lymphocyte activating 3 (Lag3). These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed clinical paradox of simultaneous autoinflammatory and immunodeficiency syndromes and provide further insight into the regulatory programs that control chronically stimulated T cells.

Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis. Tolcapone also increased ROS while simultaneously decreasing ATP-per-cell in NB cells. Additionally, COMT was inhibited by siRNA in NB cells and showed similar increases in apoptotic markers compared to Tolcapone. In vivo xenograft models displayed inhibition of tumor growth and a significant decrease in time-to-event in mice treated with Tolcapone compared to untreated mice. These results indicate that Tolcapone is cytotoxic to neuroblastoma cells and invite further studies into Tolcapone as a promising novel therapy for the treatment of neuroblastoma.

Probing the activity of NTHL1 orthologs by targeting conserved amino acid residues.

The base excision repair DNA glycosylases, EcoNth and hNTHL1, are homologous, with reported overlapping yet different substrate specificities. The catalytic amino acid residues are known and are identical between the two enzymes although the exact structures of the substrate binding pockets remain to be determined. We sought to explore the sequence basis of substrate differences using a phylogeny-based design of site-directed mutations. Mutations were made for each enzyme in the vicinity of the active site and we examined these variants for glycosylase and lyase activity. Single turnover kinetics were done on a subgroup of these, comparing activity on two lesions, 5,6-dihydrouracil and 5,6-dihydrothymine, with different opposite bases. We report that wild type hNTHL1 and EcoNth are remarkably alike with respect to the specificity of the glycosylase reaction, and although hNTHL1 is a much slower enzyme than EcoNth, the tighter binding of hNTHL1 compensates, resulting in similar kcat/Kd values for both enzymes with each of the substrates tested. For the hNTHL1 variant Gln287Ala, the specificity for substrates positioned opposite G is lost, but not that of substrates positioned opposite A, suggesting a discrimination role for this residue. The EcoNth Thr121 residue influences enzyme binding to DNA, as binding is significantly reduced with the Thr121Ala variant. Finally, we present evidence that hNTHL1 Asp144, unlike the analogous EcoNth residue Asp44, may be involved in resolving the glycosylase transition state.

RAD51 variant proteins from human lung and kidney tumors exhibit DNA strand exchange defects.

In human cells, error-free repair of DNA double-strand breaks requires the DNA pairing and strand exchange activities of RAD51 recombinase. Activation of RAD51 recombination activities requires the assembly of RAD51 presynaptic filaments on the single-stranded DNA that forms at resected DSB ends. Mutations in proteins that control presynaptic filament assembly, such as BRCA2, and in RAD51 itself, are associated with human breast cancer. Here we describe the properties of two mutations in RAD51 protein that derive from human lung and kidney tumors, respectively. Sequence variants Q268P and Q272L both map to the DNA binding loop 2 (L2) region of RAD51, a motif that is involved in DNA binding and in the allosteric activation of ATP hydrolysis and DNA strand exchange activities. Both mutations alter the thermal stability, DNA binding, and ATPase properties of RAD51, however both variants retain intrinsic DNA strand exchange activity towards oligonucleotide substrates under optimized conditions. In contrast, both Q268P and Q272L variants exhibit drastically reduced DNA strand exchange activity in reaction mixtures containing long homologous ssDNA and dsDNA substrates and human RPA protein. Mixtures of wild-type and variant proteins also exhibit reduced DNA strand exchange activity, suggesting that heterozygous mutations could negatively affect DNA recombination and repair processes in vivo. Together, the findings of this study suggest that hypomorphic missense mutations in RAD51 protein could be drivers of genomic instability in cancer cells, and thereby contribute to the etiology of metastatic disease.

A simple method of measuring tibial tubercle to trochlear groove distance on MRI: description of a novel and reliable technique.

PURPOSE: Tibial tubercle-trochlear groove (TT-TG) distance is a variable that helps guide surgical decision-making in patients with patellar instability. The purpose of this study was to compare the accuracy and reliability of an MRI TT-TG measuring technique using a simple external alignment method to a previously validated gold standard technique that requires advanced software read by radiologists. METHODS: TT-TG was calculated by MRI on 59 knees with a clinical diagnosis of patellar instability in a blinded and randomized fashion by two musculoskeletal radiologists using advanced software and by two orthopaedists using the study technique which utilizes measurements taken on a simple electronic imaging platform. Interrater reliability between the two radiologists and the two orthopaedists and intermethods reliability between the two techniques were calculated using interclass correlation coefficients (ICC) and concordance correlation coefficients (CCC). ICC and CCC values greater than 0.75 were considered to represent excellent agreement. RESULTS: The mean TT-TG distance was 14.7 mm (Standard Deviation (SD) 4.87 mm) and 15.4 mm (SD 5.41) as measured by the radiologists and orthopaedists, respectively. Excellent interobserver agreement was noted between the radiologists (ICC 0.941; CCC 0.941), the orthopaedists (ICC 0.978; CCC 0.976), and the two techniques (ICC 0.941; CCC 0.933). CONCLUSION: The simple TT-TG distance measurement technique analysed in this study resulted in excellent agreement and reliability as compared to the gold standard technique. This method can predictably be performed by orthopaedic surgeons without advanced radiologic software. LEVEL OF EVIDENCE: II.

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. METHODS AND FINDINGS: Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). CONCLUSIONS: DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. TRIAL REGISTRATION: Clinicaltrials.gov NCT#01059071.

Variability of the Ischiofemoral Space Relative to Femur Position: An Ultrasound Study.

BACKGROUND: Ischiofemoral impingement is caused by compression of the quadratus femoris muscle between the ischial tuberosity and lesser trochanter. The evaluation of ischiofemoral impingement includes radiologic studies to evaluate the ischiofemoral space dimensions. No prior study has evaluated the effect of femoral position on ischiofemoral space dimensions. OBJECTIVE: To determine whether the dimensions of the ischiofemoral space vary with changes in femoral position. DESIGN: Cross-sectional study. SETTING: Academic institution. PARTICIPANTS: Six male and four female subjects with no hip pain and no history of hip disorders or surgery were selected to participate in the study. The subjects' mean age was 31.5 years; mean height, 176.8 cm; mean weight, 70.2 kg; and mean body mass index, 23.6 kg/m(2). METHODS: Ultrasound was used to measure the ischiofemoral space in bilateral gluteal regions of each volunteer. The volunteers underwent imaging in a prone position. The ischiofemoral space was measured with the femur in 9 different positions created through various combinations of frontal (15° abduction, neutral, and 15° adduction) and transverse (30° internal rotation, neutral, and 30° external rotation) plane hip motions. MAIN OUTCOME MEASUREMENTS: The narrowest ischiofemoral interval, defined as the narrowest distance between the medial cortex of the lesser trochanter and the lateral cortex of the ischial tuberosity. RESULTS: The anatomic landmarks used to measure the ischiofemoral space were easily identified in all subjects. The frontal plane main effect (F2,18 = 38.611) was statistically significant (P < .001), as was the transverse plane main effect (F2,18 = 82.452, P < .001). These findings indicated that there was a statistically significant difference in ischiofemoral space according to hip position in the frontal and transverse planes. The largest ischiofemoral space measurement occurred with the hip in abduction and internal rotation (51.8 mm; 95% confidence interval [CI], 49.2-54.5 mm), whereas hip adduction and external rotation resulted in the narrowest ischiofemoral space measurement (30.8 mm; 95% CI, 25.5-36.0 mm). The largest difference was between the adduction-external rotation and the abduction-internal rotation positions (mean difference = 21.1 mm; 95% CI, 13.7-28.5 mm; P < .001), and the smallest difference was between the adducted-neutral rotation and the abducted-external rotation positions (mean difference = 0.23 mm; 95% CI, -8.07-8.55 mm; P = .99). CONCLUSIONS: Femoral position affects ischiofemoral space dimensions. The ischiofemoral space widens with abduction and internal rotation and narrows with adduction and external rotation, and thus femoral position should be considered when imaging and measuring the ischiofemoral space.

Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma.

The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.

Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma.

LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.

Posttraumatic fat necrosis presenting as prepatellar loose bodies in an adolescent football player.

A 16-year-old high school football player presented with 4 months of anterior knee pain and small, mobile, prepatellar "lumps" after falling onto an opponent's cleat. He reported knee pain primarily during knee flexion and direct pressure during squatting and kneeling. Knee radiographs were unremarkable. Ultrasonography revealed multiple, freely mobile, subcutaneous nodules of variable size and echogenicity in the prepatellar region. Analysis of magnetic resonance imaging suggested possible fat necrosis but was nondiagnostic. The patient opted for surgical exploration, at which time multiple, opalescent subcutaneous nodules were removed. Pathology was consistent with encapsulated fat necrosis. After surgery, his symptoms resolved, and he returned to sports without restrictions.