Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is ...known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.
Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).
A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.
These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.
Pilocytic astrocytomas (PA) are a common, benign childhood tumor known for their slow growth rates and excellent prognosis. The aim of our study was to characterize patient, tumor, and ...imaging-related risk factors for recurrence and progression of disease.
We identified 116 patients with PA who underwent surgery at our institution between 2000 and 2015. Data were collected retrospectively from the clinical charts.
The mean age at resection was 7 ± 5 years (range 0.5-31) and mean follow-up was 6 ± 3 years. Initial resection was complete in 33 patients (29%), subtotal in 78 patients (67%), and biopsy in 5 patients (4%). A total of 45/116 (40%) patients experienced either recurrence or progression after initial resection with a mean time to recurrence or progression of 2.2 years. Bivariate analysis identified subtotal resection, tumor location, age at diagnosis, and imaging features (i.e., T2 invasion, exophytic component, hemorrhage, and solid tumors) as factors significantly associated with recurrence or progression (p < 0.05). Conversely, PAs that were completely resected, predominately cystic, and located in the cerebellum were significantly associated with no recurrence or progression (p < 0.05). Multivariate regression analysis narrowed down 4 robust risk factors: extent of resection, T2 invasion, predominantly solid lesions, and presence of an exophytic component (p < 0.05).
Total surgical removal of PA has been the most important prognostic factor for the clinical course of PA. Our study reveals additional risk factors for the recurrence or progression of disease: tumor invasion, solid composition, and tumors with an exophytic component.
Intracranial germ-cell tumors (GCTs) are a heterogeneous group of tumors that vary in their response to treatment. Standard treatment consists of chemotherapy and radiation therapy, with the ...consideration of second-look surgery in resistant disease. The present study aims to inform therapy by characterizing features on pretreatment imaging associated with recurrence.
Children with intracranial GCTs treated at a single institution between January 2000 and October 2016 were retrospectively reviewed under an Institutional Review Board-approved protocol. Imaging variables identified on pretreatment imaging were calcifications, cysts, heterogeneity of enhancement, blood products, hydrocephalus, gradient echo susceptibility, restricted diffusion, invasiveness, and extent of edema. Tumor recurrence was used as the primary outcome variable.
Fifty-two patients (39 males, mean age at diagnosis: 13 ± 5 years, 34 germinoma, 18 nongerminomatous GCT NGGCT) were reviewed. Thirty-three percent of the patients reviewed had recurrence (7 germinoma, 11 NGGCT). Recurrence was associated with invasiveness as seen on preoperative imaging (p = 0.0385) and cystic tumor (p = 0.048).
OBJECT Even with improved prenatal and neonatal care, intraventricular hemorrhage (IVH) occurs in approximately 25%-30% of preterm infants, with a subset of these patients developing hydrocephalus. ...This study was undertaken to describe current trends in hospitalization of preterm infants with posthemorrhagic hydrocephalus (PHH) using the Nationwide Inpatient Sample (NIS) and the Kids' Inpatient Database (KID). METHODS The KID and NIS were combined to generate data for the years 2000-2010. All neonatal discharges with ICD-9-CM codes for preterm birth with IVH alone or with IVH and hydrocephalus were included. RESULTS There were 147,823 preterm neonates with IVH, and 9% of this group developed hydrocephalus during the same admission. Of patients with Grade 3 and 4 IVH, 25% and 28%, respectively, developed hydrocephalus in comparison with 1% and 4% of patients with Grade 1 and 2 IVH, respectively. Thirty-eight percent of patients with PHH had permanent ventricular shunts inserted. Mortality rates were 4%, 10%, 18%, and 40%, respectively, for Grade 1, 2, 3, and 4 IVH during initial hospitalization. Length of stay has been trending upward for both groups of IVH (49 days in 2000, 56 days in 2010) and PHH (59 days in 2000, 70 days in 2010). The average hospital cost per patient (adjusted for inflation) has also increased, from $201,578 to $353,554 (for IVH) and $260,077 to $495,697 (for PHH) over 11 years. CONCLUSIONS The number of neonates admitted with IVH has increased despite a decrease in the number of preterm births. Rates of hydrocephalus and mortality correlated closely with IVH grade. The incidence of hydrocephalus in preterm infants with IVH remained stable between 8% and 10%. Over an 11-year period, there was a progressive increase in hospital cost and length of stay for preterm neonates with IVH and PHH that may be explained by a concurrent increase in the proportion of patients with congenital cardiac anomalies.
The optimal timing of ventricular shunt placement in low-weight and preterm infants remains an unresolved topic in modern pediatric neurosurgery. Shunt placement for hydrocephalus is performed over a ...wide range of infant weights, and the standard weight threshold for shunt placement can vary substantially across institutions. The aim of this study was to investigate shunt outcome in infants of low body weight.
An IRB-approved retrospective analysis of 76 infants (29 females, 47 males) who received primary shunt placement between 2003 and 2018 was performed. Uniform criteria were used over the entire dataset to determine the safety for ventriculoperitoneal (VP) shunt placement: 1) weight near or above 1500 g, 2) feeding tolerance, and 3) lack of necrotizing enterocolitis or active systemic infection. Infants were classified into a low-weight (LW) (< 2000 g) or standard weight (SW) (2000-3000 g) group based on their body weight at the time of initial shunt placement. Shunt survival was compared between the groups. The threshold weight separating the LW and SW groups and outcomes was additionally varied and systematically reanalyzed.
Shunts were placed in 24 LW infants and 52 SW infants over the inclusion period. Etiologies for hydrocephalus were similar across groups: predominantly intraventricular hemorrhage (54%) (p = 0.13) and open neural tube defect (29%) (p = 0.61). Both LW and SW groups had 58% 1-year shunt survival rates. Overall, 46% of shunts failed in the LW group compared with 54% in the SW group over a median follow-up of 47 months (range 0-170 months). A log-rank test comparing shunt survival rates did not show significance (p = 0.43). Groups were repartitioned using a range of threshold weights (1600-2400 g) to divide LW from SW infants. The lack of association between VP shunt placement in LW infants and time frame of revision was consistently observed over the full range of varied threshold weights.
There was no significant difference in overall time to shunt revision between infants weighing < 2000 g and infants weighing 2000-3000 g. No correlation between weight and shunt survival was detected. Combined with other clinical features pertinent to the management of hydrocephalus in the neonatal population, this investigation provides insight toward clinical decision-making regarding infants of low birth weight and suggests that further multi-institutional study on this topic is warranted.
Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA ...sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.
Standard MRI protocols lack a quantitative sequence that can be used to evaluate shunt-treated patients with a history of hydrocephalus. The objective of this study was to investigate the use of ...phase-contrast MRI (PC-MRI), a quantitative MR sequence, to measure CSF flow through the shunt and demonstrate PC-MRI as a useful adjunct in the clinical monitoring of shunt-treated patients.
The rapid (96 seconds) PC-MRI sequence was calibrated using a flow phantom with known flow rates ranging from 0 to 24 mL/hr. Following phantom calibration, 21 patients were scanned with the PC-MRI sequence. Multiple, successive proximal and distal measurements were gathered in 5 patients to test for measurement error in different portions of the shunt system and to determine intrapatient CSF flow variability. The study also includes the first in vivo validations of PC-MRI for CSF shunt flow by comparing phase-contrast-measured flow rate with CSF accumulation in a collection burette obtained in patients with externalized distal shunts.
The PC-MRI sequence successfully measured CSF flow rates ranging from 6 to 54 mL/hr in 21 consecutive pediatric patients. Comparison of PC-MRI flow measurement and CSF volume collected in a bedside burette showed good agreement in a patient with an externalized distal shunt. Notably, the distal portion of the shunt demonstrated lower measurement error when compared with PC-MRI measurements acquired in the proximal catheter.
The PC-MRI sequence provided accurate and reliable clinical measurements of CSF flow in shunt-treated patients. This work provides the necessary framework to include PC-MRI as an immediate addition to the clinical setting in the noninvasive evaluation of shunt function and in future clinical investigations of CSF physiology.
Objective: Fontan surgical planning involves designing grafts to perform optimized hemodynamic performance for the patient's long-term health benefit. The uncertainty of post-operative boundary ...conditions (BC) and graft anastomosis displacements can significantly affect optimized graft designs and lead to undesirable outcomes, especially for hepatic flow distribution (HFD). We aim to develop a computation framework to automatically optimize patient-specific Fontan grafts with the maximized possibility of keeping post-operative results within clinical acceptable thresholds. Methods: The uncertainties of BC and anastomosis displacements were modeled using Gaussian distributions according to prior research studies. By parameterizing the Fontan grafts, we built surrogate models of hemodynamic parameters taking the design parameters and BC as input. A two-phase reliability-based robust optimization (RBRO) strategy was developed by combining deterministic optimization (DO) and optimization under uncertainty (OUU) to reduce computational cost. Results: We evaluated the performance of the RBRO framework by comparing it with the DO method in four cases of Fontan patients. The results showed that the surgical plans computed from the proposed method yield up to 79.2% improvement in the reliability of the HFD than those of the DO method (<inline-formula><tex-math notation="LaTeX">p< 0.0001</tex-math></inline-formula>). The mean values of indexed power loss (iPL) and the percentage of non-physiologic wall shear stress (%WSS) for the optimized surgical plans met the clinically acceptable thresholds. Conclusion: This study demonstrated the effectiveness of our RBRO framework to address the uncertainties of BC and anastomosis displacements for Fontan surgical planning. Significance: The technique developed in this paper demonstrates a significant improvement in the reliability of the predicted post-operative outcomes for Fontan surgical planning. This planning technique is immediately applicable as a building block to enable technology for optimal long-term outcomes for pediatric Fontan patients and can also be used in other pediatric and adult cardiac surgeries.
Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive ...treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination.
MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors.
Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve AUC = 0.88).
The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups.
PDF
