A Novel Sand Dollar and Staves Technique for Unilateral Lambdoid Craniosynostosis.

BACKGROUND: Unilateral lambdoid synostosis (ULS) is the rarest form of craniosynostosis. Due to the associated cranio-caudal shift seen in ULS, surgical correction is technically challenging from a morphological standpoint. Herein, the authors present a novel "Sand-Dollar and Staves" technique for the repair of ULS. METHODS: A zigzag coronal incision is performed, and an anteriorly-based pericranial flaps are elevated. Prefabricated cutting guides are placed and the calvarium is marked. To treat the flattening on the ipsilateral side, a wedged suturectomy is performed with additional barrel staves. A large circle centered over the bulging on the contralateral side is cut out above the open lambdoid suture. This piece is barrel staved in a radial fashion, leaving the center intact and creating a Sand-Dollar appearance. This disk is then flattened and trimmed. The modified Sand-Dollar is fixed using an absorbable plating system. While gentle pressure is applied to the Sand-Dollar piece as it is being secured, the ipsilateral side demonstrates compensatory filling. Results are evaluated using the Whitaker Classification. RESULTS: Four patients underwent surgical correction with this technique. The procedure was performed at mean age of 11.7 months. The mean operative time was 2.5 hours. Intraoperative blood loss was 50 to 100 ml. Total hospitalization time was 2 to 3 days. No post-operative complications were encountered. Whitaker scores ranged from 1 to 1.5. The mean follow-up was 10 months. CONCLUSION: The Sand-Dollar and Staves procedure is a novel, single-stage approach for the management of ULS with decreased operative time, blood loss, and hospital stay with satisfactory aesthetic outcomes.

Chicken or the Egg: A Case Report of Endoscopic-Assisted Treatment of Concomitant Sagittal Craniosynostosis With Calcified Cephalohematoma.

Nonsyndromic craniosynostosis results in premature fusion of cranial sutures and is rarely found in the context of other craniofacial abnormalities. Here the authors present the case of a 3-month-old male infant with a rare presentation of sagittal craniosynostosis and concomitant calcified cephalohematoma repaired by endoscopic-assisted sagittal strip craniectomy with good cosmetic and functional outcomes. The authors discuss the advantages of endoscopic repair of craniosynostosis when found in the presence of a cephalohematoma and the need for further research to investigate a possible causal relationship between these 2 pathologies.

Progression-free survival of children with localized ependymoma treated with intensity-modulated radiation therapy or proton-beam radiation therapy.

BACKGROUND: The treatment for childhood intracranial ependymoma includes maximal surgical resection followed by involved-field radiotherapy, commonly in the form of intensity-modulated radiation therapy (IMRT). Proton-beam radiation therapy (PRT) is used at some centers in an effort to decrease long-term toxicity. Although protons have the theoretical advantage of a minimal exit dose to the surrounding uninvolved brain tissue, it is unknown whether they have the same efficacy as photons in preventing local recurrence. METHODS: A retrospective review of medical records from September 2000 to April 2013 was performed. Seventy-nine children with newly diagnosed localized intracranial ependymomas treated with either IMRT (n = 38) or PRT (n = 41) were identified, and progression-free survival (PFS) was analyzed with Kaplan-Meier and Cox multivariate analyses. RESULTS: The median age at diagnosis was 3.7 years for all patients (range, 0.4-18.7 years). There were 54 patients with infratentorial tumors (68% of the total population). Patients treated with PRT were younger (median age, 2.5 vs 5.7 years; P = .001) and had a shorter median follow-up (2.6 vs 4.9 years; P < .0001). Gross total resection (GTR) was achieved in 67 patients (85%) and was more frequent in the PRT group versus the IMRT group (93% vs 76%; P = .043). The 3-year PFS rates were 60% and 82% with IMRT and PRT, respectively (P = .031). CONCLUSIONS: Children with localized ependymomas treated with PRT have a 3-year PFS rate comparable to that of children treated with IMRT. This analysis suggests that local control is not compromised by the use of PRT. The data also support GTR as the only prognostic factor for PFS. Cancer 2017;123:2570-78. © 2017 American Cancer Society.

Management of ruptured dissecting intracranial aneurysms in infants: report of four cases and review of the literature.

BACKGROUND: Intracranial cerebral aneurysms in the pediatric population are infrequent, and those occurring in infants less than 1 year old are extremely rare. Of intracranial aneurysms in children, dissecting aneurysms are the most common type seen. While spontaneous dissecting aneurysms usually present with ischemia, hemorrhage can also occur. METHODS: A retrospective review of our patients revealed that from July 1, 2007 to June 30, 2012, four infants were treated for ruptured distal dissecting intracranial aneurysms at Texas Children's Hospital. Mycotic aneurysms and collagen vascular disorder were excluded in all four cases. All patients presented in our series presented with subarachnoid hemorrhage, and three had intraventricular hemorrhage. All patients underwent conventional catheter angiography for diagnosis. All patients in this series were managed in the acute or subacute period with surgical or endovascular trapping without distal bypass procedures. All four patients tolerated sacrifice of the parent vessels feeding these distal aneurysms well. CASE REPORT AND REVIEW OF LITERATURE: We describe the presentation and management of these rare cases and then review the current literature on the management of these dissecting aneurysms in infants.

Socioeconomic and demographic factors in the diagnosis and treatment of Chiari malformation type I and syringomyelia.

OBJECTIVE: The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). METHODS: The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. RESULTS: A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). CONCLUSIONS: Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.

The variable position of the ear in lambdoid synostosis.

Isolated unilateral lambdoid craniosynostosis is often confused with posterior positional plagiocephaly because of a general overlap in their clinical presentations; however, distinction between these 2 entities is important because of the differences in appropriate management. Historical literature teaches that ear position is posterior in lambdoid synostosis, whereas it is anterior in positional plagiocephaly. Recently, several cases of anterior ear position in isolated unilateral lambdoid synostosis presented to the Texas Children's Hospital. A review of the cases and literature revealed that there are now 37 cases of unilateral lambdoid synostosis in the literature in which ipsilateral ear position is reported. Twelve cases (32%) had anteriorly displaced ears, 6 cases (16%) were nondisplaced, 7 cases (19%) were displaced posteriorly, 4 cases (11%) anteroinferiorly, 1 case (3%) inferiorly, and 7 cases (19%) posteroinferiorly. Based on this review, it seems that the diagnostic significance of the external ear position is unclear at this point.

Comparison of multimodal surgical and radiation treatment methods for pediatric craniopharyngioma: long-term analysis of progression-free survival and morbidity.

OBJECTIVE: The authors compared survival and multiple comorbidities in children diagnosed with craniopharyngioma who underwent gross-total resection (GTR) versus subtotal resection (STR) with radiation therapy (RT), either intensity-modulated radiation therapy (IMRT) or proton beam therapy (PBT). The authors hypothesized that there are differences between multimodal treatment methods with respect to morbidity and progression-free survival (PFS). METHODS: The medical records of children diagnosed with craniopharyngioma and treated surgically between February 1997 and December 2018 at Texas Children's Hospital were reviewed. Surgical treatment was stratified as GTR or STR + RT. RT was further stratified as PBT or IMRT; PBT was stratified as STR + PBT versus cyst decompression (CD) + PBT. The authors used Kaplan-Meier analysis to compare PFS and overall survival, and chi-square analysis to compare rates for hypopituitarism, vision loss, and hypothalamic obesity (HyOb). RESULTS: Sixty-three children were included in the analysis; 49% were female. The mean age was 8.16 years (95% CI 7.08-9.27). Twelve of 14 children in the IMRT cohort underwent CD. The 5-year PFS rates were as follows: 73% for GTR (n = 31), 54% for IMRT (n = 14), 100% for STR + PBT (n = 7), and 77% for CD + PBT (n = 11; p = 0.202). The overall survival rates were similar in all groups. Rates of hypopituitarism (96% GTR vs 75% IMRT vs 100% STR + PBT, 50% CD + PBT; p = 0.023) and diabetes insipidus (DI) (90% GTR vs 61% IMRT vs 85% STR + PBT, 20% CD + PBT; p = 0.004) were significantly higher in the GTR group. There was no significant difference in the HyOb or vision loss at the end of study follow-up among the different groups. Within the PBT group, 2 patients presented a progressive vasculopathy with subsequent strokes. One patient experienced a PBT-induced tumor. CONCLUSIONS: GTR and CD + PBT presented similar rates of 5-year PFS. Hypopituitarism and DI rates were higher with GTR, but the rate of HyOb was similar among different treatment modalities. PBT may reduce the burden of hypopituitarism and DI, although radiation carries a risk of potential serious complications, including progressive vasculopathy and secondary malignancy. Further prospective study comparing neurocognitive outcomes is necessary.

Occipital-Cervical Fusion and Ventral Decompression in the Surgical Management of Chiari-1 Malformation and Syringomyelia: Analysis of Data From the Park-Reeves Syringomyelia Research Consortium.

BACKGROUND: Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology. OBJECTIVE: To examine factors influencing the use of OCF and OCF/VD in a multicenter cohort of pediatric CM-1 and SM subjects treated with PFD. METHODS: The Park-Reeves Syringomyelia Research Consortium registry was used to examine 637 subjects with cerebellar tonsillar ectopia ≥ 5 mm, syrinx diameter ≥ 3 mm, and at least 1 yr of follow-up after their index PFD. Comparisons were made between subjects who received PFD alone and those with PFD + OCF or PFD + OCF/VD. RESULTS: All 637 patients underwent PFD, 505 (79.2%) with and 132 (20.8%) without duraplasty. A total of 12 subjects went on to have OCF at some point in their management (PFD + OCF), whereas 4 had OCF and VD (PFD + OCF/VD). Of those with complete data, a history of platybasia (3/10, P = .011), Klippel-Feil (2/10, P = .015), and basilar invagination (3/12, P < .001) were increased within the OCF group, whereas only basilar invagination (1/4, P < .001) was increased in the OCF/VD group. Clivo-axial angle (CXA) was significantly lower for both OCF (128.8 ± 15.3°, P = .008) and OCF/VD (115.0 ± 11.6°, P = .025) groups when compared to PFD-only group (145.3 ± 12.7°). pB-C2 did not differ among groups. CONCLUSION: Although PFD alone is adequate for treating the vast majority of CM-1/SM patients, OCF or OCF/VD may be occasionally utilized. Cranial base and spine pathologies and CXA may provide insight into the need for OCF and/or OCF/VD.

The high risks of ventriculoperitoneal shunt procedures for hydrocephalus associated with vein of Galen malformations in childhood: case report and literature review.

Little to no pediatric or neurosurgical literature has been published about the complications of ventriculoperitoneal shunt procedures for hydrocephalus associated with vein of Galen malformations in childhood. The interventional neuroradiology literature, however, suggests that ventriculoperitoneal shunting as first-line treatment for hydrocephalus in children with vein of Galen malformations is fraught with short- and long-term dangers, including status epilepticus, intraventricular hemorrhage, subdural hematoma and hygroma, venous infarction, malignant dystrophic calcification, and worsening developmental delay. We present a single pediatric case where a ventriculoperitoneal shunt procedure for symptomatic hydrocephalus seemed to be the major contributing factor to the rapid neurological deterioration and eventual death of an infant with a vein of Galen malformation. Based on this experience and our review of the literature, we suggest the use of endovascular embolization of the vein of Galen malformation to reestablish a balance in hydrovenous dynamics as first-line treatment rather than directly addressing hydrocephalus with CSF diversion. The ventriculoperitoneal shunt procedure should be reserved for cases with symptomatic hydrocephalus in which the patient is a poor candidate for embolization, or for cases where endovascular therapy has already been maximized. The role of endoscopy in the treatment of hydrocephalus associated with vein of Galen malformations is not clear.

Superior Intellectual Outcomes After Proton Radiotherapy Compared With Photon Radiotherapy for Pediatric Medulloblastoma.

PURPOSE: Proton radiotherapy (PRT) may lessen the neuropsychological risk traditionally associated with cranial radiotherapy for the treatment of pediatric brain tumors by reducing the dose to normal tissue compared with that of photon radiotherapy (XRT). We examined the change in intellectual scores over time in patients with pediatric medulloblastoma treated with craniospinal PRT versus XRT. METHODS: Intelligence test scores were obtained for a sample of pediatric patients treated between 2007 and 2018 on the same medulloblastoma protocols that differed only in radiotherapy modality (PRT v XRT). Growth curve analyses compared change in scores over time since diagnosis between groups. RESULTS: Longitudinal intelligence data from 79 patients (37 PRT, 42 XRT) were examined. Groups were similar on most demographic/clinical variables, including sex (67.1% male), age at diagnosis (mean, 8.6 years), craniospinal irradiation dose (median, 23.4 Gy), length of follow-up (mean, 4.3 years), and parental education (mean, 14.3 years). Boost dose (P < .001) and boost margin (P = .001) differed between groups. Adjusting for covariates, the PRT group exhibited superior long-term outcomes in global intelligence quotient (IQ), perceptual reasoning, and working memory compared with the XRT group (all P < .05). The XRT group exhibited a significant decline in global IQ, working memory, and processing speed (all P < .05). The PRT group exhibited stable scores over time in all domains with the exception of processing speed (P = .003). CONCLUSION: To our knowledge, this is the first study to compare intellectual trajectories between pediatric patients treated for medulloblastoma with PRT versus those treated with XRT on comparable, contemporary protocols. PRT was associated with more favorable intellectual outcomes in most domains compared with XRT, although processing speed emerged as a vulnerable domain for both groups. This study provides the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.

Direct orthotopic transplantation of fresh surgical specimen preserves CD133+ tumor cells in clinically relevant mouse models of medulloblastoma and glioma.

Recent identification of cancer stem cells in medulloblastoma (MB) and high-grade glioma has stimulated an urgent need for animal models that will not only replicate the biology of these tumors, but also preserve their cancer stem cell pool. We hypothesize that direct injection of fresh surgical specimen of MB and high-grade glioma tissues into anatomically equivalent locations in immune-deficient mouse brains will facilitate the formation of clinically accurate xenograft tumors by allowing brain tumor stem cells, together with their non-stem tumor and stromal cells, to grow in a microenvironment that is the closest to human brains. Eight of the 14 MBs (57.1%) and two of the three high-grade gliomas (66.7%) in this study developed transplantable (up to 12 passages) xenografts in mouse cerebellum and cerebrum, respectively. These xenografts are patient specific, replicating the histopathologic, immunophenotypic, invasive/metastatic, and major genetic (analyzed with 10K single nucleotide polymorphism array) abnormalities of the original tumors. The xenograft tumor cells have also been successfully cryopreserved for long-term preservation of tumorigenicity, ensuring a sustained supply of the animal models. More importantly, the CD133(+) tumor cells, ranging from 0.2%-10.4%, were preserved in all the xenograft models following repeated orthotopic subtransplantations in vivo. The isolated CD133(+) tumor cells formed neurospheres and displayed multi-lineage differentiation capabilities in vitro. In summary, our study demonstrates that direct orthotopic transplantation of fresh primary tumor cells is a powerful approach in developing novel clinical relevant animal models that can reliably preserve CD133(+) tumor cell pools even during serial in vivo subtransplantations. Disclosure of potential conflicts of interest is found at the end of this article.

Primary disseminated intradural malignant peripheral nerve sheath tumor of the spine in a child: case report and review of the literature.

The authors report a rare case of primary disseminated intradural malignant peripheral nerve sheath tumor (MPNST) of the spine in a 5-year-old child without neurofibromatosis type I (NF-I). This child presented with abdominal pain and gait disturbance. MRI revealed a large intradural extramedullary tumor at C4-5 with dissemination to the thoracic spine, cauda equina and leptomeninges. Following a 2-level cervical laminectomy, the tumor was biopsied and debulked. Based on pathological and immunohistological findings, the tumor was diagnosed as an MPNST. Because of the rarity of this pathological entity, a review of the literature was performed. The reported clinical outcomes for adult and pediatric patients with intradural MPNST are very poor. No established standard for the treatment of these tumors exists. We report the first pediatric case--without or with NF-I--of disseminated intradural MPNST primarily localized proximal to the conus medullaris. It must always be considered in the differential diagnosis for intradural extramedullary tumors of the pediatric spine, along with neurofibromas and schwannomas, even in children without NF-I.

Nonsyndromic Craniosynostosis.

Nonsyndromic craniosynostosis is significantly more common than syndromic craniosynostosis, affecting the sagittal, coronal, metopic, and lambdoid sutures in decreasing order of frequency. Nonsyndromic craniosynostosis is most frequently associated with only 1 fused suture, creating a predictable head shape. Repair of craniosynostosis is recommended to avoid potential neurodevelopmental delay. Early intervention at 3 to 4 months of age allows minimally invasive approaches, but requires postoperative molding helmet therapy and good family compliance. Open techniques are deferred until the child is older to better tolerate the associated surgical stress. Cranial vault remodeling is generally well-tolerated with a low rate of complications.

Increased risk of pseudoprogression among pediatric low-grade glioma patients treated with proton versus photon radiotherapy.

BACKGROUND: Pseudoprogression (PsP) is a recognized phenomenon after radiotherapy (RT) for high-grade glioma but is poorly characterized for low-grade glioma (LGG). We sought to characterize PsP for pediatric LGG patients treated with RT, with particular focus on the role of RT modality using photon-based intensity-modulated RT (IMRT) or proton beam therapy (PBT). METHODS: Serial MRI scans from 83 pediatric LGG patients managed at 2 institutions between 1998 and 2017 were evaluated. PsP was scored when a progressive lesion subsequently decreased or stabilized for at least a year without therapy. RESULTS: Thirty-two patients (39%) were treated with IMRT, and 51 (61%) were treated with PBT. Median RT dose for the cohort was 50.4 Gy(RBE) (range, 45-59.4 Gy[RBE]). PsP was identified in 31 patients (37%), including 8/32 IMRT patients (25%) and 23/51 PBT patients (45%). PBT patients were significantly more likely to have post-RT enlargement (hazard ratio [HR] 2.15, 95% CI: 1.06-4.38, P = 0.048). RT dose >50.4 Gy(RBE) similarly predicted higher rates of PsP (HR 2.61, 95% CI: 1.20-5.68, P = 0.016). Multivariable analysis confirmed the independent effects of RT modality (P = 0.03) and RT dose (P = 0.01) on PsP incidence. Local progression occurred in 10 patients: 7 IMRT patients (22%) and 3 PBT patients (6%), with a trend toward improved local control for PBT patients (HR 0.34, 95% CI: 0.10-1.18, P = 0.099). CONCLUSIONS: These data highlight substantial rates of PsP among pediatric LGG patients, particularly those treated with PBT. PsP should be considered when assessing response to RT in LGG patients within the first year after RT.

Genome-wide allelic imbalance analysis of pediatric gliomas by single nucleotide polymorphic allele array.

Using single nucleotide polymorphic (SNP) allele arrays, we analyzed 28 pediatric gliomas consisting of 14 high-grade gliomas and 14 low-grade gliomas. Most of the low-grade gliomas had no detectable loss of heterozygosity (LOH) in any of the 11,562 SNP loci; exceptions were two gangliogliomas (3q and 9p), one astrocytoma (6q), and two subependymal giant cell astrocytomas (16p and 21q). On the other hand, all high-grade gliomas had various degrees of LOH affecting 52 to 2,168 SNP loci on various chromosomes. LOH occurred most frequently in regions located at 4q (54%), 6q (46%), 9p (38%), 10q (38%), 11p (38%), 12 (38%), 13q (69%), 14q (54%), 17 (38%), 18p (46%), and 19q (38%). We also detected amplifications of epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRalpha) in a few of the 13 cases of glioblastoma multiforme analyzed. Interestingly, the amplified EGFR and PDGFRalpha were located within regions of LOH. SNP loci with LOH and copy number changes were validated by sequencing and quantitative PCR, respectively. Our results indicate that, in some pediatric glioblastoma multiforme, one allele each of EGFR and PDGFRalpha was lost but the remaining allele was amplified. This may represent a new molecular mechanism underlying tumor progression.

Indirect revascularization with the dural inversion technique for pediatric moyamoya disease: 20-year experience.

OBJECTIVENumerous surgical procedures facilitate revascularization of the ischemic brain in patients with moyamoya disease. Dural inversion is a technique in which flaps of dura mater centered around the middle meningeal artery are inverted, encouraging the formation of a rich collateral blood supply. This procedure has been used in combination with encephaloduroarteriosynangiosis for more than 20 years at the authors' institution for the treatment of pediatric moyamoya disease. The objective of this study was to describe the clinical and radiographic outcomes for a cohort of consecutive pediatric moyamoya patients undergoing dural inversion.METHODSClinical and radiographic data on patients who had undergone dural inversion in the period from 1997 to 2016 were reviewed. Univariate and multivariate logistic regression and Kaplan-Meier analyses were performed to assess the risk of postoperative stroke, functional outcome, and the angiographic degree of revascularization.RESULTSDural inversion was performed on 169 hemispheres in 102 patients. Median follow-up was 4.3 years. Six patients (3.6% of hemispheres) suffered postoperative ischemic or hemorrhagic stroke. Overall mortality was 1.0%. Good postoperative neurological status (modified Rankin Scale [mRS] score ≤ 2) was observed in 90 patients (88%); preoperative and postoperative mRS scores showed significant improvement (p < 0.001). Eighty-six percent of hemispheres had Matsushima grade A or B revascularization. Younger age was associated with postoperative stroke and poor functional outcome. Patients with secondary moyamoya syndrome had a significantly worse radiographic outcome. The cumulative 5-year Kaplan-Meier risk for stroke was 6.4%.CONCLUSIONSDural inversion is a useful technique of cerebral revascularization in pediatric moyamoya disease. A 20-year experience demonstrates the safety and efficacy of this technique with a relatively low rate of postoperative stroke, good functional outcomes, and favorable angiographic results.

Cytomorphologic characteristics, differential diagnosis and utility during intraoperative consultation for medulloblastoma.

OBJECTIVE: To study the cytologic findings that differentiate LC/A and non-LC/A (NLCA) types. STUDY DESIGN: Cytologic smears, prepared during intraoperative consultation (IOC) of 43 cases of pure histologic type, defined as > 80% of the tumor being composed of 1 of 3 major histologic types--classic, nodular and LC/A--were reviewed and graded semiquantitatively (0-3+) for 14 cytologic features: cellularity, nuclear streaming, endothelial proliferation, necrosis, lymphoglandular bodies, rosette formation, apoptosis, nuclear cannibalism, pleomorphism, macronucleoli, paranuclear inclusions, cytoplasmic vacuoles, mitoses and multinucleation. The grades were compared between the 2 histologic groups, LC/A vs. NLCA, as well as between the preparation methods, squash vs. touch (TP). Values of p < 0.05 were accepted as statistically significant. RESULTS: "Cell wrapping" (cannibalism), pleomorphism, macronucleoli, apoptosis, mitoses and cytoplasmic vacuoles were more significantly observed in LC/A than in NLCA. CONCLUSION: Intraoperative cytologic evaluation of these cytologic parameters allows distinction between LC/A and NLCA, which can be prognostically useful during IOC. Rosette formation, the histologic hallmark of classic medulloblastoma, is not a discriminator. Given the fewer artifacts and sufficient cellularity, TP is the preferred method of cytologic preparation.

Long-term disease control and toxicity outcomes following surgery and intensity modulated radiation therapy (IMRT) in pediatric craniopharyngioma.

PURPOSE: To report long-term progression-free survival (PFS) and late-toxicity outcomes in pediatric craniopharyngioma patients treated with IMRT. PATIENTS AND METHODS: Twenty-four children were treated with IMRT to a median dose of 50.4Gy (range, 49.8-54Gy). The clinical target volume (CTV) was the gross tumor volume (GTV) with a 1cm margin. The planning target volume (PTV) was the CTV with a 3-5mm margin. Median follow-up was 107.3months. RESULTS: The 5- and 10-year PFS rates were 65.8% and 60.7%. The 5- and 10-year cystic PFS rates were 70.2% and 65.2% while the 5- and 10-year solid PFS were the same at 90.7%. Endocrinopathy was seen in 42% at initial diagnosis and in 74% after surgical intervention, prior to IMRT. Hypothalamic dysfunction and visual deficits were associated with increasing PTV and number of surgical interventions. CONCLUSIONS: IMRT is a viable treatment option for pediatric craniopharyngioma. Despite the use of IMRT, majority of the craniopharyngioma patients experienced long-term toxicity, many of which present prior to radiotherapy. Limitations of retrospective analyses on small patient cohort elicit the need for a prospective multi-institutional study to determine the absolute benefit of IMRT in pediatric craniopharyngioma.

Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.

Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.