Cerebellar Medulloblastoma Research Articles

The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma.

Cerebellar granule cells precursors are derived from the upper rhombic lip and migrate tangentially independent of glia along the subpial stream pathway to form the external germinal zone. Postnatally, granule cells migrate from the external germinal zone radially through the Purkinje cell layer, guided by Bergmann glia fibers, to the internal granular cell layer.Medulloblastomas (MBs) are the most common malignant childhood brain tumor. Many of these tumors develop from precursor cells of the embryonic rhombic lips. Four main groups of MB are recognized. The WNT group of MBs arise primarily from the lower rhombic lip and embryonic brainstem. The SHH group of MBs originate from cerebellar granule cell precursors in the external germinal zone of the embryonic cerebellum. The cellular origins of type 3 and type 4 MBs are not clear.Several ubiquitin ligases are revealed to be significant factors in development of the cerebellum as well as in the initiation and maintenance of MBs. Proteasome dysfunction at a critical stage of development may be a major factor in determining whether progenitor cells which are destined to become granule cells differentiate normally or become MB cells. We propose the hypothesis that proteasomal activity is essential to regulate the critical transition between proliferating granule cells and differentiated granule cells and that proteasome dysfunction may lead to MB. Proteasome dysfunction could also account for various mutations in MBs resulting from deficiencies in DNA checkpoint and repair mechanisms prior to development of MBs.Data showing a role for the ubiquitin ligases β-TrCP, FBW7, Huwe1, and SKP2 in MBs suggest the possibility of a classification of MBs based on the expression (over expression or under expression) of specific ubiquitin ligases which function as oncogenes, tumor suppressors or cell cycle regulators.

Expression levels of vascular endothelial cell growth factor and microRNA-210 are increased in medulloblastoma and metastatic medulloblastoma.

The present study aimed to investigate the roles of the vascular endothelial cell growth factor (VEGF) and micro (mi)RNA-210 in the metastasis of primary medulloblastoma (MB) tumors. A total of 86 adult patients diagnosed with cerebellar MB were enrolled in the present study, of which 11 patients had metastatic MB in the subarachnoid space. The following samples were collected: MB primary tumor tissue, MB secondary tumor tissue, tumor adjacent tissues and cerebrospinal fluid (CSF). Immunohistochemical analyses of the tissue samples were conducted in order to detect patterns of VEGF expression. In addition, the expression levels of VEGF mRNA and miRNA-210 were analyzed using reverse transcription-quantititative polymerase chain reaction, and western blot analyses were used to investigate VEGF protein expression levels. The positive expression rate of VEGF was significantly higher in MB tumor tissue, as compared with adjacent tissues (P<0.01). In addition, VEGF mRNA and protein expression levels in MB primary and secondary tumor tissues, and in the CSF of patients with metastatic MB, were significantly upregulated, as compared with tumor adjacent tissues and the CSF of patients with non-metastatic MB, respectively (P<0.01). miRNA-210 expression levels were significantly upregulated in MB tumor tissues, the CSF of patients with metastatic MB and in tumor tissues of metastatic MB (P<0.01). In the present study, the expression levels of VEGF and miRNA-210 were upregulated in patients with MB and metastatic MB; thus suggesting that miRNA-210 may promote the metastasis of MB primary tumors by regulating the expression of VEGF.

Cerebellar medulloblastomas in children (age-related aspect)

Introduction. Cerebellar medulloblastomas are high-malignant embryonic brain tumours, which are diagnosed mainly in children and characterized by early dissemination of tumors. According to the data of literature there are some features of course and results of treatment of medulloblastomas depending on age of child.Materials and methods. The analysis of 653 supervisions of cerebellar medulloblastoma is conducted. The peaks of formation of tumours are educed in 4 years old (84 supervisions) and 7 years old (74 supervisions). All patients were operated, the diagnosis of medulloblastoma was verified histologically.Results. A total resection of tumour was executed at 36.8% of patients, subtotal — at 52%, partial — at 11.2%. At 166 (25.4%) patients resection of tumours was complemented by the shunt operations. During 30 days after resection 49 (7.5%) patients died. A catamnesis was estimated in 488 (74.7%) children in terms from one month to 10 years. Median of survivability was 18 months. Two-year survivability is established in 42.0%, five-year in 6.0%.Conclusions. Medulloblastomas formed 18.2% of all brain tumours in children, in the structure of embryonic tumours — 92.6%. For the children of the early age the total resection of tumours was possible in 40.3% cases, subtotal — in 42.0%. Frequency of early dissemination of tumors in the different age-related groups of children statistically does not differ with small predominance in the children of early age. Influence of volume of combined therapy requires a study in the different age-related groups of children on survivability in postoperative period.

Histogram Analysis of Diffusion Tensor Imaging Parameters in Pediatric Cerebellar Tumors.

Apparent diffusion coefficient (ADC) values have been shown to assist in differentiating cerebellar pilocytic astrocytomas and medulloblastomas. Previous studies have applied only ADC measurements and calculated the mean/median values. Here we investigated the value of diffusion tensor imaging (DTI) histogram characteristics of the entire tumor for differentiation of cerebellar pilocytic astrocytomas and medulloblastomas. Presurgical DTI data were analyzed with a region of interest (ROI) approach to include the entire tumor. For each tumor, histogram-derived metrics including the 25th percentile, 75th percentile, and skewness were calculated for fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity. The histogram metrics were used as primary predictors of interest in a logistic regression model. Statistical significance levels were set at p < .01. The study population included 17 children with pilocytic astrocytoma and 16 with medulloblastoma (mean age, 9.21 ± 5.18 years and 7.66 ± 4.97 years, respectively). Compared to children with medulloblastoma, children with pilocytic astrocytoma showed higher MD (P = .003 and P = .008), AD (P = .004 and P = .007), and RD (P = .003 and P = .009) values for the 25th and 75th percentile. In addition, histogram skewness showed statistically significant differences for MD between low- and high-grade tumors (P = .008). The 25th percentile for MD yields the best results for the presurgical differentiation between pediatric cerebellar pilocytic astrocytomas and medulloblastomas. The analysis of other DTI metrics does not provide additional diagnostic value. Our study confirms the diagnostic value of the quantitative histogram analysis of DTI data in pediatric neuro-oncology.

Hedgehog regulates cerebellar progenitor cell and medulloblastoma apoptosis

The external granule layer (EGL) is a proliferative region that produces over 90% of the neurons in the cerebellum but can also malignantly transform into a cerebellar tumor called the medulloblastoma (the most common malignant brain tumor in children). Current dogma considers Hedgehog stimulation a potent proliferative signal for EGL neural progenitor cells (NPCs) and medulloblastomas. However, the Hedgehog pathway also acts as a survival signal in the neural tube where it regulates dorsoventral patterning by controlling NPC apoptosis. Here we show that Hedgehog stimulation is also a potent survival signal in the EGL and medulloblastomas that produces a massive apoptotic response within hours of signal loss in mice. This toxicity can be produced by numerous Hedgehog antagonists (vismodegib, cyclopamine, and jervine) and is Bax/Bak dependent but p53 independent. Finally, since glucocorticoids can also induce EGL and medulloblastoma apoptosis, we show that Hedgehog's effects on apoptosis can occur independent of glucocorticoid stimulation. This effect may play a major role in cerebellar development by directing where EGL proliferation occurs thereby morphologically sculpting growth. It may also be a previously unknown major therapeutic effect of Hedgehog antagonists during medulloblastoma therapy. Results are discussed in terms of their implications for both cerebellar development and medulloblastoma treatment.

Allergic encephalitis with gelastic status epilepticus induced by wasp sting.

Wasp stings are ubiquitous worldwide and generally cause self-limiting local reaction. Occasionally more serious systemic reactions such as anaphylaxis, rhabdomyolysis, and intravascular hemolysis may occur, especially with multiple stings.1,–,3 Although exceedingly rare, neurologic complications of the wasp sting have been described.3,–,6 We report a case of allergic encephalitis with gelastic status epilepticus (SE) due to a delayed reaction to the wasp venom. ### Case report. A 49-year-old right-handed white man with a history of left cerebellar medulloblastoma resected 10 years prior with no residual neurologic deficits presented with a worsening left-sided headache after being repeatedly stung by a swarm of wasps in the left head …

MB-10 * GSK-3 PROMOTES PROLIFERATION DURING POSTNATAL CEREBELLAR DEVELOPMENT AND MAY BE TARGETED IN MEDULLOBLASTOMA THERAPY

In light of prior studies showing that GSK-3 is required to prevent overgrowth of cerebral neural progenitors, we examined whether deletion of GSK-3 in the cerebellum would produce hyperplasia and support medulloblastoma tumorigenesis. GSK-3 regulates diverse intracellular processes, including signaling through Wnt and N-myc, which have both been implicated in tumorigenesis. We deleted both isoforms of GSK-3 conditionally in the cerebellum by crossing GSKα -/-:GSKβ f/f mice with the Math1-cre transgenic line. We found that GSK-3 deletion induced marked hypoproliferation in the cerebellum, contrary to the hyperproliferation seen when GSK in deleted in cortical progenitors. Transcription analysis by microarray revealed that hypoplasia was preceded by a strong activation of WNT signaling. Deleting GSK-3 in medulloblastoma-prone SmoM2 mice markedly reduced tumor growth. Ongoing studies will determine if WNT signaling is activated in GSK-deleted tumors and may mediate the reduced growth. Our data show that the predominant effect of GSK-3 during cerebellar development and medulloblastoma formation is to promote growth, and that disruption of GSK-3 function may exert a significant restriction on tumor growth.

Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma.

Chemokines and its receptors have significant impact on physiological and pathological processes and studies concerning their association with tumor biology are subject of great interest in scientific community. CXCL12/CXCR4 axis has been widely studied due to its significant role in tumor microenvironment, but it is also important to development and maintenance of tissues and organs, for example, in the brain and cerebellum. Studies have demonstrated that CXCL12 and CXCR4 are required for normal cerebellar development and that dysfunction in this pathway may be involved with medulloblastoma pathogenesis. In this context, a new molecular subgroup has been suggested based on the importance of the association between CXCR4 overexpression and sonic hedgehog subgroup. Treatment using CXCR4 antagonists showed significant results, evidencing the important role and possible therapeutic capacity of CXCR4 in MB. This review summarizes studies on MB cell biology, focusing on a chemokine-receptor axis, CXCL12/CXCR4, that may have implications for treatment strategies once it can improve life expectancy and reduce neurocognitive sequelae of patients with this neoplasia.

DS-03 * SONIC HEDGEHOG ANTAGONISTS POTENTLY INDUCE APOPTOSIS IN THE CEREBELLAR EXTERNAL GRANULE LAYER: IMPLICATIONS FOR MEDULLOBLASTOMA TREATMENT

There is a great interest in Hedgehog signaling both for its role in cerebellar development and medulloblastoma (MB) treatment. The cerebellum maintains its own proliferative layer called the external granule layer (EGL) that produces over 90% of its neurons. During development, the established dogma views Hedgehog signaling as a robust mitogenic stimulator of EGL proliferation. However, in other regions of the body, Hedgehog stimulation acts as a survival signal by potently inducing NPC apoptosis when signaling is lost. In this manner, the sonic hedgehog ligand's concentration gradient determines NPC survival or death thereby morphologically sculpting the developing nervous system. Therefore, we tested whether Hedgehog signaling also acts as a survival signal in the EGL by administering several Hedgehog antagonists (vismodegib, cyclopamine, and jervine). Remarkably, we found all Hedgehog antagonists (HAs) potently induced EGL apoptosis within a few hours of administration. This suggests a large portion of the HAs' anti-proliferative effects are due to the apoptotic loss of a large number of EGL NPCs. This research may also have important implications for MB formation and treatment. There is convincing evidence that EGL neural progenitor cells (NPCs) can be the tumor initiating cells for MBs (the most common malignant brain tumor in children). Therefore, we examined if HAs can also produce apoptosis in Patched mice which exhibit constitutive Hedgehog stimulation and are prone to MB formation. We found HA administration also potently increased apoptosis in both EGL NPCs and preneoplasms. This may have important implications for the treatment of MBs with HAs. For example, apoptosis involves signaling mechanisms distinct from proliferation that may need to be disabled for malignant transformation. In addition, the requirement for Hedgehog signaling may prevent metastasis by killing tumor cells as they spread to regions where such signaling is absent.

Zfx facilitates tumorigenesis caused by activation of the Hedgehog pathway.

The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies.

Medulloblastoma metastatic to the pancreas: a case report

We present a case of medulloblastoma metastatic to the pancreas in a 41-year-old woman with recurrent cerebellar medulloblastoma. On presentation, computed tomography of the abdomen and pelvis showed a 2.2 cm × 2.6 cm hypodense pancreatic head mass associated with obstruction of the pancreatic duct. Endosonography with fine needle aspiration (EUS-FNA) was performed. Cytology showed a malignant small cell neoplasm that was consistent with medulloblastoma and was morphologically identical to the primary cerebellar medulloblastoma. Metastatic medulloblastoma to the pancreas is an extremely rare form of a secondary pancreatic tumor and very few case reports exist in the literature. The diagnosis rests on comparing cytological features when primary and secondary tumors are both available.

The transcription factor Cux1 in cerebellar granule cell development and medulloblastoma pathogenesis.

Cux1, also known as Cutl1, CDP or Cut is a homeodomain transcription factor implicated in the regulation of normal and oncogenic development in diverse peripheral tissues and organs. We studied the expression and functional role of Cux1 in cerebellar granule cells and medulloblastoma. Cux1 is robustly expressed in proliferating granule cell precursors and in postmitotic, migrating granule cells. Expression is lost as postmigratory granule cells mature. Moreover, Cux1 is also strongly expressed in a well-established mouse model of medulloblastoma. In contrast, expression of CUX1 in human medulloblastoma tissue samples is lower than in normal fetal cerebellum. In these tumors, CUX1 expression tightly correlates with a set of genes which, when mapped on a global protein-protein interaction dataset, yields a tight network that constitutes a cell cycle control signature and may be related to p53 and the DNA damage response pathway. Antisense-mediated reduction of CUX1 levels in two human medulloblastoma cell lines led to a decrease in proliferation and altered motility. The developmental expression of Cux1 in the cerebellum and its action in cell lines support a role in granule cell and medulloblastoma proliferation. Its expression in human medulloblastoma shifts that perspective, suggesting that CUX1 is part of a network involved in cell cycle control and maintenance of DNA integrity. The constituents of this network may be rational targets to therapeutically approach medulloblastomas.

Shh Signaling Protects Atoh1 from Degradation Mediated by the E3 Ubiquitin Ligase Huwe1 in Neural Precursors

Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.

Disrupted sensorimotor synchronization, but intact rhythm discrimination, in children treated for a cerebellar medulloblastoma.

The aim of this study was to investigate the temporal abilities of children treated by surgery for a malignant tumor in the cerebellum, both in the perception and the production of rhythm. Children with a diagnosed medulloblastoma and age-matched control children were tested in a rhythm discrimination task and a sensorimotor synchronization task. Their motor and cognitive capabilities were also assessed through a battery of age-adapted neuropsychological tests. The results did not show any significant difference in performance between groups for the discrimination task. On the contrary, children with cerebellar lesions produced longer and more variable inter-tap intervals (ITI) in their spontaneous motor tempo (SMT) than did the control children. However, the length and, to a lesser extent, the variability of their SMT decreased after a synchronization phase, when they had been instructed to tap in synchrony with a beep. During the synchronization task, the children with medulloblastoma succeeded to modify the length of their ITI in response to an auditory rhythm, although with better success when the inter-stimuli intervals (ISI) were shorter than when they were longer than the ITIs of their own SMT. Correlational analyses revealed that children's poorer synchronization performance was related to lower scores in neuropsychological tests assessing motor dexterity and processing speed.

Intra-operative 5-aminolevulinic acid (ALA)-induced fluorescence of medulloblastoma: phenotypic variability and CD133+ expression according to different fluorescence patterns

5-Aminolevulinic acid (5-ALA) fluorescence has been proved advantageous in glioma surgery. Conflicting results have been reported by few studies published in literature about intra-operative 5-ALA-induced fluorescence of medulloblastoma (MDB). The aim of this study is to verify if these conflicting results could be explained by intra-tumoral histological and phenotypic differences. In the present case of a 45-year-old patient affected by a cerebellar MDB, histological analysis of cell phenotype and 5-ALA and CD133 correlation were performed in multiple samples according to different fluorescence patterns. Intra-operatively, the tumor appeared unevenly fluorescent under blue-violet light. Histologically, 5-ALA-intense biopsies from inner areas were characterized by a significant amount of cancer cells, whereas 5-ALA faint regions from peripheral areas displayed normal cerebellar features, with MDB cells infiltrating healthy tissues. Presenting our findings, we show the correlation between different 5-ALA fluorescence patterns of medulloblastoma with specific histological and phenotypical features. Thus, we hypothesize that a distinct relationship between CD133 expression and fluorescence accumulation presented in our study could partially explain the divergent results published in literature.

Physical functioning in pediatric survivors of childhood posterior fossa brain tumors

Survival rates for children diagnosed with posterior fossa brain tumors (PFBTs) have improved significantly over the past several decades, and long-term functioning assessments have become priorities. These evaluations have occurred frequently in adults but only rarely in children. This study describes a cross-sectional assessment of physical functioning in pediatric survivors of PFBTs using the Bruininks-Osteretsky Test of Motor Performance, Second Edition (BOT-2). Primary analyses compared BOT-2 scores to normative data using 1-sample t tests for each gross motor subscale (Bilateral Coordination, Balance, Running Speed/Agility, Strength) and motor-area composite (Body Coordination and Strength and Agility). Second, the cohort was stratified by diagnostic or treatment variables. Group differences and groups vs norms were evaluated using independent 2-sample and 1-sample t tests, respectively. Primary analyses compared BOT-2 scores with normative data using 1-sample t tests for each gross motor subscale (Bilateral Coordinationcoordination, Balance, Running Speed/Agility, Strength) and motor-area composite (Body Coordination and Strength and Agility). Second, the cohort was stratified by diagnostic or treatment variables. Group differences and groups vs norms were evaluated using independent 2-sample and 1-sample t tests, respectively. Mean age of 30 participants was 11.4 years (range, 4.9y-18.2y), and mean time from diagnosis was 6.1 years (range, 1.1y-16.7y). Cerebellar astrocytoma (43.3%) and medulloblastoma (40%) were the most common diagnoses. As a group, significantly decreased functioning, compared with norms, was observed in Balance (P < .001) and Running Speed/Agility (P = .005). Specifically in Balance, 21 (70%) participants performed below or well-below average. Participants with a non-astrocytoma performed significantly lower than norms in all areas, independent of age at diagnosis. Survivors with tumors infiltrating the vermis demonstrated significantly lower Body Coordination than norms (P < .001). Pediatric survivors of PFBTs demonstrated decreased physical functioning, most notably in Balance. These data underscore the need for further research and implementation of physical activity programs aimed specifically at approaches to minimize physical limitations.

A gene signature based method for identifying subtypes and subtype-specific drivers in cancer with an application to medulloblastoma

BackgroundSubtypes are widely found in cancer. They are characterized with different behaviors in clinical and molecular profiles, such as survival rates, gene signature and copy number aberrations (CNAs). While cancer is generally believed to have been caused by genetic aberrations, the number of such events is tremendous in the cancer tissue and only a small subset of them may be tumorigenic. On the other hand, gene expression signature of a subtype represents residuals of the subtype-specific cancer mechanisms. Using high-throughput data to link these factors to define subtype boundaries and identify subtype-specific drivers, is a promising yet largely unexplored topic.ResultsWe report a systematic method to automate the identification of cancer subtypes and candidate drivers. Specifically, we propose an iterative algorithm that alternates between gene expression clustering and gene signature selection. We applied the method to datasets of the pediatric cerebellar tumor medulloblastoma (MB). The subtyping algorithm consistently converges on multiple datasets of medulloblastoma, and the converged signatures and copy number landscapes are also found to be highly reproducible across the datasets. Based on the identified subtypes, we developed a PCA-based approach for subtype-specific identification of cancer drivers. The top-ranked driver candidates are found to be enriched with known pathways in certain subtypes of MB. This might reveal new understandings for these subtypes.This article is an extended abstract of our ICCABS '12 paper (Chen et al. 2012), with revised methods in iterative subtyping, the use of canonical correlation analysis for driver-identification, and an extra dataset (Northcott90 dataset) for cross-validations. Discussions of the algorithm performance and of the slightly different gene lists identified are also added.ConclusionsOur study indicates that subtype-signature defines the subtype boundaries, characterizes the subtype-specific processes and can be used to prioritize signature-related drivers.

Adenomatous polyposis coli gene involvement in ileal enterochromaffin cell neuroendocrine neoplasms

The adenomatous polyposis coli gene is a key tumor suppressor gene. Alterations in this gene have been found in most sporadic colon cancers; associated with familial adenomatous polyposis; and found in neoplasms of other organs, such as the liver, stomach, lung, breast, and cerebellar medulloblastoma. In the heterogeneous group of neuroendocrine neoplasms of the gastrointestinal tract, the involvement of adenomatous polyposis coli is debated, and only occasional reports found adenomatous polyposis coli alterations in foregut and midgut neuroendocrine neoplasms, with adenomatous polyposis coli mutations only in the latter. To elucidate the penetrance of adenomatous polyposis coli alterations in ileal neuroendocrine neoplasms, we performed DNA fragment analysis (loss of heterozygosity for 5q22-23 and 5q23) and sequencing on the mutation cluster region of the adenomatous polyposis coli gene on 30 ileal enterochromaffin cell neuroendocrine neoplasms. Adenomatous polyposis coli gene mutations were detected in 23% of cases (7/30); in particular, 57% were missense and 14%, nonsense/frameshift, all novel and different from those reported in colorectal or other cancers. Loss of heterozygosity analysis demonstrated a deletion frequency of 15% (4/27). No association was found with features of tumor progression. Our observations support the involvement of somatic adenomatous polyposis coli alterations in tumorigenesis of ileal enterochromaffin cell neuroendocrine neoplasms; the mechanisms of adenomatous polyposis coli gene inactivation appear to be different from those reported in other tumor types.

Occipital diploic cranial fasciitis after radiotherapy for a cerebellar medulloblastoma

Radiation-induced cranial fasciitis is a rare complication of radiotherapy, especially in an intradiploic location. The authors report such a case of cranial fasciitis in a 13-year-old girl previously subjected to cranial radiotherapy for a recurrent cerebellar medulloblastoma. The patient had undergone a gross-total removal of a medulloblastoma followed by no radiation therapy at the age of 10 years. The tumor recurred at the original site 2 years later, warranting a repeat operation with a gross-total tumor removal and subsequent radiation therapy. The follow-up MRI sequence demonstrated no abnormal appearance for 1 year, until a new enhancing mass was found within the occipital bone adjacent to the prior bone window. Following its resection, the new lesion was histologically identified as cranial fasciitis. Differential diagnosis of a well-circumscribed bone lesion should include cranial fasciitis, especially in young children with radiotherapy for a previous intracranial malignancy. Radiotherapy should be considered among the inciting factors in the development of cranial fasciitis. The osteolytic lesions of cranial fasciitis, although nontumoral and self-limited in duration, should be eligible candidates for early, total resection to avoid potential intracranial expansion.

Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma

Central nervous system tumors carry grave clinical prognoses due to limited effectiveness of surgical resection, radiation, and chemotherapy. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. We demonstrate that mouse cerebellar medulloblastoma (MB) can be targeted and illuminated with a fluorescent, engineered cystine knot (knottin) peptide that binds with high affinity to αvβ3, αvβ5, and α5β1 integrin receptors. This integrin-binding knottin peptide, denoted EETI 2.5F, was evaluated as a molecular imaging probe in both orthotopic and genetic models of MB. Following tail vein injection, fluorescence arising from dye-conjugated EETI 2.5F was localized to the tumor compared with the normal surrounding brain tissue, as measured by optical imaging. The imaging signal intensity correlated with tumor volume. Due to its unique ability to bind to α5β1 integrin, EETI 2.5F showed superior in vivo and ex vivo brain tumor imaging contrast compared with other engineered integrin-binding knottin peptides and with c(RGDfK), a well-studied integrin-binding peptidomimetic. Next, EETI 2.5F was fused to an antibody fragment crystallizable (Fc) domain (EETI 2.5F-Fc) to determine if a larger integrin-binding protein could also target intracranial brain tumors. EETI 2.5F-Fc, conjugated to a fluorescent dye, illuminated MB following i.v. injection and was able to distribute throughout the tumor parenchyma. In contrast, brain tumor imaging signals were not detected in mice injected with EETI 2.5F proteins containing a scrambled integrin-binding sequence, demonstrating the importance of target specificity. These results highlight the potential of using EETI 2.5F and EETI 2.5-Fc as targeted molecular probes for brain tumor imaging.