Predictors of mortality and tumor recurrence in desmoplastic infantile ganglioglioma and astrocytoma-and individual participant data meta-analysis (IPDMA).

PURPOSE: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are classified together as grade I neuronal and mixed neuronal-glial tumor of the central nervous system by the World Health Organization (WHO). These tumors are rare and have not been well characterized in terms of clinical outcomes. We aimed to identify clinical predictors of mortality and tumor recurrence/progression by performing an individual patient data meta-analysis (IPDMA) of the literature. METHODS: A systematic literature review from 1970 to 2020 was performed, and individualized clinical data for patients diagnosed with DIA/DIG were extracted. Aggregated data were excluded from collection. Outcome measures of interest were mortality and tumor recurrence/progression, as well as time-to-event (TTE) for each of these. Participants without information on these outcome measures were excluded. Cox regression survival analyses were performed to determine predictors of mortality and tumor recurrence / progression. RESULTS: We identified 98 articles and extracted individual patient data from 188 patients. The cohort consisted of 58.9% males with a median age of 7 months. The majority (68.1%) were DIGs, while 24.5% were DIAs and 7.5% were non-specific desmoplastic infantile tumors; DIAs presented more commonly in deep locations (p = 0.001), with leptomeningeal metastasis (p = 0.001), and was associated with decreased probability of gross total resection (GTR; p = 0.001). Gender, age, and tumor pathology were not statistically significant predictors of either mortality or tumor recurrence/progression. On multivariate survival analysis, GTR was a predictor of survival (HR = 0.058; p = 0.007) while leptomeningeal metastasis at presentation was a predictor of mortality (HR = 3.27; p = 0.025). Deep tumor location (HR = 2.93; p = 0.001) and chemotherapy administration (HR = 2.02; p = 0.017) were associated with tumor recurrence/progression. CONCLUSION: Our IPDMA of DIA/DIG cases reported in the literature revealed that GTR was a predictor of survival while leptomeningeal metastasis at presentation was associated with mortality. Deep tumor location and chemotherapy were associated with tumor recurrence / progression.

Radiation dose reduction during intra-arterial chemotherapy for retinoblastoma: a retrospective analysis of 96 consecutive pediatric interventions using five distinct protocols.

BACKGROUND: Intra-arterial chemotherapy (IAC) represents a mainstay of retinoblastoma treatment in children. Patients with retinoblastoma are uniquely at risk for secondary malignancies and are sensitive to the ionizing effects of radiation. OBJECTIVE: To retrospectively review a single institution's experience with IAC for retinoblastoma and the effect of variable intra-procedural imaging techniques on radiation exposure. MATERIALS AND METHODS: Twenty-four consecutive patients, with a mean age of 30.8±16.3 months (range: 3.2-83.4 months), undergoing IAC for retinoblastoma between May 2014 and May 2020 (72 months) were included. No patients were excluded. The primary outcome was radiation exposure and secondary outcomes included technical success and procedural adverse events. Technical success was defined as catheterization of the ophthalmic or meningolacrimal artery and complete delivery of chemotherapy. Each procedure was retrospectively reviewed and categorized as one of five imaging protocol types. Protocol types were characterized by uniplanar versus multiplanar imaging and digital subtraction angiographic versus roadmap angiographic techniques. Radiation exposure, protocol utilization, the association of protocol and radiation exposure were assessed. RESULTS: During 96 consecutive interventions, 109 ocular treatments were performed. Thirteen of the 96 (15.5%) treatments were bilateral. Ocular technical success was 106 of 109 (97.2%). All three treatment failures were successfully repeated within a week. Mean fluoroscopy time was 6.4±6.2 min (range: 0.7-31.1 min). Mean air kerma was 36.2±52.2 mGy (range: 1.4-215.0 mGy). There were two major (1.8%) complications and four (3.7%) minor complications. Of the 96 procedures, 10 (10.4%), 9 (9.4%), 13 (13.5%), 28 (29.2%) and 36 (37.5%) were performed using protocol types A, B, C, D and E, respectively. For protocol type A, mean fluoroscopy time was 10.3±6.8 min (range: 3.0-25.4 min) and mean air kerma was 118.2±61.2 mGy (range: 24.5-167.3 mGy). For protocol type E, mean fluoroscopy time was 3.1±3.2 min (range: 0.7-15.1 min) and mean air kerma was 5.4±4.2 mGy (range: 1.4-19.5 mGy). Fluoroscopy time and air kerma decreased over time, corresponding to the reduced use of multiplanar imaging and digital subtraction angiography. In the first quartile (procedures 1-24), 8 (33.3%), 7 (29.2%), 2 (8.3%), 6 (25.0%) and 1 (4.2%) were performed using protocol types A, B, C, D and E, respectively. Mean fluoroscopy time was 10.5±8.2 min (range: 2.4-28.1 min) and mean air kerma was 84.2±71.6 mGy (range: 12.8-215.0 mGy). In the final quartile (procedures 73-96), 24 (100%) procedures were performed using protocol type E. Mean fluoroscopy time was 3.5±4.0 min (range: 0.7-15.1 min) and mean air kerma was 5.0±4.3 mGy (range: 1.4-18.0 mGy), representing 66.7% and 94.1% reductions from the first quartile, respectively. Technical success in the second half of the experience was 100%. CONCLUSION: Sequence elimination, consolidation from biplane imaging to lateral-only imaging, and replacing digital subtraction with roadmap angiography dramatically reduced radiation exposure during IAC for retinoblastoma without adversely affecting technical success or safety.

Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.

INTRODUCTION: Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation. METHODS: We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated. RESULTS: Median age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG. CONCLUSION: Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

Real-time transmission of 16 Tb/s over 1020km using 200Gb/s CFP2-DCO.

We demonstrate real-time transmission of 16 Tb/s (80x200Gb/s) over 1020km TeraWave ULL fiber with 170km span length using the world's first 200Gb/s CFP2-DCO module with a record low power consumption less than 0.1W/Gbps.

Effects of supplementing rumen-protected niacin on fiber composition and metabolism of skeletal muscle in dairy cows during early lactation.

Nicotinic acid (NA) has been shown to induce muscle fiber switching toward oxidative type I fibers and a muscle metabolic phenotype that favors fatty acid (FA) utilization in growing rats, pigs, and lambs. The hypothesis of the present study was that supplementation of NA in cows during the periparturient phase also induces muscle fiber switching from type II to type I fibers in skeletal muscle and increases the capacity of the muscle to use free FA, which may help to reduce nonesterified fatty acid (NEFA) flow to the liver, liver triglyceride (TG) accumulation, and ketogenesis. Thirty multiparous Holstein dairy cows were allocated to 2 groups and fed a total mixed ration without (control group) or with ∼55 g of rumen-protected NA per cow per day (NA group) from 21 d before expected calving until 3 wk postpartum (p.p.). Blood samples were collected on d -21, -14, -7, 7, 14, 21, 35, and 63 relative to parturition for analysis of TG, NEFA, and ß-hydroxybutyrate. Muscle and liver biopsies were collected on d 7 and 21 for gene expression analysis and to determine muscle fiber composition in the musculus semitendinosus, semimembranosus, and longissimus lumborum by immunohistochemistry, and liver TG concentrations. Supplementation of NA did not affect the proportions of type I (oxidative) or the type II:type I ratio in the 3 muscles considered. A slight shift from glycolytic IIx fibers toward oxidative-glycolytic fast-twitch IIa fibers was found in the semitendinosus, and a tendency in the longissimus lumborum, but not in the semimembranosus. The transcript levels of the genes encoding the muscle fiber type isoforms and involved in FA uptake and oxidation, carnitine transport, tricarboxylic acid cycle, oxidative phosphorylation, and glucose utilization were largely unaffected by NA supplementation in all 3 muscles. Supplementation of NA had no effect on plasma TG and NEFA concentrations, liver TG concentrations, and hepatic expression of genes involved in hepatic FA utilization and lipogenesis. However, it reduced plasma ß-hydroxybutyrate concentrations in wk 2 and 3 p.p. by 18 and 26% and reduced hepatic gene expression of fibroblast growth factor 21, a stress hormone involved in the regulation of ketogenesis, by 74 and 56%. In conclusion, a high dosage of rumen-protected NA reduced plasma ß-hydroxybutyrate concentrations in cows during early lactation, but failed to cause an alteration in muscle fiber composition and muscle metabolic phenotype.

Current insights into the sulfatase pathway in human testis and cultured Sertoli cells.

Within the human testis, large amounts of sulfated steroid hormones are produced. As shown in breast tissue and placenta, these might not only be excretion intermediates, but re-activated in target cells by steroid sulfatase (STS). This process is called sulfatase pathway and may play a pivotal role in para- and/or intracrine regulation by creating a local supply for steroid hormones. This requires a facilitated transport via uptake carriers and efflux transporters as these hydrophilic molecules cannot pass the cell membrane. Moreover, blood-testis barrier formation in the testis requires a transport through Sertoli cells (SCs) to reach germ cells (GCs). Sertoli cells are therefore expected to play a key role as gate-keepers for sulfatase pathway in human seminiferous epithelium. We analyzed the mRNA and protein expression of uptake carriers and efflux transporters like organic anion-transporting polypeptides (OATP2B1, OATP3A1) and multidrug resistance-related proteins (MRP1, MRP4) in testicular tissue and cultured Sertoli cells (FS1, HSEC). Additionally, expression pattern of STS as well as sulfonating enzymes (SULTs) were assessed. OATP2B1, OATP3A1 and STS were detected in SCs as well as GCs, whereas MRP1 is only expressed in SCs, and SULT1E1 only in Leydig cells, respectively. By transcellular transport of [H3]DHEAS in HSEC, we showed a functional transport of sulfated steroids in vitro. Our data indicate that steroid synthesis via sulfatase pathway in Sertoli cells in vivo and in vitro is possible and may contribute to paracrine and intracrine regulation employing the local supply of sulfated and free steroid hormones inside seminiferous tubules.

Survival After Relapse of Medulloblastoma.

Survival after recurrence of medulloblastoma has not been reported in an unselected cohort of patients in the contemporary era. We reviewed 55 patients diagnosed with medulloblastoma between 2000 and 2010, and treated at Seattle Children's Hospital to evaluate patterns of relapse treatment and survival. Fourteen of 47 patients (30%) over the age of 3 experienced recurrent or progressive medulloblastoma after standard therapy. The median time from diagnosis to recurrence was 18.0 months (range, 3.6 to 62.6 mo), and site of recurrence was metastatic in 86%. The median survival after relapse was 10.3 months (range, 1.3 to 80.5 mo); 3-year survival after relapse was 18%. There were trend associations between longer survival and having received additional chemotherapy (median survival 12.8 vs. 1.3 mo, P=0.16) and radiation therapy (15.4 vs. 5.9 mo, P=0.20). Isolated local relapse was significantly associated with shorter survival (1.3 vs. 12.8 mo, P=0.009). Recurrence of medulloblastoma is more likely to be metastatic than reported in previous eras. Within the limits of our small sample, our data suggest a potential survival benefit from retreatment with cytotoxic chemotherapy and radiation even in heavily pretreated patients. This report serves as a baseline against which to evaluate novel therapy combinations.

Transfection of Sertoli cells with androgen receptor alters gene expression without androgen stimulation.

BACKGROUND: Androgens play an important role for the development of male fertility and gained interest as growth and survival factors for certain types of cancer. Androgens act via the androgen receptor (AR/Ar), which is involved in various cell biological processes such as sex differentiation. To study the functional mechanisms of androgen action, cell culture systems and AR-transfected cell lines are needed. Transfection of AR into cell lines and subsequent gene expression analysis after androgen treatment is well established to investigate the molecular biology of target cells. However, it remains unclear how the transfection with AR itself can modulate the gene expression even without androgen stimulation. Therefore, we transfected Ar-deficient rat Sertoli cells 93RS2 by electroporation using a full length human AR. RESULTS: Transfection success was confirmed by Western Blotting, immunofluorescence and RT-PCR. AR transfection-related gene expression alterations were detected with microarray-based genome-wide expression profiling of transfected and non-transfected 93RS2 cells without androgen stimulation. Microarray analysis revealed 672 differentially regulated genes with 200 up- and 472 down-regulated genes. These genes could be assigned to four major biological categories (development, hormone response, immune response and metabolism). Microarray results were confirmed by quantitative RT-PCR analysis for 22 candidate genes. CONCLUSION: We conclude from our data, that the transfection of Ar-deficient Sertoli cells with AR has a measurable effect on gene expression even without androgen stimulation and cause Sertoli cell damage. Studies using AR-transfected cells, subsequently stimulated, should consider alterations in AR-dependent gene expression as off-target effects of the AR transfection itself.

Medical management of invasive fungal infections of the central nervous system in pediatric cancer patients.

Fungal infections of the central nervous system (CNS) are associated with high mortality rates in immunocompromised patients. Surgical intervention is a mainstay of therapy, but not always possible. We describe the use of medical therapy for the treatment of CNS fungal infections in four pediatric cancer patients. Definitive resection was not performed in any patient. All patients initially received combination antifungal therapy with good clinical response; long-term survival was documented in two patients able to transition to long-term azole therapy. Prolonged antifungal therapy is an important option for treating invasive CNS fungal infections when surgery is not feasible.

Brain penetration of emodepside is increased in P-glycoprotein-deficient mice and leads to neurotoxicosis.

The antiparasitic drug emodepside (EMO) is a substrate of the P-glycoprotein multidrug efflux carrier (P-gp; syn. MDR1, ABCB1), which has an important function in protecting the brain from potentially toxic compounds by functional drug efflux at the blood-brain barrier (BBB). Many dogs of the Collie breed and even dogs of many other breeds have a loss-of-function 4-bp deletion mutation in the MDR1 gene. In these dogs, brain penetration of many P-gp-transported drugs is increased and so their therapeutic usage is restricted. To elucidate the role of P-gp at the BBB for the brain penetration of EMO, we applied EMO at 1 mg/kg to mdr1-deficient (PGP(mut) ) and mdr1-intact (PGP(WT) ) CF1 mice. Whereas in the brain of the PGP(WT) mice, EMO was below the detection level of 10 ng/g, its concentration was at 43.7 ng/g in the PGP(mut) mice. Furthermore, appearance of neurological toxicity was analyzed in these mice after application of 1 mg/kg EMO using a rotarod setup. In all PGP(mut) mice, but not in the PGP(WT) mice, the walking performance on the rotarod was impaired by EMO with clear differences in the degree and duration of neurological toxicity. Some of the mice were completely unable to walk on the rotarod already at 2 h after drug application and showed long-lasting ataxia over >24 h. Others even showed significantly reduced walking performance, but completely recovered within 1 day. In conclusion, P-gp restricts brain penetration of EMO and prevents neurological toxicity of this drug in mice.

A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study.

High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m² dose bid for 7-14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1-6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10-20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m² dose bid. The median number of courses in the phase II trial was two (range 1-12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4-26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.

Diffusion tensor imaging of the superior cerebellar peduncle identifies patients with posterior fossa syndrome.

INTRODUCTION: Posterior fossa tumors are the most common brain tumor of children. Aggressive resection correlates with long-term survival. A high incidence of posterior fossa syndrome (PFS), impairing the quality of life in many survivors, has been attributed to damage to bilateral dentate nucleus or to cerebellar output pathways. Using diffusion tensor imaging (DTI), we examined the involvement of the dentothalamic tracts, specifically the superior cerebellar peduncle (SCP), in patients with posterior fossa tumors and the association with PFS. METHODS: DTI studies were performed postoperatively in patients with midline (n = 12), lateral cerebellar tumors (n = 4), and controls. The location and visibility of the SCP were determined. The postoperative course was recorded, especially with regard to PFS, cranial nerve deficits, and oculomotor function. RESULTS: The SCP travels immediately adjacent to the lateral wall of the fourth ventricle and just medial to the middle cerebellar peduncle. Patients with midline tumors that still had observable SCP did not develop posterior fossa syndrome (N = 7). SCPs were absent, on either preoperative (N = 1, no postoperative study available) or postoperative studies (N = 4), in the five patients who developed PFS. Oculomotor deficits of tracking were observed in patients independent of PFS or SCP involvement. CONCLUSION: PFS can occur with bilateral injury to the outflow from dentate nuclei. In children with PFS, this may occur due to bilateral injury to the superior cerebellar peduncle. These tracts sit immediately adjacent to the wall of the ventricle and are highly vulnerable when an aggressive resection for these tumors is performed.

Moxidectin has a lower neurotoxic potential but comparable brain penetration in P-glycoprotein-deficient CF-1 mice compared to ivermectin.

The anti-parasitic drugs ivermectin (IVM) and moxidectin (MOX) normally show limited brain penetration in vertebrates because of effective drug efflux at the blood-brain barrier by P-glycoprotein, encoded by the multi-drug resistance (MDR1) gene. However, dogs with homozygous nt230(del4) mutation in the MDR1 gene do not express a functionally active P-glycoprotein and show increased brain penetration of these drugs, resulting in neurological toxicity to different degrees. Thus, whereas IVM provokes neurological toxicity at 0.1 mg/kg, MOX is tolerated at this dosage. To investigate whether this difference is attributable to lower brain penetration of MOX in the absence of P-glycoprotein or to their neurotoxic potential, we applied IVM and MOX to P-glycoprotein-deficient CF-1 mice and comparatively analysed the absolute drug concentrations in the brain. Furthermore, we quantified drug-induced neurotoxicity by measuring the walking performance of the mice on a rotarod setup. We found that at a dosage of 0.2 mg/kg, representing 0.23 µmol/kg IVM and 0.31 µmol/kg MOX, the absolute drug concentrations in the brain were comparable with 100.8 pmol/g and 140.2 pmol/g, respectively. However, MOX induced the same degree of neurotoxicosis at the higher dosage of 1.09 µmol/kg (0.7 mg/kg) compared with IVM at 0.40 µmol/kg (0.35 mg/kg), demonstrating the 2.7-fold lower neurotoxic potential of MOX compared to IVM. This could be explained by a lower binding affinity or lower intrinsic activity of MOX at the relevant central nervous system receptors compared with IVM.

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study.

To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.

Vorinostat and isotretinoin with chemotherapy in young children with embryonal brain tumors: A report from the Pediatric Brain Tumor Consortium (PBTC-026).

BACKGROUND: Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone. METHODS: PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array. RESULTS: Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6). CONCLUSION: It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group.

BACKGROUND: Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of 3. Stratification of patients by risk group may allow toxic treatment to be avoided. METHODS: Seventy-six patients diagnosed with medulloblastoma and enrolled on CCG-9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or nondesmoplastic. Nonparametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates, and the log-rank test was used to compare survival according to histologic subtype. RESULTS: Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77% ± 9% and OS of 85% ± 8% compared with EFS of 17% ± 5% and OS of 29% ± 6% for patients with tumors in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy. CONCLUSIONS: Children less than 3 with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy.

BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.

The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma.

OBJECT: Intrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution. MATERIAL AND METHODS: The clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata. RESULTS: Routine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology. CONCLUSION: DTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive.

MRI changes associated with vigabatrin treatment mimicking tumor progression.

Vigabatrin has been used as first-line treatment of infantile spasms. Reversible cerebral MRI signal changes have been reported to be associated with vigabatrin treatments. We report a case of a 5-month-old female who, following resection of an anaplastic oligodendroglioma developed, while treated with vigabatrin for seizures, abnormal DWI and FLAIR MRI signal changes worrisome for tumor progression or recurrence. Discontinuation of vigabatrin led to reversal of the MRI changes. This report highlights the fact that vigabatrin treatment can mimic tumor progression on MRI and confound management of tumors associated with seizures in pediatric patients.

Utility of cerebrospinal fluid cytology in newly diagnosed childhood ependymoma.

SUMMARY: The role of cytology of cerebrospinal fluid (CSF) has not been established in pediatric ependymoma. Thirty-two children with metastatic ependymoma were analyzed: 11 patients had only positive CSF cytology, 6 had only positive magnetic resonance imaging (MRI) findings, and 15 had both CSF cytology and MRI positive. Twenty-two patients relapsed. Five-year event-free survival was 27.3%+/-13.4% for children with only CSF positive (M1) versus 26.1%+/-10.2% for patients with positive spine MRI positive (with or without CSF positive, M3) (P=0.87). In conclusion, 34% of the patients with metastatic ependymoma were identified based on CSF cytology only and their outcome was comparable to patients with macroscopic disease. CSF cytology is a useful tool to stage newly diagnosed patients with ependymoma.