Formaldehyde production from isoprene oxidation across NOx regimes.

The chemical link between isoprene and formaldehyde (HCHO) is a strong, non-linear function of NOx (= NO + NO2). This relationship is a linchpin for top-down isoprene emission inventory verification from orbital HCHO column observations. It is also a benchmark for overall photochemical mechanism performance with regard to VOC oxidation. Using a comprehensive suite of airborne in situ observations over the Southeast U.S., we quantify HCHO production across the urban-rural spectrum. Analysis of isoprene and its major first-generation oxidation products allows us to define both a "prompt" yield of HCHO (molecules of HCHO produced per molecule of freshly-emitted isoprene) and the background HCHO mixing ratio (from oxidation of longer-lived hydrocarbons). Over the range of observed NOx values (roughly 0.1 - 2 ppbv), the prompt yield increases by a factor of 3 (from 0.3 to 0.9 ppbv ppbv-1), while background HCHO increases by a factor of 2 (from 1.6 to 3.3 ppbv). We apply the same method to evaluate the performance of both a global chemical transport model (AM3) and a measurement-constrained 0-D steady state box model. Both models reproduce the NOx dependence of the prompt HCHO yield, illustrating that models with updated isoprene oxidation mechanisms can adequately capture the link between HCHO and recent isoprene emissions. On the other hand, both models under-estimate background HCHO mixing ratios, suggesting missing HCHO precursors, inadequate representation of later-generation isoprene degradation and/or under-estimated hydroxyl radical concentrations. Detailed process rates from the box model simulation demonstrate a 3-fold increase in HCHO production across the range of observed NOx values, driven by a 100% increase in OH and a 40% increase in branching of organic peroxy radical reactions to produce HCHO.

Instrumentation and Measurement Strategy for the NOAA SENEX Aircraft Campaign as Part of the Southeast Atmosphere Study 2013.

Natural emissions of ozone-and-aerosol-precursor gases such as isoprene and monoterpenes are high in the southeast of the US. In addition, anthropogenic emissions are significant in the Southeast US and summertime photochemistry is rapid. The NOAA-led SENEX (Southeast Nexus) aircraft campaign was one of the major components of the Southeast Atmosphere Study (SAS) and was focused on studying the interactions between biogenic and anthropogenic emissions to form secondary pollutants. During SENEX, the NOAA WP-3D aircraft conducted 20 research flights between 27 May and 10 July 2013 based out of Smyrna, TN. Here we describe the experimental approach, the science goals and early results of the NOAA SENEX campaign. The aircraft, its capabilities and standard measurements are described. The instrument payload is summarized including detection limits, accuracy, precision and time resolutions for all gas-and-aerosol phase instruments. The inter-comparisons of compounds measured with multiple instruments on the NOAA WP-3D are presented and were all within the stated uncertainties, except two of the three NO2 measurements. The SENEX flights included day- and nighttime flights in the Southeast as well as flights over areas with intense shale gas extraction (Marcellus, Fayetteville and Haynesville shale). We present one example flight on 16 June 2013, which was a daytime flight over the Atlanta region, where several crosswind transects of plumes from the city and nearby point sources, such as power plants, paper mills and landfills, were flown. The area around Atlanta has large biogenic isoprene emissions, which provided an excellent case for studying the interactions between biogenic and anthropogenic emissions. In this example flight, chemistry in and outside the Atlanta plumes was observed for several hours after emission. The analysis of this flight showcases the strategies implemented to answer some of the main SENEX science questions.

Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and may disrupt an effective therapy. This study assesses whether serial parametric response mapping (a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: From 2009 to 2012, 21 children, 4-18 years of age, with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiation therapy. DWI was acquired before immunotherapy and at 6-week intervals during vaccine treatment. Pseudoprogression was identified retrospectively on the basis of clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from the first vaccine to up to 12 weeks after the vaccine was halted) with prevaccine baseline values. Log-transformed fractional increased ADC, fractional decreased ADC, and parametric response mapping ratio (fractional increased ADC/fractional decreased ADC) were compared between patients with and without pseudoprogression, by using generalized estimating equations with inverse weighting by cluster size. RESULTS: Median survival was 13.1 months from diagnosis (range, 6.4-24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (P = .01) and fractional decreased ADCs (P = .0004), compared with patients without pseudoprogression. CONCLUSIONS: Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination.

Mass spectral analysis of organic aerosol formed downwind of the Deepwater Horizon oil spill: field studies and laboratory confirmations.

In June 2010, the NOAA WP-3D aircraft conducted two survey flights around the Deepwater Horizon (DWH) oil spill. The Gulf oil spill resulted in an isolated source of secondary organic aerosol (SOA) precursors in a relatively clean environment. Measurements of aerosol composition and volatile organic species (VOCs) indicated formation of SOA from intermediate-volatility organic compounds (IVOCs) downwind of the oil spill (Science2011, 331, doi 10.1126/science.1200320). In an effort to better understand formation of SOA in this environment, we present mass spectral characteristics of SOA in the Gulf and of SOA formed in the laboratory from evaporated light crude oil. Compared to urban primary organic aerosol, high-mass-resolution analysis of the background-subtracted SOA spectra in the Gulf (for short, "Gulf SOA") showed higher contribution of C(x)H(y)O(+) relative to C(x)H(y)(+) fragments at the same nominal mass. In each transect downwind of the DWH spill site, a gradient in the degree of oxidation of the Gulf SOA was observed: more oxidized SOA (oxygen/carbon = O/C ∼0.4) was observed in the area impacted by fresher oil; less oxidized SOA (O/C ∼0.3), with contribution from fragments with a hydrocarbon backbone, was found in a broader region of more-aged surface oil. Furthermore, in the plumes originating from the more-aged oil, contribution of oxygenated fragments to SOA decreased with downwind distance. Despite differences between experimental conditions in the laboratory and the ambient environment, mass spectra of SOA formed from gas-phase oxidation of crude oil by OH radicals in a smog chamber and a flow tube reactor strongly resembled the mass spectra of Gulf SOA (r(2) > 0.94). Processes that led to the observed Gulf SOA characteristics are also likely to occur in polluted regions where VOCs and IVOCs are coemitted.

Organic aerosol formation downwind from the Deepwater Horizon oil spill.

A large fraction of atmospheric aerosols are derived from organic compounds with various volatilities. A National Oceanic and Atmospheric Administration (NOAA) WP-3D research aircraft made airborne measurements of the gaseous and aerosol composition of air over the Deepwater Horizon (DWH) oil spill in the Gulf of Mexico that occurred from April to August 2010. A narrow plume of hydrocarbons was observed downwind of DWH that is attributed to the evaporation of fresh oil on the sea surface. A much wider plume with high concentrations of organic aerosol (>25 micrograms per cubic meter) was attributed to the formation of secondary organic aerosol (SOA) from unmeasured, less volatile hydrocarbons that were emitted from a wider area around DWH. These observations provide direct and compelling evidence for the importance of formation of SOA from less volatile hydrocarbons.

Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas.

OBJECTIVE: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-α-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). METHODS: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. RESULTS: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 µg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 µg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 µg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 µg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. CONCLUSIONS: The RP2D of PI for pediatric patients with PN is 1 µg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that pegylated interferon-α-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size.

Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha.

Hypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.

Sequential delivery of interferon-alpha gene and DCs to intracranial gliomas promotes an effective antitumor response.

Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-alpha (Ad-IFN-alpha) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-alpha and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (> 60 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent re-challenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.

Age and TP53 mutation frequency in childhood malignant gliomas: results in a multi-institutional cohort.

Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.

Sudden death from fulminant acute cerebellitis.

Acute cerebellitis is postulated to result from viral and/or autoimmune etiologies. This disease has been reported to have a variable course. We report a case of sudden death from acute fulminant cerebellitis in a 13-year-old ballet dancer. Serial CT and MRI demonstrated rapid progression of the disease. Histopathologic correlation is provided. The etiologies, clinical course, therapeutic interventions and postmortem evaluation of this potentially life-threatening condition are briefly reviewed.

Cytokine gene therapy of gliomas: effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells.

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-alpha (9L-IFNalpha). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokine-expressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mock-transfected 9L-neo, but to a lesser degree than i.d. cytokine-expressing tumors. Tumor angiogenesis was suppressed in cytokine-transfected tumors. In a prophylaxis model, i.d. vaccination with 9L-IL4 resulted in long-term survival of 90% of rats challenged i.c. with parental 9L; whereas 40% of 9L-GM-CSF, 40% of 9L-IFNalpha and 0% of 9L-IL12-immunized rats were protected. In a therapy model (day 3 i.c. 9L tumors), only i.d. immunization with 9L-IL4 had long-term therapeutic benefits as 43% of rats survived >100 days. These data indicate that peripheral immunization with 9L-IL4 had the most potent therapeutic benefit among various cytokines and approaches tested against established, i.c. 9L tumors.

Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells.

Apo2 ligand tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the tumor necrosis factor family that interacts with cell surface "death receptors" (DR4 and DR5) to initiate programmed cell death. Apo2L/TRAIL also binds to "decoy" receptors (DcR1 and DcR2) that can antagonize its interaction with DR4 and DR5. In recent studies, Apo2L/TRAIL has been noted to produce selective toxicity toward certain neoplastic cells versus normal cells. The decoy receptors may in part contribute to this selectivity, because they are expressed in various normal tissues but are present at low or undetectable levels in certain types of neoplastic cells. In the current study, we examined the potential therapeutic applicability of recombinant soluble Apo2L/TRAIL by investigating its effects in vitro and in vivo against a series of cell lines derived from malignant gliomas, which are often resistant to conventional treatment modalities. In cell proliferation assays, Apo2L/TRAIL produced a striking decrease in cell numbers, with a median inhibitory concentration of 30-100 ng/ml, in the TP53 wild-type high-grade glioma cell lines U87 and A172, the TP53-mutated T98G, and the TP53-deleted LN-Z308. In contrast, no significant effects were observed in non-neoplastic astrocytes at concentrations up to 3000 ng/ml. Clonogenic assays showed that exposure to Apo2L produced a time-dependent decrease in the viability of glioma-derived cell lines. This correlated with the induction of apoptosis as assessed by a terminal transferase-catalyzed in situ end-labeling assay. Pretreatment of the cells with the caspase inhibitors Acetyl-Asp-Glu-Val-L-aspartic acid aldehyde or Acetyl-Tyr-Val-Ala-Asp-chlormethylketone (200 microM) largely eliminated the effects of Apo2L/TRAIL. Administration of Apo2L/TRAIL (0.3, 1, 3, 10, and 30 mg/kg/day for 7 days via i.p. infusion) to nude mice harboring established intracranial U87 xenografts produced a significant, dose-dependent prolongation of survival versus control animals. Survival in the control group was 27 +/- 1.7 days, compared with more than 50 days in each of the treatment groups (P < 0.001). At the 30 mg/kg dose level, 100% of animals survived for 120 days without evidence of tumor, a substantial improvement in comparison with lower dose levels (P < 0.01). No overt toxicity was apparent even at the highest Apo2L dose. We conclude that soluble Apo2L/TRAIL is effective in inducing apoptosis in high-grade glioma cells in vitro. Because this ligand appears to exhibit selective cytotoxicity for glioma cells versus non-neoplastic cells in vitro and demonstrates significant activity in vivo when administered systemically in an otherwise uniformly fatal central nervous system glioma model system, Apo2L may constitute a useful therapeutic agent for these challenging tumors.

A Phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants: a North American Brain Tumor Consortium report.

BACKGROUND: The primary objective of the current study was to determine the response rate of paclitaxel in patients with recurrent malignant glioma by using different doses dependent on the concomitant use of anticonvulsants. Secondary objectives were to determine the time period to treatment failure, to evaluate toxicities, and to obtain pharmacokinetic data. METHODS: Adult patients who had recurrent malignant glioma were treated with paclitaxel. Patients were treated at different doses depending on the concomitant use of anticonvulsants known to induce the p450 hepatic enzyme system. Patients on such agents were treated at a dose of 330 mg/m2, whereas those not on these anticonvulsants were treated at a dose of 210 mg/m2. Tumor response was assessed at 6-week intervals. Treatment was continued until documented tumor progression or unacceptable toxicity occurred, or a total of 12 paclitaxel infusions was completed. RESULTS: From January 1997 to June 1997, 23 patients were treated with paclitaxel. Four patients were ineligible for the current study. Of the 19 eligible patients, there were no responses seen. Four (21%) had stabilization of disease. Median time to treatment failure was 1 month (95% confidence interval [CI], 1-2 mos) and median survival was 7 months (95% CI, 6-10 mos). Three patients were removed from the current study because they had toxicity. Pharmacokinetic studies demonstrated that drug levels and clearance values were consistent with previously reported findings. CONCLUSION: Even though higher doses were administered to patients who had recurrent malignant glioma and who were on concomitant anticonvulsants, there were no objective responses to paclitaxel. Time to tumor progression was 1 month. Further testing of paclitaxel at this dose schedule does not appear to be warranted in this patient population.

Congenital reactive myofibroblastic tumor of the petrous bone: case report.

OBJECTIVE AND IMPORTANCE: Myofibroblastic tumors are members of a diverse spectrum of neoplastic and quasineoplastic lesions that occur most commonly during childhood and typically involve soft tissues. We present a case of a congenital reactive myofibroblastic tumor of the petrous bone (i.e., cranial fasciitis) that was successfully treated with surgical excision. CLINICAL PRESENTATION: A newborn girl with congenital right facial palsy and deafness was noted during imaging evaluation to have a large enhancing mass that was destroying the right petrous bone and extending into the posterior and middle cranial fossae. INTERVENTION: After embolization, an open biopsy was performed, which revealed a moderately cellular, spindle cell neoplasm without mitosis or necrosis, with scattered lymphocytes, eosinophils, and multinucleated giant cells. The spindle cells demonstrated strong immunoreactivity for vimentin, muscle-specific actin, and alpha-smooth muscle actin, with prominent reticulin staining between individual cells. Staining for CD68, a histiocyte marker, was positive within the multinucleated giant cells and many of the spindle cells; CD34, S-100, and desmin staining was absent. On the basis of these findings, the lesion was classified as a reactive myofibroblastic tumor, consistent with a cranial variant of nodular fasciitis. Because of the large size and significant mass effect of the tumor, a resection was performed several days later, using a combined supra- and infratentorial approach. Dense adherence of the mass to the walls of the sigmoid sinus and the carotid artery precluded complete resection without sacrifice of these vessels, which was not performed because of the known potential of these tumors to remain stable or regress after extensive subtotal resection. The presumed residual tumor subsequently regressed, and the patient has exhibited no detectable residual disease in 2 years of follow-up monitoring. CONCLUSION: Reactive myofibroblastic tumors of the calvarium are uncommon lesions that superficially resemble sarcomas. Recognition of this diagnostic entity is important, to avoid unnecessary treatment with intensive adjuvant therapy. Although the management of these tumors relies predominantly on surgical resection, surgical decision-making should take into account the fact that small areas of residual disease can regress spontaneously.

Combination of stereotactic radiosurgery and cytokine gene-transduced tumor cell vaccination: a new strategy against metastatic brain tumors.

OBJECT: To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine. METHODS: Fifty-five rats underwent intracranial implantation of 5 x 10(3) MADB 106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB 106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5. No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by ra diosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB 106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days. CONCLUSIONS: The combination of radiosurgery and cytokine gene-transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.

Correlation of neurosurgical subspecialization with outcomes in children with malignant brain tumors.

OBJECTIVE: This study was performed to evaluate the association between the type of neurosurgeon (general or pediatric) and either the extent of tumor removal or the frequency of complications in children undergoing malignant brain tumor resections. METHODS: Data were analyzed from three recent Children's Cancer Group studies: two on medulloblastomas/primitive neuroectodermal tumors and one on malignant gliomas. Neurosurgeons were classified as general neurosurgeons, as designated pediatric neurosurgeons in their institutions, or as members of the American Society of Pediatric Neurosurgeons (ASPN), which requires pediatric neurosurgical experience and practice standards. RESULTS: Data forms from 732 children were analyzed; 485 were from children with medulloblastomas/primitive neuroectodermal tumors, and 247 were from children with malignant gliomas. Operations were performed by 269 neurosurgeons, including 213 general neurosurgeons, 29 designated pediatric neurosurgeons, and 27 ASPN members. The mean number of operations per surgeon was 1.8, 4.9, and 7.6 for general neurosurgeons, designated pediatric neurosurgeons, and ASPN members, respectively. There was a significant relationship between the extent of tumor resection or the amount of residual tumor and the type of neurosurgeon. Designated pediatric neurosurgeons and ASPN members were more likely to remove more than 90% of the tumor and to leave less than 1.5 cc of residual tumor than were general neurosurgeons (P<0.05). In these studies, the probability of extensive tumor removal correlated with the number of operations the neurosurgeon performed (P<0.01). Neurological complications occurred in the following proportion of cases: general neurosurgeons, 23%; designated pediatric neurosurgeons, 32%; and ASPN members, 18%. CONCLUSION: Pediatric neurosurgeons are more likely than general neurosurgeons to extensively remove malignant pediatric brain tumors. In these tumors, extent of removal has been demonstrated to influence survival.

Postoperative evaluation for disseminated medulloblastoma involving the spine: contrast-enhanced MR findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes.

BACKGROUND AND PURPOSE: Postoperative MR imaging is routinely performed for staging of medulloblastoma because of frequent tumor dissemination along CSF pathways. The goals of this study were to: 1) determine the timing of disease occurrence and contrast-enhanced MR imaging features of disseminated medulloblastoma involving the spine and their relationship to patient outcomes; and 2) compare the diagnostic accuracy of MR imaging findings with CSF cytologic analysis. METHODS: Medical records, pathologic reports, and unenhanced and contrast-enhanced postoperative MR images of the spine and head from 112 patients who had resection of medulloblastoma were retrospectively reviewed. MR images of the spine were evaluated for abnormal contrast enhancement in the meninges and vertebral bone marrow. MR images of the head were evaluated for recurrent or residual intracranial tumor. Imaging data were correlated with available CSF cytologic results and patient outcomes. RESULTS: Twelve patients (11%) had tumor within the spinal leptomeninges depicted on MR images at the time of diagnosis. Twenty-five patients (22%) had disseminated disease in the spine (leptomeninges, n = 22; vertebral marrow, n = 1; or both locations, n = 2) on MR images 2 months to 5.5 years (mean, 2 years) after initial surgery and earlier negative imaging examinations. Eleven other patients (10%) had recurrent intracranial medulloblastoma without spinal involvement seen with MR imaging. Spinal MR imaging had a sensitivity of 83% in the detection of disseminated tumor, whereas contemporaneous CSF cytologic analysis had a sensitivity of 60%. The sensitivity of CSF cytologic analysis increased to 78% with acquisition of multiple subsequent samples, although diagnosis would have been delayed by more than 6 months compared with diagnosis by spinal MR imaging in six patients. Spinal MR imaging was found to have greater overall diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated tumor (P = .03). Spinal MR imaging confirmed disseminated tumor when contemporaneous CSF cytologic findings were negative in 13 patients, whereas the opposite situation occurred in only two patients. False-positive results for spinal MR imaging and CSF cytologic analysis occurred when these examinations were obtained earlier than 2 weeks after surgery. The 5-year survival probability for patients with spinal tumor was 0.24 +/- 0.08 versus 0.68 +/- 0.05 for the entire study group. CONCLUSION: Spinal MR imaging was found to have greater diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated medulloblastoma. CSF cytologic analysis infrequently confirmed disseminated tumor when spinal MR imaging results were negative. Delaying spinal MR imaging and CSF cytologic analysis by more than 2 weeks after surgery can reduce false-positive results for both methods. The presence of disseminated medulloblastoma in the spine seen with MR imaging is associated with a poor prognosis.

Chiari malformation and sleep-disordered breathing: a review of diagnostic and management issues.

Chiari Malformation (CM) encompasses several patterns of congenital or acquired cerebellar herniation through the foramen magnum. This may result in brain-stem compression that impacts control of breathing and is associated with obstructive and central apneas. A high clinical suspicion for sleep-disordered breathing is needed in the care of such patients after as well as before corrective surgery. To introduce a review of CM with a focus on the relevance to sleep medicine, we present a case of a 13-year-old female who was diagnosed with CM Type 1 in the course of an evaluation of symptomatic central sleep apnea. After initial improvement following surgery there was recurrence of brain-stem compression. The only clinical expression of which was polysomnographically evident recurrence of sleep apnea.

Exploitation of immune mechanisms in the treatment of central nervous system cancer.

Malignant gliomas are among the most common intrinsic brain tumors of both children and adults, and, because of unique aspects of their biology and anatomic site, they are the most refractory to conventional therapeutic strategies involving surgery, radiotherapy, or chemotherapy. Given the failure of standard therapies to improve the outlook of affected patients, significant attention has been focused on development of alternative treatments, particularly immunotherapy. Attempts have been made to treat gliomas using a variety of immunologically based strategies, including passive immunization, adoptive cellular immunotherapy, local and systemic delivery of biological response modifiers, and vaccination with tumor cells. Although preclinical modeling of these therapies provided an impetus for translation of their results into clinical protocols, these therapies have failed to yield consistently promising results in initial trials. However, significant insights into the immunobiology of the central nervous system (CNS) and gliomas have been gained from these studies, and have established that a number of immunobiological features of the brain and of gliomas themselves may be critical determinants in regulating efficacious treatment of these tumors. These include the following: (1) the presence of a blood-brain barrier that, although partially disrupted by the tumor, functions to exclude elements of the immune system from the tumor or brain parenchyma; (2) a lack of organized secondary lymphatic tissues supporting efficient immune responses locally in the CNS; (3) low levels of expression of major histocompatibility complex proteins in the CNS; (4) an apparent paucity of the most efficient antigen-presenting cells; and (5) glioma-derived immunosuppressive factors, such as transforming growth factor-beta, that interfere with the induction of local as well as systemic immune responses to the tumor. Recognition of these factors, and an appreciation of the underlying need for and validity of developing immunologically based therapies for gliomas, supports continued development of novel immunotherapeutic approaches, particularly those attempting to enhance the immunogenicity of glioma cells. This review addresses the current state of knowledge regarding the immunobiology of gliomas, recent developments in immunotherapy of gliomas, and promising future directions for development and implementation of cellular immunotherapy of gliomas.