Children's Oncology Group's 2013 blueprint for research: central nervous system tumors.

In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5-year survival ranges from >80% (standard-risk) to 60% (high-risk). For those with high-grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5-year survival remains <10%. Sixty-five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk-based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma.

The threshold signal:noise ratio in the perception of fragmented figures.

Perception thresholds were measured for fragmented outline figures (the Gollin test). A new approach to the question of the perception of incomplete images was developed. In this approach, figure fragmentation consisted of masking with multiplicative texture-like noise--this interference was termed "invisible" masking. The first series of studies established that the "similarity" between the amplitude-frequency spectra of test figures and "invisible" masks, expressed as a linear correlation coefficient, had significant effects on the recognition thresholds of these figures. The second series of experiments showed that progressing formation of the figures was accompanied by increases in the correlation between their spatial-frequency characteristics and the corresponding characteristics of the incomplete figure, while the correlation with the "invisible" mask decreased. It is suggested that the ratio of the correlation coefficients, characterizing the "similarity" of the fragmented figure with the intact figure and the "invisible" mask, corresponds to the signal:noise ratio. The psychophysical recognition threshold for figures for naive subjects not familiar with the test image alphabet was reached after the particular level of fragmentation at which this ratio was unity.

The time course of pattern discrimination in the human brain.

In electrophysiological experiments on visual pattern discrimination, decision difficulty was manipulated either via the physical characteristics of the test stimuli, or by changing the instruction given to the observer. Visual stimuli were rectangular matrices each composed of 100 Gabor patches having different orientations. Matrices differed in the number of Gabor patches with vertical, or horizontal, orientation. The observers' task was either to discriminate the dominant orientation or to detect collinear elements in the matrix. Relating task difficulty to performance, in the first experimental paradigm (detection of orientation) we obtained the conventional S-like psychometric function but in the second (detection of collinearity) the psychometric function showed a complicated U-curve. Matching between electrophysiological and psychophysical data and image statistical functions allowed us to establish the relative timing of the cortical processes underlying perception and decision making in relation to textural features. In the first 170ms after stimulus onset coding of the low-level properties of the image takes place. In the time interval 170-400ms, ERP amplitude correlated only with complex image properties, but not with task difficulty. The first effects arising from decision difficulty were observable at 400ms after stimulus onset, and therefore this is probably the earliest electrophysiological signature of the decision making processes, in the given experimental paradigm.

High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.

PURPOSE: To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors. PATIENTS AND METHODS: Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded. RESULTS: There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34). CONCLUSION: The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.

The optical-geometrical characteristics and thresholds of perception of fragmented outline figures.

Measurements were made of the threshold of recognition of cumulatively forming line figures. The threshold value of the outline, expressed in pixels, depended on the length of the outline of the whole unfragmented figure. Relative threshold values were constant, and for the measures of figure fragments used in the present study, averaged 12.5%. A spatial frequency analysis of the test images was performed. Variation of the amplitude-frequency parameters of the spectra of the images of various figures with threshold fragmentation was minimal as compared with the variation of these parameters in figures with subthreshold or suprathreshold levels of fragmentation.

Retrovirus-mediated gene transfer as an approach to analyze neuroblastoma relapse after autologous bone marrow transplantation.

Disseminated neuroblastoma is a malignancy of children often treated by intensive chemotherapy/radiotherapy followed by autologous bone marrow transplantation (ABMT). A high proportion of those treated subsequently relapse. It is unknown if relapse is a consequence of residual disease in the patient or of contaminating malignant cells remaining in the infused marrow, which, of necessity, is harvested and stored prior to ablative chemotherapy/radiotherapy. The assumption that residual cells in the infused marrow contribute to relapse has lead to the adoption of marrow purging prior to reinfusion. However, neither the necessity nor the efficacy of the procedure have been established. We now show how retroviral-mediated gene transfer using the LNL6 vector may resolve this issue. Clonogenic neuroblastoma cells in patient marrow can be transduced and the NEOR gene detected by observing individual neuroblastoma cell colony growth in G418, and by polymerase chain reaction (PCR) of individual colonies. Efficiency of transduction is between 0 and 13.5%. If marrow is exposed to LNL6 prior to infusion and marked cells are detected at the time of relapse, this would demonstrate that infused marrow contributed to disease recurrence. The technique could then be used to analyze the efficacy of marrow purging techniques. Since normal progenitor cells from these patients are also marked, the technique can be used to study factors that modify reconstitution and transducibility of infused marrow. Clinical studies using this approach have now begun.

Immunomodulatory effects of human neuroblastoma cells transduced with a retroviral vector encoding interleukin-2.

We have investigated whether retroviral mediated transfer of the IL-2 gene renders human neuroblastoma cells immunogenic, justifying their use in a clinical tumor immunization study. Fourteen neuroblastoma cell lines were established from patients with disseminated neuroblastoma and transduced with the vector G1Ncvl2, which contains the neomycin phosphotransferase gene and the cDNA of the human interleukin-2 gene. Clones secreting > 150 pg/10(6) cells/24 h of IL-2 were selected for further study. Secretion of IL-2 was maintained for at least 3 weeks in nonselective media, implying that production of the cytokine would continue under in vivo conditions. Co-culture of IL-2 transduced cell lines with patient lymphocytes induced potent cytotoxic activity against both transduced and parental neuroblastoma cell lines. This activity was HLA unrestricted, and predominantly mediated by CD16+ or CD56+ and CD8- lymphocytes. These data form the preclinical justification for our current immunization protocol for patients with relapsed or resistant neuroblastoma.

Radon in Devon and Cornwall and paediatric malignancies.

Exposure to radon in dwellings may cause cancer including paediatric malignancies. Devon and Cornwall have the highest exposure to radon of the counties of England. However, within these counties there is considerable variation in exposure. Exposure to radon in the 283 postcode sectors of the two counties has been published. The incidence of childhood malignancies between 1976 and 1985 was studied to compare postcode sectors of radon exposures > or = 100 Bq/m3 with sectors < 100 Bq/m3. No significant difference in the incidence rate of 106.7 per million child years in the high radon postcode sectors and 121.7 in the low (P = 0.29) was found. When the incidences of individual tumours were examined, a significantly increased rate of neuroblastoma (P = 0.02) and a non-significant increased rate of acute myeloid leukaemia were found in the high exposure postcode sectors. No association between radon exposure and overall rate of childhood malignancy was found.

Object exploration and reactions to spatial and nonspatial changes in hooded rats following damage to parietal cortex or hippocampal formation.

Hooded rats with bilateral lesions of the anterior part of the hippocampal formation (HIP), anterior region of the posterior parietal cortex (APC), or posterior region of the posterior parietal cortex (PPC) were compared with controls for their exploration of 5 objects in an open field, habituation of locomotion and object investigation, and response to spatial and nonspatial change. First, all groups displayed habituation of both locomotor and exploratory activity. Second, controls selectively reexplored displaced objects, and APC-lesioned rats reexplored all objects, whereas PPC- and HIP-lesioned rats failed to react to the spatial change. Third, a novel object induced reexploration in all groups. The results are consistent with the roles of the HIP and PPC in spatial information processing. Moreover, the APC and PPC are involved in attentional effortful processing and visuospatial information processing necessary for spatial representation, respectively.

Visually guided locomotion, distractibility, and the missing-stimulus effect in hooded rats with unilateral or bilateral lesions of parietal cortex.

When hooded rats with bilateral lesions of Krieg's area 7 (parietal cortex) were trained to locomote toward visual targets in a runway, they ran less accurately than did controls, although unilaterals ran accurately. When flashing lights were presented unexpectedly during their run, bilateral parietals were less disrupted than were controls, but they failed to show total neglect. Unilateral paritals turned toward distracters on either side but turned preferentially toward distracters contralateral to the intact hemisphere, particularly when distracters occurred bilaterally and simultaneously. Effects due to the omission of expected distracters were similar in parietals and controls. Rat parietal cortex is not essential for the redirection of attention to stimuli notable for their unexpected presence or absence, but parietal cortex may resolve interhemispheric competition. The results suggest a homology between parietal cortex in rat and primate.

Distractibility following simultaneous bilateral lesions of the superior colliculus or medial frontal cortex in the rat.

Hooded rats with bilateral lesions of the superior colliculus or medial frontal cortex were compared with controls for locomotor guidance in shuttling back and forth between goal-doors at two opposite ends of a large arena. Colliculectomized rats accomplished this with great accuracy. When flashing distractor lights were introduced midway down the runway, frontal corticals and controls were severely disrupted but colliculars continued to run normally. This result was obtained both when all training occurred postoperatively (Experiment 1) and when runway performance had been stabilized preoperatively (Experiment 2), thus after a long or short postoperative recovery interval. The results offer support for previous studies with rats which have demonstrated sensory 'neglect' but good locomotor guidance after collicular ablation. Frontal corticals differed from controls only in terms of their elevated rate of repeat door-pressing upon postoperative resumption of testing in Experiment 2. Despite the similarity between effects reported elsewhere of collicular and frontal lesions made unilaterally, bilateral deficits clearly demonstrable after collicular ablation were absent here after frontal lesions. The results imply that the functional responsibilities of superior colliculus and frontal cortex in the rat are separable; at least, they have different rates of functional recovery.

Distractibility and locomotor activity in rat following intra-collicular injection of a serotonin 1B-1D agonist.

The superior colliculus (SC) is thought to be the decision center for reactions to novel and/or moving stimuli in the peripheral visual field. Serotonin 1B (5-HT1B) receptors were previously demonstrated to be located on collicular axon terminals of retinal ganglion cells and their activation might depress afferent inputs from the retina. The effects of intra-collicular injections of 5-HT1 drugs on distractibility were studied in hooded rats trained to run toward illuminated targets for a food reward in a 2-choice runway. 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), a 5-HT1A receptor agonist, RU 24969, a mixed 5-HT1A and 5-HT1B agonist, serotonin-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2), a mixed 5-HT1B and 5-HT1D receptor agonist and saline (control) were alternately injected. Following the S-CM-GTNH2 treatment alone, animals exhibited an erratic running style, involving side-to-side movements of the head, without change in the overall accuracy of their locomotor trajectories, but with substantial decrease in their running speed. When distracting peripheral lights were introduced at the mid-points of the animals' run, in the weaker distracting condition (unilateral distractor) only, distraction indexes were found lower following the S-CM-GTNH2 treatment than following the other drug or saline treatments. It is concluded that serotonin, via 5-HT1B-1D receptors, may induce an elevation of the visual distractibility threshold by modulating directly the transmission of the primary visual signal.

Exploratory activity and response to a spatial change in rats with hippocampal or posterior parietal cortical lesions.

Rats with bilateral lesions of posterior parietal cortex (PPC: Krieg's Area 7) or dorsal hippocampus (HIP) were compared with controls for their response to environmental change. In the first experiment, following subjects' exploration of a relatively homogeneous open-field environment, a stimulus-rat was introduced at a particular location beneath the glass floor. All groups selectively explored the location of the stimulus-rat, but only the control and PPC groups displayed habituation. On removal of the stimulus-rat, only the control group selectively re-explored the place where the stimulus-rat had been. A second experiment, similar to the first, used additional prominent visual cues beneath the floor. When the cues were spatially separate from the location of the stimulus-rat (Dissociated object condition), the same results were obtained as in the first experiment. When the additional cues were positioned close to the stimulus-rat location (Associated object condition), habituation occurred in all groups including the hippocampal group, and again the removal of the stimulus-rat resulted in a selective re-exploration of its former location in the control group only. However, a selective preference for staying at the stimulus-rat's previous location was found in PPC animals as in controls. Hippocampal rats failed to investigate the location of the missing stimulus in all conditions. The results confirm the role played by the hippocampus in spatial memory and suggest that the posterior parietal cortex is involved in the cognitive-demanding aspects of spatial encoding, particularly in environments that are poorly visually differentiated.

Effects of parietal cortex lesions on spatial problem solving in the rat.

The Maier 3-table task was used to examine spatial representations in rats with lesions of the parietal cortex. Some animals had anteriorly placed lesions, some posteriorly placed in cortical areas, sometimes regarded as 'parietal' in earlier studies. After 5 days of familiarization, animals were given 18 days of testing on the standard Maier task. Both parietal groups were initially impaired, but reached the same level of performance as controls by the end of the test period. Learning occurred both within and between sessions for the anterior group, but only between sessions for the posterior group. There was no major functional differentiation apparent on this task between the two 'parietal' areas. Rate of exploration increased in both parietal groups across test sessions as task performance improved. It is argued that the change in exploratory activity across sessions in parietal groups may reflect the adoption of a compensatory strategy which improved performance, but that improvement could also have been due to neural changes, as structures, such as the frontal cortex or hippocampus, assume some functions normally mediated by the parietal area.

Spatial information transfer from virtual to real versions of the Kiel locomotor maze.

The Kiel locomotor maze requires participants to choose five targets from among 20 locations marked by small red lights on the floor of a dimly lit circular environment having four wall-mounted extramaze cues and two intramaze cues at floor level. In the present study, acquisition of the real task was examined in 11-year-old children following prior accurate training in a virtual version, following misleading virtual training, or following no training. The virtual version was displayed on a desk-top computer monitor. Acquisition testing in the real maze was either locomotor or non-locomotor. Good transfer was achieved from virtual to real versions. Children's exploration of the real maze prior to real maze acquisition training revealed a clear transfer of spatial information previously learned in the virtual version. Children taught the correct target configuration in the simulation made fewer errors and more rapid, confident responses to targets in the real maze than children given no training. However, acquisition was also better following misleading training than no training, suggesting that a non-specific components of performance also transferred. Male superiority was only seen following misleading training, which was interpreted in terms of male superiority in mental rotation. After acquisition, a single probe trial was performed, in which proximal cues and participants' starting position were rotated, but this had equivalent effects on all groups' performance. It is clear that transfer of spatial information occurs from the simulated Kiel maze to the real version. This has implications for its use in diagnosis and training.

Second-look surgery for incompletely resected fourth ventricle ependymomas: technical case report.

OBJECTIVE AND IMPORTANCE: The prognosis for patients with ependymomas is related to the adequacy of surgical clearance. It is, however, often not possible to obtain a macroscopically complete resection of tumors arising in the posterior fossa. This may be because of the involvement of structures, the sacrifice of which would result in unacceptable morbidity, or because of metastatic lesions at diagnosis. For those patients in whom initial surgery was incomplete, elective second-look surgery may allow more complete clearance of tumor. INTERVENTION: We have performed second-look surgery for fourth ventricle ependymomas in five patients: two women, aged 26 and 27 years, and three male patients, aged 4 months, 19 months, and 18 years. The 19-month-old male patient underwent early second-look surgery without receiving any interim chemotherapy. Second-look surgery on the other four patients was performed after they had received chemotherapy. No additional major morbidity was associated with the subsequent surgery, which achieved macroscopically complete clearances in four of the five patients. Three of four patients who underwent macroscopically complete resections were well, without clinical or radiological evidence of recurrent tumor, at 23, 25, and 34 months after their second operations. The 10-month-old patient who underwent early second-look complete resection relapsed locally at 33 months after surgery. Complete resection was not possible in one patient who had progressive tumor 8 months after second-look surgery. CONCLUSION: For patients in whom complete excision of fourth ventricle ependymomas is not possible at initial surgery, second-look procedures may enable macroscopic clearance to be achieved with little morbidity. A larger study is needed to evaluate this approach to treatment.

Tamoxifen radiosensitization in human glioblastoma cell lines.

OBJECT: A combined tamoxifen and radiation therapy is being used in clinical trials to treat glioblastoma multiforme (GBM). The rationale behind this therapy is that tamoxifen is a radiosensitizer. However, the evidence for this is weak. The authors, therefore, examined the effect of combined radiation-tamoxifen therapy in three GBM cell lines of human origin. METHODS: The GBM cell lines were exposed to different concentrations (0.3-5 microg/ml) of tamoxifen and subsequently irradiated at varying doses (0.8-5 Gy). Tumor growth inhibition was measured using a proliferation assay. The interaction of tamoxifen and radiation therapies was quantified using the combination index method, which distinguishes whether a combined antitumor effect is synergistic, additive, or antagonistic. At high doses of tamoxifen or radiation there was significant inhibition of tumor cell proliferation. At low doses of either therapeutic agent, there was little effect. In one cell line, synergism occurred at high doses of tamoxifen and radiation. In the other two cell lines, an additive effect was observed. In only one of the three cell lines was there synergy between tamoxifen and radiation at doses that significantly inhibited tumor proliferation. CONCLUSIONS: Because synergy could not be demonstrated in all three cell lines at active dosages, the clinical combination of tamoxifen and radiation therapies may not be of benefit to all patients.

Congenital malignant rhabdoid tumour of the gum margin.

The case of an infant born with a large polypoid tumour arising from the mouth is described. The tumour had the histological, immunohistochemical and ultrastructural phenotype of an extrarenal malignant rhabdoid tumour and followed an aggressive clinical course. This is one of the few reported cases of malignant rhabdoid tumour to present at birth. The oral tumour was associated with a mass in the posterior cranial fossa. This was most likely to be a simultaneous second primary tumour.

Head-dipping in rats with superior collicular, medial frontal cortical and hippocampal lesions.

When tested in a modified "holeboard" apparatus, hooded rats with deep superior collicular lesions were hyperactive, reared less than controls and spent a great deal of time at the apparatus perimeter. They failed to explore holes in the floor and frequently fell into them. Those with lesions restricted to superficial laminae showed reduced rearing, and preference for the perimeter but were normally active and explored floor holes as frequently as controls. The frontal cortical group failed to differ from controls on any measure. Hippocampals exhibited reduced intersession habituation of locomotor activity. It was concluded that superior colliculus, hippocampus and medial frontal cortex have separate functional roles. Differences between deep and superficial collicular lesion effects might arise because deep lesions disrupt both motor integration and attention while superficial lesions disrupt only the latter. Alternatively, since superficial lesions spare lateral tissue subserving attention to stimuli in lower portions of the visual field, they may produce a less global attentional deficiency which has less impact upon motor function.

A rapid test of rodents' vision using a modified open field apparatus.

Rats' responses to visual change in the environment were recorded in open field arenas in which a part or all of the visual environment could be altered without changing nonvisual features. Rats responded to a change in the appearance of one quadrant of a field by selectively reexploring the changed quadrant, and to a change in the whole environment by generally increasing their locomotor activity. The latter effect was equally large whether the change was from a patterned to a blank environment, or vice-versa. The present paradigms provide a rapid means of testing animals' vision.