Pediatric Atypical Teratoid/Rhabdoid Tumors of the Brain: Identification of Metabolic Subgroups Using In Vivo 1H-MR Spectroscopy.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

Myeloid PTEN deficiency impairs tumor-immune surveillance via immune-checkpoint inhibition.

Tumor-host interaction is determined by constant immune surveillance, characterized by tumor infiltration of myeloid and lymphoid cells. A malfunctioning or diverted immune response promotes tumor growth and metastasis. Recent advances had been made, by treating of certain tumor types, such as melanoma, with T-cell checkpoint inhibitors. This highlights the importance of understanding the molecular mechanisms underlying the crosstalk between tumors and their environment, in particular myeloid and lymphoid cells. Our aim was to study the contribution of the myeloid PI3K/PTEN-signaling pathway in the regulation of tumor-immune surveillance in murine models of cancer. We made use of conditional PTEN-deficient mice, which exhibit sustained activation of the PI3K-signaling axis in a variety of myeloid cell subsets such as macrophages and dendritic cells (DCs). In colitis-associated colon cancer (CAC), mice deficient in myeloid PTEN showed a markedly higher tumor burden and decreased survival. We attributed this observation to the increased presence of immune-modulatory conventional CD8α(+) DCs in the spleen, whereas other relevant myeloid cell subsets were largely unaffected. Notably, we detected enhanced surface expression of PD-L1 and PD-L2 on these DCs. As a consequence, tumoricidal T-cell responses were hampered or redirected. Taken together, our findings indicated an unanticipated role for the PI3K/PTEN-signaling axis in the functional regulation of splenic antigen-presenting cells (APCs). Our data pointed at potential, indirect, tumoricidal effects of subclass-specific PI3K inhibitors, which are currently under clinical investigation for treatment of tumors, via myeloid cell activation.

Abnormal microstructure of the atrophic thalamus in preterm survivors with periventricular leukomalacia.

BACKGROUND AND PURPOSE: The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions. MATERIALS AND METHODS: We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years). RESULTS: The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ(⊥) (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network. CONCLUSIONS: There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.

Apparent diffusion and fractional anisotropy of diffuse intrinsic brain stem gliomas.

BACKGROUND AND PURPOSE: DIBSGs have the worst prognosis among pediatric brain tumors with no improvement of outcome for several decades. In this study, we determined whether diffusion imaging could improve patient stratification and our understanding of the impact of therapies. MATERIALS AND METHODS: Nine baseline and 24 follow-up DTI studies performed in 9 patients on a 1.5T clinical MR imaging scanner were reviewed. ADC and FA were measured for the whole lesion and at 5 anatomic levels: the rostral medulla, caudal pons, midpons, rostral pons, and caudal midbrain. Reference data were obtained from 8 controls with normal brain stem, 6 patients with medulloblastoma, and 7 patients with pilocytic astrocytoma. RESULTS: ADC was higher in untreated DIBSG than in normal brain stem and medulloblastoma (1.14 ± 0.18 [×10⁻³ mm²/s] versus 0.75 ± 0.06 and 0.56 ± 0.05, both P < .001). FA was lower in DIBSG than in normal brain stem (0.24 ± 0.04 versus 0.43 ± 0.02, P < .001) but was higher than that in pilocytic astrocytoma (0.17 ± 0.05, P < .05). Lower baseline ADC and higher FA correlated with a worse clinical course. Correlations were more significant at the caudal midbrain than in other regions. ADC decreased and FA increased after RT. Changes of FA after RT at the caudal midbrain correlated with event-free survival. CONCLUSIONS: Baseline ADC and FA of DIBSG revealed hypocellular tumors with extensive edema. Diffusion changes after therapy implied reduced edema but did not support a significant response to therapy. The significance of diffusion properties varied with anatomic locations, the caudal midbrain being particularly important.

Citrate in pediatric CNS tumors?

BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors. MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute "apparent" concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined. RESULTS: "Apparent" citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 +/- 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. "Apparent" citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 +/- 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 +/- 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 +/- 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 +/- 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,. CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.

Quantitative short echo time 1H-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization.

PURPOSE: Our aims were to evaluate the metabolic profiles of pediatric brain tumors with short echo time (TE) MR spectroscopy and absolute quantitation of metabolite concentrations (in mmol/kg of tissue) and to describe metabolic features that distinguish individual tumor types and that may help to improve preoperative diagnosis of specific tumors. METHODS: MR imaging examinations of 60 patients with untreated brain tumors (14 medulloblastomas, 5 anaplastic astrocytomas, 3 low-grade astrocytomas, 17 pilocytic astrocytomas, 4 anaplastic ependymomas, 5 ependymomas, 3 choroid plexus papillomas, 3 choroid plexus carcinomas, and 6 pineal germinomas) were reviewed. Single-voxel proton MR spectroscopy with a TE of 35 ms was performed and absolute metabolite concentrations were determined by using fully automated quantitation. RESULTS: Taurine (Tau) was significantly elevated in medulloblastomas (P < .00001) compared with all other tumors pooled (All Other). Tau was also observed consistently, at lower concentration, in pineal germinomas. Creatine (Cr) was significantly reduced in pilocytic astrocytomas, distinguishing them from All Other (P < .000001). The MR spectra of choroid plexus papillomas exhibited low Cr (P < .01) concentrations; however, myoinositol was elevated (P < .01) and total choline (tCho) (P < .0001) was reduced relative to All Other. Choroid plexus carcinomas had low Cr (P < .01 versus All Other) and the lowest Cr/tCho ratio (P < .0001 versus All Other) among all tumors studied. Guanidinoacetate was reduced in low-grade astrocytomas and anaplastic astrocytomas (P < .00001) versus All Other, whereas ependymoma and anaplastic ependymomas exhibited particularly low N-acetylaspartate (P < .00001 versus All Other). CONCLUSION: Quantitative proton MR spectroscopy reveals features of pediatric brain tumors that are likely to improve preoperative diagnoses.

Oligotide, a defibrotide derivative, protects human microvascular endothelial cells against fludarabine-induced activation, damage and allogenicity.

Fludarabine is a nonmyeloablative immunosuppressant increasingly used as a component of alternative reduced-intensity conditioning regimens prior to allogeneic stem cell transplantation (SCT). However, we have previously shown that 2-fluoroadenine 9-beta-D-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine induces damage, activation and allogenicity in human microvascular endothelial cells (HMEC). We had also identified the pharmaceutic compound Defibrotide (DF), originally used in the treatment of veno-occlusive disease and thrombotic microangiopathy, as being protective against F-Ara-induced dysfunction of HMEC, importantly, without affecting the antileukemic effect of F-Ara. In the present report, we show that a recently developed derivative of DF, Oligotide, similarly downregulates F-Ara-induced activation and damage of HMEC as well as their antigenicity for allogeneic CD8+ T cells. In addition, Oligotide could also block F-Ara-mediated transendothelial migration of peripheral blood cells across the HMEC barrier. Taken together, these observations argue for a potential clinical use of both DF and Oligotide in pre transplant conditioning.

Efficacy of proton magnetic resonance spectroscopy in clinical decision making for patients with suspected malignant brain tumors.

We wished to determine the utility of single voxel proton (1H) magnetic resonance spectroscopy (MRS) when used as an alternative or adjunct to brain biopsy in patients harboring lesions suggestive of brain tumors identified by MRI scan. Fifteen patients (age 7-58 years) with MRI scans and clinical histories suggestive of primary brain tumors underwent single voxel 1H-MRS. MRS (16 regions of interest in 15 patients) was used to aid in differentiation between tumor and other pathologies such as stroke or demyelinating plaque (n = 6), radiation necrosis (n = 5), or edema (n = 5). Spectra were quantified to determine absolute molar values of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), lactate (LAC), and myo-inositol (mI), metabolite ratios relative to Cr were calculated, and spectra were interpreted based on metabolite ratios. Subsequent clinical management was based on MRS interpretation, and patients were then followed to determine if MRS interpretation accurately predicted clinical outcome or surgical findings. Mean follow-up was 12.5 months (range 3-28 months). MRS suggested the presence of recurrent tumor in 7 cases, all of which were subsequently 'confirmed' by tumor resection (n = 4) or disease progression (n = 3). MRS suggested the presence of new tumor in 1 case, subsequently confirmed by surgical resection. MRS suggested the presence of necrosis in 3 patients; all 3 remained radiographically stable during the follow-up period, and one was confirmed by stereotactic biopsy. MRS suggested non-neoplastic lesions in 4 cases, 3 of whom were followed until radiographic resolution of lesions and one of which was confirmed as a pyogenic abscess via stereotactic aspiration. Overall, MRS accurately predicted the pathological nature and clinical outcome of lesions in 15/16 (96%) situations, influenced clinical decision making in 12 cases, and altered surgery planning in 7 patients. In appropriate circumstances MRS can reduce the need for biopsy, and provide an important guide for clinical decision-making in difficult cases.

Proton-decoupled 31P magnetic resonance spectroscopy reveals osmotic and metabolic disturbances in human hepatic encephalopathy.

Quantitative proton and quantitative proton-decoupled 31P magnetic resonance spectroscopy (MRS) of the brain was performed in 16 patients with liver disease (10 with and six without chronic hepatic encephalopathy) and four patients with hyponatremia, as well as 20 age-matched normal subjects. Patients with hepatic encephalopathy were distinguished from controls by significant reduction in levels of cerebral nucleoside triphosphate (2.45 +/- 0.20 vs. 2.91 +/- 0.21 mmol/kg of brain; p < 0.0003), inorganic phosphate (p < 0.03), and phosphocreatine (p < 0.04). In addition of increased levels of cerebral glutamate plus glutamine and decreased concentrations of myo-inositol, patients with hepatic encephalopathy showed a reduction of total visible choline and of glycerophosphorylcholine (0.67 +/- 0.13 vs. 0.92 +/- 0.20 mmol/kg of brain in controls; p < 0.005) in 1H MRS, and of glycerophosphorylethanolamine (0.40 +/- 0.12 vs. 0.68 +/- 0.12 mmol/kg of brain in controls; p < 0.0003) in proton-decoupled 31P MRS. Of the reduction of "total choline," 61% was accounted for by glycerophosphorylcholine, a cerebral osmolyte. Similar metabolic abnormalities were seen in hyponatremic patients. The results are consistent with disturbances of cerebral osmoregulation and energy metabolism in patients with chronic hepatic encephalopathy.

Quantitative proton-decoupled 31P MRS and 1H MRS in the evaluation of Huntington's and Parkinson's diseases.

OBJECTIVE: To determine cerebral energy status in patients with Huntington's disease (HD) and Parkinson's disease (PD). METHODS: The study included 15 patients with DNA-proven, symptomatic HD and five patients with medically treated, idiopathic PD, all of whom were candidates for neurotransplant treatment, as well as 20 age-related normal subjects. Quantitative noninvasive, MRI-guided proton MRS was performed of single volumes in putamen of basal ganglia (BG), occipital gray matter, and posterior parietal white matter; in addition, quantitative phosphorus and proton-decoupled phosphorus MRS of superior biparietal white and gray matter was done. Outcome measures were quantitative metabolite ratios and millimolar concentrations of neuronal and glial markers, creatine (Cr) and adenosine triphosphate (ATP), and intracellular pH. RESULTS: In volume-corrected control BG (10.46 +/- 0.37 mM), [Cr] was 29% (p < 0.05) higher than in control gray matter (8.10 +/- 1.04 mM). In HD and PD, energy metabolism was not abnormal in the four cerebral locations measured by MRS. No increase in cerebral lactate or decrease in phosphocreatine and ATP was detected. Small, systematic abnormalities in N-acetylaspartate (NAA, decreased), Cr (decreased), choline-containing compounds (Cho, increased), and myoinositol (mI, increased) were demonstrable in all patient's individually and in summed spectra but were insufficient to make diagnosis possible in the individual patient. CONCLUSION: Previously described failure of global energy metabolism in HD was not confirmed. However, quantitative 1-hydrogen MRS and decoupled 31-phosphorus MRS are sensitive to +/-10% alterations in key cerebral metabolites, and may be of value in noninvasive monitoring of appropriate therapies.

A comparison of magnetization prepared 3D gradient-echo (MP-RAGE) sequences for imaging of intracranial lesions.

In a pilot study including 64 patients with different types of brain tumors we investigated four types of MP-RAGE sequences. The sequences differ in the length of the recovery period and the data acquisition mode (sequential vs. centric phase-encoding). The sequence with sequential encoding and a short recovery period provided images that reached the quality and reliability of spin-echo images. The other MP-RAGE sequences failed in providing equivalent information. In particular, a considerable number of small lesions identified in spin-echo images were not detected in MP-RAGE images. The impact of the evolving magnetization on the point spread function was analyzed by performing simulation calculations. It was found that lesions with short T1 times are rendered with low spatial resolution when sequence parameters are not set appropriately. The low overall quality of images obtained by sequences applying centric encoding may be explained by eddy current effects as reported in other recently published studies.

[MR tomography of lung metastases with rapid gradient echo sequences. Initial results in diagnostic applications]. / MR-Tomographie von Lungenmetastasen mit schnellen Gradientenechosequenzen. Erste Ergebnisse in der diagnostischen Anwendung.

Rapid gradient echo sequences enable MR imaging (MRI) of pulmonary metastases with acquisition times of less than 1 s per slice. By optimization of this technique, density, T1- and T2-weighted images can be obtained (FLASH: TR 6.5 ms, TE2 = 3 ms, alpha = 10 degrees; T1w-Turbo-FLASH: TI 200 ms, TR 6.5 ms, TE2 = 3 ms, alpha = 10 degrees; T2w-Turbo-FLASH: TE1 = 50 ms, TR = 6.5 ms, TE2 = 3.5 ms; alpha = 10 degrees). In a prospective study 25 patients in whom pulmonary metastases were suspected were examined with three techniques in all three anatomical planes prior to surgery. All lung metastases revealed a high signal intensity on the FLASH as well as the T2w-Turbo-FLASH images, whereas vascular structures revealed a low signal intensity on the T2-weighted Turbo-FLASH images. Analysis regarding detection and correct number of lung metastases per patient with MRI compared with the histology revealed (n = 25): sensitivity of 82%, specificity 67%, positive predictive value of 95% and negative predictive value of 33%. While MRI does not currently have any diagnostic advantages over CT, the excellent differentiation of parenchymal lesions and vascular structures without the use of contrast medium and the variability of imaging planes are significant methodological advantages.

Improved target volume definition for precision radiotherapy planning of meningiomas by correlation of CT and dynamic, Gd-DTPA-enhanced FLASH MR imaging.

In this methodological paper the authors report a fast, T1-weighted gradient-echo sequence (FLASH) for dynamic, Gd-DTPA-enhanced magnetic resonance (MR) imaging of meningiomas and its application in precision radiotherapy planning. Indications for radiotherapy included unresected tumors, tumor remaining after surgery, and recurrences. The patient's head was fixed in a stereotactic localization system which is usable at the CT, MR and the linear accelerator installations. By phantom measurements different materials (steel, aluminum, titanium, plastic, wood, ceramics) used for the stereotactic system were tested for mechanical stability and geometric MR image distortion. All metallic stereotactic rings (closed rings made of massive metal) led to a more or less dramatic geometric distortion and signal cancellation in the MR images. The best properties--nearly no distortion and high mechanic stability--are provided by a ceramic ring. If necessary, the remaining geometric MR image distortion can be 'corrected' (reducing displacements to the size of a pixel) by calculations based on modeling the distortion as a fourth order two-dimensional polynomial. The target volume was defined in dynamic, T1-weighted FLASH MR images, which were measured before, during, and after the controlled intravenous infusion of 0.1 mmol/kg body weight Gd-DTPA. The stereotactic localization technique allows the precise transfer of the target volume information from MR onto CT data to provide a map of the radiation attenuation coefficient for dose calculation. In genera, the superior soft tissue contrast of MR showed an excellent tumor delineation, especially in regions, such as the base of the skull, where the target often was obscured in CT images.(ABSTRACT TRUNCATED AT 250 WORDS)

3D MPRAGE evaluation of lesions in the posterior cranial fossa.

Standard spin-echo images of the posterior cranial fossa are usually impaired by pulsation artifacts. We evaluated a heavily T1 weighted MPRAGE sequence (TR/TE/alpha/TI = 10/4/10-15 degrees/200-350) for detection of intracerebral lesions in the posterior fossa in 11 patients. Overall quality of the MPRAGE images was superior due to the lack of pulsation artifacts, high S/N and excellent gray-white matter contrast. Lesion detection was better in one patient, equal in six and inferior in four patients compared to SE technique. A cerebellar metastasis (8 mm) in one patient was completely blurred from pulsation artifacts on the SE images. Whereas multiple small lesions (< or = 4 mm) with discrete contrast enhancement were missed on the MPRAGE images in three patients. We conclude, that the MPRAGE sequence yields high quality images with isotropic spatial resolution in a reasonable time. But MPRAGE with these parameters can not replace standard SE images in screening the posterior fossa, because of a decreased sensitivity in the detection of small contrast-enhancing lesions.

Radiosurgical treatment planning of brain metastases based on a fast, three-dimensional MR imaging technique.

A fast, three-dimensional (3D) sequence for magnetic resonance (MR) imaging of the brain and its application in radiosurgical treatment planning of brain metastases is reported. The measuring sequence (MPRAGE) requires magnetization-prepared 180 degrees inversion pulses followed by rapid low angle excitation pulses and gradient-echoes for image generation. The resulting T1-weighted MPRAGE images were compared with two-dimensional (2D) T1-weighted spin-echo (SE) images after administration of 0.1 mmol/kg b.w. Gd-DTPA in 10 patients with known brain metastases. Original or multiplanar reformatted images obtained from a 128 partition data set of the 3D MPRAGE sequence offered comparable diagnostic quality to that of 2D SE imaging. Gd-DTPA enhancement and lesion targeting was similar in most of the patients in SE as well as MPRAGE imaging. During imaging and therapy the patient's head was fixed in a stereotactic localization system which is usable at the MR and the linear accelerator installations. The dose calculation of the radiosurgery planning was based on 3D MR imaging data assuming a homogenous attenuation value inside the head which was sufficient for an accurate dose calculation since tissue inhomogeneities do not significantly influence the shape of the relative dose distribution especially for radiosurgery of the brain. Under this circumstance the dose calculation can be based only on the 3D geometric conformation of the patient's head. A simple algorithm for treatment planning can be used if the MR data are free of geometric distortion.(ABSTRACT TRUNCATED AT 250 WORDS)

MR image texture analysis--an approach to tissue characterization.

The role and value of texture analysis in the quantification of medical images is reviewed and the various methods described. The promise in magnetic resonance imaging is discussed and the coordinated research programme being carried out within the framework of the European Economic Community Concerted Action on Tissue Characterization by MRS and MRI is outlined. Tissue characterization of the human brain has been performed by texture analysis of proton relaxation time images using a standard MR whole body imager operating at 1.5 T and the results are presented.

MR tissue characterization of intracranial tumors by means of texture analysis.

Tissue characterization of the human brain has been performed by texture analysis of proton relaxation time images using a standard MR whole body imager operating at 1.5 T. A combined CP/CPMG multi-echo, multislice sequence was used to measure T1 and T2 in each pixel with an uncertainty not exceeding 10%. In a prospective clinical study, 12 patients with histologically confirmed brain tumors were investigated. For each ROI in the calculated T1 and T2 parameter images, texture parameters originating from the grey level distribution, the gradient distribution, the grey level co-occurrence matrix, and the grey level runlength histogram were used for classification and discrimination between tissues. All regions corresponding to the normal brain tissue (white matter, grey matter, cerebrospinal fluid) were successfully discriminated from each other as well as from the pathological tissue parts (edema and tumor). The classification of 10 edematous and 8 tumorous tissue regions yielded only one misclassification. Together with additional rules, these discrimination rules formed the knowledge base of an expert system for segmentation of the brain images. In cases of tumors without Gd-DTPA contrast medium uptake or in cases of Gd-DTPA contraindication, segmentated images can help solve nontrivial diagnostical problems such as delineating the target volume in radiation therapy.