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Forest soils (mainly soil organic carbon) play an important role in the retention of nitrogen and mercury, and loss of the forest floor during wildfires can stimulate N and Hg losses. In this paper, we investigate long-term impacts of forest fire on soil N and Hg concentrations at Acadia National Park (ANP) in Maine. Acadia National Park experienced a severe fire in 1947. Within the national park, Hadlock Brook watershed was left unburned, whereas most of Cadillac Brook watershed was intensely burned, with substantial loss of the forest floor. Post-fire regeneration in Cadillac was mostly as hardwood species, whereas vegetation in Hadlock remained predominantly softwood. We sampled soils in both watersheds in 2015, approximately 70 years after the fire. The soils were analyzed for total carbon (TC), total nitrogen (TN), total mercury (THg), and methylmercury (MeHg) content. Compared to Hadlock, Cadillac soils had ~ 50% lower TC, ~ 40% lower TN, and ~ 50% lower THg content, reflecting the loss of forest floor 70 years ago. Methylmercury concentrations in Cadillac were approximately 2 times the concentrations in Hadlock, indicating that conditions were more conducive to methylation, potentially due to differences in forest type. Long-term comparisons of stream DOC, NO3−, and THg concentrations between the two watersheds demonstrated that concentrations were significantly lower in Cadillac Brook, reflecting greater retention in Cadillac and a legacy of lower atmospheric deposition in the hardwood as compared to softwood watershed. This study provides insights on the multi-decadal recovery from a stand-replacing disturbance and underscores the persistence of altered soil biogeochemistry.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.

As a result of reductions in sulfate deposition and changing climate, dissolved organic carbon (DOC) concentrations have increased in many lakes situated in forests of northeastern North America and northern Europe since the 1990s. Although this increase is well documented, the associated ecological implications remain unclear. In particular, DOC strongly influences the vertical temperature structure of lakes, with increasing DOC often leading to a shallower epilimnion. We investigated the effect of increased DOC concentrations on lake thermal structure using fossil diatom records from six remote Maine lakes. Sedimentary diatom profiles from three pairs of small (

This study evaluated the contribution of winter rain-on-snow (ROS) events to annual and seasonal nitrate (N-NO3) export and identified the regional meteorological drivers of inter-annual variability in ROS N-NO3 export (ROS-N) at 9 headwater streams located across Ontario, Canada and the northeastern United States. Although on average only 3.3 % of annual precipitation fell as ROS during winter over the study period, these events contributed a significant proportion of annual and winter N-NO3 export at the majority of sites (average of 12 and 42 %, respectively); with the exception of the most northern catchment, where total winter precipitation was exceptionally low (average 77 mm). In years with a greater magnitude of ROS events, the timing of the peak N-NO3 export period (during spring melt) was redistributed to earlier in the year. Variability in ROS frequency and magnitude amongst sites was high and a generalised linear model demonstrated that this spatial variability could be explained by interactive effects between regional and site-specific drivers. Snowpack coverage was particularly important for explaining the site-specific ROS response. Specifically, ROS events were less common when higher temperatures eliminated snow cover despite increasing the proportion of winter rainfall, whereas ROS event frequency was greater at sites where sufficient snow cover remained. This research suggests that catchment response to changes in N deposition is sensitive to climate change; a vulnerability which appears to vary in intensity throughout the seasonally snow-covered temperate region. Furthermore, the sensitivity of stream N-NO3 export to ROS events and potential shifts (earlier) in the timing of N-NO3 export relative to other nutrients affect downstream nutrient stoichiometry and the community composition of phytoplankton and other algae.

Purpose To develop a compressed sensing (CS) acceleration method with a high spectral bandwidth exploiting the spatial-spectral sparsity of MR spectroscopic imaging (MRSI). Methods Accelerations were achieved using blip gradients during the readout to perform nonoverlapped and stochastically delayed random walks in kx-ky-t space, combined with block-Hankel matrix completion for efficient reconstruction. Both retrospective and prospective CS accelerations were applied to 13C MRSI experiments, including in vivo rodent brain and liver studies with administrations of hyperpolarized [1-13C] pyruvate at 7.0 Tesla (T) and [2-13C] dihydroxyacetone at 3.0 T, respectively. Results In retrospective undersampling experiments using in vivo 7.0 T data, the proposed method preserved spectral, spatial, and dynamic fidelities with R2 ≥ 0.96 and ≥ 0.87 for pyruvate and lactate signals, respectively, 750-Hz spectral separation, and up to 6.6-fold accelerations. In prospective in vivo experiments, with 3.8-fold acceleration, the proposed method exhibited excellent spatial localization of metabolites and peak recovery for pyruvate and lactate at 7.0 T as well as for dihydroxyacetone and its metabolic products with a 4.5-kHz spectral span (140 ppm at 3.0 T). Conclusions This study demonstrated the feasibility of a new CS approach to accelerate high spectral bandwidth MRSI experiments. Magn Reson Med, 2016. © 2016 Wiley Periodicals, Inc.

Purpose The purpose of this study was to characterize tissue-specific alterations in metabolism of hyperpolarized (HP) gluconeogenic precursors 13 C-lactate and 13 C-pyruvate by rat liver and kidneys under conditions of fasting or insulin-deprived diabetes. Methods Seven normal rats were studied by MR spectroscopic imaging of both HP 13 C-lactate and 13 C-pyruvate in both normal fed and 24 h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with insulin withdrawal. Phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ-treated rats. Results Multiple sets of significant signal modulations were detected, with graded intensity in general between fasting and diabetic states. An approximate two-fold reduction in the ratio of 13 C-bicarbonate to total 13 C signal was observed in both organs in fasting. The ratio of HP lactate-to-alanine was markedly altered, ranging from a liver-specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86-fold and 2.73-fold increases in PEPCK expression in liver and kidney, respectively. Conclusion MRI of HP 13 C gluconeogenic precursors may advance diabetes research by clarifying organ-specific roles in abnormal diabetic metabolism. Magn Reson Med 77:1429-1437, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

PURPOSE Dissolution dynamic nuclear polarization (DNP) enables the acquisition of 13 C magnetic resonance data with a high sensitivity. Recently, metabolically inactive hyperpolarized 13 C-labeled compounds have shown to be potentially useful for perfusion imaging. The purpose of this study was to validate hyperpolarized perfusion imaging methods by comparing with conventional gadolinium (Gd)-based perfusion MRI techniques and pathology. METHODS Dynamic 13 C data using metabolically inactive hyperpolarized bis-1,1-(hydroxymethyl)-[1-13 C]cyclopropane-d8 (HMCP) were obtained from an orthotopic human glioblastoma (GBM) model for the characterization of tumor perfusion and compared with standard Gd-based dynamic susceptibility contrast (DSC) MRI data and immunohistochemical analysis from resected brains. RESULTS Distinct HMCP perfusion characteristics were observed within the GBM tumors compared with contralateral normal brain tissue. The perfusion parameters obtained from the hyperpolarized HMCP data in tumor were strongly correlated with normalized peak height measured from the DSC images. The results from immunohistochemical analysis supported these findings by showing a high level of vascular staining for tumor that exhibited high levels of hyperpolarized HMCP signal. CONCLUSION The results from this study have demonstrated that hyperpolarized HMCP data can be used as an indicator of tumor perfusion in an orthotopic xenograft model for GBM. Magn Reson Med 77:841-847, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Infiltrating low-grade gliomas (LGGs) are a class of terminal central nervous system tumors that comprise malignant neuroglia. Histopathological diagnosis of tumor grade is performed using criteria set by the World Health Organization (WHO) and is based on factors that include nuclear atypia, proliferative capacity, tumor neovascularization, and necrosis.1 The clinical outcome for patients with LGG is variable, with some lesions following a more indolent disease course, while others recur more rapidly and often after undergoing malignant transformation (MT) to a higher grade.2 Lesions that have thus transformed to a grade III anaplastic glioma or grade IV secondary glioblastoma multiforme (GBM) are managed with additional, more aggressive treatments. To date, little is known regarding the nature of recurrent disease, and the most significant prognostic factors for patients diagnosed with LGG are the presence of somatic driver mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes and the codeletion of the 1p and 19q chromosomal arms, which have been associated with increased survival and sensitivity to the treatment given.2–5 IDH mutations have been implicated as an initiating event in gliomagenesis and are key to reprogramming the tumor epigenome and metabolome, largely through neomorphic production and accumulation of 2-hydroxyglutarate.6 Given uncertainties regarding the effectiveness of options available for treating LGGs, IDH mutations have garnered significant attention as a targetable therapeutic pathway, and there are several novel therapies on the horizon.7–9 Until these therapeutics become available, the clinical mainstay of treatment for patients with LGG consists of surgical resection, with radiation therapy and alkylating chemotherapy being typically reserved for recurrences that were either subtotally resected or have undergone MT. MRI is an integral component of brain tumor diagnosis and monitoring. Recent advances in state-of-the-art techniques have enabled the noninvasive assessment of tumor morphology and physiology, with primary GBM having been studied most extensively. Although the ability to noninvasively detect MT would be of significant clinical interest for diagnosis and treatment planning, few studies have focused on addressing this question. Multiparametric MRI holds significant promise for comprehensively characterizing the structural and physiological properties of the tumor. We hypothesize that these advanced imaging techniques may also provide improved characterization of MT in patients with recurrent LGG. The objective of this study was to establish multiparametric MRI profiles of patients with tumors prior to image-guided surgery in order to relate metrics obtained from these methodologies to histopathological grade. Volumetric regions with abnormal imaging features were calculated to provide a robust assessment of the entire recurrent tumor lesion. Regions of viable tumor were targeted for image-guided tissue sampling in order to associate in vivo parameters with histopathological features and to strengthen our understanding of the link between glioma tumor biology and parameters from noninvasive imaging.

Interannual climate variability is expected to increase over the next century, but the extent to which hydroclimatic variability influences biogeochemical processes is unclear. To determine the effects of extreme weather on surface water chemistry, a 30-year record of surface water geochemistry for 84 lakes in the northeastern U.S. was combined with landscape data and watershed-specific weather data. With these data, responses in sulfate (SO4 2−) and dissolved organic carbon (DOC) concentrations were characterized during an extreme wet year and an extreme dry year across the region. Redundancy analysis was used to model lake chemical response to extreme weather as a function of watershed features. A response was observed in DOC and SO4 2− concentration in response to extreme wet and dry years in lakes across the northeastern U.S. Acidification was observed during drought and brownification was observed during wet years. Lake chemical response was related to landscape characteristics in different ways depending on the type of extreme year. A linear relationship between wetland coverage and DOC and SO4 2− deviations was observed during extreme wet years. The results presented here help to clarify the variability observed in long-term recovery from acidification and regional increases in DOC. Understanding the chemical response to weather variability is becoming increasingly important as temporal variation in precipitation is likely to intensify with continued atmospheric warming.

PURPOSE: To evaluate the time course and association with survival of anatomic lesion volumes and diffusion imaging parameters for patients with newly diagnosed glioblastoma who were treated with radiation and concurrently with either temozolomide and enzastaurin (TMZ+enza cohort) or temozolomide, erlotonib, and bevaciumab (TMZ+erl+bev cohort). MATERIALS AND METHODS: Regions of interest corresponding to the contrast-enhancing and hyperintense lesions on T2-weighted images were generated. Diffusion-weighted images were processed to provide maps of apparent diffusion coefficient, fractional anisotropy, and longitudinal and radial eigenvalues. Histograms of diffusion values were generated and summary statistics calculated. Cox proportional hazards models were employed to assess the association of representative imaging parameters with survival with adjustments for age, Karnofsky performance status, and extent of resection. RESULTS: Although progression-free survival was significantly longer for the TMZ+erl+bev cohort (12.8 vs 7.3 months), there was no significant difference in overall survival between the two populations (17.0 vs 17.8 months). The median contrast-enhancing lesion volumes decreased from 6.3 to 1.9 cm3 from baseline to the postradiotherapy scan for patients in the TMZ+enza cohort and from 2.8 to 0.9cm3 for the TMZ+erl+bev cohort. Changes in the T2 lesion volumes were only significant for the latter cohort (26.5 to 11.9 cm3). The median apparent diffusion coefficient and related diffusion parameters were significantly increased for the TMZ+enza cohort (1054 to 1225 μm2/s). More of the anatomic parameters were associated with survival for the TMZ+enza cohort, whereas more diffusion parameters were associated with survival for the TMZ+erl+bev cohort. CONCLUSION: The early changes in anatomic and diffusion imaging parameters and their association with survival reflected differences in the mechanisms of action of the treatments that were being given. This suggests that integrating diffusion metrics and anatomic lesion volumes into the Response Assessment in Neuro-Oncology criteria would assist in interpreting treatment-induced changes and predicting outcome in patients with newly diagnosed glioblastoma who are receiving such combination treatments.

Winter is often understudied in ecosystem sciences and viewed as a burden for human systems and infrastructure. However, the importance of winter in regulating ecological processes and shaping human communities has emerged as a topic of great interest, particularly in areas that experience seasonal snow cover. Traditional seasonal definitions may not fully represent below freezing winters and snow accumulation that have historically characterized these areas. Here we: (1) propose the concept of ‘frigid winter’ to address longstanding problems with traditional delineations of winter; and (2) define frigid winter as a period of sustained temperatures below freezing and snow accumulation that together regulate ecological processes and their services. We explore this definition and the changes occurring within it using 100 years of meteorological data from northeastern North America. Trend analysis demonstrates that frigid winters have shortened by ∼3 weeks over the last century, that cold, snowy conditions have become more intermittent, and that the choice of winter delineation (astronomical, meteorological, hibernal, or frigid) influences the apparent rate at which winter conditions disappear.

Noninvasive tools that target tumor cells could improve the management of glioma. Cancer generally has a high demand for Fe(III), an essential nutrient for a variety of biochemical processes. We tested whether 68Ga-citrate, an Fe(III) biomimetic that binds to apo-transferrin in blood, detects glioma in preclinical models and patients using hybrid PET/MRI. Mouse PET/CT studies showed that 68Ga-citrate accumulates in subcutaneous U87MG xenografts in a transferrin receptor-dependent fashion within 4 hours after injection. Seventeen patients with WHO grade III or IV glioma received 3.7-10.2 mCi 68Ga-citrate and were imaged with PET/MR 123-307 minutes after injection to establish that the radiotracer can localize to human tumors. Multiple contrast-enhancing lesions were PET avid, and tumor to adjacent normal white matter ratios were consistently greater than 10:1. Several contrast-enhancing lesions were not PET avid. One minimally enhancing lesion and another tumor with significantly reduced enhancement following bevacizumab therapy were PET avid. Advanced MR imaging analysis of one patient with contrast-enhancing glioblastoma showed that metabolic hallmarks of viable tumor spatially overlaid with 68Ga-citrate accumulation. These early data underscore that high-grade glioma may be detectable with a radiotracer that targets Fe(III) transport.

Recurrent high grade gliomas (rHGG) are difficult to diagnose accurately as they are often confounded with treatment-induced effects (TxE) because on conventional T1w and T2w anatomical MR imaging these two phenomena appear identical. This could result in removing a patient from an effective second-line therapy, confound the results of a clinical trial of a new therapeutic, and expose a patient to unnecessary surgical intervention. Advanced MR imaging modalities have shown promise in distinguishing between TxE and rHGG, but prior studies are unable to account for heterogeneity within the same lesion and often lack pathological confirmation. The goal of this study was to identify imaging parameters that could spatially map directly to pathology to account for heterogeneity within lesions. 1–8 tissue samples were collected upon surgical resection of suspected rHGG. A total of 484 samples were collected from 183 patients; 332 of these (163 patients) were labeled as either pathologically confirmed treatment effect or having no tumor cells (tumor score=0) within the imaging abnormality (TxE; 80/51 samples/patients) or rHGG (tumor score=2–3; 252/118 samples/patients) by a pathologist. Preoperative 3T MRI scans included T1w-Gd and T2w FLAIR; diffusion tensor imaging (b=1000s/mm2); 3D MRSI; and dynamic susceptibility-contrast perfusion MRI. Univariate models were created using generalized estimating equations to evaluate each variable’s ability to distinguish TxE from rHGG tissue samples. Normalized choline (median=1.1 TxE & 1.2 rHGG), choline-to-NAA index (CNI, median=2.4 TxE & 3.5 rHGG), and normalized cerebral blood volume (nCBV, median=1.2 TxE & 1.4 rHGG) were significantly associated with biopsy-level classification (p=0.034, 0.015, 0.017). These results are being consolidated into a multiparametric algorithm for predicting TxE or rHGG, which could be of clinical importance in managing patients with recurrent rHGG. Downstream analysis will create a spatial map of rHGG to help guide future surgical sampling.

Although the overall prognostic significance of maximal surgical resection of contrast-enhancing tumor in glioblastoma patients is well established, prior studies have not evaluated the combined importance of resection, molecular markers, patient characteristics, and chemoradiation. Incorporation of these factors may redefine the relative benefit of cytoreductive surgery and establish differing thresholds for extent of resection in varying clinical presentations. In the first study of its kind, we examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 850 glioblastoma patients who had initial surgery at UCSF, we employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS), both in the entire cohort as well as a subset diagnosed since 2005 (Stupp-era) with IDH1 mutation status available (n=470). For the entire cohort and the Stupp-era subset, the RPAs elucidate the combinatorial consequence of treatment, age, IDH1 status (in the subset), and resection of both enhancing and non-enhancing tumor. In the Stupp-era, temozolomide-treated patients that are IDH-wildtype and >65 clearly benefit from a reduction of the enhancing tumor (median OS: 10.1 vs 15.8 months). IDH-wildtype, temozolomide-treated patients under 65 benefit from reduction of both enhancing and non-enhancing tumor with a median survival similar to that of IDH-mutant, temozolomide-treated patients (combined median OS: 33.7 months). The patients faring worst are those that did not receive temozolomide that are >65 and/or have ≥0.3 cm(3) residual enhancing tumor (median OS: 4 months). These risk models outperform all published prognostic models. This is the first study to combine resection of contrast-enhancing and non-enhancing tumor in conjunction with molecular and clinical information in a large single-institution study, and paves the way for rethinking surgical strategies for individual patients with newly diagnosed glioblastoma.

INTRODUCTION: The safety and efficacy of a heat shock protein peptide complex- 96 vaccine (HSPPC-96, Prophage) has been previously studied in phase II single-arm trials for the treatment of newly diagnosed and recurrent glioblastoma (GBM). These studies demonstrated modest improvements in survival compared with historical standards. PTEN loss has been recently associated with immunoresistance in GBM patients, mediated in part by B7-H1. PTEN status has not shown clear prognostic value in GBM patients treated with standard of care therapies. The aim of this study is to evaluate the prognostic significance of PTEN status in newly diagnosed GBM patients treated with autologous HSP vaccine and standard chemoradiation. METHODS: Our institutional cohort of patients enrolled in a single arm, phase II study of adult GBM patients treated with autologous HSP vaccine and standard chemoradiation (n=27) was analyzed. Differences in overall survival (OS) by PTEN status were evaluated via Kaplan-Meier curves and Log-rank test. RESULTS: Median overall survival (n=27) was 26 months. 23 patients had PTEN status available. PTEN loss was found in 16 patients (69.6%) whereas retained PTEN was present in 7 patients (30.4%). Median OS was 59 months (95% CI, 0–120 months) in patients with retained PTEN and 23 months (95% CI, 15–30 months) in patients with PTEN loss. The difference in OS was statistically significant (p=0.037). CONCLUSION: Retained PTEN expression was associated with extended survival in GBM patients treated with HSP vaccine. This finding suggests that PTEN loss may be associated with resistance to vaccine treatment and emphasizes the need for subgroup analysis in further immunotherapy studies.

Recent studies have highlighted the importance of using molecular biomarkers (IDH, 1p19q, TERT) to group gliomas that have similar clinical behavior, response to therapy, and outcome. An emerging hypothesis is that glioma specific genetic and/or molecular alterations manifest as specific observable changes in MR anatomical imaging. Morphologic and texture features, originating from anatomical MRI, have been investigated as imaging biomarkers to predict MGMT and glioma group status. These texture or morphologic based approaches pose several challenges including requirements for several preprocessing steps such as intensity standardization, skull stripping, and tumor segmentation. Deep learning is an important evolving technology in many different fields, including anatomic imaging, and can be used to empirically identify important features in a variety of modalities, including MRI. Importantly deep learning precludes the need for extensive pre-processing. We describe a convolutional neural network, evaluating resnet50, vgg16, inception and xception neural network architectures, that can predict IDH, 1p19q and TERT status utilizing conventional T2 weighted MRI imaging with intensity normalization and nonuniform intensity normalization (N4) bias corrections. The dataset consisted of 432 images (340 for training and 92 for validation) from patients published by Eckel-Passow et al New England Journal of Medicine (2015). The system achieved a weighted f1 score of 0.901, 0.937 and 0.924 for IDH, 1p19q and TERT prediction on the test dataset, respectively. IDH status was misclassified in 9 out of 92 patients, while 1p19q and TERT status was misclassified in 6 and 7 patients respectively. Our results demonstrate the potential of deep learning architectures applied to conventional MRI to predict molecular glioma groups.

Proton magnetic resonance spectroscopic imaging (1H MRSI) is a powerful noninvasive method for assessing the spatial extent and properties of abnormal metabolism in patients with glioma. Hyperpolarized 13C metabolic imaging is a new molecular imaging modality that can be used to assess real-time changes in metabolism and has been shown to be safe and feasible in patients with glioma. In this study, both 3D 1H lactate-edited MRSI and hyperpolarized [1-13C]pyruvate imaging data were obtained and compared in thirteen patients with glioma to assess steady state versus dynamic brain metabolism. FLAIR images from the 1H examination were registered to the FSE images from the 13C examination for each subject. The corresponding transformation matrix was then applied to spectra and metabolite maps from the excitation volume of the 1H MRSI data. The volumes of the anatomic and metabolic lesions varied between patients, and using a multi-slice frequency specific EPI sequence allowed improved coverage of the lesion of interest compared to a 2D dynamic EPSI sequence. The choline-to-NAA index values and levels of steady state lactate peak heights from the 1H MRSI data were elevated in the lesion, while 13C bicarbonate levels were reduced and 13C lactate levels were similar or lower compared with normal appearing brain. The initial results indicated that there was a negative association between estimates of hyperpolarized 13C lactate/pyruvate and steady state normalized lactate peak heights, and a positive association between hyperpolarized 13C lactate/pyruvate and Cho/NAA in the T2 lesion. For one patient who received repeated examinations within 2 months and was assessed as having stable disease after treatment, the 13C lactate-to-pyruvate ratio in the T2 lesion was 0.65 vs. 0.35 and 0.43 vs. 0.43 in normal appearing brain. Future studies will evaluate a larger patient population to see whether these relationships hold up.

OBJECTIVE: To assess feasibility and effect on cognitive function and Health-Related Quality of Life (HRQoL) of an iPad-based intervention in grade 2 and 3 glioma patients stable off treatment. Patients with lower grade glioma suffer significant cognitive dysfunctions that impact their HRQoL. Formal cognitive rehabilitation is a limited resource that may be more available if deployed with a mobile device such as an iPad. METHODS: Stable, grade 2 and 3 glioma patients with subjective cognitive complaints, complete a baseline computerized battery of standardized cognitive tests using the NIH Toolbox and HRQOL assessment with the FACT-BR. Patients then completed a novel, evidence-based, iPad based, brain tumor specific, cognitive rehabilitation program called ReMind over the next 3 months (~3 hours per week). NIH Toolbox and HRQOL assessments were repeated after completion of the rehabilitation, and again 9 months after baseline. Primary endpoint was feasibility with secondary endpoints of changes in cognitive scores and HRQOL assessments. RESULTS: To date, 10 patients have enrolled and completed baseline testing, of whom 5 have completed ReMind rehabilitation. Median age is 56 years. Median disease duration is 7.6 years. 5 patients have Oligodendrogliomas (IDH mutated and 1p19q deleted), 3 patients have Astrocytomas, IDH mutated, and 2 patients have Astrocytomas NOS. 5 are grade II and 5 are grade III. 5 had left hemisphere tumors, 4 had right hemisphere tumors, and 1 was bilateral. 10 had prior chemotherapy and 8 prior radiation. We anticipate enrolling another 5 – 10 patients and will present the updated feasibility data as well as changes in cognitive and HRQOL scores. CONCLUSION: As patients with lower grade tumors live longer, it is important to increase availability of cognitive interventions to improve HRQOL and outcomes. This iPad based approach provides in-home access to cognitive training and compensation strategies for patients with brain tumors.

Purpose To develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 (13 C) applications. Methods Initial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1-13 C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral-spatial RF pulse and signal was rapidly encoded with a single-shot echo planar readout on a slice-by-slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies. Results High pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off-resonance. Conclusion This study demonstrated the feasibility of symmetric EPI to acquire HP 13 C metabolite maps in a clinical setting. As an advance over prior single-slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite-specific EPI acquisition provided robust whole-organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution.

PURPOSE: To compare the performance of an 8-channel surface coil/clamshell transmitter and 32-channel head array coil/birdcage transmitter for hyperpolarized (13)C brain metabolic imaging. METHODS: In order to determine the field homogeneity of the RF transmitters, B(1)+ mapping was performed on an ethylene glycol head phantom and evaluated via the double angle method. Using a 3-D echo-planar imaging (EPI) sequence, coil sensitivity and noise-only phantom data were acquired with the 8- and 32-channel receiver arrays, and compared against data from the birdcage in transceiver mode. Multislice frequency-specific (13)C dynamic EPI was performed on a patient with a brain tumor for each hardware configuration following injection of hyperpolarized [1-(13)C]pyruvate. SNR was evaluated from pre-whitened phantom and temporally summed patient data after coil combination based on optimal weights. RESULTS: The birdcage transmitter produced more uniform B(1)+ compared to the clamshell: 0.07 versus 0.12 (fractional error). Phantom experiments conducted with matched lateral housing separation demonstrated 8- versus 32-channel mean transceiver-normalized SNR performance: 0.91 versus 0.97 at the head center; 6.67 versus 2.08 on the sides; 0.66 versus 2.73 at the anterior; and 0.67 versus 3.17 on the posterior aspect. While the 8-channel receiver array showed SNR benefits along lateral aspects, the 32-channel array exhibited greater coverage and a more uniform coil-combined profile. Temporally-summed, parameter-normalized patient data showed SNR(mean, slice) ratios (8-channel/32-channel) ranging 0.5–2.00 from apical to central brain. White matter lactate-to-pyruvate ratios were conserved across hardware: 0.45±0.12 (8-channel) versus 0.43±0.14 (32-channel). CONCLUSION: The 8- and 32-channel hardware configurations each have advantages in particular brain anatomy.

The goal of this research was to elucidate the relationship between WHO 2016 molecular classifications of newly diagnosed, nonenhancing lower grade gliomas (LrGG), tissue sample histopathology, and magnetic resonance (MR) parameters derived from diffusion, perfusion, and 1H spectroscopic imaging from the tissue sample locations and the entire tumor. A total of 135 patients were scanned prior to initial surgery, with tumor cellularity scores obtained from 88 image-guided tissue samples. MR parameters were obtained from corresponding sample locations, and histograms of normalized MR parameters within the T2 fluid-attenuated inversion recovery lesion were analyzed in order to evaluate differences between subgroups. For tissue samples, higher tumor scores were related to increased normalized apparent diffusion coefficient (nADC), lower fractional anisotropy (nFA), lower cerebral blood volume (nCBV), higher choline (nCho), and lower N-acetylaspartate (nNAA). Within the T2 lesion, higher tumor grade was associated with higher nADC, lower nFA, and higher Cho to NAA index. Pathological analysis confirmed that diffusion and metabolic parameters increased and perfusion decreased with tumor cellularity. This information can be used to select targets for tissue sampling and to aid in making decisions about treating residual disease.

This paper describes a record of air and soil temperature collected from 2001 to 2016 in temperate forests at the Bear Brook Watershed in Maine (BBWM). BBWM is a long-term research site established to study the response of forest ecosystem function to various environmental disturbances, including chronic acidic deposition. Replicate HOBO data loggers were deployed in BBWM’s two forest types (coniferous and deciduous), to record temperatures at four positions: (1) air temperature, 100 cm above the forest floor; (2) surface organic soil, 2 cm below the forest floor surface; (3) mineral soil, 10 cm below the organic–mineral horizon interface; and (4) mineral soil, 25 cm below the organic–mineral horizon interface. Data were recorded every three hours, and these raw data were used to compute daily maximum, daily minimum, daily average, and monthly average values. This fifteen–year record represents one of the few readily–available soil temperature datasets in the region, and provides information on long-term changes in climatology, and seasonal and episodic weather patterns.

BackgroundIn the current study, we pooled imaging data in newly diagnosed glioblastoma (GBM) patients from international multicenter clinical trials, single institution databases, and multicenter clinical trial consortiums to identify the relationship between postoperative residual enhancing tumor volume and overall survival (OS).MethodsData from 1511 newly diagnosed GBM patients from 5 data sources were included in the current study: (i) a single institution database from UCLA (N = 398; Discovery); (ii) patients from the Ben and Cathy Ivy Foundation for Early Phase Clinical Trials Network Radiogenomics Database (N = 262 from 8 centers; Confirmation); (iii) the chemoradiation placebo arm from an international phase III trial (AVAglio; N = 394 from 120 locations in 23 countries; Validation); (iv) the experimental arm from AVAglio examining chemoradiation plus bevacizumab (N = 404 from 120 locations in 23 countries; Exploratory Set 1); and (v) an Alliance (N0874) phase I/II trial of vorinostat plus chemoradiation (N = 53; Exploratory Set 2). Postsurgical, residual enhancing disease was quantified using T1 subtraction maps. Multivariate Cox regression models were used to determine influence of clinical variables, O6-methylguanine-DNA methyltransferase (MGMT) status, and residual tumor volume on OS.ResultsA log-linear relationship was observed between postoperative, residual enhancing tumor volume and OS in newly diagnosed GBM treated with standard chemoradiation. Postoperative tumor volume is a prognostic factor for OS (P < 0.01), regardless of therapy, age, and MGMT promoter methylation status.ConclusionPostsurgical, residual contrast-enhancing disease significantly negatively influences survival in patients with newly diagnosed GBM treated with chemoradiation with or without concomitant experimental therapy.

MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-(13)C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, k(PL), as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an “inputless” method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in k(PL), signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B(1) variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate k(PL) maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless k(PL) fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-(13)C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-(13)C]pyruvate parameters (SNR, k(PL), bolus characteristics) in the human prostate.

BACKGROUND Previous studies of solid tumors have been restricted in their ability to map how heterogeneous cell populations evolved within the tumor in three-dimensional (3D) space due to insufficient sampling, typically one sample per tumor, and a lack of knowledge of where within the tumor the sample was obtained. Knowledge of the extensivity of heterogeneity and how it is spatially distributed is crucial for assessing whether a therapeutic target is truly tumor-wide, and for exploring how mutations relate to heterogeneity in the local microenvironment. METHODS We developed a novel platform to integrate and visualize in 3D multi-omics data generated from each of 8–10 spatially mapped samples per tumor. Together, the 171 samples collected using this approach from 16 adult diffuse glioma at diagnosis and recurrence form a novel resource – the 3D Glioma Atlas. RESULTS By maximally sampling the tumor geography without excluding samples based on low cancer cell fraction (CCF), we identify a subpopulation of glioblastoma with pervasively lower CCF likely excluded by other atlases, such as the TCGA, that used stringent CCF cutoffs. Exome sequencing of 3D-mapped samples from lower-grade tumors revealed that clonal expansions are typically spatially segregated, implying minimal tumor-wide intermixing of genetically heterogenous cells. Heterogeneity is less spatially segregated for faster-growing high-grade tumors, suggesting that cell populations expand in these tumors differently. Recurrent low-grade tumors have greater intratumoral mutational heterogeneity than newly diagnosed tumors, though this did not translate into greater dissimilarity in gene expression profiles for recurrent tumors, suggesting minimal functional impact of this additional mutational diversity on gene expression. CONCLUSIONS The delineation of spatial patterns of heterogeneity that our work provides enables more informed interpretation of biopsies and greater insight into the factors shaping intratumoral variation of gene expression patterns. Ongoing work is exploring the spatial patterning of amplification events and the tumor microenvironment.

BACKGROUND: Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh−) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh− and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Methods: Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. Results: The Enh+ and Enh− tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N -acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. CONCLUSIONS: The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh− tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM.

PURPOSE To develop a lump-element double-tuned common-mode-differential-mode (CMDM) radiofrequency (RF) surface coil with independent frequency tuning capacity for MRS and MRI applications. METHODS The presented design has two modes that can operate with different current paths, allowing independent frequency adjustment. The coil prototype was tested on the bench and then examined in phantom and in vivo experiments. RESULTS Standard deviations of frequency and impedance fluctuations measured in one resonator, while changing the tuning capacitor of another resonator, were less than 13 kHz and 0.55 Ω. The unloaded S21 was -36 dB and -41 dB, while the unloaded Q factor was 260 and 287, for 13 C and 1 H, respectively. In vivo hyperpolarized 13 C MR spectroscopy data demonstrated the feasibility of using the CMDM coil to measure the dynamics of lactate, alanine, pyruvate and bicarbonate signal in a normal rat head along with acquiring 1 H anatomical reference images. CONCLUSION Independent frequency tuning capacity was demonstrated in the presented lump-element double-tuned CMDM coil. This CMDM coil maintained intrinsically decoupled magnetic fields, which provided sufficient isolation between the two resonators. The results from in vivo experiments demonstrated high sensitivity of both the 1 H and 13 C resonators. Magn Reson Med 76:1612-1620, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Background. Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study’s goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process. Methods. Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients’ microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed. Results. The number of microbleeds increased with time for all patients, with initial onset occurring at 8– 22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P , .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P , .05) and a significant reduction in initial rate of microbleed appearance (P ¼ .01). Conclusions. We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.

Magnetic resonance spectroscopy (MRS) is a powerful tool for noninvasively investigating normal and abnormal metabolism. When used in combination with imaging strategies, multinuclear MRS methods provide detailed biochemical information that can be directly correlated with anatomical features. Hyperpolarized C MRS is a new technology that reflects real-time metabolic conversion and is likely to be extremely valuable in managing patients with cancer. This article reviews the use of in vivo P, H, and C MRS for assessing cancer metabolism in order to provide information for diagnosis, planning treatment, assessing response to therapy, and predicting survival for patients with cancer.

Radiation Therapy (RT) is a widely used treatment in the management of patients with malignant brain tumors.1 It is often used either in conjunction with chemotherapy after surgical resection to reduce residual tumor burden or alone in surgically inaccessible tumors.1 Despite its effectiveness and recent modern advances to constrain dose distribution more effectively to the tumor, collateral injury to normal brain tissue is always present and includes coagulative necrosis, white matter demyelization, cortical atrophy, and endothelial proliferation.2 RT is also correlated with the development of vascular abnormalities including cavernous malformations,3 moyamoya-like progressive steno-occlusive disease,4 accelerated atherosclerosis, and other forms of large vessel arteriopathy.5 At the microvascular level, histopathological analyses reveal a spectrum of radiation injury that includes endothelial disruption, fibrinoid necrosis, luminal narrowing, and occlusion, which leads to the formation of cerebral microbleeds (CMBs) in otherwise normal-appearing brain tissue.6,7 These hemosiderin-containing deposits begin to appear approximately two years post-RT and continue to increase in number over time.8–11 More recent studies have demonstrated a correlation between the number of CMBs and the dose and the target volume defined for radiation therapy,10,11 pointing to the potential use of these lesions as a surrogate quantitative marker of radiation injury. While the origin of CMBs has not been completely defined, ionizing radiation is known to have a greater effect on smaller caliber vasculature and is more likely to damage arteries than veins.6 A strategy to noninvasively image arteries and veins simultaneously, and to assess the spatial distribution of CMBs relative to these structures would help to establish a relationship between CMB formation and underlying vascular pathology, and aid in clinical and basic science studies of CMB that arise in cerebral amyloid angiopathy (CAA),12 stroke,13 Alzheimer’s disease,14 traumatic brain injury (TBI),15 mild cognitive impairment,16 and dementia.17 CMBs can be observed noninvasively on MR images using T2*-weighted gradient echo sequences as small hypointense lesions, often with spherical shape.18 These imaging features are enhanced by susceptibility-weighted imaging (SWI), an MR imaging technique that is more sensitive to CMBs than conventional T2*-weighted imaging 8–10,19 and permits accurate visualization of intracranial veins as hypointense due to the presence of iron-containing deoxyhemoglobin.20 In contradistinction, arterial contrast in three-dimensional (3D) time-of-flight (TOF) MR angiography (MRA) is determined by flow-related enhancement and background suppression.21 While the utility of these sequences for characterizing CMBs 8–10,19 and intracranial vessels20–24 has been demonstrated, accounting for prescanning, the combined time spent on the two separate sequences can be 15 to 20 min. Also, accurate registration is nearly impossible to attain due to the lack of both anatomical contrast and structural similarity between the TOF-MRA and SWI, in addition to the blurring of sub-millimeter CMBs and microvasculature after the interpolation step of the registration. Thus, a combined MRA-SWI sequence using multiple gradient echoes can not only reduce scan time but also obviate the need for image coregistration, which would benefit our understanding of CMB formation by providing metrics that reflect the interaction among vascular structures that are not confounded by inaccuracies in the coregistration. The ability to obtain a simultaneous acquisition of 3D TOF-MRA and SWI in a single imaging sequence with multiple echoes has been recently demonstrated in a normal volunteer at 3 Tesla (T).25 The elevated SNR, heightened background suppression for TOF-MRA, and amplified susceptibility contrast for SWI available at 7T demonstrates the potential of this platform to provide excellent delineation of both CMBs and microvasculature.8,22 While previous studies have demonstrated the capability of implementing a dual- or multi-echo acquisition on normal volunteers,25–28 there have been no efforts at simultaneously optimizing contrast of CMBs and microvasculature, creating combined SWI images from multiple echoes, reconstruction and processing improvements, or clinical evaluation. The purpose of this study was to design a 7T multi-echo sequence and SWI reconstruction pipeline using data from multiple echoes, and assess resulting image quality by comparing it with that of separate TOF-MRA and SWI acquisitions. By using the sequence, we aim to obtain high-resolution vascular images for the simultaneous depiction of arteries, veins, and CMBs in patients with brain tumors treated with prior radiation therapy.

SUMMARY: This study demonstrated the feasibility of using hyperpolarized 13 C-MR spectroscopic imaging with [1- 13 C]-pyruvate to evaluate in vivo spinal cord metabolism. High pyruvate and relatively small lactate signal were observed in the cervical spinal cords of naive rats. Lactate and pyruvate measures were similar for spinal cord and supratentorial brain. The results from this study establish baseline measures for spinal cord hyperpolarized MRS imaging with 13 C pyruvate. This technique holds promise as a valuable molecular imaging tool for monitoring biochemical processes in the normal and diseased spinal cord.

Most cancers result from multiple clonal expansion events, resulting in tumors comprised of many subclones. The coexistence of these genetically distinct populations within a single tumor is thought to underlie the failure of most current treatments. Ascertaining how diverse populations of cells evolve within tumors, and the functional implications of this diversity, are the next steps to developing more informed treatments that overcome the barrier currently posed by intratumoral heterogeneity (ITH). Previous studies of adult diffuse glioma have been restricted in their ability to provide a detailed understanding of the spatial evolution of solid tumors due to insufficient sampling, typically just one biopsy per patient, and a lack of knowledge of where within the heterogeneous tumor the sample was obtained. We have developed a unique sample collection protocol, in which we record the precise, three-dimensional (3D) coordinate for each of 10 spatially-distinct samples obtained from each patient’s tumor. Whole exome data from IDH1 mutant grade II astrocytomas analyzed in this manner have revealed that expansion events are typically spatially segregated, suggesting minimal tumor-wide intermixing of subclonal cell populations in these low grade gliomas. Expression profiling of one particular case has furthermore revealed ITH of the immune microenvironment, uncovering a region of increased PD-L1 expression and IFN-gamma signaling. Ongoing analysis is focused on integrating genetic and expression profiles from these and additional spatially-mapped cases. This integrative analysis aims to dissect the relative contributions of subclonal variation and location within the tumor on gene expression patterns and ITH of the immune microenvironment. The delineation of the spatial patterns of ITH our work provides will enable more informed selection of biopsy targets in the future. It also lends greater insight into the factors shaping intratumoral variation of gene expression patterns and the immune microenvironment in adult diffuse glioma.

Neurocognitive function and quality of life are important clinical outcome measures for patients with lower grade glioma. Here, we performed neurocognitive testing and quality of life assessments in radiologically and clinically stable grade 2 and 3 glioma patients who are not receiving active treatment.

Infiltrating gliomas are primary brain tumors that express significant biological and clinical heterogeneity in adults, which complicates their treatment and prognosis. Characterization of tumor subtypes using spectroscopic analysis may assist in predicting malignant transformation and quantification of response to therapy. To implement an automated algorithm for classification of metabolomic profiles for the classification of glioma pathological grades and the prediction of malignant progression using spectra obtained by high-resolution magic angle spinning (HR-MAS) spectroscopy of patient-derived tissue samples. 237 image-guided tissue samples were obtained from 152 patients who underwent surgery for newly diagnosed or recurrent glioma and analyzed via HR-MAS spectroscopy. Orthogonal projection to latent structures discriminant analysis was used as a classifier and the variable-influence-on-projection values were evaluated to identify signature spectral regions. The accuracy of classifiers developed for discriminating glioma subtypes was 68% for newly diagnosed grade II versus III samples; 86 and 92% for new and recurrent grade III versus IV, respectively; 95% for newly diagnosed grade II versus IV; and 88% for recurrent grade II versus IV lesions. Classifiers distinguished between samples from newly diagnosed vs. recurrent lesions with an accuracy of 78% for grade III and 99% for grade IV glioma. Classifying metabolomic profiles for new and recurrent glioma without prior assumptions regarding spectral components identified candidate in vivo biomarkers for use in assessing changes that are likely to impact treatment decisions.

Background Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution. Methods In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions. Results One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second. Conclusions Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Understanding the factors that affect water quality and the ecological services provided by freshwater ecosystems is an urgent global environmental issue. Predicting how water quality will respond to global changes not only requires water quality data, but also information about the ecological context of individual water bodies across broad spatial extents. Because lake water quality is usually sampled in limited geographic regions, often for limited time periods, assessing the environmental controls of water quality requires compilation of many data sets across broad regions and across time into an integrated database. LAGOS-NE accomplishes this goal for lakes in the northeastern-most 17 US states. LAGOS-NE contains data for 51 101 lakes and reservoirs larger than 4 ha in 17 lake-rich US states. The database includes 3 data modules for: lake location and physical characteristics for all lakes; ecological context (i.e., the land use, geologic, climatic, and hydrologic setting of lakes) for all lakes; and in situ measurements of lake water quality for a subset of the lakes from the past 3 decades for approximately 2600–12 000 lakes depending on the variable. The database contains approximately 150 000 measures of total phosphorus, 200 000 measures of chlorophyll, and 900 000 measures of Secchi depth. The water quality data were compiled from 87 lake water quality data sets from federal, state, tribal, and non-profit agencies, university researchers, and citizen scientists. This database is one of the largest and most comprehensive databases of its type because it includes both in situ measurements and ecological context data. Because ecological context can be used to study a variety of other questions about lakes, streams, and wetlands, this database can also be used as the foundation for other studies of freshwaters at broad spatial and ecological scales.

Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) is a powerful non-invasive tool for characterizing spatial variations in metabolic profiles for patients with glioma. Metabolic parameters obtained using this technique have been shown to predict treatment response, disease progression, and transformation to a more malignant phenotype. The availability of ultra-high-field MR systems has the potential to improve the characterization of metabolites. The purpose of this study was to compare the metabolite profiles acquired with conventional long echo time (TE) MRSI at 3T with those obtained with short TE MRSI at 3T and 7T in patients with glioma. The data acquisition parameters were optimized separately for each echo time and field strength to obtain volumetric coverage within clinically feasible data acquisition times of 5-10 min. While a higher field strength did provide better detection of metabolites with overlapping peaks, spatial coverage was reduced and the use of inversion recovery to reduce lipid precluded the detection of lipid in regions of necrosis. For serial evaluation of large, heterogeneous lesions, the use of 3T short TE MRSI may thus be preferred. Despite the limited number of metabolites that it is able to detect, the use of 3T long TE MRSI gives the best contrast in choline/N-acetyl aspartate between normal appearing brain and tumor and also allows the separate detection of lactate and lipid. It may therefore be preferred for serial evaluation of patients with high-grade glioma and for detection of malignant transformation in patients with low-grade glioma.

Despite the longstanding role of radiation in cancer treatment and the presence of advanced, high-resolution imaging techniques, delineation of voxels at-risk for progression remains purely a geometric expansion of anatomic images, missing subclinical disease at risk for recurrence while treating potentially uninvolved tissue and increasing toxicity. This remains despite the modern ability to precisely shape radiation fields. A striking example of this is the treatment of glioblastoma, a highly infiltrative tumor that may benefit from accurate identification of subclinical disease. In this study, we hypothesize that parameters from physiologic and metabolic magnetic resonance imaging (MRI) at diagnosis could predict the likelihood of voxel progression at radiographic recurrence in glioblastoma by identifying voxel characteristics that indicate subclinical disease. Integrating dosimetry can reveal its effect on voxel outcome, enabling risk-adapted voxel dosing. As a system example, 24 patients with glioblastoma treated with radiotherapy, temozolomide and an anti-angiogenic agent were analyzed. Pretreatment median apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative cerebral blood volume (rCBV), vessel leakage (percentage recovery), cho-line-to-NAA index (CNI) and dose of voxels in the T2 nonenhancing lesion (NEL), T1 post-contrast enhancing lesion (CEL) or normal-appearing volume (NAV) of brain, were calculated for voxels that progressed [NAV→NEL, CEL (N = 8,765)] and compared against those that remained stable [NAV→NAV (N = 98,665)]. Voxels that progressed (NAV→NEL) had significantly different (P < 0.01) ADC (860), FA (0.36) and CNI (0.67) versus stable voxels (804, 0.43 and 0.05, respectively), indicating increased cell turnover, edema and decreased directionality, consistent with subclinical disease. NAV→CEL voxels were more abnormal (1,014, 0.28, 2.67, respectively) and leakier (percentage recovery = 70). A predictive model identified areas of recurrence, demonstrating that elevated CNI potentiates abnormal diffusion, even far (>2 cm) from the tumor and dose escalation >45 Gy has diminishing benefits. Integrating advanced MRI with dosimetry can identify at voxels at risk for progression and may allow voxel-level risk-adapted dose escalation to subclinical disease while sparing normal tissue. When combined with modern planning software, this technique may enable risk-adapted radiotherapy in any disease site with multimodal imaging.

Activation of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is common in patients with low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population.Fifty-eight patients with pathologic evidence of recurrence after they had initially been diagnosed with World Health Organization (WHO) grade II gliomas were enrolled into a prospective phase 2 clinical trial and received daily everolimus (RAD001) for 1 year or until progression. Tissue at the time of enrollment was analyzed for markers of PI3K/mTOR pathway activation. Thirty-eight patients underwent serial multiparametric magnetic resonance imaging, with the tumor volume and the perfusion metrics (the fractional blood volume [fBV] for capillary density and the transfer coefficient [KFor patients with WHO II gliomas at enrollment, the PFS-6 rate was 84%, and this met the primary endpoint (P .001 for an improvement from the historical rate of 17%). Evidence of PI3K/mTOR activation by immunohistochemistry for phosphorylated ribosomal S6Patients with recurrent LGGs demonstrated a high degree of disease stability during treatment with everolimus. PI3K/mTOR activation, as measured by immunohistochemistry for p-S6, was associated with a worse prognosis. Tumor vascular changes were observed that were consistent with the antiangiogenic effects of mTOR inhibitors. These results support further study of everolimus for LGGs. Cancer 2017;123:4631-4639. © 2017 American Cancer Society.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.

Low-Grade Gliomas can vary widely in disease course and therefore patient outcome. While current characterization relies on both histological and molecular analysis of tissue resected during surgery, there remains high variability within glioma subtypes in terms of response to treatment and outcome. In this study we hypothesized that parameters obtained from Magnetic Resonance (MR) data would be associated with progression-free survival (PFS) for patients with recurrent low-grade glioma. The values considered were derived from the analysis of anatomic imaging, diffusion weighted imaging, and 1H Magnetic Resonance Spectroscopic Imaging (MRSI) data. Metrics obtained from diffusion and spectroscopic imaging presented strong prognostic capability within the entire population as well as when restricted to astrocytomas, but demonstrated more limited efficacy in the oligodendrogliomas. The results indicate that multi-parametric imaging data may be applied as a non-invasive means of assessing prognosis and may contribute to developing personalized treatment plans for patients with recurrent low-grade glioma.

Recent findings show that exposure to temozolomide (TMZ), a DNA-damaging drug used to treat glioblastoma (GBM), can suppress the conversion of pyruvate to lactate. To understand the mechanistic basis for this effect and its potential utility as a TMZ response biomarker, we compared the response of isogenic GBM cell populations differing only in expression of the DNA repair protein methyltransferase (MGMT), a TMZ-sensitivity determinant, after exposure to TMZ in vitro and in vivo. Hyperpolarized [1-(13)C]-pyruvate–based MRI was used to monitor temporal effects on pyruvate metabolism in parallel with DNA-damage responses and tumor cell growth. TMZ exposure decreased conversion of pyruvate to lactate only in MGMT-deficient cells. This effect coincided temporally with TMZ-induced increases in levels of the DNA-damage response protein pChk1. Changes in pyruvate to lactate conversion triggered by TMZ preceded tumor growth suppression and were not associated with changes in levels of NADH or lactate dehydrogenase activity in tumors. Instead, they were associated with a TMZ-induced decrease in the expression and activity of pyruvate kinase PKM2, a glycolytic enzyme that indirectly controls pyruvate metabolism. PKM2 silencing decreased PK activity, intracellular lactate levels, and conversion of pyruvate to lactate in the same manner as TMZ, and Chk1 silencing blocked the TMZ-induced decrease in PKM2 expression. Overall, our findings showed how TMZ-induced DNA damage is linked through PKM2 to changes in pyruvate metabolism, and how these changes can be exploited by MRI methods as an early sensor of TMZ therapeutic response. Cancer Res; 74(23); 7115–24. ©2014 AACR.

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine-that is, the application of information technology to medicine-has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real-time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence-based medicine, support shared decision making, and ultimately lead to improved outcomes.

Purpose A chemical shift separation technique for hyperpolarized 13C metabolic imaging with high spatial and temporal resolution was developed. Specifically, a fast three-dimensional pulse sequence and a reconstruction method were implemented to acquire signals from multiple 13C species simultaneously with subsequent separation into individual images. Theory and Methods A stack of flyback echo-planar imaging readouts and a set of multiband excitation radiofrequency pulses were designed to spatially modulate aliasing patterns of the acquired metabolite images, which translated the chemical shift separation problem into parallel imaging reconstruction problem. An eight-channel coil array was used for data acquisition and a parallel imaging method based on nonlinear inversion was developed to separate the aliased images. Results Simultaneous acquisitions of pyruvate and lactate in a phantom study and in vivo rat experiments were performed. The results demonstrated successful separation of the metabolite distributions into individual images having high spatial resolution. Conclusion This method demonstrated the ability to provide accelerated metabolite imaging in hyperpolarized 13C MR using multichannel coils, tailored readout, and specialized RF pulses. Magn Reson Med 74:978–989, 2015. © 2014 Wiley Periodicals, Inc.

To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of treatment with radiation (RT), temozolomide, erlatonib and bevacizumab. Thirty six patients were imaged after surgery but prior to therapy and at regular follow-up time points. The following ADC metrics were evaluated: (1) histogram percentiles within the T2-hyperintense lesion (T2L) at serial follow-ups; (2) parameters obtained by fitting a two-mixture normal distribution to the histogram within the contrast-enhancing lesion (CEL) at baseline; (3) parameters obtained using both traditional and graded functional diffusion maps within the CEL and T2L. Cox Proportional Hazards models were employed to assess the association of the ADC parameters with overall survival (OS) and progression-free survival (PFS). A lower ADC percentile value within the T2L at early follow-up time points was associated with worse outcome. Of particular interest is that, even when adjusting for clinical prognostic factors, the ADC10% within the T2L at 2 months was strongly associated with OS (p

Objective There is increasing evidence that altered glutamate (Glu) homeostasis is involved in the pathophysiology of multiple sclerosis (MS). The aim of this study was to evaluate the in vivo effects of excess brain Glu on neuroaxonal integrity measured by N-acetylaspartate (NAA), brain volume, and clinical outcomes in a large, prospectively followed cohort of MS subjects. Methods We used multivoxel spectroscopy at 3T to longitudinally estimate Glu and NAA concentrations from large areas of normal-appearing white and gray matter (NAWM and GM) in MS patients (n = 343) with a mean follow-up time of 5 years. Using linear mixed-effects models, Glu was examined as a predictor of NAA decline, annualized percentage brain volume change, and evolution of clinical outcomes (Multiple Sclerosis Functional Composite [MSFC], Paced Auditory Serial Addition Test-3 [PASAT], and Expanded Disability Status Scale). Glu/NAA ratio was tested as a predictor of brain volume loss and clinical outcomes. Results Baseline Glu[NAWM] was predictive of accelerated longitudinal decline in NAA[GM] (-0.06mM change in NAA[GM]/yr for each unit increase in Glu; p = 0.004). The sustained elevation of Glu[NAWM] was predictive of a loss of 0.28mM/yr in NAA[NAWM] (p < 0.001) and 0.15mM/yr in NAA[GM] (p = 0.056). Each 10% increase in Glu/NAA [NAWM] was associated with a loss of 0.33% brain volume/yr (p = 0.001), 0.009 standard deviations/yr in MSFC z-score (p < 0.001), and 0.17 points/yr on the PASAT (p < 0.001). Interpretation These results indicate that higher Glu concentrations increase the rate of NAA decline, and higher Glu/NAA[NAWM] ratio increases the rate of decline of brain volume, MSFC, and PASAT. This provides evidence of a relationship between brain Glu and markers of disease progression in MS. © 2014 American Neurological Association.

BACKGROUND: Patients with tumors that recur from a prior LGG have quite different outcomes depending on their histological subtype, grade, and molecular/cytogenetic features. Non-invasive biomarkers that accurately reflect the biological properties of the lesion are urgently needed to make informed decisions about patient care. The primary objective of this study was to evaluate the role of noninvasive imaging parameters as biomarkers of malignant progression in diffuse LGG (WHO II) and to use these parameters to select the most metabolically active regions of tumors for characterization of their histological features. METHODS: After obtaining informed consent, 125 patients undergoing surgical resection of tumors that recurred from a prior LGG were prospectively enrolled from 2008-2012 in an institutional review board approved protocol. Preoperative MR metabolic and physiological images were used to select image guided tissue sample targets for histological status, IDH1 mutation and ex vivo metabolic profiles. H&E and immunohistochemistry of the tissue samples provided the following parameters: tumor score, necrosis, CA9 status (measure of hypoxia), MIB-1 status, cellularity, SMI-31 status and vascular status. RESULTS: 44% of the 125 tumors were grade II at recurrence, with 56% having upgraded in histology (44% grade III and 12% grade IV). Significant differences were observed for in vivo measures of maximum choline to N-acetylasparate index (CNI) and lactate, normalized apparent diffusion coefficient 2 for patients with upgraded versus non-upgraded lesions. CONCLUSIONS: The results from this study highlight tumor heterogeneity and underline the use of metabolic and physiologic imaging for non-invasively predicting upgrade status for patients with recurrent LGG who are not surgical candidates and also for directing the surgeon to the most malignant region of the lesion to get representative tissue for evaluation. These enhanced parameters will be utilized in a new cohort of 100 patients with recurrent LGG and their tissue will be used to characterize the genomic properties of non-upgraded versus upgraded samples. SECONDARY CATEGORY: n/a.