Separating indolent from aggressive prostate cancer is an important clinical challenge for identifying patients eligible for active surveillance, thereby reducing the risk of overtreatment. The ...purpose of this study was to assess prostate cancer aggressiveness by metabolic profiling of prostatectomy tissue and to identify specific metabolites as biomarkers for aggressiveness. Prostate tissue samples (n = 158, 48 patients) with a high cancer content (mean: 61.8%) were obtained using a new harvesting method, and metabolic profiles of samples representing different Gleason scores (GS) were acquired by high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS). Multivariate analysis (PLS, PLS-DA) and absolute quantification (LCModel) were used to examine the ability to predict cancer aggressiveness by comparing low grade (GS = 6, n = 30) and high grade (GS≥7, n = 81) cancer with normal adjacent tissue (n = 47). High grade cancer tissue was distinguished from low grade cancer tissue by decreased concentrations of spermine (p = 0.0044) and citrate (p = 7.73·10(-4)), and an increase in the clinically applied (total choline+creatine+polyamines)/citrate (CCP/C) ratio (p = 2.17·10(-4)). The metabolic profiles were significantly correlated to the GS obtained from each tissue sample (r = 0.71), and cancer tissue could be distinguished from normal tissue with sensitivity 86.9% and specificity 85.2%. Overall, our findings show that metabolic profiling can separate aggressive from indolent prostate cancer. This holds promise for the benefit of applying in vivo magnetic resonance spectroscopy (MRS) within clinical MR imaging investigations, and HR-MAS analysis of transrectal ultrasound-guided biopsies has a potential as an additional diagnostic tool.
Purpose
Until now, 1H MRSI of the prostate has been performed with suppression of the large water signal to avoid distortions of metabolite signals. However, this signal can be used for absolute ...quantification and spectral corrections. We investigated the feasibility of water‐unsuppressed MRSI in patients with prostate cancer for water signal–mediated spectral quality improvement and determination of absolute tissue levels of choline.
Methods
Eight prostate cancer patients scheduled for radical prostatectomy underwent multi‐parametric MRI at 3 T, including 3D water‐unsuppressed semi‐LASER MRSI. A postprocessing algorithm was developed to remove the water signal and its artifacts and use the extracted water signal as intravoxel reference for phase and frequency correction of metabolite signals and for absolute metabolite quantification.
Results
Water‐unsuppressed MRSI with dedicated postprocessing produced water signal and artifact‐free MR spectra throughout the prostate. In all patients, the absolute choline tissue concentration was significantly higher in tumorous than in benign tissue areas (mean ± SD: 7.2 ± 1.4 vs 3.8 ± 0.7 mM), facilitating tumor localization by choline mapping. Tumor tissue levels of choline correlated better with the commonly used (choline + spermine + creatine)/citrate ratio (r = 0.78 ± 0.1) than that of citrate (r = 0.21 ± 0.06). The highest maximum choline concentrations occurred in high‐risk cancer foci.
Conclusion
This report presents the first successful water‐unsuppressed MRSI of the whole prostate. The water signal enabled amelioration of spectral quality and absolute metabolite quantification. In this way, choline tissue levels were identified as tumor biomarker. Choline mapping may serve as a tool in prostate cancer localization and risk scoring in multi‐parametric MRI for diagnosis and biopsy procedures.
The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating ...nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (
= 64) and show that tumor size and cell proliferation, but not the integrity of the blood-brain barrier or cell death, affect the release of ctDNA in treatment-naïve GBM PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (<0.2× coverage) of host (rat) and tumor (human) circulating DNA identified a peak at 145 bp in the human DNA fragments, indicating a difference in the origin or processing of the ctDNA. The concentration of ctDNA correlated with cell death only after treatment with temozolomide and radiotherapy. Digital PCR detection of plasma tumor mitochondrial DNA (tmtDNA), an alternative to detection of nuclear ctDNA, improved plasma DNA detection rate (82% vs. 24%) and allowed detection in cerebrospinal fluid and urine. Mitochondrial mutations are prevalent across all cancers and can be detected with high sensitivity, at low cost, and without prior knowledge of tumor mutations via capture-panel sequencing. Coupled with the observation that mitochondrial copy number increases in glioma, these data suggest analyzing tmtDNA as a more sensitive method to detect and monitor tumor burden in cancer, specifically in GBM, where current methods have largely failed. SIGNIFICANCE: These findings show that detection of tumor mitochondrial DNA is more sensitive than circulating tumor DNA analysis to detect and monitor tumor burden in patient-derived orthotopic xenografts of glioblastoma.
Until now,
H MRSI of the prostate has been performed with suppression of the large water signal to avoid distortions of metabolite signals. However, this signal can be used for absolute ...quantification and spectral corrections. We investigated the feasibility of water-unsuppressed MRSI in patients with prostate cancer for water signal-mediated spectral quality improvement and determination of absolute tissue levels of choline.
Eight prostate cancer patients scheduled for radical prostatectomy underwent multi-parametric MRI at 3 T, including 3D water-unsuppressed semi-LASER MRSI. A postprocessing algorithm was developed to remove the water signal and its artifacts and use the extracted water signal as intravoxel reference for phase and frequency correction of metabolite signals and for absolute metabolite quantification.
Water-unsuppressed MRSI with dedicated postprocessing produced water signal and artifact-free MR spectra throughout the prostate. In all patients, the absolute choline tissue concentration was significantly higher in tumorous than in benign tissue areas (mean ± SD: 7.2 ± 1.4 vs 3.8 ± 0.7 mM), facilitating tumor localization by choline mapping. Tumor tissue levels of choline correlated better with the commonly used (choline + spermine + creatine)/citrate ratio (r = 0.78 ± 0.1) than that of citrate (r = 0.21 ± 0.06). The highest maximum choline concentrations occurred in high-risk cancer foci.
This report presents the first successful water-unsuppressed MRSI of the whole prostate. The water signal enabled amelioration of spectral quality and absolute metabolite quantification. In this way, choline tissue levels were identified as tumor biomarker. Choline mapping may serve as a tool in prostate cancer localization and risk scoring in multi-parametric MRI for diagnosis and biopsy procedures.
IMPORTANCE: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. OBJECTIVE: To evaluate the effect of intensive blood pressure control on risk of ...dementia. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. INTERVENTIONS: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). MAIN OUTCOMES AND MEASURES: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. RESULTS: Among 9361 randomized participants (mean age, 67.9 years; 3332 women 35.6%), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio HR, 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). CONCLUSIONS AND RELEVANCE: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01206062
Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in ...humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.
Background Tumor cells frequently show high rates of aerobic glycolysis, which provides the glycolytic intermediates needed for the increased biosynthetic demands of rapid cell growth and ...proliferation. Existing clinical methods (fluorodeoxyglucose PET and carbon 13 MRI and spectroscopy) do not allow quantitative images of glycolytic flux. Purpose To evaluate the use of deuterium (hydrogen 2
H) MR spectroscopic imaging for quantitative mapping of tumor glycolytic flux and to assess response to chemotherapy. Materials and Methods A fast three-dimensional
H MR spectroscopic imaging pulse sequence, with a time resolution of 10 minutes, was used to image glycolytic flux in a murine tumor model after bolus injection of D-6,6'-
H
glucose before and 48 hours after treatment with a chemotherapeutic agent. Tumor lactate labeling, expressed as the lactate-to-water and lactate-to-glucose signal ratios, was also assessed in localized
H MR spectra. Statistical significance was tested with a one-sided paired
test. Results
H MR spectroscopic imaging showed heterogeneity in glycolytic flux across the tumor and an early decrease in flux following treatment with a chemotherapeutic drug. Spectroscopy measurements on five animals showed a decrease in the lactate-to-water signal ratio, from 0.33 ± 0.10 to 0.089 ± 0.039 (
= .005), and in the lactate-to-glucose ratio, from 0.27 ± 0.12 to 0.12 ± 0.06 (
= .04), following drug treatment. Conclusion Rapidly acquired deuterium (hydrogen 2) MR spectroscopic images can provide quantitative and spatially resolved measurements of glycolytic flux in tumors that can be used to assess treatment response. Published under a CC BY 4.0 license.
See also the editorial by Ouwerkerk in this issue.
H magnetic resonance spectroscopic imaging has been shown recently to be a viable technique for metabolic imaging in the clinic. We show here that
H MR spectroscopy and spectroscopic imaging ...measurements of 2,3-
H
malate production from 2,3-
H
fumarate can be used to detect tumor cell death in vivo via the production of labeled malate. Production of 2,3-
H
malate, following injection of 2,3-
H
fumarate (1 g/kg) into tumor-bearing mice, was measured in a murine lymphoma (EL4) treated with etoposide, and in human breast (MDA-MB-231) and colorectal (Colo205) xenografts treated with a TRAILR2 agonist, using surface-coil localized
H MR spectroscopy at 7 T. Malate production was also imaged in EL4 tumors using a fast
H chemical shift imaging sequence. The malate/fumarate ratio increased from 0.016 ± 0.02 to 0.16 ± 0.14 in EL4 tumors 48 h after drug treatment (
= 0.0024,
= 3), and from 0.019 ± 0.03 to 0.25 ± 0.23 in MDA-MB-231 tumors (
= 0.0001,
= 5) and from 0.016 ± 0.04 to 0.28 ± 0.26 in Colo205 tumors (
= 0.0002,
= 5) 24 h after drug treatment. These increases were correlated with increased levels of cell death measured in excised tumor sections obtained immediately after imaging.
H MR measurements of 2,3-
H
malate production from 2,3-
H
fumarate provide a potentially less expensive and more sensitive method for detecting cell death in vivo than
C MR measurements of hyperpolarized 1,4-
C
fumarate metabolism, which have been used previously for this purpose.
Drought disproportionately affects larger trees in tropical forests, but implications for forest composition and carbon (C) cycling in relation to dry season intensity remain poorly understood.
In ...order to characterize how C cycling is shaped by tree size and drought adaptations and how these patterns relate to spatial and temporal variation in water deficit, we analyze data from three forest dynamics plots spanning a moisture gradient in Panama that have experienced El Niño droughts.
At all sites, aboveground C cycle contributions peaked below 50-cm stem diameter, with stems ≥ 50 cm accounting for on average 59% of live aboveground biomass, 45% of woody productivity and 49% of woody mortality. The dominance of drought-avoidance strategies increased interactively with stem diameter and dry season intensity. Although size-related C cycle contributions did not vary systematically across the moisture gradient under non-drought conditions, woody mortality of larger trees was disproportionately elevated under El Niño drought stress.
Thus, large (> 50 cm) stems, which strongly mediate but do not necessarily dominate C cycling, have drought adaptations that compensate for their more challenging hydraulic environment, particularly in drier climates. However, these adaptations do not fully buffer the effects of severe drought, and increased large tree mortality dominates ecosystem-level drought responses.
Background Chronic kidney disease is common and is associated with cardiovascular disease, cerebrovascular disease, and cognitive function, although the nature of this relationship remains uncertain. ...Study Design Cross-sectional cohort using baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). Setting & Participants Participants in SPRINT, a randomized clinical trial of blood pressure targets in older community-dwelling adults with cardiovascular disease, chronic kidney disease, or high cardiovascular disease risk and without diabetes or known stroke, who underwent detailed neurocognitive testing in the cognition substudy, SPRINT−Memory and Cognition in Decreased Hypertension (SPRINT-MIND). Predictors Urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). Outcomes Cognitive function, a priori defined as 5 cognitive domains based on 11 cognitive tests using z scores, and abnormal white matter volume quantified by brain magnetic resonance imaging. Results Of 9,361 SPRINT participants, 2,800 participated in SPRINT-MIND and 2,707 had complete data; 637 had brain imaging. Mean age was 68 years, 37% were women, 30% were black, and 20% had known cardiovascular disease. Mean eGFR was 70.8 ± 20.9 mL/min/1.73 m2 and median urine ACR was 9.7 (IQR, 5.7-22.5) mg/g. In adjusted analyses, higher ACR was associated with worse global cognitive function, executive function, memory, and attention, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6, and 14 months older, respectively. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher ACR, but not eGFR, was associated with larger abnormal white matter volume. Limitations Cross-sectional only, no patients with diabetes were included. Conclusions In older adults, higher urine ACR and lower eGFR have independent associations with global cognitive performance with different affected domains. Albuminuria concurrently identifies a higher burden of abnormal brain white matter disease, suggesting that vascular disease may mediate these relationships.
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