Metabolic Imaging Biomarkers Research Articles

Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis.

People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD). Neuropathology consistent with AD is present by 40 years of age and dementia may develop up to a decade later. In this review, we describe metabolic and vascular neuroimaging studies in DS that suggest these functional changes are a key feature of aging, linked to cognitive decline and AD in this vulnerable cohort. FDG-PET imaging in DS suggests systematic reductions in glucose metabolism in posterior cingulate and parietotemporal cortex. Magentic resonance spectroscopy studies show consistent decreases in neuronal health and increased myoinositol, suggesting inflammation. There are few vascular imaging studies in DS suggesting a gap in our knowledge. Future studies would benefit from longitudinal measures and combining various imaging approaches to identify early signs of dementia in DS that may be amenable to intervention.

Abstract 1857: Early detection of pancreatic intraepithelial neoplasms (PanINs) in transgenic mouse model by hyperpolarized 13C metabolic magnetic resonance imaging

Abstract Pancreatic cancer, one of the most lethal solid tumors, is an aggressive disease that develops relatively symptom-free. Pre-invasive pancreatic intraepithelial neoplasias (PanINs) have been identified as precursor lesions to pancreatic cancer. While there is growing evidence supporting PanIN's genetic links to pancreatic cancer, there is no non-invasive method to detect them. There is an unmet need of novel strategies for detection of pancreatic cancer at the earliest stages, preferably at the stage of PanINs. Hyperpolarized magnetic resonance imaging (HP-MRI) has shown potential for early detection of cancers and monitoring therapeutic efficacy. Here we have employed in-vivo 13C pyruvate metabolic imaging and ex-vivo nuclear magnetic resonance (1H-NMR) metabolomics to identify and understand metabolic changes, to enable detection of early PanINs and its progression to advanced PanINs and pancreatic cancer. Genetically engineered mouse (GEM) models with progression of PanIN lesions and control animals, with no pancreatic lesions, were employed in this study. Hyperpolarization of pyruvate and in-vivo 13C MRS were performed using Hypersense (Oxford Instruments) and 7T MRI scanner with a dual tuned 1H/13C volume coil respectively. Tissue alanine and lactate concentrations were determined using a Bruker 500 MHz NMR spectrometer coupled with cryo-probe. Histology and immunohistochemistry were performed on excised tissue samples. P48Cre mice were used as controls and P48Cre;LSLKrasG12D mice were used for detection of early and advanced PanINs, which usually develop in these mice between 12 and 20 months. The imaging experiments were performed at the different stages of the disease. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate concentration ratio. Real time in-vivo 13C MRS was used to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice, following injection of hyperpolarized pyruvate. The alanine-to-lactate (Ala/Lac) signal intensity ratio was found decreased as the disease progressed from low-grade PanINs to high-grade PanINs. These results demonstrate that there are significant alterations of alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities which favor the transformation of aggressive pancreatic cancer from PanINs lesion. Our results suggest that real-time conversion kinetic rate constants kPA(pyruvate-to-alanine) and kPL(pyruvate-to-lactate) can be used as metabolic imaging biomarkers for assessing the early stage of pancreatic diseases. Findings from this highly promising HP-MRI technique could be rapidly translated to the clinic for early detection of pancreatic cancer in patients at high risk for developing the disease. Citation Format: Prasanta Dutta, Yu Zhang, Michelle Zoltan, Marilina Mascaro, Erick Riquelme, Jaehyuk Lee, Anirban Maitra, Florencia McAllister, Pratip Bhattacharya. Early detection of pancreatic intraepithelial neoplasms (PanINs) in transgenic mouse model by hyperpolarized 13C metabolic magnetic resonance imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1857. doi:10.1158/1538-7445.AM2017-1857

Refining prognosis in patients with hepatocellular carcinoma through incorporation of metabolic imaging biomarkers.

18F-fluorodeoxyglucose positron emission tomopraphy/computed tomography (FDGPET/CT) has been proven to be useful for imaging many types of cancer; however, its role is not well defined in hepatocellular carcinoma (HCC). We assessed the prognostic value of metabolic imaging biomarkers as established by baseline pretreatment FDG PET/CT in patients with HCC. We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal-liver SUV ratio (TNR). Optimal cut-off values for the PET/CT parameters to stratify patients in terms of overall survival (OS) were determined. Multivariate analysis was performed to determine whether the PET/CT parameters could add to the prognostic value of the Cancer of the Liver Italian Program (CLIP) scoring system and the Barcelona-Clinic Liver Cancer (BCLC) staging system. The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUVmax, TLG, tumor size, total bilirubin level, and alkaline phosphatase level were significant predictors of OS. SUVmax ≥11.7, TLG ≥1,341, MTV ≥230mL, and TNR ≥4.8 were identified as cut-off values. Multivariate analysis revealed that SUVmax ≥11.7 and TNR ≥4.8 were independent factors predicting a poor prognosis in both the CLIP scoring system and the BCLC staging system, as was TLG in the BCLC staging system. Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered.

Abstract 5293: Redox imaging biomarkers for breast cancer diagnosis/prognosis: a pilot study

Abstract Metastasis accounts for 90% of cancer death and there are no reliable clinical biomarkers predicting metastatic risk. Our studies using preclinical models have shown that tumors with higher propensity for metastasis have distinct metabolic profiles. We aim to evaluate the prognostic value of several optical metabolic imaging biomarkers as previously demonstrated by our group to have diagnostic/prognostic potential in mouse tumor models. As a pilot study, we have successfully employed the 3D cryogenic NADH/oxidized flavoproteins (Fp) fluorescence imager (the Chance redox scanner) to imaging the breast tissue core biopsies of 16 breast cancer patients. We found that the redox indices (including Fp, NADH, Fp/(NADH+Fp), NADH/Fp, and their standard deviations) could readily differentiate cancer from non-cancer and the cancerous tissues were more oxidized and more heterogeneous. To test the prognostic power of this technique, we acquired the frozen breast tumor tissue collected at the time of the patient's primary breast cancer surgery (n = 29) selected from a fully annotated breast tumor tissue bank. The clinical breast cancer subtypes in our cohort (65% ER+/PR+ (luminal A), 20% TNBC, 15% Her2+ (including both luminal B and Her2+)) follow the expected distribution. Of the 29 patients, six of them have developed metastatic disease (MET) while the remaining patients have no evidence of disease (NED) at the time of study. Three to four tissue sections (spacing 100-200 μm) of each specimen were scanned with the Chance redox scanner. Comparison of redox indices between MET and NED, calculated by averaging indices globally, demonstrated no significant differences. However, as the redox state was heterogeneous within the tumor tissue, we developed heterogeneity-associated mitochondrial redox indices (HAMRI) based on the observed intra-specimen redox heterogeneity. By fitting the histogram of the Fp redox ratio, Fp/(NADH+Fp) for each of the image sections with 2-4 Gaussian functions, whereby each Gaussian curve represented a subpopulation of image pixels with a unique averaged redox ratio, we identified the most reduced (the smallest Fp redox ratio - br) and the most oxidized (the largest Fp redox ratio - bo) redox ratios for each patient (br< bo). HAMRI indices were then derived for each patient's tumor sample and were statistically tested for their prognostic power. Our results from this pilot study showed that HAMRI is a strong predictor of MET (sensitivity 83%, specificity 88%, AUC = 0.93, p = 0.01), more robust than conventional prognostic factors (e.g. tumor grade, size, molecular types, nodal status). HAMRI indices also predicted the nodal status in our cohort. Our findings suggest that our quantitative redox scanning technique has prognostic value and warrants further investigation. Citation Format: He N. Xu, Julia Tchou, Min Feng, Huaqing Zhao, Nannan Sun, Sophia Zhang, Lily Moon, Lin Z. Li. Redox imaging biomarkers for breast cancer diagnosis/prognosis: a pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5293. doi:10.1158/1538-7445.AM2015-5293

(Tissue PET) Vascular metabolic imaging and peripheral plasma biomarkers in the evolution of chronic aortic dissections.

Despite adequate medical management, dissection of the descending aorta (type B) may develop complications, including aneurysmal progression and eventually rupture. Partial false lumen thrombosis has been identified as a marker of adverse evolution in chronic dissection. The aim of this study was to test the ability of complementary information, provided by (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and peripheral biomarkers, to add pathophysiological significance and a prognostic value to morphological data. We explored serial aortic (18)F-FDG uptake by PET/CT imaging and plasma biomarkers in a series of 23 patients with type B dissection to predict complications from initial data and to investigate potential associations with aneurysmal expansion during follow-up. Complications occurred in 17 patients. Acute initial characteristics associated with complications were male gender (P = 0.021), arterial hypertension (P = 0.040), aortic dissection diameter (P = 0.0086), partial thrombosis of the false channel (P = 0.0046), and enhanced focal (18)F-FDG uptake (P = 0.045). During follow-up (mean 16.7 ± 8.0 months), aneurysmal expansion was associated with false lumen morphology (P< 0.0001), quantitative (18)F-FDG uptake, (P = 0.0029), elevated plasma concentrations of biomarkers of platelets (P-selectin, P = 0.0009) and thrombin activation (TAT complexes, P = 0.0075), and fibrinolysis (PAP complexes, P < 0.0001; D-dimers, P = 0.0006). Plasma markers of coagulation and fibrinolysis were related to false channel morphology, suggesting that thrombus biological dynamics may drive progressive expansion of type B dissections. Enhanced FDG uptake may be considered as a complementary imaging marker associated with secondary complications in type B dissections. During follow-up, aneurysmal progression is related to PET/CT and biomarkers of thrombus renewal and lysis.

Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients.

Despite multimodal treatment, the prognosis of high-grade gliomas is grim. As tumor growth is critically dependent on new blood vessel formation, antiangiogenic treatment approaches offer an innovative treatment strategy. Bevacizumab, a humanized monoclonal antibody, has been in the spotlight of antiangiogenic approaches for several years. Currently, MRI including contrast-enhanced T1-weighted and T2/fluid-attenuated inversion recovery (FLAIR) images is routinely used to evaluate antiangiogenic treatment response (Response Assessment in Neuro-Oncology criteria). However, by restoring the blood-brain barrier, bevacizumab may reduce T1 contrast enhancement and T2/FLAIR hyperintensity, thereby obscuring the imaging-based detection of progression. The aim of this review is to highlight the recent role of imaging biomarkers from MR and PET imaging on measurement of disease progression and treatment effectiveness in antiangiogenic therapies. Based on the reviewed studies, multimodal imaging combining standard MRI with new physiological MRI techniques and metabolic PET imaging, in particular amino acid tracers, may have the ability to detect antiangiogenic drug susceptibility or resistance prior to morphological changes. As advances occur in the development of therapies that target specific biochemical or molecular pathways and alter tumor physiology in potentially predictable ways, the validation of physiological and metabolic imaging biomarkers will become increasingly important in the near future.

Hyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.

Taui, A high-resolution metabolic imaging biomarker for myocardium

Background Contrast-enhanced H2O T1-weighted cardiovascular MRI is usually interpreted using tracer paradigms; e.g., the extra-/intravascular contrast agent (CA) partition coefficient. However, the signal molecule is water, not CA. Consequently, the myocardial extracellular volume fraction (ECV) is underestimated in proportion to its magnitude. Even more importantly, intercompartmental water exchange kinetics are inaccessible. The mean intracellular water molecule lifetime [taui] is assumed effectively 0; though it is a fraction of a second. For cylindrical myocytes with mean cytolemmal water permeability coefficient PW and diameter d: taui = 4(PW/d). taui -1 is linearly related to PW and to d . However, PW dominates and is itself dominated by active trans-membrane water cycling. Thus, taui -1 is proportional to the driving cytolemmal ATPase ion pump activity.

Redox Imaging of Human Breast Cancer Core Biopsies: A Preliminary Investigation

The clinical gold standard for breast cancer diagnosis relies on invasive biopsies followed by tissue fixation for subsequent histopathological examination. This process renders the specimens to be much less suitable for biochemical or metabolic analysis. Our previous metabolic imaging data in tumor xenograft models showed that the mitochondrial redox state is a sensitive indicator that can distinguish between normal and tumor tissue. In this study, we investigated whether the same redox imaging technique can be applied to core biopsy samples of human breast cancer and whether the mitochondrial redox state may serve as a novel metabolic biomarker that may be used to distinguish between normal and malignant breast tissue in the clinic. Our long-term objective was to identify novel metabolic imaging biomarkers for breast cancer diagnosis. Both normal and cancerous tissue specimens were collected from the cancer-bearing breasts of three patients shortly after surgical resection. Core biopsies and tissue blocks were obtained from tumor and normal adjacent breast tissue, respectively. All specimens were snap-frozen with liquid nitrogen, embedded in chilled mounting medium with flavin adenine dinucleotide and reduced nicotinamide adenine dinucleotide reference standards adjacently placed, and scanned using the Chance redox scanner (ie, cryogenic nicotinamide adenine dinucleotide/oxidized flavoprotein fluorescence imager). Our preliminary data showed cancerous tissues had up to 10-fold higher oxidized flavoprotein signals and had elevated oxidized redox state compared to the normal tissues from the same patient. A high degree of tumor tissue heterogeneity in the redox indices was observed. Our finding suggests that the identified redox imaging indices could differentiate between cancer and noncancer breast tissues without subjecting tissues to fixatives. We propose that this novel redox scanning procedure may assist in tissue diagnosis in freshly procured biopsy samples before tissue fixation.

Histopathology of lung adenocarcinoma based on new IASLC/ATS/ERS classification: Prognostic stratification with functional and metabolic imaging biomarkers

To correlate the results of histopathologic subtyping and grading of lung adenocarcinoma with maximum standardized uptake values (SUVmax) on positron emission tomography (PET)/computed tomography and apparent diffusion coefficient (ADC) values on diffusion-weighted MRI (DWI). Forty-three patients were included. The SUVmax and mean ADC values of tumors were measured and correlated with the histologic subtypes and grades of lung adenocarcinomas based on the IASLC/ATS/ERS classification scheme. Disease-free survival (DFS) was estimated by using the Kaplan-Meier method, and the log-rank test was used to evaluate differences among three histologic grades or subgroups classified with imaging biomarker study results. Five (12.5%) tumors belonged to low grade, 30 (70%) to intermediate grade, and 8 (18.5%) to high grade, and patients with low-grade histology had lower risk of recurrence than those with intermediate- or high-grade histology (P = 0.048). A significant difference in SUVmax and mean ADC values was observed among three histologic grades (Ps < 0.001). Regarding DFS, lower metabolic (PET) activity or higher functional (DWI) diffusivity showed longer DFS. When patients (n = 30; 70% of patients) with intermediate histologic grade were subgrouped in consideration of both SUVmax and mean ADC results, combining metabolic and functional criteria helped stratify patients more precisely (P = 0.006). SUVmax and mean ADC value correlate well with the histologic grades in lung adenocarcinomas, and combining both imaging biomarker study results leads to more useful stratification of patients into different prognostic subsets than the results of each study.

Morphological, functional and metabolic imaging biomarkers: assessment of vascular-disrupting effect on rodent liver tumours

To evaluate effects of a vascular-disrupting agent on rodent tumour models. Twenty rats with liver rhabdomyosarcomas received ZD6126 intravenously at 20 mg/kg, and 10 vehicle-treated rats were used as controls. Multiple sequences, including diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) with the microvascular permeability constant (K), were acquired at baseline, 1 h, 24 h and 48 h post-treatment by using 1.5-T MRI. [(18)F]fluorodeoxyglucose micro-positron emission tomography ((18)F-FDG microPET) was acquired pre- and post-treatment. The imaging biomarkers including tumour volume, enhancement ratio, necrosis ratio, apparent diffusion coefficient (ADC) and K from MRI, and maximal standardised uptake value (SUV(max)) from FDG microPET were quantified and correlated with postmortem microangiography and histopathology. In the ZD6126-treated group, tumours grew slower with higher necrosis ratio at 48 h (P < 0.05), corresponding well to histopathology; tumour K decreased from 1 h until 24 h, and partially recovered at 48 h (P < 0.05), parallel to the evolving enhancement ratios (P < 0.05); ADCs varied with tumour viability and perfusion; and SUV(max) dropped at 24 h (P < 0.01). Relative K of tumour versus liver at 48 h correlated with relative vascular density on microangiography (r = 0.93, P < 0.05). The imaging biomarkers allowed morphological, functional and metabolic quantifications of vascular shutdown, necrosis formation and tumour relapse shortly after treatment. A single dose of ZD6126 significantly diminished tumour blood supply and growth until 48 h post-treatment.

Integration of targeted agents in the neo-adjuvant treatment of gastro-esophageal cancers.

Pre- and peri-operative strategies are becoming standard for the management of localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5-10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre-operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo-adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging and predictive biomarkers.