Fast and High-Resolution T2 Mapping Based on Echo Merging Plus k-t Undersampling with Reduced Refocusing Flip Angles (TEMPURA) as Methods for Human Renal MRI.

PURPOSE: To develop a highly accelerated multi-echo spin-echo method, TEMPURA, for reducing the acquisition time and/or increasing spatial resolution for kidney T2 mapping. METHODS: TEMPURA merges several adjacent echoes into one k-space by either combining independent echoes or sharing one echo between k-spaces. The combined k-space is reconstructed based on compressed sensing theory. Reduced flip angles are used for the refocusing pulses, and the extended phase graph algorithm is used to correct the effects of indirect echoes. Two sequences were developed: a fast breath-hold sequence; and a high-resolution sequence. The performance was evaluated prospectively on a phantom, 16 healthy subjects, and two patients with different types of renal tumors. RESULTS: The fast TEMPURA method reduced the acquisition time from 3-5 min to one breath-hold (18 s). Phantom measurements showed that fast TEMPURA had a mean absolute percentage error (MAPE) of 8.2%, which was comparable to a standardized respiratory-triggered sequence (7.4%), but much lower than a sequence accelerated by purely k-t undersampling (21.8%). High-resolution TEMPURA reduced the in-plane voxel size from 3 × 3 to 1 × 1 mm2, resulting in improved visualization of the detailed anatomical structure. In vivo T2 measurements demonstrated good agreement (fast: MAPE = 1.3%-2.5%; high-resolution: MAPE = 2.8%-3.3%) and high correlation coefficients (fast: R = 0.85-0.98; high-resolution: 0.82-0.96) with the standardized method, outperforming k-t undersampling alone (MAPE = 3.3-4.5%, R = 0.57-0.59). CONCLUSION: TEMPURA provides fast and high-resolution renal T2 measurements. It has the potential to improve clinical throughput and delineate intratumoral heterogeneity and tissue habitats at unprecedented spatial resolution.

New Horizons in Hyperpolarized 13C MRI.

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.

Imaging tumor lactate is feasible for identifying intermediate-risk prostate cancer patients with postsurgical biochemical recurrence.

While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care diagnostic tools. Here, we show that imaging tumor lactate using hyperpolarized 13C MRI and spatial metabolomics identifies BCR-positive patients in two prospective intermediate-risk surgical cohorts. Supported by spatially resolved tissue analysis of established glycolytic biomarkers, this study provides the rationale for multicenter trials of tumor metabolic imaging as an auxiliary tool to support PCa treatment decision-making.

Hyperpolarized Carbon 13 MRI: Clinical Applications and Future Directions in Oncology.

Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology. Keywords: Hyperpolarized Carbon 13 MRI, Molecular Imaging, Cancer, Tissue Metabolism © RSNA, 2023.

Hyperpolarised 13C-MRI using 13C-pyruvate in breast cancer: A review.

Tumour metabolism can be imaged with a novel imaging technique termed hyperpolarised carbon-13 (13C)-MRI using probes, i.e., endogenously found molecules that are labeled with 13C. Hyperpolarisation of the 13C label increases the sensitivity to a level that allows dynamic imaging of the distribution and metabolism of the probes. Dynamic imaging of [1-13C]pyruvate metabolism is of particular biological interest in cancer because of the Warburg effect resulting in the intratumoural accumulation of [1-13C]pyruvate and conversion to [1-13C]lactate. Numerous preclinical studies in breast cancer and other tumours have shown that hyperpolarised 13C-pyruvate has potential for metabolic phenotyping and response assessment at earlier timepoints than the current clinical imaging techniques allow. The clinical feasibility of hyperpolarised 13C-MRI after the injection of pyruvate in patients with breast cancer has now been demonstrated, with increased 13C-label exchange between pyruvate and lactate present in higher grade tumours with associated increased expression of the monocarboxylate transporter 1 (MCT1), the transmembrane transporter mediating intracellular pyruvate uptake, and lactate dehydrogenase (LDH) as the enzyme catalysing the conversion of pyruvate to lactate. Furthermore, a study in patients with breast cancer undergoing neoadjuvant chemotherapy suggested that early changes in 13C-label exchange can distinguish between patients who reach pathologic complete response (pCR) and those who do not. This review summarises the current literature on preclinical and clinical research on hyperpolarised 13C-MRI with [1-13C]-pyruvate in breast cancer imaging.

Open source code for the generation of digital reference objects for dynamic contrast-enhanced MRI analysis software validation.

OBJECTIVES: Dynamic contrast-enhanced MR images can be analyzed through the application of a wide range of kinetic models. This process is prone to variability and a lack of standardization that can affect the measured metrics. There is a need for customized digital reference objects (DROs) for the validation of DCE-MRI software packages that undertake kinetic model analysis. DROs are currently available only for a small subset of the kinetic models commonly applied to DCE-MRI data. This work aimed to address this gap. METHODS: Code was written in the MATLAB programming environment to generate customizable DROs. This modular code allows the insertion of a plug-in to describe the kinetic model to be tested. We input our generated DROs into three commercial and open-source analysis packages and assessed the agreement of kinetic model parameter values output with the 'ground-truth' values used in the DRO generation. RESULTS: For the five kinetic models tested, the concordance correlation coefficient values were >98%, indicating excellent agreement of the results with 'ground-truth'. CONCLUSIONS: Testing our DROs on three independent software packages produced concordant results, strongly suggesting our DRO generation code is correct. This implies that our DROs can be used to validate other third party software for the kinetic model analysis of DCE-MRI data. ADVANCES IN KNOWLEDGE: This work extends published work of others to allow customized generation of test objects for any applied kinetic model and allows the incorporation of B1 mapping into the DRO for application at higher field strengths.

The use of temozolomide in paediatric metastatic phaeochromocytoma/paraganglioma: A case report and literature review.

There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.

MRI techniques for immunotherapy monitoring.

MRI is a widely available clinical tool for cancer diagnosis and treatment monitoring. MRI provides excellent soft tissue imaging, using a wide range of contrast mechanisms, and can non-invasively detect tissue metabolites. These approaches can be used to distinguish cancer from normal tissues, to stratify tumor aggressiveness, and to identify changes within both the tumor and its microenvironment in response to therapy. In this review, the role of MRI in immunotherapy monitoring will be discussed and how it could be utilized in the future to address some of the unique clinical questions that arise from immunotherapy. For example, MRI could play a role in identifying pseudoprogression, mixed response, T cell infiltration, cell tracking, and some of the characteristic immune-related adverse events associated with these agents. The factors to be considered when developing MRI imaging biomarkers for immunotherapy will be reviewed. Finally, the advantages and limitations of each approach will be discussed, as well as the challenges for future clinical translation into routine clinical care. Given the increasing use of immunotherapy in a wide range of cancers and the ability of MRI to detect the microstructural and functional changes associated with successful response to immunotherapy, the technique has great potential for more widespread and routine use in the future for these applications.

Magnetization transfer imaging of ovarian cancer: initial experiences of correlation with tissue cellularity and changes following neoadjuvant chemotherapy.

Objectives: To investigate the relationship between magnetization transfer (MT) imaging and tissue macromolecules in high-grade serous ovarian cancer (HGSOC) and whether MT ratio (MTR) changes following neoadjuvant chemotherapy (NACT). Methods: This was a prospective observational study. 12 HGSOC patients were imaged before treatment. MTR was compared to quantified tissue histology and immunohistochemistry. For a subset of patients (n = 5), MT imaging was repeated after NACT. The Shapiro-Wilk test was used to assess for normality of data and Spearman's rank-order or Pearson's correlation tests were then used to compare MTR with tissue quantifications. The Wilcoxon signed-rank test was used to assess for changes in MTR after treatment. Results: Treatment-naïve tumour MTR was 21.9 ± 3.1% (mean ± S.D.). MTR had a positive correlation with cellularity, rho = 0.56 (p < 0.05) and a negative correlation with tumour volume, ρ = -0.72 (p = 0.01). MTR did not correlate with the extracellular proteins, collagen IV or laminin (p = 0.40 and p = 0.90). For those patients imaged before and after NACT, an increase in MTR was observed in each case with mean MTR 20.6 ± 3.1% (median 21.1) pre-treatment and 25.6 ± 3.4% (median 26.5) post-treatment (p = 0.06). Conclusion: In treatment-naïve HGSOC, MTR is associated with cellularity, possibly reflecting intracellular macromolecular concentration. MT may also detect the HGSOC response to NACT, however larger studies are required to validate this finding. Advances in knowledge: MTR in HGSOC is influenced by cellularity. This may be applied to assess for cell changes following treatment.

Imaging Glioblastoma Metabolism by Using Hyperpolarized [1-13C]Pyruvate Demonstrates Heterogeneity in Lactate Labeling: A Proof of Principle Study.

Purpose To evaluate glioblastoma (GBM) metabolism by using hyperpolarized carbon 13 (13C) MRI to monitor the exchange of the hyperpolarized 13C label between injected [1-13C]pyruvate and tumor lactate and bicarbonate. Materials and Methods In this prospective study, seven treatment-naive patients (age [mean ± SD], 60 years ± 11; five men) with GBM were imaged at 3 T by using a dual-tuned 13C-hydrogen 1 head coil. Hyperpolarized [1-13C]pyruvate was injected, and signal was acquired by using a dynamic MRI spiral sequence. Metabolism was assessed within the tumor, in the normal-appearing brain parenchyma (NABP), and in healthy volunteers by using paired or unpaired t tests and a Wilcoxon signed rank test. The Spearman ρ correlation coefficient was used to correlate metabolite labeling with lactate dehydrogenase A (LDH-A) expression and some immunohistochemical markers. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results The bicarbonate-to-pyruvate (BP) ratio was lower in the tumor than in the contralateral NABP (P < .01). The tumor lactate-to-pyruvate (LP) ratio was not different from that in the NABP (P = .38). The LP and BP ratios in the NABP were higher than those observed previously in healthy volunteers (P < .05). Tumor lactate and bicarbonate signal intensities were strongly correlated with the pyruvate signal intensity (ρ = 0.92, P < .001, and ρ = 0.66, P < .001, respectively), and the LP ratio was weakly correlated with LDH-A expression in biopsy samples (ρ = 0.43, P = .04). Conclusion Hyperpolarized 13C MRI demonstrated variation in lactate labeling in GBM, both within and between tumors. In contrast, bicarbonate labeling was consistently lower in tumors than in the surrounding NABP. Keywords: Hyperpolarized 13C MRI, Glioblastoma, Metabolism, Cancer, MRI, Neuro-oncology Supplemental material is available for this article. Published under a CC BY 4.0 license.

A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA).

BACKGROUND: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor. METHODS: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity. RESULTS: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype. CONCLUSIONS: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery. CLINICAL TRIAL REGISTRATION: NCT03494816.

The potential of hyperpolarised 13C-MRI to target glycolytic tumour core in prostate cancer.

Hyperpolarised [1-13C]pyruvate MRI (HP-13C-MRI) is an emerging metabolic imaging technique that has shown promise for evaluating prostate cancer (PCa) aggressiveness. Accurate tumour delineation on HP-13C-MRI is vital for quantitative assessment of the underlying tissue metabolism. However, there is no consensus on the optimum method for segmenting HP-13C-MRI, and whole-mount pathology (WMP) as the histopathological gold-standard is only available for surgical patients. Although proton MRI can be used for tumour delineation, this approach significantly underestimates tumour volume, and metabolic tumour segmentation based on HP-13C-MRI could provide an important functional metric of tumour volume. In this study, we quantified metabolism using HP-13C-MRI and segmentation approaches based on WMP maps, 1H-MRI-derived T2-weighted imaging (T2WI), and HP-13C-MRI-derived total carbon signal-to-noise ratio maps (TC-SNR) with an SNR threshold of 5.0. 13C-labelled pyruvate SNR, lactate SNR, TC-SNR, and the pyruvate-to-lactate exchange rate constant (kPL) were significantly higher when measured using the TC-SNR-guided approach, which also corresponded to a significantly higher tumour epithelial expression on RNAscope imaging of the enzyme catalysing pyruvate-to-lactate metabolism (lactate dehydrogenase (LDH)). However, linear regression and Bland-Altman analyses demonstrated a strong linear relationship between all three segmentation approaches, which correlated significantly with RNA-scope-derived epithelial LDH expression. These results suggest that standard-of-care T2WI and TC-SNR maps could be used as clinical reference tools for segmenting localised PCa on HP-13C-MRI in the absence of the WMP gold standard. The TC-SNR-guided approach could be used clinically to target biopsies towards highly glycolytic tumour areas and therefore to sample aggressive disease with higher precision. KEY POINTS: • T2WI- and TC-SNR-guided segmentations can be used in all PCa patients and do not explicitly require WMP maps. • Agreement between the three segmentation approaches is biologically validated by their strong relationship with epithelial LDH mRNA expression. • The TC-SNR-guided approach can potentially be used to identify occult disease on 1H-MRI and target the most glycolytically active regions.

Quantification and reduction of cross-vendor variation in multicenter DWI MR imaging: results of the Cancer Core Europe imaging task force.

OBJECTIVES: In the Cancer Core Europe Consortium (CCE), standardized biomarkers are required for therapy monitoring oncologic multicenter clinical trials. Multiparametric functional MRI and particularly diffusion-weighted MRI offer evident advantages for noninvasive characterization of tumor viability compared to CT and RECIST. A quantification of the inter- and intraindividual variation occurring in this setting using different hardware is missing. In this study, the MRI protocol including DWI was standardized and the residual variability of measurement parameters quantified. METHODS: Phantom and volunteer measurements (single-shot T2w and DW-EPI) were performed at the seven CCE sites using the MR hardware produced by three different vendors. Repeated measurements were performed at the sites and across the sites including a traveling volunteer, comparing qualitative and quantitative ROI-based results including an explorative radiomics analysis. RESULTS: For DWI/ADC phantom measurements using a central post-processing algorithm, the maximum deviation could be decreased to 2%. However, there is no significant difference compared to a decentralized ADC value calculation at the respective MRI devices. In volunteers, the measurement variation in 2 repeated scans did not exceed 11% for ADC and is below 20% for single-shot T2w in systematic liver ROIs. The measurement variation between sites amounted to 20% for ADC and < 25% for single-shot T2w. Explorative radiomics classification experiments yield better results for ADC than for single-shot T2w. CONCLUSION: Harmonization of MR acquisition and post-processing parameters results in acceptable standard deviations for MR/DW imaging. MRI could be the tool in oncologic multicenter trials to overcome the limitations of RECIST-based response evaluation. KEY POINTS: • Harmonizing acquisition parameters and post-processing homogenization, standardized protocols result in acceptable standard deviations for multicenter MR-DWI studies. • Total measurement variation does not to exceed 11% for ADC in repeated measurements in repeated MR acquisitions, and below 20% for an identical volunteer travelling between sites. • Radiomic classification experiments were able to identify stable features allowing for reliable discrimination of different physiological tissue samples, even when using heterogeneous imaging data.

Deuterium metabolic imaging and hyperpolarized 13C-MRI of the normal human brain at clinical field strength reveals differential cerebral metabolism.

Deuterium metabolic imaging (DMI) and hyperpolarized 13C-pyruvate MRI (13C-HPMRI) are two emerging methods for non-invasive and non-ionizing imaging of tissue metabolism. Imaging cerebral metabolism has potential applications in cancer, neurodegeneration, multiple sclerosis, traumatic brain injury, stroke, and inborn errors of metabolism. Here we directly compare these two non-invasive methods at 3 T for the first time in humans and show how they simultaneously probe both oxidative and non-oxidative metabolism. DMI was undertaken 1-2 h after oral administration of [6,6'-2H2]glucose, and 13C-MRI was performed immediately following intravenous injection of hyperpolarized [1-13C]pyruvate in ten and nine normal volunteers within each arm respectively. DMI was used to generate maps of deuterium-labelled water, glucose, lactate, and glutamate/glutamine (Glx) and the spectral separation demonstrated that DMI is feasible at 3 T. 13C-HPMRI generated maps of hyperpolarized carbon-13 labelled pyruvate, lactate, and bicarbonate. The ratio of 13C-lactate/13C-bicarbonate (mean 3.7 ± 1.2) acquired with 13C-HPMRI was higher than the equivalent 2H-lactate/2H-Glx ratio (mean 0.18 ± 0.09) acquired using DMI. These differences can be explained by the route of administering each probe, the timing of imaging after ingestion or injection, as well as the biological differences in cerebral uptake and cellular physiology between the two molecules. The results demonstrate these two metabolic imaging methods provide different yet complementary readouts of oxidative and reductive metabolism within a clinically feasible timescale. Furthermore, as DMI was undertaken at a clinical field strength within a ten-minute scan time, it demonstrates its potential as a routine clinical tool in the future.

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer.

Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.

Enhancing the spatial resolution of hyperpolarized carbon-13 MRI of human brain metabolism using structure guidance.

PURPOSE: Dynamic nuclear polarization is an emerging imaging method that allows noninvasive investigation of tissue metabolism. However, the relatively low metabolic spatial resolution that can be achieved limits some applications, and improving this resolution could have important implications for the technique. METHODS: We propose to enhance the 3D resolution of carbon-13 magnetic resonance imaging (13 C-MRI) using the structural information provided by hydrogen-1 MRI (1 H-MRI). The proposed approach relies on variational regularization in 3D with a directional total variation regularizer, resulting in a convex optimization problem which is robust with respect to the parameters and can efficiently be solved by many standard optimization algorithms. Validation was carried out using an in silico phantom, an in vitro phantom and in vivo data from four human volunteers. RESULTS: The clinical data used in this study were upsampled by a factor of 4 in-plane and by a factor of 15 out-of-plane, thereby revealing occult information. A key finding is that 3D super-resolution shows superior performance compared to several 2D super-resolution approaches: for example, for the in silico data, the mean-squared-error was reduced by around 40% and for all data produced increased anatomical definition of the metabolic imaging. CONCLUSION: The proposed approach generates images with enhanced anatomical resolution while largely preserving the quantitative measurements of metabolism. Although the work requires clinical validation against tissue measures of metabolism, it offers great potential in the field of 13 C-MRI and could significantly improve image quality in the future.

Clinical Translation of Neutrophil Imaging and Its Role in Cancer.

Neutrophils are the first line of defense against pathogens and abnormal cells. They regulate many biological processes such as infections and inflammation. Increasing evidence demonstrated a role for neutrophils in cancer, where different subpopulations have been found to possess both pro- or anti-tumorigenic functions in the tumor microenvironment. In this review, we discuss the phenotypic and functional diversity of neutrophils in cancer, their prognostic significance, and therapeutic relevance in human and preclinical models. Molecular imaging methods are increasingly used to probe neutrophil biology in vivo, as well as the cellular changes that occur during tumor progression and over the course of treatment. This review will discuss the role of neutrophil imaging in oncology and the lessons that can be drawn from imaging in infectious diseases and inflammatory disorders. The major factors to be considered when developing imaging techniques and biomarkers for neutrophils in cancer are reviewed. Finally, the potential clinical applications and the limitations of each method are discussed, as well as the challenges for future clinical translation.

Dynamic biomarker and imaging changes from a phase II study of pre- and post-surgical sunitinib.

OBJECTIVE: To explore translational biological and imaging biomarkers for sunitinib treatment before and after debulking nephrectomy in the NeoSun (European Union Drug Regulating Authorities Clinical Trials Database [EudraCT] number: 2005-004502-82) single-centre, single-arm, single-agent, Phase II trial. PATIENTS AND METHODS: Treatment-naïve patients with metastatic renal cell carcinoma (mRCC) received 50 mg once daily sunitinib for 12 days pre-surgically, then post-surgery on 4 week-on, 2 week-off, repeating 6-week cycles until disease progression in a single arm phase II trial. Structural and dynamic contrast-enhanced magnet resonance imaging (DCE-MRI) and research blood sampling were performed at baseline and after 12 days. Computed tomography imaging was performed at baseline and post-surgery then every two cycles. The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors [RECIST]) excluding the resected kidney. Secondary endpoints included changes in DCE-MRI of the tumour following pre-surgery sunitinib, overall survival (OS), progression-free survival (PFS), response duration, surgical morbidity/mortality, and toxicity. Translational and imaging endpoints were exploratory. RESULTS: A total of 14 patients received pre-surgery sunitinib, 71% (10/14) took the planned 12 doses. All underwent nephrectomy, and 13 recommenced sunitinib postoperatively. In all, 58.3% (seven of 12) of patients achieved partial or complete response (PR or CR) (95% confidence interval 27.7-84.8%). The median OS was 33.7 months and median PFS was 15.7 months. Amongst those achieving a PR or CR, the median response duration was 8.7 months. No unexpected surgical complications, sunitinib-related toxicities, or surgical delays occurred. Within the translational endpoints, pre-surgical sunitinib significantly increased necrosis, and reduced cluster of differentiation-31 (CD31), Ki67, circulating vascular endothelial growth factor-C (VEGF-C), and transfer constant (KTrans , measured using DCE-MRI; all P < 0.05). There was a trend for improved OS in patients with high baseline plasma VEGF-C expression (P = 0.02). Reduction in radiological tumour volume after pre-surgical sunitinib correlated with high percentage of solid tumour components at baseline (Spearman's coefficient ρ = 0.69, P = 0.02). Conversely, the percentage tumour volume reduction correlated with lower baseline percentage necrosis (coefficient = -0.51, P = 0.03). CONCLUSION: Neoadjuvant studies such as the NeoSun can safely and effectively explore translational biological and imaging endpoints.