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Background Prognosis in Palliative care Study (PiPS) models predict survival probabilities in advanced cancer. PiPS-A (clinical observations only) and PiPS-B (additionally requiring blood results) consist of 14- and 56-day models (PiPS-A14; PiPS-A56; PiPS-B14; PiPS-B56) to create survival risk categories: days, weeks, months. The primary aim was to compare PIPS-B risk categories against agreed multi-professional estimates of survival (AMPES) and to validate PiPS-A and PiPS-B. Secondary aims were to assess acceptability of PiPS to patients, caregivers and health professionals (HPs). Methods and findings A national, multi-centre, prospective, observational, cohort study with nested qualitative sub-study using interviews with patients, caregivers and HPs. Validation study participants were adults with incurable cancer; with or without capacity; recently referred to community, hospital and hospice palliative care services across England and Wales. Sub-study participants were patients, caregivers and HPs. 1833 participants were recruited. PiPS-B risk categories were as accurate as AMPES [PiPS-B accuracy (910/1484; 61%); AMPES (914/1484; 61%); p = 0.851]. PiPS-B14 discrimination (C-statistic 0.837) and PiPS-B56 (0.810) were excellent. PiPS-B14 predictions were too high in the 57–74% risk group (Calibration-in-the-large [CiL] -0.202; Calibration slope [CS] 0.840). PiPS-B56 was well-calibrated (CiL 0.152; CS 0.914). PiPS-A risk categories were less accurate than AMPES (p Conclusions PiPS-B risk categories are as accurate as AMPES made by experienced doctors and nurses. PiPS-A categories are less accurate. Patients, carers and HPs regard PiPS as potentially helpful in clinical practice. Study registration ISRCTN13688211.

Purpose The Palliative Prognostic (PaP) score; Palliative Prognostic Index (PPI); Feliu Prognostic Nomogram (FPN) and Palliative Performance Scale (PPS) have all been proposed as prognostic tools for palliative cancer care. However, clinical judgement remains the principal way by which palliative care professionals determine prognoses and it is important that the performance of prognostic tools is compared against clinical predictions of survival (CPS). Methods This was a multi-centre, cohort validation study of prognostic tools. Study participants were adults with advanced cancer receiving palliative care, with or without capacity to consent. Key prognostic data were collected at baseline, shortly after referral to palliative care services. CPS were obtained independently from a doctor and a nurse. Results Prognostic data were collected on 1833 participants. All prognostic tools showed acceptable discrimination and calibration, but none showed superiority to CPS. Both PaP and CPS were equally able to accurately categorise patients according to their risk of dying within 30 days. There was no difference in performance between CPS and FPN at stratifying patients according to their risk of dying at 15, 30 or 60 days. PPI was significantly (p Conclusions Although four commonly used prognostic algorithms for palliative care generally showed good discrimination and calibration, none of them demonstrated superiority to CPS. Prognostic tools which are less accurate than CPS are of no clinical use. However, prognostic tools which perform similarly to CPS may have other advantages to recommend them for use in clinical practice (e.g. being more objective, more reproducible, acting as a second opinion or as an educational tool). Future studies should therefore assess the impact of prognostic tools on clinical practice and decision-making.

Purpose: The aim of the study was to investigate the potential of diffusion-weighted magnetic resonance imaging (DW-MRI) and 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) as early biomarkers of treatment response of 5-fluorouracil (5-FU) in a syngeneic rat model of colorectal cancer liver metastases. Procedures: Wag/Rij rats with intrahepatic syngeneic CC531 tumors were treated with 5-FU (15, 30, or 60 mg/kg in weekly intervals). Before treatment and at days 1, 3, 7, and 14 after treatment rats underwent DW-MRI and [18F]FLT PET. Tumors were analyzed immunohistochemically for Ki67, TK1, and ENT1 expression. Results: 5-FU inhibited the growth of CC531 tumors in a dose-dependent manner. Immunohistochemical analysis did not show significant changes in Ki67, TK1, and ENT1 expression. However, [18F]FLT SUVmean and SUVmax were significantly increased at days 4 and 7 after treatment with 5-FU (60 mg/kg) and returned to baseline at day 14 (SUVmax at days −1, 4, 7, and 14 was 1.1 ± 0.1, 2.3 ± 0.5, 2.3 ± 0.6, and 1.5 ± 0.4, respectively). No changes in [18F]FLT uptake were observed in the nontreated animals. Furthermore, the apparent diffusion coefficient (ADCmean) did not change in 5-FU-treated rats compared to untreated rats. Conclusion: This study suggests that 5-FU treatment induces a flare in [18F]FLT uptake of responsive CC531 tumors in the liver, while the ADCmean did not change significantly. Future studies in larger groups are warranted to further investigate whether [18F]FLT PET can discriminate between disease progression and treatment response.

PURPOSE: To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the measured T1 relaxation times of normal breast tissue and malignant lesions and (b) the pharmacokinetically derived parameters of malignant breast lesions at 3 T. MATERIALS AND METHODS: Ethics approval and informed consent were obtained. Between May 2013 and January 2014, 30 women (median age, 58 years; range, 32-83 years) with invasive ductal carcinoma of at least 10 mm were recruited to undergo dynamic contrast material-enhanced magnetic resonance (MR) imaging before surgery. B1(+) and T1 mapping sequences were performed to determine the effect of B1(+) correction on the native tissue relaxation time (T10) of fat, parenchyma, and malignant lesions in both breasts. Pharmacokinetic parameters were calculated before and after correction for B1(+) variations. Results were correlated with histologic grade by using the Kruskal-Wallis test. RESULTS: Measurements showed a mean 37% flip angle difference between the right and left breast, which resulted in a 61% T10 difference in fat and a 41.5% difference in parenchyma between the two breasts. The T1 of lesions in the right breast increased by 58%, whereas that of lesions in the left breast decreased by 30% after B1(+) correction. The whole-tumor transendothelial permeability across the vascular compartment(K(trans)) of lesions in the right breast decreased by 41%, and that of lesions in the left breast increased by 46% after correction. A systematic increase in K(trans) was observed, with significant differences found across the histologic grades (P < .001). The effect size of B1(+) correction on K(trans) calculation was large for lesions in the right breast and moderate for lesions in the left breast (Cohen effect size, d = 0.86 and d = 0.59, respectively). CONCLUSION: B1(+) correction demonstrates a substantial effect on the results of quantitative dynamic contrast-enhanced analysis of breast tissue at 3 T, which propagates into the pharmacokinetic analysis of tumors that is dependent on whether the tumor is located in the right or left breast.

PURPOSE: We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models. PROCEDURES: Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [(18)F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations. RESULTS: Expression of TP correlated positively with [(18)F]FLT SUVmax (ρ = 0.549, P

Purpose To use perfusion and magnetic resonance (MR) spectroscopy to compare the diffusion tensor imaging (DTI)-defined invasive and noninvasive regions. Invasion of normal brain is a cardinal feature of glioblastomas (GBM) and a major cause of treatment failure. DTI can identify invasive regions. Materials and Methods In all, 50 GBM patients were imaged preoperatively at 3T with anatomic sequences, DTI, dynamic susceptibility perfusion MR (DSCI), and multivoxel spectroscopy. The DTI and DSCI data were coregistered to the spectroscopy data and regions of interest (ROIs) were made in the invasive (determined by DTI), noninvasive regions, and normal brain. Values of relative cerebral blood volume (rCBV), N-acetyl aspartate (NAA), myoinositol (mI), total choline (Cho), and glutamate + glutamine (Glx) normalized to creatine (Cr) and Cho/NAA were measured at each ROI. Results Invasive regions showed significant increases in rCBV, suggesting angiogenesis (invasive rCBV 1.64 [95% confidence interval, CI: 1.5–1.76] vs. noninvasive 1.14 [1.09–1.18]; P

Purpose: To evaluate between-site agreement of apparent diffusion coefficient (ADC) measurements in preclinical magnetic resonance imaging (MRI) systems. Materials and Methods: A miniaturized thermally stable ice-water phantom was devised. ADC (mean and interquartile range) was measured over several days, on 4.7T, 7T, and 9.4T Bruker, Agilent, and Magnex small-animal MRI systems using a common protocol across seven sites. Day-to-day repeatability was expressed as percent variation of mean ADC between acquisitions. Cross-site reproducibility was expressed as 1.96 x standard deviation of percent deviation of ADC values. Results: ADC measurements were equivalent across all seven sites with a cross-site ADC reproducibility of 6.3%. Mean day-to-day repeatability of ADC measurements was 2.3%, and no site was identified as presenting different measurements than others (analysis of variance [ANOVA] P = 0.02, post-hoc test n.s.). Between-slice ADC variability was negligible and similar between sites (P = 0.15). Mean within-region-of-interest ADC variability was 5.5%, with one site presenting a significantly greater variation than the others (P = 0.0013). Conclusion: Absolute ADC values in preclinical studies are comparable between sites and equipment, provided standardized protocols are employed.

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.

Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. Methods: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by 18F-FDG and 18F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2′-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography–mass spectrometry. Results: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. 18F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in 18F-FDG uptake were only marginal. No clear relationship between 18F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence 18F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. Conclusion: A direct relationship of 18F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.

3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

INTRODUCTION: The androgen receptor (AR) is the master regulator of prostate cancer cell metabolism. Degarelix is a novel gonadotrophin-releasing hormone blocker, used to decrease serum androgen levels in order to treat advanced human prostate cancer. Little is known of the rapid metabolic response of the human prostate cancer tissue samples to the decreased androgen levels. OBJECTIVES: To investigate the metabolic responses in benign and cancerous tissue samples from patients after treatment with Degarelix by using HRMAS 1H NMR spectroscopy. METHODS: Using non-destructive HR-MAS 1H NMR spectroscopy we analysed the metabolic changes induced by decreased AR signalling in human prostate cancer tissue samples. Absolute concentrations of the metabolites alanine, lactate, glutamine, glutamate, citrate, choline compounds [t-choline = choline + phosphocholine (PC) + glycerophosphocholine (GPC)], creatine compounds [t-creatine = creatine (Cr) + phosphocreatine (PCr)], taurine, myo-inositol and polyamines were measured in benign prostate tissue samples (n = 10), in prostate cancer specimens from untreated patients (n = 7) and prostate cancer specimens from patients treated with Degarelix (n = 6). RESULTS: Lactate, alanine and t-choline concentrations were significantly elevated in high-grade prostate cancer samples when compared to benign samples in untreated patients. Decreased androgen levels resulted in significant decreases of lactate and t-choline concentrations in human prostate cancer biopsies. CONCLUSIONS: The reduced concentrations of lactate and t-choline metabolites due to Degarelix could in principle be monitored by in vivo 1H MRS, which suggests that it would be possible to monitor the effects of physical or chemical castration in patients by that non-invasive method.

Purpose The sensitivity of the magnetization transfer ratio (MTR) and apparent diffusion coefficient (ADC) for early detection of brain metastases was investigated in mice and humans. Methods Mice underwent MRI twice weekly for up to 31 d following intracardiac injection of the brain-homing breast cancer cell line MDA-MB231-BR. Patients with small cell lung cancer underwent quarterly MRI for 1 year. MTR and ADC were measured in regions of metastasis and matched contralateral tissue at the final time point and in registered regions at earlier time points. Texture analysis and linear discriminant analysis were performed to detect metastasis-containing slices. Results Compared with contralateral tissue, mouse metastases had significantly lower MTR and higher ADC at the final time point. Some lesions were visible at earlier time points on the MTR and ADC maps: 24% of these were not visible on corresponding T2-weighted images. Texture analysis using the MTR maps showed 100% specificity and 98% sensitivity for metastasis at the final time point, with 77% sensitivity 2–4 d earlier and 46% 5–8 d earlier. Only 2 of 16 patients developed metastases, and their penultimate scans were normal. Conclusions Some brain metastases may be detected earlier on MTR than conventional T2; however, the small gain is unlikely to justify “predictive” MRI. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The purpose of this study was to evaluate whether single-voxel 1H MRS could add useful information to conventional MRI in the preoperative characterisation of the type and grade of brain tumours. MRI and MRS examinations from a prospective cohort of 40 consecutive patients were analysed double blind by radiologists and spectroscopists before the histological diagnosis was known. The spectroscopists had only the MR spectra, whereas the radiologists had both the MR images and basic clinical details (age, sex and presenting symptoms). Then, the radiologists and spectroscopists exchanged their predictions and re-evaluated their initial opinions, taking into account the new evidence. Spectroscopists used four different systems of analysis for 1H MRS data, and the efficacy of each of these methods was also evaluated. Information extracted from 1H MRS significantly improved the radiologists' MRI-based characterisation of grade IV tumours (glioblastomas, metastases, medulloblastomas and lymphomas) in the cohort [area under the curve (AUC) in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.85], and also of the less malignant glial tumours (AUC in the MRI re-evaluation 0.93 versus AUC in the MRI evaluation 0.81). One of the MRS analysis systems used, the INTERPRET (International Network for Pattern Recognition of Tumours Using Magnetic Resonance) decision support system, outperformed the others, as well as being better than the MRI evaluation for the characterisation of grade III astrocytomas. Thus, preoperative MRS data improve the radiologists' performance in diagnosing grade IV tumours and, for those of grade II–III, MRS data help them to recognise the glial lineage. Even in cases in which their diagnoses were not improved, the provision of MRS data to the radiologists had no negative influence on their predictions. Copyright © 2011 John Wiley & Sons, Ltd.

In the last decade, machine learning (ML) techniques have been used for developing classifiers for automatic brain tumour diagnosis. However, the development of these ML models rely on a unique training set and learning stops once this set has been processed. Training these classifiers requires a representative amount of data, but the gathering, preprocess, and validation of samples is expensive and time-consuming. Therefore, for a classical, non-incremental approach to ML, it is necessary to wait long enough to collect all the required data. In contrast, an incremental learning approach may allow us to build an initial classifier with a smaller number of samples and update it incrementally when new data are collected. In this study, an incremental learning algorithm for Gaussian Discriminant Analysis (iGDA) based on the Graybill and Deal weighted combination of estimators is introduced. Each time a new set of data becomes available, a new estimation is carried out and a combination with a previous estimation is performed. iGDA does not require access to the previously used data and is able to include new classes that were not in the original analysis, thus allowing the customization of the models to the distribution of data at a particular clinical center. An evaluation using five benchmark databases has been used to evaluate the behaviour of the iGDA algorithm in terms of stability-plasticity, class inclusion and order effect. Finally, the iGDA algorithm has been applied to automatic brain tumour classification with magnetic resonance spectroscopy, and compared with two state-of-the-art incremental algorithms. The empirical results obtained show the ability of the algorithm to learn in an incremental fashion, improving the performance of the models when new information is available, and converging in the course of time. Furthermore, the algorithm shows a negligible instance and concept order effect, avoiding the bias that such effects could introduce. © 2011 Elsevier Inc., This work has been partially funded by the Spanish Institut de Salud Carlos III (ISCiii) through the RETICS Combiomed (RD07/0067/2001). The authors thank the Programa Torres Quevedo from Ministerio de Educacion y Ciencia, co-founded by the European Social Fund (PTQ05-02-03386 and PTQ08-01-06802). We thank eTUMOUR, HEALTHAGENTS and INTERPRET partners for providing data, in particular W. Gajewicz (MUL), J. Calvar (FLENI), A. Heerschap (RUNMC), J. Capellades (IDI-Badalona), C. Majos (IDI-Bellvitge), and W. Semmier (DKFZ-Heidelberg). CIBER-BBN is an initiative funded by the VI National R&D&D&I Plan 2008-2011, CIBER Actions are financed by the Institut de Salud Carlos III with assistance from the European Regional Development Fund.

1H magnetic resonance spectroscopic imaging was performed on 16 men with suspected prostate cancer using an 8-channel external receive coil at 3 T. Choline and citrate (Cit) signals were measured in prostate lesions and normal-appearing peripheral zone as identified on T2-weighted images. Metabolites were quantified relative to unsuppressed water from a separately acquired magnetic resonance spectroscopic imaging dataset using LCModel. Validation experiments were also performed in a phantom containing physiological concentrations of choline, Cit, and creatine. In vitro, fair agreement between measured and true concentrations was observed, with the greatest discrepancy being a 35% underestimation of Cit. In vivo, one dataset was rejected for failure to meet the quality criterion of linewidth

Purpose: To evaluate the accuracy of H-1-MR spectroscopy (H-1-MRS) as an intervention limiting diagnostic tool for glioblastoma multiforme. GBM is the most common and aggressive primary brain tumor, with mean survival under a year. Onco logical practice currently requires histopathological diagnosis before radiotherapy. Materials and Methods: Eighty-nine patients had clinical computed tomography (CT) and MR imaging and 1.5T SV SE H-1-MRS with PRESS localization for neuroradiological diagnosis and tumor classification with spectroscopic and automated pattern recognition analysis (TE 30 ms, TR 2000 ms, spectral width 2500 Hz and 2048 data points, 128-256 signal averages were acquired, depending on voxel size (8 cm(3) to 4 cm(3)). Eighteen patients from a cohort of 89 underwent stereotactic biopsy. Results: The 18 stereotactic biopsies revealed 14 GBM, 2 grade II astrocytomas, 1 lymphoma, and 1 anaplastic astrocytoma. All 14 biopsied GBMs were diagnosed as GBM by a protocol combining an individual radiologist and an automated spectral pattern recognition program. Conclusion: In patients undergoing stereotactic biopsy combined neuroradiological and spectroscopic evaluation diagnoses GBM with accuracy that could replace the need for biopsy. We do not advocate the replacement of biopsy in all patients: instead our data suggest a specific intervention limiting role for the use of H-1-MRS in brain tumor diagnosis.

Gliomas are the most common primary brain tumors and the majority are highly malignant, with one of the worst prognoses for patients. Gliomas are characterized by invasive growth into normal brain tissue that makes complete surgical resection and accurate radiotherapy planning extremely difficult. We have performed independent component analysis of magnetic resonance spectroscopy imaging data from human gliomas to segment brain tissue into tumor core, tumor infiltration, and normal brain, with confirmation by diffusion tensor imaging analysis. Our data are consistent with previous studies that compared anomalies in isotropic and anisotropic diffusion images to determine regions of potential glioma infiltration. We show that coefficients of independent components can be used to create colored images for easy visual identification of regions of infiltrative tumor growth. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.

This prospective study aims to evaluate the feasibility of DWI at 3 Tesla in patients with advanced ovarian cancer and investigate the differences in vascular signal fraction (VSF) and apparent diffusion coefficient (ADC) values between primary ovarian mass and metastatic disease. Twenty patients with suspected advanced ovarian carcinoma were enrolled in the study. High-resolution T2W FRFSE images were used to confirm the position of three marker lesions: primary ovarian mass, omental cake and peritoneal deposit. Multislice DWI was acquired in a single breath-hold using multiple b-values. The three marker lesions were outlined by an experienced radiologist on ADC and VSF maps. Ovarian lesions showed the highest ADC values. The mean ADC value for peritoneal deposits was significantly lower than for both ovarian lesions (p = 0.03) and omental cake (p = 0.03). The VSF for omental cake was significantly higher than for ovarian lesions (p = 0.01) and peritoneal deposits (p = 0.04). There was a significant positive correlation between ADC and VSF for peritoneal deposits (p = 0.04). DWI in advanced ovarian cancer is feasible at 3 T. There are significant differences in baseline ADC and VSF values between ovarian cancer, omental cake and peritoneal deposits that may explain the mixed treatment response that occurs at different disease sites.

(1)H-MRS was performed on 12 women (age range 45-72) with ovarian cancer of FIGO stage 3 or above using a 3T MRI system with an 8-channel cardiac receive coil. Respiratory-triggered PRESS-localized spectra (TE = 144 ms) were obtained separately from an ovarian mass and from metastatic disease. Peak areas were quantified relative to unsuppressed water using LCModel and spectra were discarded if LCModel reported signal-to-noise ratio (SNR) < 3 or if no metabolites were reported with standard deviation (SD) < 30%. The cystic fraction of each voxel was estimated by thresholding T(2)-weighted images, and this was used both to correct the reported metabolite concentrations and to calculate an expected SNR of choline using the measured SNR of water. Choline was detected in 10/12 primary tumors and 5/11 metastatic lesions (range 2.0-16.6 mM). Of the 8/23 failures, 7 had a predicted choline SNR < 2, confirming that the failure to detect choline could be explained by technical problems. Glycine was observed in one benign lesion. (1)H-MRS can be used to quantify choline in primary and metastatic masses in ovarian cancer, but the moderately high rate of failure to detect choline necessitates careful recording of data quality parameters to discriminate true from false negatives.

Objectives We sought to decipher metabolic processes servicing the increased energy demand during persistent atrial fibrillation (AF) and to ascertain whether metabolic derangements might instigate this arrhythmia. Background Whereas electrical, structural, and contractile remodeling processes are well-recognized contributors to the self-perpetuating nature of AF, the impact of cardiac metabolism upon the persistence/initiation of this resilient arrhythmia has not been explored in detail. Methods Human atrial appendage tissues from matched cohorts in sinus rhythm (SR), from those who developed AF post-operatively, and from patients in persistent AF undergoing cardiac surgery were analyzed using a combined metabolomic and proteomic approach. Results High-resolution proton nuclear magnetic resonance (NMR) spectroscopy of cardiac tissue from patients in persistent AF revealed a rise in beta-hydroxybutyrate, the major substrate in ketone body metabolism, along with an increase in ketogenic amino acids and glycine. These metabolomic findings were substantiated by proteomic experiments demonstrating differential expression of 3-oxoacid transferase, the key enzyme for ketolytic energy production. Notably, compared with the SR cohort, the group susceptible to post-operative AF showed a discordant regulation of energy metabolites. Combined principal component and linear discriminant analyses of metabolic profiles from proton NMR spectroscopy correctly classified more than 80% of patients at risk of AF at the time of coronary artery bypass grafting. Conclusions The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.

Purpose To investigate the use of the transverse magnetic resonance imaging (MRI) relaxation rate R 2 ∗ (s -1 ) as a biomarker of tumor vascular response to monitor vascular disrupting agent (VDA) therapy. Methods and Materials Multigradient echo MRI was used to quantify R 2 ∗ in rat GH3 prolactinomas. R 2 ∗ is a sensitive index of deoxyhemoglobin in the blood and can therefore be used to give an index of tissue oxygenation. Tumor R 2 ∗ was measured before and up to 35 min after treatment, and 24 h after treatment with either 350 mg/kg 5,6-dimethylxanthenone-4-acetic acid (DMXAA) or 100 mg/kg combretastatin-A4-phosphate (CA4P). After acquisition of the MRI data, functional tumor blood vessels remaining after VDA treatment were quantified using fluorescence microscopy of the perfusion marker Hoechst 33342. Results DMXAA induced a transient, significant ( p 2 ∗ 7 min after treatment, whereas CA4P induced no significant changes in tumor R 2 ∗ over the first 35 min. Twenty-four hours after treatment, some DMXAA-treated tumors demonstrated a decrease in R 2 ∗ , but overall, reduction in R 2 ∗ was not significant for this cohort. Tumors treated with CA4P showed a significant ( p 2 ∗ 24 h after treatment. The degree of Hoechst 33342 uptake was associated with the degree of R 2 ∗ reduction at 24 h for both agents. Conclusions The reduction in tumor R 2 ∗ or deoxyhemoglobin levels 24 h after VDA treatment was a result of reduced blood volume caused by prolonged vascular collapse. Our results suggest that DMXAA was less effective than CA4P in this rat tumor model.

The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using Ktrans and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers. Highperformance liquid chromatography (HPLC) was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor Ktrans and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in Ktrans or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.

Contains fulltext : 51298.pdf (Publisher’s version ) (Closed access) The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

Vascular and angiogenic processes provide an important target for novel cancer therapeutics. Dynamic contrast-enhanced magnetic resonance imaging is being used increasingly to noninvasively monitor the action of these therapeutics in early-stage clinical trials. This publication reports the outcome of a workshop that considered the methodology and design of magnetic resonance studies, recommending how this new tool might best be used.\ud \ud \ud

Purpose The objective was to present a method for the repeated noninvasive measurement of tumor oxygenation (Po 2 ) over the whole period of tumor growth. Methods and materials A mixture of tumor homogenate (GH3 prolactinoma) and alginate capsules loaded with perfluoro-15-crown-5-ether (15C5) was injected into the flanks of Wistar Furth rats. The temporal behavior of tumor Po 2 was monitored between Day 1 and 26 after injection using fluorine-19 ( 19 F) magnetic resonance imaging (MRI). In addition, the response of tumor Po 2 to modifiers of the tumor microenvironment (carbogen [95% O 2 /5% CO 2 ], nicotinamide, and hydralazine) was investigated. Results An initial increase of tumor Po 2 , probably reflecting neovascularization, followed by a decrease after Week 2, probably indicating tumor hypoxia or necrosis, were observed. The minimum and maximum average Po 2 ± SEM observed were 3.3 ± 2.0 mm Hg on Day 2 and 25.7 ± 3.8 mm Hg on Day 13, respectively. Carbogen increased the tumor Po 2 , whereas nicotinamide caused no significant change and hydralazine induced a significant decrease in tumor oxygenation. Conclusions A preclinical method for the repeated noninvasive determination of tumor Po 2 was presented. It might help to investigate tumor physiology and the mechanisms of modifiers of the tumor microenvironment and their role in different therapeutic approaches.

It is now well established that uncontrolled proliferation of tumour cells together with the chaotic and poorly regulated blood supply of solid tumours result in tissue hypoxia, and that hypoxic regions of tumours are resistant to radiotherapy and chemotherapy. The development and application of non–invasive methods to rapidly determine the degree and extent of tumour hypoxia in an individual tumour would clearly enhance cancer treatment strategies. This review describes the current status of two 19 F nuclear magnetic resonance (NMR) methodologies that have been exploited to investigate tumour hypoxia, namely: (i) 19 F NMR oximetry following administration of perfluorocarbons, from which tumour p O 2 measurements can be made; and (ii) 19 F NMR measurements of the tumour retention of fluorinated 2–nitroimidazoles.

Dynamic contrast-enhanced MRI is widely used for the evaluation of the response of experimental rodent tumours to antitumour therapy, particularly for the newly developing antiangiogenic and antivascular agents. However, standard models require a time-course for the plasma concentration of contrast agent (usually referred to as the arterial input function) to calculate the transfer constant Ktrans from the dynamic time-course data. Ideally, the plasma concentration time-course should be measured during each experiment to obtain the most accurate measure of Ktrans. This is technically difficult in rodents, so assumed values are generally used. A method is presented here using interleaved acquisitions from a tail coil to obtain the plasma concentration simultaneously with DCE-MRI data obtained from a solenoid coil around the tumour. The SNR of the resulting vascular input function data is high compared with methods using a volume coil to acquire plasma concentrations from the aorta and vena cava. Copyright © 2004 John Wiley & Sons, Ltd.

Purpose To determine if short echo time (TE) 1H magnetic resonance spectroscopy (MRS) can distinguish between intracranial metastases and glioblastomas. Materials and Methods TE 30-msec spectra were acquired (1.5 T) from voxels entirely within tumors from 23 glioblastoma patients and 24 metastases patients (3 breast carcinomas, 1 bladder carcinoma, 8 lung carcinomas, 3 probable lung carcinomas, 6 melanomas, 1 stomach carcinoma, and 2 undetermined). Spectra were analyzed quantitatively (LCModel) to determine metabolite, lipid, and macromolecule concentrations. All tumors were previously untreated and classified histopathologically. Results The lipid peak area (LPA) ratio (total peak area at ca. δ1.3 to that at ca. δ0.9) was 2.6 ± 0.6 (N = 25) for glioblastomas and 3.8 ± 1.4 (N = 34) for metastases (P < 0.0001). There were no significant differences in metabolite or lipid concentrations between the tumor groups. The LPA ratio provided 80% sensitivity and 80% specificity for discriminating metastases from glioblastomas. Conclusion Lipid and macromolecule (LM) signals can dominate 1H spectra of high-grade tumors and have characteristics that allow significant discrimination of metastases from glioblastomas. Work is now needed to determine the source and biophysical characteristics of these LM signals to further improve differentiation by optimizing the data acquisition and analysis protocol. J. Magn. Reson. Imaging 2004;20:187–192. © 2004 Wiley-Liss, Inc.

Purpose To test the prognostic potential of tumor R2* with respect to radiotherapeutic outcome. Blood oxygenation level dependent (BOLD) MRI images are sensitive to changes in deoxyhemoglobin concentration through the transverse MRI relaxation rate R2* of tissue water, hence the quantitative measurement of tumor R2* may be related to tissue oxygenation. Methods and Materials Tumor growth inhibition in response to radiation was established for both GH3 prolactinomas and RIF-1 fibrosarcomas with animals breathing either air or carbogen during radiation. In a separate cohort, the baseline R2* and carbogen (95% O2, 5% CO2)-induced ΔR2* of rat GH3 prolactinomas and murine RIF-1 fibrosarcomas were quantified using multigradient echo (MGRE) MRI prior to radiotherapy, and correlated with subsequent tumor growth inhibition in response to ionizing radiation, while the animals breathed air. Results A radiation dose of 15 Gy caused pronounced growth delay in both tumor models and transient regression of the GH3 prolactinomas. When the animals breathed carbogen during radiation, the growth delay/regression was enhanced only in the GH3 prolactinomas. The GH3 prolactinomas, which exhibit a relatively fast baseline R2* and large ΔR2* in response to carbogen breathing prior to radiotherapy, showed a substantial reduction in normalized tumor volume to 66 ± 3% with air breathing and 36 ± 5% with carbogen seven days after 15 Gy irradiation. In contrast, the effect of 15 Gy on the RIF-1 fibrosarcomas, which give a relatively slow baseline R2* and negligible ΔR2* response to carbogen prior to treatment, showed a much smaller growth inhibition (143 ± 3% with air, 133 ± 12% with carbogen). Conclusion Quantitation of tumor R2* and carbogen-induced ΔR2* by MGRE MRI provides completely noninvasive prognostic indicators of a potential acute radiotherapeutic response. J. Magn. Reson. Imaging 2004;19:482–488. © 2004 Wiley-Liss, Inc.

Automated pattern recognition techniques are needed to help radiologists categorize MRS data of brain tumors according to histological type and grade. A major question is whether a computer program “trained” on spectra from one hospital will be able to classify those from another, particularly if the acquisition protocol is different. A subset of 144 histopathologically validated brain tumor spectra in the INTERPRET database, obtained from three of the collaborating centers, was grouped into meningiomas, low-grade astrocytomas, and “aggressive tumors” (glioblastomas and metastases). Spectra from two centers formed the training set (94 spectra) while the third acted as the test set (50 spectra). Linear discriminant analysis successfully classified 48/50 in the test set; the remaining two were atypical cases. When the training and test sets were combined, 133 of the 144 spectra were correctly classified using the leave-one-out procedure. These spectra had been obtained using different sequences (STEAM and PRESS), different echo times (20, 30, 31, and 32 ms), different repetition times (1600 and 2000 ms), and different manufacturers' instruments (GE and Philips). Pattern recognition algorithms are less sensitive to acquisition parameters than had been expected. Magn Reson Med 49:29–36, 2003. © 2003 Wiley-Liss, Inc.

Object. In a number of clinical studies magnetic resonance (MR) neurography has been used to examine patients with peripheral nerve damage, but little is understood about the sequence of imaging changes following nerve injuries, and how they correlate with functional deficit. The goal of this study was to further understanding of these changes and their implications. Methods. Using the rat sciatic nerve crush model, the sciatic nerve was imaged at intervals over 70 days in 12 rats. Sham-operated contralateral nerves served as controls. A 4.7-tesla MR imager with a custom-made surface coil was used. The T2 maps were calculated from images obtained at four echo times and from regions of interest designated on the nerve at three sites. Walking-track analysis was performed at the same intervals as imaging. Magnetic resonance neurography revealed a mean T2 of normal sciatic nerve of 36 msec (standard deviation [SD] 1.2 msec). Crushed nerves demonstrated a sequence of changes in signal intensity that were maximal at 14 days, with a mean T2 of 64 msec (SD 5.2 msec), then falling to a T2 of 53 msec (SD 3.7 msec). Sham-operated nerves had a short and nonsustained rise in signal at 7 days. Walking-track analysis revealed maximum deficit immediately postinjury, with an improvement in function approaching that of control nerves at 30 days. Conclusions. In this study the authors demonstrate that quantitative assessment of nerve signals with MR neurography allows the sequence of events following nerve crush injury to be followed in vivo, and that a return toward a normal signal correlates with functional improvement. Assessment of peripheral nerve injury in patients by using MR neurography has the potential to confirm acute nerve injury as well as to monitor the recovery process.

Proton magnetic resonance spectroscopy ( 1 HMRS) provides biochemical information from tissue non-invasively, and has an evolving role in brain tumour diagnosis and management. We present 100 consecutive patients with brain tumours who had single voxel 1HMRS as part of their preoperative investigations. We report the histopathological findings and the diagnostic contribution of spectroscopy in an adjunctive role. On the basis of clinical and radiological information the preoperative diagnosis was unclear or inaccurate in 26 out of 100 cases. The discrepancy was of lesion grade in 17 cases and lesion type in 9 cases. In 6 of 100 patients with brain tumours 1HMRS could have made a significant contribution to the preoperative diagnosis if used as part of the routine assessment. There is therefore a useful role for 1HMRS in the evaluation of intracranial mass lesions.

Non-invasive magnetic resonance spectroscopy (MRS) can be used in the clinic to monitor the pharmacokinetics of the chemotherapeutic drug 5-fluorouracil (5-FU) and the effects of modifiers. We report two studies of 5-FU toxicity in normal tissue--one with patients and the other an animal study. 1) 19F MRS signals from fluoronucleotides, cytotoxic anabolites of 5-FU metabolism, were observed in the livers of two patients treated with 5-FU for colorectal cancer, shown by computed tomography (CT) and ultrasound (US) to have no liver metastases. This is the first report of non-invasive monitoring of toxic 5-FU metabolites in normal human tissues. 2) In animals, carbogen-breathing enhances tumour uptake and the efficacy of 5-FU, and the method is under trial in patients. This study demonstrates that there were no significant effects of carbogen breathing on the levels of 5-FU and its metabolites in normal rat tissues, or on the histology of the tissues assessed after treatment.

The purpose of this study was to examine the effect of aging on brain metabolite concentrations, including N-acetyl aspartate (NAA), the major marker of neurones, using short echo proton spectroscopy. Single-voxel proton spectra (TE 30 msec, TR 2 seconds) were obtained from white and gray matter using automated software (PROBE, G.E., Milwaukee, WI). Spectra were analyzed using the variable projection technique. Thirty healthy volunteers were studied within the age range 24-89 years. No significant trend in change of concentrations of NAA, total creatine, total choline or myo-inositol were seen with age. The total creatine concentration of parietal white matter in the over 60 age group (6.5 +/- 0.3 mmol/l) was significantly higher than the under 60 age group (6.0 +/- 0.4 mmol/l:; P < 0.05). No other significant difference between the two age groups was seen. The tissue concentration of the major neuronal marker, NAA, does not decline with age. No age-related changes in the concentrations of choline and myo-inositol and occipital gray matter total creatine were observed. These results provide a normal range of values for spectroscopically detectable metabolites within the regions studied, against which neurological diseases such as Alzheimer's disease can be compared in vivo.

The application of functional magnetic resonance (MR) imaging techniques to the measurement of oxygenation and blood flow in tumors is described. Gradient recalled echo MR imaging (GRE-MRI) offers a real-time noninvasive method for monitoring tumor response to vasomodulators such as carbogen (95% O2/5% CO2) breathing in attempts to overcome tumor hypoxia and improve treatment efficacy. Although the response is tumor-type dependent, increases in signal intensity of up to 100% have been observed in several animal tumor types. Responses are also seen in human tumors. The observed increases in GRE-MRI signal intensity are due to a combination of a reduction of deoxyhemoglobin in the blood causing changes in the MR imaging relaxation time T2* and changes in blood flow and may also reflect the capillary density. Thus, the magnitude of the GRE image intensity change gives an indication of the potential response of an individual tumor to treatments that aim to improve tissue oxygenation and therefore how the tumor may respond to therapy. In addition, carbogen breathing by the host has been shown to increase the uptake and efficacy of chemotherapeutic agents in animal tumors.

Recent studies have shown that MRS can substantially improve the non-invasive categorization of human brain tumours. However, in order for MRS to be used routinely by clinicians, it will be necessary to develop reliable automated classification methods that can be fully validated. This paper is in two parts: the first part reviews the progress that has been made towards this goal, together with the problems that are involved in the design of automated methods to process and classify the spectra. The second part describes the development of a simple prototype system for classifying H-1 single voxel spectra, obtained at an echo time (TE) of 135 ms, of the four most common types of brain tumour (meningioma (MM), astrocytic (AST), oligodendroglioma (OD) and metastasis (ME)) and cysts. This system was developed in two stages: firstly, an initial database of spectra was used to develop a prototype classifier, based on a linear discriminant analysis (LDA) of selected data points. Secondly, this classifier was tested on an independent test set of 15 newly acquired spectra, and the system was refined on the basis of these results. The system correctly classified all the non-astrocytic tumours. However, the results for the the astrocytic group were poorer (between 55 and 100%, depending on the binary comparison). Approximately 50% of high grade astrocytoma (glioblastoma) spectra in our data base showed very little lipid signal, which may account for the poorer results for this class. Consequently, far the refined system, the astrocytomas were subdivided into two subgroups for comparison against other tumour classes: those with high lipid content and those without

Purpose: Gradient-Recalled Echo (GRE) Magnetic Resonance Imaging (MRI), which detects changes in blood vessel deoxyhaemoglobin content, has been investigated as a noninvasive monitor of changes in human tumor oxygenation and blood flow, in response to carbogen (95% 02, 5% CO*) breathing. Methods and Materials: GRE images (TE = 60 ms, TR = 200 ms, (Y = 40”, 256’ matrix) were acquired from 31 patients with primary and metastatic disease, prior to and during carbogen breathing. Three patients underwent a follow-up examination after radiotherapy. Results: Seventeen out of 34 tumors showed enhanced image intensity, consistent with an improvement in tumor oxygenation and blood flow, while 11 showed no response; 6 studies were technical failures. In one patient a metastatic node that had eluded orthodox investigation was visualized. A reduction in response was observed in the three patients studied postradiotherapy. Conclusion: This method, which can be performed on a standard clinical MRI instrument, provides a noninvasive measurement of tumor response to oxygenation/blood flow modification. In principle, this should enable the clinician to optimize treatment protocols, such as carbogen breathing, for individual radiotherapy patients. 0 1997 Elsevier Science Inc.

Item does not contain fulltext PURPOSE: To evaluate and histologically qualify carbogen-induced DeltaR2 as a noninvasive magnetic resonance imaging biomarker of improved tumor oxygenation using a double 2-nitroimidazole hypoxia marker approach. METHODS AND MATERIALS: Multigradient echo images were acquired from mice bearing GH3 prolactinomas, preadministered with the hypoxia marker CCI-103F, to quantify tumor R2 during air breathing. With the mouse remaining positioned within the magnet bore, the gas supply was switched to carbogen (95% O2, 5% CO2), during which a second hypoxia marker, pimonidazole, was administered via an intraperitoneal line, and an additional set of identical multigradient echo images acquired to quantify any changes in tumor R2. Hypoxic fraction was quantified histologically using immunofluorescence detection of CCI-103F and pimonidazole adduct formation from the same whole tumor section. Carbogen-induced changes in tumor pO2 were further validated using the Oxylite fiberoptic probe. RESULTS: Carbogen challenge significantly reduced mean tumor R2 from 116 +/- 13 s(-1) to 97 +/- 9 s(-1) (P

Contains fulltext : 140536.pdf (Publisher’s version ) (Closed access) Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy.The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine.On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001).The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

Gradient recalled echo (GRE) 1 H images can be used to monitor changes in blood oxygenation via the dephasing effects of paramagnetic deoxyhaemoglobin (Hb). We have modulated the blood flow/oxygenation of GH3 rat tumours by i.v. calcitonin gene-related peptide (CGRP) or carbogen (95% O 2 , 5% CO 2 ) inhalation, and obtained GRE 1 H images interleaved with 31 P spectra before, during and after the insult. With CGRP the GRE image intensity decreased (6/10) by >10% with a concomitant 40% decrease (4/4) in βNTP/P i and a small decrease in pH. Both the image intensity and 31 P spectra returned to near their pre-CGRP levels after 50 min, consistent with a transient episode of hypoxia. Carbogen breathing (5/5) caused >40% increases in average GRE image intensity, with no significant changes in the 31 P spectra (4/4). Three-dimensional GRE images were obtained to confirm that a T 2 * increase, rather than just an 'in-flow' effect due to increased blood flow, was responsible for the GRE enhancement. Increases in average image intensity >40% were observed for the three-dimensional GRE images (2/2), indicating a T 2 * increase. Using Hb as an endogenous contrast agent, the high sensitivity of the GRE technique may provide a method of monitoring heterogeneous tumour perfusion and oxygenation, both in the laboratory and the clinic.

✓ Currently, diagnosis and management of disorders involving nerves are generally undertaken without images of the nerves themselves. The authors evaluated whether direct nerve images obtained using the new technique of magnetic resonance (MR) neurography could be used to make clinically important diagnostic distinctions that cannot be readily accomplished using existing methods. The authors obtained T2-weighted fast spin—echo fat-suppressed (chemical shift selection or inversion recovery) and T1-weighted images with planes parallel or transverse to the long axis of nerves using standard or phased-array coils in healthy volunteers and referred patients in 242 sessions. Longitudinal and cross-sectional fascicular images readily distinguished perineural from intraneural masses, thus predicting both resectability and requirement for intraoperative electrophysiological monitoring. Fascicle pattern and longitudinal anatomy firmly identified nerves and thus improved the safety of image-guided procedures. In severe trauma, MR neurography identified nerve discontinuity at the fascicular level preoperatively, thus verifying the need for surgical repair. Direct images readily demonstrated increased diameter in injured nerves and showed the linear extent and time course of image hyperintensity associated with nerve injury. These findings confirm and precisely localize focal nerve compressions, thus avoiding some exploratory surgery and allowing for smaller targeted exposures when surgery is indicated. Direct nerve imaging can demonstrate nerve continuity, distinguish intraneural from perineural masses, and localize nerve compressions prior to surgical exploration. Magnetic resonance neurography can add clinically useful diagnostic information in many situations in which physical examinations, electrodiagnostic tests, and existing image techniques are inconclusive.

Purpose : The response of tumors to radiotherapy can be enhanced if carbogen (95% O 2 , 5% CO 2 ) is breathed. The timing of carbogen administration is critical, and a noninvasive method of monitoring the response of individual tumors would have obvious utility. Functional gradient recalled echo (GRE) magnetic resonance imaging (MRI) techniques are sensitive to changes in the concentrations of deoxyhemoglobin, which, thus, acts as an endogenous contrast agent for oxygenation status and blood flow. Methods and Materials : Subcutaneous GH3 prolactinomas in three rats were imaged at 4.7 Tesla with a GRE 1 H sequence [echo time (TE) = 20 ms, repetition time (TR) = 80 ms, flip angle = 45°, 1 mm slice, 256 phase encode steps, 4 cm field of view, in-plane resolution 0.08 x 0.08 mm, acquisition time = 4 min]. The rats breathed air or carbogen for four periods of 20 min ; three control rats breathed only air. Results : Carbogen breathing caused increases of up to 100% in the GRE image intensity of the tumors. Reversion to air breathing caused the image intensity to fall ; essentially the same response was observed with the second cycle of carbogen and air breathing. Control rat tumors showed no significant change. Conclusions : The response of tumors to carbogen can be monitored noninvasively by GRE MRI. In principle, this could be due to an increase in oxygen content of the blood, a decrease in tumor cell oxygen consumption, or an increase in tumor blood flow. The very large changes in signal intensity suggest that a blood flow increase is the most probable explanation. If this technique can be successfully applied in man, it should be possible to optimize carbogen treatment for individual radiotherapy patients, and perhaps also to enhance tumor uptake of chemotherapeutic agents.

To investigate the role of multiparametric magnetic resonance (MR) imaging in the evaluation of response to platinum-based neoadjuvant chemotherapy in advanced ovarian cancer and to compare imaging parameters between primary ovarian mass and metastatic disease.Evaluable patients suspected of having advanced ovarian carcinoma were enrolled in a prospective protocol-driven study. Research ethics committee approval and written informed consent were obtained. Multiparametric MR imaging (diffusion-weighted MR imaging, dynamic contrast material-enhanced [DCE] MR imaging, and hydrogen 1 MR spectroscopy) was performed with a 3.0-T wholebody MR imaging system. Three marker lesions-primary ovarian mass, omental cake, and peritoneal deposit-were outlined by a radiologist on apparent diffusion coefficient (ADC) and vascular signal fraction (VSF) maps and on DCE MR images. Comparisons of mean ADC, mean VSF, DCE MR imaging parameters, and choline concentration between responders and nonresponders were based on Response Evaluation Criteria in Solid Tumors and CA-125 criteria.Twenty-two patients were evaluable. The mean ADC for peritoneal metastases was lower than that for ovarian (P = .015) and omental (P = .006) sites. There were no differences in pretreatment DCE MR imaging parameters between tumor sites. After treatment, responders showed a significantly larger increase in ADC (P = .021) and fractional volume of the extravascular extracellular space (v(e)) (P = .025) of ovarian lesions compared with nonresponders, but there was no change in ADC at other sites. Pre- and posttreatment values of choline concentration of ovarian lesions were lower in responders (P = .025) than in nonresponders (P = .010).The significant differences in baseline ADCs among primary ovarian cancer, omental cake, and peritoneal deposits indicate that diffusivity profiles may be tumor-site dependent, suggesting biologic heterogeneity of disease. ADC and v(e) parameters correlated with the cytotoxic effects of platinum-based therapy and may be useful response markers, while choline concentration predicted but did not reflect response.

A magnetic resonance imaging sequence, combining fat and flow suppression with T2 weighting, has been used to produce high conspicuity images of the median nerve within the carpal tunnel. Standard maximum intensity projection techniques were then used to produce three-dimensional (3D) reconstructions of the nerve. Comparison of 3D projections with the wrist in a neutral position and wrist flexed at 45° depicted changes in the shape and course of the median nerve through the carpal tunnel of normal volunteers. In some cases of carpal tunnel syndrome evidence of a localized compression was observed. A 3D image of a nerve may help in the diagnosis of peripheral neuropathy and be an aid to surgery of or near major nerves.

Background: An estimated 220,800 cases and 27,540 deaths from prostate cancer (PCa) will occur in the USA during 2015. Altered PI3K/AKT/mTOR signalling contributes to prostate cancer progression and transition to androgen-independent disease, for example one study reported 42% of primary and 100% of metastatic PCa tumours exhibited mutations, altered expression or copy number variations within this pathway. First generation mTOR inhibitors (preferentially inhibit mTORC1), have had limited anti-cancer effect in patients with PCa, possibly due to negative feedback activation of the AKT pathway via mTORC2. The dual mTORC1/2 inhibitor, AZD2014, may overcome this liability. Using a genetically engineered PTEN conditional mouse model (Ptenloxp/loxp;PB-Cre4), we have investigated the effects of AZD2014. The studies complement a clinical trial (NCT02064608) of AZD2014, given to men before radical prostatectomy and are timed for when invasive prostate carcinomas develop in the model around 10-14 months prior to onset of resistance to castration through AKT pathway activation. AZD2014, 15mg/kg daily, oral (with or without castration) or vehicle were administered for 14 days. Results: AZD2014 was well tolerated with no overt toxicity observed. Pharmacokinetic (PK) analysis revealed mean concentrations of 4.4±2.1μM of AZD2014 in the plasma samples collected 4 hours after day 14 dose. AZD2014 alone or combined with castration inhibited mTORC1 and mTORC2 measured by reductions in p4EBP1(Thr37/46) by approximately 48%±27% (p Conclusions: Short term (14 days) treatment with AZD2014 with or without castration was associated with both pharmacodynamic and anti-tumour effects. The t-Cho/Cr ratio, previously reported as positively correlated with Gleason score in PCa patients, might be, in addition to our standard mTOR PD markers, utilised as a non-invasive biomarker of AZD2014 activity. The primary and phenotypic biomarker effects of monotherapy with AZD2014 in this relevant genetically engineered mouse model of prostate cancer will be compared with paired biopsies from the ongoing exploratory window study in the prostate cancer patients prior to prostatectomy, and may inform potential novel combination approaches that are translatable to the clinic. Citation Format: Chiranjeevi Sandi, Antonio Ramos-Montoya, Sergio L. Felisbino, Sarah Jurmeister, Basetti Madhu, Karan Wadhwa, John R. Griffiths, Frances M. Richards, Duncan I. Jodrell, David E. Neal, Sabina Cosulich, Barry Davies, Simon Pacey. Preclinical evaluation of dual mTOR inhibitor, AZD2014, in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A123.

Cancer was an obvious disease to study by magnetic resonance spectroscopy (MRS); it produces large lesions that give clearly abnormal spectra, all treatment methods leave much to be desired, and radiotherapy, in particular, is limited by tissue hypoxia, a process that can be investigated by MRS.31P MRS has shown that tumor cells are not acidic, as had been thought; instead, the pH gradient across the tumor cell membrane is the reverse of that in a normal cell. This change in hydrogen-ion gradient is accompanied by changes in gradients of many other ions. Tumor oxygenation can be monitored in animal tumor models using the techniques employed for functional magnetic resonance imaging (MRI) of the brain. Large changes in signal are observed when drugs that reduce tumor blood flow are administered. 1H NMR spectra of acid extracts of tumor or normal tissue biopsies contain sufficient information to permit classification (and thus, perhaps, diagnosis) if computer-based pattern recognition techniques are employed. Surprisingly, the same technique gives quite good classification of31P spectra takenin vivo. Can MRS beappliedin cancer therapy? Studies on tumor ion balance will help in the design of anticancer drugs and other therapies. Tumor blood flow studies using MRI could be applied to individual patients to predict the usefulness of radiotherapy and to assist in radiotherapy planning. Pattern recognition methods could automate the screening of biopsies and could also assist in interpretation of human spectra takenin vivo.