Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

Variation of T2 relaxation times in pediatric brain tumors and their effect on metabolite quantification.

BACKGROUND: Metabolite concentrations are fundamental biomarkers of disease and prognosis. Magnetic resonance spectroscopy (MRS) is a noninvasive method for measuring metabolite concentrations; however, quantitation is affected by T2 relaxation. PURPOSE: To estimate T2 relaxation times in pediatric brain tumors and assess how variation in T2 relaxation affects metabolite quantification. STUDY TYPE: Retrospective. POPULATION: Twenty-seven pediatric brain tumor patients (n = 17 pilocytic astrocytoma and n = 10 medulloblastoma) and 24 age-matched normal controls. FIELD STRENGTH/SEQUENCE: Short- (30 msec) and long-echo (135 msec) single-voxel MRS acquired at 1.5T. ASSESSMENT: T2 relaxation times were estimated by fitting signal amplitudes at two echo times to a monoexponential decay function and were used to correct metabolite concentration estimates for relaxation effects. STATISTICAL TESTS: One-way analysis of variance (ANOVA) on ranks were used to analyze the mean T2 relaxation times and metabolite concentrations for each tissue group and paired Mann-Whitney U-tests were performed. RESULTS: The mean T2 relaxation of water was measured as 181 msec, 123 msec, 90 msec, and 86 msec in pilocytic astrocytomas, medulloblastomas, basal ganglia, and white matter, respectively. The T2 of water was significantly longer in both tumor groups than normal brain (P < 0.001) and in pilocytic astrocytomas compared with medulloblastomas (P < 0.01). The choline T2 relaxation time was significantly longer in medulloblastomas compared with pilocytic astrocytomas (P < 0.05), while the T2 relaxation time of NAA was significantly shorter in pilocytic astrocytomas compared with normal brain (P < 0.001). Overall, the metabolite concentrations were underestimated by ∼22% when default T2 values were used compared with case-specific T2 values at short echo time. The difference was reduced to 4% when individually measured water T2 s were used. DATA CONCLUSION: Differences exist in water and metabolite T2 relaxation times for pediatric brain tumors, which lead to significant underestimation of metabolite concentrations when using default water T2 relaxation times. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:195-203.

Evaluation of diffusion-weighted MRI and (18F) fluorothymidine-PET biomarkers for early response assessment in patients with operable non-small cell lung cancer treated with neoadjuvant chemotherapy.

OBJECTIVE: To correlate changes in the apparent diffusion coefficient (ADC) from diffusion-weighted (DW)-MRI and standardised uptake value (SUV) from fluorothymidine (18FLT)-PET/CT with histopathological estimates of response in patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant chemotherapy and track longitudinal changes in these biomarkers in a multicentre, multivendor setting. METHODS: 14 patients with operable NSCLC recruited to a prospective, multicentre imaging trial (EORTC-1217) were treated with platinum-based neoadjuvant chemotherapy. 13 patients had DW-MRI and FLT-PET/CT at baseline (10 had both), 12 were re-imaged at Day 14 (eight dual-modality) and nine after completing chemotherapy, immediately before surgery (six dual-modality). Surgical specimens (haematoxylin-eosin and Ki67 stained) estimated the percentage of residual viable tumour/necrosis and proliferation index. RESULTS: Despite the small numbers,significant findings were possible. ADCmedian increased (p < 0.001) and SUVmean decreased (p < 0.001) significantly between baseline and Day 14; changes between Day 14 and surgery were less marked. All responding tumours (>30% reduction in unidimensional measurement pre-surgery), showed an increase at Day 14 in ADC75th centile and reduction in total lesion proliferation (SUVmean x proliferative volume) greater than established measurement variability. Change in imaging biomarkers did not correlate with histological response (residual viable tumour, necrosis). CONCLUSION: Changes in ADC and FLT-SUV following neoadjuvant chemotherapy in NSCLC were measurable by Day 14 and preceded changes in unidimensional size but did not correlate with histopathological response. However, the magnitude of the changes and their utility in predicting (non-) response (tumour size/clinical outcome) remains to be established. ADVANCES IN KNOWLEDGE: During treatment, ADC increase precedes size reductions, but does not reflect histopathological necrosis.

Short-acquisition-time JPRESS and its application to paediatric brain tumours.

OBJECTIVE: To develop and assess a short-duration JPRESS protocol for detection of overlapping metabolite biomarkers and its application to paediatric brain tumours at 3 Tesla. MATERIALS AND METHODS: The short-duration protocol (6 min) was optimised and compared for spectral quality to a high-resolution (38 min) JPRESS protocol in a phantom and five healthy volunteers. The 6-min JPRESS was acquired from four paediatric brain tumours and compared with short-TE PRESS. RESULTS: Metabolite identification between the 6- and 38-min protocols was comparable in phantom and volunteer data. For metabolites with Cramer-Rao lower bounds > 50%, interpretation of JPRESS increased confidence in assignment of lactate, myo-Inositol and scyllo-Inositol. JPRESS also showed promise for the detection of glycine and taurine in paediatric brain tumours when compared to short-TE MRS. CONCLUSION: A 6-min JPRESS protocol is well tolerated in paediatric brain tumour patients. Visual inspection of a 6-min JPRESS spectrum enables identification of a range of metabolite biomarkers of clinical interest.

Probing structure of normal and malignant prostate tissue before and after radiation therapy with luminal water fraction and diffusion-weighted MRI.

BACKGROUND: Interpretation of diffusion in conjunction with T2 -weighted MRI is essential for assessing prostate cancer; however, the combination of apparent diffusion coefficient (ADC) with quantitative T2 mapping remains unexplored. PURPOSE: To document the T2 components and ADC of untreated and irradiated nonmalignant prostate tissue as a measure of their glandular luminal and cellular compartments and to compare values with those of tumor. STUDY TYPE: Prospective. POPULATION: Twenty-four men with prostate cancer (14 untreated; 10 with biochemical recurrence following radiation therapy). FIELD STRENGTH/SEQUENCES: Endorectal 3 T MRI including a 32-echo gradient echo and spin echo (GRASE) and an 8 b-value diffusion-weighted sequence. ASSESSMENT: Regions of interest were drawn on ADC maps and T2 -weighted images around focal lesions in areas of biopsy-positive prostate cancer and in nonmalignant areas of untreated and irradiated peripheral zone (PZ), and untreated transitional zone (TZ). Multiecho T2 data were fitted with mono-/biexponential decay and nonnegative least squares functions. The luminal water fraction (LWF) was derived. STATISTICAL TESTS: The preference between mono- and biexponential decay was assessed using the Bayesian information criterion. Differences in fitted parameters between tissue types were compared (paired t-test within groups, Kruskal-Wallis and Wilcoxon rank-sum test between groups) and correlations between ADC and T2 components assessed (Spearman rank correlation test). RESULTS: LWF in tumor (0.09) was significantly lower than in PZ or TZ (0.27 and 0.18, P < 0.01, respectively), but tumor values were comparable to nonmalignant irradiated prostate (0.08). The short T2 relaxation rate was lower in tumor than in nonmalignant untreated or irradiated tissue (significant compared with TZ, P = 0.01). There was a strong correlation between LWF and ADC in normal untreated tissue (r = 0.88, P < 0.001). This relationship was absent in nonmalignant irradiated prostrate (r = -0.35, P = 0.42) and in tumor (r = -0.04, P = 0.88). DATA CONCLUSION: T2 components in conjunction with ADC can be used to characterize untreated and irradiated nonmalignant prostate and tumor. LWF is most useful at discriminating tumor in the untreated prostate. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:619-627.

Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo Assessment of the Cognitive and Structural Impact of Steroid Hormones.

Context: Brain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis. Objective: To examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure. Design, Setting, and Participants: A cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women. Main Outcome Measure: Recruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes. Results: Patients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance. Conclusion: We demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.