Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study.

BACKGROUND: Gemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms. METHODS: Sixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed. RESULTS: Sixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle. CONCLUSIONS: NUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.

Preliminary qualification of a novel, hypoxic-based radiologic signature for trans-arterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Survival advantage following trans-arterial chemoembolization (TACE) is variable in patients with hepatocellular carcinoma (HCC). We combined pre-TACE radiologic features to derive a novel prognostic signature in HCC. METHODS: A multi-institutional dataset of 98 patients was generated from two retrospective cohorts from United Kingdom (65%) and Italy (36%). The prognostic impact of a number baseline imaging parameters was assessed and factors significant on univariate analysis were combined to create a novel radiologic signature on multivariable analyses predictive of overall survival (OS) following TACE. RESULTS: Median OS was 15.4 months. Tumour size > 7 cm (p < 0.001), intra-tumour necrosis (ITN) (p = 0.02) and arterial ectatic neovascularisation (AEN) (p = 0.03) emerged as individual prognostic factors together with radiologic response (p < 0.001) and elevated alpha-fetoprotein (AFP) (p = 0.01). Combination of tumour size > 7 cm, ITN and AEN identified patients with poor prognosis (p < 0.001). CONCLUSIONS: We identified a coherent signature based on commonly available imaging biomarkers likely to be reflective of differential patterns of relative hypoxia and neovascularisation. Large tumours displaying AEN and ITN are characterised by a shorter survival after TACE.

Beyond T2-FLAIR mismatch sign in isocitrate dehydrogenase mutant 1p19q non-codeleted astrocytoma: Analysis of tumor core and evolution with multiparametric magnetic resonance imaging.

Background: The T2-FLAIR mismatch sign is an imaging correlate for isocitrate dehydrogenase (IDH)-mutant 1p19q non-codeleted astrocytomas. However, it is only seen in a part of the cases at certain stages. Many of the tumors likely lose T2 homogeneity as they grow in size, and become heterogenous. The aim of this study was to investigate the timecourse of T2-FLAIR mismatch sign, and assess intratumoral heterogeneity using multiparametric magnetic resonance imaging techniques. Methods: A total of 128 IDH-mutant gliomas were retrospectively analyzed. Observers blinded to molecular status used strict criteria to select T2-FLAIR mismatch astrocytomas. Pre-biopsy and follow-up standard structural sequences of T2, FLAIR and apparent diffusion coefficient, MR spectroscopy (both single- and multi-voxel techniques), and DSC perfusion were observed. Results: Nine T2-FLAIR mismatch astrocytomas were identified. 7 had MR spectroscopy and perfusion data. The smallest astrocytomas began as rounded T2 homogeneous lesions without FLAIR suppression, and developed T2-FLAIR mismatch during follow-up with falls in NAA and raised Cho/Cr ratio. Larger tumors at baseline with T2-FLAIR mismatch signs developed intratumoral heterogeneity, and showed elevated Cho/Cr ratio and raised relative cerebral blood volume (rCBV). The highest levels of intratumoral Cho/Cr and rCBV changes were located within the tumor core, and this area signifies the progression of the tumors toward high grade. Conclusions: T2-FLAIR mismatch sign is seen at a specific stage in the development of astrocytoma. By assessing the subsequent heterogeneity, MR spectroscopy and perfusion imaging are able to predict the progression of the tumor towards high grade, thereby can assist targeting for biopsy and selective debulking.

Assessing the Performance of Models from the 2022 RSNA Cervical Spine Fracture Detection Competition at a Level I Trauma Center.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To evaluate the performance of the top models from the RSNA 2022 Cervical Spine Fracture Detection challenge on a clinical test dataset of both noncontrast and contrast-enhanced CT scans acquired at a level I trauma center. Materials and Methods Seven top-performing models in the RSNA 2022 Cervical Spine Fracture Detection challenge were retrospectively evaluated on a clinical test set of 1,828 CT scans (1,829 series: 130 positive for fracture, 1,699 negative for fracture; 1,308 noncontrast, 521 contrast-enhanced) from 1,779 patients (mean age, 55.8 ± 22.1 years; 1,154 male). Scans were acquired without exclusion criteria over one year (January to December 2022) from the emergency department of a neurosurgical and level I trauma center. Model performance was assessed using area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. False positive and false negative cases were further analyzed by a neuroradiologist. Results Although all 7 models showed decreased performance on the clinical test set compared with the challenge dataset, the models maintained high performances. On noncontrast CT scans, the models achieved a mean AUC of 0.89 (range: 0.81-0.92), sensitivity of 67.0% (range: 30.9%-80.0%), and specificity of 92.9% (range: 82.1%-99.0%). On contrast-enhanced CT scans, the models had a mean AUC of 0.88 (range: 0.76-0.94), sensitivity of 81.9% (range: 42.7%-100.0%), and specificity of 72.1% (range: 16.4%-92.8%). The models identified 10 fractures missed by radiologists. False-positives were more common in contrast-enhanced scans and observed in patients with degenerative changes on noncontrast scans, while false-negatives were often associated with degenerative changes and osteopenia. Conclusion The winning models from the 2022 RSNA AI Challenge demonstrated a high performance for cervical spine fracture detection on a clinical test dataset, warranting further evaluation for their use as clinical support tools. ©RSNA, 2024.

Distribution and fibre field similarity mapping of the human anterior commissure fibres by diffusion tensor imaging.

OBJECT: The anterior commissure is a critical interhemispheric pathway in animals, yet its connections in humans are not clearly understood. Its distribution has shown to vary greatly between species, and it is thought that in humans it may convey axons from a larger territory than previously thought. The aim was to use an anatomical mapping tool to look at the anterior commissure fibres and to compare the distribution findings with published anatomical understanding. MATERIALS AND METHODS: Two different diffusion-weighted imaging data sets were acquired from eight healthy subjects using a 3 Tesla MR scanner with 32 gradient directions. Diffusion tensor imaging tractography was performed, and the anterior commissure fibres were selected using three-dimensional regions of interest. Distribution of the fibres was observed by means of registration with T2-weighted images. The fibre field similarity maps were produced for five of the eight subjects by comparing each subject's fibres to the combined map of the five data sets. RESULTS: Fibres were shown to lead into the temporal lobe and towards the orbitofrontal cortex in the majority of subjects. Fibres were also distributed to the parietal or occipital lobes in all five subjects in whom the anterior commissure was large enough for interhemispheric fibres to be tracked through. The fibre field similarity maps highlighted areas where the local distances of fibre tracts were displayed for each subject compared to the combined bundle map. CONCLUSION: The anterior commissure may play a more important role in interhemispheric communication than currently presumed by conveying axons from a wider territory, and the fibre field similarity maps give a novel approach to quantifying and visualising characteristics of fibre tracts.

Machine learning-based radiomic, clinical and semantic feature analysis for predicting overall survival and MGMT promoter methylation status in patients with glioblastoma.

INTRODUCTION: Survival varies in patients with glioblastoma due to intratumoral heterogeneity and radiomics/imaging biomarkers have potential to demonstrate heterogeneity. The objective was to combine radiomic, semantic and clinical features to improve prediction of overall survival (OS) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status from pre-operative MRI in patients with glioblastoma. METHODS: A retrospective study of 181 MRI studies (mean age 58 ± 13 years, mean OS 497 ± 354 days) performed in patients with histopathology-proven glioblastoma. Tumour mass, contrast-enhancement and necrosis were segmented from volumetric contrast-enhanced T1-weighted imaging (CE-T1WI). 333 radiomic features were extracted and 16 Visually Accessible Rembrandt Images (VASARI) features were evaluated by two experienced neuroradiologists. Top radiomic, VASARI and clinical features were used to build machine learning models to predict MGMT status, and all features including MGMT status were used to build Cox proportional hazards regression (Cox) and random survival forest (RSF) models for OS prediction. RESULTS: The optimal cut-off value for MGMT promoter methylation index was 12.75%; 42 radiomic features exhibited significant differences between high and low-methylation groups. However, model performance accuracy combining radiomic, VASARI and clinical features for MGMT status prediction varied between 45 and 67%. For OS predication, the RSF model based on clinical, VASARI and CE radiomic features achieved the best performance with an average iAUC of 96.2 ± 1.7 and C-index of 90.0 ± 0.3. CONCLUSIONS: VASARI features in combination with clinical and radiomic features from the enhancing tumour show promise for predicting OS with a high accuracy in patients with glioblastoma from pre-operative volumetric CE-T1WI.

Multiparametric MRI: practical approach and pictorial review of a useful tool in the evaluation of brain tumours and tumour-like lesions.

MRI has a vital role in the assessment of intracranial lesions. Conventional MRI has limited specificity and multiparametric MRI using diffusion-weighted imaging, perfusion-weighted imaging and magnetic resonance spectroscopy allows more accurate assessment of the tissue microenvironment. The purpose of this educational pictorial review is to demonstrate the role of multiparametric MRI for diagnosis, treatment planning and for assessing treatment response, as well as providing a practical approach for performing and interpreting multiparametric MRI in the clinical setting. A variety of cases are presented to demonstrate how multiparametric MRI can help differentiate neoplastic from non-neoplastic lesions compared to conventional MRI alone.

Improving adherence to guidelines for extended venous thromboembolism prophylaxis in patients with colorectal cancer.

Extended venous thromboembolism prophylaxis (EVTEP) with low-molecular weight heparin such as enoxaparin for 28 days following surgery for cancer significantly reduces venous thromboembolic events compared to a standard 6-10 day course. National Institute of Clinical Excellence (NICE) guidelines suggest EVTEP should be offered to patients undergoing colorectal cancer surgery. Local EVTEP prescribing and monitoring guidelines in a busy inner city teaching hospital colorectal surgery unit, were devised to ensure NICE guidelines are followed. Adherence to local EVTEP guidelines was recorded through a retrospective audit of patients undergoing elective colorectal cancer surgery during February 2011 (n=19). Prospective re-audit cycles were undertaken during April-May (n=17) and September-December 2012 (n=17). The first audit cycle revealed that overall standards were not being met with just 11% of 'at risk' patients being correctly identified in pre-operative assessment clinic and continued low adherence to guidelines on the ward with only 44% of patients being prescribed EVTEP at discharge. Following each audit cycle, educational interventions were directed towards the multi-disciplinary team involved in the care of patients undergoing colorectal cancer surgery. This involved education of the team members regarding EVTEP, presentation of the audit results with instruction for improvement. Results of the second and third audit cycles showed improvements in guideline adherence with 100% of patients in these cohorts having been prescribed EVTEP at discharge. Marked improvements were also seen in the correct identification of 'at risk' patients, patient education in pre-operative assessment clinic, and warning of potential side-effects. This project has shown a significant global improvement in EVTEP-related patient care and adherence to local guidelines following education of the multi-disciplinary team involved, which consequently reduced the risk of venous thromboembolism within this patient cohort.