Molecular imaging coupled to pattern recognition distinguishes response to temozolomide in preclinical glioblastoma.

Non-invasive monitoring of response to treatment of glioblastoma (GB) is nowadays carried out using MRI. MRS and MR spectroscopic imaging (MRSI) constitute promising tools for this undertaking. A temozolomide (TMZ) protocol was optimized for GL261 GB.

Development of a hybrid magnetic resonance and ultrasound imaging system.

A system which allows magnetic resonance (MR) and ultrasound (US) image data to be acquired simultaneously has been developed. B-mode and Doppler US were performed inside the bore of a clinical 1.5 T MRI scanner using a clinical 1-4 MHz US transducer with an 8-metre cable.

Independent calculation of dose distributions for helical tomotherapy using a conventional treatment planning system.

Purpose: The dosimetric verification of treatment plans in helical tomotherapy usually is carried out via verification measurements. In this study, a method for independent dose calculation of tomotherapy treatment plans is presented, that uses a conventional treatment planning system with a pencil kernel dose calculation algorithm for generation of verification dose distributions based on patient CT data.

Methods: A pencil beam algorithm that directly uses measured beam data was configured for dose calculation for a tomotherapy machine.

Lactate and choline metabolites detected in vitro by nuclear magnetic resonance spectroscopy are potential metabolic biomarkers for PI3K inhibition in pediatric glioblastoma.

The phosphoinositide 3-kinase (PI3K) pathway is believed to be of key importance in pediatric glioblastoma. Novel inhibitors of the PI3K pathway are being developed and are entering clinical trials. Our aim is to identify potential non-invasive biomarkers of PI3K signaling pathway inhibition in pediatric glioblastoma using in vitro nuclear magnetic resonance (NMR) spectroscopy, to aid identification of target inhibition and therapeutic response in early phase clinical trials of PI3K inhibitors in childhood cancer.

A randomised phase 2 trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor-prognosis germ cell tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604).

Background: Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required.

Objective: To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial.

Design, Setting, And Participants: We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features.

Metastatic dormancy: a complex network between cancer stem cells and their microenvironment.

Metastasis represents the major threat of cancer progression and generally emerges years after the detection of the primary tumor. An important rate-limiting step resides in cellular dormancy, where a disseminated tumor cell remains in a quiescent state at a remote organ. Herein we review the molecular mechanisms leading to tumor dormancy, mainly in regards to cellular quiescence and the tumor microenvironment.

Proteomics and metabolomics for mechanistic insights and biomarker discovery in cardiovascular disease.

In the last decade, proteomics and metabolomics have contributed substantially to our understanding of cardiovascular diseases. The unbiased assessment of pathophysiological processes without a priori assumptions complements other molecular biology techniques that are currently used in a reductionist approach. In this review, we highlight some of the "omics" methods used to assess protein and metabolite changes in cardiovascular disease.

External validation of a prognostic model predicting overall survival in metastatic castrate-resistant prostate cancer patients treated with abiraterone.

A prognostic model was derived from the population of the COU-AA-301 phase 3 trial for metastatic castrate-resistant prostate cancer patients treated with abiraterone after docetaxel, and it stratifies patients into three risk groups based on clinical parameters. We validated this model in an independent cohort of patients treated with abiraterone after docetaxel outside a clinical trial (group A; n=94) and explored its utility in patients treated with abiraterone in the prechemotherapy setting (group B; n=64). For group A, median overall survival (mOS) was significantly different across the three prognostic groups (good: n=39, mOS: 21.

4D ultrasound speckle tracking of intra-fraction prostate motion: a phantom-based comparison with x-ray fiducial tracking using CyberKnife.

This study investigates the use of a mechanically-swept 3D ultrasound (3D-US) probe for soft-tissue displacement monitoring during prostate irradiation, with emphasis on quantifying the accuracy relative to CyberKnife® x-ray fiducial tracking. An US phantom, implanted with x-ray fiducial markers was placed on a motion platform and translated in 3D using five real prostate motion traces acquired using the Calypso system. Motion traces were representative of all types of motion as classified by studying Calypso data for 22 patients.

Portal dosimetry for VMAT using integrated images obtained during treatment.

Purpose: Portal dosimetry provides an accurate and convenient means of verifying dose delivered to the patient. A simple method for carrying out portal dosimetry for volumetric modulated arc therapy (VMAT) is described, together with phantom measurements demonstrating the validity of the approach.

Methods: Portal images were predicted by projecting dose in the isocentric plane through to the portal image plane, with exponential attenuation and convolution with a double-Gaussian scatter function.

First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

Purpose: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors.

Experimental Design: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed.

Acute tumour response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) evaluated by non-invasive diffusion-weighted MRI.

Background: Non-invasive imaging biomarkers underpin the development of molecularly targeted anti-cancer drugs. This study evaluates tumour apparent diffusion coefficient (ADC), measured by diffusion-weighted magnetic resonance imaging (DW-MRI), as a biomarker of response to the MEK1/2 inhibitor selumetinib (AZD6244, ARRY-142886) in human tumour xenografts.

Methods: Nude mice bearing human BRAF(V600D) WM266.

Randomised pilot study of dose escalation using conformal radiotherapy in prostate cancer: long-term follow-up.

Background: Radical three-dimensional conformal radiotherapy (CFRT) with initial androgen suppression (AS) is a standard management for localised prostate cancer (PC). This pilot study evaluated the role of dose escalation and appropriate target volume margin. Here, we report long-term follow-up.

An experimental evaluation of the Agility MLC for motion-compensated VMAT delivery.

An algorithm for dynamic multileaf-collimator (dMLC) tracking of a target performing a known a priori, rigid-body motion during volumetric modulated arc therapy (VMAT), has been experimentally validated and applied to investigate the potential of the Agility (Elekta AB, Stockholm, Sweden) multileaf-collimator (MLC) for use in motion-compensated VMAT delivery. For five VMAT patients, dosimetric measurements were performed using the Delta(4) radiation detector (ScandiDos, Uppsala, Sweden) and the accuracy of dMLC tracking was evaluated using a gamma-analysis, with threshold levels of 3% for dose and 3 mm for distance-to-agreement. For a motion trajectory with components in two orthogonal directions, the mean gamma-analysis pass rate without tracking was found to be 58.

Towards real-time VMAT verification using a prototype, high-speed CMOS active pixel sensor.

This work investigates the feasibility of using a prototype complementary metal oxide semiconductor active pixel sensor (CMOS APS) for real-time verification of volumetric modulated arc therapy (VMAT) treatment. The prototype CMOS APS used region of interest read out on the chip to allow fast imaging of up to 403.6 frames per second (f/s).

The validation index: a new metric for validation of segmentation algorithms using two or more expert outlines with application to radiotherapy planning.

Validation is required to ensure automated segmentation algorithms are suitable for radiotherapy target definition. In the absence of true segmentation, algorithmic segmentation is validated against expert outlining of the region of interest. Multiple experts are used to overcome inter-expert variability.

Normalized mean glandular dose computation from mammography using GATE: a validation study.

Mean glandular dose (MGD) is the figure of merit to assess breast dose after a mammographic acquisition. The use of normalized MGD obtained from Monte Carlo computations with measured incident air kerma determines the MGD delivered to patients. The Geant4 Application for Tomographic Emission (GATE) toolkit is a modern Monte Carlo application specifically designed for medical imaging systems modelling.

Beam modeling and VMAT performance with the Agility 160-leaf multileaf collimator.

The Agility multileaf collimator (Elekta AB, Stockholm, Sweden) has 160 leaves of projected width 0.5 cm at the isocenter, with maximum leaf speed 3.5 cms-1.

An experimental comparison of conventional two-bank and novel four-bank dynamic MLC tracking.

The AccuLeaf mMLC featuring four multileaf-collimator (MLC) banks has been used for the first time for an experimental comparison of conventional two-bank with novel four-bank dynamic MLC tracking of a two-dimensional sinusoidal respiratory motion. This comparison was performed for a square aperture, and for three conformal treatment apertures from clinical radiotherapy lung cancer patients. The system latency of this prototype tracking system was evaluated and found to be 1.

Sinogram analysis of aperture optimization by iterative least-squares in volumetric modulated arc therapy.

Iterative least-squares (ILS) has been used in CT image reconstruction for many years and has also been successfully applied to fluence optimization in intensity-modulated radiation therapy. However, most optimization schemes use aperture optimization, where it is not so clear how to apply ILS. This study therefore proposes a method of using ILS for aperture optimization in volumetric modulated arc therapy (VMAT) and evaluates the performance by comparing with segment weight optimization.

Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance.

The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer.

A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens.

Background: KRAS mutation testing is required to select patients with metastatic colorectal cancer (CRC) to receive anti-epidermal growth factor receptor antibodies, but the optimal KRAS mutation test method is uncertain.

Methods: We conducted a two-site comparison of two commercial KRAS mutation kits - the cobas KRAS Mutation Test and the Qiagen therascreen KRAS Kit - and Sanger sequencing. A panel of 120 CRC specimens was tested with all three methods.