Reference ranges for ambulatory heart rate measurements in a middle-aged population.

BACKGROUND: Elevated heart rate (HR) predicts cardiovascular disease and mortality, but there are no established normal limits for ambulatory HR. We used data from the Swedish CArdioPulmonary Imaging Study to determine reference ranges for ambulatory HR in a middle-aged population. We also studied clinical correlates of ambulatory HR. METHODS: A 24-hour ECG was registered in 5809 atrial fibrillation-free individuals, aged 50-65 years. A healthy subset (n=3942) was used to establish reference values (excluding persons with beta-blockers, cardiovascular disease, hypertension, heart failure, anaemia, diabetes, sleep apnoea or chronic obstructive pulmonary disease).Minimum HR was defined as the lowest 1-minute HR. Reference ranges are reported as means±SDs and 2.5th-97.5th percentiles. Clinical correlates of ambulatory HR were analysed with multivariable linear regression. RESULTS: The average mean and minimum HRs were 73±9 and 48±7 beats per minute (bpm) in men and 76±8 and 51±7 bpm in women; the reference range for mean ambulatory HR was 57-90 bpm in men and 61-92 bpm in women. Average daytime and night-time HRs are also reported. Clinical correlates, including age, sex, height, body mass index, physical activity, smoking, alcohol intake, diabetes, hypertension, haemoglobin level, use of beta-blockers, estimated glomerular filtration rate, per cent of predicted forced expiratory volume in 1 s and coronary artery calcium score, explained <15% of the interindividual differences in HR. CONCLUSION: Ambulatory HR varies widely in healthy middle-aged individuals, a finding with relevance for the management of patients with a perception of tachycardia. Differences in ambulatory HR between individuals are largely independent of common clinical correlates.

A prospective study comparing the quality of coronary computed tomography angiography images from photon counting and energy integrating detector systems.

BACKGROUND: As guidelines endorse the use of computed tomography (CT) for examining coronary artery disease (CAD), it is important to compare the advantages and disadvantages of the novel photon counting detector CT (PCD-CT) technology with the established energy integrating detector CT (EID-CT). PURPOSE: To compare the image quality of coronary computed tomography angiography (CCTA) and the Agatston scores (AS) derived from EID-CT and PCD-CT. MATERIAL AND METHODS: In this prospective observational study, 28 patients underwent clinical calcium score and CCTA scans on an EID-CT and a PCD-CT scanner. CCTA images were qualitatively analyzed by five observers using visual grading characteristics. The correlation and agreement of the AS were assessed using Spearman's rank correlation and Bland-Altman plots. RESULTS: This qualitative analyses demonstrated a high fraction of "good" or "excellent" ratings for the image criteria in both CT systems. The sharpness of the distal lumen and image quality regarding motion artifacts were rated significantly higher for EID-CT (P < 0.05). However, the sharpness of coronary calcification was rated significantly higher for PCD-CT (P < 0.05). Spearman's rank correlation and Bland-Altman plots showed good correlation (P = 0.95) and agreement regarding the AS between EID-CT and PCD-CT. CONCLUSION: Both CT systems exhibited high CCTA image quality. The sharpness of calcifications was rated significantly higher for PCD-CT. A good correlation was observed between the AS derived from the two systems.

Increased mortality after total hip prosthetic joint infection is mainly caused by the comorbidities rather than the infection itself.

BACKGROUND AND PURPOSE: Periprosthetic joint infection (PJI) is a feared complication of arthroplasty surgery. There is controversy as to whether PJI also correlates with increased mortality. Our aim was to investigate in a nationwide cohort if PJI is an independent risk factor for dying. PATIENTS AND METHODS: We performed a retrospective cohort study based on data from the Swedish Hip Arthroplasty Register (SHAR). All patients with a revision THA performed between 1998 and 2017 were included. The outcome is mortality; exposure is PJI according to SHAR. The control group was study participants who underwent aseptic revision. Confounders were age, sex, diagnosis, and comorbidity according to the Elixhauser index. The outcome was analyzed with a Cox proportional hazards model. RESULTS: 4,943 PJI revisions and 12,529 non-infected revisions were included in the analysis. The median follow-up time was 4.1 years. In the PJI group, 1,972 patients died and in the control group, 4,512. The incidence rate ratio was 1.19 (95% confidence interval [CI] 1.13-1.25), the crude hazard ratio (HR) 1.19 (CI 1.13-1.25), and the adjusted HR 1.05 (CI 0.99-1.12) for the exposed versus the unexposed group. The strongest confounder was comorbidity. CONCLUSION: The increased mortality risk after revision due to PJI is mainly caused by the comorbidity of the patient, rather than by the infection itself.

Dynamics of urine proteomics biomarker and disease progression in patients with IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) frequently leads to kidney failure. The urinary proteomics-based classifier IgAN237 may predict disease progression at the time of kidney biopsy. We studied whether IgAN237 also predicts progression later in the course of IgAN. METHODS: Urine from patients with biopsy-proven IgAN was analyzed using capillary electrophoresis-mass spectrometry at baseline (IgAN237-1, n = 103) and at follow-up (IgAN237-2, n = 89). Patients were categorized as "non-progressors" (IgAN237 ≤0.38) and "progressors" (IgAN237 >0.38). Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio slopes were calculated. RESULTS: Median age at biopsy was 44 years, interval between biopsy and IgAN237-1 was 65 months and interval between IgAN237-1 and IgAN237-2 was 258 days (interquartile range 71-531). IgAN237-1 and IgAN237-2 values did not differ significantly and were correlated (rho = 0.44, P < .001). Twenty-eight percent and 26% of patients were progressors based on IgAN237-1 and IgAN237-2, respectively. IgAN237 inversely correlated with chronic eGFR slopes (rho = -0.278, P = .02 for score-1; rho = -0.409, P = .002 for score-2) and with ±180 days eGFR slopes (rho = -0.31, P = .009 and rho = -0.439, P = .001, respectively). The ±180 days eGFR slopes were worse for progressors than for non-progressors (median -5.98 versus -1.22 mL/min/1.73 m2 per year for IgAN237-1, P < .001; -3.02 vs 1.08 mL/min/1.73 m2 per year for IgAN237-2, P = .0047). In multiple regression analysis baseline progressor/non-progressor according to IgAN237 was an independent predictor of eGFR180days-slope (P = .001). CONCLUSION: The urinary IgAN237 classifier represents a risk stratification tool in IgAN also later in the course of the dynamic disease. It may guide patient management in an individualized manner.

Modeling and Evaluation of a Rate-Based Transcutaneous Blood Gas Monitor.

OBJECTIVE: Current methods for transcutaneous blood gas monitoring (TBM) - a common health monitoring method in neonatal care - comes with a suite of challenges like limited attachment opportunities, and risks of infections from burning and tearing of the skin, which limits its use. This study presents a novel system and method for rate-based transcutaneous CO2 measurements with a soft, unheated skin-interface that can address many of these problems. Additionally, a theoretical model for the gas transport from the blood to the system's sensor is derived. METHODS: By simulating CO2 advection and diffusion through the cutaneous microvasculature and epidermis to the system's skin interface, the effect of a wide range of physiological properties on the measurement has been modeled. Following these simulations, a theoretical model for the relationship between the measured CO2 concentration and that in the blood was derived and compared to empirical data. RESULTS: Applying the model on measured blood gas levels, even when the theory was based solely on the simulations, produced blood CO2 concentrations within ∼35% of empirical measurements from a state-of-the-art device. Further calibration of the framework, also using the empirical data, yielded an output with a Pearson correlation of 0.84 between the two methods. CONCLUSION: Compared to the state-of-the-art device the proposed system measured the partial CO2 pressure in the blood with an average deviation of 0.04 kPa and 1.97σ of ±1.1 kPa. However, the model indicated that this performance could be hampered by different skin properties. SIGNIFICANCE: Given its soft and gentle skin interface and lack of heating, the proposed system could significantly decrease health risks like, burns, tears, and pain, currently associated with TBM on premature neonates.

Assessment of visibility of bone structures in the wrist using normal and half of the radiation dose with photon-counting detector CT.

PURPOSE: To quantitatively and qualitatively assess the visibility of bone structures in the wrist on photon-counting detector computed tomography (PCD-CT) images compared to state-of-the-art energy-integrating detector CT (EID-CT). METHOD: Four human cadaveric wrist specimens were scanned with EID-CT and PCD-CT at identical CTDIvol of 12.2 mGy and with 6.1 mGy (half dose PCD-CT). Axial images were reconstructed using the thinnest possible slice thickness, i.e. 0.4 mm on EID-CT and 0.2 mm on PCD-CT, with the largest image matrix size possible using reconstruction kernels optimized for bone (EID-CT: Ur68, PCD-CT: Br92). Quantitative evaluation was performed to determine contrast-noise ratio (CNR) of bone/ fat, cortical and trabecular sharpness. An observer study using visual grading characteristics (VGC) analysis was performed by six observers to assess the visibility of nutrient canals, trabecular architecture, cortical bone and the general image quality. RESULTS: At equal dose, images obtained with PCD-CT had 39 ± 6 % lower CNR (p = 0.001), 71 ± 57 % higher trabecular sharpness in the radius (p = 0.02) and 42 ± 8 % (p < 0.05) sharper cortical edges than those obtained with EID-CT. This was confirmed by VGC analysis showing a superior visibility of nutrient canals, trabeculae and cortical bone area under the curve (AUC) > 0.89) for PCD-CT, even at half dose. CONCLUSIONS: Despite a lower CNR and increased noise, the trabecular and cortical sharpness were twofold higher with PCD-CT. Visual grading analysis demonstrated superior visibility of cortical bone, trabeculae, nutrient canals and an overall improved image quality with PCD-CT over EID-CT. At half dose, PCD-CT also yielded superior image quality, both in quantitative measures and as evaluated by radiologists.

Standardised lesion segmentation for imaging biomarker quantitation: a consensus recommendation from ESR and EORTC.

BACKGROUND: Lesion/tissue segmentation on digital medical images enables biomarker extraction, image-guided therapy delivery, treatment response measurement, and training/validation for developing artificial intelligence algorithms and workflows. To ensure data reproducibility, criteria for standardised segmentation are critical but currently unavailable. METHODS: A modified Delphi process initiated by the European Imaging Biomarker Alliance (EIBALL) of the European Society of Radiology (ESR) and the European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group was undertaken. Three multidisciplinary task forces addressed modality and image acquisition, segmentation methodology itself, and standards and logistics. Devised survey questions were fed via a facilitator to expert participants. The 58 respondents to Round 1 were invited to participate in Rounds 2-4. Subsequent rounds were informed by responses of previous rounds. RESULTS/CONCLUSIONS: Items with ≥ 75% consensus are considered a recommendation. These include system performance certification, thresholds for image signal-to-noise, contrast-to-noise and tumour-to-background ratios, spatial resolution, and artefact levels. Direct, iterative, and machine or deep learning reconstruction methods, use of a mixture of CE marked and verified research tools were agreed and use of specified reference standards and validation processes considered essential. Operator training and refreshment were considered mandatory for clinical trials and clinical research. Items with a 60-74% agreement require reporting (site-specific accreditation for clinical research, minimal pixel number within lesion segmented, use of post-reconstruction algorithms, operator training refreshment for clinical practice). Items with ≤ 60% agreement are outside current recommendations for segmentation (frequency of system performance tests, use of only CE-marked tools, board certification of operators, frequency of operator refresher training). Recommendations by anatomical area are also specified.

Calmangafodipir for Prevention of Oxaliplatin-Induced Peripheral Neuropathy: Two Placebo-Controlled, Randomized Phase 3 Studies (POLAR-A/POLAR-M).

BACKGROUND: Calmangafodipir (CaM, PledOx) demonstrated efficacy in preventing patient-reported chemotherapy-induced peripheral neuropathy (CIPN) in a randomized phase 2 study in patients with metastatic colorectal cancer. The Preventive Treatment of OxaLiplatin Induced peripherAl neuRopathy (POLAR) program aimed to assess efficacy and safety of CaM in the prevention of CIPN in patients treated with oxaliplatin in adjuvant (POLAR-A, ClinicalTrials.gov.NCT04034355) or metastatic (POLAR-M, ClinicalTrials.gov.NCT03654729) settings. METHODS: Two randomized, placebo-controlled phase 3 trials investigated patient-reported, moderate-to-severe CIPN 9 months after beginning folinic acid, 5-fluorouracil, and oxaliplatin therapy with or without CaM. In POLAR-A, patients with stage III or high-risk stage II colorectal cancer were randomly assigned 1:1 to receive CaM 5 µmol/kg or placebo. In POLAR-M, patients with metastatic colorectal cancer were randomly assigned 1:1:1 to receive CaM 5 µmol/kg, CaM 2 µmol/kg, or placebo. RESULTS: POLAR-A (n = 301) and POLAR-M (n = 291) were terminated early following unexpected hypersensitivity reactions in CaM-treated patients. In a combined analysis of month 9 CIPN (primary endpoint) data from both trials (CaM 5 µmol/kg, n = 175; placebo, n = 176), 54.3% of patients in the CaM group had moderate-to-severe CIPN compared with 40.3% in the placebo group. The estimated relative risk for moderate-to-severe CIPN at month 9 was 1.37 (95% confidence interval = 1.01 to 1.86; P = .045). A higher proportion of patients experienced serious hypersensitivity reactions across both trials with CaM treatment (3.6%) than with placebo (0.8%). CONCLUSION: The POLAR clinical studies failed to meet their primary endpoint. These results highlight the challenges of targeting oxidative stress for preventing CIPN in both the adjuvant and metastatic settings.

Elevated premature ventricular complex counts on 24-hour electrocardiogram predict incident atrial fibrillation and heart failure-A prospective population-based cohort study.

Background: Premature ventricular complexes (PVCs) are known to predict heart failure (HF) and premature atrial contractions (PACs) are known to predict atrial fibrillation (AF) and stroke. PVCs and PACs share pathophysiological mechanisms; however, the combined effects of PVCs and PACs on HF, AF, and stroke risk have not been studied. Objectives: To study elevated PVC counts on 24-hour electrocardiogram monitoring (24hECG) in relation to incidence of AF, HF, and stroke, and whether this effect is altered by PAC frequency. Methods: The prospective population-based Malmö Diet and Cancer study includes 24hECG registrations in 375 AF- and HF-free subjects (mean age 65 years, 55% women). During 17 years of follow-up there were 28 HF, 89 AF, and 28 stroke events. The hazard ratios (HR) of elevated PVC counts (defined as the top quartile, ≥77/24 hours) vs lower quartiles were assessed using multivariable adjusted Cox regression models. Results: Elevated PVC counts predicted incident AF (HR 1.9, 95% confidence interval [CI] 1.2-3.0) and HF (HR 3.1, 95% CI 1.4-7.0). Results were similar after adjustment for NT-proBNP and PACs. Multiform PVCs were associated with even higher risks (HR 2.8, 95% CI: 1.7-4.6 for AF; HR 5.0, 95% CI 2.2-11.7 for HF), as was the presence of both elevated PACs and PVCs (9% of the population, HR 4.1, 95% CI 2.4-6.8 for AF and HR 4.3, 95% CI 1.7-11.4 for HF). No significant association was found between elevated PVC counts and incident stroke. Conclusion: Elevated PVC counts predict incident AF and HF, particularly if PVCs are multiform or occur in combination with elevated PAC counts.

EPOS trial: the effect of air filtration through a plasma chamber on the incidence of surgical site infection in orthopaedic surgery: a study protocol of a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: There is controversy regarding the importance of air-transmitted infections for surgical site infections (SSIs) after orthopaedic surgery. Research has been hindered by both the inability in blinding the exposure, and by the need for recruiting large enough cohorts. The aim of this study is to investigate whether using a new form of air purifier using plasma air purification (PAP) in operating rooms (ORs) lowers the SSI rate or not. METHODS AND ANALYSIS: Multicentre, double-blind, cluster-randomised, placebo-controlled trial conducted at seven hospitals in 2017-2022. All patients that undergo orthopaedic surgery for minimum 30 min are included. Intervention group: patients operated in OR with PAP devices turned on. CONTROL GROUP: patients operated in OR with PAP devices turned off. Randomisation: each OR will be randomised in periods of 4 weeks, 6 weeks or 8 weeks to either have the devices on or off. PRIMARY OUTCOME: any SSI postoperatively defined as a composite endpoint of any of the following: use of isoxazolylpenicillin, clindamycin or rifampicin for 2 days or more, International Classification of Diseases codes or Nordic Medico-Statistical Committee codes indicating postoperative infection. In a second step, we will perform a chart review on those patients with positive indicators of SSI to further validate the outcome. Secondary outcomes are described in the Methods section. Power: we assume an SSI rate of 2%, an SSI reduction rate of 25% and we need approximately 45 000 patients to attain a power of 80% at a significance level of 0.05. ETHICS AND DISSEMINATION: The study is approved by the Swedish Ethical Review Authority. The interim analysis results from the study will be presented only to the researchers involved unless the study thereafter is interrupted for whatever reason. Publication in a medical journal will be presented after inclusion of the last patient. TRIAL REGISTRATION NUMBER: NCT02695368.

A focused very high energy electron beam for fractionated stereotactic radiotherapy.

An electron beam of very high energy (50-250 MeV) can potentially produce a more favourable radiotherapy dose distribution compared to a state-of-the-art photon based radiotherapy technique. To produce an electron beam of sufficiently high energy to allow for a long penetration depth (several cm), very large accelerating structures are needed when using conventional radio-frequency technology, which may not be possible due to economical or spatial constraints. In this paper, we show transport and focusing of laser wakefield accelerated electron beams with a maximum energy of 160 MeV using electromagnetic quadrupole magnets in a point-to-point imaging configuration, yielding a spatial uncertainty of less than 0.1 mm, a total charge variation below [Formula: see text] and a focal spot of [Formula: see text]. The electron beam was focused to control the depth dose distribution and to improve the dose conformality inside a phantom of cast acrylic slabs and radiochromic film. The phantom was irradiated from 36 different angles to obtain a dose distribution mimicking a stereotactic radiotherapy treatment, with a peak fractional dose of 2.72 Gy and a total maximum dose of 65 Gy. This was achieved with realistic constraints, including 23 cm of propagation through air before any dose deposition in the phantom.

Laser wakefield accelerated electron beams and betatron radiation from multijet gas targets.

Laser Plasma Wakefield Accelerated (LWFA) electron beams and efficiency of betatron X-ray sources is studied using laser micromachined supersonic gas jet nozzle arrays. Separate sections of the target are used for the injection, acceleration and enhancement of electron oscillation. In this report, we present the results of LWFA and X-ray generation using dynamic gas density grid built by shock-waves of colliding jets. The experiment was done with the 40 TW, 35 fs laser at the Lund Laser Centre. Electron energies of 30-150 MeV and 1.0 × 108-5.5 × 108 photons per shot of betatron radiation have been measured. The implementation of the betatron source with separate regions of LWFA and plasma density grid raised the efficiency of X-ray generation and increased the number of photons per shot by a factor of 2-3 relative to a single-jet gas target source.

Compliance of a microstructured, soft sampling device for transcutaneous blood gas monitoring.

Premature neonates are too small for repeated blood sampling, but still require precise monitoring of blood gas levels. The standard method therefore involves transcutaneous blood gas monitoring (TBM), i.e. analyzing gas that permeates the skin. The method involves skin heating and requires frequent relocation of a rigid sensor that is adhesively mounted to the skin, which makes the monitoring intermittent and can cause tissue damage. To mitigate this, this paper introduces a TBM concept that replaces the sensor with a small, non-adhesive, flexible, polydimethylsiloxane patch, routing the gases through skin-facing microchannels laid out in various configurations, to an external optical emission spectroscopy system (OES). As the OES depends on a constant flow of gas, we have investigated the effects external loads, both vertical and with a transverse component, have on the aerodynamic resistance of the patches. The experiments show that patches with 200 µm wide channels can withstand uniformly distributed forces up to 25 N with a change in aerodynamic resistance of about 0.01 mbar per sccm per newton. In subsequent measurements, the proof of concept (POC) TBM system showed a strong and fast blood gas signal that was unaffected by all likely loads in the intended application. Moreover, the rise time of the signal is shown to be inversely proportional to the aerodynamic resistance, and the signal strength to be proportional to the skin area exposed to the microchannels. With these results, the POC TBM system is a viable first step towards truly continuous blood gas monitoring of prematurely born children.

Heart rate and premature atrial contractions at 24hECG independently predict atrial fibrillation in a population-based study.

BACKGROUND: Low resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats. OBJECTIVE: To study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort. METHODS: In the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance. RESULTS: There were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001). CONCLUSION: Low mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Diagnostic accuracy of dual-energy CT for detection of bone marrow lesions in the subacutely injured knee with MRI as reference method.

BACKGROUND: Dual-energy computer tomography (DECT) can detect post-traumatic bone marrow lesions. Prospective studies of the knee with large numbers of participants and intra-observer agreement assessment are limited. PURPOSE: To investigate the diagnostic accuracy of DECT in detecting bone marrow lesions as well as estimating the bone marrow lesion volume in patients with suspected anterior cruciate ligament trauma with magnetic resonance imaging (MRI) as reference standard. MATERIAL AND METHODS: Forty-eight consecutive patients with suspected anterior cruciate ligament injury were imaged bilaterally with DECT within a mean of 25 days (range 4-55 days) following injury and MRI within seven days of DECT. Two readers analyzed DECT virtual non-calcium-blinded images. Consensus MRI was reference standard. Intra- and inter-observer agreement were determined using weighted kappa statistics. Sensitivity, specificity, and negative and positive predictive values were calculated. Bone marrow lesion volumes were measured; for comparison, intra-class correlation coefficient was used. RESULTS: The 48 patients (26 men, 22 women; mean age 23 years, age range 15-37 years) were imaged bilaterally yielding 52 knees with bone marrow lesions, of which 44 were in the femur and 41 were in the tibia. Intra- and inter-observer agreement to detect bone marrow lesions was moderate and fair to moderate (κ 0.54-0.66, 95% confidence interval [CI] 0.39-0.80 and 0.37-0.41, 95% CI 0.20-0.57) and overall sensitivity and specificity were 70.1% and 69.1%, respectively. Positive and negative predictive values were 72.9% and 66.1%, respectively. Bone marrow lesion volumes showed excellent intra- and inter-observer agreement (0.83-0.91, 95% CI 0.74-0.94 and 0.76-0.78, 95% CI 0.57-0.87). CONCLUSION: The diagnostic performance of DECT to detect bone marrow lesions in the subacutely injured knee was moderate with intra- and inter-observer agreement ranging from moderate to substantial and fair to moderate. Bone marrow lesion volume correlation was excellent.

Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR).

Observer-driven pattern recognition is the standard for interpretation of medical images. To achieve global parity in interpretation, semi-quantitative scoring systems have been developed based on observer assessments; these are widely used in scoring coronary artery disease, the arthritides and neurological conditions and for indicating the likelihood of malignancy. However, in an era of machine learning and artificial intelligence, it is increasingly desirable that we extract quantitative biomarkers from medical images that inform on disease detection, characterisation, monitoring and assessment of response to treatment. Quantitation has the potential to provide objective decision-support tools in the management pathway of patients. Despite this, the quantitative potential of imaging remains under-exploited because of variability of the measurement, lack of harmonised systems for data acquisition and analysis, and crucially, a paucity of evidence on how such quantitation potentially affects clinical decision-making and patient outcome. This article reviews the current evidence for the use of semi-quantitative and quantitative biomarkers in clinical settings at various stages of the disease pathway including diagnosis, staging and prognosis, as well as predicting and detecting treatment response. It critically appraises current practice and sets out recommendations for using imaging objectively to drive patient management decisions.

Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness.

Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.

High density is a property of slow-cycling and treatment-resistant human glioblastoma cells.

Slow-cycling and treatment-resistant cancer cells escape therapy, providing a rationale for regrowth and recurrence in patients. Much interest has focused on identifying the properties of slow-cycling tumor cells in glioblastoma (GBM), the most common and lethal primary brain tumor. Despite aggressive ionizing radiation (IR) and treatment with the alkylating agent temozolomide (TMZ), GBM patients invariably relapse and ultimately succumb to the disease. In patient biopsies, we demonstrated that GBM cells expressing the proliferation markers Ki67 and MCM2 displayed a larger cell volume compared to rare slow-cycling tumor cells. In optimized density gradients, we isolated a minor fraction of slow-cycling GBM cells in patient biopsies and tumorsphere cultures. Transcriptional profiling, self-renewal, and tumorigenicity assays reflected the slow-cycling state of high-density GBM cells (HDGCs) compared to the tumor bulk of low-density GBM cells (LDGCs). Slow-cycling HDGCs enriched for stem cell antigens proliferated a few days after isolation to generate LDGCs. Both in vitro and in vivo, we demonstrated that HDGCs show increased treatment-resistance to IR and TMZ treatment compared to LDGCs. In conclusion, density gradients represent a non-marker based approach to isolate slow-cycling and treatment-resistant GBM cells across GBM subgroups.

Unlocking the Dangers of a Stiffening Brain.

Mechanical cues regulate neuronal function and reactivity of glial cells, the origin of gliomas. In this issue of Neuron, Chen et al. (2018) uncover a feedforward loop mediated by the mechanosensitive ion channel Piezo1 and tissue stiffness that drives glioma aggression.