Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

Restless legs syndrome/Willis–Ekbom disease prevalence in beta thalassemia patients

Purpose Both beta thalassemia and restless legs syndrome (RLS) patients share some common pathophysiological characteristics related to iron handling. In the present study, the aim was to explore the prevalence of RLS as well as to explore potential association between the syndrome and various quality of life-related parameters in a sample of beta thalassemia patients. Methods One hundred fourteen (age 40 ± 11 yr, 59 M/55F) beta thalassemia patients participated in this cross-sectional descriptive study. Patients were screened for RLS based on the international RLS study group diagnostic criteria as well as a battery of validated questionnaires. Results The prevalence of RLS in this sample of beta thalassemia patients was zero. The quality of life score was low (78 ± 18). Iron levels were within normal range (191 ± 66 mcg/dL) while ferritin levels were high as expected (1836 ± 225 ng/dL). Conclusions Our sample of patients comes from central Greece where the prevalence of RLS in the general population is 4% while in renal failure patients is 27%. To our surprise, there was no presence of RLS among this sample of beta thalassemia patients. The adequate levels of iron and ferritin often seen in these patients could be the reason of the absence of RLS symptoms

Development and evaluation of machine learning in whole-body magnetic resonance imaging for detecting metastases in patients with lung or colon cancer: a diagnostic test accuracy study.

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient specificity in both groups was 76.3% (0% difference; 95% CI, -15.0%, 15.0%; P = 0.613), with sensitivity of 73.3% (ML) and 60.0% (non-ML) (13.3% difference; 95% CI, -7.9%, 34.5%; P = 0.313). Per-site specificity was high (>90%) for all metastatic sites and experience levels. There was high sensitivity for the detection of primary tumors (lung cancer detection rate of 98.6% with and without ML [0.0% difference; 95% CI, -2.0%, 2.0%; P = 1.00], colon cancer detection rate of 89.0% with and 90.6% without ML [-1.7% difference; 95% CI, -5.6%, 2.2%; P = 0.65]). When combining all reads from rounds 1 and 2, reading times fell by 6.2% (95% CI, -22.8%, 10.0%) when using ML. Round 2 read-times fell by 32% (95% CI, 20.8%, 42.8%) compared with round 1. Within round 2, there was a significant decrease in read-time when using ML support, estimated as 286 seconds (or 11%) quicker (P = 0.0281), using regression analysis to account for reader experience, read round, and tumor type. Interobserver variance suggests moderate agreement, Cohen κ = 0.64; 95% CI, 0.47, 0.81 (with ML), and Cohen κ = 0.66; 95% CI, 0.47, 0.81 (without ML). CONCLUSIONS: There was no evidence of a significant difference in per-patient sensitivity and specificity for detecting metastases or the primary tumor using concurrent ML compared with standard WB-MRI. Radiology read-times with or without ML support fell for round 2 reads compared with round 1, suggesting that readers familiarized themselves with the study reading method. During the second reading round, there was a significant reduction in reading time when using ML support

Embryonic Stem Cell-Derived L1 Overexpressing Neural Aggregates Enhance Recovery after Spinal Cord Injury in Mice

An obstacle to early stem cell transplantation into the acutely injured spinal cord is poor survival of transplanted cells. Transplantation of embryonic stem cells as substrate adherent embryonic stem cell-derived neural aggregates (SENAs) consisting mainly of neurons and radial glial cells has been shown to enhance survival of grafted cells in the injured mouse brain. In the attempt to promote the beneficial function of these SENAs, murine embryonic stem cells constitutively overexpressing the neural cell adhesion molecule L1 which favors axonal growth and survival of grafted and imperiled cells in the inhibitory environment of the adult mammalian central nervous system were differentiated into SENAs and transplanted into the spinal cord three days after compression lesion. Mice transplanted with L1 overexpressing SENAs showed improved locomotor function when compared to mice injected with wild-type SENAs. L1 overexpressing SENAs showed an increased number of surviving cells, enhanced neuronal differentiation and reduced glial differentiation after transplantation when compared to SENAs not engineered to overexpress L1. Furthermore, L1 overexpressing SENAs rescued imperiled host motoneurons and parvalbumin-positive interneurons and increased numbers of catecholaminergic nerve fibers distal to the lesion. In addition to encouraging the use of embryonic stem cells for early therapy after spinal cord injury L1 overexpression in the microenvironment of the lesioned spinal cord is a novel finding in its functions that would make it more attractive for pre-clinical studies in spinal cord regeneration and most likely other diseases of the nervous system

Evidence of Increased Muscle Atrophy and Impaired Quality of Life Parameters in Patients with Uremic Restless Legs Syndrome

BACKGROUND: Restless Legs Syndrome is a very common disorder in hemodialysis patients. Restless Legs Syndrome negatively affects quality of life; however it is not clear whether this is due to mental or physical parameters and whether an association exists between the syndrome and parameters affecting survival. METHOD#ENTITYSTARTX003BF;LOGY/PRINCIPAL FINDINGS: Using the Restless Legs Syndrome criteria and the presence of Periodic Limb Movements in Sleep (PLMS/h >15), 70 clinically stable hemodialysis patients were assessed and divided into the RLS (n = 30) and non-RLS (n = 40) groups. Physical performance was evaluated by a battery of tests: body composition by dual energy X ray absorptiometry, muscle size and composition by computer tomography, while depression symptoms, perception of sleep quality and quality of life were assessed through validated questionnaires. In this cross sectional analysis, the RLS group showed evidence of thigh muscle atrophy compared to the non-RLS group. Sleep quality and depression score were found to be significantly impaired in the RLS group. The mental component of the quality of life questionnaire appeared significantly diminished in the RLS group, reducing thus the overall quality of life score. In contrast, there were no significant differences between groups in any of the physical performance tests, body and muscle composition. CONCLUSIONS: The low level of quality of life reported by the HD patients with Restless Legs Syndrome seems to be due mainly to mental health and sleep related aspects. Increased evidence of muscle atrophy is also observed in the RLS group and possibly can be attributed to the lack of restorative sleep

Effect of exercise training and dopamine agonists in patients with uremic restless legs syndrome: A six-month randomized, partially double-blind, placebo-controlled comparative study

© 2013 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1186/1471-2369-14-194Background: Restless Legs Syndrome is very common in hemodialysis patients however there are no comparative studies assessing the effectiveness of a non-pharmacological treatment to a classical treatment on parameters related to syndromes' severity and quality of life. Methods. In this randomized, partially double blind, placebo controlled trial, thirty two hemodialysis patients with restless legs syndrome were randomly assigned into three groups: 1) the exercise training group (N = 16), 2) the dopamine agonists group (ropinirole 0.25 mg/d) (N = 8) and 3) the placebo group (N = 8). The intervention programs lasted 6 months. Restless Legs Syndrome severity was assessed using the international severity scale, physical performance by a battery of tests, muscle size and composition by computed tomography, body composition by Dual Energy X Ray Absorptiometry, while depression score, sleep quality, daily sleepiness and quality of life were assessed through questionnaires. Results: Exercise training and dopamine agonists were effective in reducing syndrome's symptoms by 46% (P = 0.009) and 54% (P = 0.001) respectively. Within group changes revealed that both approaches significantly improved quality of life (P 0.05) in various tests. Between group changes detect significant improvements with both exercise and dopamine agonists in depression score (P = 0.003), while only the dopamine agonist treatment was able to significantly improve sleep quality, compared to exercise and placebo (P = 0.016). Conclusions: A 6-month exercise training regime was as effective as a 6-month low dosage dopamine agonist treatment in reducing restless legs syndrome symptoms and improving depression score in uremic patients. Further research is needed in order to show whether a combination treatment could be more beneficial for the amelioration of RLS. Trial registration. NCT00942253. © 2013 Giannaki et al.; licensee BioMed Central Ltd.This study was supported by the National and Community Funds of the Greek Ministry of Development-General Secretariat of Research and Technology and by the European Social Fund.Published versio

Magnetic resonance imaging compatible remote catheter navigation system with 3 degrees of freedom

Purpose: To facilitate MRI-guided catheterization procedures, we present an MRI-compatible remote catheter navigation system that allows remote navigation of steerable catheters with 3 degrees of freedom. Methods: The system consists of a user interface (master), a robot (slave), and an ultrasonic motor control servomechanism. The interventionalist applies conventional motions (axial, radial and plunger manipulations) on an input catheter in the master unit; this user input is measured and used by the servomechanism to control a compact catheter manipulating robot, such that it replicates the interventionalist’s input motion on the patient catheter. The performance of the system was evaluated in terms of MRI compatibility (SNR and artifact), feasibility of remote navigation under real-time MRI guidance, and motion replication accuracy. Results: Real-time MRI experiments demonstrated that catheter was successfully navigated remotely to desired target references in all 3 degrees of freedom. The system had an absolute value error of \u3c 1 mm in axial catheter motion replication over 30 mm of travel and 3 ± 2 for radial catheter motion replication over 180 . The worst case SNR drop was observed to be \u3c 3 %; the robot did not introduce any artifacts in the MR images. Conclusion: An MRI-compatible compact remote catheter navigation system has been developed that allows remote navigation of steerable catheters with 3 degrees of freedom. The proposed system allows for safe and accurate remote catheter navigation, within conventional closed-bore scanners, without degrading MR image quality. ∘ ∘

Texture analysis of articular cartilage traumatic changes in the knee calculated from morphological 3.0 T MR imaging

Objectives: In the present work, we aim to identify changes in the cartilage texture of the injured knee in young, physically active, patients by computer analysis of MRI images based on 3.0 T morphological sequences. Methods: Fifty-three young patients with training injury or trauma in one knee underwent MRI and arthroscopy. Textural features were computed from the MRI images of the knee-cartilages and two classes were formed of 28 normal and 16 with pathology only in the medial femoral condyle (MFC) cartilage. Results: Textural features with statistically significant differences between the two classes were found only at the MFC and the medial tibial condyle (MTC) areas. Three features-combinations, at the MFC or the MTC, maximized the between classes separation, thus, rendering alterations in cartilage texture due to injury more evident. The MFC cartilage in the pathology class was found more inhomogeneous in the distribution of gray-levels and of lower texture anisotropy and the opposed MTC cartilage, though normal on MRI and arthroscopy, was found to have lower texture anisotropy than cartilage in the normal class. Conclusion: Texture analysis may be used as an adjunct to morphological MR imaging for improving the detection of subtle cartilage changes and contributes to early therapeutic approach. (C) 2013 Elsevier Ireland Ltd. All rights reserved