Patients with end-stage kidney disease have markedly abnormal cortical hip parameters by dual-energy X-ray absorptiometry.

BACKGROUND: Patients with end-stage kidney disease (ESKD) have higher fracture rates and post-fracture mortality than the general population, but bone mineral density by dual-energy X-ray absorptiometry (DXA) is less predictive of fracture in this patient group. Bone biopsy and high-resolution imaging indicate that cortical thickness (CT) is reduced and cortical porosity is increased in ESKD. The aim of this study was to assess cortical parameters using DXA in patients with ESKD. It was hypothesized that these parameters would show deterioration and be associated with fracture. METHODS: Using advanced hip analysis, normal age-related ranges were determined from 752 female and 861 male femur scans and were compared with scans of 226 patients with ESKD at the time of transplantation. RESULTS: Compared with controls, female patients had lower mean±SD CT (mms) at the femoral neck (FN) (2.59 ± 1.42 versus 5.23 ± 1.85), calcar (3.46 ± 1.07 versus 5.09 ± 1.30) and shaft (4.42 ± 1.21 versus 7.44 ± 2.07; P < 0.001 for each), and buckling ratios were higher (8.21 ± 4.6 versus 3.63 ± 1.42; P < 0.001), indicating greater FN instability. All findings were similar for men. Prevalent fracture was documented in 28.8% of patients; 12.4% vertebral only, 8.4% non-vertebral only and 8% vertebral plus non-vertebral. In adjusted models, each 1 SD reduction in FN CT and increase in the buckling ratio was associated with a respective 1.73 (1.22-2.46)- and 1.82 (1.49-2.86)-fold increase in the risk of prevalent vertebral fracture. CONCLUSIONS: In patients with ESKD, DXA-derived cortical parameters are markedly abnormal compared with age- and sex-matched controls. These parameters should be assessed for incident fracture prediction and targeting treatment.

Evaluation of absolute and normalized apparent diffusion coefficient (ADC) values within the post-operative T2/FLAIR volume as adverse prognostic indicators in glioblastoma.

To evaluate the association of normalized and absolute ADC metrics with progression free survival (PFS) and overall survival (OS) in patients treated for glioblastoma multiforme (GBM). Fifty-two patients with preradiotherapy diffusion weighted imaging treated with post-operative chemoradiation for GBM were evaluated. Region of interest analysis for ADC metrics including mean and minimum ADC value (ADCmean) and (ADCmin) was performed within the T2/FLAIR volume. Normalized (N)ADC values were generated relative to contralateral white matter. PFS and OS were analyzed relative to ADC parameters using a regression model. Kaplan-Meier and Cox proportional hazards analysis with respect to (N)ADCmean, and (N)ADCmin was performed. A (N)ADC threshold <1.3 within the T2/FLAIR volume was analyzed with respect to PFS and OS. Regression analysis indicated that normalized ADC values provide the strongest association with PFS and OS. Kaplan-Meier analysis revealed a non-significant trend toward inferior PFS and OS associated with (N)ADCmean <1.7, and a significant decrement to PFS and OS associated with (N)ADCmin <0.3. (N)ADCmin was a significant prognostic factor when taking into account age, performance status, and extent of resection. ADC thresholding analysis revealed that a retained volume of >0.45 cc per mL FLAIR volume was associated with a trend toward inferior PFS and OS. In the post-operative, pre-radiotherapy setting, the (N)ADCmin is the strongest predictor of outcomes in patients treated for GBM. ADC thresholding analysis indicates that a large volume of normalized ADC value <1.3 may be associated with adverse outcomes.

Evaluation of pre-radiotherapy apparent diffusion coefficient (ADC): patterns of recurrence and survival outcomes analysis in patients treated for glioblastoma multiforme.

PURPOSE: To investigate the association of pre-radiotherapy apparent diffusion coefficient (ADC) abnormalities with patterns of recurrence and outcomes in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: Fifty-two patients with recurrent GBM were retrospectively evaluated. Diffusion MRI images were acquired for all patients postoperatively prior to radiotherapy. ADC images were evaluated for geographic regions of diffusion restriction (hypointensity) within the FLAIR volume. If identified, the ADC map and the T1+C MRI at the time of recurrence were registered to the original plan to determine the pattern of recurrence and the coverage of the ADC abnormality by the 60 Gy isodose line (IDL). Progression-free and overall survival was determined for patients with and without an ADC hypointensity. RESULTS: An ADC hypointensity was identified in 32 (62%) of cases. The recurrence pattern in these cases was central in 27/32 (84%), marginal in 4/32 (13%) and distant in 1/32 (3%). The recurrence overlapped with the ADC hypointensity in 28 (88%) patients. The ADC hypointensity was covered by 95% of the 60 Gy IDL in all cases. Kaplan-Meier analysis revealed inferior progression free survival and overall survival in patients with an ADC hypointensity compared to those without, despite similarities between the groups in terms of age, RT dose, performance status, and extent of resection. CONCLUSIONS: The presence of an ADC hypointensity on pre-radiotherapy diffusion-weighted imaging is associated with the location of tumor recurrence as demonstrated by frequent overlap in this series, and is associated with a trend toward inferior outcomes. This abnormality may reflect a high risk region of hypercellularity and warrants consideration with respect to radiotherapy planning.

Development of a comprehensive cardiac atlas on a 1.5 Tesla Magnetic Resonance Linear Accelerator.

Background and purpose: The 1.5 Tesla (T) Magnetic Resonance Linear Accelerator (MRL) provides an innovative modality for improved cardiac imaging when planning radiation treatment. No MRL based cardiac atlases currently exist, thus, we sought to comprehensively characterize cardiac substructures, including the conduction system, from cardiac images acquired using a 1.5 T MRL and provide contouring guidelines. Materials and methods: Five volunteers were enrolled in a prospective protocol (NCT03500081) and were imaged on the 1.5 T MRL with Half Fourier Single-Shot Turbo Spin-Echo (HASTE) and 3D Balanced Steady-State Free Precession (bSSFP) sequences in axial, short axis, and vertical long axis. Cardiac anatomy was contoured by (AS) and confirmed by a board certified cardiologist (JR) with expertise in cardiac MR imaging. Results: A total of five volunteers had images acquired with the HASTE sequence, with 21 contours created on each image. One of these volunteers had additional images obtained with 3D bSSFP sequences in the axial plane and additional images obtained with HASTE sequences in the key cardiac planes. Contouring guidelines were created and outlined. 15-16 contours were made for the short axis and vertical long axis. The cardiac conduction system was demonstrated with eleven representative contours. There was reasonable variation of contour volume across volunteers, with structures more clearly delineated on the 3D bSSFP sequence. Conclusions: We present a comprehensive cardiac atlas using novel images acquired prospectively on a 1.5 T MRL. This cardiac atlas provides a novel resource for radiation oncologists in delineating cardiac structures for treatment with radiotherapy, with special focus on the cardiac conduction system.

Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤ 6 brain metastases: a multi-institutional phase II trial.

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.

Initial clinical experience of Stereotactic Body Radiation Therapy (SBRT) for liver metastases, primary liver malignancy, and pancreatic cancer with 4D-MRI based online adaptation and real-time MRI monitoring using a 1.5 Tesla MR-Linac.

PURPOSE/OBJECTIVES: Recently a 1.5 Tesla MR Linac has been FDA approved and is commercially available. Clinical series describing treatment methods and outcomes for upper abdominal tumors using a 1.5 Tesla MR Linac are lacking. We present the first clinical series of upper abdominal tumors treated using a 1.5 Tesla MR Linac along with the acquisition of intra-treatment quantitative imaging. MATERIALS/METHODS: 10 patients with abdominal tumors were treated at our institution. Each patient enrolled in an IRB approved advanced imaging protocol. Both daily real-time adaptive and non-adaptive methods were used, and selection criteria are described. Adaptive plans were based on pre-beam motion-averaged or mid-position images derived from respiratory-correlated 4D-MRI. Quantitative intravoxel incoherent motion diffusion-weighted imaging and T2 mapping were acquired during plan adaptation. Real-time motion monitoring using cine MRI was performed during beam-on. RESULTS: Median patient age was 68.2, five patients were female. Tumor types included liver metastatic lesions from melanoma and sarcoma, primary liver hepatocellular carcinoma (HCC), and regional abdominal tumors included pancreatic metastatic lesions from renal cell carcinoma (RCC) along with two cases of recurrent pancreatic cancer. Doses included 30 Gy in 6 fractions, 33 Gy in 5 fractions, 50 Gy in 5 fractions, 45 Gy in 3 fractions, and 60 Gy in 3 fractions, depending on the location and clinical circumstances. Treatments were feasible and were successfully completed in all patients without significant acute toxicity, technical complications, or need for back up CT based treatment plans. CONCLUSIONS: We present a first clinical series of patients treated for pancreatic tumors, primary liver tumors, and secondary liver tumors with a 1.5 Tesla MR Linear accelerator using adapt-to-position and adapt-to-shape strategies. Treatments were well tolerated by all patients. Acquisition of fully quantitative MR imaging was feasible during the course of the treatment delivery workflow without extending overall treatment times.

R-IDEAL: A Framework for Systematic Clinical Evaluation of Technical Innovations in Radiation Oncology.

The pace of innovation in radiation oncology is high and the window of opportunity for evaluation narrow. Financial incentives, industry pressure, and patients' demand for high-tech treatments have led to widespread implementation of innovations before, or even without, robust evidence of improved outcomes has been generated. The standard phase I-IV framework for drug evaluation is not the most efficient and desirable framework for assessment of technological innovations. In order to provide a standard assessment methodology for clinical evaluation of innovations in radiotherapy, we adapted the surgical IDEAL framework to fit the radiation oncology setting. Like surgery, clinical evaluation of innovations in radiation oncology is complicated by continuous technical development, team and operator dependence, and differences in quality control. Contrary to surgery, radiotherapy innovations may be used in various ways, e.g., at different tumor sites and with different aims, such as radiation volume reduction and dose escalation. Also, the effect of radiation treatment can be modeled, allowing better prediction of potential benefits and improved patient selection. Key distinctive features of R-IDEAL include the important role of predicate and modeling studies (Stage 0), randomization at an early stage in the development of the technology, and long-term follow-up for late toxicity. We implemented R-IDEAL for clinical evaluation of a recent innovation in radiation oncology, the MRI-guided linear accelerator (MR-Linac). MR-Linac combines a radiotherapy linear accelerator with a 1.5-T MRI, aiming for improved targeting, dose escalation, and margin reduction, and is expected to increase the use of hypofractionation, improve tumor control, leading to higher cure rates and less toxicity. An international consortium, with participants from seven large cancer institutes from Europe and North America, has adopted the R-IDEAL framework to work toward coordinated, evidence-based introduction of the MR-Linac. R-IDEAL holds the promise for timely, evidence-based introduction of radiotherapy innovations with proven superior effectiveness, while preventing unnecessary exposure of patients to potentially harmful interventions.

Longitudinal changes in anthropometrics and impact on self-reported physical function after traumatic brain injury.

BACKGROUND AND AIMS: Patients admitted to the ICU with a traumatic brain injury (TBI) are at risk of muscle wasting but this has not been quantified. Our aims were to describe longitudinal changes in anthropometrical data, compare the accuracy of non-invasive methodologies to the validated dual-energy x-ray absorptiometry (DXA), and assess the relationships between anthropometrical data and self-reported physical function. METHODS: In a prospective observational study, we recruited patients admitted to the ICU with a moderate-to-severe TBI over 12 months. Anthropometric measurements included the subjective global assessment (SGA), bodyweight and ultrasoundderived quadriceps muscle layer thickness (QMLT), which we performed weekly in hospital and 3 months after admission. We assessed total body composition using DXA within 7 days of ICU discharge, and compared the total lean muscle mass with ultrasound-derived QMLT taken within 5 days of the DXA measurement. We assessed functional outcomes at 3 months using the physical component score of the Short Form-36 (SF- 36) and the Extended Glasgow Outcome Scale (GOS-E). RESULTS: Thirty-seven patients were included, with a mean age of 45 years (SD, 16 years), and 87% were men. Participants were admitted to the ICU for a mean of 13 days (IQR, 6-18 days) and to hospital for a mean of 38 days (IQR, 19-52 days). They had significant weight loss in hospital (mean, 4.9% [SD, 7.7%]; P = 0.001). Malnutrition, measured with the SGA, was twice as prevalent at hospital discharge than at admission (P = 0.005). A reduction in QMLT occurred in the ICU but stabilised after ICU discharge. DXA-derived total lean mass taken within 7 days of ICU discharge strongly correlated with ultrasound-derived QMLT taken within 5 days of DXA measurements (ρ = 0.74, P = 0.037). Improvements in self-reported physical function, using the SF- 36 and GOS-E at 3 months, were associated with a greater QMLT at hospital discharge (SF-36: ρ = 0.536, P = 0.010; GOS-E: ρ = 0.595, P = 0.003, n = 23) and at 3 months (SF-36: ρ = 0.658, P = 0.020; GOS-E: ρ = 0.642, P = 0.025, n = 12). CONCLUSIONS: Patients with a TBI lose muscle thickness while in the ICU but the trajectory of loss stabilises after ICU discharge. Ultrasound-derived QMLT is related to total lean mass and physical function after discharge. Further studies are needed to confirm that ultrasound measurement of QMLT is a useful surrogate measure of muscle mass and functional outcomes after trauma and critical illness.

Interacting with Large 3D Datasets on a Mobile Device.

A detail-on-demand scheme can alleviate both memory and GPU pressure on mobile devices caused by volume rendering. This approach allows a user to explore an entire dataset at its native resolution while simultaneously constraining the texture size being rendered to a dimension that does not exceed the processing capabilities of a portable device. This scheme produces higher-quality, more focused images rendered at interactive frame rates, while preserving the native resolution of the dataset.

The MRI-Linear Accelerator Consortium: Evidence-Based Clinical Introduction of an Innovation in Radiation Oncology Connecting Researchers, Methodology, Data Collection, Quality Assurance, and Technical Development.

An international research consortium has been formed to facilitate evidence-based introduction of MR-guided radiotherapy (MR-linac) and to address how the MR-linac could be used to achieve an optimized radiation treatment approach to improve patients' survival, local, and regional tumor control and quality of life. The present paper describes the organizational structure of the clinical part of the MR-linac consortium. Furthermore, it elucidates why collaboration on this large project is necessary, and how a central data registry program will be implemented.

Comprehensive MRI simulation methodology using a dedicated MRI scanner in radiation oncology for external beam radiation treatment planning.

PURPOSE: The use of magnetic resonance imaging (MRI) in radiation oncology is expanding rapidly, and more clinics are integrating MRI into their radiation therapy workflows. However, radiation therapy presents a new set of challenges and places additional constraints on MRI compared to diagnostic radiology that, if not properly addressed, can undermine the advantages MRI offers for radiation treatment planning (RTP). The authors introduce here strategies to manage several challenges of using MRI for virtual simulation in external beam RTP. METHODS: A total of 810 clinical MRI simulation exams were performed using a dedicated MRI scanner for external beam RTP of brain, breast, cervix, head and neck, liver, pancreas, prostate, and sarcoma cancers. Patients were imaged in treatment position using MRI-optimal immobilization devices. Radiofrequency (RF) coil configurations and scan protocols were optimized based on RTP constraints. Off-resonance and gradient nonlinearity-induced geometric distortions were minimized or corrected prior to using images for RTP. A multidisciplinary MRI simulation guide, along with window width and level presets, was created to standardize use of MR images during RTP. A quality assurance program was implemented to maintain accuracy and repeatability of MRI simulation exams. RESULTS: The combination of a large bore scanner, high field strength, and circumferentially wrapped, flexible phased array RF receive coils permitted acquisition of thin slice images with high contrast-to-noise ratio (CNR) and image intensity uniformity, while simultaneously accommodating patient setup and immobilization devices. Postprocessing corrections and alternative acquisition methods were required to reduce or correct off-resonance and gradient nonlinearity induced geometric distortions. CONCLUSIONS: The methodology described herein contains practical strategies the authors have implemented through lessons learned performing clinical MRI simulation exams. In their experience, these strategies provide robust, high fidelity, high contrast MR images suitable for external beam RTP.

pH dependence of ferrous sorption onto two smectite clays.

This work examines the abilities of two smectite minerals (SWa-1 and Wyoming montmorillonite) to adsorb ferrous iron at concentrations from 0.037 mM (2 ppm) to 2.5 mM (240 ppm) over a range of pHs from 4.0 to 8.0. Both sorption isotherm and sorption edge data are presented. Ferrous sorption (Fe(aq)2+ = 0.1 mM) to both SWa-1 and Wyoming montmorillonite over the pH range 4.0-6.75 is relatively constant at approximately 1000 l kg(-1) for both minerals. Sorption in this pH range is attributed to the cation exchange capacity of the clay along the basal surfaces. At pH values above 6.75 the amount of ferrous iron sorbed increases dramatically. At pH 8, sorption (Fe(aq)+ = 0.1 mM) reaches 6600 l kg(-1) and 8000 l kg(-1) for Swa-1 and Wyoming montmorillonite respectively. This is attributed to the specific interaction between ferrous ions and surface sites along mineral edges. The overriding geochemical implication is that in reduced sediments containing more than a few percent clay, the pool of sorbed ferrous iron is vast. This pool of reduced iron is both redox labile and bio-available and is not readily indicated by simple measurement of dissolved Fe2+.

Effect of treatment modality on the hypothalamic-pituitary function of patients treated with radiation therapy for pituitary adenomas: hypothalamic dose and endocrine outcomes.

BACKGROUND: Both fractionated external beam radiotherapy and single fraction radiosurgery for pituitary adenomas are associated with the risk of hypothalamic-pituitary (HP) axis dysfunction. OBJECTIVE: To analyze the effect of treatment modality (Linac, TomoTherapy, or gamma knife) on hypothalamic dose and correlate these with HP-axis deficits after radiotherapy. METHODS: Radiation plans of patients treated post-operatively for pituitary adenomas using Linac-based 3D-conformal radiotherapy (CRT) (n = 11), TomoTherapy-based intensity modulated radiation therapy (IMRT) (n = 10), or gamma knife stereotactic radiosurgery (n = 12) were retrospectively reviewed. Dose to the hypothalamus was analyzed and post-radiotherapy hormone function including growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, and gonadotropins (follicle stimulating hormone/luteinizing hormone) were assessed. RESULTS: Post-radiation, 13 of 27 (48%) patients eligible for analysis developed at least one new hormone deficit, of which 8 of 11 (72%) occurred in the Linac group, 4 of 8 (50%) occurred in the TomoTherapy group, and 1 of 8 (12.5%) occurred in the gamma knife group. Compared with fractionated techniques, gamma knife showed improved hypothalamic sparing for DMax Hypo and V12Gy. For fractionated modalities, TomoTherapy showed improved dosimetric characteristics over Linac-based treatment with hypothalamic DMean (44.8 vs. 26.8 Gy p = 0.02), DMax (49.8 vs. 39.1 Gy p = 0.04), and V12Gy (100 vs. 76% p = 0.004). CONCLUSION: Maximal dosimetric avoidance of the hypothalamus was achieved using gamma knife-based radiosurgery followed by TomoTherapy-based IMRT, and Linac-based 3D conformal radiation therapy, respectively.

Prognostic value of H-MLH1 after adjusting for RPA class in GBM patients.

Repair of DNA adducts appears to be an important mechanism in chemotherapy responsiveness in glioblastoma multiforme (GBM). Meta-analyses have suggested that the addition of chemotherapy increases the percentage of long-term survivors. Because GBM is characterized by multiplicity of pathways that characterize growth and treatment resistance, we hypothesized probing a multiplicity of repair factors may be able to identify more than one prognostic factor that may be utilized in molecularly targeted therapy that might improve survival and QOL. Seven DNA repair factors showed statistical significance when added to the initial logistic model of RPA class on length of survival status. After adjusting for RPA class the only statistically significant result of the multivariable logistic regressions for these 7 DNA repair factors was that as hMLH1-MF1 increased, the odds of being a short-term survivor versus a long-term survivor decreased (OR: 0.913, 95 per cent CI: 0.838-0.995, p=0.0385), multivariable analysis showed no associations between survival status and MGMT and p53 status, and the only statistically significant prognostic DNA repair factor was human Mut L Homologue 1 (hMLH1).