Prevalence of preexisting articular bone pathology in patients with osteoarthritis screened for fasinumab clinical trials identified by X-ray or magnetic resonance imaging.

OBJECTIVE: To examine the prevalence of preexisting articular bone pathology in patients with hip or knee pain due to osteoarthritis (OA) screened for fasinumab clinical trials. METHOD: This post-hoc analysis included patients with OA screened for three phase 3 fasinumab studies (NCT02683239, NCT03161093, NCT03304379). During screening, participants who met other clinical inclusion/exclusion criteria underwent radiography of knees, hips, and shoulders. Those with Kellgren-Lawrence grade (KLG) ≥ 2 for index joint and without an exclusionary finding proceeded to magnetic resonance imaging (MRI) of index, contralateral, and KLG ≥ 3 joints. Exclusionary findings included bone fragmentation/collapse, bone loss/resorption, osteonecrosis, and fracture, by either X-ray or MRI. Participants with extensive subchondral cysts were also excluded. Prevalence of abnormalities on radiographs and MRIs are reported. RESULTS: Of 27,633 participants screened, 21,997 proceeded to imaging. Of these, 1203 (5.5%) were excluded due to the presence of ≥ 1 joint with severe articular bone pathology (X-ray or MRI): bone fragmentation/collapse (2.60%), subchondral insufficiency fracture (SIF; 1.67%), osteonecrosis (1.11%), and significant bone loss (0.32%). Additionally, 3.13% screen-failed due to extensive subchondral cysts. More than half of the exclusions due to bone fragmentation/collapse (386/572), osteonecrosis (141/245) and significant bone loss (59/71), and approximately one third of SIF (133/367) and extensive subchondral cysts (229/689) were evident on X-rays. CONCLUSIONS: Approximately one in 20 participants with OA who met the clinical screening criteria for fasinumab phase 3 trials were later excluded due to preexisting severe articular bone pathology findings by X-ray or MRI.

Enhanced vertebra to disk ratio as a new semi-quantitative imaging biomarker for Gaucher disease patients.

PURPOSE: Gaucher disease (GD) is an inherited lysosomal storage disorder. The Vertebral Disk Ratio (VDR) is a semi-quantitative imaging biomarker designed to diagnose and monitor GD. Computed from standard T1 MRI images, the VDR is derived from 2D segmentations. This study aimed to evaluate the 3D version of VDR, namely eVDR, and analyze the performances of two eVDR-derived response criteria for GD patients. METHODS: Three datasets were used: 8 longitudinal GD patients, 13 non-GD patients, and 2 longitudinal GD patients with known Bone Marrow Burden (BMB) scores. Two eVDR-derived response criteria were tested: 1) a parametric version (PeVDR) averaging all eVDR measures recorded for the 5 lumbar vertebrae; and 2) a non-parametric version (NPeVDR), considering all eVDR measures as independent and evaluating therapeutic response in a paired fashion. Analyses included assessment of reader variability in eVDR (3D) versus VDR (2D) and comparison with BMB response criteria. RESULTS: The repeatability of eVDR (3D) versus VDR (2D) demonstrated no difference in mean values but a lower variance (p < 0.004). The PeVDR intra-reader variability had a standard deviation < 0.1 with a coefficient of variation < 5%; the inter-reader variability featured a Limit of Agreement < 5% and a Bias < 3%. Observational comparison of eVDR and BMB scoring and sensitivity indicated a correlation between PeVDR and BMB, with an improved sensitivity with the NPeVDR version. CONCLUSIONS: Based on a standard MRI sequence, the eVDR imaging biomarker and its derived response criteria improved GD assessments and could help assessing other bone marrow diseases.

Comparison of central and local serial CT assessments of metastatic renal cell carcinoma patients in a clinical phase IIB study.

Background Clinical oncological studies attempt to improve precision of data by central radiological assessments. However, it is unclear, to which extent local and central assessments diverge. Purpose To quantify inter-reader variability and the deviation of local from central radiological assessments of computed tomography (CT) scans. Material and Methods This was a sub-study of a randomized clinical phase IIb trial in metastatic renal cell carcinoma (RCC), comparing first-line sorafenib with interferon-alpha-2a (IFN-α-2a). It analyzed agreements of local with central RECIST CT assessments by Cohen's kappa (κ), symmetry tests, deviations in waterfall plots, Bland-Altman plots, and parametric survival analyses. Results The concordance between local and central radiologic review was quantified by κ = 0.53. While local assessment yielded progressive disease (PD) in 18.6%, central assessment classified 22.5% of patient time points as PD exhibiting only a partial overlap with the 18.6% The tumor shrinkage rates in waterfall plots were 68.1% in local and 55.8% in central review (57.8% and 59% by Reader 1 and Reader 2). Bland-Altman plots identified a systematic shift of tumor change rates by -7.5% in local compared to central assessments, that may reflect a systematic tendency of more favorable results in local assessments. The discordance between local and central review was reflected by a time to progression (TTP) hazard ratio (HR) of 1.73 ( P = 0.0003). Conclusion These data suggest that central radiologic review may reduce technical measurement variability in clinical trials, which should be scrutinized in future studies compared to a volumetric reference.

High Kellgren-Lawrence Grade and Bone Marrow Lesions Predict Worsening Rates of Radiographic Joint Space Narrowing; The SEKOIA Study.

OBJECTIVE: Determinants of radiographic progression in osteoarthritis (OA) are poorly understood. We investigated which features on baseline magnetic resonance imaging (MRI) acted as predictors of change in joint space width (JSW). METHODS: A total of 559 men and women over the age of 50 years with clinical knee OA [Kellgren-Lawrence (KL) grade 2-3] were recruited to the placebo arm of the SEKOIA study (98 centers; 18 countries). Minimal tibiofemoral joint space and KL grade on plain radiograph of the knee were assessed at baseline and at yearly followup up to 3 years. In a subset, serial knee MRI examinations were performed. Individuals with a bone marrow lesion (BML) ≥ grade 2 at the tibiofemoral joint at baseline were classified as BML-positive. Relationships between change in JSW and risk factors were assessed using linear regression. RESULTS: The mean age of study participants was 62.8 (SD 7.5) years and 73% were female; 38.6% had BML. Mean baseline JSW was 3.65 mm. This reduced by 0.18 (0.30) mm/year in men and 0.13 (0.23) mm/year in women. Those with BML had a significantly higher rate of annualized change in JSW; this relationship remained robust after adjustment for age, sex, and baseline KL grade [ß = -0.10 (95% CI -0.18, -0.02) mm/yr]. Age, sex, baseline KL grade, and other MRI findings did not influence the rate of change in JSW. CONCLUSION: The rate of change in JSW was similar in men and women. BML on knee MRI predicted the rate of radiographic change in JSW. This relationship was independent of age, sex, and baseline KL grade.

Comparison of volumetric and linear serial CT assessments of lung metastases in renal cell carcinoma patients in a clinical phase IIB study.

RATIONALE AND OBJECTIVES: Accuracy of radiologic assessment may have a crucial impact on clinical studies and therapeutic decisions. We compared the variability of a central radiologic assessment (RECIST) and computer-aided volume-based assessment of lung lesions in patients with metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS: The investigation was prospectively planned as a substudy of a clinical randomized phase IIB therapeutic trial in patients with RCC. Starting with the manual study diameter (SDM) of the central readers using RECIST in the clinical study, we performed computer-aided volume measurements. We compared SDM to an automated RECIST diameter (aRDM) and the diameter of a volume-equivalent sphere (effective diameter [EDM]), both for the individual size measurements and for the change rate (CR) between consecutive time points. One hundred thirty diameter pairs of 30 lung lesions from 14 patients were evaluable, forming 55 change pairs over two consecutive time points each. RESULTS: The SDMs of two different readers showed a correlation of 95.6%, whereas the EDMs exhibited an excellent correlation of 99.4%. Evaluation of CRs showed an SDM-CR correlation of 63.9%, which is substantially weaker than the EDM-CR correlation of 87.6%. The variability of SDM-CR is characterized by a median absolute difference of 11.4% points versus the significantly lower 1.8% points EDM-CRs variability (aRDM: 3.2% points). The limits of agreement between readers suggest that an EDM change of 10% or 1 mm can already be significant. CONCLUSIONS: Computer-aided volume-based assessments result in markedly reduced variability of parameters describing size and change, which may offer an advantage of earlier response evaluations and treatment decisions for patients.

Gastroenteropancreatic neuroendocrine tumors: multimodality imaging features with pathological correlation.

Neuroendocrine tumors of the gastrointestinal tract are rare entities. Functioning neuroendocrine tumors tend to present early because of hormone-induced clinical symptoms, but detection of the primary lesion may be difficult owing to their small size. Neuroendocrine tumors are typically hypervascular and show enhancement after contrast administration on computed tomography (CT) or magnetic resonance imaging (MRI). Large nonfunctioning tumors may be found in asymptomatic patients. In such cases, the synchronous presence of hypervascular hepatic metastases should be explored. This pictorial review illustrates imaging features of functioning and nonfunctioning neuroendocrine tumors arising in the gastrointestinal tract and the pancreas. Modalities included are CT, MRI, ultrasonography, and nuclear medicine. Characteristic histological specimens of these lesions are presented.

MRI features of cystic lesions around the knee.

Cystic lesions around the knee are a diverse group of entities, frequently encountered during routine MRI of the knee. These lesions range from benign cysts to complications of underlying diseases such as infection, arthritis, and malignancy. MRI is the technique of choice in characterizing lesions around the knee: to confirm the cystic nature of the lesion, to evaluate the anatomical relationship to the joint and surrounding tissues, and to identify associated intra-articular disorders. We will discuss the etiology, clinical presentation, MRI findings, and differential diagnosis of various cystic lesions around the knee including meniscal and popliteal (Baker's) cysts, intra-articular and extra-articular ganglia, intra-osseous cysts at the insertion of the cruciate ligaments and meniscotibial attachments, proximal tibiofibular joint cysts, degenerative cystic lesions (subchondral cyst), cystic lesions arising from the bursae (pes anserine, prepatellar, superficial and deep infrapatellar, iliotibial, tibial collateral ligament, and suprapatellar), and lesions that may mimic cysts around the knee including normal anatomical recesses. Clinicians must be aware about the MRI features and the differential diagnosis of cystic lesions around the knee to avoid misdiagnosis.

Multispectral analysis of bone lesions in the hands of patients with rheumatoid arthritis.

Quantitative measures of rheumatoid arthritis (RA) disease progression can provide valuable tools for evaluation of new treatments during clinical trials. In this study, a novel multispectral (MS) MRI analysis method is presented to quantify changes in bone lesion volume (DeltaBLV) in the hands of RA patients. Image registration and MS analysis were employed to identify MS tissue class transitions between two serial MRI exams. DeltaBLV was determined from MS class transitions between two time points. The following three classifiers were investigated: (a) multivariate Gaussian (MVG), (b) k-nearest neighbor (k-NN), and (c) K-means (KM). Unlike supervised classifiers (MVG, k-NN), KM, an unsupervised classifier, does not require labeled training data, resulting in potentially greater clinical utility. All MS estimates of DeltaBLV were linearly correlated (r(p)) with manual estimates. KM and k-NN estimates also exhibited a significant rank-order correlation (r(s)) with manual estimates. For KM, r(p) = 0.94 p < 0.0001, r(s) = 0.76 p = 0.002; for k-NN, r(p) = 0.86 p = 0.0001, r(s) = 0.69 p = 0.009; and for MVG, r(p) = 0.84 p = 0.0003, r(s) = 0.49 p = 0.09. Temporal classification rates were as follows: for KM, 90.1%; for MVG, 89.5%; and for k-NN, 86.7%. KM matched the performance of k-NN, offering strong potential for use in multicenter clinical trials. This study demonstrates that MS tissue class transitions provide a quantitative measure of DeltaBLV.

Use of the modified three-point Dixon technique in obtaining T1-weighted contrast-enhanced fat-saturated images on an open magnet.

The purpose of this study was to investigate the modified three-point Dixon technique as a method for obtaining fat-saturated T1-weighted sequences before and after intravenous gadolinium administration using an open MR imaging scanner. A preliminary experiment using an oil/gadolinium phantom was performed on a 0.35-T open magnet and an advanced 1.5-T unit. Fat saturation was achieved at 1.5 T using a frequency selective presaturation technique and a modified three-point Dixon technique on the low-field scanner. The modified three-point Dixon sequence was then evaluated in ten patients undergoing MRI examinations of the spine with gadolinium enhancement to determine image characteristics and diagnostic potential. The phantom study demonstrated a homogenous suppression of signal from oil and a good distinction between fat and a gadolinium chelate on the 0.35-T unit comparable to that on the 1.5-T scanner. By applying the modified three-point Dixon technique on the open-magnet, the distinction between fat and gadolinium dimeglumine was rated as very good in 139 and good in 17 axial slices in a total of 156 images. No image was rated as difficult or not possible. Motion artifacts that hampered the reading were detected in the lower cervical spine due to respiratory movement in four (3% of all) images. The modified three-point Dixon technique provides the combination of gadolinium enhancement with fat saturation on an open magnet. Early clinical applications appear promising.

Rheumatoid arthritis of the hand and wrist: comparison of three imaging techniques.

OBJECTIVE: The purpose of this study was to compare the relative results from conventional high-field-strength 1.5-T MRI, 0.2-T low-field-strength dedicated extremity MRI, and radiography to detect and grade bone erosions, joint-space narrowing, and synovitis in the hands and wrists of patients with rheumatoid arthritis. SUBJECTS AND METHODS: Eighteen patients with rheumatoid arthritis underwent conventional high-field-strength MRI, low-field-strength dedicated extremity MRI, and conventional radiography of both hands and wrists. Two independent reviewers searched for the presence and extent of bone erosions, joint-space narrowing, and synovitis. Bone erosions (E scores) and joint-space narrowing (J scores) were evaluated at 14 and 13 sites, respectively, on conventional high-field-strength MRI, low-field-strength dedicated extremity MRI, and radiography, using the Sharp-Genant scoring system. Synovitis (S scores) were evaluated at 13 sites on conventional high-field-strength MRI and low-field-strength dedicated extremity MRI. RESULTS: For the detection of bone erosions, we found no significant difference (p = 0.71) between conventional high-field-strength MRI (mean +/- SD E score, 27.5 +/- 9.8) and low-field-strength dedicated extremity MRI (28.8 +/- 10.0), but a significant difference (p < 0.001) appeared between MRI and radiography (13.1 +/- 8.3). J scores derived from MRI (conventional high-field-strength MRI, 15.2 +/- 8.3; low-field-strength dedicated extremity MRI, 14.5 +/- 10.4) were higher than those derived from radiography (12.7 +/- 9.6), although the difference was not significant (p = 0.70). Conventional high-field-strength MRI (S score, 35.1 +/- 8.6) and low-field-strength dedicated extremity MRI (30.8 +/- 10.2) were equivalent (p = 0.14) for the evaluation of synovitis. The interobserver agreement for MRI scores was good to excellent (intraclass correlation coefficients, 0.83-0.94). CONCLUSION: Conventional high-field-strength MRI and low-field-strength dedicated extremity MRI showed similar results in terms of cross-sectional grading of bone erosions, joint-space narrowing, and synovitis in the hands and wrists of patients with rheumatoid arthritis.

Measurement of changes in trabecular bone at fracture sites using X-ray CT and automated image registration and processing.

Currently, there are no in vivo techniques for quantifying healing within fractures involving mainly trabecular bone. Methods for quantitatively assessing healing would aid the investigation of new treatment regimes, and might also be useful for predicting whether a patient may be undergoing delayed union. Using CT and automated image registration, we have developed an image processing technique for measuring changes in CT image intensity at fracture sites. The technique focuses on quantifying the formation of new mineralised tissue within fracture gaps, while ignoring loss of bone mineral due to disuse osteoporosis. Seven patients with fractures of the distal radius were examined for 12 weeks following fracture. To assess reproducibility of measurements of change in CT intensity at the fracture line, measurements were performed on two separate occasions, by each of two independent readers. Reproducibility was compared to rates of change over time, to determine detectable differences in individual progression. Scans were scored qualitatively for features of healing and scores compared to the quantitative measurements. The mean (SD) change in CT intensity was +128 (65) Hounsfield Units (HU) over the 12 week follow-up. Inter- and intra-observer reproducibilities were both similar (+/- 17 HU), 1/7 of the change seen during the study. In this small patient cohort, a significant increase in CT intensity was seen 2 weeks post-fracture. Large early increases in CT intensity were associated with early visual appearance of sclerosis and blurring of the fracture line. In this preliminary, prospective study, we have developed a reproducible quantitative technique for measuring changes in CT intensity of trabecular bone at the fracture line in the distal radius. Further work is required to determine whether it can be used to identify, or monitor patients who are undergoing delayed fracture repair. The technique appears sensitive for measuring changes immediately post-fracture, and could have a role in examining potential effects of new therapies in patient cohorts.

Use of multispectral magnetic resonance imaging analysis to quantify erosive changes in the hands of patients with rheumatoid arthritis: short-term and long-term longitudinal studies.

OBJECTIVE: Magnetic resonance imaging (MRI) has been shown to be more sensitive than radiography for detecting bone erosions in rheumatoid arthritis (RA). Semiquantitative scoring based on visual image assessment has been introduced. However, there is considerable interest in true quantitative measures, particularly in the context of clinical trials designed to show differences between treatment groups. This study was undertaken to investigate the use of a new quantitative approach, multispectral (MS) image analysis, for assessing erosive change. METHODS: T1-weighted spin-echo (SE) and fat-suppressed gradient-echo (GE) sequences of metacarpophalangeal joints of the dominant hand were acquired at various time points throughout a 2-year period. MS analysis was applied to all images, resulting in segmentation into a generalized bone and a soft tissue class. Voxel changes from one to the other class identified apparent bone lesion volume change (Delta BLV). MR images were also visually scored for erosions (E score). All analyses were performed separately, on a per-joint basis, for short-term and long-term data sets. RESULTS: Analysis of variance with adjustment for individual effect revealed similar results in the short-term and the long-term studies, using either GE or SE images for visual assessment. Patients with an increase in E score on visual assessment had a significantly higher Delta BLV than those without. CONCLUSION: Temporal MS analysis of MRIs can be used to detect and quantify erosive changes in RA. This semiautomated method may be useful for demonstrating differences between treatment groups in clinical trials.

MR findings in knee osteoarthritis.

Knee osteoarthritis (OA) is a leading cause of disability. Recent advances in drug discovery techniques and improvements in understanding the pathophysiology of osteoarthritic disorders have resulted in an unprecedented number of new therapeutic agents. Of all imaging modalities, radiography has been the most widely used for the diagnosis and management of the progression of knee OA. Magnetic resonance imaging is a relatively recent technique and its applications to osteoarthritis have been limited. Compared with conventional radiography, MR imaging offers unparalleled discrimination among articular soft tissues by directly visualizing all components of the knee joint simultaneously and therefore allowing the knee joint to be evaluated as a whole organ. In this article we present the MR findings in knee OA including cartilage abnormalities, osteophytes, bone edema, subarticular cysts, bone attrition, meniscal tears, ligament abnormalities, synovial thickening, joint effusion, intra-articular loose bodies, and periarticular cysts.