Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease.

In Gaucher disease, several macrophage-specific biomarkers have been validated for use in the clinic. However, Gaucher disease is more complex involving system-wide pathophysiology beyond the macrophage, and based on gene array analysis in our Gaucher disease mouse model and other emerging pathophysiologic insights, we evaluated serum levels of cathepsins D and S, YKL-40 and progranulin in Gaucher disease patients. We assessed their biomarker potential in Gaucher disease and compared them to established Gaucher disease biomarkers, chitotriosidase, chemokine ligand 18 (CCL18), and other indicators of disease severity and response to therapy. Mean YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls; in contrast, mean progranulin levels were lower in Gaucher disease patients compared to healthy controls. Enzyme replacement therapy resulted in a significant reversal of elevated cathepsin D and S but there was no change in progranulin and YKL-40 levels. Patients with persistent splenomegaly after long-term enzyme replacement therapy had significantly higher serum YKL-40 than patients with smaller spleens (63.0 ±â€¯6.4 ng/ml vs. 46.4 ±â€¯4.3 ng/ml, p = .03). Serum YKL-40 levels were higher in subjects with severe bone involvement (Hermann Score 3 to 5) compared to those with milder bone involvement (Hermann Score 1 to 2) (70.1 ±â€¯4.3 ng/ml vs. 48.1 ±â€¯3.7 ng/ml, p = .0002). YKL-40 was only weakly associated with chitotriosidase (r = 0.2, p = .008) and CCL18 (r = 0.3, p = .0004), and cathepsin S was moderately associated with chitotriosidase (r = 0.4, p = .01) and CCL18 (r = 0.6, p < .0001). Receiver operating curves for progranulin and YKL-40 demonstrated areas under the curves of 0.80 and 0.70, respectively. In conclusion, while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations. These findings, including markedly low progranulin levels that do not change upon enzyme replacement therapy, are intriguing to prompt further investigations to decipher their role in pathophysiology and relevance to diverse phenotypes of Gaucher disease.

Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease.

In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms.

Glucosylsphingosine is a key biomarker of Gaucher disease.

Gaucher disease (GD) involves the accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of plasma LGL1 were assessed by Pearson's correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs. Eliglustat Tartrate SRT (ELI-SRT). Plasma Lyso-GL1 levels in healthy controls averaged 1.5 ng/ml (1.3-1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4-216.5) and imiglucerase ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2-129.4) (P < 0.001). Lyso-GL1 correlated with chitotriosidase (r = 0.59 P < 0.001), CCL18 (r = 0.62 P <0.001), hepatomegaly (r = 0.28 P < 0.001), splenomegaly (r = 0.27 P = 0.003), splenectomy (P = 0.01) and treatment mode (P < 0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (P < 0.001), splenectomy (P = 0.02), Chitotriosidase (P < 0.001) and CCL18 levels (P = 0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136-90.3 ng/ml P < 0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT. Am. J. Hematol. 91:1082-1089, 2016. © 2016 Wiley Periodicals, Inc.

3D-FSE Isotropic MRI of the Lumbar Spine: Novel Application of an Existing Technology.

STUDY DESIGN: Retrospective diagnostic trial. OBJECTIVE: To determine the diagnostic performance of 3-dimensional isotropic fast/turbo spin-echo (3D-TSE) in routine lumbar spine magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Conventional 2-dimensional fast spin-echo (2D-FSE) MRI requires independent acquisition of each desired imaging plane. This is time consuming and potentially problematic in spine imaging, as the plane of interest varies along the vertical axis due to lordosis, kyphosis, or possible deformity. 3D-TSE provides the capability to acquire volumetric data sets that can be dynamically reformatted to create images in any desired plane. METHODS: Eighty subjects scheduled for routine lumbar MRI were included in a retrospective trial. Each subject underwent both 3D-TSE and conventional 2D-FSE axial and sagittal MRI sequences. For each subject, the 3D-TSE and 2D-FSE sequences were separately evaluated (minimum 4 wk apart) in a randomized order and read independently by 4 reviewers. Images were evaluated using specific criteria for stenosis, herniation, and degenerative changes. RESULTS: The intermethod reliability for the 4 reviewers was 85.3%. Modified intermethod reliability analysis, disregarding disagreements between the lowest 2 descriptors for appropriate criteria (equivalent to "none" and "mild"), revealed average overall agreement of 94.6%. Using the above, modified criteria, interobserver variability for 3D-TSE was 89.1% and 88.3% for 2D-FSE (P=0.05), and intraobserver variability for 3D-TSE was 87.2% and 82.0% for 2D-FSE (P<0.01). The intermethod agreement between 3D-TSE and 2D-FSE was statistically noninferior to intraobserver 2D-FSE variability (P<0.01). CONCLUSIONS: This systematic evaluation showed that there is a very high degree of agreement between diagnostic findings assessed on 3D-TSE and conventional 2D-FSE sequences. Overall, intermethod agreement was statistically noninferior to the intraobserver agreement between repeated 2D-FSE evaluations. Overall, this study shows that 3D-TSE performs equivalently, if not superiorly to 2D-FSE sequences. Reviewers found particular utility for the ability to manipulate image planes with the 3D-TSE if there was greater pathology or anatomic variation.

Osteonecrosis in Gaucher disease in the era of multiple therapies: Biomarker set for risk stratification from a tertiary referral center.

Background: A salutary effect of treatments for Gaucher disease (GD) has been a reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT) , and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity, or anti-drug antibodies. Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center. Methods: Longitudinal follow-ups of 155 GD patients between 2001 and 2021 were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment. Results: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI, 1.5-67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI, 1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001). Conclusions: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found that increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization. Funding: LSD Training Fellowship from Sanofi to MB.

Development of a computed tomography-based scoring system for necrotizing soft-tissue infections.

BACKGROUND: Necrotizing soft-tissue infections (NSTIs) are associated with significant morbidity and mortality, but a definitive nonsurgical diagnostic test remains elusive. Despite the widespread use of computed tomography (CT) as a diagnostic adjunct, there is little data that definitively correlate CT findings with the presence of NSTI. Our goal was the development of a CT-based scoring system to discriminate non-NSTI from NSTI. METHODS: Patients older than 17 years undergoing CT for evaluation of soft-tissue infection at a tertiary care medical center over a 10-year period (2000-2009) were included. Abstracted data included comorbidities and social history, physical examination, laboratory findings, and operative and pathologic findings. NSTI was defined as soft-tissue necrosis in the dictated operative note or the accompanying pathology report. CT scans were reviewed by a radiologist blinded to clinical and laboratory data. A scoring system was developed and the area under the receiver operating characteristic curve was calculated. RESULTS: During the study period, 305 patients underwent CT scanning (57% men; mean age, 47.4 years). Forty-four patients (14.4%) evaluated had an NSTI. A scoring system was retrospectively developed (table). A score >6 points was 86.3% sensitive and 91.5% specific for the diagnosis of NSTI (positive predictive value, 63.3%; negative predictive value, 85.5%). The area under the receiver operating characteristic curve was 0.928 (95% confidence interval, 0.893-0.964). The mean score of the non-NSTI group was 2.74. CONCLUSIONS: We have developed a CT scoring system that is both sensitive and specific for the diagnosis of NSTIs. This system may allow clinicians to more accurately diagnose NSTIs. Prospective validation of this scoring system is planned.

Comparison of agreement of cervical spine degenerative pathology findings in magnetic resonance imaging studies.

BACKGROUND CONTEXT: Magnetic resonance imaging (MRI) is often used in the evaluation of degenerative conditions of the cervical spine. However, the agreement of interpreting and reporting varying degenerative findings on cervical MRI has not been well assessed. PURPOSE: This study aimed to compare the inter-rater and intra-rater agreement of MRI findings between common degenerative findings of the cervical spine. STUDY DESIGN: A retrospective diagnostic study was used as study design. PATIENT SAMPLE: The sample consisted of 48 patients who underwent routine cervical spine MRI at our institution between January 2011 and June 2012. OUTCOME MEASURES: Reviewers evaluated each MRI study at each vertebral level for disc hydration, disc space height, central stenosis, foraminal stenosis, end plate changes, spondylolisthesis, and cord signal change. METHODS: A panel of two orthopedic spine surgeons and four musculoskeletal radiologists independently reviewed 48 sets of T2-weighted axial and sagittal MRI sequences for a series of preselected criteria, and their findings were compared with those of the other panelists to determine inter-rater agreement. Each panelist also re-reviewed the first 10 studies to determine intra-rater agreement. Absolute inter-rater and intra-rater agreements were then calculated and compared for different findings. A modified analysis ignored disagreements between the least severe grades of findings to determine the inter-rater and intra-rater agreements of the most clinically important severity grades. RESULTS: Absolute inter-rater agreement ranged from 54.6% to 95.0%. Disc hydration (54.6%), central stenosis (72.7%), and foraminal stenosis (73.1%) demonstrated the lowest inter-rater agreement, whereas spondylolisthesis (95.0%) and cord signal change (92.9%) demonstrated the highest agreement. The modified analysis found better inter-rater agreement, ranging from 80.9% to 95.0%. Absolute intra-rater agreement ranged from 74.2% to 94.7%. The modified analysis again found better agreement, ranging from 85.0% to 94.7%. As would be expected, overall intra-rater agreement (81.6%, 95% CI 78.9%-84.3%) was higher than inter-rater agreement (75.7%, 95% CI 74.4%-77.0%). The clinical specialty of the reviewer had no significant impact on inter- or intra-rater agreement. CONCLUSIONS: MRI findings play an important role in the management of patients with cervical spine conditions. For this reason, consistent descriptions of these findings are essential and physicians should be aware of the relative reliability of these findings. This systematic study developed standardized grading criteria and nomenclature for common clinically significant MRI findings in the cervical spine. Even in this optimized research setting, we found significant ranges in agreement across these MRI findings. In the clinical setting, inter- and intra-rater agreements may be lower, and the range of agreements between findings may be greater. Physicians should be aware of inconsistencies inherent in the interpretation of cervical MRI findings and should be aware that some findings demonstrate lower agreement than others.

Three-Dimensional Isotropic MRI of the Cervical Spine: A Diagnostic Comparison With Conventional MRI.

STUDY DESIGN: Retrospective diagnostic trial. OBJECTIVE: To determine the diagnostic performance of 3-dimensional turbo spin-echo (3D-TSE) isotropic magnetic resonance imaging (MRI) in the assessment of cervical spine pathology. SUMMARY OF BACKGROUND DATA: MRI is the imaging modality of choice for many cervical spine pathologies. However, axial imaging may be suboptimal if the image plane is oriented differently than the plane of interest, due to lordosis, kyphosis, or deformity. 3D-TSE isotropic MRI is a promising novel technology that bypasses this limitation by enabling dynamic image reformation in any desired orientation. METHODS: Forty-eight patients who underwent 3D-TSE and conventional 2-dimensional fast spin-echo (2D-FSE) T2-weighted cervical spine MRI at our institution were randomly selected. 3D-TSE and 2D-FSE sequences from each subject were independently evaluated by 2 orthopedic spine surgeons and 4 musculoskeletal radiologists. Images were assessed using specific pilot-tested criteria for stenosis, herniation, and degenerative changes. Intermethod, interrater, and intrarater agreements for 3D-TSE and 2D-FSE, and Fleiss κ coefficients were determined. RESULTS: The overall intermethod agreement was 80.7%. The interrater agreement was 75.9% for 3D-TSE and 75.7% for 2D-FSE (P=0.47). The intrarater agreement was 82.2% for 3D-TSE and 81.5% for 2D-FSE (P=0.71). Fleiss κ coefficients were 0.42 for 3D-TSE and 0.43 for 2D-FSE (P=0.62), indicating moderate interrater reliability. The intermethod agreement and the 2D-FSE intrarater agreement were statistically similar (P=0.49). CONCLUSIONS: There is a high degree of agreement between 3D-TSE and 2D-FSE MRI in assessing the cervical spine. The intermethod variability was statistically similar to the intrinsic intrarater variability of 2D-FSE MRI. This study demonstrates that 3D-TSE yields at least equivalent diagnostic information as conventional 2D-FSE in the cervical spine. In addition, reviewers noted subjective advantages of 3D-TSE image reprocessing, especially when evaluating greater pathology or deformity, with a simplified image acquisition process.

Interrater and intrarater agreements of magnetic resonance imaging findings in the lumbar spine: significant variability across degenerative conditions.

BACKGROUND CONTEXT: Magnetic resonance imaging (MRI) is frequently used in the evaluation of degenerative conditions in the lumbar spine. The relative interrater and intrarater agreements of MRI findings across different pathologic conditions are underexplored, as most studies are focused on specific findings. PURPOSE: The purpose of this study was to characterize the interrater and intrarater agreements of MRI findings used to assess the degenerative lumbar spine. STUDY DESIGN: A retrospective diagnostic study at a large academic medical center was undertaken with a panel of orthopedic surgeons and musculoskeletal radiologists to assess lumbar MRIs using standardized criteria. PATIENT SAMPLE: Seventy-five subjects who underwent routine lumbar spine MRI at our institution were included. OUTCOME MEASURES: Each MRI study was assessed for 10 lumbar degenerative findings using standardized criteria. Lumbar vertebral levels were assessed independently, where applicable, for a total of 52 data points collected per study. METHODS: T2-weighted axial and sagittal MRI sequences were presented in random order to the four reviewers (two orthopedic spine surgeons and two musculoskeletal radiologists) independently to determine interrater agreement. The first 10 studies were reevaluated at the end to determine intrarater agreement. Images were assessed using standardized and pilot-tested criteria to assess disc degeneration, stenosis, and other degenerative changes. Interrater and intrarater absolute percent agreements were calculated. To highlight the most clinically important MRI disagreements, a modified agreement analysis was also performed (in which disagreements between the lowest two severity grades for applicable conditions were ignored). Fleiss kappa coefficients for interrater agreement were determined. RESULTS: The overall absolute and modified interrater agreements were 76.9% and 93.5%, respectively. The absolute and modified intrarater agreements were 81.3% and 92.7%, respectively. Average Fleiss kappa coefficient was 0.431, suggesting moderate overall agreement. However, when stratified by condition, absolute interrater agreement ranged from 65.1% to 92.0%. Disc hydration, disc space height, and bone marrow changes exhibited the lowest absolute interrater agreements. The absolute intrarater agreement had a narrower range, from 74.5% to 91.5%. Fleiss kappa coefficients ranged from fair-to-substantial agreement (0.282-0.618). CONCLUSIONS: Even in a study using standardized evaluation criteria, there was significant variability in the interrater and intrarater agreements of MRI in assessing different degenerative conditions of the lumbar spine. Clinicians should be aware of the condition-specific diagnostic limitations of MRI interpretation.

Medical students' preferences in radiology education a comparison between the Socratic and didactic methods utilizing powerpoint features in radiology education.

RATIONALE AND OBJECTIVES: The Socratic method has long been a traditional teaching method in medicine and law. It is currently accepted as the standard of teaching in clinical wards, while the didactic teaching method is widely used during the first 2 years of medical school. There are arguments in support of both styles of teaching. MATERIALS AND METHODS: After attending a radiology conference demonstrating different teaching methods, third-year and fourth-year medical students were invited to participate in an online anonymous survey. RESULTS: Of the 74 students who responded, 72% preferred to learn radiology in an active context. They preferred being given adequate time to find abnormalities on images, with feedback afterward from instructors, and they thought the best approach was a volunteer-based system of answering questions using the Socratic method in the small group. They desired to be asked questions in a way that was constructive and not belittling, to realize their knowledge deficits and to have daily pressure to come prepared. The respondents thought that pimping was an effective teaching tool, supporting previous studies. CONCLUSIONS: When teaching radiology, instructors should use the Socratic method to a greater extent. Combining Socratic teaching with gentle questioning by an instructor through the use of PowerPoint is a preferred method among medical students. This information is useful to improve medical education in the future, especially in radiology education.

Imaging of sports-related hip and groin injuries.

A normally functioning hip joint is imperative for athletes who use their lower extremities with running, jumping, or kicking activities. Sports-related injuries of the hip and groin are far less frequent than injuries to the more distal aspect of the extremity, accounting for less than 10% of lower extremity injuries. Despite the lower incidence, hip and groin injuries can lead to significant clinical and diagnostic challenges related to the complex anatomy and biomechanical considerations of this region. Loads up to 8 times normal body weight have been documented in the joint in common daily activities, such as jogging, with significantly greater force expected during competitive athletics. Additionally, treatment for hip and groin injuries can obviate the participation of medical and surgical specialties, with a multidisciplinary approach frequently required. Delay in diagnosis and triage of these injuries may cause loss of time from competition and, potentially, early onset of degenerative changes. Magnetic resonance imaging (MRI) of the hip has proven to be the gold standard for the diagnosis of sports-related hip and groin injuries in the setting of negative radiographs. With its exquisite soft tissue contrast, multiplanar capabilities, and lack of ionizing radiation, MRI is unmatched in the noninvasive diagnosis of intra-articular and extra-articular pathology, as well as intraosseous processes. This review focuses on MRI of common athletic injuries of the hip and groin, including acetabular labral tears, femoral acetabular impingement syndrome, muscle injuries around the hip and groin (including athletic pubalgia), and athletic osseous injuries.