Expanding the molecular landscape of undifferentiated sarcomas of bone with a novel EWSR1-SSX3 gene fusion.

Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non-specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34-year-old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break-apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.

Prevalence of sarcopenia after remission of hypercortisolism and its impact on HRQoL.

BACKGROUND: Cushing's syndrome (CS) is associated with skeletal muscle structural and functional impairment which may persist long-term despite surgical removal of the source of cortisol excess. Prevalence of sarcopenia and its impact on Health-Related-Quality of Life (HRQoL) in 'cured' CS is not known. There is a need to identify easy biomarkers to help the clinicians recognise patients at elevated risk of suffering sustained muscle function. PATIENTS AND METHODS: We studied 36 women with CS in remission, and 36 controls matched for age, body mass index, menopausal status, and level of physical activity. We analysed the skeletal muscle mass using dual-energy X-ray absorptiometry, muscle fat fraction using two-point Dixon magnetic resonance imaging and muscle performance and strength using the following tests: hand grip strength, gait speed, timed up and go and 30-s chair stand. We assessed HRQoL with the following questionnaires: SarQoL, CushingQoL, SF-36. We calculated the sarcopenia index (SI; serum creatinine/serum cystatin C × 100). RESULTS: Prevalence of sarcopenia, according to the European Working Group on Sarcopenia in Older People (EWGSOP), was greater in CS as compared with controls (19% vs. 3%; p < .05). Patients with sarcopenia had a lower SarQoL score than those without sarcopenia (61 ± 17 vs. 75 ± 14; p < .05), and scored worse on the items pain, easy bruising and worries on physical appearance (p < .05 for all comparisons) of the CushingQoL questionnaire. Patients with sarcopenia had poorer physical functioning on SF-36 than those without sarcopenia (60 ± 23 vs. 85 ± 15; p < .01). SI was lower in patients with sarcopenia than those without (71 ± 3 vs. 77 ± 2; p = .032), and was associated with intramuscular fatty infiltration, worse performance on the 30-s chair stand test, slower gait speed, and worse muscle weakness-related HRQoL, as measured using the SarQoL questionnaire (p < .05). The optimised cut-off value for the SI ratio to diagnose sarcopenia was 72, which yielded a sensitivity of 73% and a specificity of 90%. CONCLUSIONS: Sarcopenia is common in patients with CS in long-term remission, and associated with impaired quality of life. The SI is a potential biomarker allowing clinicians to identify patients at high risk of muscle dysfunction.

A new computed tomography scoring system to assess osteochondral allograft transplantation for the knee: inter-observer and intra-observer agreement.

AIM OF THE STUDY: To describe a new semiquantitative computed tomography (CT) scoring system for multi-feature analysis of cartilage defect repair by osteochondral allografts for the knee and to assess its intra-observer and inter-observer variability. METHOD: A semiquantitative assessment CT osteochondral allograft (ACTOCA) scoring system was designed based on fresh osteochondral allograft transplantations for the knee. The system includes five CT features: density relative to host bone, integration at the host-graft junction, surface percentage with a discernible cleft at the host-graft junction, cystic changes, and intra-articular fragments. Inter-observer variability was calculated by three observers blinded to the patient's medical history and treatment. Intra-observer variability was also determined. RESULTS: Inter-observer agreement was moderate to substantial for all CT score components and intra-observer agreement was moderate to almost perfect for all CT score components (κ > 0.5, p < 0.05). CONCLUSION: The ACTOCA score is a reliable tool to evaluate integration of osteochondral allograft transplantations. It provides an accurate evaluation of bone changes and may help to standardize CT scan reports following osteochondral allograft transplantation for the knee.

Follow-up of late-onset Pompe disease patients with muscle magnetic resonance imaging reveals increase in fat replacement in skeletal muscles.

BACKGROUND: Late-onset Pompe disease (LOPD) is a genetic disorder characterized by progressive degeneration of the skeletal muscles produced by a deficiency of the enzyme acid alpha-glucosidase. Enzymatic replacement therapy with recombinant human alpha-glucosidase seems to reduce the progression of the disease; although at the moment, it is not completely clear to what extent. Quantitative muscle magnetic resonance imaging (qMRI) is a good biomarker for the follow-up of fat replacement in neuromuscular disorders. The aim of this study was to describe the changes observed in fat replacement in skeletal muscles using qMRI in a cohort of LOPD patients followed prospectively. METHODS: A total of 36 LOPD patients were seen once every year for 4 years. qMRI, several muscle function tests, spirometry, activities of daily living scales, and quality-of-life scales were performed on each visit. Muscle MRI consisted of two-point Dixon studies of the trunk and thigh muscles. Computer analysis of the images provided the percentage of muscle degenerated and replaced by fat in every muscle (known as fat fraction). Longitudinal analysis of the measures was performed using linear mixed models applying the Greenhouse-Geisser test. RESULTS: We detected a statistically significant and continuous increase in mean thigh fat fraction both in treated (+5.8% in 3 years) and in pre-symptomatic patients (+2.6% in 3years) (Greenhouse-Geisser p < 0.05). As an average, fat fraction increased by 1.9% per year in treated patients, compared with 0.8% in pre-symptomatic patients. Fat fraction significantly increased in every muscle of the thighs. We observed a significant correlation between changes observed in fat fraction in qMRI and changes observed in the results of the muscle function tests performed. Moreover, we identified that muscle performance and mean thigh fat fraction at baseline visit were independent parameters influencing fat fraction progression over 4 years (analysis of covariance, p < 0.05). CONCLUSIONS: Our study identifies that skeletal muscle fat fraction continues to increase in patients with LOPD despite the treatment with enzymatic replacement therapy. These results suggest that the process of muscle degeneration is not stopped by the treatment and could impact muscle function over the years. Hereby, we show that fat fraction along with muscle function tests can be considered a good outcome measures for clinical trials in LOPD patients.

Accuracy of a machine learning muscle MRI-based tool for the diagnosis of muscular dystrophies.

OBJECTIVE: Genetic diagnosis of muscular dystrophies (MDs) has classically been guided by clinical presentation, muscle biopsy, and muscle MRI data. Muscle MRI suggests diagnosis based on the pattern of muscle fatty replacement. However, patterns overlap between different disorders and knowledge about disease-specific patterns is limited. Our aim was to develop a software-based tool that can recognize muscle MRI patterns and thus aid diagnosis of MDs. METHODS: We collected 976 pelvic and lower limbs T1-weighted muscle MRIs from 10 different MDs. Fatty replacement was quantified using Mercuri score and files containing the numeric data were generated. Random forest supervised machine learning was applied to develop a model useful to identify the correct diagnosis. Two thousand different models were generated and the one with highest accuracy was selected. A new set of 20 MRIs was used to test the accuracy of the model, and the results were compared with diagnoses proposed by 4 specialists in the field. RESULTS: A total of 976 lower limbs MRIs from 10 different MDs were used. The best model obtained had 95.7% accuracy, with 92.1% sensitivity and 99.4% specificity. When compared with experts on the field, the diagnostic accuracy of the model generated was significantly higher in a new set of 20 MRIs. CONCLUSION: Machine learning can help doctors in the diagnosis of muscle dystrophies by analyzing patterns of muscle fatty replacement in muscle MRI. This tool can be helpful in daily clinics and in the interpretation of the results of next-generation sequencing tests. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a muscle MRI-based artificial intelligence tool accurately diagnoses muscular dystrophies.

Acetabular overcoverage in the horizontal plane: an underdiagnosed trigger of early hip arthritis. A CT scan study in young adults.

INTRODUCTION: Acetabular overcoverage promotes hip osteoarthritis causing a pincer-type femoroacetabular impingement. Acetabular coverage in the horizontal plane is usually poorly defined in imaging studies and may be misdiagnosed. The goal of this study was to analyze the role of acetabular overcoverage measured in the frontal plane and in the horizontal plane by CT scan and to determine its relationship with other anatomic features in the onset of hip arthritis in young adults. MATERIALS AND METHODS: We compared prospectively CT scans from two groups of adults of 55 years or younger: the patient group (n = 30) consisted of subjects with diagnosis of early hip arthritis (Tönnis Grade I or II) and the control group (n = 31) consisted of subjects with healthy hips. Two independent observers analyzed centre edge angle (CEA), acetabular anteversion angle (AAA), anterior sector acetabular angle (AASA), posterior sector acetabular angle (PASA), horizontal acetabular sector angle (HASA), femoral anteversion angle (FAVA), alpha angle (AA), and Mckibbin Instability Index (MI). RESULTS: Angles measuring the acetabular coverage on the horizontal plane (AASA, PASA and, HASA) were significantly higher in the patient group (p < 0.001, p = 0.03 and p < 0.001, respectively). Pearson's correlation coefficient showed a positive correlation between CEA and HASA in patients (r = 0.628) and in controls (r = 0.660). However, a high CEA (> 35º) was strongly associated with a high HASA (> 160º) in patients (p = 0.024) but not in controls (p = 0.21), suggesting that pincer should be simultaneously present in the horizontal and frontal plane to trigger hip degeneration. No significant association was detected between a high alpha angle (> 60º) and a high CEA (> 35º suggesting that a mixed pincer-cam aetiology was not prevalent in our series. Multivariate regression analysis showed the most significant predictors of degenerative joint disease were HASA (p = 0.008), AA (p = 0.048) and ASAA (p = 0.004). CONCLUSIONS: Acetabular overcoverage in the horizontal plane plays an important role in the onset of early hip arthritis. Considering that this condition is usually underdiagnosed, we suggest the anterior sector acetabular angle, the posterior sector acetabular angle, and the horizontal acetabular sector angles be routinely included in decision-making algorithms in hip conservative surgery to better define hips-at-risk of developing early hip osteoarthritis.

Bethlem Myopathy Phenotypes and Follow Up: Description of 8 Patients at the Mildest End of the Spectrum.

The classical phenotypes of collagen VI-associated myopathies are well described. Little is known, however, about the progression of patients at the mildest end of the clinical spectrum. In this report, we describe the clinical findings and the results of MRI, muscle biopsy, collagen VI expression in cultured skin fibroblasts and genetic tests of a series of patients with Bethlem myopathy. Our series highlights the existence of mild presentations of this disorder that progresses only slightly and can easily be overlooked. Analysis of the genetic studies suggests that missense mutations can be associated to a milder clinical presentation. Muscle MRI is extremely useful as it shows a pathognomonic pattern in most patients, especially those with some degree of muscle weakness.

Role of tumor-associated macrophages and angiogenesis in desmoid-type fibromatosis.

Desmoid-type fibromatosis (DTF) is a rare soft tissue tumor with fibroblastic features affecting two to four individuals per million population per year. Despite its bland microscopic appearance, the tumor behaves aggressively. Although unable to metastasize, DTF tends to recur and local recurrences in anatomically critical sites can be fatal. Tumor-associated macrophages (TAM) play an important role in tumor development through the activation of angiogenesis, particularly in cases of epithelial malignancies. The aim of this study is to investigate the prognostic significance of TAMs and the number of microvessels in DTF. Tumor macrophages (CD163), microvessel density (CD31), and beta-catenin were investigated on 69 primary DTF cases with follow-up information. CTNNB1 mutations were also studied. High density of tumor macrophages and high number of microvessels were associated with a significantly worse recurrence-free survival (P = 0.03 and P = 0.007, respectively). There was a significant correlation between microvessel density and CD163 macrophages (P = 0.02). Furthermore, combination of high number of tumor macrophages and high microvessel density greatly improved the statistical significance (P = 0.000005). Macrophages and microvessels may play an important role in the biologic behavior of DTF. This finding could help in the clinical management of patients with DTF.

Meningioma of the scapula.

Meningiomas account for approximately 15% of all intracranial tumors and are the most common non-glial primary tumors of the central nervous system. Most meningiomas are benign neoplasms with characteristic imaging features. Primary extradural meningiomas account for only 1-2% of all meningiomas. They must be differentiated from intradural meningiomas with secondary extradural extension and/or metastases. The vast majority of extradural meningiomas are found in the skull or in the head and neck region. We report on an extremely rare case of primary extradural meningioma that was located in the scapula. The lesion was resected. Radiographic findings and pathologic features are discussed. To the best of our knowledge, this form of presentation of an extradural meningioma has not been previously described.

Focal myositis of the thigh: unusual MR pattern.

Focal myositis is a commonly referenced, infrequently reported and poorly documented benign inflammatory pseudotumor which may be misdiagnosed clinically as a malignant tumor. We report the clinicopathologic features and magnetic resonance imaging findings in a case of focal myositis in the thigh of a 55-year-old woman. A different radiologic presentation of this disorder is described. The gross appearance of the lesion, previously undescribed, appears to be rather specific for such a pseudoneoplastic disorder, and correlates very well with the magnetic resonance imaging features.