Chondroblastomas in Children and Young Adults: Revision of 55 Cases.

BACKGROUND: Chondroblastomas are uncommon primary bone tumors localized in long bone epiphyses in children and young adults. The risk of metastasis is rare, but they have a high capacity for local recurrence. Surgical curettage with bone grafting or bone substitute is the preferred treatment. METHODS: We performed an observational retrospective study of chondroblastomas treated in 2 hospitals in Barcelona from 1988 to 2018. We reviewed the location of the tumor, clinical presentation, imaging, histopathology, initial treatment, and cases of recurrence with a review of their treatment. We assessed the correlation between recurrence and index surgery, anatomic location, and certain histopathologic findings (presence of mitotic figures, necrosis, and positivity for protein S-100). RESULTS: The series included 55 patients treated from 1988 to 2018, with ages ranging from 6 to 26, and a mean follow-up of 6.1 years (±3.7). The most common location was the distal femur metaphyseal/epiphyseal region. The most frequent clinical presentation was pain in the affected. Forty-five cases (81.8%) were treated with curettage of the tumor, and 4 cases (7.3%) with a wide resection. Forty-two cases (85.7%) received bone substitutes after curettage or resection. We found 5 cases of recurrence (9.1% recurrence rate); however, we could not find a statistically significant correlation between index surgery and recurrence ( P =0.24), anatomic location and recurrence ( P =0.49), or recurrence and histopathologic findings (mitotic figures, P =0.49; necrosis, P =0.60; positivity for protein S-100, P =0.52). In all the cases the treatment for the local recurrence was surgical, with a final healing rate of 100%. CONCLUSIONS: Chondroblastomas should be considered in children and adolescents when presenting with pain and an image suggestive of a tumoral lesion on plain x-ray, most frequently in epiphyses of long bones.Surgical treatment is preferred, obtaining good results after curettage and bone substitute. Chondroblastomas are tumors with a high capacity for recurrence, therefore an adequate surgical technique and surgeon experience are paramount to achieve good outcomes. LEVEL OF EVIDENCE: Level IV (case series). Therapeutic studies-investigating results or treatment.

MRI of Rhabdomyosarcoma and Other Soft-Tissue Sarcomas in Children.

Soft-tissue sarcomas in children comprise a heterogeneous group of entities with variable manifestation depending on the age of the patient and the location of the tumor. MRI is the modality of choice for evaluating musculoskeletal soft-tissue tumors and plays a paramount role in both initial diagnosis and assessment of tumor response during and after treatment. Conventional MRI sequences, such as T1- and T2-weighted imaging, offer morphologic information, which is important for localizing the lesion and describing anatomic relationships but not accurate for determining its malignant or benign nature and may be limited in differentiating tumor response from therapy-related changes. Advanced multiparametric MRI offers further functional information that can help with these tasks by using different imaging sequences and biomarkers. The authors present the role of MRI in rhabdomyosarcoma and other soft-tissue sarcomas in children, emphasizing a multiparametric approach with focus on the utility and potential added value of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI in characterization and staging, determination of pretreatment extent, and evaluation of tumor response and recurrence after treatment. ©RSNA, 2020.

Osteopoikilosis With Germline LEMD3 Mutation Mimicking Bone Metastases in a Girl With a Concurrent Secreting Mixed Germ Cell Tumor.

Osteopoikilosis (OPK) is a rare, benign, asymptomatic bone disease causing dense bone lesions, which could be interpreted as bone metastasis. The symmetric distribution, lack of bone destruction, and location differentiate OPK from metastatic disease. It is essential to be aware of this benign condition to prevent diagnostic errors. We present the case of a 10-year-old female patient with the concurrent diagnosis of secreting mixed germ cell tumor with Yolk Salk Tumor compound and OPK. Physical examination disclosed an abdominal mass, and blood tests showed increased alfa-fetoprotein and human chorionic gonadotropin levels. Computed tomography revealed a pelvic tumor associated with multiple radiodense lesions distributed throughout the bone skeleton. Lesions were inactive on scintigraphy and FDG-PET. Pathology of the bone showed normal bone tissue and ruled out metastasis. The patient achieved complete remission after chemotherapy and surgery and remains in continued complete remission 28 months from diagnosis. The genetic analysis confirmed the LEMD3 germline mutation confirming OPK.

Knee Arthritis in Children: When Can It Be Safely Treated With Needle Joint Aspiration? A Large Children's Tertiary Hospital Study.

BACKGROUND: Early joint decompression associated to antibiotic therapy is the most important procedure to reduce joint damage in septic knee arthritis in children. Several joint decompression methods have been described such as arthrotomy with open debriding, arthroscopic drainage or needle joint aspiration. The aim of the present study was to determinate which patients with acute septic knee arthritis could be safely treated with needle joint aspiration. METHODS: Patients with an acute knee arthritis diagnosed between September 2003 and December 2013 in our children's tertiary hospital were retrospective review. All cases were initially treated with needle joint aspiration. Primary end-point was failure of joint aspiration. RESULTS: A total of 74 patients were included in the study. Forty-two (56.8%) were male and median age was 1.49 years. Mean delay between onset of symptoms and diagnosis was 3.6 days and in 25 (33.8%) cases patients needed more than 1 visit to the emergency room. Median C-reactive protein (CRP) value was 36.3 mg/L and was >20 mg/L in 59 (79.7%) cases. A total of 11 (14.9%) patients showed failure of the joint aspiration treatment between 3 and 21 days after initial joint aspiration. The stepwise forward logistic regression model only identified as independent predictor of joint aspiration failure an age older than 3 years old (odds ratio, 5.64; 95% confidence interval, 1.38-29.61; P=0.018). Joint aspiration did not fail in any patient younger than 12 months and neither in any patient younger than 3 years old with CRP value <20 mg/L. Otherwise, treatment failed in 38% of patients older than 3 years and in 16% of patients between 1 and 3 years with a CRP>20 mg/L. CONCLUSIONS: Septic knee arthritis treated with needle joint aspiration succeed in all patients younger than 1 year and in all patients between 1 and 3 years with a CRP<20 mg/L. Alternative treatment such as arthroscopy debridement should be early considered in patients older than 3 years and patients between 1 and 3 years with CRP>20 mg/L. LEVEL OF EVIDENCE: Level III.

Vascularized fibular grafts extended with vascularized periosteum in children.

PURPOSE: The purpose of this report is to evaluate the results of extending vascularized fibular grafts (VFG) with vascularized periosteum (VPG) in bone defect reconstruction in children. METHODS: Retrospective study of 10 children, mean age at surgery was 9.8 years (range, 4-16 years). Origin of one defect was oncological (n = 5), septical (n = 2), traumatic (n = 2), or congenital (n = 1). In five cases the flap consisted of a VFG and a vascularized epiphyseal transfer (VFET) in five. Mean bone defect was 8.5 cm .Mean length of the vascularized periosteal extension was 5.5 cm (range 3.5-8) for VFET, 4.8 cm for VFG (range 3-8). Bone union was assessed with monthly radiographs. RESULTS: Radiographs showed a periosteal callus at 4 weeks in all cases. Bone union was achieved at a mean of 8.4 weeks (range 4-12). Donor site complications included two cases of flexor hallucis longus contracture, and one case of surgical wound marginal necrosis following FVG. One transient tibialis anterior weakness and one tibialis anterior contracture occurred following VFET harvest. None required surgical treatment. Mean follow-up was 28.7 months (range 7-72). CONCLUSIONS: The association of a vascularized periosteal extension with fibular flaps seems to accelerate flap to recipient bone union. © 2016 Wiley Periodicals, Inc. Microsurgery 37:410-415, 2017.

Non-invasive expandable prosthesis in musculoskeletal oncology paediatric patients for the distal and proximal femur. First results.

PURPOSE: The non-invasive expandable prosthesis for skeletally immature patients is used after limb salvage surgery following tumor resection. The aim of the study was to assess the effectiveness of this treatment. METHODS: Seven paediatric patients with femoral tumors had resection and limb salvage with an uncemented non-invasive growing prosthesis. Mean age at the time of surgery was 9.8 (range 8-12) years. There were six distal femur osteosarcomas and one proximal femur Ewing sarcoma. Six total knee prosthesis were implanted at the time of primary tumor resection and one bipolar hip prosthesis was a revision from a failed osteoarticular hip allograft. Functional outcomes and emotional acceptance were assessed using the MSTS score. RESULTS: The mean follow-up was 65.3 months (range 29-91) months. Two patients died of pulmonary metastasis and there was no local recurrence. The mean femoral resection was 18 cm (range 17-19) on the knee, and 24 cm on the hip. Mean total expansion was 36.4 mm (range 12.3-63.5). The mean MSTS score after rehabilitation was 26.3 (range 21-29). There was one lengthening device failure, one late infection and one patient who required iliofemoral bypass grafting surgery for a pelvic metastasis. No local recurrence occurred. CONCLUSIONS: The non-invasive expandable prosthesis reduces the final limb-length discrepancy in growing patients with an acceptable function and appears to have an advantage as compared to invasive expandable prostheses which require multiple surgical procedures, but the complications rate is still high.

Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies.

BACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. RESULTS: We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. CONCLUSION: Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required.

Total calcaneal allograft reconstruction of an Ewing's sarcoma in a child: Outcome and review of the literature.

BACKGROUND: Ewing's sarcoma rarely presents in bones of the feet. Surgical management usually includes amputation. Limb sparing surgery is anecdotal. CASE: We report the case of a 13-year-old boy with an Ewing sarcoma in his calcaneus who had a calcaneal reconstruction with total calcaneus allograft after induction chemotherapy. CONCLUSIONS: At 42 months of follow-up our patient remains disease free and functionally intact. A review of the exceptional limb salvage procedure options for malignant calcaneus tumor was performed.

Multiparametric MRI evaluation of bone sarcomas in children.

Osteosarcoma and Ewing sarcoma are the most common bone sarcomas in children. Their clinical presentation is very variable depending on the age of the patient and tumor location. MRI is the modality of choice to assess these bone sarcomas and has an important function at diagnosis and also for monitoring recurrence or tumor response. Anatomic sequences include T1- and T2-weighted images and provide morphological assessment that is crucial to localize the tumor and describe anatomical boundaries. Multiparametric MRI provides functional information that helps in the assessment of tumor response to therapy by using different imaging sequences and biomarkers. This review manuscript illustrates the role of MRI in osteosarcoma and Ewing sarcoma in the pediatric population, with emphasis on a functional perspective, highlighting the use of diffusion-weighted imaging and dynamic contrast-enhanced MRI at diagnosis, and during and after treatment.

Treatment of Ewing sarcoma family of tumors with a modified P6 protocol in children and adolescents.

BACKGROUND: Reported overall survival (OS) rates of patients with localized Ewing sarcoma family of tumors (ESFT) are >80% when treated with the MSKCC P6 protocol. However, it has been associated with a 5.8% incidence of secondary leukemias. A modified P6 (mP6) protocol with reduced exposure to chemotherapy is presented. PROCEDURE: Thirty-one newly diagnosed ESFT patients were enrolled onto this phase II, single-arm, non-randomized protocol. Courses 1, 2 and 4 consisted of cyclophosphamide 4.2 g/m², doxorubicin 75 mg/m², and vincristine 2 mg/m² (CDV). Cycles 3 and 5 consisted of ifosfamide 9 g/m² and etoposide 500 mg/m² (IE). Course 5 ifosfamide was 14 g/m² if necrosis was <90%. RESULTS: Twenty-four patients had loco-regional disease and seven had metastases. The 4-year event-free survival (EFS) rate for patients with localized tumors is 83% and overall survival (OS) is 92%. The 3-year EFS rate for patients with distant metastases is 28% and OS rate is 42%. EWS-FLI1 fusion genes were detected in 17 cases (74%) and EWS-ERG in six cases (26%). Type 1 EWS-FLI1 variant was present in 6/7 metastatic patients and 3/16 loco-regional cases (P = 0.001). None of the patients experienced tumor progression before remission. All relapses occurred within 2 years from the end of treatment and local relapses (n = 3) happened in patients who did not receive radiation therapy. No secondary malignancies have been observed, median follow-up of 4.3 years for surviving patients. CONCLUSIONS: In this pilot study, the mP6 protocol produced a complete remission rate of 83% at 4 years in non-metastatic ESFT reducing the risk of secondary malignancies.

Percutaneous cryoablation of chondroblastoma and osteoblastoma in pediatric patients.

BACKGROUND: To review the safety and efficacy of percutaneous cryoablation for the treatment of chondroblastoma and osteoblastoma in the pediatric and adolescent population. MATERIALS AND METHODS: A retrospective review from 2016 to 2020 was performed to evaluate clinical and imaging response to percutaneous cryoablation in 11 symptomatic patients with diagnosis of chondroblastoma and osteoblastoma treated from two pediatric hospitals with at least 12-month follow-up. Technical success (correct needle placement and potential full coverage of the tumor with the planned ablation zone) and clinical success (relief of the symptoms) were evaluated. The primary objective was to alleviate pain related to the lesion(s). Immediate and late complications were recorded. Patients were followed in clinic and with imaging studies such as MRI or CT for a minimum of 6 months. RESULTS: A total of 11 patients were included (mean 14 years, age range 9-17; male n = 8). Diagnoses were osteoblastoma (n = 4) and chondroblastoma (n = 7). Locations were proximal humerus (n = 1), femur condyle (n = 1), and proximal femur (n = 1) tibia (n = 3), acetabulum (n = 3), thoracic vertebra (n = 1) and lumbar vertebra (n = 1). Cryoablation was technically successful in all patients. Clinical success (cessation of pain) was achieved in all patients. No signs of recurrence were observed on imaging follow-up in any of the patients. One of the patients developed periprocedural right L2-L3 transient radiculopathy as major immediate complication. CONCLUSIONS: Percutaneous image-guided cryoablation can be considered potentially safe and effective treatment for chondroblastoma and osteoblastoma in children and adolescents.

Prognostic value of patient-derived xenograft engraftment in pediatric sarcomas.

The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.

Oldest epiphyseal osteochondroma in a subadult from Ancient Egypt.

Benign bone tumours are pathologies frequently encountered in archaeological human remains, with the most common being osteoma and osteochondroma. We present the case of a juvenile individual recovered from the Necropolis of Sharuna, Middle Egypt and dated to the end of Old Kingdom and First Intermediate Period of Ancient Egypt (circa 2150 BC), showing an osteochondroma arising from the proximal epiphysis of the right tibia which, in all likelihood, affected the patellar tendon in life. Osteochondromas are usually discovered during childhood and adolescence. These lesions are commonly located at the metaphysis and diaphysis of long bones and directed away from the joint, with the epiphysis being a rare location. To our knowledge, there have been no similar cases published to date from ancient times and we conclude that this is the oldest case of epiphyseal osteochondroma reported.

Incidence study of nosocomial infection in pediatric trauma patients.

In this article we intend to describe the epidemiological profile of nosocomial infection in pediatric patients with multiple trauma. We conducted a prospective study from July to November 2003 in a pediatric teaching hospital in Barcelona. We used US Centers for Disease Control and Prevention standard criteria to define nosocomial infection. Of the 121 patients included in the study, 33% had at least one episode of nosocomial infection, with an incidence rate of 9.9 infections per 100 admissions and 1.1 infections per 100 patient-days. The most frequent episode of nosocomial infection was bacteremia. Coagulase-negative staphylococci were the most common pathogens. Nosocomial infection rates per 100 device-days were 3.2 for bacteremia, 1.6 for respiratory infection and 1.0 for urinary tract infection. These findings suggest the need to evaluate infection control measures aimed at reducing the morbidity associated with infections.

Gene expression profiling identifies molecular pathways associated with collagen VI deficiency and provides novel therapeutic targets.

Ullrich congenital muscular dystrophy (UCMD), caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.

Muscle fiber atrophy and regeneration coexist in collagen VI-deficient human muscle: role of calpain-3 and nuclear factor-κB signaling.

Ullrich congenital muscular dystrophy (UCMD) is a common form of muscular dystrophy associated with defects in collagen VI. It is characterized by loss of individual muscle fibers and muscle mass and proliferation of connective and adipose tissues. We sought to investigate the mechanisms by which collagen VI regulates muscle cell survival, size, and regeneration and, in particular, the potential role of the ubiquitin-proteasome and calpain-proteolytic systems. We studied muscle biopsies of UCMD (n = 6), other myopathy (n = 12), and control patients (n = 10) and found reduced expression of atrogin-1, MURF1, and calpain-3 mRNAs in UCMD cases. Downregulation of calpain-3 was associated with changes in the nuclear immunolocalization of nuclear factor-κB. We also observed increased expression versus controls of regeneration markers at the protein and RNA levels. Satellite cell numbers did not differ in collagen VI-deficient muscle versus normal nonregenerating muscle, indicating that collagen VI does not play a key role in the maintenance of the satellite cell pool. Our results indicate that alterations in calpain-3 and nuclear factor-κB signaling pathways may contribute to muscle mass loss in UCMD muscle, whereas atrogin-1 and MURF1 are not likely to play a major role.