Author Correction: Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

The 'Competing interests' statement of this Article has been updated; see accompanying Amendment for further details.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

Evidence of spinal stiffening following fusionless bipolar fixation for neuromuscular scoliosis: a shear wave elastography assessment of lumbar annulus fibrosus.

OBJECTIVES: There are no established criteria for stiffness after fusionless surgery for neuromuscular scoliosis (NMS). As a result, there is no consensus regarding the surgical strategy to propose at long-term follow-up. This study reports the first use of shear wave elastography for assessing the mechanical response of lumbar intervertebral discs (IVDs) after fusionless bipolar fixation (FBF) for NMS and compares them with healthy controls. The aim was to acquire evidence from the stiffness of the spine following FBF. PATIENTS AND METHODS: Nineteen NMS operated on with FBF (18 ± 2y at last follow-up, 6 ± 1 y after surgery) were included prospectively. Preoperative Cobb was 89 ± 20° and 35 ± 1° at latest follow-up. All patients had reached skeletal maturity. Eighteen healthy patients (20 ± 4 y) were also included. Shear wave speed (SWS) was measured in the annulus fibrosus of L3L4, L4L5 and L5S1 IVDs and compared between the two groups. A measurement reliability was performed. RESULTS: In healthy subjects, average SWS (all disc levels pooled) was 7.5 ± 2.6 m/s. In NMS patients, SWS was significantly higher at 9.9 ± 1.4 m/s (p < 0.05). Differences were significant between L3L4 (9.3 ± 1.8 m/s vs. 7.0 ± 2.5 m/s, p = 0.004) and L4L5 (10.3 ± 2.3 m/s vs. 7.1 ± 1.1 m/s, p = 0.0006). No difference was observed for L5S1 (p = 0.2). No correlation was found with age at surgery, Cobb angle correction and age at the SWE measurement. CONCLUSIONS: This study shows a significant increase in disc stiffness at the end of growth for NMS patients treated by FBF. These findings are a useful adjunct to CT-scan in assessing stiffness of the spine allowing the avoidance of surgical final fusion at skeletal maturity.

Improvements in Pediatric Bone Loss Reconstruction With the Induced Membrane Technique.

BACKGROUND: The induced membrane technique is now widely used for pediatric diaphyseal bone loss due to various etiologies. Although consolidation rates remain satisfactory, complications, and healing delays may occur requiring additional procedures. We studied a series of induced membrane bone reconstructions in which the second stage included an embedded endomembranous non vascularized fibular shaft, in addition to iliac bone grafts. The purpose of this study was to analyze the results in terms of bone consolidation and complications. METHODS: This is a retrospective comparative and multicentric study of 32 children with large bone loss treated with the induced membrane reconstruction technique. Patients were divided into 2 groups according to the graft used during the second stage. The first group (G1) of 16 patients had a nonvascularized fibula embedded inside the membrane in addition with the corticocancellous grafts from the iliac crest. The second group (G2) of 16 patients underwent reconstruction using the original technique, with iliac crest graft only. RESULTS: The 2 groups were similar in terms of etiologies of bone loss and follow-up (mean: 44 mo for G1 and 49 mo for G2). Mean bone losses were 15.4 cm (range: 2 to 25; SD: 5.6) for G1 and 10.6 cm (range: 3 to 19; SD: 5.2) for G2. In the first group, all patients healed primarily, with a mean time of 5.9 months (range: 4 to 8; SD: 1.6). In the second group, 2 of 16 patients did not healed; for the others 14, healing mean time was 6.9 months (range: 3 to 12; SD: 2.7). The short-term and long-term complications rates were 38% to 19% for G1 and 50% to 31% for G2, respectively. Regarding the donor site, the fibulas reconstructed spontaneously with a mean time of 4.8 months (range: 3 to 6; SD: 1.2). CONCLUSIONS: The integration of a nonvascularized fibula during the second stage of the induced membrane technique appears to improve the consolidation rate in the pediatric population. LEVEL OF EVIDENCE: Level III-Retrospective comparative study.

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Bone allografting: an original method for biological osteosynthesis and bone reinforcement in children with osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) is a genetic disorder responsible for various symptoms including deformities and frequent fractures. Bone allografting is poorly documented in this condition. The objective of this study was to describe our experience and assessments in a consecutive series of OI patients. METHODS: Thirty-nine lower limb allograft procedures (28 femurs, 11 tibias) were performed in 26OI patients (mean age, 12.9 years). They were classified as type III of Sillence (17), type IV (6), and 3 recessive forms. The indications for surgery were correction of deformity (19), fracture (16), and non-union (4). In all cases, bone allografting was added to reinforce areas of fragility and in 28 cases for osteosynthesis to lock the rotations at the osteotomy site and to avoid screwed metallic plate. The duration of bone consolidation and allograft fusion was assessed. Complications and Gillette functional score were reported. RESULTS: The mean follow-up was 6.7years (range, 2 to 10 years). On average, bone consolidation was achieved after 3.3 months and graft fusion after 7.7 months. No bone allograft-related complications were observed and there was any secondary displacement. The Gillette functional score was improved in 23 patients and stable in three cases. Complications were reported in two cases: one partial allograft resorption and one delayed consolidation of a non-union. One refracture was observed but after a significant trauma in a child who had regained significant physical activity. CONCLUSIONS: Bone allografting in children with OI is a reliable method of biological fixation, allowing efficient fusion and contributing to increased bone capital and functional outcome.

Atypical Presentation of Juvenile Hyaline Fibromatosis of Hands.

Juvenile hyaline fibromatosis is a rare disorder characterized by an extracellular accumulation of hyaline deposit. In the extremities, lesions may remain quiescent or gradually increase in size, eventually resulting in skin ulceration. There is no curative treatment. Surgery may allow some recovery of function, but recurrence is possible. We report a case of juvenile hyaline fibromatosis in both hands of a 25-year-old man who required multiple surgical procedures to address problems with function, pain, and appearance.

Tibial Sliding Elastic Nailing Technique in Moderate-to-Severe Osteogenesis Imperfecta: Long-term Outcomes.

BACKGROUND: Osteosynthesis of leg fractures and deformities in children with osteogenesis imperfecta should align the skeleton and overcome its fragility during growth with a telescopic effect. A high rate of mechanical complications is associated with various surgical techniques described in the literature. PURPOSE: The objective of this work was to assess the long-term clinical and radiologic outcomes of tibial sliding elastic nailing technique. METHODS: A total of 22 children with an average age of 4.7 years were operated using the technique between 2004 and 2018 unilaterally (6) or bilaterally (16), that is, 38 operations. They were listed according to the Sillence classification into type I (3), III (17), or V (2). The nails were introduced percutaneously at the distal tibial epiphysis through the medial malleolus, and in the prespinal area for the proximal tibial epiphysis. The stainless-steel rods diameter was 1.5 to 2.5 mm, adapted to the size and weight of the patient. Realignment osteotomies were performed if necessary. Radiographic data including the correction of the deformation in the frontal and sagittal planes, as well as the width at mid-shaft of the tibia in the frontal and sagittal planes, were reviewed. Gillette Functional Score, assessment of pain, mechanical and infectious complications were collected. RESULTS: The average follow-up was 8.6 years. In the frontal plane, preoperative average varus was 8 degrees (maximum, 40 degrees), 5 degrees (maximum, 13 degrees) postoperatively, and 6 degrees (maximum, 12 degrees) at last follow-up. Preoperative valgus was 11 degrees (maximum, 22 degrees), 9 degrees (maximum, 15 degrees) postoperatively, and 9 degrees (maximum, 14 degrees) at the last follow-up. In the sagittal plane, the mean sagittal bowling of the tibia was 32 degrees (4 to 75 degrees) preoperatively, 9 degree (1 to 26 degrees) postoperatively, and 9 degrees (1 to 24 degrees) at last follow-up. The width at mid-shaft of the tibia in the frontal plane was 1.1 cm (0.6 to 1.8 cm) preoperatively and 1.3 cm at the last follow-up (0.7 to 2.0 cm). In the sagittal plane, it was 1.25 cm (0.7 to 2.7 cm) preoperatively and 1.27 cm (0.8 to 2.8 cm) at the last follow-up. Ten patients did not require revision surgery during their follow-up. Sixteen mechanical complications occurred in 12 patients (12 fractures or deformities following a lack of overlap of the 2 rods at an average time of 4.9 years after the initial surgery, 3 prominence of the nail, 1 pseudarthrosis). No infectious complication was reported. Gillette Functional Score was 20.54/65. Fifteen patients were able to walk at last follow-up, and 18 had no painful discomfort. CONCLUSIONS: The tibial sliding elastic nailing technique provides satisfactory clinical and radiologic results over time. Performed in case of fracture or as a preventive treatment, it allows a good correction of angular deformations. It is particularly suitable for young patients with a narrow medullary shaft. LEVEL OF EVIDENCE: Level IV-therapeutic study.

Long-term outcomes of non-invasive expandable endoprostheses for primary malignant tumors around the knee in skeletally-immature patients.

INTRODUCTION: Expandable endoprostheses are used to restore limb function and compensate for the sacrifice physis involved in carcinologic resection. Long-term outcomes of the last generation of knee "non-invasive" expandable endoprostheses are required. Objectives were to report on oncologic results of bone sarcoma resection around the knee with expandable endoprosthesis reconstruction and to compare the surgical outcomes of the "non-invasive" expandable endoprostheses used in our department. MATERIALS AND METHODS: Retrospective study that included all children with bone sarcoma around the knee that underwent tumor resection reconstructed with non-invasive expandable prosthesis. Phenix-Repiphysis was used from 1994 to 2008 followed by Stanmore JTS non-invasive from 2008 to 2016. Survival and complications were recorded. Functional outcomes included Musculoskeletal Tumor Society (MSTS) score, knee range of motion, lower limb discrepancy (LLD). RESULTS: Forty children (Sex Ratio = 1) aged a mean 8.8 years (range, 5.6-13.8) at surgery were included in the study. There were 36 osteosarcoma and 4 Ewing sarcoma that involved 33 distal femur and 7 proximal tibia. Cohort (n = 40) consisted of 28 Phenix-Repiphysis and 12 Stanmore with a mean follow-up of 9.8 ± 5.8 years and 6.1 ± 3.1 years, respectively. Postoperative infection rate was 7.5% in the cohort (3 Repiphysis). Functional results were significantly better in the Stanmore group with a mean MSTS of 87.6 ± 5.4% and knee flexion of 112 ± 38°. At last follow-up, implant survival was 100% in Stanmore group, whereas all living Phenix-Repiphysis were explanted. Mechanical failure was the primary cause for revision of Phenix-Repiphysis. Limb length equality was noted in 79% patients with Phenix-Repiphysis and 84% with Stanmore at last follow-up. CONCLUSION: Chemotherapy and limb-salvage surgery yield good oncologic outcomes. Expandable endoprostheses are effective in maintaining satisfactory function and lower limb equality. With improvements made in the last generation of "non-invasive" prostheses, implants' survival has been substantially lengthened.

Pattern of relapse in pediatric localized extremity rhabdomyosarcomas correlated with locoregional therapies administered.

BACKGROUND: Treatment of extremity rhabdomyosarcomas (RMS) includes chemotherapy, surgery, and radiotherapy. Lymph node irradiation is recommended in the presence of regional node involvement at diagnosis. The aim of this study was to analyze the correlation between the pattern of relapse of non-metastatic extremity RMS and the initial therapies delivered. METHODS: All patients with localized extremity RMS prospectively treated in France in the MMT-95 and RMS-05 protocols were selected. Extent of disease and pattern of relapse were evaluated by clinical examination and imaging. RESULTS: We identified 59 patients with clinical characteristics corresponding to unfavorable prognostic factors. Twenty patients (34%) were considered to have lymph node involvement at diagnosis. Regional node biopsy was performed in 32 patients (54%) and modified the lymph node stage in 8 of the 59 patients (14%). Seventy-three percent of patients received radiotherapy. Fifty-two patients achieved first remission. Overall, 26 patients underwent complete tumor resection, 17 had R1 margins, and 5 were not operated due to early tumor progression. With a median follow-up of 82 months (range: 5-287), 18 relapses had occurred, at least locoregional in 12 cases. The 5­year local and nodal control rates were 73% (63-86%) and 86% (77-95%), respectively. Five-year progression-free and overall survival were 57% (95%CI [45-72%]) and 70% (95%CI [58-84%]), respectively. CONCLUSION: The main sites of extremity RMS relapse are locoregional. Nodal failures in non-irradiated fields are not uncommon. We recommend systematic biopsy of in-transit nodes, especially in alveolar RMS and/or RMS with regional positive nodes at diagnosis to ensure their negativity.

Soft tissue angiomatosis: another PIK3CA-related disorder.

AIM: Angiomatosis of soft tissue (AST) is a rare, high-flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non-syndromic AST arises as a consequence of a somatic mutation. METHODS AND RESULTS: Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients' personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio -0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups. CONCLUSIONS: AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.

Multicentric carpotarsal osteolysis syndrome: long-term follow-up of three patients.

Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal disorder characterized by progressive carpal and tarsal destruction. The upper and lower limbs may be involved, leading to deformities and joint limitation. These anatomic features may be associated with progressive renal failure. The radiographs obtained during childhood showed a carpal and tarsal osteolysis and an asymmetrical involvement. Here, we report on the long-term clinical and radiological findings of three patients with skeletal manifestations of MCTO.

Surgical Treatment of Enchondromas of the Hand During Childhood in Ollier Disease.

PURPOSE: The objective of the present study was to evaluate the outcome of surgical treatment of hand lesions in Ollier disease (OD) carried out during childhood. METHODS: A retrospective review was carried out of 10 pediatric patients with hand involvement of OD, who had undergone surgery for metacarpal or phalangeal enchondromas. The technique comprised curettage and cortical bone reconstruction with corticoplasty, to restore a near-normal phalangeal volume. The range of finger motion (pulp-to-palm distance), the shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire score, cosmetic improvement, radiological findings (according to Tordai's classification), and recurrence were recorded after a mean follow-up of 7.5 years (range, 4-11.3 years). RESULTS: The mean age at surgery was 10.7 years (range, 6-14 years). Curettage was performed on 35 enchondromas, and 9 cavities were filled with a bone graft. The mean pulp-to-palm distance was significantly lower after surgery (from 1.5 cm to 0.25 cm; P < .05). The mean QuickDASH score was 3.84 (range, 0-11.4). A marked cosmetic improvement was noted for 83% of the hands. Three enchondromas recurred in 1 patient, requiring a second curettage. Fifty-seven percent of the cavities were completely filled with bone (Tordai stage 1) at last follow-up. The outcome did not depend on the presence or absence of a bone graft. CONCLUSIONS: Our results suggest that early surgical treatment comprising curettage and corticoplasty leads to good clinical, cosmetic, and radiological outcomes. Early surgical treatment of well-developed and/or symptomatic enchondromas of the hand in OD should be considered. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Synovial sarcoma in children and adolescents.

Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient's age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the "rhabdomyosarcoma philosophy." In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults.

MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-ß and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

Alveolar soft part sarcomas in young patients: The French national NETSARC+ network experience.

BACKGROUND AND AIMS: Alveolar soft part sarcoma (ASPS) is an ultra-rare chemo-resistant sarcoma in children, occurring preferentially in young adults. We aimed to describe and compare its clinical presentation and behaviour in children and young adults to determine whether the same therapeutic strategy should be addressed for both populations. METHODS: National retrospective multicentre study of children (0-18 years) vs. young adults (19-30 years) included in the "ConticaBase" sarcoma database, treated for ASPS between 2010 and 2019 with pathology reviewed via the NETSARC + network. RESULTS: Overall, 45 patients were identified, 19 children (42%) and 26 young adults (58%). All ASPS diagnoses were confirmed with TFE3 rearrangement by immunohistochemistry or FISH. All clinical characteristics were balanced between both populations with frequent metastases at diagnosis (8/19 vs. 10/26). The therapeutic strategy was based on surgery (17/19 vs. 21/26), radiotherapy (8/19 vs. 12/26) ± systemic treatment (8/19 vs. 9/26). In patients with initially localized disease, metastatic relapse occurred only in adults (8/16), whereas metastatic progression was present in both metastatic groups (5/8 vs. 8/10). After a median follow-up of 5.2 years (range, 0.2-12.2), 5-year EFS was 74% [95%CI, 56-96] vs. 47% [30-74] (p = 0.071) respectively, and 5-year OS was 95% [85-100] vs. 85% [70-100] (p = 0.84). For localized tumours, 5-year MFS was 100% [100-100] vs. 60% [39-91] (p = 0.005). The 5-year OS of all patients with metastasis at diagnosis was 80.2% (62.2%-100%). CONCLUSIONS: ASPS appears to have the overall same clinical characteristics, but a more aggressive behaviour in young adults than in children. However, despite frequent metastases at diagnosis, long-term survival is high in both groups. Overall, the same therapeutic strategies may be considered for both populations.

Voluminous arteriovenous malformation of a child's forearm treated by sequential embolizations: case report.

An arteriovenous malformation (AVM) is a congenital lesion with high vascular flow resulting from direct connections between arteries and veins. Its treatment is often complex, and most authors recommend a multidisciplinary approach combining surgical and endovascular treatments. We report the case of a 6-month-old boy with a voluminous AVM of the left forearm inducing osteolysis of the radius, with bowing of its diaphysis and subsequent radial head dislocation. Surgical excision of the AVM was not possible, but 2 sequential coil embolizations achieved control of the lesion. After 3.5 years, the AVM was undetectable, and notable improvement was noted both in symptoms and radiographic findings. This case underlines how an AVM can have noteworthy influence on surrounding tissues and shows that embolization alone can achieve a satisfying midterm outcome even when surgery is not possible.

[The reconstruction of limbs after a malignant tumor in children]. / La reconstruction des membres après une tumeur maligne chez l'enfant.

Large segmental resections of malignant bone tumours in children require a reconstruction of the segment which has been removed by oncology surgery. A number of prosthetic and biological techniques are now used. The child's capacity to repair the limb sometimes enables high quality reconstructions to be performed.