LIM Kinases in Osteosarcoma Development

Tumorigenesis is a long-term and multistage process that often leads to the formation of metastases. During this pathological course, two major events appear to be crucial: primary tumour growth and metastatic expansion. In this context, despite research and clinical advances during the past decades, bone cancers remain a leading cause of death worldwide among paediatric cancer patients. Osteosarcomas are the most common malignant bone tumours in children and adolescents. Notwithstanding advances in therapeutic treatments, many patients succumb to these diseases. In particular, less than 30% of patients who demonstrate metastases at diagnosis or are poor responders to chemotherapy survive 5 years after initial diagnosis. LIM kinases (LIMKs), comprising LIMK1 and LIMK2, are common downstream effectors of several signalization pathways, and function as a signalling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. In recent decades, several reports have indicated that the functions of LIMKs are mainly implicated in the regulation of actin microfilament and the control of microtubule dynamics. Previous studies have thus identified LIMKs as cancer-promoting regulators in multiple organ cancers, such as breast cancer or prostate cancer. This review updates the current understanding of LIMK involvement in osteosarcoma progression.

Fibrocartilagenous dysplasia in distal femur: A rare histopathological finding

Fibrocartilaginous dysplasia (FCD) or massive cartilaginous differentiation in fibrous dysplasia are interchangeably used terms. It is a rare variant of fibrous dysplasia (FD) which is benign, lytic, and expansile bone lesion and causes progressive deformity in the bones and may lead to pathological fracture. Radiologically, FCD may confused with cartilaginous benign and malignant bone tumours. FCD usually shows calcification in imaging. Surgical curettage or corrective osteotomy and histopathological examination of these lesions is necessary to differentiate it from other cartilaginous tumours. Here we report case of fibrocartilaginous dysplasia of distal femur in a 4-year-old male child.

Diagnosis and staging of malignant bone tumours in children: what is due and what is new?

Purpose Although malignant bone tumours in children are infrequent, it is important to know how to properly diagnose and stage them, in order to establish an adequate treatment. Methods We present a review of the diagnostic workflow of malignant bone tumours in children, including history and clinical examination, imaging, laboratory tests and biopsy techniques. Moreover, the two most commonly used staging systems are reviewed. Results History, clinical examination and laboratory tests are nonspecific for diagnosing malignant bone tumours in children. Radiographs remain the mainstay for initial diagnosis, with MRI the modality of choice for local assessment and staging. Fluorine-18 labelled fluoro-deoxy-glucose-positron emission tomography scans provide a noninvasive method to assess the aggressiveness of the tumour and to rule out metastasis and is replacing the use of the bone scintigraphy. Biopsy must be always performed under the direction of the surgeon who is to perform the surgical treatment and after all diagnostic evaluation has been done. Staging systems are useful to study the extent of the tumour and its prognosis. They are expected to evolve as we better understand new molecular and genetic findings. Conclusion When a malignant bone tumour is suspected in a child, it is essential to make a correct diagnosis and referral to an experienced centre. Following an appropriate workflow for diagnosis and staging facilitates, prompt access to treatment improves outcomes. Level of Evidence Level V Expert opinion

Biology and technology in the surgical treatment of malignant bone tumours in children and adolescents, with a special note on the very young

Purpose The main challenge in reconstruction after malignant bone tumour resection in young children remains how and when growth-plates can be preserved and which options remain if impossible. Methods We describe different strategies to assure best possible long-term function for young children undergoing resection of malignant bone tumours. Results Different resources are available to treat children with malignant bones tumours: a) preoperative planning simulates scenarios for tumour resection and limb reconstruction, facilitating decision-making for surgical and reconstructive techniques in individual patients; b) allograft reconstruction offers bone-stock preservation for future needs. Most allografts are intact at long-term follow-up, but limb-length inequalities and corrective/revision surgery are common in young patients; c) free vascularized fibula can be used as stand-alone reconstruction, vascularized augmentation of structural allograft or devitalized autograft. Longitudinal growth and joint remodelling potential can be preserved, if transferred with vascularized proximal physis; d) epiphysiolysis before resection with continuous physeal distraction provides safe resection margins and maintains growth-plate and epiphysis; e) 3D printing may facilitate joint salvage by reconstruction with patient-specific instruments. Very short stems can be created for fixation in (epi-)metaphysis, preserving native joints; f) growing endoprosthesis can provide for remaining growth after resection of epi-metaphyseal tumours. At ten-year follow-up, limb survival was 89%, but multiple surgeries are often required; g) rotationplasty and amputation should be considered if limb salvage is impossible and/or would result in decreased function and quality of life. Conclusion Several biological and technological reconstruction options must be merged and used to yield best outcomes when treating young children with malignant bone tumours. Level of Evidence Level V Expert opinion

Tricks and pitfalls in the surgical treatment of malignant bone tumours of the forearm in children and adolescents

Malignant bone tumours around the forearm are rare. Nowadays, oncological and surgical management of bone sarcomas of this region has improved significantly. Although the anatomical features are complex, limb-sparing surgery is possible with wide surgical resection. Biological reconstruction methods are promising in this anatomically unique region. In addition, meticulous soft-tissue reconstruction yields good functional results in the hand and wrist. This study reviews malignant bone tumours of the forearm and their oncological and surgical management. Malignant bone tumours should be treated with a multidisciplinary approach based on chemotherapy, radiotherapy and limb salvage procedures.

Primary malignant bone tumours of spine and pelvis in children

Purpose Axial malignant bone tumours are rare in children and adolescents, and their prognosis is still relatively poor due to non-specific symptoms, such as back or groin pain, which may result in late hospital presentation. Therefore, it is very important to raise awareness regarding this pathology. Methods We performed a narrative review, including scientific publications published in English. We searched Medline and Google Scholar databases for information on the incidence and prognosis of axial malignant bone tumours in children and adolescents (< 18 years). Outcomes of different surgical management strategies and reconstruction options were assessed. Results The incidence of primary malignant bone tumours before the age of 18 years is approximately five per one million population; around 25% of these tumours are located in the axial skeleton. With a five-year survival rate of 50%, tumours in an axial location (chest cage, spine, pelvis) are associated with a poorer prognosis than tumours in more peripheral locations. En bloc excision with clear margins has been shown to improve local control and overall survival, even though obtaining adequate surgical margins is difficult due to the close location of large neurovascular structures and other major organs. Spinal reconstruction options include instrumented fusion with allograft or expandable cage. Pelvic reconstruction is needed in internal hemipelvectomy, and the options include biological, endoprosthetic reconstructions, hip transposition, arthrodesis or creation of pseudoarthrosis and lumbopelvic instrumentation. Conclusion Early diagnosis, a timely adequate multidisciplinary management, appropriate en bloc excision, and reconstruction improve survival and quality of life in these patients. Level of Evidence V

Bone sarcoma: success through interdisciplinary collaboration

Purpose Osteosarcoma and Ewing sarcoma are the most frequent malignant bone tumours of childhood and adolescence. This review summarizes the oncologist’s view of these diseases and their treatment. Methods A non-systematic literature review was performed, the personal impressions and experience of the authors is described. Results Local therapy and chemotherapy, each on their own, will not cure patients with malignant bone sarcomas. Together, they present a highly efficacious combination. While the most effective drugs were defined decades ago, progress since then has been limited. It is hoped that substances shown to be active in relapsed disease will be forwarded into even more efficacious frontline treatments. Good palliative therapy is necessary when cure is no longer an option. Conclusion Close interdisciplinary collaboration is the key to successful treatment of bone sarcomas in paediatric patients.

Lower limb reconstruction for malignant bone tumours in children

Malignant bone tumours of the lower limb represent the majority of cases in both osteosarcoma and Ewing sarcoma in the growth period. Surgical treatment represents a key element of treatment. Different localizations and age groups require a differentiated surgical approach. Life and limb salvage are first on the list of treatment goals, followed by functional and cosmetic considerations. This review article delivers and discusses current surgical treatment strategies and outcomes for lower limb malignant bone tumours in children.

Toxoplasma gondii infection in patients with malignant and benign bone tumours

Toxoplasma gondii (T. gondii) is an intracellular parasite that infects humans and seroprevalence of its infection varies from about 10 to 80 percent in different countries with a higher prevalence in warmer and humid regions. In this study, the rate of acute and chronic toxoplasmosis in patients with benign or malignant bone tumours was investigated. Fifty-three patients who suffered from various bone tumours, as well as sixty-five healthy controls with an unknown serological profile for anti-Toxoplasma antibodies, were enrolled in this cross-sectional study. Anti-toxoplasma antibodies were detected in serum samples using enzyme-linked immunosorbent assay (ELISA) and blood samples of them were used for real-time PCR. Thirty-two (60.32%) and twenty-one (39.63%) of patients had malignant tumours and benign tumours, respectively. The results showed a higher and significant seropositivity rate of IgM antibodies in primary bone tumour patients compared to the control group and Toxoplasma DNA became positive in 18.86% of patients with primary bone tumours and 6.15% of controls. Surprisingly, the high presence of parasite DNA was detected in patients with malignant tumours. The seroprevalence of T. gondii IgM antibody and DNA positivity among the cancer patients were significantly higher than healthy individuals. Also, chronic toxoplasmosis (it was shown with IgG positive) appears to be more common in people with benign cancers than malignancies. The study showed a relatively high seroprevalence of anti-T. gondii antibodies in patients with primary bone cancer. However, the considerable rate of positive blood samples for the presence of parasite’s DNA should not be ignored. A key to the effective management of diseases in immunosuppressed individuals is prompt and accurate diagnosis of toxoplasmosis. Moreover, it seems that PCR tests may be more reliable than serological methods and it could be considered as a precise method for diagnosis of acute toxoplasmosis.