Chongqi Tu

Autophagy as a potential target for sarcoma treatment

Autophagy is a constitutively active, evolutionary conserved, catabolic process for maintaining homeostasis in cellular stress responses and cell survival. Although its mechanism has not been fully illustrated, recent work on autophagy in various types of sarcomas has demonstrated that autophagy exerts an important role in sarcoma cell growth and proliferation, in pro-survival response to therapies and stresses, and in therapeutic resistance of sarcoma. Thus, the autophagic process is being seen as a possibly novel therapeutic target of sarcoma. Additionally, some co-regulators of autophagy have also been investigated as promising biomarkers for the diagnosis and prognosis of sarcoma. In this review, we summarize contemporary advances in the role of autophagy in sarcoma and discuss the potential of autophagy as a new target for sarcoma treatment.

The roles and implications of exosomes in sarcoma

Better diagnostic biomarkers and therapeutic options are still necessary for patients with sarcomas due to the current limitations of diagnosis and treatment. Exosomes are small extracellular membrane vesicles that are released by various cells and are found in most body fluids. Tumor-derived exosomes have been proven to mediate tumorigenesis, intercellular communication, microenvironment modulation, and metastasis in different cancers, including in sarcomas. Recently, exosomes have been considered as potential biomarkers for sarcoma diagnosis and prognosis, and as possible targets for sarcoma therapy. Moreover, due to their specific cell tropism and bioavailability, exosomes can also be engineered as vehicles for drug delivery. In this review, we discuss recent advances in the roles of tumor-derived exosomes in sarcoma and their potential clinical applications.

Potentials of Long Noncoding RNAs (LncRNAs) in Sarcoma: From Biomarkers to Therapeutic Targets

Sarcoma includes some of the most heterogeneous tumors, which make the diagnosis, prognosis and treatment of these rare yet diverse neoplasms especially challenging. Long noncoding RNAs (lncRNAs) are important regulators of cancer initiation and progression, which implies their potential as neoteric prognostic and diagnostic markers in cancer, including sarcoma. A relationship between lncRNAs and sarcoma pathogenesis and progression is emerging. Recent studies demonstrate that lncRNAs influence sarcoma cell proliferation, metastasis, and drug resistance. Additionally, lncRNA expression profiles are predictive of sarcoma prognosis. In this review, we summarize contemporary advances in the research of lncRNA biogenesis and functions in sarcoma. We also highlight the potential for lncRNAs to become innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma.

Therapeutic applications of histone deacetylase inhibitors in sarcoma

Sarcomas are a rare group of malignant tumors originating from mesenchymal stem cells. Surgery, radiation and chemotherapy are currently the only standard treatments for sarcoma. However, their response rates to chemotherapy are quite low. Toxic side effects and multi-drug chemoresistance make treatment even more challenging. Therefore, better drugs to treat sarcomas are needed. Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are epigenetic modifying agents that can inhibit sarcoma growth in vitro and in vivo through a variety of pathways, including inducing tumor cell apoptosis, causing cell cycle arrest, impairing tumor invasion and preventing metastasis. Importantly, preclinical studies have revealed that HDIs can not only sensitize sarcomas to chemotherapy and radiotherapy, but also increase treatment responses when combined with other chemotherapeutic drugs. Several phase I and II clinical trials have been conducted to assess the efficacy of HDIs either as monotherapy or in combination with standard chemotherapeutic agents or targeted therapeutic drugs for sarcomas. Combination regimen for sarcomas appear to be more promising than monotherapy when using HDIs. This review summarizes our current understanding and therapeutic applications of HDIs in sarcomas.

A locking compression plate as an external fixator for treating infected nonunion of the humeral diaphysis

BackgroundInfected nonunion of the humeral diaphysis is a challenging problem for orthopedic surgeons. This study aimed to evaluate the outcome of using a locking compression plate (LCP) as a definitive external fixator in the management of infected nonunion of the humeral diaphysis after failure of internal fixation.MethodsWe retrospectively reviewed a series of seven patients with infected nonunion of the humeral diaphysis treated with an LCP as an external fixator between June 2010 and August 2014. There were five males and two females, with an average age of 40.9xa0years. Six out of seven patients had been definitively diagnosed with infection due to known bacteria by germiculture. The clinical and radiographic outcomes were retrospectively evaluated.ResultsAll patients were followed-up for a mean period of 26.3xa0months (range 12–48 months). All fractures obtained complete bone union, and the average time to bone union was 7.9xa0months (range 3.5–15 months). All infections were eventually resolved without any recurrence of deep infection. Pin tract infection was only seen in one case. Only one patient had transient radial nerve palsy after surgery for traction. The average shortening length of the affected upper limb was 3xa0cm (range 2–4xa0cm) compared with the contralateral limb. At the last follow-up, the average Disabilities of the Arm, Shoulder and Hand score of the involved limbs was 3.2 (range 0–13.4). All patients obtained excellent or good functional results, and returned to their original work.ConclusionsThe novel use of an LCP as a definitive external fixator was an effective method for treating infected nonunion of the humeral diaphysis. However, a large-scale prospective clinical study is still needed to verify these findings.

Cemented allograft-prosthesis composite reconstruction for the proximal femur tumor.

Introduction Cemented allograft-prosthesis composite (APC) reconstruction is one option following resection of the proximal femur tumor. However, rare studies have focused on the indications and complications. The goal of the present study was to (1) ascertain the indications for cemented APC arthroplasty in the proximal femur; (2) identify the detailed perioperative management; and (3) illustrate our experiences to avoid the complications of cemented APC. Materials and methods A total 28 patients who underwent cemented APC reconstruction of the proximal femur after tumor resection were retrospectively evaluated at a median follow-up of 56 months. Clinical records and radiographs were reviewed to evaluate patients’ outcome. Results In our series, excluding three cases of death that had a short follow-up period, union occurred in 22 (88.0%) patients (range 9–18 months). Nonunion of the greater trochanter was seen in six of the 12 patients (50.0%). Eight (32.0%) hips had resorption. There were two (8.0%) hips that were observed to have asymptomatic wear of the acetabulum. The average Musculoskeletal Tumor Society (MSTS) score was 26.5 points. The average Harris Hip Score (HHS) score was 80.6 points. There were no cases of recurrence, but metastasis was found in two hips. Conclusions Mastering indications, perioperative management, and complication prevention are all very important in the APC reconstruction after resection of the proximal femur.

Application of metabolomics in sarcoma: From biomarkers to therapeutic targets

Sarcomas are a large and heterogeneous group of more than 70 malignant primary neoplasms derived from mesenchymal origin [1, 2]. Bone and soft tissue sarcoma are the main types of sarcoma. Although sarcoma causes approximately 1% of all cancer-related deaths, it accounts for 19-21% of cancer-related deaths in children and adolescents [2, 3]. At present, the diagnosis remains dependent on clinical description, radiographic assessment, and histopathologic staging systems in sarcoma. Despite an increased understanding of the molecular pathogenesis of sarcoma during the past two decades, reliable biomarkers to enable screening and surveillance of sarcoma are still unavailable. Importantly, identifying specific biomarkers to detect sarcoma at the onset and monitor disease progression continues to be an overwhelming challenge. Furthermore, surgery combined with neoadjuvant chemotherapy and irradiation therapy represent the current standard treatments for sarcoma, which have significantly raised the prognosis of this disease to a plateau that has been maintained for the last 30 years [2]. New therapeutic strategies as well as diagnostic, prognostic and predictive biomarkers remain unmet clinical needs for the management of sarcoma. n n“Omic” technologies entail high-throughput approaches for systems-level studies of all genes or gene products, and promise a better understanding of tumor oncogenesis that can improve tumor diagnosis to facilitate the emergence of personalized tumor management [4, 5]. Although genomics, transcriptomics and proteomics have a significant impact on the general understanding of cancer-related processes, some limitations in the discovery of diagnostic biomarkers and treatment targets through gene/protein expression data have been recognized in recent years [6]. The major challenge is to identify the key “signals” in the data that drive traits of interest (e.g. disease, drug response, etc.), such as the genomic changes and their real influence on sarcoma phenotype. Therefore, other methods that directly affect sarcoma phenotypes, such as metabolomics have shed light on the search for diagnostic and prognostic biomarkers, and therapeutic targets. n nMetabolomics is a new discipline that evaluates diverse metabolite concentrations in biological specimens to gain insight into the ongoing metabolism [7, 8]. Metabolites are highly stable end products of various metabolic pathways and are the closest link between the genotype and phenotypes of a cell. Thus metabolites may have applications as biomarkers for cancer diagnosis, prognosis, and therapeutic evaluation [9]. The number of metabolites present in a human organism is currently more than 40,000 and still expanding [10]. Metabolomics provides a comprehensive measurement of the entire metabolome that reflects the genome, epigenome, transcriptome and proteome, and their interactions with the environment [11]. Moreover, metabolomics detects an array of metabolites rather than a single metabolite in a single assay, so that the process is more convenient and the result is believed to be more indicative of sarcoma status [7]. In particular, tumor cells are known to possess unique metabolic signatures when compared with normal cells [12]. To date, metabolomic signatures have already been published from investigations aimed to discover biomarkers and treatment targets for several cancers such as colorectal, breast, liver, lung, ovarian, prostate, and pancreatic [13-19]. The integration of “omic” data reveals more than the simple sum of the individual “omic” experiments and possibly provides access to understand the interactions among all of the cellular contents [20, 21]. n nIn this review, we summarize the current state of knowledge regarding the contribution of metabolomics to sarcomas, and its clinical applications from biomarkers to potential therapeutic targets.

Pelvis metastasis from primary choroidal melanoma: a case report.

The patient, a 16-year-old girl, was admitted to our hospital with complaints of right hip pain and claudication. Her past medical history indicated that 2 years earlier she had undergone enucleation of her left eye for a primary choroidal melanoma. Imaging studies revealed a osteolytic destruction with soft tissue mass involving the right hemipelvis (zone I–II). Single-photon emission computed tomography (SPECT) and positron emission tomography–computed tomography (PET–CT) showed no other sites of metastases. Consequently, the patient underwent hemipelvic prosthesis reconstruction after tumor resection. Postoperative pathological diagnosis was metastatic malignant melanoma. Thirty months after treatment, imaging studies indicated no evidence of recurrence, and functional recovery was excellent. To our knowledge, the literature does not reveal any previously reported cases of ocular choroidal melanoma that metastasized to pelvis, meanwhile was carried out hemipelvic prosthesis reconstruction after pelvic tumor resection.

Uncemented three-dimensional-printed prosthetic reconstruction for massive bone defects of the proximal tibia

BackgroundCurrently, it is challenging to treat massive bone defects of proximal tibia. Although numerous methods are available for reconstruction with epiphysis preservation, limitations in knee function and complications are noted with these methods. Our paper describes our attempt to reconstruct a marked defect in the proximal tibia with an uncemented three-dimensional (3D)-printed prosthesis and to evaluate the prosthesis design and short-term outcomes.Case presentationA 15-year-old boy with metaphyseal osteosarcoma of the tibia underwent intercalary allograft reconstruction following wide tumour resection with epiphysis preservation. However, chronic allograft rejection and/or infection occurred after the surgery and a sinus tract was formed. The rejection and/or infection process was successfully stopped by the removal of the graft and implantation of an antibiotic-loaded cement spacer; however, the limb function was poor. Because of the irregular shape of the defect and the excessively short length of the residual proximal tibia, we used the 3D printing technology to design and fabricate a personalised prosthesis to reconstruct the defect, with the preservation of the knee joint. At the last follow-up at 26xa0months, the patient had satisfactory limb function.ConclusionsThe 3D-printed prosthesis may be a feasible option in the reconstruction of tibial metaphyseal defects with the preservation of the knee joint. Moreover, it can result in good postoperative function and low complication rates. However, a long-term follow-up is required to clarify its long-term outcomes.

Total talar replacement with a novel 3D printed modular prosthesis for tumors

Purpose Arthrodesis is one of the most widely accepted surgical recommended methods for tumors of the talus, but it may be associated with poor limb functions. The aim of this study was to present a novel reconstruction with ankle function preserved after en bloc talus tumor resection. Patient and method A 43-year-old female with mesenchymal sarcoma of the talus was admitted in West China Hospital. Total talar replacement with three-dimensional (3D) printed modular prosthesis was prepared for reconstruction. The 3D printed modular prosthesis was designed exactly as the mirror image of the contralateral talus with complete filling of the sinus tarsi and subtalar joint space. The upper modular component of prosthesis was made of ultra high molecular weight polyethylene, and the lower component, titanium alloy. Pre-drilled holes in three directions were prepared for screw fixation of the subtalar joint. Results The patient underwent en bloc talus resection through anterior approach, followed by reconstruction with the 3D printed prosthesis. The whole procedure took 2 hours, and intra-operative blood loss was 50 mL. At the last follow-up, our patient was disease free and she could walk almost normally without any aid or pain. The Musculoskeletal Tumor Society score was 26/30. The American Orthopedic Foot and Ankle Society score was 91/100. The range of motion for dorsiflexion and plantar flexion was 40°. And no abnormalities were observed in the roentgenograph. Conclusion Total talar replacement with a 3D printed modular prosthesis may be an effective procedure for patients with tumors of the talus as it could maintain ankle function.