High-grade Chondrosarcoma Research Articles

Magnetic Resonance Imaging-Based Grading of Cartilaginous Bone Tumors: Added Value of Quantitative Texture Analysis.

The aim of this study was to assess the interreader agreement and diagnostic accuracy of morphologic magnetic resonance imaging (MRI) analysis and quantitative MRI-based texture analysis (TA) for grading of cartilaginous bone tumors. This retrospective study was approved by our local ethics committee. Magnetic resonance imaging scans of 116 cartilaginous bone neoplasms were included (53 chondromas, 26 low-grade chondrosarcomas, 37 high-grade chondrosarcomas). Two musculoskeletal radiologists blinded to patient data separately analyzed 14 morphologic MRI features consisting of tumor and peritumoral characteristics. In addition, 2 different musculoskeletal radiologists separately performed TA including 19 quantitative TA parameters in a similar fashion. Interreader reliability, univariate, multivariate, and receiver operating characteristics analyses were performed for MRI and TA parameters separately and for combined models to determine independent predictors and diagnostic accuracy for grading of cartilaginous neoplasms. P values of 0.05 and less were considered statistically significant. Between both readers, MRI and TA features showed a mean kappa value of 0.49 (range, 0.08-0.82) and a mean intraclass correlation coefficient of 0.79 (range, 0.43-0.99), respectively. Independent morphological MRI predictors for grading of cartilaginous neoplasms were bone marrow edema, soft tissue mass, maximum tumor extent, and active periostitis, whereas TA predictors consisted of short-run high gray-level emphasis, skewness, and gray-level and run-length nonuniformity. Diagnostic accuracies for differentiation of benign from malignant as well as for benign from low-grade cartilaginous lesions were 87.0% and 77.4% using MRI predictors exclusively, 89.8% and 89.5% using TA predictors exclusively, and 92.9% and 91.2% using a combined model of MRI and TA predictors, respectively. For differentiation of low-grade from high-grade chondrosarcoma, no statistically significant independent TA predictors existed, whereas a model containing MRI predictors exclusively had a diagnostic accuracy of 84.8%. Texture analysis improves diagnostic accuracy for differentiation of benign and malignant as well as for benign and low-grade cartilaginous lesions when compared with morphologic MRI analysis.

Amphiregulin enhances cell migration and resistance to doxorubicin in chondrosarcoma cells through the MAPK pathway.

Chondrosarcoma is characterized by the ability to produce extracellular matrix of cartilage. Curative surgical resection becomes difficult when high-grade chondrosarcoma metastasizes to other parts of the body. Doxorubicin (Dox) has been widely used clinically to treat many different types of cancers, including chondrosarcomas. However, chondrosarcoma is often resistant to chemotherapy and radiotherapy. New systemic treatment regimens are needed to improve the prognosis. Amphiregulin (AR) has been reported to be involved in cancer metastasis and drug resistance. The aim of the present study was to investigate the role of AR on cell migration and Dox sensitivity. To gain insight into the mechanisms used by AR to mediate its effects, we generated two chondrosarcoma cell lines, migration-prone JJ012 and Dox-resistant SW1353, to analyze the relationship between AR levels and cell functions. AR was highly expressed and secreted in mobile and drug-resistant cells. Next, we used the lentivirus-mediated RNAi system to knock down AR expression and found that AR silencing was significantly attenuated in cell migration and drug resistance. In addition, we used exogenous recombinant AR (r-AR) to confirm cell function and we introduced antibody array analysis to investigate pathways of AR activation. The results showed that AR can promote migratory activity and Dox resistance through activation of the MAPK pathway. Whereas the inhibition of the MAPK pathway has the potential to inhibit chondrosarcoma cell migration, p38 inhibition, and ERK activation may render cells more sensitive to Dox. These findings suggest that combining AR with MAPK blockade may effectively treat chondrosarcoma.

Prognostic factors for patients with chondrosarcoma: A survival analysis based on the Surveillance, Epidemiology, and End Results (SEER) database (1973–2012)

Current reports on prognostic factors for chondrosarcoma mainly involve patients in treatment centers. Few are based on multicenter or multi-eras. We analyzed existing data from the Surveillance, Epidemiology, and End Results (SEER) database to investigate the risk factors for survival outcomes. All patients with chondrosarcoma from 1973 to 2012 were identified. 3737 patients were eligible and included. In survival analysis, patient had good survival outcome if the patient was female, young, with localized stage, well grade, small tumor size, treated with surgery, while patient was male, old, with distant stage, undifferentiated grade, tumor size <50 mm, located in vertebral or pelvic bones, underwent radiation had bad survival outcome. Surgery types from having best survival outcomes to worst were local excision, radical excision, amputation, no surgery. ‘Well’ and ‘moderately’ grade seems to be suitable for local excision, but ‘poorly’ and ‘undifferentiated’ grade suitable for wide local excision. Multivariate COX regression analysis showed year of diagnosis, sex, age of diagnosis, stage, grade, tumor site, surgery, radiation were independent risk factors. Year of diagnosis, sex, age of diagnosis, stage, grade, tumor site, surgery, radiation were independent risk factors. Excision is a better treatment than amputation. Doctors can use wide local excision to treat chondrosarcoma, especially when encountering high grade chondrosarcoma or pelvic chondrosarcoma.

Enchondromas and atypical cartilaginous tumors at the proximal humerus treated with intralesional resection and bone cement filling with or without osteosynthesis: retrospective analysis of 42 cases with 6\xa0years mean follow-up

BackgroundEnchondromas and atypical cartilaginous tumors (ACT) are often located at the proximal humerus. Most lesions can be followed conservatively, but surgical resection may alleviate pain, avoid pathological fractures, and prevent transformation into higher grade chondrosarcomas. Rigorous intralesional resection and filling with polymethylmethacrylate bone cement has been proposed for enchondromas but also for ACT, as an alternative for extralesional resection. We intended to analyze radiological, clinical, and functional outcome of this strategy and compare bone cement without osteosynthesis to bone cement compound osteosynthesis, which has not been analyzed so far.MethodsWe retrospectively analyzed 42 consecutive patients (mean follow-up 73 months; range 8–224) after curettage and bone cement filling with or without osteosynthesis. Exclusion criteria were Ollier’s disease and cancellous bone filling. Twenty-five patients only received bone cement. Seventeen patients received additional proximal humerus plate for compound osteosynthesis to increase stability after curettage. Demographics and radiological and clinical outcome were analyzed including surgery time, blood loss, hospitalization, recurrences, and complications. An additional telephone interview at the final follow-up assessed postoperative satisfaction, pain, and function in the quick disabilities of the arm, shoulder, and hand (DASH) score and the Musculoskeletal Tumor Society (MSTS) score. Statistics included the Student T tests, Mann-Whitney U tests, and chi-square tests.ResultsNo osteosynthesis compared to compound osteosynthesis showed smaller tumors (4.2 (± 1.5) cm versus 6.6 (± 3.0) cm; p = 0.005) and smaller bone cement fillings after curettage (5.7 (± 2.1) cm versus 9.6 (± 3.2) cm; p = 0.0001). A score evaluating preoperative scalloping and soft-tissue extension did not significantly differ (1.9 (± 0.9) versus 2.0 (± 1.0); rating scale 0–4; p = 0.7). Both groups showed high satisfaction (9.2 (± 1.5) versus 9.2 (± 0.9); p = 0.5) and low pain (1.0(±1.7) versus 1.9(±1.8); p = 0.1) in a rating scale from 0 to 10. Clinical and functional outcome was excellent for both groups in the DASH score (6.0 (± 11.8) versus 11.0 (± 13.2); rating scale 0–100; p = 0.2) and the MSTS score (29.0 (± 1.7) versus 28.7 (± 1.1); rating scale 0–30; p = 0.3). One enchondroma recurrence was found in the group without osteosynthesis. Complications (one fracture and one intra-articular screw) were only detected after osteosynthesis. Osteosynthesis had longer surgery time (70 (± 21) min versus 127 (± 22) min; p < 0.0001), more blood loss (220 (± 130) ml versus 460 (± 210) ml; p < 0.0001), and longer stay in the hospital (6 (± 2) days versus 8 (± 2) days; p = 0.004).ConclusionsIntralesional tumor resection was oncologically safe and clinically successful with or without osteosynthesis. Osteosynthesis did not reduce the risk for fracture but was more invasive.

Chondrosarcoma of the Osseous Spine Treated by Surgery With or Without Radiotherapy: A Propensity Score Matched and Grade/Stage-stratified Study.

This was a longitudinal cohort study. The main objective of this study was to investigate the outcomes of surgery with or without radiotherapy during treatment of patients with chondrosarcoma of the osseous spine. Chondrosarcoma is a primary spinal malignant tumor; chemotherapy and radiotherapy (RT) are generally unsuccessful, and thus, the main treatment of choice is complete en bloc resection. However, even with complete resection, these patients still have a significant rate of recurrence, morbidity, and mortality. Although there have been reports that the addition of RT to surgery may lead to increased survival and better cancer control, the evidence of the efficacy of RT remains controversial. Patients diagnosed with chondrosarcoma who are then treated by surgery alone or surgery+RT were identified and extracted from the SEER (Surveillance, Epidemiology, and End Results) database (1973-2013). Propensity score matched (PSM) analysis was performed to balance patient characteristics between surgery alone and surgery+RT groups. Patients with a different grade and stage were stratified and analyzed. A total of 778 patients with chondrosarcoma of the osseous spine treated by surgery alone or surgery+RT were extracted from the SEER database. Before PSM, the unadjusted Kaplan-Meier curve and bivariable Cox proportional hazard regression models showed that the surgery alone group had higher chondrosarcoma cancer-specific survival and overall survival than the surgery+RT group (both P<0.001), while the difference was attenuated after PSM. Stratified analysis found that RT was worse for low-grade chondrosarcoma patients and had a better trend for high-grade chondrosarcoma patients. The results of our present study suggest that low-grade chondrosarcoma of the osseous spine is resistant to RT, while high-grade chondrosarcoma patients had a better trend with RT. Level III.

Pelvic Chondrosarcoma - The Role of the Biopsy and the Correlation Between the Histopathological Bioptic Diagnosis and the Excisional One

Abstract Chondrosarcoma is one of the most frequent malignant bone tumors. We included in the initial study population 110 patients with pelvis biopsies and the histopathological result of chondrosarcoma. We excluded the cases with incomplete data. Thirty-five in block resections were included in the final study population. In the rest of the cases, the surgery was not made because of many considerations (multiple metastases, patient’s refusal, and surgical contraindications). In three cases, discrepancies were noted between the grade of malignancy found after biopsy and the one confirmed through the surgical excision. This corresponds to a precision rate of 91,42 % (32/ 35) in the confirmation of chondrosarcoma. The accuracy of the histopathological diagnosis between low grade chondrosarcoma and high grade chondrosarcoma was of 94,27 % (33/ 35). We concluded that the image-guided biopsy is useful in determining the grade of malignancy of the chondrosarcoma and in the planning of the subsequent treatment. A multidisciplinary team (orthopaedic surgeon, radiologist, and pathologist) is needed to improve the diagnosis of the pelvic chondrosarcoma.

Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas

BackgroundThere are few studies detailing the incidence, patient outcomes and prognostic factors for chondrosarcomas (CS). Those that do exist have small sample sizes and/or use older datasets. The purpose of this study was to determine the incidence, overall survival (OS) and prognostic factors for OS of CS patients, as well as investigate the efficacy of curettage. MethodsWe analyzed data of 2186 patients diagnosed with chondrosarcomas between ’89-‘13 from the Netherlands Cancer Registry. The effect of risk factors on OS was assessed with a multivariate Cox regression. Median Follow-up was determined with reversed Kaplan-Meier. OS was estimated using Kaplan-Meier method. ResultsThe relative incidence of CS was 2.88 per million citizens between ’89-’96, 4.15 between ’96-‘04 and 8.78 between ’05-’13. Most of the increase in incidence came from atypical cartilaginous tumours/grade I chondrosarcoma (ACT/CS I). The 3-, 5- and 10-years survival were, respectively, 96%, 93% and 88% for ACT/CS I, 82%, 74% and 62% for grade II CS and 38%, 31% and 26% for grade III CS. Prognostics factors significantly associated with OS were age, histological grade, year of diagnosis, tumour location and size. ConclusionThe incidence of CS, and especially ACT/CS I, has increased over time, which could be driven by both an ageing population and increased diagnostic imaging. With the increased number of diagnosed ACT/CS I, the number of preventative curettages of this tumour has also increased. Despite the supposed preventative character of this treatment, the incidence of high-grade CS did not decrease.

Retrospective audit of 957 consecutive 18F-FDG PET\u2013CT scans compared to CT and MRI in 493 patients with different histological subtypes of bone and soft tissue sarcoma

BackgroundThe use of 18F-FDG PET–CT (PET–CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET–CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with 18FDG SUVmax, secondly, the practical uses of PET–CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET–CT over concurrent conventional CT and MRI.MethodsA total of 957 consecutive PET–CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET–CT SUVmax values in relation to histology and FNCCC grading. We compared PET–CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and treatment responses.ResultsHigh-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma. Lower SUVmax values were observed in sarcomas of low histological grade (grade I), and in rare subtypes of intermediate grade soft tissue sarcoma (e.g. alveolar soft part sarcoma and solitary fibrous tumour). SUVmax variation was noted in malignant peripheral nerve sheath tumours, compared to the histologically benign plexiform neurofibroma, whereas PET–CT could clearly differentiate low from high-grade chondrosarcoma. We identified added utility of PET–CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues. An estimated 21% overall potential benefit was observed for PET–CT over CT/MRI, and in particular, in ‘upstaging’ of high-grade disease (from M0 to M1) where an additional 12% of cases were deemed M1 following PET–CT.ConclusionsPET–CT in high-grade bone and soft tissue sarcoma can add significant benefit to routine CT/MRI staging. Further prospective and multi-centre evaluation of PET–CT is warranted to determine the actual predictive value and cost-effectiveness of PET–CT in directing clinical management of clinically complex and heterogeneous high-grade sarcomas.

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation.

IntroductionChondrosarcoma is a malignant cartilage-forming bone tumour in which mutations in IDH1 and IDH2 frequently occur. Previous studies suggest an increased dependency on glutaminolysis in IDH1/2 mutant cells, which resulted in clinical trials with the drugs CB-839, metformin and chloroquine. In this study, the preclinical rationale for using these drugs as a treatment for chondrosarcoma was evaluated.MethodsExpression of glutaminase was determined in 120 cartilage tumours by immunohistochemistry. Ten chondrosarcoma cell lines were treated with the metabolic compounds CB-849, metformin, phenformin (lipophilic analogue of metformin) and chloroquine.ResultsA difference in glutaminase expression levels between the different tumour grades (p = 0.001, one-way ANOVA) was identified, with the highest expression observed in high-grade chondrosarcomas. Treatment with CB-839, metformin, phenformin or chloroquine revealed that chondrosarcoma cell lines are sensitive to glutaminolysis inhibition. Metformin and phenformin decreased mTOR activity in chondrosarcoma cells, and metformin decreased LC3B-II levels, which is counteracted by chloroquine.ConclusionTargeting glutaminolysis with CB-839, metformin, phenformin or chloroquine is a potential therapeutic strategy for a subset of high-grade chondrosarcomas, irrespective of the presence or absence of an IDH1/2 mutation.

GABAB receptor regulates proliferation in the high-grade chondrosarcoma cell line OUMS-27 via apoptotic pathways

BackgroundHigh-grade chondrosarcoma, which has a high incidence of local recurrence and pulmonary metastasis despite surgical resection, is associated with poor prognosis. Therefore, new and effective adjuvant therapies are urgently required for this disease. Gamma-aminobutyric acid (GABA), which acts as a neurotrophic factor during nervous system development, is related to the proliferation and migration of certain cancer cells. The GABAergic system, which is composed of GABA, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), and GABA receptors, has an important function in nerve growth and development of neural crest. Therefore, the GABAergic system may play important functional roles in the proliferation of chondrosarcoma cells, which are derived from neural crest cells. We examined the anti-tumor effects of the GABAergic system on a chondrosarcoma cell line.MethodsWe evaluated the underlying mechanisms of the anti-tumor effects of the GABAergic system, such as the involvement of different signaling pathways, apoptosis, and cell cycle arrest, in the high-grade chondrosarcoma cell line OUMS-27. In addition, we performed whole-cell patch-clamp recordings for Ca2+ currents and evaluated the changes in intracellular Ca2+ concentration via Ca2+ channels, which are related to the GABAB receptor in high-grade chondrosarcoma cells.ResultsThe GABAB receptor antagonist CGP had anti-tumor effects on high-grade chondrosarcoma cells in a dose-dependent manner. The activities of caspase 3 and caspase 9 were significantly elevated in CGP-treated cells compared to in untreated cells. The activity of caspase 8 did not differ significantly between untreated cells and CGP-treated cells. However, caspase 8 tended to be up-regulated in CGP-treated cells. The GABAB receptor antagonist exhibited anti-tumor effects at the G1/S cell cycle checkpoint and induced apoptosis via dual inhibition of the PI3/Akt/mTOR and MAPK signaling pathways. Furthermore, the changes in intracellular Ca2+ via GABAB receptor-related Ca2+ channels inhibited the proliferation of high-grade chondrosarcoma cells by inducing and modulating apoptotic pathways.ConclusionsThe GABAB receptor antagonist may improve the prognosis of high-grade chondrosarcoma by exerting anti-tumor effects via different signaling pathways, apoptosis, cell cycle arrest, and Ca2+ channels in high-grade chondrosarcoma cells.

Controversy over the Use of Proton Therapy for the Treatment of Tumors of Central Nervous System

Proton beam therapy (PBT) is one of the most discussed topics in contemporary oncology. PBT is characterized by certain physical properties that make it theoretically better as a treatment than standard photon therapy. On the other hand, there are some uncertainties regarding the localization of the dose peak (Bragg peak) in real clinical situations and the value of radiobiological effectiveness at the end of proton beam. Unfortunately, the high expectations of PBT have not been fulfilled in published clinical studies. In the present article, the results of PBT are compared with those of standard photon therapy for the treatment of low-and high-grade gliomas, pituitary adenomas, vestibular schwannomas, chordomas and chondrosarcomas, and pediatric central nervous system tumors. PBT was not better in tumor control or in reducing toxicity than photon therapy. The higher risk of post-radiation brain tissue necrosis after PBT is alarming. PBT is mostly considered for pediatric tumors, because the radiobiological models predict lower damage to neurocognitive functions and a reduction in secondary malignancies. However, this hypothesis has its opponents and sufficient clinical data to justify the models are still lacking. The cost of PBT is several times higher than that of photon therapy. PBT is a revolutionary technology in modern radiotherapy, but so far, clinical data have not proved it to be superior to that of standard photon therapy. PBT should be considered on an individual basis in cases where modern photon therapy cannot meet the dose limits of healthy tissues.Key words: proton therapy - neoplasms - central nervous systemSubmitted: 24. 10. 2017Accepted: 23. 11. 2017 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Synergistic anti-proliferative effects of mTOR and MEK inhibitors in high-grade chondrosarcoma cell line OUMS-27

Chondrosarcoma is a malignant bone tumor that produces cartilaginous neoplastic tissue. Owing to the absence of an effective adjuvant therapy, high-grade chondrosarcoma has a poor prognosis. Therefore, it is important to develop an effective adjuvant therapy to prevent the recurrence and metastasis. Mammalian target of rapamycin (mTOR), a central regulator of cell growth, metabolism, proliferation, and survival, is considered an important target for anticancer drug development. The mitogen activated protein kinase (MAPK) pathway is another highly implicated cellular pathway in cancer and is thought to have compensatory effects in response to the inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway. We investigated the mechanism of anti-proliferative effect of the mTOR inhibitor rapamycin and MAPK/ERK (MEK) inhibitor PD 0325901, and the combined effect of rapamycin and PD 0325901 on human chondrosarcoma cell line (OUMS-27). Combination therapy with rapamycin and PD 0325901 showed a stronger anti-proliferative effect on OUMS-27 cells than rapamycin monotherapy. We confirmed that the dual inhibition of the PI3K/Akt/mTOR and RAF/MEK/ERK signaling pathways had synergistic anti-proliferative effects in OUMS-27. Our results suggest that combination therapy of mTOR and MEK inhibitor could be an effective therapeutic approach against chondrosarcoma.

Knee joint reconstruction using liquid nitrogen recycled autograft prosthesis composite after wide resection for high-grade chondrosarcoma

Background: Chondrosarcoma is the second most common malignant primary tumor of bone. The prognosis for chondrosarcoma depends mainly on its histologic grading and location. High-grade chondrosarcoma has higher a tendency to recur and metastasize. The standard treatment for chondrosarcoma is wide resection without adjuvant therapy. Numerous reconstructive options are available, varying from endoprostheses, biological reconstruction using allografts or osteoarticular allografts, and recycling of tumor-bearing segment. Methods: We retrospectively reviewed seven patients with high-grade chondrosarcoma who underwent wide resection of the tumor mass and reconstruction using liquid nitrogen treated recycled autograft prosthesis composite. Evaluation was done for local recurrence, metastasis, graft-bone union, osteosynthesis, implant, or graft-related complications. The functional outcome was assessed by the Musculoskeletal Tumour Society scoring system. Results: The mean follow-up period was 46 mo (range 24-65 mo). The average duration for graft union was 8.2 mo (range 7-10 mo). No local recurrence was detected in any patient. None of them had any metastatic deposits. One had a superficial wound infection. One had fulminant infection that required hip disarticulation. The mean Musculoskeletal Tumour Society functional score was 67.7% (range 60-78). Conclusions: Recycled autograft prosthesis composite using liquid nitrogen is an oncologically safe and effective reconstructive option for the management of chondrosarcoma around the knee. It maintains knee function and restores the bone stock. It overcomes endoprosthesis-related problems, overcoming the obstacles of allograft in countries where it is not available or not socially or religiously acceptable.

NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma.

Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714-21. ©2017 AACR.

Highlights of This Issue

The receptor tyrosine kinase AXL is aberrantly expressed in many tumors, is a potent driver of invasive cell motility and has become increasingly recognized as a broadly relevant mechanism in cancer drug resistance. Here, it is reported that exposure of cancer cells to phosphatidylserine (PS)-expressing apoptotic bodies enhances migration of tumor cells via a PS-AXL signaling axis. These findings suggest that anti-cancer therapies that induce fractional cell killing contribute to the motility of surviving cells in AXL-expressing tumors, hence generating potentially problematic invasive and metastatic behavior.Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway. In this study, in vitro experiments reveal that chondrosarcoma cells exhibit a dose-dependent decrease in cell viability, 3D collagen invasion and colony formation upon treatment with NAMPT inhibitors. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. Therefore, chondrosarcoma patients, especially those of high histological grade with lower expression and hypermethylation of NAPRT, may benefit clinically from inhibition of the NAD synthesis pathway.Few actionable oncogenic driver mutations have been identified in nasopharyngeal carcinoma (NPC). However, a marked lymphocytic infiltrate and association with viral infection make immunotherapy an intriguing treatment option. Zhang and colleagues perform the first integrated analysis of gene expression, mutation, copy number, and clinical data in NPC, identifying gene expression subtypes characterized by distinct immune and Epstein-Barr virus (EBV) associated gene expression patterns. Prognostic associations with stromal tumor-infiltrating lymphocytes and a proliferation signature were also identified. This study is an important step in understanding how NPC tumor cells and EBV influence the tumor microenvironment (TME), and may help guide immunotherapy strategies in this disease.TWIST1 promotes tumorigenesis through induction of EMT, invasion and metastasis, as well as suppression of oncogene-induced senescence and apoptosis. Additionally, TWIST1 expression is required for oncogene-driven lung cancer, including tumors driven by mutant KRAS. Using a chemical-bioinformatic approach, Yochum and colleagues identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC. Targeting TWIST1 with a small-molecule therapeutic such as harmine and its potential analogues/derivatives, represents a novel treatment strategy in oncogene-driven lung cancer and other solid malignancies in which TWIST1 promotes tumorigenesis.

5'-methylschweinfurthin G reduces chondrosarcoma tumor growth .

New treatment options are urgently required in the field of chondrosarcoma, particularly of chondrosarcomas with a well-differentiated hyaline cartilage-like extracellular matrix (e.g., collagen II and proteoglycan-rich) phenotype, notoriously resistant to drug penetration, and having potential of progression towards higher grade. We investigated the feasibility of using 5'-methylschweinfurthin G (MeSG) as a tumor suppressor agent in the Swarm rat chondrosarcoma, an intermediate- to high-grade chondrosarcoma model, having a hyaline cartilage-like phenotype. Tumor cell culture studies were performed to identify their proliferative and cytotoxicity sensitivity to MeSG. Tumor burden mice were treated with MeSG and analyzed for tumor growth, morphology and regression. The chondrosarcoma tumor cells had a half maximum cytotoxicity concentration (IC50 ) of 35 nM MeSG; approximately 300-fold less than freshly isolated rat chondrocytes (IC50 of 11 µM). Multiple injections of MeSG (20 mg/kg, body weight) resulted in reduced/eliminated tumor growth over a 17-day period in mice, and an 83% reduction (p = 0.023) in tumor mass. Three out of ten MeSG treated mice had complete elimination of tumor. Tumors of treated mice had a decrease in chondrosarcoma cell proliferation (p = 0.012) and an increase in cell death (p = 0.030) compared with tumors of control mice. These findings in an animal model demonstrate the effectiveness of MeSG for treatment of rat chondrosarcomas, and may have the potential use as a therapeutic option for the difficult-to-treat intermediate-to high-grade hyaline cartilage-like chondrosarcoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1283-1293, 2018.

Chondrosarcoma of bone: A retrospective study of surgical management of 30 cases

Background: Chondrosarcomas are tumors that predominantly consist of cartilage and account for approximately 25% of all bone sarcomas. These tumors are relatively resistant to chemo and radiotherapy. They are classified into conventional Chondrosarcomas, de-differentiated Chondrosarcoma, mesenchymal Chondrosarcoma, juxtracortical Chondrosarcoma and secondary Chondrosarcoma on the basis of histopathology and whether or not they have occurred in a previously benign cartilaginous lesion. They are further subdivided into low grade, intermediate grade and high grade Chondrosarcoma on the basis of cellularity, atypia and pleomorphism. The clinical features of Chondrosarcoma include dull aching pain especially during night time, neurological symptoms (due to nerve involvement) and pathological fractures. Diagnosis is done by imaging and histopathology. Surgery is the primary treatment and consists of complete and wide excision whenever possible. Chemo and radiotherapy has got a limited role. We conducted this retrospective study of 30 patients with Chondrosarcoma treated with uniform surgical protocol at our institution. Materials and Methods: After obtaining approval from institutional ethical committee we conducted a retrospective study of 30 patients diagnosed with chondrosarcoma. Since Chondrosarcomas are rare we searched for the patients records diagnosed with Chondrosarcoma and details were studied from case papers and patient examination during follow up. All patients had undergone surgical treatment of primary tumors. The various surgeries done in these patients included wide excision, Tikhoff-Linberg procedures, wide chest wall resections and hemipelvectomies depending upon the site and size of the tumors. Minimum follow up was 24 months. The data was tabulated and analyzed using SPSS 16.0 version software. Results: This study consisted of 30 patients having been diagnosed with Chondrosarcoma. There were 18 men and 12 women with a mean age of 34 years (range 18–50 years). The most common clinical features these patients presented with were swelling (76.66%) followed by pain (66.66 %), neurological symptoms due to nerve involvement (16.66%), fumigating skin lesion (13.33%) and pathological fractures (6.66%). Patients were diagnosed on the basis of Imaging (XRAY/CT /MRI) and biopsy followed by histopathological examination. Most common bones involved were femur (30%) followed by pelvic bones (26.67%) and humerus (13.33%). Various surgical procedures done included complete excision in 15 patients (50%) followed by Likhoff-Linberg procedure (20%), chest wall resections (16.66%) and hemipelvectomy (13.33%). 9 patients were lost to follow up. Out of remaining 21 patients 15 patients (50%) remained recurrence free during a follow up period of 24 months while 6 patients (20%) presented with either localized recurrence or metastasis. Conclusions: Chondrosarcomas are heterogeneous group of tumors ranging from low-grade to very aggressive, high-grade forms. In individuals presenting with localized disease wide surgical resection represents the primary treatment modality. Recurrences and metastatic disease is difficult to manage as chemotherapy is usually ineffective. Radiotherapy may be used in such cases as a palliation therapy.

Utility of VS38c in the diagnostic and prognostic assessment of osteosarcoma and other bone tumours/tumour-like lesions

BackgroundVS38c is a monoclonal antibody that recognises a rough endoplasmic reticulum (rER) intracellular antigen termed cytoskeleton-linking membrane protein 63. rER is typically found in viable tumour cells and is abundant in osteosarcoma cells. The aim of this study was to determine the diagnostic and prognostic utility of VS38c in the histological assessment of osteosarcoma and other bone tumours/tumour-like leisons.MethodsImmunohistochemical staining with VS38c was carried out on formalin-fixed specimens of osteosarcoma (pre/post-chemotherapy) and a wide range of benign and malignant bone lesions. In addition, VS38c staining of cultures of MG63 and Sa0S2 osteosarcoma cell cultures. (±cisplatin and actinomycin D-treatment) was analysed.ResultsVS38c strongly stained tumour cells in all low-grade and high-grade osteosarcomas and in undifferentiated sarcomas and high-grade chondrosarcomas. There was little or no VS38c staining of low-grade chondrosarcomas or chordomas and variable staining of Ewing sarcomas. Osteoblasts in benign bone-forming tumours and mononuclear stromal cells in chondroblastomas, giant cell tumours and non-ossifying fibromas strongly stained for VS38c. VS38c staining was absent in cisplatin and actinomycin D treated Sa0S2 and MG63 cells. In specimens of osteosarcoma post-neoadjuvant therapy, VS38c staining was absent in most morphologically necrotic areas of tumor although some cells with pyknotic nuclei stained for VS38c in these areas. Most tumour cells exhibiting atypical nuclear forms were not stained by VS38c.ConclusionsOur findings show that VS38c is a sensitive but not specific diagnostic marker of osteosarcoma. Staining with VS38c identifies viable osteosarcoma cells, a feature which may be useful in the assessment of percentage tumour necrosis post-neoadjuvant chemotherapy.

Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines

Synovial sarcoma and high grade chondrosarcoma are characterized by their lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates.Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using histone deacetylases inhibitors (HDACi) have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of different HDACi on synovial- and chondrosarcoma cells has not been investigated. In this study, vorinostat (SAHA), panobinostat (LBH-589), and belinostat (PXD101) decreased cell viability of synovial sarcoma (SW-982) and chondrosarcoma (SW-1353) cells in a time- and dose dependent manner and arrested SW-982 cells in the G1/S phase. Western blot analysis determined the responsible cell cycle regulator proteins. In addition, we found apoptotic induction by caspase 3/7 activity, caspase 3 cleavage, and PARP cleavage. In SW-1353 cells only SAHA showed comparable effects. Noteworthy, all HDACi tested had synergistic effects with the topoisomerase II inhibitor doxorubicin in SW-1353 chondrosarcoma cells making the cells more sensitive to the chemotherapeutic drug.Our results show for the first time that SAHA and LBH-589 reduced viability of sarcoma cells and arrested them at the G1/S checkpoint, while also inducing apoptosis and enhancing chemotherapeutic sensitivity, especially in chondrosarcoma cells. These data demonstrate the exciting potential of HDACi for use in sarcoma treatment.

What are the differentiating clinical and MRI-features of enchondromas from low-grade chondrosarcomas?

To evaluate the role of clinical assessment, conventional and dynamic contrast-enhanced MRI in differentiating enchondromas from chondrosarcomas of long bone. The following clinical and MRI findings were assessed: age, gender, pain, pain attributable to lesion, tumour location, tumour length, presence, depth of endosteal scalloping, bone marrow oedema, soft tissue oedema, cortical destruction, periosteal reaction, bone expansion, macroscopic fat, calcification, soft tissue mass, haemorrhage, dynamic contrast-enhanced MRI. Clinical and MRI findings were compared with histopathological grading. Sixty patients with central chondroid tumours were included (27 enchondromas, 10 cartilaginous lesions of unknown malignant potential, 15 grade 1 chondrosarcomas, 8 high-grade chondrosarcomas). Pain attributed to lesion, tumour length, endosteal scalloping > 2/3, cortical destruction, bone expansion and soft tissue mass were differentiating features between enchondromas and grade 1 chondrosarcomas. Dynamic contrast-enhanced MRI could not differentiate enchondromas from grade 1 chondrosarcomas. Previously reported imaging signs of chondrosarcomas are useful in the diagnosis of grade 1 lesions but have lower sensitivity than in higher grade lesions. Deep endosteal scalloping is the most sensitive imaging sign of grade 1 chondrosarcomas. Pain due to the lesion is an important clinical sign of grade 1 chondrosarcomas. Dynamic contrast-enhanced MRI is not useful in differentiating enchondromas from grade 1 chondrosarcomas. • Differentiation of enchondroma from low-grade chondrosarcoma is challenging for radiologists and pathologists. • The utility of clinical assessment, conventional and dynamic contrast-enhanced MRI was uncertain. • Clinical assessment and conventional MRI aid in differentiating enchondromas from low-grade chondrosarcoma. • Dynamic contrast-enhanced MRI cannot differentiate enchondromas from grade 1 chondrosarcoma.