Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma.

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 µmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.

Extraskeletal myxoid chondrosarcoma: A high incidence of metastatic disease to lymph nodes.

BACKGROUND: Extraskeletal myxoid chondrosarcoma (ESMC) is a rare type of soft-tissue sarcoma with limited series reporting outcome of treatment. Currently there is limited data on the incidence and impact on patient outcome in those with metastatic disease to lymph nodes in ESMC. METHODS: Thirty (21 males, 9 females) patients, mean age 50 ± 16 years, with ESMC were reviewed. The tumors were most commonly located in the lower extremity (n = 23, 77%) and the mean tumor size and volume were 9 ± 5 cm and 490 ± 833 cm3 . Mean follow up was 7 ± 4 years. RESULTS: Six (20%) patients either presented (n = 3, 10%) or developed (n = 3, 10%) lymph node metastatic disease. When comparing patients without, with lymph node metastasis and metastasis elsewhere, patients with lymph nodes metastasis had worse survival than those without metastasis, however better 10-year disease specific survival than those with metastasis elsewhere (100% vs 62% vs 0%; P < .001). CONCLUSION: There is a high incidence of lymph node metastatic disease in patients with ESMC. Although survival in these patients is worse compared to those without metastasis, their survival is better than those with metastasis elsewhere. Due to the high incidence of lymph node metastatic disease, preoperative staging of the lymph node should be considered.

Ablation of soft tissue tumours by long needle variable electrode-geometry electrochemotherapy: final report from a single-arm, single-centre phase-2 study.

Standard electrochemotherapy (ECT) is effective in many tumour types but is confined to the treatment of small superficial lesions. Variable electrode-geometry ECT (VEG-ECT) may overcome these limitations by using long freely-placeable electrodes. Patients with bulky or deep-seated soft-tissue malignancies not amenable to resection participated in a single-arm phase-2 study (ISRCTN.11667954) and received a single course of VEG-ECT with intravenous bleomycin (15,000 IU/m2) and concomitant electric pulses applied through an adjustable electrode array. The primary outcome was radiologic complete response rate (CRR) per RECIST; secondary endpoints included feasibility, metabolic response, toxicity (CTCAE), local progression-free survival (LPFS) and patient perception (EQ-5D). During 2009-2014, we enrolled 30 patients with trunk/limb sarcomas, melanoma, Merkel-cell carcinoma, and colorectal/lung cancer. Median tumour size was 4.7 cm. Electrode probes were placed under US/TC guidance (28 and 2 patients, respectively). Median procedure duration was 80 minutes. Tumour coverage rate was 97% (29 of 30 patients). Perioperative side-effects were negligible; one patient experienced grade-3 ulceration and infection. One-month 18F-FDG-SUV decreased by 86%; CRR was 63% (95% CI 44-79%). Local control was durable in 24 of 30 patients (two-year LPFS, 62%). Patients reported an improvement in "usual activities", "anxiety/depression", and "overall health" scores. VEG-ECT demonstrated encouraging antitumour activity in soft-tissue malignancies; a single course of treatment produced high and durable responses, with low complications.

Extraskeletal Myxoid Chondrosarcomas: Combined Modality Therapy With Both Radiation and Surgery Improves Local Control.

OBJECTIVE: We evaluated our experience treating patients with localized extraskeletal myxoid chondrosarcomas (EMCs) to evaluate outcomes and relapse rates in order to better inform treatment decisions for these rare soft tissue sarcomas. MATERIALS AND METHODS: We reviewed the records of 41 consecutive patients with localized EMC treated at our institution from 1990 to 2016. Most patients (n=33, 80%) received combined modality therapy with surgery and radiation therapy, whereas only 8 (20%) underwent surgery alone. The Kaplan-Meier method was used to estimate rates of overall survival, disease-specific survival, local control (LC), and distant metastatic-free survival (DMFS). RESULTS: Median follow-up time was 94 months (range, 8 to 316). The 10-year LC, DMFS, disease-specific survival, and overall survival rates were 90%, 69%, 85%, and 66%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range, 13 to 176). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10 y LC, 63% vs. 100% for combined modality therapy, P=0.004), which remained the only factor also significant on the multivariable analysis (P=0.02; hazard ratio [HR], 12.7; 95% confidence interval [CI], 1.4-115.3). In total, 13 patients (32%) developed distant metastatic at a median time of 28 months (range, 3 to 154). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04; HR, 3.9; 95% CI, 1.1-14.7). CONCLUSIONS: For patients with EMC, surgery alone was associated with a higher risk of local recurrence. Therefore, we recommend optimal local therapeutic strategies upfront with both surgery and radiation therapy to reduce the risk of local and ultimately distant recurrence.

Results and functional outcomes of en-bloc resection and vascular reconstruction in extremity musculoskeletal tumors.

OBJECTIVES: This paper aims to evaluate the extremity function and vascular outcome after limb-sparing surgery for extremity musculoskeletal tumors invading vascular structure required reconstruction. METHODS: Of the 507 patients with musculoskeletal tumors, who underwent surgery between 2004 and 2007, 17 (3,3%) patients with major vessel involvement were included in the study. The mean age was 37.8 ± 14.5, with a female/male ratio of 8/9. Thirteen (76.4%) patients had Stage IIb disease, and 2 (11,7%) patients had Stage III disease. In 2 (11,7%) patients have locally aggressive tumor that had Stage 3. Fifteen (88.2%) of the cases involved lower extremity, whilst 2 (11.8%) of them involved upper extremity. An arterial reconstruction was carried out in all patients. Wide tumor resection and endoprosthetic reconstruction were performed in 6 (35.2%) patients. Other 11 (65.8%) patients were treated with wide resection and soft tissue reconstruction. Postoperative data included; perioperative morbidities such as bleeding, infection, graft thrombosis, rupture, metastatic local recurrence and mortality. Ankle brachial index (ABI) and color-flow-duplex-scan (CFDS) were done at the final follow-up of the study, in order to prove the efficacy of reconstruction. Functional outcome was evaluated with International Society of Limb Salvage (ISOLS) criteria. RESULTS: The mean follow-up was of 39 months (range 3-120). Perioperative complications were arterial graft thrombosis occurred in 3 (17.6%) patients treated acutely with thrombectomy, uncontrolled deep wound infection occurred in 2 patients whom extremities were amputated. The most frequent complication after surgery was limb edema according to possibly venous and lymphatic obstruction, staged as C1, C2 and C3 disease was established in 6 patients (two patients in each group), and 1 patient was classified as C6 disease. Three (17.6%) patients had local recurrence (1/3 patient died and 2/3 (11.7%) patients underwent transfemoral amputation). At the last follow-up, 9 (52.9%) patients were alive without evidence of disease, 8 (47.1%) patients were died due to primary disease. There were 8 (47.1%) patients alive with an intact limb. Although functional outcome scores were satisfactory, emotional acceptance scores were low. The limb salvage probability was 74.0%. CONCLUSION: Limb-sparing oncological surgery in musculoskeletal tumors with vascular invasion provides a satisfactory limb function, which may lead to an improved life quality. Arterial reconstruction has a high rate of patency in the long term. The surgeon should be aware of early perioperative complication related to vascular reconstruction and infection that effect on the rate of extremity survival. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma.

Chondrosarcoma is the most common bone sarcoma in adults. Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy. There have been anecdotal reports of durable clinical benefit with antiangiogenic agents in this disease. A retrospective search of patients treated at three sarcoma referral centers was performed to identify patients with advanced chondrosarcoma treated with antiangiogenic agents. The aim of this study was to evaluate the efficacy and safety of antiangiogenic agents in advanced chondrosarcoma. Ten patients were identified; seven with conventional, one each with clear cell, extraskeletal mesenchymal chondrosarcoma and extraskeletal myxoid chondrosarcoma. The median progression-free survival for patients with conventional and clear cell sarcoma was 22.6 months. Median overall survival has not been met. Antiangiogenic therapy was well tolerated in this series of patients. Our retrospective data suggest that antiangiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients. Further prospective trials are required to precisely define the role of this class of agent in advanced chondrosarcoma.

Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma.

BACKGROUND: Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study. METHODS: Five subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review. RESULTS: The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4-not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3-1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4-26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive. CONCLUSIONS: This sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy. TRIAL REGISTRATION: The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Clinicopathologic and radiologic features of extraskeletal myxoid chondrosarcoma: a retrospective study of 40 Chinese cases with literature review.

The aim of this study is to describe the clinicopathologic and radiologic features of 40 cases of extraskeletal myxoid chondrosarcoma (EMC) from China. There were 25 males and 15 females (sex ratio, 1.7:1). Apart from an adolescent, all patients were adults with a median age of 49years. Twenty-four tumors (60%) occurred in the lower limb and limb girdles, especially the thigh, followed by the upper limb and limb girdles (20%) and trunk (10%). Other less commonly involved locations included the head and neck, sacrococcygeal region, and perineum. Tumors ranged in size from 1.5 to 19cm (mean, 7cm). By radiology, they appeared as hypoattenuated or isoattenuated masses on computed tomography with hyperintense signal on T2-weighted magnetic resonance imaging. Intralesional hypointense septa were present in most cases. Of the 40 tumors, 30 belonged to the classic subtype, whereas 9 cases were cellular, and 1 case had a rhabdoid phenotype. Tumor cells showed variable expression of synaptophysin (36%), S-100 protein (29%), epithelial membrane antigen (11%), and neuron-specific enolase (7%). Ki-67 index was remarkably higher in the cellular variant (mean, 30%). EWSR1-related rearrangement was detected in 12 of 14 cases tested by fluorescence in situ hybridization using break-apart probes. The overall 5- and 7-year survival was 71% and 60%, respectively. Awareness of the imaging features may help pathologists in the diagnosis of EMC. Fluorescence in situ hybridization also serves as a useful diagnostic tool for EMC, especially in the distinction from its mimics.

Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.

Extraskeletal myxoid chondrosarcomas (EMC) are rare soft tissue sarcomas with distinctive histology and uncertain histogenesis, characterized by Ewing sarcoma breakpoint region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3) fusion in 75% of the cases. A smaller proportion of cases show NR4A3 fused to other gene partners including TATA binding protein-associated factor 15 (TAF15), transcription factor 12 (TCF12), and TRK-fused gene (TFG). The impact of various gene fusions on morphology and outcome has not been previously evaluated. We investigated 26 consecutive EMCs and correlated the genetic findings with morphology and clinical outcome. There were 5 females and 21 males (median age, 49.5 years). Mean size of the tumors was 11 cm. Fluorescence in situ hybridization analysis showed EWSR1-NR4A3 gene fusion in 16 cases (62%), TAF15-NR4A3 gene fusion in 7 cases (27%), and TCF12-NR4A3 gene fusion in 1 case (4%). Two cases showed only NR4A3 gene rearrangements. Morphologically, most EWSR1-rearranged tumors (10/16) showed low cellularity, minimal cytologic atypia, and low mitotic counts. In contrast, 80% of EMCs with variant (non-EWSR1) NR4A3 gene fusions (TAF15, TCF12) had high-grade morphology with increased cellularity, proliferation, and cytologic atypia, showing a plasmacytoid/rhabdoid morphology in half the cases. Follow-up showed that only 1 of 16 patients with EWSR1-rearranged tumors died of disease, in contrast to 3 (43%) of 7 TAF15-rearranged tumors. In conclusion, EMCs with variant NR4A3 gene fusions show a higher incidence of rhabdoid phenotype, high-grade morphology, and a more aggressive outcome compared with the EWSR1-NR4A3 positive tumors. Furthermore, fluorescence in situ hybridization assay for NR4A3, along with EWSR1, may be an additional ancillary test to confirm diagnosis of EMCs.

Expression of insulin-like growth factor 2 in mesenchymal neoplasms.

The insulin-like growth factor (IGF) system plays an important role in the growth and development of cells and has been implicated in oncogenesis and tumor progression. Gene expression profiling studies on limited numbers of specimens have shown high expression of IGF2, encoding the activating ligand for this system, in gastrointestinal stromal tumors (GISTs) and in synovial sarcomas. This data may have concrete clinical implications, as several reports exist of patients with GISTs suffering from severe hypoglycemia, a predicted effect of IGF2. Furthermore, new drugs targeting IGF signaling are entering clinical trials. The purpose of this study is to survey IGF2 expression at the protein level on a broad number of mesenchymal tumors representing all major diagnostic classes. By immunostaining tissue microarrays, results were obtained for 51 diagnostic categories of bone and soft-tissue tumors representing 1288 cases. Distinct membranous and/or cytoplasmic IGF2 immunoreactivity was assessed according to published criteria. Solitary fibrous tumors had the highest expression. Of 20 tumor types represented by more than 10 cases, synovial sarcomas, myxoid liposarcomas, GISTs, malignant peripheral nerve sheath tumors, chondrosarcomas, undifferentiated pleomorphic sarcomas (MFH), Ewing's sarcomas and tenosynovial giant cell tumors showed high levels of expression in more than 20% of cases. Of the 445 GIST cases with clinical information, those with high expression of IGF2 had a significantly worse outcome than those with low or no expression. IGF2 protein expression among mesenchymal tumors is largely consistent with gene expression studies and suggests a potential for molecular therapy targeting the IGF signaling pathway system in these neoplasms.

Outcome after surgical treatment of suspected gastrointestinal stromal tumors involving the duodenum: is limited resection appropriate?

INTRODUCTION: Present surgical opinion is divided regarding the optimal method for the treatment of duodenal gastrointestinal stromal tumor (GIST) with some supporting the selective use of limited resection (LR) versus others who prefer pancreaticoduodenectomy (PD). METHODS: A retrospective review of 22 patients who underwent surgery for suspected GIST involving the duodenum. RESULTS: There were 15 GISTs, 1 leiomyosarcoma and 6 other non-GIST benign submucosal tumors. Seven patients underwent LR and seven underwent PD for GIST. The median follow-up was 42 (range, 2-174) months. Patients who underwent LR versus PD had similar mean disease-specific survival [144 (95% CI, 92-196) vs. 130 (95% CI, 82-127) months, P = 0.808] and recurrence rates (14% vs. 29%, P = 0.515). All recurrences occurred at distant sites. Comparison between LR versus PD demonstrated that LR was associated with a significantly shorter operation time [125 (range, 50-305) vs. 350 (range, 210-465) min., P = 0.001] but similar morbidity rate (23% vs. 43%, P = 0.357). Comparison between GIST and other benign tumors demonstrated that size was the only statistically significant distinguishing factor [8.5 (range, 2.5-18.0) vs. 2.5 (range, 1.5-8.0) cm, P = 0.014]. CONCLUSION: Benign non-GIST tumors may be distinguished from duodenal GIST as they are smaller in size. LR is a viable treatment option for suspected GIST involving the duodenum.

Expression of decorin, a small leucine-rich proteoglycan, as a prognostic factor in soft tissue tumors.

BACKGROUND AND OBJECTIVES: Decorin is a major extracellular matrix protein which has recently become the focus of various cancer studies. However, there have so far been no reports describing the clinicopathological implications of decorin in soft tissue tumors. The aim of this study was to examine whether decorin expression is a prognostic factor in soft tissue tumors. METHODS: Decorin expression was examined in 85 samples obtained from 77 patients by real-time quantitative PCR and immunohistochemistry. RESULTS: Lower levels of decorin were expressed in liposarcoma and malignant peripheral nerve sheath tumor than in lipoma (<0.01) and neurofibroma (P < 0.05), respectively. An immunohistochemical analysis for spindle-cell sarcomas demonstrated decorin protein to be produced by myofibroblastic cells in the peripheral stromal extracellular spaces. On a Kaplan-Meier analysis, lower levels of decorin were associated with lower disease-free and overall survival rates (P < 0.05) in 31 spindle-cell sarcomas. A multivariate analysis revealed a significant correlation between a reduced decorin expression and a poor disease-free survival (P = 0.04). In all seven patients with recurrent or metastatic lesions, the decorin expression levels were lower in secondary lesions than in primary lesions. CONCLUSIONS: A reduced decorin expression was found to be a useful biomarker of aggressiveness in soft tissue tumor.