Treatment Outcomes of Pediatric Patients With Ewing Sarcoma in a War-Torn Nation: A Single-Institute Experience From Iraq.

PURPOSE: Ewing sarcoma (ES) is a relatively rare, highly malignant tumor of the musculoskeletal system. It is the second most common malignant bone tumor in children and adolescents in the age group of 5 to 20 years. The aim of this study was to identify the treatment outcomes of pediatric patients with ES in Sulaimani governorate, Iraq. PATIENTS AND METHODS: This was a retrospective study that reviewed the medical records of pediatric patients with ES who were managed between 2009 and 2015, with follow-up until late 2017. Patient- and tumor-related factors were correlated with clinical outcomes. RESULTS: A total of 31 pediatric patients with ES were included in this study. All the patients received chemotherapy and radiotherapy, whereas only 14 patients underwent surgical resection and just eight had free surgical margins. The median age at diagnosis was 13 years, 58% were male, and 42% were female. The presenting symptoms at diagnosis were mostly pain (67.7%) and palpable mass (25.8%). The primary tumor was located in the extremities (51.6%), the thoracic cage (19.4%), the pelvis (16.1%), and the lumbar vertebrae (12.9%). Approximately two thirds of the patients (61.3%) had localized disease at the time of presentation. The 5-year overall survival was 19%, and the 5-year recurrence-free survival was 34%. CONCLUSION: Clinical outcomes of ES in pediatric patients in our war-torn nation, Iraq, are still markedly inferior to the published outcomes from stable, developed nations. Additional large and multicenter national studies are required. Diagnostic and therapeutic measures need improvement, and multidisciplinary and comprehensive cancer-integrated approaches are vital for better outcomes.

Antitumor effects of ß-elemene via targeting the phosphorylation of insulin receptor.

Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein ß-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. ß-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of ß-elemene on IR signaling pathway. ß-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by ß-elemene specifically in tumor cells other than normal hepatocytes. In addition, ß-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the ß-elemene-treated xenografts. These data suggest that ß-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by ß-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.

Preclinical Justification of pbi-shRNA EWS/FLI1 Lipoplex (LPX) Treatment for Ewing's Sarcoma.

The EWS/FLI1 fusion gene is well characterized as a driver of Ewing's sarcoma. Bi-shRNA EWS/FLI1 is a functional plasmid DNA construct that transcribes both siRNA and miRNA-like effectors each of which targets the identical type 1 translocation junction region of the EWS/FLI1 transcribed mRNA sequence. Previous preclinical and clinical studies confirm the safety of this RNA interference platform technology and consistently demonstrate designated mRNA and protein target knockdown at greater than 90% efficiency. We initiated development of pbi-shRNA EWS/FLI1 lipoplex (LPX) for the treatment of type 1 Ewing's sarcoma. Clinical-grade plasmid was manufactured and both sequence and activity verified. Target protein and RNA knockdown of 85-92% was demonstrated in vitro in type 1 human Ewing's sarcoma tumor cell lines with the optimal bi-shRNA EWS/FLI1 plasmid. This functional plasmid was placed in a clinically tested, liposomal (LP) delivery vehicle followed by in vivo verification of activity. Type 1 Ewing's sarcoma xenograft modeling confirmed dose related safety and tumor response to pbi-shRNA EWS/FLI1 LPX. Toxicology studies in mini-pigs with doses comparable to the demonstrated in vivo efficacy dose resulted in transient fever, occasional limited hypertension at low- and high-dose assessment and transient liver enzyme elevation at high dose. These results provide the justification to initiate clinical testing.

Extraskeletal Ewing sarcomas in late adolescence and adults: a study of 37 patients.

BACKGROUND: Extraskeletal Ewing sarcoma (EES)/primitive neuroectodermal tumours (PNET) are rare soft tissue sarcomas. Prognostic factors and optimal therapy are still unconfirmed. MATERIALS AND METHODS: We performed a retrospective analysis on patients to explore the clinic characteristics and prognostic factors of this rare disease. A total of 37 patients older than 15 years referred to our institute from Jan., 2002 to Jan., 2012 were reviewed. The characteristics, treatment and outcome were collected and analyzed. RESULTS: The median age was 28 years (range 15-65); the median size of primary tumours was 8.2 cm (range 2-19). Sixteen patients (43%) had metastatic disease at the initial presentation. Wide surgical margins were achieved in 14 cases (38%). Anthracycline or platinum-based chemotherapy was performed on 29 patients (74%). Radiotherapy was delivered in 13 (35%). At a median follow-up visit of 24 months (range 2-81), the media event-free survival (EFS) and overall survival (OS) were 15.8 and 30.2 months, respectively. The 3-year EFS and OS rates were 24% and 43%, respectively. Metastases at presentation and wide surgical margins were significantly associated with OS and EFS. Tumour size was significantly associated with OS but not EFS. There were no significant differences between anthracycline and platinum based chemotherapy regarding EFS and OS. CONCLUSIONS: EES/PNET is a malignant tumour with high recurrence and frequent distant metastasis. Multimodality therapy featuring wide surgical margins, aggressive chemotherapy and adjuvant local radiotherapy is necessary for this rare disease. Platinum-based chemotherapy can be used as an adjuvant therapy.

Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival.

PURPOSE: Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models. EXPERIMENTAL DESIGN: The sensitivity of osteosarcoma and Ewing's sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing's sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells. RESULTS: In vitro, both osteosarcoma and Ewing's sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8-mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model. CONCLUSION: These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors.

Adjusting survival curves for confounders: a review and a new method.

When reporting results from survival analysis, investigators often present crude Kaplan-Meier survival curves and adjusted relative hazards from the Cox proportional hazards model. Occasionally, the investigators will also provide a graphical representation of adjusted survival curves based on regression estimates and the average covariate values in the study groups. In this paper, the authors review the limitations of this approach and examine alternative approaches to obtaining adjusted survival curves that have been proposed. Furthermore, a new method to obtain multivariate adjusted survival curves is described. This method is based on direct adjustment of the observed conditional probability of survival at the time of each event. When an unexposed group is used as a standard for adjusting an exposed group, the survival curve in the exposed group is adjusted to the covariate distribution among the unexposed at the time of the event. This method has the advantage over the average covariate method of allowing for the possibility that the adjusted survival curves differ in shape. The method can handle multiple fixed or time-dependent categorical covariates as well as left truncated data, and it allows for estimation of confidence intervals. The authors have written a macro in SAS language that produces the adjusted survival estimates and graphs. This macro is available on request and can be downloaded through the World Wide Web.

[Regional cytostatic perfusion of the extremities in patients with malignant melanoma and soft tissue sarcoma--therapeutic applications and results]. / Die regionale zytostatische Extremitätenperfusion bei Patienten mit malignem Melanom und Weichteilsarkom--therapeutische Anwendungen und Ergebnisse.

94 patients with malignant melanoma or soft tissue sarcoma of the extremities were submitted to isolated cytostatic limb perfusion. With palliative indication for treatment of malignant melanoma, the 5 year survival rate was 25% after perfusion with methotrexate and 50% after perfusion with melphalan. The adjuvant perfusion showed very good results, too. Furthermore, the authors report on their first experiences in regional cytostatic perfusion of soft tissue sarcoma and bone sarcoma.

A prospective, randomized study of adjuvant parenteral nutrition in the treatment of sarcomas: results of metabolic and survival studies.

A prospective, randomized study was performed to evaluate the use of total parenteral nutrition (TPN) in a group of young patients receiving aggressive chemotherapy for metastatic or locally recurrent sarcomas. Fourteen patients were randomly selected to receive TPN and 18 to receive conventional oral nutritional support (CN). During the study period (from first dose of chemotherapy to recovery from myelosuppression), the TPN patients received between 1020 and 2100 calories/m2/day (median 1650) and between 5.3 and 12.4 gmN/m2/day (median 8.9), while the CN patients received between 380 and 880 calories/m2/day (median 685) and between 0.0 and 3.7 gmN/m2/day (median 1.5). The mean daily nitrogen balance during the study period for the TPN group (-3.0 to + 1.3 gmN/m2/day, median -0.7) was significantly higher (p = 0.005) than that of the CN group (-6.2 to -0.7 gmN/m2/day, median -2.6). Serum protein levels (albumin, total protein, and transferrin) did not differ between the two treatment groups. The proportion of patients responding to therapy and the long-term survival rates were similar in the treatment groups. Thus despite established improvement in nitrogen balance, no survival or therapeutic advantage was demonstrated for the adjuvant parenteral nutrition group. Further studies of the role of parenteral nutrition as an adjuvant to cancer chemotherapy are needed to determine which populations of patients will benefit from its use.