Detection of early prognostic biomarkers for metastasis of Ewing's sarcoma in pediatric patients.

AIMS: Ewing's Sarcoma is an extremely aggressive tumor in children. The disease is associated with highly metastatic rate, especially at the time of diagnosis, contributing to a lower survival rate and poor prognosis. The study aimed to identify predictive biomarkers for metastatic Ewing's sarcoma through in-depth analysis of the plasma proteome profile of pediatric Ewing's sarcoma patients. MAIN METHODS: Plasma samples from Ewing's sarcoma patients and control individuals were profiled using both shotgun and dimethyl-labeled proteomics analysis. Subsequently, Ewing's sarcoma patients were further stratified according to their metastatic state and chemotherapy response. Western blot was used for validation. Univariate and multivariate analyses were performed to determine proteome metastasis predictors. Receiver operating characteristic (ROC) analysis was done to assess the diagnostic significance of the potential plasma Ewing's sarcoma biomarkers. KEY FINDINGS: Our results revealed a set of proteins significantly associated with the metastatic Ewing's sarcoma disease profile. These proteins include ceruloplasmin and several immunoglobulins. Additionally, our study disclosed significant differentially expressed proteins in pediatric Ewing's sarcoma, including CD5 antigen-like, clusterin, and dermcidin. Stable isotope dimethyl labeling and western blot further confirmed our results, strengthening the impact of such proteins in disease development. Furthermore, an unbiased ROC curve evaluated and confirmed the predictive power of these biomarker candidates. SIGNIFICANCE: This study presented potential empirical predictive circulating biomarkers for determining the disease status of pediatric Ewing's sarcoma, which is vital for early prediction.

Comparative Shotgun Proteomics Reveals the Characteristic Protein Signature of Osteosarcoma Subtypes.

Osteosarcoma is a primary malignant bone tumor affecting adolescents and young adults. This study aimed to identify proteomic signatures that distinguish between different osteosarcoma subtypes, providing insights into their molecular heterogeneity and potential implications for personalized treatment approaches. Using advanced proteomic techniques, we analyzed FFPE tumor samples from a cohort of pediatric osteosarcoma patients representing four various subtypes. Differential expression analysis revealed a significant proteomic signature that discriminated between these subtypes, highlighting distinct molecular profiles associated with different tumor characteristics. In contrast, clinical determinants did not correlate with the proteome signature of pediatric osteosarcoma. The identified proteomics signature encompassed a diverse array of proteins involved in focal adhesion, ECM-receptor interaction, PI3K-Akt signaling pathways, and proteoglycans in cancer, among the top enriched pathways. These findings underscore the importance of considering the molecular heterogeneity of osteosarcoma during diagnosis or even when developing personalized treatment strategies. By identifying subtype-specific proteomics signatures, clinicians may be able to tailor therapy regimens to individual patients, optimizing treatment efficacy and minimizing adverse effects.

Cross-cultural adaptation and validation of a self-reporting tool to assess health-related quality of life for Egyptians with extremity bone sarcomas in childhood or adolescence.

BACKGROUND: Validated self-reporting tools are required to evaluate the functional outcome and health-related quality of life (HRQOL) for those who had extremity bone sarcomas in their childhood or adolescence. Our study pursued cross-cultural adaptation and validation of the pediatric Toronto Extremity Salvage Score (pTESS) and Toronto Extremity Salvage Score (TESS) to assess the functional outcome for Egyptian children and adult survivors following surgeries of extremity bone sarcomas. In the modified versions of pTESS and TESS, mental domains were added to allow the evaluation of HRQOL using a specific instrument for childhood bone cancer. METHODS: The internal consistency and test-retest reliability of the studied forms were assessed with Cronbach's alpha and Intra-class coefficients (ICC), respectively. For convergent validity, correlations between scores of the generic Pediatric Quality of Life Inventory (PedsQL 4.0) and pTESS /TESS scores were reported. Factor Analysis was feasible for pTESS-leg; due to the insufficient samples, only the average inter-item correlation coefficients were reported for the remaining versions. RESULTS: Out of 233 participants, 134 responded to pTESS-leg, 53 to TESS-leg, 36 to pTESS-arm, and only 10 to TESS-arm. All versions showed excellent internal consistency (Cronbach's alpha >0.9), good test-retest reliability (ICC >0.8), moderate to strong correlations with PedsQL, and acceptable average inter-item correlation coefficients (≥0.3). Three factors were extracted for the pTESS-leg, in which all mental items were loaded on one separate factor with factor loadings exceeding 0.4. Active chemotherapy, less than one year from primary surgery, or tibial tumors were associated with significantly inferior pTESS/TESS scores in the lower extremity group. CONCLUSION: The Egyptian pTESS and TESS are valid and reliable self-reporting tools for assessing the functional outcome following surgeries for extremity bone sarcomas. The modified pTESS and TESS versions, which include additional mental domains, enabled the assessment of the overall health status of our population. Future studies should include a larger sample size and evaluate the ability of pTESS/TESS to track progress over time.

What is the Cumulative Incidence of Revision Surgery and What Are the Complications Associated With Stemmed Cementless Nonextendable Endoprostheses in Patients 18 Years or Younger With Primary Bone Sarcomas About the Knee.

BACKGROUND: Osteosarcoma and Ewing sarcoma are more common diagnoses in preadolescent and adolescent children compared with the adult population. A greater percentage of patients are treated with limb salvage and reconstruction using modular tumor endoprostheses. Implant-to-bone fixation can be cemented or cementless. Cementless tumor endoprostheses rely on biologic osteointegration for implant stability, and chemotherapy during childhood and adolescence can disturb the bone turnover rate and reduce bone mineral density, which in turn may predispose patients with uncemented endoprostheses to a high rate of revision surgeries. QUESTIONS/PURPOSES: (1) What is the cumulative incidence of revision operations for any cause (wound dehiscence, periprosthetic fracture, hinge breakage, aseptic loosening, infection, local recurrence, implant removal, and amputation) of cementless tumor endoprostheses around the knee? (2) What is the cumulative incidence of aseptic loosening, periprosthetic fracture, hinge breakage, and infection, and what proportion of patients had other complications? (3) What was the mean limb length discrepancy (LLD) at the time of skeletal maturity? (4) What was the median Musculoskeletal Tumor Society (MSTS) score at most recent follow-up or just before implant removal/amputation if implant removal/amputation were performed? METHODS: Between 2008 and 2019, we treated 328 patients younger than 18 years for a primary bone sarcoma around the knee at our institution. Of those, 138 were treated with resection and reconstruction using two different types of modular tumor endoprostheses. During this period, our general indications for an endoprosthesis were patients who were candidates for an intraarticular resection of the distal femur or proximal tibia and who were at least 10 years of age. Uncemented fixation was always preferred. Cemented fixation was only done when intraoperative press-fitting of a cementless stem was not possible. Among uncemented implants, 26 patients died before completing 2 years of follow-up with intact implants and without further surgery, three were lost to follow-up before 2 years, and four patients received implants as a secondary salvage surgery after a failed primary biologic reconstruction with a vascularized fibular bone graft, leaving 94 patients for evaluation in this retrospective study. The mean age was 15 ± 2 years and the median (interquartile range) follow-up duration was 51 months (39 to 74). We did a competing risks analysis to tally cumulative incidence of all-cause revision procedures and cumulative incidence of aseptic loosening, periprosthetic fracture, hinge breakage, and infection. Other complications, including wound dehiscence, local recurrence, and stem breakage, were characterized descriptively and ascertained by review of electronic records of a longitudinally maintained institutional database by the treating surgeons. LLD was measured by serial clinical assessments and CT scans, starting since primary salvage surgery and until the latest follow-up of every patient. For the analysis of remaining LLD, we included only patients who were skeletally immature at time of primary resection and who had reached skeletal maturity by their latest follow-up (73% [69 of 94]). Functional outcome was assessed using MSTS scores obtained from a review of electronic records of a longitudinally maintained institutional database. RESULTS: The 8-year cumulative incidence of revision surgery for any cause was 32% (95% confidence interval 23% to 42%). The 8-year cumulative incidence of aseptic loosening was 5% (95% CI 2% to 11%), periprosthetic fracture was 9% (95% CI 4% to 15%), hinge breakage was 19% (95% CI 12% to 28%), and infection was 7% (95% CI 3% to 14%). Other complications included wound dehiscence in 2% (2 of 94), stem breakage in 2% (2 of 94), and local recurrence in 2% (2 of 94) of patients. Stress shielding of the cortical bone around implanted stems was observed in 26% (24 of 94). The mean LLD for those who were skeletally immature at the time of primary resection and who reached skeletal maturity was 3.5 ± 2.6 cm. At latest follow-up, the median (IQR) MSTS score for all patients, excluding those who had complete implant removal or amputation, was 26 (24 to 27) of a maximum score of 30. CONCLUSION: We observed a high rate of early revision and relatively frequent complications associated with the use of cementless fixation, and although this was not a comparative study, the findings were not superior to those reported by others who have studied cemented fixation for this indication. Furthermore, there may be some disadvantages with cementless fixation, such as stress shielding. Comparative studies about fixation methods are needed. The prevalence of bushing breakage in the current study highlights the importance of future modifications in the hinge design of both types of prostheses used in this study. Patients who were skeletally immature at the time of primary surgery had a LLD no more than 5 cm at skeletal maturity; consequently, nonexpandable endoprostheses may be appropriate for some adolescent patients who have limited remaining growth, although which patients are best suited for this approach would require specific study. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Different 18 F-FDG PET parameters for the prediction of histological response to neoadjuvant chemotherapy in pediatric Ewing sarcoma family of tumors.

BACKGROUND: The histological response to neoadjuvant chemotherapy (NAC) in pediatric patients with Ewing sarcoma family of tumors (ESFT) can predict the disease-free survival. Therefore, a noninvasive method for response assessment is needed. Using the currently established imaging modalities, mass reduction does not always correlate with the percentage of necrosis. OBJECTIVE: To determine the potential role of 18 fluorine-labeled fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET) metabolic parameters in the prediction of poor histological response to NAC in pediatric patients with ESFT. METHODS: Thirty-six patients who were treated with NAC and surgery at the Children's Cancer Hospital, Egypt, were prospectively included in this study. All patients underwent two studies; a PET/CT study before NAC and another one after NAC completion. Metabolic PET parameters were measured in each study. The ability of each of these parameters, their pretreatment and pre-local control values, as well as the percentage reduction between their pretreatment and pre-local control values, were evaluated to differentiate between good and poor responders using the histological response as a standard reference. RESULTS: Neither the pretreatment value nor the percentage reduction of any of the measured PET parameters predicted poor histological response. After NACcompletion, metabolic tumor volume (MTV) at the threshold of an SUV of 2.5 isocontour (MTV(2.5)post ), MTV at the threshold of hepatic reference SUVmean (MTV(HR)post ), and total lesion glycolysis at the threshold of hepatic reference SUVmean (TLG(HR)post ) predicted poor histological response (P  = 0.006, 0.018, and 0.003, respectively). The cutoff values of 90% reduction of TLG(HR) and maximum standardized uptake value (SUVmax)post ≤2.5 could differentiate between good and poor responders. CONCLUSION: FDG PET parameters can predict poor histological response to NAC in ESFT patients. MTV and TLG at the thresholds of an SUV of 2.5 isocontour and hepatic reference SUVmean are the two most promising thresholds in predicting the response of patients. The cutoff value of SUVmaxpost ≤2.5 predicts poor histological response.

Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma.

Aim: Scarce data assessing the real value of whole lung irradiation (WLI) in Ewing's sarcoma (ES) with lung-only metastasis, with published conflicting results. We studied the impact of WLI in a homogenous pediatric population. Materials & methods: Retrospective study evaluating the survival outcomes of WLI in these patients. Results: Out of 163 metastatic ES; 41 patients were eligible for WLI. 30 patients (73.1%) received WLI (+ve) while 11 patients (26.8%) did not receive WLI (-ve). Five-year event-free survival was statistically significant in WLI (+ve). Five-year pulmonary relapse-free survival showed trend for improvement with WLI (+ve), while 5-year overall survival was not statistically significant between the two arms. Conclusion: WLI added significantly to the long term clinical outcome of metastatic ES patients, with no irreversible toxicity.