High-grade Osteosarcoma Research Articles

Prognostic Significance of Microvessel Density and Hypoxic Markers in Canine Osteosarcoma: Insights into Angiogenesis and Tumor Aggressiveness

Canine osteosarcoma (OSA) is an aggressive and highly malignant tumor of bone with a poor prognosis and it mirrors the disease in humans. Angiogenesis, the formation of new blood vessels, is driven by hypoxia-induced factors such as HIF-1α and VEGF, both of which play a crucial role in tumor growth and metastasis. However, the role of angiogenesis in OSA remains a topic of ongoing debate. This study aimed to investigate the relationship between angiogenesis, measured by intratumoral microvessel density (MVD), hypoxic markers, and clinical outcomes in 28 dogs diagnosed with appendicular OSA. Clinicopathological data such as age, breed distribution, tumor localization, histopathological subtypes, and metastatic behavior were consistent with reported epidemiologic characteristics of canine OSA, though no significant correlation was found among these variables. The results indicated a significant association between higher MVD and high-grade OSA (p = 0.029), suggesting that increased tumor vascularization is linked to more aggressive tumor behavior. Additionally, elevated VEGF expression was strongly correlated with disease-free interval DFI), with a p-value of 0.045. Although HIF-1α positivity showed a trend towards poorer survival, the results did not reach statistical significance (p = 0.07). These findings highlight the potential role of VEGF as a valuable prognostic marker in canine OSA, which could have potentially important implications for therapeutic targeting and clinical management of the disease. This study advances the understanding of angiogenesis in canine OSA, while emphasizing the need for continued research into the complex mechanisms regulating the interplay between hypoxia, angiogenesis and tumor progression.

Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma

The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines. To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma. The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock). The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review. The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics. A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm. Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design. ClinicalTrials.gov Identifier: NCT04154189.

Osteoblastoma Recurring as High-grade Osteosarcoma

Abstract Introduction/Objective Osteoblastoma is a benign, bone-forming neoplasm that presents as a well-circumscribed lesion amenable to excision. The prognosis is good despite a 20% recurrence risk. Malignant transformation is very rare. Osteoblastoma-like osteosarcoma is a rare form of osteosarcoma that shares similar clinical, radiographic, and pathological characteristics Methods/Case Report A 24-year-old female presented with a large palpable mass in the posterior occiput. The lesion progressively enlarged over 2 years, finally becoming symptomatic. Magnetic resonance imaging demonstrated an extradural posterior fossa expansile skull mass measuring 6.0 x 5.7 x 4.7 cm that showed multiple fluid/fluid levels. The mass was resected. Pathology demonstrated a well-circumscribed neoplasm that was cellular and composed of large polyhedral osteoblasts with eccentric oval nuclei and abundant amphophilic cytoplasm. Tumor cells were intimately associated with numerous small interconnecting, irregular bony trabeculae. Scattered mitotic figures of normal configuration were noted. The findings were compatible with an epithelioid osteoblastoma with prominent secondary aneurysmal bone cyst-like changes. The patient was lost to follow-up but presented 3 years later with severe migraines. Imaging demonstrated a large heterogeneous enhancing mass centered about the occipital cranioplasty with both intracranial and extracranial components. Reexcision was performed. Sections showed a well- circumscribed tumor, delineated by a rim of subperiosteal reactive bone, with an epithelioid morphology. However, it also demonstrated areas of necrosis, extensive sheet-like growth, conspicuous mitoses, and cytological atypia not seen in the previous specimen. Therefore, diagnosis of osteoblastoma-like osteosarcoma was rendered after expert consultation. Results (if a Case Study enter NA) NA Conclusion This case highlights the exceedingly rare evolving nature of osteoblastomas and their high-grade transformation potential.

Extra-Skeletal Osteosarcoma of the Prostate After Treated Prostatic Acinar Adenocarcinoma: A Case Report and Review of the Literature.

Extra-skeletal osteosarcoma is a rare form of malignant soft tissue sarcoma. Its occurrence in the prostate gland is particularly uncommon. In this case report, we present a patient diagnosed with osteosarcoma arising within the prostatic gland. A 58-year-old man was initially diagnosed with Gleason 8 prostate acinar adenocarcinoma following a transurethral resection (TUR) of the prostate. This diagnosis was accompanied by locoregional involvement and multiple bone metastases. The patient underwent a treatment regimen including complete androgen blockade, chemotherapy, greenlight laser prostate vaporization, and palliative radiotherapy. After treatment, he achieved a complete biochemical response, and his bone metastases remained stable. However, at 16 months post-diagnosis, clinical follow-up by means of radiological examinations revealed an increase in the size of the prostatic lesion, along with additional infiltration of the tumor into the rectum and bladder walls. Remarkably, a mesenchymal tumor proliferation with intratumor calcifications was observed. A subsequent TUR biopsy of the prostate showed a malignant tumor spindle and ovoid cell proliferation with high-grade nuclear atypia, necrosis, and islets of osteoid formation, leading to a final diagnosis of high-grade prostatic extra-skeletal osteosarcoma. Despite undergoing chemotherapy, the patient's condition progressed with the development of pulmonary and liver metastases, culminating in his demise.

Long term survival in adult osteosarcoma patients treated with a two-drug regimen: Final results of the OSAD93 phase II study of the FSG-GETO

RationaleWe report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. Patients and methodsThis is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m2 and CDDP 100 mg/m2 on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie ≤ 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. ResultsFrom Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16–63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3–4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. ConclusionThough the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.

Dynamic Prediction of Overall Survival for Patients with Osteosarcoma: A Retrospective Analysis of the EURAMOS-1 Clinical Trial Data.

Current prediction models for patients with ostosarcoma are restricted to predictions from a single, static point in time, such as diagnosis or surgery. These approaches discard information which becomes available during follow-up and may have an impact on patient's prognosis. This study aims at developing a dynamic prediction model providing 5-year overall survival (OS) predictions from different time points during follow-up. The developed model considers relevant baseline prognostic factors, accounting for where appropriate time-varying effects and time-varying intermediate events such as local recurrence (LR) and new metastatic disease (NM). A landmarking approach is applied to 1965 patients with high-grade resectable osteosarcoma from the EURAMOS-1 trial (NCT00143030). Results show that LR and NM negatively affected 5-year OS (HRs: 2.634, 95% CI 1.845-3.761; 8.558, 95% CI 7.367-9.942, respectively). Baseline factors with strong prognostic value (HRs > 2) included poor histological response (≥10% viable tumor), axial tumor location, and the presence of lung metastases. The effect of poor versus good histological response changed over time, becoming non-significant from 3.25 years post-surgery onwards. This time-varying effect, as well as the strong impact of disease-related time-varying variables, show the importance of including updated information collected during follow-up in the model to provide more accurate survival predictions.

A dynamic microRNA profile that tracks a chemotherapy resistance phenotype in osteosarcoma. Implications for novel therapeutics.

Osteosarcoma is a rare primary bone tumor for which no significant therapeutic advancement has been made since the late 1980s despite ongoing efforts. Overall, the five-year survival rate remains about 65%, and is much lower in patients with tumors unresponsive to methotrexate, doxorubicin, and cisplatin therapy. Genetic studies have not revealed actionable drug targets, but our group, and others, have reported that epigenomic biomarkers, including regulatory RNAs, may be useful prognostic tools for osteosarcoma. We tested if microRNA (miRNA) transcriptional patterns mark the transition from a chemotherapy sensitive to resistant tumor phenotype. Small RNA sequencing was performed using 14 patient matched pre-chemotherapy biopsy and post-chemotherapy resection high-grade osteosarcoma frozen tumor samples. Independently, small RNA sequencing was performed using 14 patient matched biopsy and resection samples from untreated tumors. Separately, miRNA specific Illumina DASL arrays were used to assay an independent cohort of 65 pre-chemotherapy biopsy and 26 patient matched post-chemotherapy resection formalin fixed paraffin embedded (FFPE) tumor samples. mRNA specific Illumina DASL arrays were used to profile 37 pre-chemotherapy biopsy and five post-chemotherapy resection FFPE samples, all of which were also used for Illumina DASL miRNA profiling. The National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatments dataset, including PCR based miRNA profiling and RNA-seq data for 86 and 93 pre-chemotherapy tumor samples, respectively, was also used. Paired differential expression testing revealed a profile of 17 miRNAs with significantly different transcriptional levels following chemotherapy. Genes targeted by the miRNAs were differentially expressed following chemotherapy, suggesting the miRNAs may regulate transcriptional networks. Finally, an in vitro pharmacogenomic screen using miRNAs and their target transcripts predicted response to a set of candidate small molecule therapeutics which potentially reverse the chemotherapy resistance phenotype and synergize with chemotherapy in otherwise treatment resistant tumors. Importantly, these novel therapeutic targets are distinct from targets identified by a similar pharmacogenomic analysis of previously published prognostic miRNA profiles from pre chemotherapy biopsy specimens.

Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study

BackgroundThe prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting.Patients and methodsThe study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5.ResultsThe trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3–4 non-haematological toxicities.Conclusions14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Preoperative prediction of high-grade osteosarcoma response to neoadjuvant therapy based on a plain CT radiomics model: A dual-center study

ObjectiveTo develop a model combining clinical and radiomics features from CT scans for a preoperative noninvasive evaluation of Huvos grading of neoadjuvant chemotherapy in patients with HOS. Methods183 patients from center A and 42 from center B were categorized into training and validation sets. Features derived from radiomics were obtained from unenhanced CT scans.Following dimensionality reduction, the most optimal features were selected and utilized in creating a radiomics model through logistic regression analysis. Integrating clinical features, a composite clinical radiomics model was developed, and a nomogram was constructed. Predictive performance of the model was evaluated using ROC curves and calibration curves. Additionally, decision curve analysis was conducted to assess practical utility of nomogram in clinical settings. ResultsLASSO LR analysis was performed, and finally, three selected image omics features were obtained.Radiomics model yielded AUC values with a good diagnostic effect for both patient sets (AUCs: 0.69 and 0.68, respectively). Clinical models (including sex, age, pre-chemotherapy ALP and LDH levels, new lung metastases within 1 year after surgery, and incidence) performed well in terms of Huvos grade prediction, with an AUC of 0.74 for training set. The AUC for independent validation set stood at 0.70. Notably, the amalgamation of radiomics and clinical features exhibited commendable predictive prowess in training set, registering an AUC of 0.78. This robust performance was subsequently validated in the independent validation set, where the AUC remained high at 0.75. Calibration curves of nomogram showed that the predictions were in good agreement with actual observations. ConclusionCombined model can be used for Huvos grading in patients with HOS after preoperative chemotherapy, which is helpful for adjuvant treatment decisions.

High-grade surface osteosarcoma: A National Cancer Database study of demographic characteristics.

e23508 Background: High-grade surface osteosarcoma (HGSO) is an extremely rare malignant subtype of osteosarcoma. HGSO often affects long bones, particularly the femur, and is the rarest subtype of surface osteosarcomas. Though data is limited, current information suggests this cancer presents with a poor prognosis, generally affecting adults aged 20 to 40. Current treatment standards involve wide resection and chemotherapy. The National Cancer Database (NCDB) was examined to establish the demographic factors among HGSO patients and identify diagnostic and treatment trends. Methods: A retrospective cohort study from 2005-2020 was conducted using the NCDB. A total of 99 patients were found with a histologically confirmed diagnosis of high-grade surface osteosarcoma (ICD-9194-3). Factors such as gender, age, race, insurance status, rural/urban residence, treatments, mortality rates, and Charles/Deyo scores were analyzed using descriptive statistics, and trends in incidence were interpreted via regression analysis. Results: Yearly HGSO incidence rates increased from 2005 to 2020 (R2 = 0.19). The average age of diagnosis was 41 years (SD = 24.9, range = 10-90) with men diagnosed (54%) slightly more than women. The majority of patients were non-Hispanic white (73%), had private insurance (55%), and lived in a metropolitan area with over 250,000 in population (89%). The average patient was diagnosed at a hospital 40.4 miles away from their home (SD = 84.9, range 0.4-648.4 miles). Most patients (55%) were in stage II at diagnosis, and 86% of patients had a Charlson-Deyo comorbidity score of 0. The most common primary site of this malignancy was the long bones of the lower limb and associated joints (67%), while the upper extremities (8%) and pelvic bone (8%) served as less common primary sites. Surgery was the most common primary treatment (62%). Data from 69 patients revealed the 90-day mortality post-surgery was 3%. The mean survival rate was 70% at two years and 52% at five years. Conclusions: To the best of our knowledge, this study represents the first NCDB analysis of HGSO. Our analysis demonstrated that HGSO occurs most often, but not exclusively, within the lower extremity long bones, which may be an important diagnostic distinction. It was previously indicated that the average age at HGSO diagnosis is 20-40 years, but our analysis suggested it is closer to 40. Our analysis revealed a five-year survival rate of 52% which is worse than prior studies have indicated. Demographic data has revealed the majority of patients were non-Hispanic white, privately insured, and living within a metropolitan area. This trend may suggest access to healthcare resources is influencing this cancer’s diagnosis and treatment. Further research is warranted to explore whether the demographic patterns seen in HGSO are indicative of biological causes or socioeconomic factors that are significantly influencing diagnosis.

Evaluation of tumor immune microenvironment for PD-L1 score and tumor infiltrating lymphocytes in high grade osteosarcomas and their correlation with disease progression.

e23510 Background: Tumor Immune Micro-environment is being increasingly recognised as a potential target for improving overall survival for osteosarcomas, especially in the metastatic setting. Our study purpose was to evaluate the PD- L1 (Programmed cell Death- Ligand 1) expression in neoplastic cells well as Tumor Infiltrating Lymphocyte (TIL) density of osteosarcoma specimens and correlate it with oncological outcomes. Materials & Methods: A prospective cohort study was conducted between March 2017 and March 2022 among osteosarcoma patients who underwent primary biopsy and neo-adjuvant chemotherapy followed by surgical excision at our centre. We excluded patients who had alternative diagnoses such as low grade osteosarcoma, secondary osteosarcoma, recurrent osteosarcoma as well as patients who had undergone initial treatment (chemotherapy/ surgery) outside our institute. De-paraffinized sections (4μ) incubated with primary antibody (PDL1) and a universal secondary detection kit used. Average percentage of positive cells calculated from at least 10 representative fields at 400X magnification. Positive staining was considered when ≥1% cells showed positivity. IHC scoring of PD-L1 was graded as negative, low positive and high positive. We calculated the number of TILs under 400X magnification in ten fields and then took their average. TILs staining was scored semi quantitatively using a 3 tiered scale. Results: Forty patients who fulfilled the inclusion & exclusion criteria were included in the study with most common age group being 10 to 19 years (27 patient, 68%). The male: female ratio was 1.6: 1 and the most common location of tumor was distal femur. Majority of patients had the histological subtype of conventional osteosarcoma (37 patients, 92.5%). Lung metastasis was present at time of initial diagnosis in 27 patients (67.5%). At the end of 2 years, 27 patients were alive (60%) while 13 patients had died due to disease. PD-L1 expression was negative in 17.5%, low positive in 15% and high positive in 67.5%. Among TIL category, 19 patients belonged to category 1, 10 belonged to category 2 & 11 belonged to category 3. There was significant correlation between PD-L1 expression score & TIL category. PD-L1 score did not correlate with percentage of necrosis following chemotherapy, metastasis on presentation or overall survival. Conclusions: PD-L1 score had significant correlation with density of Tumor Infiltrating lymphocytes (TIL). However, PD-L1 score did not correlate with overall survival, tumor-free survival, progression of metastasis or local recurrence.

Relative Wash-In Rate in Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a New Prognostic Biomarker for Event-Free Survival in 82 Patients with Osteosarcoma: A Multicenter Study.

The decreased perfusion of osteosarcoma in dynamic contrast-enhanced (DCE) MRI, reflecting a good histological response to neoadjuvant chemotherapy, has been described. In this study, we aim to explore the potential of the relative wash-in rate as a prognostic factor for event-free survival (EFS). Skeletal high-grade osteosarcoma patients, treated in two tertiary referral centers between 2005 and 2022, were retrospectively included. The relative wash-in rate (rWIR) was determined with DCE-MRI before, after, or during the second cycle of chemotherapy (pre-resection). A previously determined cut-off was used to categorize patients, where rWIR < 2.3 was considered poor and rWIR ≥ 2.3 a good radiological response. EFS was defined as the time from resection to the first event: local recurrence, new metastases, or tumor-related death. EFS was estimated using Kaplan-Meier's methodology. Multivariate Cox proportional hazard model was used to estimate the effect of histological response and rWIR on EFS, adjusted for traditional prognostic factors. Eighty-two patients (median age: 17 years; IQR: 14-28) were included. The median follow-up duration was 11.8 years (95% CI: 11.0-12.7). During follow-up, 33 events occurred. Poor histological response was not significantly associated with EFS (HR: 1.8; 95% CI: 0.9-3.8), whereas a poor radiological response was associated with a worse EFS (HR: 2.4; 95% CI: 1.1-5.0). In a subpopulation without initial metastases, the binary assessment of rWIR approached statistical significance (HR: 2.3; 95% CI: 1.0-5.2), whereas its continuous evaluation demonstrated a significant association between higher rWIR and improved EFS (HR: 0.7; 95% CI: 0.5-0.9), underlining the effect of response to chemotherapy. The 2- and 5-year EFS for patients with a rWIR ≥ 2.3 were 85% and 75% versus 55% and 50% for patients with a rWIR < 2.3. The predicted poor chemo response with MRI (rWIR < 2.3) is associated with shorter EFS even when adjusted for known clinical covariates and shows similar results to histological response evaluation. rWIR is a potential tool for future response-based individualized healthcare in osteosarcoma patients before surgical resection.

Correlation of High-Grade Osteosarcoma Response to Chemotherapy with Enhanced Tissue Immunological Response: Analysis of CD95R, IFN-γ, Catalase, Hsp70, and VEGF

High-grade osteosarcoma, a primary malignant bone tumour, is experiencing a global increase in reported incidence with varied prevalence. Despite advances in management, which include surgery and neoadjuvant chemotherapy often an unsatisfactory outcome is found due to poor or heterogeneous response to chemotherapy. Our study delved into chemotherapy responses in osteosarcoma patients and associated molecular expressions, focusing on CD95 receptor (CD95R), interferon (IFN)-γ, catalase, heat-shock protein (Hsp)70, and vascular endothelial growth factor (VEGF). Employing immunohistochemistry and Huvos grading of post-chemo specimens, we analysed formalin-fixed paraffin-embedded (FFPE) osteosarcoma tissue of resected post-chemotherapy specimens from Dr. Soetomo General Academic Hospital in Surabaya, Indonesia (DSGAH), spanning from 2016 to 2020. Results revealed varied responses (poor 40.38%, moderate 48.08%, good 11.54%) and distinct patterns in CD95R, IFN-γ, catalase, Hsp70, and VEGF expression. Significant differences among response groups were observed in CD95R and IFN-γ expression in tumour-infiltrating lymphocytes. The trend of diminishing CD95R expression from poor to good responses, accompanied by an increase in IFN-γ, implied a reduction in the count of viable osteosarcoma cells with the progression of Huvos grading. Catalase expression in osteosarcoma cells was consistently elevated in the poor response group, while Hsp70 expression was highest. VEGF expression in macrophages was significantly higher in the good response group. In conclusion, this study enhances our understanding of immune-chemotherapy interactions in osteosarcoma and identifies potential biomarkers for targeted interventions.

Incidence and survival outcomes of patients with high-grade appendicular bone sarcoma and isolated regional lymph node metastasis: A national cohort database study

BackgroundWhile distant metastases in primary bone sarcomas have been extensively studied, the impact of isolated regional lymph node (LN) metastasis on survival remains unknown. In patients with primary bone sarcomas, we sought to assess the prevalence of isolated regional LN metastasis and the survival of this population. MethodsA total of 6651 patients with histologically-confirmed high-grade osteosarcoma, Ewing sarcoma, or chondrosarcoma were retrieved from the SEER database. We defined four subgroups for our analysis: localized disease (N0 M0), isolated regional LN metastasis (N1 M0), isolated distant metastasis (N0 M1), and combined regional LN and distant metastasis (N1 M1). Disease-specific survival (DSS) was assessed using the Kaplan-Meier method. ResultsPrevalence of isolated regional LN metastasis (N1 M0) was highest in Ewing sarcoma (27/1097; 3.3 %), followed by chondrosarcoma (18/1702; 1.4 %) and osteosarcoma (26/3740; 0.9 %). In all three histologies, patients with isolated regional LN metastasis had a worse 2-year, 5-year, and 10-year DSS than those with localized disease. Chondrosarcoma patients with isolated regional LN (N1 M0) metastasis had a significantly higher DSS in comparison to those with only distant metastasis (N0 M1) at the 5- and 10-year marks; for osteosarcoma and Ewing sarcoma, only a pattern towards higher survival was seen. Risk factors for presenting isolated regional LN metastasis included tumor location in lower-limb (OR = 2.01) or pelvis (OR = 2.49), diagnosis of Ewing sarcoma (OR = 2.98), and tumor >10 cm (OR = 1.96). ConclusionsIsolated regional LN metastases in primary bone sarcomas is an infrequent presentation associated with worse survival than localized disease. Level of evidenceIII.

Joint-Sparing Resection around the Knee for Osteosarcoma: Long-Term Outcomes of Biologic Reconstruction with Vascularized Fibula Graft Combined with Massive Allograft.

(1) Background: We aim to address the following questions. What was the complication rate of vascularized fibula graft (VFG) combined with massive allograft in patients treated with joint-sparing resection around the knee for a high-grade osteosarcoma? What was the long-term survivorship of VFG free from revision and graft removal? What were the functional results as assessed by the Musculoskeletal Tumor Society (MSTS) score? (2) Methods: 39 patients treated in our unit for osteosarcoma around the knee with intercalary resection and reconstruction with VFG combined with massive allograft were included; 26 patients underwent intercalary tibial resection, while 13 underwent intercalary femoral resection. (3) Results: Mean Follow-Up was 205 months (28 to 424). Complications that required surgery were assessed in requiring surgical revision in 19 patients (49%) after a mean of 31 months (0 to 107), while VFG removal was necessary in three patients (8%). The revision-free survival of the reconstructions was 59% at 5 years and 50% at 10 to 30 years. The overall survival of the reconstructions was 95% at 5 to 15 years and 89% at 20 to 30 years. The mean MSTS score was 29.3 (23 to 30). (4) Conclusions: VFG represents an effective reconstructive option after joint-sparing intercalary resection around the knee for osteosarcoma.

From biology to personalized medicine: Recent knowledge in osteosarcoma

High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival.

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

Intercalary Resection of the Tibia for Primary Bone Tumors: Are Vascularized Fibula Autografts With or Without Allografts a Durable Reconstruction?

Prognostic factors for overall survival of conventional osteosarcoma of the appendicular skeleton.

The aim of this study is to determine the predictors of overall survival (OS) and predictive factors of poor prognosis of conventional high-grade osteosarcoma of the limbs in a single-centre in South Africa. We performed a retrospective cross-sectional analysis to identify the prognostic factors that predict the OS of patients with histologically confirmed high-grade conventional osteosarcoma of the limbs over ten years. We employed the Cox proportional regression model and the Kaplan-Meier method for statistical analysis. This study comprised 77 patients at a three-year minimum follow-up. The predictors of poor OS were: the median age of ≤ 19 years (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.92 to 0.99; p = 0.021); median duration of symptoms ≥ five months (HR 0.91; 95% CI 0.83 to 0.99; p < 0.037); metastasis at diagnosis (i.e. Enneking stage III) (HR 3.33; 95% CI 1.81 to 6.00; p < 0.001); increased alkaline phosphatase (HR 3.28; 95% CI 1.33 to 8.11; p < 0.010); palliative treatment (HR 7.27; 95% CI 2.69 to 19.70); p < 0.001); and amputation (HR 3.71; 95% CI 1.12 to 12.25; p < 0.032). In contrast, definitive surgery (HR 0.11; 95% CI 0.03 to 0.38; p < 0.001) and curative treatment (HR 0.18; 95% CI 0.10 to 0.33; p < 0.001) were a protective factor. The Kaplan-Meier median survival time was 24 months, with OS of 57.1% at the three years. The projected five-year event-free survival was 10.3% and OS of 29.8% (HR 0.76; 95% CI 0.52 to 1.12; p = 0.128). In this series of high-grade conventional osteosarcoma of the appendicular skeleton from South Africa, 58.4% (n = 45) had detectable metastases at presentation; hence, an impoverished OS of five years was 29.8%. Large-scale future research is needed to validate our results.

Prognostic factors in high-grade pediatric osteosarcoma among children and young adults: Greek Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data along with a systematic review and meta-analysis

The 5-year overall survival of children and adolescents with osteosarcoma has been in plateau during the last 30 years. The present systematic review (1976–2023) and meta-analysis aimed to explore factors implicated in the prognosis of children and young adults with high-grade osteosarcoma. Original studies including patients ≤30 years and the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data (2010–2021) referred to children ≤14 years were analysed. Individual participant data (IPD) and summary estimates were used to assess the n-year survival rates, as well as the association of risk factors with overall survival (OS) and event-free survival (EFS). IPD and the n-year survival rates were pooled using Kaplan-Meier and Cox regression models, and random effects models, respectively.Data from 8412 patients, including 46 publications, NARECHEM-ST data, and 277 IPD from 10 studies were analysed. The summary 5-year OS rate was 64% [95% confidence interval (95%CI): 62%-66%, 37 studies, 6661 patients] and the EFS was 52% (95%CI: 49%-56%, 30 studies, 5010 patients). The survival rates generally differed in the pre-specified subgroups. Limb-salvage surgery showed a higher 5-year OS rate (69%) versus amputation (47%). Good responders had higher OS rates at 3 years (94%) and 5 years (81%), compared to poor responders at 3 years (66%), and 5 years (56%). Patients with metastatic disease had a higher risk of death [Hazard Ratio (HR): 3.60, 95%CI: 2.52, 5.15, 11 studies]. Sex did not have an impact on EFS (HR females/males: 0.90, 95%CI: 0.54, 1.48, 3 studies), whereas age>18 years seems to adversely affect EFS (HR 18+/<10 years: 1.36, 95%CI: 1.09, 1.86, 3 studies).Our results summarize the collective experience on prognostic factors of high-grade osteosarcoma among children and young adults. Poor response to neoadjuvant chemotherapy and metastatic disease at diagnosis were confirmed as primary risk factors of poor outcome. International collaboration of osteosarcoma study groups is essential to improve survival.

PD-L1, STAT3, IL6, and EGFR Immunoexpressions in High-Grade Osteosarcoma.

Immunotherapy has been widely used in the treatment of various malignancies with satisfactory results. One of the agents for immunotherapy is an inhibitor of programmed cell death-1 and its ligands (PD-1 and PD-L1). However, attempts at utilizing PD-1/PD-L1 immunotherapy in osteosarcoma have not yielded favorable results. This may be due to differences in PD-L1 regulation and the immune landscape in osteosarcoma, as the mechanism is still poorly understood. Therefore, elucidating PD-L1 regulation in osteosarcoma is paramount in order to improve treatment results using immunotherapy. This is a cross-sectional study conducted in the Department of Anatomical Pathology of Saiful Anwar Hospital using 33 paraffin blocks of confirmed cases of osteosarcoma. Immunohistochemical staining using PD-L1, STAT3, IL6, and EGFR was performed. Statistical analyses were subsequently performed on the immunoexpression data of these antibodies. PD-L1, STAT3, IL6, and EGFR expressions were found in 6 (18.2%), 6 (18.2%), 28 (84.8%), and 30 (90.9%) cases, respectively. There were significant correlations between PD-L1 and STAT3 (r = 0.620, p=<0.001), PD-L1 and EGFR (r = 0.449, p=0.009), as well as STAT3 and EGFR (r = 0.351, p=0.045). The existence of a correlation between PD-L1, STAT3, and EGFR indicates the potential role of STAT3 and EGFR in PD-L1 regulation in osteosarcoma, which may become the basis for targeted therapy.