High-grade Osteosarcoma Research Articles

Cell Cycle Checkpoints p16 and p21-Strong Predictors of Clinicopathologic Outcomes in High-Grade Osteosarcoma.

In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.

Primary Multi-Systemic Metastases in Osteosarcoma: Presentation, Treatment, and Survival of 83 Patients of the Cooperative Osteosarcoma Study Group.

To evaluate patient and tumour characteristics, treatment, and their impact on survival in patients with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma. Precedure: Eighty-three consecutive patients who presented with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma were retrospectively reviewed. In cases of curative intent, the Cooperative Osteosarcoma Study Group recommended surgical removal of all detectable metastases in addition to complete resection of the primary tumour and chemotherapy. Eighty-three eligible patients (1.8%) were identified among a total of 4605 individuals with high-grade osteosarcoma. Nine (10.8%) of these achieved complete surgical remission, of whom seven later had recurrences. The median follow-up time was 12 (range, 1-165) months for all patients. Actuarial event-free survival after 1, 2, and 5 years was 9.6 ± 3.2%, 1.4 ± 1.4%, and 1.4 ± 1.4%, and overall survival was 54.0 ± 5.6%, 23.2 ± 4.9%, and 8.7 ± 3.3%. In univariate analyses, elevated alkaline phosphatase before chemotherapy, pleural effusion, distant bones as metastatic sites, and more than one bone metastasis were negative prognostic factors. Among treatment-related factors, the microscopically complete resection of the primary tumour, a good response to first-line chemotherapy, the macroscopically complete resection of all affected tumour sites, and local treatment (surgery ± radiotherapy) of all bone metastases were associated with better outcomes. Tumour progression under first-line treatment significantly correlated with shorter survival times. The outlook for patients with multi-systemic primary metastases from osteosarcoma remains very poor. The utmost importance of surgical resection of all tumour sites was confirmed. For unresectable bone metastases, radiotherapy might be considered. In the patient group studied, standard chemotherapy was often insufficiently effective. In the case of such advanced disease, alternative treatment options are urgently required.

Beyond 5-year survival. A report from the Cooperative Osteosarcoma Study Group (COSS).

Prognostic factors have been well described for osteosarcoma, but analyses evaluating the further course of long-term survivors are lacking. We used the large database of the Cooperative Osteosarcoma Study Group (COSS) to perform such an analysis. The COSS database 1980-04/2019 was searched for 5-year survivors of primary high-grade central osteosarcoma of the extremities or trunk. Identified patients were analyzed for their further survival outcomes, assessing potentially prognostic and predictive factors already evident at initial disease presentation and treatment as well as their disease course during the first 5 years of follow-up. Two thousand and nine former eligible patients were identified (median age at initial diagnosis 15.1 (2.5-63.0) years; male vs. female 1149 (57.2%) vs. 860 (42.8%); extremities vs. trunk 1927 (95.9%) vs. 82 (4.1%); extremity primaries <1/3 vs. ≥1/3 of the involved bone 997 (67.8%) vs. 474 (32.2%) (456 unknown); localized vs. primary metastatic 1881 (93.6%) vs. 128 (6.4%); osteosarcoma as a secondary malignancy 41/2009 (2.0%)). Therapy starting by chemotherapy versus primary surgery 1860 (92.6%) versus 149 (7.4%); definitive tumor surgery by limb salvage versus ablative 1347 (67.0%) versus 659 (1 no surgery, 2 unknown); tumor response to preoperative chemotherapy documented for 1765 (94.9%) patients receiving neoadjuvant chemotherapy, good (<10% viable tumor) versus poor 1130 (64.0%) versus 635 (36.0%), local radiotherapy documented for 19 (0.9%) tumors. Recurrence during preceding 5 years no versus yes 1681 (83.7%) versus 328 (16.3%). Median follow-up starting 5 years after initial diagnosis 6.1 (0.002-32.2) years; 1815 survivors and 194 deaths. Overall survival after another 5/10/15/20 years 91.7%/88.9%/85.8%/83.4% for all patients; 97.5%/95.2%/92.4%/89.9% if in remission years 1-5 versus 62.7%/57.3%/53.0%/51.2% if recurrence year 1-5 (p < 0.001). Significant predictors of survival for all patients age at diagnosis (p = 0.038), tumor site (p = 0.030), having experienced the osteosarcoma as secondary malignancy (p < 0.001), tumor response to preoperative chemotherapy (p = 0.002). Multivariate Cox regression testing possible for 1759 (87.6%) patients with complete dataset: Having had a recurrence in years 1-5 (p < 0.001), older age at diagnosis (p = 0.009), and osteosarcoma as secondary malignancy (p = 0.013) retained significance. Highly important predictors of death such as the extent of tumor response to chemotherapy no longer remain valid after 5-year survival. The individual history of malignancies and their outcomes seems to gain pivotal importance. This benchmark analysis clearly defined risk factors for the further course of 5-year survivors from osteosarcoma. It argues for large disease-oriented databases as well as for very long follow-up periods. Novel findings will most likely require innovative statistical models to analyze such cohorts.

CtDNA quantification improves estimation of outcomes in patients with high-grade osteosarcoma: a translational study from the OS2006 trial

Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event. ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR)= 3.5, P= 0.002 and 3.51, P= 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR= 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression. The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.

Significance of the Pretreatment Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Predicting the Response to Neoadjuvant Chemotherapy and Survival Rates in Extremity Osteosarcoma: A Multicentre Prospective Study

Objectives We aimed to assess the effects of pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios on the response to neoadjuvant chemotherapy and survival rates in patients with extremity osteosarcoma. Patients and methods Patients with high-grade osteosarcoma admitted to oncologic centers affiliated with Iran University of Medical Sciences, Tehran, Iran from 2015 to 2021 were evaluated retrospectively to assess the impact of complete blood count-related parameters on the pathologic response after neoadjuvant chemotherapy. Then, patients were followed up prospectively to evaluate the survival rates. All patients received at least three cycles of cisplatin/doxorubicin regimen, preoperatively. In this study, the cut-off values for high neutrophil-to-lymphocyte and high platelet-to-lymphocyte ratio were considered 3.28 and 128, respectively. Results One hundred eighty-six patients were enrolled. Patients with high neutrophil-to-lymphocyte ratio and high platelet-to-lymphocyte ratio had a significantly lower overall survival rates (20.7 [95% CI 18–23.5] month vs. 34.6 [95% CI 33.2–36], p = 0.003 and 21.9 [95% CI 20.2–23.6] month versus 35.3 [95% CI 33.9–36.7], p = 0.002; respectively). Moreover, disease-free survival of patients with high platelet-to-lymphocyte ratio was worse than patients with low platelet-to-lymphocyte ratio (20.4 [95% CI 18.4–22.4] month vs. 32.7 [95% CI 30.8–34.7], p = 0.02). Conclusion Our study showed that neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios at the baseline can predict the survival of patients with high-grade osteosarcoma.

Single-nucleotide polymorphism profiling by multimodal-targeted next-generation sequencing in methotrexate-resistant and -sensitive human osteosarcoma cell lines

Introduction: Methotrexate (MTX) is one of the most important drugs included in the first-line protocols to treat high-grade osteosarcoma (HGOS). Although several polymorphisms have been reported to be associated with drug response or MTX-related toxicity in pharmacogenetic studies, their role in the development of MTX resistance in HGOS is still unclear.Methods: Therefore, in this study, 22 single nucleotide polymorphisms (SNPs) in 4 genes of the folate metabolism, 7 MTX transporter genes, and 2 SNPs of the tumor protein p53 (TP53) gene were investigated using a custom multimodal-targeted next-generation sequencing (mmNGS) approach in 8 MTX-resistant and 12 MTX-sensitive human HGOS cell lines. The panel was validated by TaqMan genotyping assays.Results: High instability of TP53 rs1642785 was observed in all U-2OS/MTX variants. Allele changes of the solute carrier family 19 member 1/replication factor C subunit 1 (SLC19A1, previously known as RFC1) and rs1051266 were identified in all Saos-2/MTX-resistant variants in both DNA- and RNA- derived libraries compared to the parental Saos-2 cell line. Allele changes of methylenetetrahydrofolate reductase (MTHFR) rs1801133 were identified only in the RNA-derived libraries of the two U2OS variants with the highest MTX resistance level. Significantly upregulated gene expression associated with the development of MTX resistance was revealed for dihydrofolate reductase (DHFR) whereas SLC19A1 was downregulated. In addition, a fusion transcript of DHFR (ex4) and MutS Homolog 3 (MSH3) (ex9) was identified in the RNA libraries derived from the two U-2OS variants with the highest MTX resistance level.Conclusion: This innovative mmNGS approach enabled the simultaneous exploration of SNPs at DNA and RNA levels in human HGOS cell lines, providing evidence of the functional involvement of allele changes associated with the development of MTX resistance.

High Grade Osteosarcoma at the Site of a Ceramic on Cross-Linked Polyethylene Cementless Hip Replacement: A Case Report and Review of the Literature

The following case report describes a 50-year-old male with a history of post-traumatic arthritis of the right hip after a previous open reduction of a traumatic hip dislocation as a young adult. He underwent an uncomplicated ceramic on highly cross-linked polyethylene primary total hip arthroplasty (THA), with unremarkable intra-operative pathology at that time. Three years postoperatively, the patient developed acute onset of hip and groin pain and associated radiographic findings which proved to be related to a high-grade osteosarcoma within the soft tissue juxtaposed to the ceramic on highly cross-linked polyethylene THA. While metal-associated primary bone sarcomas have been previously reported, we are unaware of any prior description of an osteosarcoma in the setting of a ceramic on highly cross-linked polyethylene articulation. This current report represents the first case of a primary osteosarcoma associated with this type of hip arthroplasty articulation.

Dedifferentiated Liposarcoma with Heterologous and Homologous Elements-A Report of Three Cases

Background: Osteosarcoma (OS) heterologous component in dedifferentiated liposarcoma (DDL) is rare, but should be considered and MDM2/ CDK-4 testing employed. Myxoid liposarcoma-like (ML) homologous differentiation with simultaneous MDM2 and DDDIT3 amplification is also unusual, and needs to be recognized as it has implications for diagnosis. Case series: We report three special cases of DDL, two in the retroperitoneum and one in the abdomen: a DDL with OS differentiation, confirmed by MDM2 and CDK4 positive testing, as well as two DDL with homologous ML differentiation confirmed by simultaneous positive MDM2 and DDIT3 testing. In case of a DDL with heterologous osseous differentiation, it is important to sample extensively and identify WDL areas, in order to exclude the diagnosis of extraosseous OS. Without the rare foci of WDL, the extensive high grade spindled DDL may have been misinterpreted as extraosseous OS. MDM2 and CDK4 were useful for the final diagnosis. FISH testing for MDM2 and DDIT3 amplification is also necessary in DDL with ML foci. WDL and DDL can contain ML component, a diagnostic challenge when confronted with a small biopsy. Such tumors have been shown to contain co-amplifications of MDM2 and DDIT3, further adding to a diagnostic dilemma. Conclusion: The presence of pleomorphic cells or lipoblasts in WDL or DDL, as seen in our two cases, should prompt considering MDM2 FISH testing in conjunction with DDIT3, rather than DDIT3 alone. Furthermore, the first case illustrates the utility of MDM2 and CDK4 testing in ruling out other high-grade sarcomas when a DDL diagnosis is uncertain due to absent WDL or presence of heterologous component, particularly high-grade OS.

1962P phase II study for nonmetastatic extremity high-grade osteosarcoma in pediatric and AYA patients with a risk-adapted strategy based on P-glycoprotein expression by the ISG (ISG/OS-2): A correlative study on tumor microenvironment

1962P phase II study for nonmetastatic extremity high-grade osteosarcoma in pediatric and AYA patients with a risk-adapted strategy based on P-glycoprotein expression by the ISG (ISG/OS-2): A correlative study on tumor microenvironment

Osteosarcoma in a free-living yellow armadillo (Euphractus sexcinctus)

An adult male free-living yellow armadillo (Euphractus sexcinctus) was found by hunters and referred for clinical evaluation because of a tumour-like lesion on the carapace. The animal was lethargic and weak with severe dehydration, enophthalmos and cachexia, and was euthanized because of its very poor clinical condition. Necropsy revealed a whitish, exophytic, irregular and moist mass (7 × 6.5 × 1.5 cm) in the caudal third of the carapace. On cut section, the mass was hard, compact, irregular and whitish. Histopathology revealed a densely cellular, expansive, poorly delimited neoplasm composed of malignant mesenchymal cells arranged in islands and cords, interspersed by numerous areas of irregularly mineralized osteoid matrix. Neoplastic cells were intensely immunolabelled for vimentin. The diagnosis of a high-grade osteosarcoma of osteoblastic subtype was based on the clinical, gross, histopathological and immunohistochemical findings. This first report of an osteosarcoma in an armadillo expands the list of armadillo diseases and will assist the management of these animals by veterinarians.

Advances in immunotherapy for osteosarcoma: a review of emerging treatment strategies

Advances in immunotherapy for osteosarcoma have shown promising results, with the use of monoclonal antibodies and immune checkpoint inhibitors. These strategies are aimed at targeting specific molecules and pathways involved in tumour immune evasion and promoting anti-tumour immune responses. Other emerging immunotherapeutic approaches include autophagy and pyroptosis induction, chimeric antigen receptor T-cell therapy, gadolinium-bisphosphonate nanoparticles and dendritic cell-based vaccines. Continued research into these emerging treatment strategies is essential for developing effective therapies for patients with high-grade osteosarcoma.

High-Grade Surface Osteosarcoma of the Rib Mimicking a Neurogenic Tumor: Radiologic and Pathologic Findings.

Osteosarcoma commonly occurs in the intramedullary cavity of long bones such as the femur, tibia, and humerus in children and adolescents. Osteosarcoma occurring as a primary tumor in the chest wall is rare. Only a limited number of such cases have been documented in the existing literature. Herein, we present radiologic and pathologic findings of a high-grade surface osteosarcoma of the rib mimicking a neurogenic tumor in a 44-year-old woman.

Solitary pulmonary metastases at first recurrence of osteosarcoma: Presentation, treatment, and survival of 219 patients of the Cooperative Osteosarcoma Study Group.

To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high-grade osteosarcoma. Two-hundred and nineteen consecutive patients who had achieved a complete surgical remission and then developed a solitary pulmonary metastasis at first recurrence of high-grade osteosarcoma were retrospectively reviewed. Two hundred and three (94.9%) of 214 patients achieved a second complete remission. After a median time from initial diagnosis of osteosarcoma to first relapse of 2.3 years (range, 0.3-18.8 years), actuarial post-relapse overall survival after 2 and 5 years was 72.0% and 51.2%. Post-relapse event-free survival was 39.1% and 31.1%. Median follow-up time was 3.2 years (range, 0.1-29.4 years). A longer time until first relapse and diagnosis due to imaging were positive prognostic factors in uni- and multivariate analyses, as were a second complete surgical remission and, in regard to death, the absence of a subsequent relapse. The use of salvage chemotherapy and radiotherapy were not associated with patient outcomes, nor was the surgical approach (thoracoscopy vs. thoracotomy) nor the exploration (uni- vs. bilateral). Approximately half of the patients who experience a solitary pulmonary relapse at first recurrence of osteosarcoma remain alive 5 years after this first relapse. Only one third will remain disease-free. A complete surgical resection of the lesion is essential for long-term survival while relapse chemotherapy does not seem to improve survival. Innovative therapies are required to improve outcomes.

Outcome of rare primary malignant bone sarcoma treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.).

Rare primary malignant bone sarcomas (RPMBS) account for 5%-10% of primary high-grade bone tumors and represent a major treatment challenge. The outcome of patients with RPMBS enrolled in the EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S) is presented. Inclusion criteria were as follows: age from 41 to 65years and a diagnosis of high-grade spindle cell, pleomorphic, or vascular RPMBS. The chemotherapy regimen included doxorubicin 60mg/m2 , ifosfamide 9g/m2 , and cisplatin 90mg/m2 ; postoperative methotrexate 8g/m2 was added in case of a poor histologic response. Version 2.0 of the Common Terminology Criteria for Adverse Events, Kaplan-Meier curves, log-rank tests, and univariate Cox regression models were used. In total, 113 patients were evaluable for analysis. The median patient age was 52years (range, 40-66 years), and 67 patients were men. Eighty-eight tumors were categorized as undifferentiated pleomorphic sarcomas (UPS), 20 were categorized as leiomyosarcomas, three were categorized as fibrosarcomas, and two were categorized as angiosarcomas. Eighty-three of 113 tumors were located in the extremities. Ninety-five of 113 patients presented with no evidence of metastases. After a median follow-up of 6.8years (interquartile range [IQR], 3.5-9.8 years), the 5-year overall survival rate for patients with localized disease was 68.4% (IQR, 56.9%-77.5%), and it was 71.7% (IQR, 58.1%-81.6%) for patients with UPS and 54.9% (IQR, 29.5%-74.5%) for patients with leiomyosarcoma. Grade III-IV hematologic toxicity was reported in 81% patients; 23% had grade II-III neurotoxicity, and 37.5% had grade I-II nephrotoxicity. Five-year overall survival was significantly better for patients with localized disease, for patients who obtained surgical complete remission, and when the primary tumor was located in the extremities. The survival of patients who had RPMBS in the current series was similar to that of age-matched patients who had high-grade osteosarcoma treated according to the same protocol. An osteosarcoma-like chemotherapy may be proposed in patients who have RPMBS.

Survival benefits and challenges of adjuvant chemotherapy for high-grade osteosarcoma: a population-based study

BackgroundOsteosarcoma is the most prevalent primary malignant bone tumor. The primary treatment for osteosarcoma is a combination of chemotherapy and surgery. However, there has been no recent progress in the role of chemotherapy in improving the long-term survival of osteosarcoma patients. This study aims to analyze the factors that affect chemotherapy in patients with osteosarcoma and explore the challenges and survival benefits of chemotherapy.MethodsPatient data were downloaded from The Surveillance, Epidemiology, and End Results database. Univariable and multivariable logistic regressions were used to analyze the factors affecting patients receiving chemotherapy. Kaplan–Meier (K–M) curve was used to analyze the survival benefit of chemotherapy in patients with osteosarcoma. Finally, we used annual percentage change (APC) to evaluate the annual changes in chemotherapy treatment rates and trends in 5-year survival rates in osteosarcoma patients.ResultsA total of 2157 osteosarcoma patients were included, of which 1887 patients received chemotherapy. Factors affecting patients receiving chemotherapy included age, primary tumor site, tumor size, N stage, M stage, and surgery. The K–M curve showed that older patients could benefit significantly from chemotherapy. The APC results showed no significant change in the chemotherapy treatment rate and 5-year overall survival rate of osteosarcoma patients.ConclusionChemotherapy is an irreplaceable treatment for patients with osteosarcoma. However, in recent years, there has been no significant progress in chemotherapy for osteosarcoma, and the long-term survival of patients has not improved significantly. New chemotherapeutic drugs or drug delivery systems are urgently needed to improve the prognosis of patients with osteosarcoma.

Does joint-sparing tumor resection jeopardize oncologic and functional outcomes in non-metastatic high-grade osteosarcoma around the knee?

BackgroundWe previously reported joint-sparing tumor resection for osteosarcoma with epiphyseal involvement in which transepiphyseal osteotomy went through the in situ ablated epiphysis. However, we do not know whether this is a safe approach when compared with joint-sacrificed tumor resection. Our objective was to compare oncologic and functional outcomes between patients who underwent joint preservation (JP) and joint replacement (JR) tumor resection. Furthermore, we identified the risk factors of local recurrence, metastasis and survival.MethodsEighty-nine patients with non-metastatic high-grade osteosarcoma around the knee were treated with limb-salvage surgery (JP in 47 and JR in 42). Age, gender, tumor location, pathologic fracture, plain radiographic pattern, limb diameter change, perivascular space alteration, surgical margin, local recurrence, metastasis, death, and the Musculoskeletal Tumor Society (MSTS)-93 scores were extracted from the records. Univariate analysis was performed to compare oncologic and functional outcomes. Binary logistic and cox regression models were used to identify predicted factors for local recurrence, metastasis, and survival.ResultsLocal recurrence, metastasis and overall survival were similar in the JP and JR group (p = 0.3; p = 0.211; p = 0.143). Major complications and limb survival were also similar in the JR and JP group (p = 0.14; p = 0.181). The MSTS score of 27.06 ± 1.77 in the JP group was higher than that of 25.88 ± 1.79 in the JR group (p = 0.005). The marginal margin of soft tissue compared with a wide margin was the only independent predictor of local recurrence (p = 0.006). Limb diameter increase and perivascular fat plane disappearance during neoadjuvant chemotherapy were independent predictors for metastasis (p = 0.002; p = 0.000) and worse survival (p = 0.000; p = 0.001).ConclusionsJoint-sparing tumor resection with the ablative bone margin offers advantage of native joint preservation with favorable functional outcomes while not jeopardizing oncologic outcomes compared with joint-sacrificed tumor resection. Surgeon should strive to obtain adequate soft tissue surgical margin decreasing risk of local recurrence. Novel drug regimens might be reasonable options for patients with obvious limb diameter increase and perivascular fat disappearance during chemotherapy.

HIGH - GRADE OSTEOBLASTIC OSTEOSARCOMA OF THE MAXILLA: DIAGNOSIS, TREATMENT, AND BUCCOMAXILLOFACIAL REHABILITATION

Osteosarcoma is one of the most common malignant bone lesions; however, it comprises only 6%-8% of all osteosarcomas. It is a lesion commonly found between the third and fourth decade of life, in addition to having a similar proportion of appearing between the mandible and maxilla. This study aims to report the case of a 64-year-old Caucasian female patient, affected by a high-grade osteoblastic osteosarcoma. The patient presented an edema in the posterior region of the maxilla, paresthesia, and nasal obstruction. Panoramic radiography and CT scans, along with anatomopathological examination, were performed. Histopathologically, an intense volume of osteoid was found. Left radial maxillectomy was the chosen treatment. The patient was first rehabilitated with a provisional palatal obturator prosthesis in order to improve her nutritional status. Her rehabilitation was planned and accomplished with a mandibular removable partial denture and a maxillary removable partial obturator denture. Osteosarcoma is one of the most common malignant bone lesions; however, it comprises only 6%-8% of all osteosarcomas. It is a lesion commonly found between the third and fourth decade of life, in addition to having a similar proportion of appearing between the mandible and maxilla. This study aims to report the case of a 64-year-old Caucasian female patient, affected by a high-grade osteoblastic osteosarcoma. The patient presented an edema in the posterior region of the maxilla, paresthesia, and nasal obstruction. Panoramic radiography and CT scans, along with anatomopathological examination, were performed. Histopathologically, an intense volume of osteoid was found. Left radial maxillectomy was the chosen treatment. The patient was first rehabilitated with a provisional palatal obturator prosthesis in order to improve her nutritional status. Her rehabilitation was planned and accomplished with a mandibular removable partial denture and a maxillary removable partial obturator denture.

Identification of New Potential Prognostic and Predictive Markers in High-Grade Osteosarcoma Using Whole Exome Sequencing.

Conventional high-grade osteosarcoma (OS) is the most common primary cancer of bone and it typically affects the extremities of adolescents. OS has a complex karyotype, and molecular mechanisms related to carcinogenesis, progression and resistance to therapy are still largely unknown. For this reason, the current standard of care is associated with considerable adverse effects. In this study, our aim was to identify gene alterations in OS patients using whole exome sequencing (WES) to find new potential prognostic biomarkers and therapeutic targets. We performed WES on formalin-fixed paraffin-embedded (FFPE) biopsy materials collected from 19 patients affected by conventional high-grade OS. The clinical and genetic data were analyzed according to response to therapy, presence of metastasis and disease status. By comparing good and poor responders to neoadjuvant therapy, we detected a clear prevalence of mutations in the ARID1A, CREBBP, BRCA2 and RAD50 genes in poor responders that negatively influence the progression-free survival time. Moreover, higher tumor mutational burden values correlated with worse prognosis. The identification of mutations in ARID1A, CREBBP, BRCA2 and RAD50 may support the use of a more specific therapy for tumors harboring these alterations. In particular, BRCA2 and RAD50 are involved in homologous recombination repair, and could thus be used as specific therapy targets of inhibitors of the enzyme Poly ADP Ribose Polymerase (PARP). Finally, tumor mutational burden is found to be a potential prognostic marker for OS.

Prolonged 14-day continuous infusion of high-dose ifosfamide (14IFO) for relapsed/refractory high-grade osteosarcoma (R/R HOS): A retrospective multicenter cohort study.

11534 Background: The prognosis of patients (pts) with relapsed/refractory (R/R) High-Grade Osteosarcoma (HOS) remains dismal without an agreement on systemic therapy. The use of 14IFO with an external pump in outpatient setting (1g/sqm/day x 14 days every 21) in R/R HOS pts is limited. This is the first retrospective cohort study focused on 14IFO activity and toxicity in this setting (NCT04651569). Methods: Five Centers of the Italian Association of Pediatric Onco-Hematology and Italian Sarcoma Group participated to the study. Primary aim is to investigate 14IFO activity in pts with R/R HOS younger than 40 years. Secondary aim is to evaluate toxicity, according to CTCAE v.5, and clinical benefit. Progression Free Survival (PFS) and Overall Survival (OS) analysis are performed using the Kaplan Meier method with 95% confidence interval (CI). Results: Between 2012 and 2021, 26 R/R HOS pts were treated with 14IFO (median follow-up: 17,5 months, range: 4,6 – 83 months). Median age is 19 years at the beginning of 14IFO; eleven pts (42%) are ≤ 18 years. Three pts (12%) have a localized HOS, twelve pts (46%) have pulmonary disease only and eleven pts (42%) have a pluri-metastatic HOS. Eleven pts (42%) have a relapsed HOS with a median disease-free interval (DFI) of 13 months before 14IFO, the remaining (58%) have a refractory disease to two or more treatments. Overall, thirteen pts (50%) receive 14IFO as second line therapy and fifteen pts (57%) are pre-treated with Ifosfamide in first line. Disease Control Rate is 57,5% (5 Partial Response + 10 Stable Disease). Seven pts (27%) receive a local treatment after 14IFO (5 surgery, 1 Radiotherapy (Rt), 1 Carbon Ion Rt). The median PFS is 4,1 months (95% CI 2.13, 7.37). 6-month and 1-year PFS are 38% (95% CI 24-63) and 8% (95% CI 2-29), respectively. The median OS is 13.7 months (95% CI 10.6 – 23.7). 1-year and 2-year OS are 51% (95% CI 35-75) and 22% (95% CI 9.5-49), respectively. Relapsed pts have both longer median PFS and OS compared to pts with a refractory disease [PFS: 7.33 months vs 2.13 months (p = 0.02); OS: 19.4 months vs 10.7 months (p = 0.1)]. Sixteen pts (61%) receive at least 4 cycles and an amount of 101 cycles are evaluated for toxicity. Grade 4 hematological toxicity is reported in 15 cycles (14,8%) as follows: i) white-blood cell decrease in 6 cycles (6%); ii) neutropenia in 7 cycles (7%); iii) thrombocytopenia in 2 cycles (2%). One patient has one episode of febrile neutropenia. No grade 3-4 non hematological toxicities are reported. Conclusions: This trial shows a non inferiority activity of 14IFO compared to other treatments in this setting, despite the small number of pts. Therefore, 14IFO should be considered as a treatment option in R/R HOS, especially for its well tolerated toxicity profile and the home-administration that improve patient’s quality of life and it could significantly reduce cancer care cost. Clinical trial information: NCT04651569 .

Optimization of a deep convolution neural network (DCNN) for osteosarcoma necrosis quantification and outcome prediction.

e13541 Background: Deep convolutional neural network is a form of artificial intelligence that gained traction recently in diagnostic and prognostic applications such as automated tissue segmentation and outcome and response to immunotherapy prediction. Herein, we optimize DCNN to accurately segment and quantify necrosis in osteosarcoma (OSA) archival slides. We also correlate the AI driven necrosis ratios with those derived from experienced sarcoma pathologists (gold standard) and show their value in predicting patient’s outcomes. Methods: A total of 44 patients with bone resections for primary high-grade osteosarcomas post neoadjuvant treatment with conventional chemotherapy were included (Male n= 26, female n=19), median age = 16.4 years. 103 slides from 21 patients were originally manually segmented and used for initial training using 3-fold cross-validation split per patient and per slide. Here, an additional 119 slides from 23 patients (total of 222 slides) were added in the retraining for automated segmentation and to update the necrosis ratio calculation, and the correlation with pathologist calculated necrosis ratio (R spearman correlation). Based on this ratio, we performed a prediction of Overall survival using the Log rank test. Results: The segmentation classifier identified viable tumor, necrosis, normal tissue and artefacts within slides with an area under the curve ranging from 0.91 to 0.96. AI necrosis ratio showed a good correlation with pathologist driven ration (R=0.74 per slide, R=0.69 per patient). Some outliers with highest discrepancy for necrosis ratio included surface high grade periosteal osteosarcomas (known for cartilaginous differentiation that is not part of the original training of the algorithm). Patients with an AI necrosis ratio of ≥ 70% had a better Overall survival at 36 months (p=0.01). Conclusions: Our results show the potential of integration of DCNN for automated segmentation and necrosis quantification of central high OSA resection enhancing efficiency in interpreting these complex surgical specimens. The data also suggests a possible prognostic application of the AI derived necrosis ratio. Further validation of the DCNN performance on an independent cohort is underway.