Conventional Osteosarcoma Research Articles

Imaging of Osteosarcoma: Presenting Findings, Metastatic Patterns, and Features Related to Prognosis

Background: Osteosarcomas are rare malignancies (<1% of all cancers) that produce an osteoid matrix. Osteosarcomas are the second most frequent type of primary bone tumor after multiple myeloma and the most prevalent primary bone tumor in children. The spectrum of imaging findings of these malignancies varies significantly, reflecting different histological subtypes. For instance, conventional osteosarcoma typically presents with a mixed radiological pattern (lytic and bone mineralization) or with a completely eburneous one; aggressive periosteal reactions such as sunburst, Codman triangle, and soft-tissue components are frequently displayed. On the other hand, telangiectatic osteosarcoma usually presents as a purely lytic lesion with multiple fluid–fluid levels on MRI fluid-sensitive sequences. Other typical and atypical radiological patterns of presentation in other subtypes of osteosarcomas are described in this review. In addition to the characteristics associated with osteosarcoma subtyping, this review article also focuses on imaging features that have been associated with patient outcomes, namely response to chemotherapy and event-free and overall survivals. This includes simple semantic radiological features (such as tumor dimensions, anatomical location with difficulty of radical surgery, occurrence of pathological fractures, and presence of distant metastases), but also quantitative imaging parameters from diffusion-weighted imaging, dynamic contrast-enhanced MRI, and 18F-FDG positron emission tomography and radiomics approaches. Other particular features are described in the text. Overall, this comprehensive literature review aims to be a practical tool for oncologists, pathologists, surgeons, and radiologists involved in these patients’ care.

Unique Gene Expression Profiles within South Africa Are Associated with Varied Chemotherapeutic Responses in Conventional Osteosarcoma.

We determined the predictive gene expression profiles associated with chemo-response in conventional osteosarcomas (COS) within South Africa. In 28 patients, we performed an RNA extraction, cDNA synthesis, and quantitative analysis using the RT-PCR 2-∆∆CT method to determine the fold change in gene expression alongside GAPDH (housekeeping gene). We observed a significant downregulation in the mRNA expression profiles of ABCB1-p-glycoprotein (p = 0.0007), ABCC3 (p = 0.002), ERCC1 (p = 0.007), p-53 (p = 0.007), and RFC1 (p = 0.003) in the COS patients compared to the healthy donors. Furthermore, ABCB1-p-glycoprotein (p = 0.008) and ABCC3 (p = 0.020) exhibited a significant downregulation in the COS tumour tissues when compared to the healthy donors. In our univariate logistic regression, the predictors of chemotherapeutic response comprised ERCC1 [restricted cubic spline (RCS) knot: OR -0.27; CI -0.504 to -0.032; p = 0.036]; osteoblastic subtype [OR -0.36; CI -0.652 to -0.092; p = 0.026); fibroblastic subtype [OR 0.91; CI 0.569 to 1.248; p < 0.001]; and mixed subtype [OR 0.53; CI 0.232 to 0.032; p = 0.032]. In our multivariable logistic regression, the significant predictors of chemotherapeutic response comprised age [RCS knot: OR -2.5; CI -3.616 to -1.378; p = 0.022]; ABCC3 [RCS knot: OR 0.67; CI 0.407 to 0.936, p = 0.016]; ERCC1 [RCS knot: OR 0.57; CI 0.235 to 0.901; p = 0.044]; RFC1 [RCS knot: OR -1.04; CI -1.592 to -0.487; p = 0.035]; chondroblastic subtype [OR -0.83; CI -1.106 to -0.520; p = 0.012]; and osteoblastic subtype [OR -1.28; CI -1.664 to -0.901; p = 0.007]. In this South African cohort, we observed the unique gene expression profiles of osteosarcoma tumourigenesis and chemotherapeutic responses. These may serve as prognostication and therapeutic targets. Larger-scale research is needed on the African continent.

Genomic Insights Into High-Grade Infarct-Associated Bone Sarcomas

Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.

DNA Mutational and Copy Number Variation Profiling of Primary Craniofacial Osteosarcomas by Next-Generation Sequencing.

Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes.

Small cell osteosarcoma: An NCDB analysis of demographic and socioeconomic factors of diagnosed patients.

e23504 Background: Small cell osteosarcoma (SCOS) is a rare subtype of osteosarcoma accounting for roughly 1.5% of all osteosarcomas. Its prognosis is slightly worse than conventional osteosarcoma. Exploring demographic trends in patients with a confirmed SCOS diagnosis may provide insight into its epidemiology and allow for earlier diagnosis. The National Cancer Database (NCDB) was analyzed to research the demographic factors in patients diagnosed with SCOS. Methods: A retrospective cohort analysis utilizing the 2004–2020 National Cancer Database (NCDB) included patients with a histologically-confirmed diagnosis of SCOS (ICD-O-3 9185). Demographic factors (age, sex, race, Hispanic status, educational attainment, insurance status, facility type, distance from facility, and Charles-Deyo score) were analyzed via descriptive statistics. Incidence trends were interpreted in regression analysis. The mean survival was compared using the Log Rank (Mantel-Cox) test. Results: A cohort of 102 cases of SCOS were retrieved from the NCDB between 2004–2020. The primary sites for SCOS were the long bones of the lower limb (41%). Most patients were male (69%), White (63%), non-Hispanic (84%) with a mean age for diagnosis of 28 (SD = 18). The mean survival for males was 117 months (95% CI [93,141]), more than twice as long as females with 58 months (95% CI [31,85]). The Log Rank (Mantel-Cox) test reported a chi-square (χ²) value of 6.434, indicating a statistically significant difference between survival curves of males and females (p = 0.01). Residence in a metropolitan area (86%) was more common than other rural or urban areas. The greatest proportion of patients lived in the Middle or South Atlantic region of the United States (68%). The majority of patients were insured (86%), with the most covered by private insurance (64%) or Medicaid (22%). The median household income for each patient was most commonly in the highest quartile of over $74,063 (29%). Patients were diagnosed with SCOS at a steady rate between 2004 to 2020 (R² = 0.0956). Using the AJCC Cancer Staging System, most patients were Stage II (40%) or Stage IV (21%) at diagnosis. As a primary treatment, 87% of patients received chemotherapy. Most patients (91%) had no comorbidities with a Charlson-Deyo score of 0. Conclusions: This is the first time that demographic and socioeconomic factors of SCOS patients have been analyzed from the NCDB, revealing that the mean survival time of patients after receiving a diagnosis was more than double for males than females. SCOS patients are also more likely to live in metropolitan areas, particularly within the Middle or South Atlantic United States. Consistent with earlier reports, SCOS is typically diagnosed in young adults in the long bones of lower limbs. To better understand the impact of demographic factors on the diagnosis, treatment, and overall survival of patients with SCOS, further research is recommended.

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 &amp; 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 &amp; 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 &amp; 11 belonged to category 3. There was significant correlation between PD-L1 expression score &amp; 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.

Clinical and Pathological Features of Osteosarcomas of the Jaws: A Retrospective Study.

Osteosarcomas of the jaw (OSJs) are rare tumors with distinct characteristics from osteosarcomas affecting other bones. This study aims to analyze the clinical, pathological, and therapeutic characteristics of OSJs. A retrospective, descriptive cross-sectional study including patients diagnosed with OSJ registered at the "La Paz" University Hospital, Madrid, was performed. Data of eight patients with a diagnosis of OSJ were obtained during the study period of 22 years (2002-2024). The mean age of the patients was 41 years. The distribution was 1:1 between the maxilla and mandible. Painful inflammation was the most frequent clinical manifestation. Conventional osteoblastic osteosarcoma was the most predominant histological type. Survival rate at 5 years was 50%, which decreased to 25% at 10 years. OSJs differ from conventional osteosarcomas of long tubular bones. Surgery continues to be the mainstay of treatment. However, more studies are needed through which more standardized protocols can be proposed for adjuvant therapeutic management.

Head and Neck Osteosarcoma: Perineural Invasion is Associated With Disease-Free Survival and Tumor Metastasis

BackgroundHead and neck osteosarcoma (HNOS) is the most common bone malignancy in the head and neck region, accounting for 10% of all osteosarcoma cases. Perineural invasion (PNI) is a notable indication of aggressive tumor behavior, which includes the phenomenon of tumor cells invading any of the three layers of the nerve sheath or tumor cells gathering, encircling one-third of the nerve circumference, and infiltrating and metastasizing along the nerve. PNI has been reported in various malignant tumors and is considered to be linked to poor prognosis. PurposeThe study's purpose is to measure the association between PNI and survival outcomes in patients with HNOS. Study design, setting, sampleThis retrospective cohort study focused on HNOS patients who underwent surgery at the Department of Oral and Maxillofacial Head and Neck Oncology, Shanghai Ninth People’s Hospital School of Medicine, Shanghai Jiao Tong University, from 01/01/2019 to 31/12/2021. Patients who did not undergo complete surgical resection of the tumor, did not receive a conventional osteosarcoma diagnosis, and had positive surgical margins were eliminated. Predictor variableThe predictor variable is PNI status. The pathological section of the tumor was consistent with any of the PNI features, which was considered PNI-positive. Main outcome variable(s)The primary outcome variables were 3-year disease-free (DFS) and 3-year overall survival (OS). Secondary outcomes were 3-year tumor local recurrence (LR) and 3-year metastasis (MT). CovariatesCovariates were categorized into the following categories: demographic variables (age, sex), clinical variables (tumor region, primary tumor), and treatment variables (chemotherapy, radiotherapy). AnalysesAnalytic statistical methods were used for the data analysis. Pearson chi-square or fishier test was used to describe the baseline data. Kaplan-Meier is used to calculate survival rates. The Cox regression model was adapted for univariate and multivariate analysis. A p-value below 0.05 indicated statistical significance. ResultsThe study sample comprised 70 patients; 33 (47.1%) were male, and the mean age was 42.2 (SD:16.7) years old. There were 15 (21.4%) cases of PNI. The 3-year DSF rate and OS rate were 67.3% and 82.0%. PNI-positive resulted in higher risk for MT (P＜0.01, HR:5.95, 95% CI:1.62-21.86) and negative impact on DFS (P＜0.01, HR:6.35, 95% CI: 2.11-19.17) for HNOS patients. Conclusions and RelevancePositive PNI status was associated with decreased DFS and increased risk of MT.

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.

Detection of MDM2 gene amplification by fluorescence in situ hybridization and its diagnostic value in low-grade osteosarcoma

Objective: To investigate the diagnostic value of detecting MDM2 gene amplification by fluorescence in situ hybridization (FISH) in low-grade osteosarcoma (LGOS). Methods: Thirty cases of parosteal osteosarcoma (POS) and 14 cases of low-grade central osteosarcoma (LGCOS) from April 2009 to August 2022 at Beijing Jishuitan Hospital, Capital Medical University were analyzed for the presence of MDM2 gene amplification by FISH. Fifty-eight additional cases were used as negative controls (including 28 cases of fibrous dysplasia, 5 cases of giant cell tumor, 4 cases of conventional osteosarcoma, 2 cases each of periosteal osteosarcoma, reparative changes after fracture, pleomorphic undifferentiated sarcoma, low grade myofibroblastic sarcoma, fibrous dysplasia with malignant transformation, one case each of leiomyosarcoma, sclerosing epithelioid fibrosarcoma, malignant peripheral nerve sheath tumor, desmoplastic fibroma of bone, solitary fibrous tumor, aneurysmal bone cyst, clear cell chondrosarcoma, osteofibrous dysplasia, and 3 cases of unclassified spindle cell tumor). Results: Among the 30 patients with POS, 15 were male and 15 were female, ranging in age from 10 to 59 years (mean 35 years, median 30.5 years). Among the 14 patients with LGCOS, four were male and 10 were female, ranging in age from 15 to 56 years (mean 37 years, median 36 years). All except one case were successfully detected by FISH. MDM2 gene amplification was detected in 27 cases of POS (27/29,91.3%) and 8 cases of LGCOS (8/14). All the negative controls were negative for MDM2 gene amplification. The positive rate of MDM2 gene amplification was significantly different between the case group and the control group (P<0.05). The sensitivity and specificity of MDM2 gene amplification in diagnosing POS and LGCOS were 91.3% and 100.0%; and 57.1% and 100.0%, respectively. The sensitivity and specificity of MDM2 gene amplification in diagnosing LGOS (including POS and LGCOS) were 81.3% and 100.0%, respectively. In cases where MDM2 gene was amplified, the MDM2 amplified signal was clustered. Nine cases showed increased CEP12 signal different from polyploidy which was displayed as small and weak signal points or cloud flocculent and cluster signals. Conclusions: Detection of MDM2 gene amplification by FISH is a highly sensitive and specific marker for LGOS. The interpretation criteria for FISH detection of MDM2 amplification are currently not unified. The signal characteristics need more attention when interpreting.

Small cell osteosarcoma versus fusion-driven round cell sarcomas of bone: retrospective clinical, radiological, pathological, and (epi)genetic comparison with clinical implications.

Small cell osteosarcoma (SCOS), a variant of conventional high-grade osteosarcoma (COS), may mimic fusion-driven round cell sarcomas (FDRCS) by overlapping clinico-radiological and histomorphological/immunohistochemical characteristics, hampering accurate diagnosis and consequently proper therapy. We retrospectively analyzed decalcified formalin-fixed paraffin-embedded (FFPE) samples of 18 bone tumors primarily diagnosed as SCOS by methylation profiling, fusion gene analysis, and immunohistochemistry.In eight cases, the diagnosis of SCOS was maintained, and in 10 cases it was changed into FDRCS, including three Ewing sarcomas (EWSR1::FLI1 in two cases and no identified fusion gene in the third case), two sarcomas with BCOR alterations (KMT2D::BCOR, CCNB3::BCOR, respectively), three mesenchymal chondrosarcomas (HEY1::NCOA2 in two cases and one case with insufficient RNA quality), and two sclerosing epithelioid fibrosarcomas (FUS::CREBL3 and EWSR1 rearrangement, respectively).Histologically, SCOS usually possessed more pleomorphic cells in contrast to the FDRCS showing mainly monomorphic cellular features. However, osteoid was seen in the latter tumors as well, often associated with slight pleomorphism. Also, the immunohistochemical profile (CD99, SATB2, and BCOR) overlapped.Clinically and radiologically, similarities between SCOS and FDRCS were observed, with by imaging only minimal presence or lack of (mineralized) osteoid in most of the SCOSs.In conclusion, discrimination of SCOS, epigenetically related to COS, versus FDRCS of bone can be challenging but is important due to different biology and therefore therapeutic strategies. Methylation profiling is a reliable and robust diagnostic test especially on decalcified FFPE material. Subsequent fusion gene analysis and/or use of specific immunohistochemical surrogate markers can be used to substantiate the diagnosis.

Histopathological Response to Neoadjuvant Chemotherapy in Patients With Enneking Stage II Conventional Osteosarcoma of Extremities: A Retrospective-Single Institution Study in Vietnam.

The standard treatment for localized osteosarcoma is neoadjuvant chemotherapy before surgery, followed by adjuvant chemotherapy. Our aim was to report the rate of histopathological response to neoadjuvant chemotherapy for the treatment of extremity osteosarcoma in Vietnam. We performed a retrospective study of stage II conventional osteosarcoma patients under 40years-old who received MAP regimen as neoadjuvant chemotherapy at the Vietnam National Cancer Hospital between June 2019 and June 2022. Histopathological response was evaluated using the Huvos grading system, in which a good histopathological response was defined as a necrotic rate of 90% or more. Thirty-five eligible patients were included in the study. Male patients accounted for 65.7%, with a median age of 16 years (range, 8-38years). Of the 35 cases, 31 were reported as stage IIB (88.6%). The femur and tibia were the most common sites in our study, accounting for 51.4% and 34.3%, respectively. The most common pathologic subtype was osteoblastic osteosarcoma (68.6%), followed by chondroblastic subtype (20%). After two cycles of MAP-regimen neoadjuvant chemotherapy, 28 of 35 patients (80%) underwent limb-sparing surgery. A good histopathological response was observed in 18 of 35 patients (51.4%). There were significant correlations between the duration of symptoms (P = 0.016), LDH (P = 0.001) serum levels at initial presentation, and ALP (P = 0.043) serum levels at initial presentation with histopathological response. This retrospective study suggests a possible association between symptom duration, pre-treatment LDH levels, and pre-treatment ALP levels with histopathological response rates. Additional clinical investigations with long-term follow-up are needed to investigate survival outcomes in the Asian population.

Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous

Osteosarcoma is the most common primary bone malignancy, often detected in children and adolescents and commonly associated with TP53 alterations along with a high number of chromosomal rearrangements. However, osteosarcoma can affect patients of any age, and some tumors display less genetic complexity. Besides TP53 variants, data on key driving mutations are lacking for many osteosarcomas, particularly those affecting adults. To detect osteosarcoma-specific alterations, we screened transcriptomic and genomic sequencing and copy number data from 150 bone tumors originally diagnosed as osteosarcomas. To increase the precision in gene fusion detection, we developed a bioinformatic tool denoted as NAFuse, which extracts gene fusions that are verified at both the genomic and transcriptomic levels. Apart from the already reported genetic subgroups of osteosarcoma with TP53 structural variants, or MDM2 and/or CDK4 amplification, we did not identify any recurrent genetic driver that signifies the remaining cases. Among the plethora of mutations identified, we found genetic alterations characteristic of, or similar to, those of other bone and soft tissue tumors in 8 cases. These mutations were found in tumors with relatively few other genetic alterations or in adults. Due to the lack of clinical context and available tissue, we can question the diagnosis only on a genetic basis. However, our findings support the notion that osteosarcomas with few chromosomal alterations or adult onset seem genetically distinct from conventional osteosarcomas of children and adolescents.

The use of weakly supervised machine learning for necrosis assessment in patients with osteosarcoma: A pilot study.

Percent necrosis (PN) following chemotherapy is a prognostic factor for survival in osteosarcoma. Pathologists estimate PN by calculating tumor viability over an average of whole-slide images (WSIs). This non-standardized, labor-intensive process requires specialized training and has high interobserver variability. Therefore, we aimed to develop a machine-learning model capable of calculating PN in osteosarcoma with similar accuracy to that of a musculoskeletal pathologist. In this proof-of-concept study, we retrospectively obtained sixWSIs from twopatients with conventional osteosarcomas. A weakly supervised learning model was trained by using coarse and incomplete annotations of viable tumor, necrotic tumor, and nontumor tissue in WSIs. Weakly supervised learning refers to processes capable of creating predictive models on the basis of partially and imprecisely annotated data. Once "trained," the model segmented areas of tissue and determined PN of the same sixWSIs. To assess model fidelity, the pathologist also estimated PN of each WSI, and we compared the estimates using Pearson's correlation and mean absolute error (MAE). MAEwas 15% over the sixsamples, and 6.4% when an outlier was removed, for which the model inaccurately labeled cartilaginous tissue. The model and pathologist estimates were strongly, positively correlated (r = 0.85). Thus, we created and trained a weakly supervised machine learning model to segment viable tumor, necrotic tumor, and nontumor and to calculate PN with accuracy similar to that of a musculoskeletal pathologist. We expect improvement can be achieved by annotating cartilaginous and other mesenchymal tissue for better representation of the histological heterogeneity in osteosarcoma.

Mandibular small cell osteosarcoma: a case report and review of literature

BackgroundSmall cell osteosarcoma is an extremely rare histopathological variant of conventional osteosarcoma. Due to nonspecific symptoms, most osteosarcomas of the jaws are misdiagnosed as periapical abscesses and mistreated by teeth extraction and drainage.Case presentationWe report, to our knowledge, the seventh case of small cell osteosarcoma in gnathic sites affecting the mandible of an old female with history of a large painful swelling related to the right mandibular molar area for 2 months. Cone-beam computed tomography scan showed an osteolytic lesion related to the lower molar area with involvement of the inferior alveolar nerve. An incisional biopsy was taken, and after histopathological examination and immunohistochemical staining, a diagnosis of small cell osteosarcoma was reached. Hemi-mandibulectomy was performed by a maxillofacial surgeon. No clinical evidence for recurrence was noted until manuscript writing.ConclusionAccurate diagnosis is very important, and general practitioners should be aware of this entity considering that small cell osteosarcoma has a poor prognosis when compared to conventional osteosarcoma.

Is Dissection and Preservation of Adherent Popliteal Vessels From a Posterior Soft Tissue Mass Associated With a Higher Proportion of Local Recurrence in Patients With a Distal Femoral Osteosarcoma?

Is Dissection and Preservation of Adherent Popliteal Vessels From a Posterior Soft Tissue Mass Associated With a Higher Proportion of Local Recurrence in Patients With a Distal Femoral Osteosarcoma?

Encasement Of Popliteal Vascular Bundle Due Local Osteosarcoma Recurrence Treated With Wide Resection And Vascular Reconstruction.

Osteosarcoma is the most common primary bone malignancy. The prognosis of patients after local recurrence is generally poor and management of the locally recurrent disease is not well defined, especially in patients who have undergone limb-sparing surgery. A 20-year-old male presented a local recurrence of conventional osteosarcoma at the popliteal fossa with encasement of popliteal vascular bundle after previous tumor-wide resection and reconstruction with proximal tibia endoprosthesis. A wide resection "en bloc" of the lesion included part of the popliteal vessel. A bypass of both popliteal vessels, the vein with polytetrafluoroethylene (PTFE) prosthesis, and the artery with contralateral saphenous vein were performed to allow a limb salvage surgery. Local management of recurrent osteosarcoma in a previously reconstructed limb is highly individualized. This case confirms that preservation of lower limb function is possible using reconstruction techniques of bone and vessels in the sarcoma of the musculoskeletal system.

Chemotherapy Regimens for Non-Metastatic Conventional Appendicular Osteosarcoma: A Literature Review Based on the Outcomes.

Osteosarcoma is a rare condition with a complex treatment. Most protocols include neoadjuvant chemotherapy, surgery, and consolidation chemotherapy as the standard of treatment. However, the use of neoadjuvant chemotherapy lacks scientific evidence proving superiority in opposition to the use of isolated chemotherapy in an adjuvant regimen after surgery. We conducted a review for studies published in English between 1980 and 2020, using the MEDLINE/PubMed and Scopus electronic databases, to evaluate the outcomes when using neoadjuvant chemotherapy or adjuvant chemotherapy strategies in the treatment of non-metastatic appendicular osteosarcoma, as well as the toxicity associated with different chemotherapeutic regimens. Patients were divided into a neoadjuvant chemotherapy group (NAC) and adjuvant chemotherapy group (ACT), depending on the chemotherapy regimen used in association with surgery. A total of 1254 articles in English were screened by title and abstract, and 146 were pre-selected for full reading and analysis. A total of 24 assays matching the inclusion criteria were selected: 10 prospective and 14 retrospective studies. This review points to an absence of significative differences in outcomes, namely overall survival, disease-free survival/event-free survival rates, or toxicity, regarding neoadjuvant or single adjuvant chemotherapy strategies used in the treatment of appendicular non-metastatic osteosarcomas. However, there is a significative difference in population dimensions between the NAC and the ACT groups. Additionally, clinical presentation, tumor localization, tumor volume, or histological type were not considered, with these variables presenting the potential to influence these results. Despite these limitations, our findings should allow a re-thinking of our current practice and promote new opportunities to optimize treatment, always looking towards better survival and lower complications rates.

CORR Insights®: Does the Clinical Presentation of Secondary Osteosarcoma in Patients Who Survive Retinoblastoma Differ From That of Conventional Osteosarcoma and How Do We Detect Them?

1Professor Orthopaedic Oncology, University of Florida, Department of Orthopaedics and Sports Medicine, Gainesville, FL, USA M. T. Scarborough, University of Florida, Department of Orthopaedics and Sports Medicine, 1600 SW Archer Rd, Gainesville, FL 32610, USA, Email: [email protected] This CORR Insights® is a commentary on the article “Does the Clinical Presentation of Secondary Osteosarcoma in Patients Who Survive Retinoblastoma Differ From That of Conventional Osteosarcoma and How Do We Detect Them?” by Kim and colleagues available at: DOI: 10.1097/CORR.0000000000002667. The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writer, and do not reflect the opinion or policy of CORR® or The Association of Bone and Joint Surgeons®.

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.