The June 2023 Oncology Roundup. 360. looks at: A size-based criteria for flap reconstruction after thigh-adductor soft-tissue sarcoma resection; Surgical treatment of infected massive endoprostheses implanted for musculoskeletal tumours; Free vascularized fibula for proximal humerus oncological reconstruction in children; The national incidence of chondrosarcoma of bone; a review; Bone sarcoma follow-up: when do events happen?; Osteosarcomas in older adults: a report from the Cooperative Osteosarcoma Study Group

Introduction and Objectives: Osteosarcomas are the most frequent malignant primitive bone tumors. Since 1980, the management of osteosarcomas has changed due to the introduction of neoadjuvant chemotherapy which allows limb salvage surgery to be performed. Nur77 is a transcription factor (nuclear receptor superfamily), when it migrates from the nucleus to the mitochondria and interacts with molecule Bcl2, it converts it into a pro-apoptotic substance that mediates the apoptotic effects of certain chemotherapeutic agents. In our study we quantify, in a relative way, the expression of the gene Nur77 in osteogenic osteosarcomas. Procedures that increase its expression and induce its translocation could increase the efficacy of chemotherapeutic agents. Materials and Methods: We took 10 frozen samples (6 osteogenic osteosarcomas, 2 metastases, 2 normal tissues) and reviewed the patient’s clinical history (age, diagnosis, treatment, evolution and degree of tumor necrosis). After extracting total RNA and synthesizing cDNA from each sample, we quantified the level of expression of the gene Nur77 by means of real-time PCR. Results: We analyzed the results using the delta-delta Ct method approximation analysis and analysis relative to normal data. Discussion and Conclusions: We observed heterogeneous behavior with reference to gene Nur77 expression. Those tumors that had Nur77 expression values lower than that of normal tissue seemed to respond worse to chemotherapy. This suggests, preliminarily, an association between the expression of Nur77 and the response to chemotherapy

Aim: Osteosarcomas represent the most common primary malignant bone tumors. However, their pathogenesis is unclear. In vitro and in vivo studies have demonstrated the participation of the JNK–c-Jun signal transduction cascade and oncoproteins c-Jun and c-Fos in osteoblast proliferation and differentiation. JNKs activate c-Jun, which forms the AP-1 transcription factor as a homo/heterodimeric complex. Alpha-NAC is an osteo-blast-specific AP-1 coactivator that potentiates c-Jun/c-Jun, but not c-Jun/c-Fos transcriptional activity. We addressed the possibility that upregulation of the JNK–c-Jun pathway, as well as expression/activation of c-Fos and á-NAC, are implicated in osteosarcoma pathogenesis. Materials and method: We assessed immunohistochemically the protein levels of the two major JNK isoforms (JNK1,2), their phosphorylated/activated species, p-JNK, their substrate, c-Jun, its phosphorylated/activated form, pc-Jun, its partner, c-Fos, and á-NAC, in 71 human osteo-sarcomas (56 high and 15 low grade). Results: Positive immunostaining for JNK1, JNK2, p-JNK, c-Jun, pc-Jun, c-Fos and á-NAC was observed in 86%, 93%, 94%, 99%, 97%, 99% and 97.5% of the samples, respectively, but not in normal bone. Cellular levels of all proteins were significantly correlated to each other (p< 0.001). Moreover, significantly higher expression levels of all proteins were detected in high-grade osteosarcomas, compared to low-grade ones (p< 0.001). Discussion: Our findings provide novel evidence that the JNK–AP-1 pathway is involved in osteoblast malignant transformation and osteosarcoma development and progression. Furthermore, the expression profile of α-NAC suggests that the active AP-1 population in human osteosarcomas is most likely comprised of c-Jun/c-Jun homodimers. Evaluation of c-Jun expression and JNK-dependent activation may facilitate an improved prediction of tumors’ clinical behaviour and potentially be exploited in designing patient-tailored treatment regimens

Osteosarcoma is the most common tumor among the primitive malignant bone tumors. When different features of these lesions are considered, we can find several varieties of this tumor, with distinct anatomo-clinical presentation, treatment and prognosis.

Until the 70s, its prognosis was very poor, the standard surgical treatment was amputation and 80% of the patients died from metastatic disease. With the development of new surgical techniques, the advent of combined chemotherapy and more accurate imaging, the outcome of these patients has improved significantly. Consequently, approximately 90% of the surgical cases are treated with limb salvage procedures.

The authors reviewed 22 cases of Osteosarcoma treated in HGSA, 20 being submitted to the T20 Rosen protocol.

Trocar biopsy was performed in 19 of the patients and 3 of the patients were submitted to incisional biopsy in order to complete diagnosis.

Regarding the anatomo-clinical pattern, Classic Osteosarcoma was present in 19 patients, 2 of the cases were Parosteal and 1 was Central low-grade Osteosarcoma.

The majority of patients underwent limb salvage surgery; only 2 had amputation surgery and 1 patient was submitted to palliative chemotherapy. Considering limb salvage procedures, several techniques were performed: arthrodesis (n=1), grafts (n=4), prosthesis (n=13) and compound prosthesis (n=1). The resection margins were wide in 19 cases, marginal in 2 cases and in 1 case intra-luminal.

Among the treated patients: 12 patients are still alive and cured, 3 have metastatic disease, 6 are deceased and 1 didn’t complete the follow-up.

The final functional score obtained was 84% for the superior limb (DASH) and 81% for the inferior limb (TESS).

Although the scarce number of cases described were not enough to make any kind of correlation, it was possible to establish the accuracy of the multidisciplinary approach involved both in the diagnosis and treatment, in agreement with the “state of art”.

Purpose: Matrix metalloproteinases are important for matrix turnover in development of metastasis and angiogenesis. Our purpose was to investigate the expression of MMP-9 and itsb prognostic significance in knee osteosarcomas.

Patients: 55 patients with osteosarcoma IIB of the knee area have been studied with respect to the expression of MMP-9 in the surviving tumour cells in the surgical resection specimens

Patients were followed up for at least two and a half years.

Methods: We studied the MMP-9 expression in the resection specimens using immunohistochemistry. The importance of the prognostic factors was assessed using single (log rank test) and multiple variable (Cox regression) analysis. Independence between the factors found significant using the log rank test was studied using the yf test. Significance was set at P< 0.05.

Results: On single variable analysis factors significantly associated with poor survival were high alkaline phosphatase at diagnosis and tumour cells expressing MMP-9 in the resection specimens. The only factor strongly associated with disease free survival was immunohistochemical status of tumour cells for MMP-9 in the resection specimens.

Percentage of necrosis after chemotherapy failed marginally to reach statistical significance.

On Cox regression analysis only MMP-9 remained significant for overall and disease free survival.

Discussion: Once new blood vessels penetrate a microscopic primary tumour or a distant metastasis, the lesions acquire the potential to grow into larger and potentially life threatening tumours. MMP-9 is a factor associated with matrix remodeling during angiogenesis and is also associated with leaky vessels because of its ability to degrade basement membranes. These two properties are very important for tumour growth and development of haematogenous metastases and we believe may explain our findings.

We looked at long-term psychological effects of limb salvage surgery on young people treated for osteosarcoma and Ewing sarcomas with limb salvage surgery and high-dose neo-adjuvant chemotherapy.

After an extensive survey of the literature, we conducted semi-structured interviews with five young adult survivors. They reported various treatment-linked psychological symptoms, some of which persisted in varying degrees for up to 10 years after completion of treatment. Depending largely upon social and family support during and after treatment, the symptoms seem to become less invasive as time passes, but the survivors reported that some of them recur at transition periods in their lives and before annual follow-up visits. All view themselves as stronger people who have learnt much from their experience, and said that counselling and the provision of information at the treatment centres had helped in their adaptation.

The multi-disciplinary team approach in the treatment of adolescents and young adults with cancer is of paramount importance.

Aims: The purpose of this study is to investigate whether the expression of MMP-9 (matrix metalloproteinase-9) is a potentially useful marker in osteosarcomas. Methods: 55 patients with stage IIB knee osteosarcomas were treated in our unit and had a median follow-up of 68 months. In addition to clinical data, MMP-1, MMP,-2, MMP-3, MMP-7, MMP-9 and MMP-13 were studied in the resection specimens, using immunohistochemical methods. The importance of all factors was studied using the log-rank test, and the overall survival of patients was calculated using Kaplan-Meier survival curves. Multiple variable analysis was carried out using Cox regression models with variables chosen forward and backward stepwise methods with deviance statistics. Signiþcance was set at p< 0.05. Results: On multiple variable analysis only the MMP-9 status of the tumour cells had a signiþcant effect on overall (p=0.032) and disease free survival (p=0.014). Conclusions: Our study shows that some post-chemotherapy osteosarcoma specimens express MMP-9 in the surviving tumour cells after chemotherapy. We believe that MMP-9 in the osteosarcoma cells which survive chemotherapy, contributes to recurrence because of the ability of these cells, to stimulate a new vascular network. The relationship between osteosarcomas and MMP-9 is worthy of further study.

Despite the recent progress, non-metastatic pediatric osteosarcomas have now a 5-year overall survival (OS) around 75% and the metastatic forms are decreasing to 20–30%. To increase these survival rates, new molecular approaches are on development to understand and highlight new candidates for targeted therapies. Tyrosine kinase receptors (TKR) are one of this target class, where new drugs were especially developped, screening now a large spectrum of TKR. After the demonstration among cancers of TKR’s clinical utility as surrogate markers to guide the selection of patients susceptible to respond to these treatments, this success was recently tempered in part because of cancers developping resistance mechanisms to these drugs. A study was conducted to evaluate the interest of these molecular targets among pediatric osteosarcomas.

Materiel and methods: 91 pediatric patients treated homogeneously with the French OS94 protocol were included in this analysis. Allelotyping, real-time quantitative PCR (QPCR), sequencing and immunhistochemistry were performed to analyse the following targets: EGFR, MET, PDGFRA, KIT and ERBB2.

Results and discussion: Most of these targets were rearranged in more than 45% of the population and mainly deleted. Only 11.4% were amplified at MET and 8.6% at PDGFRA. By QPCR, ERBB2 was normal in 78 out of 81 informative patients. Surprinsingly, wild-type KIT protein was amplified in 37%. EGFR was rearranged by allelotyping in 48% and QPCR evaluation just started. MET amplified subgroup is linked to a worst OS than normal and deleted subgroups (p=0.04) whereas PDGFRA amplified tumors tend to be significantly linked to a better patient OS (p=0.08). Considering all amplified subgroups, no ovelap was found as if an osteosarcoma could only be amplified for one gene. This observation could be considered as a way to increase the potential targeted populations where the use of large spectrum TKR inhibitors would be useful in osteosarcoma treatment.

Our study sets out to show whether vascular endothelial growth factor (VEGF) expression in stage 2B osteosarcomas around the knee influences disease-free and overall survival.

Fifty-two such patients treated in out unit were identified and followed-up for for a minimum of 92 months. All were treated according to the current MRC protocol and had resection of their tumour. Tissue from their resected tumours was stained for VEGF using immunohistochemical methods and the percentage of tumour cells staining for VEGF was assessed. The relationship between VEGF expression and survival was assessed using the log-rank test and Kaplan-Meier survival curves.

At follow-up 32 (62%) patients were dead, all from metastatic disease. Twenty-six (50%) tumours showed expression of VEGF. Statistical analysis showed that patients with tumours with VEGF expression in more than 25% of the cells had significantly shorter overall survival (p=0.019) and disease free intervals (p=0.009). Expression of VEGF also correlated with expression of the proteolytic enzyme MMP9 (p=0.02).

VEGF is peptide which acts as a stimulator of new blood vessel growth in normal tissues, as well as in some solid tumours and their metastases. A tumour which is able to induce a blood supply has an increased ability to grow, seed metastases and threaten life. Our study is the first to look at VEGF expression in the tumour cells surviving after chemotherapy. It is this population of cells which is important as it is these cells which may go on to develop into metastatic or locally recurrent tumours. The over-expression of VEGF by osteosarcoma cells is thought to be associated with a worse prognosis due to a number of mechanisms. This study shows that VEGF expression is an important prognostic factor in osteosarcomas and suggests that the mechanisms by which VEGF and MMP9 expression produce a poor prognosis may be linked. Suppression of tumour angiogenesis by inhibition of the action of VEGF has shown promise in animal models as a potential new treatment for osteosarcoma, and warrants further study.

Our study sets out to show whether vascular endothelial growth factor (VEGF) expression in stage 2B osteosarcomas around the knee influences disease-free and overall survival.

Fifty-two such patients treated in out unit were identified and followed-up for for a minimum of 92 months. All were treated according to the current MRC protocol and had resection of their tumour. Tissue from their resected tumours was stained for VEGF using immunohistochemical methods and the percentage of tumour cells staining for VEGF was assessed. The relationship between VEGF expression and survival was assessed using the log-rank test and Kaplan-Meier survival curves.

At follow-up 32 (62%) patients were dead, all from metastatic disease. Twenty-six (50%) tumours showed expression of VEGF. Statistical analysis showed that patients with tumours with VEGF expression in more than 25% of the cells had significantly shorter overall survival (p=0.019) and disease free intervals (p=0.009).

VEGF is peptide which acts as a stimulator of new blood vessel growth in normal tissues, as well as in some solid tumours and their metastases. A tumour which is able to induce a blood supply has an increased ability to grow, seed metastases and threaten life. Our study is the first to look at VEGF expression in the tumour cells surviving after chemotherapy. It is this population of cells which is important as it is these cells which may go on to develop into metastatic or locally recurrent tumours. The over-expression of VEGF by osteosarcoma cells is thought to be associated with a worse prognosis due to a number of mechanisms. This study shows that VEGF expression is an important prognostic factor in osteosarcomas. Suppression of tumour angiogenesis by inhibition of the action of VEGF has shown promise in animal models as a potential new treatment for osteosarcoma, and warrants further study.

Osteosarcomas represent a heterogeneous group of primary bone tumours that affect predominantly the long bones of patients in the first two decades of life. We aim to describe the secondary effects of a poor response (⋋90% necrosis) to chemotherapy on the effectivity of other treatment outcomes, local recurrence and survival rates. 182 cases of osteosarcoma with necrosis of less than 90% and no metastases at diagnosis have been seen at our institution over 24 years. There were 60 amputations. 122 patients underwent limb salvage, with 105 marginal margins and 17 contaminated. There was no difference in size or location between the two groups. In the 122 patients with LSS, 21 had adjuvant radiotherapy and 101 did not. In the entirety of patients with ⋋90% necrosis, survival was 64% at 2 years and 37% at 5 years. When LSS Marginal resections were compared with amputation there was a significant (P=0.006) difference in survival. LSS with a marginal margin had a 25% risk of LR. In these patients there was 25% survival, whereas the absence of a local recurrence, conferred a benefit of a 40% survival XRT was used in 21 of the 122 who underwent limb salvage. The decision to use XRT was made by the local oncologist at the treating unit. There was a 24% rate of recurrence in the XRT group and 25% with no XRT. These data demonstrated that patients who had a poor response to chemotherapy and underwent an amputation faired poorly when compared to patients with LSS. There is a selection bias in patients selected to undergo amputation. Additionally, patients who underwent amputation had a lower rate of local recurrence, but still had a poorer survival when compared to LSS

Introduction: Malignant bone tumors are rare. In a sample of 1000 pediatric tumors diagnosed in our hospital only 4% were primary bone tumors. Material and Methodology: The authors present a series of Primary Malignant Bone Tumors, in children and adolescents treated in their Department, referred to a period of 14 years (1991–2004). It’s a series of 45 cases, of which 41 were evaluated. There were excluded 3 malignant low-grade osteosarcomas and 1 Askin tumor (thoracic PNET). The authors evaluated 24 Osteosarcomas, 14 Ewing Sarcomas and 3 PNET. The cases correspond to a population of 24 girls and 17 boys. The study correlate survival rate with tumor histological characteristics, size, stage, chemotherapy protocol used, the percentage of necrotic induction after neoadjuvant chemotherapy and type of surgical plane of dissection. Results: From patients with high-grade osteosarcomas 71,2% are alive and without disease, with a minimum follow-up of 4 years (1 case) and a maximum of 17 years. On the Ewing Sarcomas/PNET the survival rate is 76%, with the same follow-up period. Discussion and Conclusions: Due to the improvement of imaging techniques a fast diagnostic orientation is possible. The stage evaluation, combined with chemo and radiotherapy advances, as well as the progress of the surgical techniques to preserve limbs, together contribute to a better prognosis of the disease. The high survival rates permit to face this pathology as a chronic disease

Aim: Sacral tumours are rare and can form a wide variety of differential diagnoses. We present a series of sacral tumour patients treated at a regional tumour centre; describing our experience of their management. Method: A retrospective study reviewing 76 sacral tumour patients, presenting to the Royal National Orthopaedic Hospital, Stanmore, from April 1976 to April 2002. The minimum follow-up period was 6 months. For each tumour type we looked at the incidence, diagnosis and outcome. Results: 69 of the lesions were primary bone tumours, 3 metastatic and 4 haematopoietic tumours. 33% of all tumours were chordomas. Osteosarcoma (10%), chondrosarcoma (8%) and giant cell tumour (8%) were the next most common. The commonest presenting symptom was lower back pain (64 cases). Good survival was demonstrated with chordomas and giant cell tumours. Osteosarcomas and chondrosarcomas had poor survival. Tissue diagnosis was accurately achieved with image-guided needle biopsy (61 cases). Magnetic resonance imaging (MRI) and computed tomography (CT) provided sufficient details for preoperative planning. Conclusion: The symptoms and signs of sacral tumours are non-specific and may lead to a misdiagnosis of degenerative disease of the spine. In our series chordomas account for only a third of all sacral tumours. Early diagnosis and staging are essential in order to determine definitive management and infl uence outcome. Surgery remains the most effective method for treating the malignant tumours

Aims

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.

To assess the performance and success of joint sparing limb salvage surgery in high grade malignancy, in terms of function, complications, recurrence and survival, as compared to joint resection. We report a ten-year experience of twenty patients with high grade malignancies of bone which did not cross the epiphyseal plate. They underwent not only limb salvage surgery but also joint preservation. The aim of this is to preserve function in the joint and to prevent the inevitable wear of prosthetic joints requiring revision surgery. The age range was 4 - 25 years (mean 13. 5). The Diagnoses were 14 Osteosarcomas and 6 Ewings sarcomas. Mean follow up was 49 months. There were 13 femoral & 7 tibial malignancies. 12 underwent complex biological fixation with a combination of reimplanted autoclaved or irradiated bone; vascularised fibular graft; femoral or humeral allograft. In 8 cases custom made hydroxyapatite coated prostheses were used to replace the resected bone. This surgery must clearly be evaluated in the context of recurrence, particularly as this is associated with an increased risk of metastases and death. Analysis of our results to date has not shown a greater rate of complications. We experienced one recurrence, and one death. The custom prostheses group had fewer complications and operations. Functionally these patients report near normal limbs and joints and do not report any limitation of activities. Joint sparing limb salvage surgery is extremely worthwhile as it produces a significantly better functioning limb and lower morbidity, with less likelihood of revision surgery. We have not found a higher risk of post-operative complications, recurrence or death. Furthermore massive prosthetic replacement is quicker, osseointegrates reliably and is associated with a lower complication and further operation rate

Background Osteosarcoma is the most common bone sarcoma, and the 3rd most common malignancy in children and adolescents. It accounts for 20% of primary malignant bone tumors. Methods A retrospective review of osteosarcomas from the Scottish National Bone Tumor Registry (1940–2000) involving the upperlimb bones is presented. Patient demography, type and location of lesions, treatment options, recurrence and survival rates, and metastasis have been analysed. Results 75 cases were identified from the registry. Sex incidence showed a slight male preponderance with male: female ratio 1.14: 1.Age at presentation ranged from 4–88 Yrs (mean 28.44 Yrs). 46.7% sarcomas occurred in the second decade (11–20 Yrs). The humerus was the bone most frequently involved (78.6% of lesions), and the proximal humerus the commonest site (60%). The scapula was involved in 9.3% and the forearm in 8%.A rare solitary lesion of the clavicle was encountered.17% presented with pathological fractures at diagnosis. Patients typically present with dull aching pain of weeks to months. All patients underwent radiological studies and diagnostic biopsy. Treatment modalities included amputation, limb-sparing surgery, adjuvant/neoadjuvant chemotherapy and radiotherapy. The cumulative 5 year survival for the series was 32%.Death was usually due to pulmonary and skeletal metastasis, and the mean survival in such patients was 21.5 mts. Patients presenting with metastatic pulmonary disease had poor prognosis. Limb-sparing surgery with wide margins does not compromise survival. Results with custom endoprosthesis are encouraging. Discussion Osteosarcomas require a multidisciplinary approach to diagnosis and treatment to optimise survival. During the first half of the study period amputation was the mainstay of treatment with high incidence of mortality due to metastatic disease. Recent advances in neoadjuvant/adjuvant chemotherapy have improved the ability to perform limb –sparing resections, and disease free and overall survival rates have improved. Regular, long follow-up is indicated in these patients

Introduction: Types of cancer occurring in children are very different from those occurring in adults. Reliable data on incidence and mortality of childhood cancers is sparse. Methods: A review of all primary malignant bone tumors in children (0–14 Yrs) from the Scottish National Bone Tumor Registry (1940–2000) is presented. Epidemiology, clinical presentation, pathology, radiological characteristics, treatment options, recurrence rates, geographic distribution and incidence are discussed. Results: Excluding myelomas and lymphomas, 154 patients were identified. 122 (80.2%) lesions were benign, and 30 (19.7%) malignant. There were 20 osteosarcomas (66%), 8 Ewing’s sarcomas (26%), 1 chondrosarcoma and 1 fibrosarcoma. Osteosarcoma – Age at presentation ranged from 4–14 Yrs (mean 10.3Yrs). 70 % involved 10–14 Yrs. Male: Female incidence was 1.5:1. 75% of lesions involved the proximal humerus.15 % presented with pathological fractures. The mean cumulative 5 year survival was 20%. Death was usually due to pulmonary metastasis.65% had pulmonary metastasis at a mean 6.3 mts after diagnosis. Mean survival in these patients was 14mts. Survival was superior with adjuvant chemotherapy and wide excision. Ewing’s Sarcomas- Age at presentation ranged from 7–14 (mean 11.2Yrs).71.4% involved 10–14Yrs. Male: Female was 1.6:1. 62.5% lesions involved the humerus and 25 % the radius and 12.5% the scapula. The mean cumulative 5 year survival was 37.5%.Death was due to pulmonary or skeletal metastasis (mean 21.5mts). All patients had radiotherapy and chemotherapy. Chondrosarcoma- A rare low-grade chondrosarcoma of the proximal humerus was encountered. Excision and grafting yielded good results. Discussion: Majority of bone lesions in this age group are benign. Osteosarcomas and Ewing’s sarcomas predominate among the malignant (93%).The peak incidence occurs with adolescent growth spurt. Mean age is lower for osteosarcomas, and the sex incidence for both show male preponderance. Survival rates for Ewing’s was higher than for osteosarcomas. Pulmonary involvement at presentation had worst prognosis

Aims

Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma.

Aims

We have previously reported cryoablation-assisted joint-sparing surgery for osteosarcoma with epiphyseal involvement. However, it is not clear whether this is a comparable alternative to conventional joint arthroplasty in terms of oncological and functional outcomes.

We describe a retrospective review of 38 cases of reconstruction following resection of the metaphysiodiaphysis of the lower limb for malignant bone tumours using free vascularised fibular grafts. The mean follow-up was for 7.6 years (0.4 to 18.4). The mean Musculoskeletal Tumor Society score was 27.2 (20 to 30). The score was significantly higher when the graft was carried out in a one-stage procedure after resection of the tumour rather than in two stages. Bony union was achieved in 89% of the cases. The overall mean time to union was 1.7 years (0.2 to 10.3).

Free vascularised fibular transfer is a major operation with frequent, but preventable, complications which allows salvage of the limb with satisfactory functional results.