Ewing sarcoma (ES) and Osteosarcoma (OS) are the 2 most common malignant primary bone tumors. A patient's response to neoadjuvant chemotherapy has important implications in subsequent patient management and prognosis, as a favourable response to chemotherapy allows orthopedic oncologists to be more aggressive in pursuing limb-sparing surgery. An accurate and non-invasive pre-operative marker of response would be ideal for planning surgical margins and as a prognostic tool. ES and OS have differing biological characterisitcs and respond differently to chemotherapy. We reviewed 18F-FDG PET imaging characteristics of ES and OS patients at baseline and following treatment to determine whether this biological variation is reflected in their imaging phenotype. A retrospective review of ES and OS patients treated with neoadjuvant chemotherapy and surgery was done, correlating PET results with histologic response to chemotherapy. Change in the maximum standardized Uptake Value (SUVmax) between baseline and post-treatment scanning was not significantly associated with histologic response for either ES or OS. Metabolic tumor volume (MTV) and the percentage of injected 18F-FDG dose (%ID) in the primary tumor were found to be different for ES and OS response subgroups. A 50% reduction in MTV (MTV2:1 < 0.5) was found to be significantly associated with histologic response in OS. Using the same criteria for ES incorrectly predicted good responders. Increasing the cut-offs for ES to a 90% reduction in MTV (MTV 2:1 < 0.1) resulted in association with histologic response. Response to neoadjuvant chemotherapy as reflected by changes in PET characteristics should be interpreted differently for ES and OS

Purpose. Ewings Sarcoma (ES) and Osteosarcoma (OS) behave and respond differently to chemotherapy and any interpretation of diagnostics tests to predict a patients response to treatment must consider this. We reviewed 18F-FDG PET imaging characteristics of consecutive series of ES and OS patients to determine if any differences in PET imaging existed between them. Method. A retrospective review was performed of 31 patients with ES and OS who received all their treatment by our group and who had pre- and post-chemotherapy 18F-FDG PET scans at the Peter MacCallum Cancer Centre from Jan 1, 1999 to December 1, 2009 (Table 1). Patients who did not have both their pre- and post-chemotherapy PET scans done at Peter MacCallum Cancer Centre were excluded from the study to remove bias from having different PET scanning protocols. Patients received neoadjuvant chemotherapy according to standard protocols, all starting within 2 weeks after the initial pre-chemotherapy PET scans (PET1). The PET scan taken after the last cycle of chemotherapy prior to surgery was considered as the post-chemotherapy scan (PET2). The ratio between pre and post-chemotherapy for each PET parameter was then associated with the histology response for both ES and OS, and positive (PPV) and negative predicting values (NPV) of each parameter were calculated. Results. Standardized Uptake Values (SUV) was not significantly associated with histologic response for both ES and OS. Metabolic tumor volume (MTV) and accumulation percentage of 18F-FDG (%ID) was found to be different for ES and OS. A 50% reduction in MTV (MTV2:1 < 0.5) was found to be significantly associated with histologic response in OS. Using the same criteria for ES incorrectly predicted good responders. Increasing the cut-offs for ES to a 90% reduction in MTV (MTV 2:1 < 0.1) resulted in association with histologic response. Conclusion. Response to neoadjuvant chemotherapy as reflected by changes in PET characteristics should be interpreted differently for ES and OS

Our purpose was to assess the role of preoperative radio-therapy +/− neoadjuvant chemotherapy in nonmetastatic soft tissue sarcoma of extremities for limb-sparing surgery and identify the role of neoadjuvant therapies on local control and survival rate. Forty-seven patients with soft tissue sarcoma of extremities who were treated at Cerrahpasa Medical Faculty within a limb salvage protocol, including preoperative radiotherapy +/− chemotherapy were retrospectively analized. Median age was 45 years (17–72 years). The tumor size was between 5–33 cm. Seventeen patients were in stage I, 11 in stage II, 19 in stage III. The most common histology was synovial sarcoma. Nine patients were treated for locally recurrent tumour. The tumour and surrounding tissues with probable microscopic tumour involvement observed clinically and radiologically, were irradiated. Thirty-two patients, with a high grade tumour and/or tumours larger than 8 cm, also received neoadjuvant chemotherapy. Neoadjuvant chemotherapy regimen was consisted of doxorubicine and ifosphamide with mesna. Preoperative radiotherapy was applied, usually between the second and third cycles of chemotherapy. Definitive surgery was administered 2–6 weeks after radiotherapy or after the third cycle of chemotherapy. Chemotherapy was completed to 6 courses after the surgery. Postoperative external beam radio-therapy boost of 16 Gy was given who had close or positive surgical margins. Median follow-up time was 67 months (12–217 months). All of the patients had limb-sparing surgery. Patients had; 30 marginal excision, 13 wide local excision, 4 radical resection. Nine patients locally recurred. Limb-sparing surgery was performed for 8 patients. 25 patients had distant metastases. Metastasectomy were applied for 10 patients with lung metastasis. The 5-year local control, disease free survival and overall survival rates were 82.3%, 50.1% and 67.2%, respectively. Preoperative radiotherapy +/− chemotherapy seems to increase the chance of extremity-sparing surgery with good local control and the survival rates which were comparable with the literature

Neoadjuvant therapy in soft-tissue sarcomas is still a controversial issues regarding indications, patients selection and treatment protocols. In the last fifteen years (1990–2005) at our Institution more than 600 patients affected by soft tissue sarcomas of the limbs and superficial trunk were surgically treated. Among these patients, 49 received preoperative chemotherapy (epirubicin plus ifosfamide, according to Italian Sarcoma Group protocol), associated to preoperative conventional external beam radiationtherapy in 36 cases (73.5%). The histologic types were liposarcoma (30,6%), synovial sarcoma (20,4%), fibrosarcoma (16,3%), pleomorphic sarcoma or malignant fibrous histiocitoma (12,1%), leiomyosarcoma (8,2%), other histotypes (12,1%). Tumor size was 10 cm or larger in 21 cases, 6 to 9 cm in 23 patients and 5 cm or smaller in 5 cases. Neoplasms were high-grade (Broders grade 3 or 4) in all cases but five.

After neoadjuvant treatment we performed a limb-sparing surgical excision of the tumor in 47 patients (96%), while a primary amputation of the limb was necessary in only two cases (4.1%). A vascularized miocutaneous flap was used in 8 cases, and adequate surgical margins were achieved in more than 70% of the cases.

Postoperative chemotherapy was given in 26 cases (53%), postoperative radiotherapy just in 5 (10%). We report the outcome data on these 49 cases, regarding overall survival, local or distant relapse, local and systemic complications, early and long-term limb salvage rate.

According to histologic examination of the resection specimen, average percent of necrosis after neoadjuvant treatment was 70.6% (range 30 – 99%). Wound dehiscence occurred in 6 patients but ultimately healed succesfully in all of them.

At an average follow-up of 23 months (range 3 – 82), 37 patients were continuously disease free (76%), two patients had local recurrence (one amputated), four patients were alive with metastatic disease, five patients had died with disseminated disease (at 4, 19, 28, 37 and 61 months after surgery), one patient had died of unrelated disease.

Due to the inconstant tumor response, neoadjuvant treatment in soft tissue tumors is still a controversial issue. On the basis of data presently available, we think that it can be a useful treatment in high-risk tumors (larger than 5 cm; high grade). In these cases, at a low and acceptable rate of local complications, the conjoined use of preoperative chemotherapy and radiotherapy can help to make a limb-salvage surgery possible and at the same time can maybe reduce the risk of distant metastasis.

Prolonged survival have been reached in the last two decades in patients with Ewing’s sarcoma due to combination of chemotherapy and radiotherapy.

We report the analysis of 493 patients treated according to 4 different protocols in 23 years (Jan1983- Dec 2006).Aim of this study was to evaluate the occurrence of late toxicities as Second Malignant Neoplasms (SMN), Cardiomyopathies and sterility.

Methods: We reviewed our database to find out all those patients aged from 1 to 40 yrs with localized Ewing’s sarcoma who were treated with chemotherapy according to 4 different protocols from 1983 to December 2006. Data were updated at Dec 2008

Results: 493 patients had adequate follow up and meet the eligibility criteria. Median age was 16 yrs (1–40) female/male: 183/310.Median overall survival 69 ms (4–302).220 patients died and 273 are alive. 44 pts received HDCT + PBSCR.Eleven SMN were found : 2 AMLeukemia, 2 parotid adenocarcinoma, 1 melanoma, 1 thyroid cancer and 5 radioinduced osteosarcoma. The interval between Ewing’s sarcoma diagnosis and leukaemia diagnosis was shorter then interval between Ewing’s sarcoma and RT osteosarcoma. Six patients reported a Cardiomyopathy : in 4 cases it was mild and pts are well compensated,2 patients needed heart transplant,. One of these two pts received also a kidney transplant due to chronic renal failure due to previous chemotherapy. Fertility: 17 women became pregnant after chemotherapy, 20 women experienced postTx amenorrea: 7 pts received RT in pelvic area, 9 did HDCT, 3 pts were over 30 yrs old. 9 male became father. 8 male patients did sperm analysis 3 azospermia, 4 oligospermia and 1 normal sperm count. No congenital abnormalities in offsprings were reported.

Conclusions: In this casuistic the Cumulative Risk to have a SMN at 5 yrs is 1.8% and 2.9% at 10 yr. The SMN cumulative incidence in Ewing’s sarcoma seems to be lower then in our previous casistic in osteosarcoma patients (ASCO 2006).

Traditional staging systems for high grade osteosarcoma (Enneking, MSTS) are based largely on gross surgical margins and were developed before the widespread use of neoadjuvant chemotherapy. It is now well known that both microscopic margins and chemotherapy are predictors of local recurrence. However, neither of these variables are used in the traditional surgical staging and the precise safe margin distance is debated. Recently, a novel staging system utilizing a 2mm margin cutoff and incorporating precent necrosis was proposed and demonstrated improved prognostic value for local recurrence free survival (LRFS) when compared to the MSTS staging system. This staging system has not been validated beyond the original patient cohort. We propose to analyze this staging system in a cohort of patients with high-grade osteosarcoma, as well as evaluate the ability of additional variables to predict the risk of local recurrence and overall survival. A retrospective review of a prospectively collected database of all sarcoma patients between 1985 and 2020 at a tertiary sarcoma care center was performed. All patients with high-grade osteosarcoma receiving neo-adjuvant chemotherapy and with no evidence of metastatic disease on presentation were isolated and analyzed. A minimum of two year follow up was used for surviving patients. A total of 225 patients were identified meeting these criteria. Univariate analysis was performed to evaluate variable that were associated with LRFS. Multivariate analysis is used to further analyze factors associated with LRFS on univariate analysis. There were 20 patients (8.9%) who had locally recurrent disease. Five-year LRFS was significantly different for patients with surgical margins 2mm or less (77.6% v. 93.3%; p=0.006) and those with a central tumor location (67.9 v. 94.4; <0.001). A four-tiered staging system using 2mm surgical margins and a percent necrosis of 90% of greater was also a significant predictor of 5-year LRFS (p=0.019) in this cohort. Notably, percent necrosis in isolation was not a predictor of LRFS in this cohort (p=0.875). Tumor size, gender, and type of surgery (amputation v. limb salvage) were also analyzed and not associated with LRFS. The MSTS surgical margin staging system did not significantly stratify groups (0.066). A 2mm surgical margin cutoff was predictive of 5-year LRFS in this cohort of patients with localized high-grade osteosarcoma and a combination of a 2mm margin and percent necrosis outperformed the prognostic value of the traditional MSTS staging system. Utilization of this system may improve the ability of surgeons to stage thier patients. Additional variables may increase the value of this system and further validation is required

We investigated the effect of adjuvant and neoadjuvant chemotherapy regimens on the tibial regenerate after removal of the external fixator in a rabbit model of distraction osteogenesis using New Zealand white rabbits. Forty rabbits were randomly distributed into two groups. In the neoadjuvant group, half of the rabbits received 1mg/kg cisplatinum & 2mg/kg adriamycin at eight weeks of age followed by 1mg/kg cisplatinum & 4mg/kg adriamycin at ten weeks of age. The remaining ten received an identical volume of normal saline using the same regimen. The adjuvant group differed only in the timing of the chemotherapy infusion. Half received the initial infusion ten days prior to the osteotomy, with the second infusion four days following the osteotomy. Again, the remaining ten rabbits received an identical volume of normal saline using the same regimen. This produced an identical interval between infusions and identical age at osteotomy in both groups. All rabbits underwent a tibial osteotomy at 12 weeks of age. Distraction started 24hours after osteotomy at a rate of 0.75mm a day for 10 days, followed by 18 days without correction to allow for consolidation of the regenerate. At week 16 there was no difference in Bone Mineral Density (BMD), Bone Mineral Content (BMC) or volumetric Bone Mineral Density (vBMD) in the adjuvant group. Neoadjuvant chemotherapy appears to have a significant detrimental effect on BMD, vBMD and BMC. Despite this there were no significant alterations in the mechanical properties of the regenerate. Histologically there was a trend for increased cortical thickness in the control groups compared to intervention however this did not prove statistically significant. In conclusion, adjuvant chemotherapy may be more beneficial for cases where distraction osteogenesis is being considered to replace segmental bone loss after tumour excision

Introduction. Telangiectatic osteosarcoma (TOS) is a rare subtype of osteosarcoma. We review our experience to characterize its prevalence, treatment, relapse and survivorship at long term follow-up. Methods. Eighty-seven patients aged from 4 to 60 years (mean 20 years), were treated from 1985 to 2008. Lesions affected the femur (38), humerus (20), tibia (19), fibula (4), pelvis (3), foot (2) and radius (1). Eight patients had metastatic disease at diagnosis. Seventy-eight patients were treated with neoadjuvant chemotherapy with three or more drugs according to different protocols, nine had surgery as first treatment. Limb salvage surgery was performed in 71 cases, amputation in 14 and rotationplasty in one. One patient died before surgery. Prognostic factors were evaluated with Kaplan-Meier analysis. Results. At a mean follow-up of 8 years, overall survival was 81%, 65% and 65% at 2, 5 and 10 years respectively. Fifty-two patients were disease-free, three were alive with disease, twenty-nine died with disease and three died of other causes. Thirteen local recurrences were observed. Twenty-three patients developed lung (20) or bone (3) metastases. Pathologic fracture did not significantly influence survivorship. Prognostic influence of age of the patients was evaluated at three different cut-off (15, 20 and 25 years-old): younger patients had better survivorship, without statistical significance. Induced necrosis according to Huvos’ classification was significant at both univariate and multivariate regression Cox analysis (p=0.0001). Conclusion. TOS does not have a poor prognosis as previously reported in the literature. A high percentage of patients can be cured with neoadjuvant chemotherapy and surgery. In most patients, limb sparing surgery is possible and safe

Introduction: Seeding of bone or soft tissue tumour along the biopsy tract is a known complication of percutaneous biopsies. Correct surgical management requires preoperative Identification and excision of the biopsy tract at time of surgery. We aim to audit how well biopsy tract sites can be identified preoperatively and investigate factors influencing their Identification. Method: Prospective audit of patients who had tissue biopsies for bone and soft tissue tumours at the RNOH Stanmore and presented for surgery between February and April 2008. Case note analysis, patient history and examination at the time of surgery used to collect data. Results: 13/23 patients had their biopsy tract site accurately identified preoperatively, with a mean time gap of 43 days (6–118) between biopsy and excision. In 10/23 patients the biopsy site could not be accurately identified preoperatively. In these patients the mean time between biopsy and excision was 106 days (55–158) (p=< 0.05). 7 patients had neoadjuvant chemotherapy with a mean time gap of 110 days; in 5/7 the tract site was unidentifiable. One patient had preoperative radiotherapy and the biopsy site was unidentifiable. Discussion: This audit has shown that Identification of the biopsy site is more difficult after 40 days. In order to ensure accurate Identification of the biopsy site an Indian ink tattoo should be considered at time of biopsy. It may be particularly advisable for patients who are likely to require neoadjuvant chemotherapy or preoperative radiotherapy. On this basis we would recommend that all patients have the biopsy site marked at the time of biopsy and a further audit will be carried out to evaluate this change in practice

Sclerosing epitheloid fibrosarcoma (SEF) is an extremely rare soft tissue sarcoma arising from connective tissue cells of mesenchymal origin. SEF mostly occurs in extraosseous sites in the soft tissue; however two cases of primary localization in the bone have been described. Despite benign cytological features the clinical course is complicated by a high local recurrence rate and late metastases. SEF represents a clinically challenging entity especially because no standardized treatment regimens are available. We report a 16-year old female patient who showed persistent load-dependent pain focused on the right proximal tibia. Radiological evaluation revealed an osteolytic lesion and the diagnosis of a benign bone cyst was consented. The tumor was surgically removed. Only after recurrence of the tumor and repeated histopathological analysis diagnosis of SEF could be established. Because of the bone localization of the tumor the patient underwent standardized neoadjuvant chemotherapy analogous to the European-American EURAMOS-1 protocol for the treatment of osteosarcoma followed by tumor resection and endoprothesis. Histopathological analysis of the resected tumor showed > 90% vital tumor cells suggesting no response to the neoadjuvant chemotherapy. Therefore, therapy was reassigned to the CWS protocol of the German Society for Pediatric Oncology and Hematology (GPOH) for treatment of soft tissue sarcoma. To date, the patient is alive and no metastases of the primary tumor can be detected. SEF represents a taunting clinical entity due to deceptive histopathological features and rare occurrence. Localization in the bone represents an additional challenge with regards to the therapeutical approach. Standardized treatment regimens are currently not available for SEF. This case report, to our knowledge, is the first outlining a therapeutic approach in detail. Our data suggest that SEF may be resistant to a chemotherapy regimen containing Cisplatin, Doxorubicin and Metho-trexate despite close association to the bone, possibly indicative of the soft tissue histogenesis of this tumor. The response to the soft tissue sarcoma targeting CWS chemotherapy remains to be determined

Patients with high-grade osteosarcoma who have been previously misdiagnosed as benign lesions or infection and accordingly been treated by curettage, internal fixation or drainage present a challenge in deciding the most appropriate treatment plan. Since one of the contraindications of limb salvage is the inability to achieve a wide surgical margin, there has been a tendency to treat these patients by amputation. Due to contamination by previous surgeries, limb salvage surgery was thought to be associated with a higher risk of local recurrence. The aim of this study was to evaluate the oncologic outcome following limb salvage surgery done for high-grade osteosarcoma patients who were initially treated inadequately by curettage, internal fixation or drainage. The study included 24 patients (14 males and 10 females) with an average age of 19 years (range 7 to 39 years). All the patients had high-grade osteosarcoma of the extremities. Seven were located in proximal tibia, six distal femur, four proximal humerus, three proximal femur, two distal tibia, one distal radius and one fibula. 14 patients were previously diagnosed as benign lesions and treated by curettage. 5 patients were diagnosed as regular fracture and internally fixed. 5 patients were diagnosed as osteomyelitis and treated by drainage. The patients were staged then treated by neoadjuvant chemotherapy and limb salvage surgery. The average time between the initial procedure and the limb salvage procedure was 7 months (range 3 to 36 months). A wide resection margin was achieved in all patients. The average follow up period was 40 months (range 18 to 110 months). Local recurrence occurred in three patients (12.5%). Three patients developed chest metastases and one patient developed bone metastases. We conclude that patients who had an inadequate surgical procedure prior to the diagnosis of a high-grade osteosarcoma could still be treated by neoadjuvant chemotherapy and limb salvage surgery without a significant increased risk of local recurrence and chest metastases

Ewing Sarcoma is the second most common primary bone sarcoma in young patients, however, there remains geographical variation in the treatment of these tumours. All patients receive neoadjuvant chemotherapy and, in most cases, the soft tissue mass diminishes significantly in volume. Controversy surrounds whether to then treat the pre- or post-chemotherapy tumour volume. Many centres advocate either (1) resection of the pre-chemotherapy volume or (2) treatment of the pre-chemotherapy volume with radiation followed by resection of the post-chemotherapy volume. These approaches increase both the short and long-term morbidity for this young patient population. In this study, we retrospectively reviewed our experience resecting only the post-chemotherapy volume without the use of (neo)adjuvant radiotherapy. A retrospective analysis of all patients with Ewing Sarcoma treated at a tertiary orthopaedic oncology centre was conducted. All patients were treated as per the consensus opinion of the multidisciplinary tumour board. Demographic and oncological variables were collected from our institutional database. Presentation and re-staging MRI scans were reviewed to evaluate pre- and post-chemotherapy tumour volumes. Operative and pathology reports were utilized to determine the extent of the surgical resection. Outcome variables included local recurrence free-, metastasis free- and overall survival. Sixty-five patients were identified in our institutional database of which 56 did not receive (neo)adjuvant radiotherapy. Median age at diagnosis was 24 years (range 13–64), 60% of patients were male and 67.6% of tumours were located in the appendicular skeleton. All 56 patients not treated with radiotherapy had resection of the post-chemotherapy tumour volume. There were 3 local recurrences in this group with a mean follow-up of 70.8 months (range 2 to 328). The median overall survival was 47 months and the mean of 70.8months. The rate of local recurrence is comparable to reports in the literature in which patients had their entire pre-chemotherapy tumour volume treated by radiation and/or surgery. Similarly, two-year overall survival for our patient cohort is not significantly different from previous studies in which more aggressive local control measures were employed. Resecting the post-chemotherapy tumour volume in Ewing Sarcoma without the use of (neo)adjuvant radiotherapy does not appear to increase the risk of local recurrence or negatively impact overall survival. This approach should be studied further as it reduces the risk of short and long-term complications for this patient population.”

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

After 25 years in orthopaedic oncology the author wishes to set a challenge for the next generation by posing 10 questions which he believes still do not have answers and which may improve outcomes for patients with sarcomas. Why are sarcomas diagnosed so late?. Can we ever decide what is a safe margin?. What is the role of neoadjuvant chemotherapy for STS?. What can we do to decrease the risk of infection after limb salvage surgery?. What is the significance of local recurrence on outcome?. What really is the best treatment for Ewing's sarcoma of the pelvis?. Is cross sectional imaging essential as part of patient follow up?. Is it possible to evaluate outcomes combining survival and function?. Why can't we run a surgical trial in orthopaedic oncology?. How can we evaluate surgical success?. The author suggests ways these questions may be answered

Osteosarcoma (OS) is a highly malignant primary tumor frequently occurring in children and adolescents. The mainstay of therapy is neoadjuvant chemotherapy and surgical removal of the lesion yielding a 50–70% of 5-year survival rate. Unfortunately, chemotherapy is currently unable to induce complete tumor necrosis leaving residual tumor cells free to metastasize or recidivate, thus resulting in a 30% mortality. The major limitation in those patients is the development of multidrug resistance (MDR) and the low water solubility of drugs such as Paclitaxel (PTX) that is in fact not included in the majority of chemotherapy protocols for OS treatment. We thus hypothesized to prevent the emergence of MDR and obtain significant tumor reduction, by engineering innovative nanoparticles (NPs) able to vehiculate the PTX and induce a dual synergic action: the cytostatic effect of PTX and the cytotoxicity generated by reactive oxygen species produced from light triggered photoactivation (PDT) of Chlorin e6 photosensitizer. To further improve the efficacy and reduce the side effects of NPs systemic administration, Mesenchymal Stromal Cells (MSC) are used as a “Trojan horse” to deliver the NPs directly to tumor cells, taking advantage of MSC ability to selectively recognize and efficiently engraft in OS tumor stroma. HSA were conjugated with photosensitizer Ce6 and the functionalized protein was used to produce PTX loaded nanoparticles through desolvation technique and drug-induced protein self-assembly (PTX-Ce6@HSA NP). Human MSC lines, isolated from the Bone marrow (BM) of different donors, were then loaded with different dosages of nanoparticles and their ability to internalize and transport the NPs, migrate and induce cytotoxic ROS upon light treatment were tested in in vitro cultures. Preliminary results showed that MSC efficiently internalize PTX-Ce6@HSA NPs and the photosensitizer Ce6 remains active inside the cells for at least 3 days after loading. Electron microscopy performed onto loaded MSC showed that NPs internalization take places via clathrin mediated transport, whereas HPLC analysis demonstrated a release kinetics of PTX mediated by exocytosis. Finally, PTX-Ce6@HSA NPs loaded MSC co-cultured with the OS tumor cell line SaOS-2 showed a significant tumor cell growth reduction. So fare, advances in drug delivery have failed to produce specific tool to improve the overall survival of OS patients. However, given our preliminary in vitro data we believe that the proposed multimodal therapy will minimize the side effects of the systemic chemotherapy and enhance the efficacy through the synergic effect of PTX and PDT. In the future, our strategy could be intended as an innovative co-adjuvant approach for OS treatment to be performed right before surgery to eliminate residual tumors cells after tumor mass removal

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

We report on a patient with an unusual pulmonary infection after resection of a high-grade osteosarcoma. In March 2007 a 30-year old female with pain and swelling of the left proximal humerus was submitted to the orthopaedic department. Rx and CT revealed a tumour with destruction and invasion of the surrounding soft tissue. Incision biopsy led to the diagnosis of osteoblastic osteosarcoma. She was enrolled into the EURAMOS protocol and received neoadjuvant chemotherapy. In July 2007 an extra-articular resection of the proximal humerus with modular endoprosthetic replacement was performed. The sarcoma had responded well to chemotherapy (regression grade 3 according to Salzer-Kunts-chik). Surprisingly, the resection specimen demonstrated a “skip lesion” of vital sarcoma in the resection line not been detected by preoperative PET or MRT. After consultation of the German study group she was stratified into the standard risk group. 12 months later a control CT revealed multiple foci in both lungs, which were highly suspicious for pulmonary metastases. All clinical parameters were normal. A lung biopsy was performed by thoracotomy and a granulomatous infection was diagnosed, which was suspicious for tuberculosis. Extended microbiological investigations by culture and PCR analysis revealed an infection by Myco-bacterium Xenopi, which is a rare form of an atypical mycobacteriosis. Since then she is treated accordingly, however the infection has progressed and involvement of the liver has been diagnosed by cutting needle biopsy

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

Neoadjuvant chemotherapy for osteosarcoma improves outcomes for the majority, but if the chemotherapy does not work then the dilemma often arises as to whether to do limb salvage with a marginal (or worse) margin of excision or to do an amputation. If limb salvage is carried out with a close margin, does post operative radiotherapy make any difference? This study aims to address these questions. Method. All patients with limb osteosarcoma, no metastases, a poor response to chemotherapy and either a marginal excision or primary amputation were identified from a prospective database. This group were investigated in terms of overall survival and local control. Results. There were 182 patients in this category of whom 60 had an amputation, 105 limb salvage with marginal margins and 17 with an intralesional margin. Local recurrence (LR) arose in 41% of those with an intralesional margin, 22% of those with a marginal margin and 13% of those with an amputation. Radiotherapy was used in 21 of the 122 patients and the risk of LR was the same as in those who did not have radiotherapy. Neither age nor sex of the patient, size or site of the tumour affected the risk of LR. The overall survival for this group was 42% at 10 years. The survival was best in those with marginal margins (38%) than those with an amputation (28%) and worst for those with an intralesional margin (20%). Survival was worst in those who did develop LR, but no worse than in those having amputation. Conclusion. A marginal resection of osteosarcoma with a poor response to chemotherapy leads to a high risk of local recurrence but also carries a poor prognosis. Carrying out an amputation to avoid the risk of LR probably has little survival benefit and the use of radiotherapy remains unclear

Of 3000 patients diagnosed with primary malignant bone tumours and treated at our unit over the past 25 years, 234 (7.8%) were considered to be spindle cell sarcomas of bone (ie not osteosarcoma, chondrosarcoma, Ewing’s, chordoma or adamantinoma). We have analyzed their management and outcomes. The diagnosis of these cases varied with fluctuations in the popularity of conditions such as MFH, fibrosarcoma and leiomyosarcoma with the passage of time. Treatment was with chemotherapy and surgery whenever possible. 36 patients had metastases at diagnosis and 17 had palliative treatment only because of age or infirmity. The most common site was the femur followed by the tibia, pelvis and humerus. The mean age was 45 and the mean tumour size 10.2cm at diagnosis. 25% of patients presented with a pathological fracture. Chemotherapy was used in 70% of patients the most common regime being cisplatin and doxorubicin. 35% of patients having neoadjuvant chemotherapy had a good (> 90% necrosis) response. The amputation rate was 22% and was higher in patients presenting with a fracture and in older patients not having chemotherapy. With a mean follow up of 8 years the overall survival was 64% at 5 yrs and 58% at 10 yrs. Adverse prognostic factors included the need for amputation, older age and poor response to chemotherapy as well as a pathological fracture at presentation. The few patients with angiosarcoma fared badly but there was no difference in outcomes between patients with other diagnoses. We conclude that patients with spindle cell sarcomas should be treated similarly to patients with osteosarcoma and can expect comparable outcomes. The histological diagnosis does not appear to predict behaviour