Mario Mercuri

Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution.

The evaluation variables influencing systemic and local recurrence and final outcome are extremely important in defining risk‐adapted treatments for patients with nonmetastatic osteosarcoma of the extremity.

Platelet-derived growth factors enhance proliferation of human stromal stem cells.

Studies on new procedures for bone reconstruction suggest that autologous cells seeded on a resorbable scaffold can improve the treatment of bone defects. It is important to develop culture conditions for ex vivo expansion of stromal stem cells (SSC) that do not compromise their self-renewing and differentiation capability. Bone marrow SSC and platelet gel (PG) obtained by platelet-rich plasma provide an invaluable source for autologous progenitor cells and growth factors for bone reconstruction. In this study the effect of platelet-rich plasma (PRP) released by PG on SSC proliferation and differentiation was investigated. MTT assay was used to investigate the effect of PRP on proliferation: results showed that PRP induced SSC proliferation. The effect was dose dependent and 10% PRP is sufficient to induce a marked cell proliferation. Untreated cells served as controls. Upon treatment with 10% PRP, cells entered logarithmic growth. Removal of PRP restored the characteristic proliferation rate. Because SSC can gradually lose their capability to differentiate along the chondrogenic and osteogenic lineage during subculture in vitro, we tested whether 10% PRP treatment affected SSC ability to mineralize. SSC were first exposed to 10% PRP for five passages, at passage 6 PRP was washed away and plated cells were treated with dexamethasone (DEX). DEX induced a three-fold increase in the number of alkaline phosphatase positive cells and induced mineralization that is consistent with the differentiation of osteochondroprogenitor cells. In conclusion, 10% PRP promotes SSC proliferation; cells expanded with 10% PRP can mineralize the extracellular matrix once PRP is withdrawn.

Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity : A joint study by the italian and scandinavian sarcoma groups

PURPOSE To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 40 years of age with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. RESULTS No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities. Results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin

Background. Neoadjuvant chemotherapy is the most accepted treatment for localized osteosarcoma. This has led to a great improvement in limb‐sparing surgery and in disease‐free survival. Patients with a good response to preoperative chemotherapy showed a higher disease‐free survival rate. Current studies examine the possibility of patients whose limbs could be rescued with a poor necrosis and a reduction of the side effects related to aggressive treatments.

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47‐month follow‐up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease‐free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Survival

PURPOSE To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide. RESULTS The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P <.0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P =.006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P <.06), RFI (5-year PRS at < or = 24 months, 20%; at > 24 months, 60%; P <.0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P <.0001) but not by the use of a second-line chemotherapy treatment. CONCLUSION RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewings sarcoma. PATIENTS AND METHODS The response to chemotherapy was evaluated from the specimens of 118 Ewings sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.

Failure Mode Classification for Tumor Endoprostheses: Retrospective Review of Five Institutions and a Literature Review

BACKGROUND Massive endoprostheses provide orthopaedic oncologists with many reconstructive options after tumor resection, although failure rates are high. Because the number of these procedures is limited, failure of these devices has not been studied or classified adequately. This investigation is a multicenter review of the use of segmental endoprostheses with a focus on the modes, frequency, and timing of failure. METHODS Retrospective reviews of the operative databases of five institutions identified 2174 skeletally mature patients who received a large endoprosthesis for tumor resection. Patients who had failure of the endoprosthesis were identified, and the etiology and timing of failure were noted. Similar failures were tabulated and classified on the basis of the risk of amputation and urgency of treatment. Statistical analysis was performed to identify dependent relationships among mode of failure, anatomic location, and failure timing. A literature review was performed, and similar analyses were done for these data. RESULTS Five hundred and thirty-four failures were identified. Five modes of failure were identified and classified: soft-tissue failures (Type 1), aseptic loosening (Type 2), structural failures (Type 3), infection (Type 4), and tumor progression (Type 5). The most common mode of failure in this series was infection; in the literature, it was aseptic loosening. Statistical dependence was found between anatomic location and mode of failure and between mode of failure and time to failure. Significant differences were found in the incidence of failure mode Types 1, 2, 3, and 4 when polyaxial and uniaxial joints were compared. Significant dependence was also found between failure mode and anatomic location in the literature data. CONCLUSIONS There are five primary modes of endoprosthetic failure, and their relative incidences are significantly different and dependent on anatomic location. Mode of failure and time to failure also show a significant dependence. Because of these relationships, cumulative reporting of segmental failures should be avoided because anatomy-specific trends will be missed. Endoprosthetic design improvements should address failure modes specific to the anatomic location.

Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities.

PURPOSE To evaluate more accurately the effectiveness of preoperative chemotherapy in the treatment of patients with Ewings sarcoma, we studied histopathologically the chemotherapeutic response and correlated it to oncologic outcome. PATIENTS AND METHODS Between June 1983 and December 1989, 68 patients with nonmetastatic Ewings sarcoma of the extremities were treated at our institute with preoperative chemotherapy (without radiation therapy) and surgery. The specimens were retrospectively evaluated for areas of viable tumor cells and graded from I to III (macroscopic, microscopic, or no residual disease, respectively) in a blinded fashion. Clinical follow-up data were available on all patients for a mean of 60 months (range, 32 to 111). RESULTS This histopathologic analysis was strongly correlated with oncologic outcome (P = .004). Patients who demonstrated grade III response (no identifiable viable tumor nodules present) had improved 5-year disease-free survival rates as compared with patients with grade II (microscopic nodes present; P = .023; 90% v 53%) and grade I responses (macroscopic nodules present; P = .0003; 90% v 32%). Patients with grade II necrosis had statistically improved survival rates over those with grade I necrosis (53% v 32%; P = .074). CONCLUSION This new histopathologic analysis technique for the evaluation of neoadjuvant chemotherapy effectiveness (which does not rely on tumor volume for its assessment) is a valuable prognostic indicator for patients with Ewings sarcoma treated with surgery. Based on this preliminary report, cases of grade I or II chemotherapeutic tumor response should be considered clinical failures and a different, more aggressive postoperative chemotherapy regimen should be considered.

Italian cooperative study for the treatment of children and young adults with localized Ewing sarcoma of bone a preliminary report of 6 years of experience

In 1991, the Italian Association for Pediatric Hematology‐Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91‐CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol).