CTLA-4 (CD152) is a cell surface receptor that behaves as a negative regulator of the proliferation and the effector function of T cells. We have previously shown that CTLA-4 is also expressed on neoplastic lymphoid and myeloid cells, and it can be targeted to induce apoptosis. In our study, we have extended our analysis and have discovered that surface expression of CTLA-4 is detectable by flow cytometry on 30 of 34 (88%) cell lines derived from a variety of human malignant solid tumors including carcinoma, melanoma, neuroblastoma, rhabdomyosarcoma and osteosarcoma (but not in primary osteoblast-like cultures). However, by reverse transcriptase-PCR, CTLA-4 expression was detected in all cell lines. We have also found, by immunohistochemistry, cytoplasmic and surface expression of CTLA-4 in the tumor cells of all 6 osteosarcoma specimens examined and in the tumour cells of all 5 cases (but only weakly or no positivity at all in neighbouring nontumor cells) of ductal breast carcinomas. Treatment of cells from CTLA-4-expressing tumor lines with recombinant forms of the CTLA-4-ligands CD80 and CD86 induced apoptosis associated with sequential activation of caspase-8 and caspase-3. The level of apoptosis was reduced by soluble CTLA-4 and by anti-CTLA-4 scFvs antibodies. The novel finding that CTLA-4 molecule is expressed and functional on human tumor cells opens up the possibility of antitumor therapeutic intervention based on targeting this molecule.

PURPOSE: The identification of prognostic factors in patients with nonmetastatic Ewing’s sarcoma could allow the use of risk-adapted therapeutic strategies of treatment. PATIENTS AND METHODS: Data on 359 patients with nonmetastatic Ewing’s sarcoma of bone treated at a single institution between January 1979 and April 1995 were retrospectively considered. The influence of clinical, hematologic, therapeutic, and histologic parameters on event-free survival was assessed. RESULTS: By univariate analysis, the following features were found to be associated with a poor prognosis: male sex (P < .02), age older than 12 years (P < .006), fever (P < .0001), anemia (P < .0025), high serum lactate dehydrogenase (LDH) level (P < .0001), axial location (P < .04), radiation therapy only for local control (P < .009), type of chemotherapy regimen (P < .0001), and poor chemotherapy-induced necrosis (P < .001). After multivariate analysis, the adverse independent prognostic factors were male sex (P < .04), age older than 12 years (P < .001), fever (P < .0002), anemia (P < .02), high serum LDH level (P < .0003), axial location (P < .02), and type of chemotherapy regimen (P < .0003). When the multivariate analysis was restricted to surgically treated patients, the adverse independent prognostic factors were poor chemotherapy-induced necrosis (P < .0001), fever (P < .015), anemia (P < .02), and high serum LDH level (P < .025). CONCLUSION: The prognosis in cases of nonmetastatic Ewing’s sarcoma is influenced by many different clinical and hematologic variables, all of which are to be considered when patients are being stratified according to the risk of relapse. In surgically treated patients, the most important prognostic factor is chemotherapy-induced necrosis.

BACKGROUND: In primary central high‐grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy.METHODS: The authors investigated whether the subtypes correlated with histologic response to chemotherapy in 1058 patients with osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy over the last 20 years. The tumors were classified as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable lung metastases.RESULTS: The response to preoperative chemotherapy was good (90% or more tumor necrosis) in 59% of patients and poor (< 90% tumor necrosis) in 41% of patients. The rate of good responses was significantly higher (P = 0.0001) in the fibroblastic (83%) and telangiectatic (80%) tumors and significantly lower in chondroblastic tumors (43%). Prognosis was significantly correlated with the histologic subtypes. The 5‐year overall survival rate was significantly higher (P = 0.0001) in fibroblastic (83%) and telangiectatic (75%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes, except for the chondroblastic subtype, the 5‐year overall survival rate was significantly higher (P = 0.0001) in good responders P = 0.0001 (68%) than in poor responders (52%).CONCLUSIONS: The authors concluded that the histologic subtype of primary central high‐grade osteosarcoma of the extremity was strictly correlated with histologic response to chemotherapy and probably, as a consequence, also with prognosis. Further studies are needed to establish whether these results justify a specific therapeutic approach based on the histologic subtype of the tumor. Cancer 2003;97:3068–75. © 2003 American Cancer Society.DOI 10.1002/cncr.11456

From 1986 to 1994, 112 bone allograft reconstructions were performed in patients with high-grade osteosarcoma in whom neoadjuvant chemotherapy was administered. The allograft reconstruction was used in arthrodesis in 44 cases (41 knees, three ankles), as an intercalary graft in 39 (28 femurs, 11 tibias), as an osteoarticular graft in 22 (three proximal and/or distal humeri, six distal femurs, 13 proximal tibias), and as an allograft and prosthesis composite in seven (two proximal humeri, one proximal femurs, four proximal tibias). In 20 patients an autologous vascularized fibula was used to augment the allograft. Functional results were excellent or good in 74% of the patients after the primary surgery, and in 83% of the patients after secondary surgery. Complications include delayed union (49%) and fracture (27%), although there were no cases of deep infection. The incidence of delayed union, but not infection or fracture, was increased by the use of chemotherapy.