Biomedical subjects

Piero Picci

Publications and source records attributed to Piero Picci.

At least 37 records · Page 2Linked to original sources

PubMed2005

Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors.

Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation.

The TP53 tumor suppressor gene is the most frequent target for genetic alterations in human cancer. TP53 gene alterations may result in the gain of oncogenic functions such as neoangiogenesis and resistance to therapy. The TP53 germ line mutation c.659A>C (p.Y220S) was identified in stored DNA from related patients with Li-Fraumeni syndrome (LFS) who died after developing clinically aggressive tumors. All of the patients were treated with protocols that included doxorubicin hydrochloride (DX) as a pivotal drug. To define the in vitro mutational phenotype of this germ line mutation, we used murine fibroblasts explanted from wild-type (wt) and p53 knockout (KO) mice from the same littermate. p53Y220S and p53R175H fibroblasts, obtained from p53KO fibroblasts transfected with expression vectors encoding the human Y220S and R175H p53 mutants, respectively, exhibited resistance to DX treatment. Moreover, p53Y220S fibroblasts exhibited angiogenetic properties, and after DX treatment, p53Y220S failed to translocate into the nucleus and showed an increase in its cytosolic levels. DX treatment does not influence p53 distribution within the nuclear and cytosolic compartments in p53R175H fibroblasts. Peroxiredoxin II (Prx II), a protein that is involved in eliminating reactive oxygen species (ROS), showed increased expression intensity in p53Y220S fibroblasts after DX treatment, as observed by two-dimensional electrophoresis analysis. Moreover, Thioredoxin (Trx), a protein that cooperates with Prx II, is overexpressed in p53Y220S mutants under basal conditions. These data suggest a relationship between the presence of the p53Y220S mutation and enhanced levels of Prx II and Trx in mutant fibroblasts. Since one of the mechanisms of the DX antitumor effect has been ascribed to production of ROS, future studies will evaluate the involvement of PrxII and Trx in the chemoresistance of p53Y220S fibroblasts to DX.

Adolescent↗

PubMed2005

Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma.

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution.

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.

Adolescent↗

PubMed2005

4-Demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a promising new candidate for chemotherapeutic treatment of osteosarcoma patients.

The effectiveness of the alkycycline 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548, ladirubicin), a new drug with high antitumour activity against a broad range of neoplasms, was evaluated by using a panel of 32 human osteosarcoma cell lines, including cell lines resistant to doxorubicin, methotrexate, or cisplatin. PNU-159548 resulted to be highly active in all cell lines. No cross-resistance was found with conventional drugs, being PNU-159548 active also in cells resistant to doxorubicin and with a multidrug resistance phenotype (associated with MDR1 gene/P-glycoprotein overexpression), as well as in cells resistant to methotrexate or to cisplatin. Analysis of drug-drug interactions showed that PNU-159548 could be successfully used in combination with all the most important drugs currently used in OS chemotherapy. In fact, the simultaneous administration of PNU-159548 and doxorubicin, methotrexate, or cisplatin produced mostly additive or synergistic effects. Sequential exposure to PNU-159548 followed immediately by doxorubicin, methotrexate, or cisplatin was the most effective sequence of administration, invariably resulting in additive or synergistic effects in both drug-sensitive and drug-resistant osteosarcoma cell lines. In conclusion, the high in vitro effectiveness, the absence of cross-resistance with doxorubicin, methotrexate, or cisplatin and the possibility to be successfully used in combination with these drugs indicate PNU-159548 as a promising candidate to be considered for planning new therapeutic regimens for osteosarcoma patients, who show a decreased response to conventional chemotherapy.

Antibiotics, Antineoplastic↗

PubMed2005

Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy.

The pattern of relapse, treatment and final outcome of 235 patients with osteosarcoma of the extremity who relapsed after neoadjuvant treatments performed between 1986 and 1998 at a single institution is reported. The 235 relapses were treated by surgery, surgery plus second line chemotherapy, and only second line chemotherapy or radiotherapy. The 5-year post-relapse-event-free-survival (PREFS) was 27.6% and the post-relapse-overall-survival (PROS) 28.7%. All 69 patients who are presently alive and free of disease were treated by surgery, alone or combined with chemotherapy. None of patients treated only by chemotherapy or radiotherapy survived. We conclude that it is possible to obtain prolonged survival and cure in about 1/4 of relapsing osteosarcoma patients with aggressive treatments. The complete removal of the recurrence is essential for outcome, while the role of the association of second-line chemotherapy remains to be defined.

Adolescent↗

PubMed2005

Adjuvant chemotherapy for soft tissue sarcoma.

PURPOSE OF REVIEW: To review current state-of-the-art knowledge about adjuvant medical therapy in adult soft tissue sarcomas. RECENT FINDINGS: Most recent contributions have added nonrandomized evidence to previously available controlled clinical trials, which were undertaken from the 1970s. Again, results are conflicting, with a limited benefit suggested by some retrospective analyses and denied by others. While a delay in relapse is likely to occur in a fraction of patients treated with adjuvant chemotherapy, a permanent benefit has been more difficult to prove. This result is consistent with findings from previous clinical trials, which pointed to a slight benefit from Doxorubicin-based adjuvant chemotherapy and a possibly higher, although less evidence-based, benefit from anthracycline plus Ifosfamide regimens. SUMMARY: Overall, adjuvant chemotherapy may give some benefit in soft tissue sarcoma. If any, it is likely to be of limited degree, confined to the highest-risk patients, and requiring a fully active chemotherapy regimen. This was mainly shown for extremity soft tissue sarcoma but may also apply to other primary sites. The value of molecular-targeted therapy as an adjuvant for high-risk gastrointestinal stromal tumor patients is a different subject awaiting long-term results of ongoing trials.

Antineoplastic Agents↗

PubMed2005

Primary high-grade osteosarcoma: comparison between preadolescent and older patients.

The medical records of patients with high-grade osteosarcoma observed at the authors' institution between 1972 and 1999 were reviewed to study whether osteosarcoma in preadolescent patients has a different biology and a worse prognosis than in older patients. To assess epidemiologic differences, the first analysis evaluated 1,603 patients regardless of tumor stage and site and treatment received. In the second analysis, only 1,136 patients (317 preadolescent and 819 older patients) with nonmetastatic extremity osteosarcoma, treated with the same protocols of chemotherapy, were evaluated to assess differences in prognosis and in the pattern of relapse. Most preadolescents were female (56% vs. 44%, P < 0.0001), and most tumors were located in the extremity (95% vs. 5%, P < 0.001). The 5-year event-free survival (60% [95% CI 53-67%] vs. 58% [95% CI 46-63%]), the overall survival (67% vs. 65%), the rate of amputation (24% vs. 25%), time (21 vs. 22 months) and type of first relapse (systemic 98% vs. 95%, local 2.3% vs. 4.7%) the site of first metastases (pulmonary, 87% vs. 89%), and good histologic response to preoperative treatment (65% vs. 63%) were essentially the same. The authors concluded that there is no need to employ different therapies for the two groups.

Adolescent↗

PubMed2005

Second malignancy in 597 patients with ewing sarcoma of bone treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999.

The relative risk of second tumors in patients with Ewing sarcoma is controversial, and little is known about their treatment and outcome. The purpose of the current study was to define the incidence and features of second tumors among 597 long-term survivors of nonmetastatic Ewing sarcoma treated with adjuvant and neoadjuvant chemotherapy, radiotherapy, and/or surgery. The authors found that the risk of secondary malignancy after adjuvant or neoadjuvant treatment of Ewing sarcoma is higher than that after other childhood or adolescent cancers only after radiotherapy. Based on this, postoperative radiotherapy should be avoided when surgery with adequate margins is feasible.

Adolescent↗

PubMed2005

Evaluation of p16 and Id1 status and endogenous reference genes in human chondrosarcoma by real-time PCR.

Both the tumour suppressor, p16, and the helix-loop-helix transcription factor, Id1, have been assigned roles in tumour growth in general and appear to be involved in chondrosarcoma. Id1 has further been found to repress the expression of p16. Therefore, the mRNA expression of these two genes was studied by real-time PCR in a search for prognostic markers in human chondrosarcoma. To get reliable quantitative data, however, the choice of endogenous reference gene for use in the assay is important. Therefore, eleven different endogenous reference genes were evaluated in chondrosarcoma cells and articular chondrocytes. 18S rRNA appeared to be the best choice to use as endogenous reference gene, since it was suitable for both kinds of cells. Several of the other reference genes tested showed variation between individuals or between normal chondrocytes and chondrosarcoma cells. This demonstrates the importance of using a correct endogenous reference gene to get reliable results from quantitative measurements. Both p16 and Id1 showed varied gene expression patterns among the samples and none of these genes could be significantly correlated to prognosis.

Bone Neoplasms↗

PubMed2004

Molecular mechanisms of CD99-induced caspase-independent cell death and cell-cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators.

CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspase-independent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with selective inhibitors indicated that only actin cytoskeleton integrity was essential for cell-cell adhesion and apoptosis of ES cells. Indeed, CD99 stimulation induced actin repolymerization, further supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling of ES cells after CD99 engagement showed modulation in the expression of 32 genes. Among the pool of upregulated genes reported to be involved in cell adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction protein found to play a role in the regulation of the actin cytoskeleton. Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and Western blot. Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein. Therefore, our findings indicate that CD99 functions occur through reorganization of cytoskeleton and identify actin and zyxin as the early signaling events driven by CD99 engagement.

Actins↗

PubMed2004

Contribution of MEK/MAPK and PI3-K signaling pathway to the malignant behavior of Ewing's sarcoma cells: therapeutic prospects.

Insulin-like growth factor receptor I (IGF-I)-mediated circuit is a major autocrine loop for Ewing's sarcoma (ES) cells and appears to be particularly important in the pathogenesis of this tumor. In this study, we analyzed the contribution of the 2 major pathways of the intracellular IGF-IR signaling cascade to the overall effects elicited by IGF-I in ES. Both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K) signaling pathways appeared to be constitutively activated in ES, likely due to the presence of the IGF-IR-mediated autocrine loop. We demonstrated that both MEK/MAPK (PD98059 or U0126) and PI3-K inhibitors (LY294002) profoundly impaired ES cell growth in monolayer and soft agar basal conditions. Both PD98059 and LY294002 inhibited ES cell cycle progression by inducing G1 blockage, whereas only LY294002 significantly affected the survival of ES cells. Exogenous IGF-I completely reverted LY294002-induced growth inhibition by abrogating antiproliferative and proapoptotic effects of the PI3-K inhibitor. By contrast, IGF-I could not rescue cells from growth inhibition induced by PD98059. MEK/MAPK blockade also significantly reduced the migratory ability of ES cells, both in basal and IGF-I-induced conditions, and increased chemosensitivity to doxorubicin, a leader drug in the treatment of ES patients. Our findings therefore identify MAPK pathway as a promising target for pharmacologic intervention in ES.

Antineoplastic Agents↗

PubMed2004

Identification of candidate genes involved in the reversal of malignant phenotype of osteosarcoma cells transfected with the liver/bone/kidney alkaline phosphatase gene.

Alkaline phosphatases (ALPs) are a family of cell surface glycoproteins that catalyze the hydrolysis of phosphomonoesters with release of inorganic phosphate. Liver/bone/kidney (L/B/K) ALP participates in bone mineralization, but its other physiological and pathological functions remain obscure. In human osteosarcoma, an inverse relationship has been found between cellular L/B/K ALP expression and aggressiveness. To explore this relationship, we employed cDNA microarray technology to characterize and compare the gene expression profile of two U-2 OS osteosarcoma clones with high L/B/K ALP activity (U-2/ALP28 and U-2/ALP40) and one with contrasting characteristics (U-2/ALP23). We identified 79 differentially expressed genes (58 upregulated in U-2/ALP28 and U-2/ALP40 compared to U-2/ALP23). Using GenMAPP/MAPPFinder, we highlighted nine functional groups strictly related to high L/B/K ALP activity, including microtubule-based movement and cell adhesion groups, two functions well related to tumor invasiveness. Notably, cadherin 13 (CDH13) and caveolin 1 (CAV1) genes were upregulated in our cells. Since these two genes are involved in cell-cell adhesion and cell growth, their co-expression with L/B/K ALP could help explain the lower levels of malignancy found in osteosarcoma cells with high L/B/K ALP activity. Although functional studies are needed to better define the role of CDH13 and CAV1 in the malignant behavior of osteosarcoma cells, the data presented here provide an aid to understanding the biological functions of L/B/K ALP in bone tumors.

Alkaline Phosphatase↗

PubMed2004

Genetic analysis of fibrosarcoma of bone, a rare tumour entity closely related to osteosarcoma and malignant fibrous histiocytoma of bone.

Fibrosarcoma (FS) of bone is an extremely rare and genetically uncharacterised malignant tumour arising in the skeleton. On the basis of clinicopathologic features it appears to be closely related to either fibroblastic osteosarcoma (OS) or malignant fibrous histiocytoma (MFH) of bone. In this study, 27 decalcified, paraffin-embedded FS of bone were collected for genetic and immunohistochemical characterisation. Good quality DNA, suitable for genetic analyses, was isolated from nine cases (7 primary tumours, 1 local recurrence, and 1 lung metastasis), which were analysed by comparative genomic hybridisation (CGH) on chromosomes and DNA microarrays. DNA sequence copy number changes were found in five out of seven primary tumours (72%), as well as in both, the local recurrence and the metastatic lesion, by CGH on chromosomes. The most frequent aberration was gain of the chromosomal region 22q, which was present in four out of the five primary tumours with genetic changes, in the local recurrence and, as the sole genetic aberration, in the lung metastasis. DNA microarray analysis showed that gain of the platelet-derived growth factor beta (PDGF-B) gene (located at 22q12.3-q13.1) was the most frequent gene imbalance, which was present in three out of the five analysed tumours. In these three cases, real-time PCR revealed a 2.1- to 2.7-fold increase of PDGF-B gene copy numbers. By immunohistochemistry, a positive reaction for B-chain-containing PDGF proteins was revealed in all the cases showing gain of 22q. A more extensive immunohistochemical analysis identified the presence of PDGF-B proteins in 8/20 primary FS of bone (40%), 3/3 lung metastases and in 1/2 local recurrences. A simultaneous positive reaction for PDGF-B proteins and PDGF receptors was found in two third of PDGF-B-positive cases (8/12). Taken together, the genetic and immunohistochemical data indicate that over-representation of the chromosomal region 22q, including particularly the PDGF-B gene, may be important for the pathogenesis of FS of bone. Our results also demonstrate that CGH on chromosomes and DNA microarrays are suitable for the genetic characterisation of decalcified, paraffin-embedded tumour tissue samples and may facilitate, combined with other techniques, the rapid acquisition of data providing insight into the molecular genetic and biologic basis of rare bone sarcomas. Moreover, these findings suggest the possible presence of an autocrine loop in FS of bone, which might be taken into account for planning innovative therapeutic strategies for patients unresponsive to conventional treatments.

Adult↗

PubMed2004

Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma: findings in 42 patients followed for 1-16 years.

BACKGROUND: The activity of matrix metalloproteinases (MMPs) in degrading extracellular matrix is controlled by activation of proenzymes and inhibition of MMP tissue inhibitors (TIMPs). PATIENTS AND METHODS: To assess the proteolytic cascade imbalance in malignancy progression, tissue expression and serum levels of MMP-2, MMP-9 and of their inhibitors TIMP-2 and TIMP-1 respectively were evaluated in 42 selected patients with high-grade osteosarcoma (OS). MMP-2, MMP-9, TIMP-2 and TIMP-1 were studied in biopsies by immunohistochemistry and in serum by ELISA test. Patients were subdivided into 3 groups according to their follow up: continuously disease-free, diagnosis of metastasis during follow-up, and metastasis at diagnosis. RESULTS: Immunohistochemistry demonstrated an imbalance between MMPs and TIMPs, with a more evident role for MMP-9 than for MMP-2 in tumor progression. TIMP-1 inhibitor in plasma was higher in patients with osteosarcoma than in a control group. This high value of TIMP-1 was particularly evident in the group of patients who later developed metastases and/or local recurrences, and in those with metastases at diagnosis. INTERPRETATION: Our findings confirm the protective action of TIMP-1, as MMP inhibitor, but also show its activity as a growth factor underlining its multifunctional role in OS.

Adolescent↗

PubMed2004

Differentially expressed genes in multidrug resistant variants of U-2 OS human osteosarcoma cells.

Multidrug resistance (MDR) to anticancer agents is a major barrier to the successful treatment of human osteosarcomas. Current understanding of the genes that contribute to the features of MDR is limited, and the mechanisms remain unclear. Here we applied differential display reverse transcription-polymerase chain reaction (DDRT-PCR) to parental and MDR-variants of U-2 OS human osteosarcoma cells, to clarify the genes involved in the MDR cells, and identified five candidate genes. These are BCRP (breast cancer resistance protein) encoding a transmembrane efflux pump; RB1CC1 (RB1-inducible coiled-coil 1), a tumor suppressor regulating RB1 (retinoblastoma 1) expression; a novel transcriptional variant of dUTPase; SSR2 (beta-signal sequence receptor), which is associated with protein translocation across ER membrane; and HSP105 encoding high molecular mass heat shock proteins. Molecular and biological characterization of these genes will yield further insight into the features between MDR and tumor progression in human osteosarcomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

C-kit receptor expression in Ewing's sarcoma: lack of prognostic value but therapeutic targeting opportunities in appropriate conditions.

PURPOSE: Autocrine/paracrine stimulation of c-kit has been recently observed in Ewing's sarcoma (ES) cell lines. In this study, we tested the prognostic and therapeutic role of the receptor in this tumor. METHODS: One hundred one ES tumor biopsies were evaluated for the expression of c-kit by the avidin-biotin-peroxidase procedure. Effectiveness of STI-571 (Gleevec; Novartis, Basel, Switzerland), a selective inhibitor of specific tyrosine kinases, was analyzed with respect to in vitro growth and migration inhibition, as single agent or in combination with doxorubicin. RESULTS: Approximately 30% of patients expressed c-kit in their primary tumors. No significant association between the expression of the receptor and the clinical outcome was observed. In vitro growth of ES cell lines showing high levels of c-kit demonstrated limited inhibition by exposure to STI-571 (10 micromol/L is required to obtain 40% to 50% of growth inhibition). A decrease of stem-cell factor-mediated ES cell migration was also found. The drug acted additively with doxorubicin in inhibiting ES cell growth. CONCLUSION: The negative prognostic findings and the limited in vitro therapeutic activity of STI-571 indicate that the putative aberrant signaling provided by c-kit overexpression may be dispensable for ES development and unlikely to constitute a critical therapeutic target. Accordingly, the dose of STI-571 required to give a significant ES growth inhibition is much higher than for those tumors in which mutations of c-kit constitute a relevant pathogenetic event. Nevertheless, in the subset of ES patients showing a high level of c-kit expression, the activity of the drug may be exploited in combination with standard therapy.

Antineoplastic Agents↗

PubMed2003

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.

Adolescent↗