Publications by authors named "Anna Paioli"

29 Publications

  • Page 1 of 1

Front-Line Window Therapy with Temozolomide and Irinotecan in Patients with Primary Disseminated Multifocal Ewing Sarcoma: Results of the ISG/AIEOP EW-2 Study.

Cancers (Basel) 2021 Jun 18;13(12). Epub 2021 Jun 18.

Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133 Milan, Italy.

Purpose: The main objective was to evaluate the activity and tolerability of TEMIRI as a front-line treatment in primary disseminated Ewing sarcoma (PDMES) using the RECIST 1.1 criteria. The secondary objectives included the assessment of toxicity and the performance status/symptom changes.

Methods: Between 2012 and 2018, patients with PDMES received two courses of temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every 3 weeks as an amendment to the Italian Sarcoma Group/Associazione Italiana EmatoIogia ed Oncologia Pediatrica (ISG/AIEOP) EW-2 protocol (EUDRACT#2009-012353-37, Vers. 1.02).

Results: Thirty-four patients were enrolled. The median age at diagnosis was 19 years (range 3-55). After TEMIRI, the RECIST response was as follows: a partial response in 20 (59%) patients, stable disease in 11 (32%), and disease progression in 3 (9%). The ECOG/Lansky score was improved in 25/34 (73.5%) cases, and a reduction or disappearance of pain was observed in 31/34 patients (91%). The incidence of grade 3-4 toxicity was 3%. The 3-year event-free survival (EFS) and overall survival (OS) were 21% (95% CI 6-35%) and 36% (95% CI: 18-54%), respectively.

Conclusion: the smooth handling and encouraging activity demonstrated by up-front TEMIRI did not change the EFS in PDMES, so this result suggests the need for the further evaluation of the efficacy of TEMIRI in combination with conventional treatments in non-metastatic patients.
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http://dx.doi.org/10.3390/cancers13123046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234176PMC
June 2021

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study.

Cancers (Basel) 2021 Jun 3;13(11). Epub 2021 Jun 3.

Paediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milano, Italy.

Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI).

Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed.

Results: After WLI, grade 1-2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1-79.3), 61.2% (48.4-71.7) and 70.5% (56.3-80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis.

Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.
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http://dx.doi.org/10.3390/cancers13112789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199967PMC
June 2021

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial.

Cancer Immunol Immunother 2021 Feb 12. Epub 2021 Feb 12.

IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Aim: To evaluate the activity and safety of the PD-1 antibody pembrolizumab in adult patients with advanced osteosarcoma.

Material And Methods: The study was a single-arm, open-label, phase 2 trial in patients with unresectable, relapsed osteosarcoma. The primary endpoint was clinical benefit rate (CBR) at 18 weeks of treatment, defined as complete response, partial response, or stable disease using RECIST v1.1. The trial had a Simon´s two-stage design, and ≥ 3 of 12 patients with clinical benefit in stage 1 were required to proceed to stage 2. The trial is registered with ClinicalTrials.gov, number NCT03013127. NanoString analysis was performed to explore tumor gene expression signatures and pathways.

Results: Twelve patients were enrolled and received study treatment. No patients had clinical benefit at 18 weeks of treatment, and patient enrollment was stopped after completion of stage 1. Estimated median progression-free survival was 1.7 months (95% CI 1.2-2.2). At time of data cut-off, 11 patients were deceased due to osteosarcoma. Median overall survival was 6.6 months (95% CI 3.8-9.3). No treatment-related deaths or drug-related grade 3 or 4 adverse events were observed. PD-L1 expression was positive in one of 11 evaluable tumor samples, and the positive sample was from a patient with a mixed treatment response.

Conclusion: In this phase 2 study in advanced osteosarcoma, pembrolizumab was well-tolerated but did not show clinically significant antitumor activity. Future trials with immunomodulatory agents in osteosarcoma should explore combination strategies in patients selected based on molecular profiles associated with response.
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http://dx.doi.org/10.1007/s00262-021-02876-wDOI Listing
February 2021

High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series.

Cells 2020 10 31;9(11). Epub 2020 Oct 31.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. : Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/- ifosfamide (MAP+/-I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m/day) continuous infusion (c.i.) days 1-5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. : 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2-7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4-9), 51%, 15 months (10-19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, = 0.034) and CR2 (HR 0.126, < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. : HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting.
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http://dx.doi.org/10.3390/cells9112389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692098PMC
October 2020

Chondroblastoma's Lung Metastases Treated with Denosumab in Pediatric Patient.

Cancer Res Treat 2021 Jan 6;53(1):279-282. Epub 2020 Aug 6.

Chemotherapy Division, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.

Chondroblastoma is a rare benign chondrogenic tumor that occurs in skeletally immature patients between ages 10 and 20 years old. In literature are reported few cases of lung metastases, mainly occurred after surgery or local recurrences. There is no evidence on the pathogenesis of lung metastasis, as well as pulmonary disease course. Few treatments for metastases with aggressive behavior were based on chemotherapy regimen employed in other sarcoma with no results or not satisfying ones. Denosumab is approved for treatment of giant cell tumors and it is under investigation for other giant cell-rich bone tumors. Here, we report a case of a 16-year-old male chondroblastoma of the left humerus with bilateral lung metastases at presentation and progressing during follow-up, treated with denosumab for almost 2 years. We confirm that denosumab treatment can be effective in controlling chondroblastoma metastasis and it has been a safe procedure in an adolescent patient.
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http://dx.doi.org/10.4143/crt.2020.384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812007PMC
January 2021

ASO Author Reflections: Extraskeletal Myxoid Chondrosarcoma: A Rare Sarcoma Associated With Prolonged Survival.

Ann Surg Oncol 2020 Dec 30;27(Suppl 3):797-798. Epub 2020 Jun 30.

Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

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http://dx.doi.org/10.1245/s10434-020-08774-2DOI Listing
December 2020

Extraskeletal Myxoid Chondrosarcoma with Molecularly Confirmed Diagnosis: A Multicenter Retrospective Study Within the Italian Sarcoma Group.

Ann Surg Oncol 2021 Feb 22;28(2):1142-1150. Epub 2020 Jun 22.

Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain origin, marked by specific chromosomal translocations involving the NR4A3 gene, and usually characterized by an indolent course. Surgery (with or without radiotherapy) is the treatment of choice in localized disease. The treatment for advanced disease remains uncertain. In order to better evaluate prognostic factors and outcome, a retrospective pooled analysis of patients with EMC treated at three Italian Sarcoma Group (ISG) referral centers was carried out.

Methods: All patients with localized EMC surgically treated from 1989 to 2016 were identified. Diagnosis was centrally reviewed according to WHO 2013. Only patients with NR4A3 rearrangement were included.

Results: Sixty-seven patients were identified: 13 (20%) female, 54 (80%) male. Median age was 56 years (range 18-84). Numbers and type of translocation were: 50 (80%) NR4A3-EWS, 10 (16%) NR4A3-TAF15, 1 (2%) NR4A3-TCF12, and 1 (2%) NR4A3-TFG. Median follow-up was 55 months (range 2-312). Five- and ten-year overall survival rates were 94% (86-100 95%CI) and 84% (69-98 95%CI). Thirty-five (52%) patients relapsed: 9 had local recurrence (LR) and 26 had distant metastasis (5 with concomitant LR). The 5- and 10-year disease-free survival rates (DFS) were 51% (38-65 95%CI) and 20% (7-33 95%CI). Size of the primary tumor was significantly related to distant metastasis-free survival (DMFS) (p = 0.004). Patients carrying the NR4A3-EWS translocation had a trend in favor of better DFS (p = 0.08) and DMFS (p = 0.09) compared with the patients with NR4A3-TAF15.

Conclusions: Prolonged survival can be expected in patients with EMC, in spite of a high rate of recurrence. Size is significantly associated with distant relapse. The type of NR4A3 translocation could influence outcome.
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http://dx.doi.org/10.1245/s10434-020-08737-7DOI Listing
February 2021

Experience with eribulin in pretreated patients with advanced liposarcoma: a case series.

Future Oncol 2020 Jan 20;16(1s):25-32. Epub 2019 Dec 20.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Systemic treatments for advanced soft tissue sarcoma are limited. Eribulin showed activity in metastatic soft tissue sarcoma, particularly liposarcomas. Data from six patients with advanced liposarcoma that received eribulin as third- or fourth-line therapy are presented herein. Eribulin treatment was well tolerated; no grade 3-4 toxicity or therapy delay was observed. Two patients had a partial response; four had a prolonged stable disease. The first case, with pre-existing chronic renal dysfunction, achieved a 6-month stable disease with dose-reduced eribulin. The second case became resectable after eribulin treatment, with a 6-month complete surgical remission. The third case obtained a 7-month stable disease with eribulin and stereotactic body radiotherapy. The last three cases were ≥65 years old, and two of them had objective response with eribulin.
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http://dx.doi.org/10.2217/fon-2019-0599DOI Listing
January 2020

Is there a role for chemotherapy after local relapse in high-grade osteosarcoma?

Pediatr Blood Cancer 2019 08 6;66(8):e27792. Epub 2019 May 6.

Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.

Background: High-grade bone osteosarcoma has a high relapse rate. The best treatment of local recurrence (LR) is under discussion. The aim of this study is to analyze LR patterns and factors prognostic for survival.

Methods: LR diagnostic modality (clinical or imaging), pattern of recurrence, and post-LR survival (PLRS) were assessed.

Results: Sixty-two patients were identified, with median age 21 years (range, 9-75 years), including 11 (18%) ≤15 years, 30 (48%) from 16 to 29 years; 21 (34%) were older. Patterns of relapse were LR only 58%, LR + distant metastases (DM) 42%. Seventy-nine percent of patients relapsed within 24 months, and diagnosis was clinical in 88%. LR treatment was surgery 85%, chemotherapy 55%, chemotherapy + surgery 45%. Surgical complete remission after LR (CR2) was achieved in 60% (LR 86%; LR + DM 23%). With a median follow-up of 43 months (range, 5-235 months), the five-year PLRS was 37%, significantly better for patients with longer LR-free interval (LRFI; ≤24 months 31% vs > 24 months 61.5%, P = 0.03), absence of DM (no DM 56% vs DM 11.5%, P = 0.0001), and achievement of CR2 (no CR2 0% vs CR2 58.5%, P = 0.0001). No difference was found according to age and chemotherapy (LR only: five-year PLRS: 53% without chemotherapy vs 58% with chemotherapy, P = 0.9; LR + DM: five-year PLRS: 25% without chemotherapy vs 9% with chemotherapy, P = 0.7).

Conclusions: Early relapse is detected by symptoms in 90% of cases and associated with worse outcome. The achievement of CR2, not age, is crucial for survival. For patients with LR only, better survival was demonstrated, as compared with DM, and no improvement with chemotherapy after surgery was found.
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http://dx.doi.org/10.1002/pbc.27792DOI Listing
August 2019

Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution.

Pediatr Blood Cancer 2019 06 5;66(6):e27653. Epub 2019 Feb 5.

Chemotherapy Section, IRCCS-Rizzoli Orthopaedic Institute, Bologna, Italy.

Background: Ewing sarcoma (ES) is the second most common bone tumor in adolescents and children. Staging workup for ES includes imaging and bone marrow biopsy (BMB). The effective role of BMB is now under discussion.

Procedure: A monoinstitutional retrospective analysis reviewed clinical charts, imaging, and histology of patients with diagnosis of ES treated at the Rizzoli Institute between 1998 and 2017.

Results: The cohort included 504 cases of ES of bone; 137 (27%) had metastases at diagnosis, while the remaining 367 had localized disease. Twelve patients had a positive BMB (2.4%). Eleven had distant metastases detected at initial workup staging with imaging assessment: six patients presented with bone metastases, five with both bone and lung metastases. Only one patient with ES of the foot (second metatarsus) was found to have bone marrow involvement with negative imaging evaluation (0.3%).

Conclusions: On the basis of our data, we suggest reconsidering the effective role of BMB in initial staging workup for patients with ES with no signs of metastases by modern imaging techniques. In metastatic disease, the assessment of the bone marrow status may remain useful to identify a group of patients at very high risk who could benefit from different treatment strategies.
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http://dx.doi.org/10.1002/pbc.27653DOI Listing
June 2019

Pazopanib in relapsed osteosarcoma patients: report on 15 cases.

Acta Oncol 2019 Jan 12;58(1):124-128. Epub 2018 Sep 12.

d Department of Oncology , Oslo University Hospital, The Norwegian Radium Hospital , Oslo , Norway.

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http://dx.doi.org/10.1080/0284186X.2018.1503714DOI Listing
January 2019

Denosumab in patients with aneurysmal bone cysts: A case series with preliminary results.

Tumori 2018 Oct 8;104(5):344-351. Epub 2018 Aug 8.

1 Chemotherapy Unit, IRCCS, Istituto Ortopedico Rizzoli, Bologna, Italy.

Purpose:: Aneurysmal bone cyst (ABC) is a rare skeletal tumor usually treated with surgery/embolization. We hypothesized that owing to similarities with giant cell tumor of bone (GCTB), denosumab was active also in ABC.

Methods:: In this observational study, a retrospective analysis of ABC patients treated with denosumab was performed. Patients underwent radiologic disease assessment every 3 months. Symptoms and adverse events were noted.

Results:: Nine patients were identified (6 male, 3 female), with a median age of 17 years (range 14-42 years). Primary sites were 6 spine-pelvis, 1 ulna, 1 tibia, and 1 humerus. Patients were followed for a median time of 23 months (range 3-55 months). Patients received a median of 8 denosumab administrations (range 3-61). All symptomatic patients had pain relief and 1 had paresthesia improvement. Signs of denosumab activity were observed after 3 to 6 months of administration: bone formation by computed tomography scan was demonstrated in all patients and magnetic resonance imaging gadolinium contrast media decrease was observed in 7/9 patients. Adverse events were negligible. At last follow-up, all patients were progression-free: 5 still on denosumab treatment, 2 off denosumab were disease-free 11 and 17 months after surgery, and the last 2 patients reported no progression 12 and 24 months after denosumab interruption and no surgery.

Conclusions:: Denosumab has substantial activity in ABCs, with favorable toxicity profile. We strongly support the use of surgery and/or embolization for the treatment of ABC, but denosumab could have a role as a therapeutic option in patients with uncontrollable, locally destructive, or recurrent disease.
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http://dx.doi.org/10.1177/0300891618784808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247581PMC
October 2018

Survival after second and subsequent recurrences in osteosarcoma: a retrospective multicenter analysis.

Tumori 2018 Jun;104(3):202-206

1 Pediatric Oncohematology, Stem Cell Transplantation and Cell Therapy Division, A.O.U. Città della Salute e della Scienza, Ospedale Infantile "Regina Margherita", Turin - Italy.

Purpose: Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse.

Methods: This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013.

Results: Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR.

Conclusions: This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.
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http://dx.doi.org/10.1177/0300891617753257DOI Listing
June 2018

Sinusoidal obstruction syndrome/veno-occlusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing Sarcoma.

Bone Marrow Transplant 2018 05 15;53(5):591-599. Epub 2018 Jan 15.

Unit of Internal Medicine, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p = 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p = 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.
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http://dx.doi.org/10.1038/s41409-017-0066-4DOI Listing
May 2018

EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma.

Tumori 2018 Jan-Feb;104(1):30-36

2 Stuttgart Cancer Center, Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart Olgahospital, Stuttgart - Germany.

Introduction: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma.

Methods: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators' choice were also eligible for the study.

Results: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity.

Conclusions: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.
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http://dx.doi.org/10.5301/tj.5000696DOI Listing
May 2018

Survival after Second and Subsequent Recurrences in Osteosarcoma: A Retrospective Multicenter Analysis.

Tumori 2017 May 1:tj5000636. Epub 2017 May 1.

1 Pediatric Oncohematology, Stem Cell Transplantation and Cell Therapy Division, A.O.U. Città della Salute e della Scienza, Ospedale Infantile "Regina Margherita", Turin - Italy.

Purpose Osteosarcoma (OS) is the most common primary bone tumor. Despite complete surgical removal and intensive chemotherapeutic treatment, 30%-35% of patients with OS have local or systemic recurrence. Some patients survive multiple recurrences, but overall survival after OS recurrence is poor. This analysis aims to describe and identify factors influencing post-relapse survival (PRS) after a second OS relapse. Methods This is a retrospective analysis of 60 patients with a second relapse of OS of the extremities in 2 Italian centers between 2003 and 2013. Results Treatment for first and subsequent relapses was planned according to institutional guidelines. After complete surgical remission (CSR) following the first recurrence, patients experienced a second OS relapse with a median disease-free interval (DFI) of 6 months. Lung disease was prevalent: 44 patients (76%) had pulmonary metastases. Survival after the second relapse was 22% at 5 years. Lung disease only correlated with better survival at 5 years (33.6%) compared with other sites of recurrence (5%; p = 0.008). Patients with a single pulmonary lesion had a better 5-year second PRS (42%; p = 0.02). Patients who achieved a second CSR had a 5-year second PRS of 33.4%. Chemotherapy (p<0.001) benefited patients without a third CSR. Conclusions This analysis confirms the importance of an aggressive, repeated surgical approach. Lung metastases only, the number of lesions, DFI and CSR influenced survival. It also confirms the importance of chemotherapy in patients in whom surgical treatment is not feasible.
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http://dx.doi.org/10.5301/tj.5000636DOI Listing
May 2017

Erratum to: Osteosarcoma follow-up: chest X-ray or computed tomography?

Clin Sarcoma Res 2017 3;7. Epub 2017 May 3.

Chemotherapy Unit, Istituto Ortopedico Rizzoli, via Pupilli, 1, 40136 Bologna, Italy.

[This corrects the article DOI: 10.1186/s13569-017-0067-5.].
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http://dx.doi.org/10.1186/s13569-017-0073-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415725PMC
May 2017

Osteosarcoma follow-up: chest X-ray or computed tomography?

Clin Sarcoma Res 2017 14;7. Epub 2017 Feb 14.

Chemotherapy Unit, Istituto Ortopedico Rizzoli, via Pupilli, 1, 40136 Bologna, Italy.

Background: In patients with relapsed osteosarcoma, the surgical excision of all metastases, defined as second complete remission (CR-2), is the factor that mainly influences post-relapse survival (PRS). Currently a validated follow-up policy for osteosarcoma is not available, both chest X-ray and computed tomography (CT) are suggested for lung surveillance. The purpose of this study is to evaluate whether the type of imaging technique used for chest surveillance, chest X-ray or CT, influenced the rate of CR-2 and prognosis in patients with recurrent osteosarcoma.

Methods: Patients up to 40 years with extremity osteosarcoma enrolled in consecutive clinical trials and treated at the Rizzoli Institute from 1986 to 2009 were identified. Only patients who had lung metastases alone as first pattern of recurrence were considered for the analysis. The rate of CR-2, overall survival (OS) and PRS were the end-points of the study.

Results: The median follow-up was 47 months (1-300), 215 patients were eligible. Lung metastases were detected by chest X-ray in 100 (47%) patients, by CT in 112 (52%) and by symptoms in 3 (1%). CR-2 rate was 60% for patients followed by X-rays and 88% for those followed by CT (p < .0001). 5-year PRS was 30% (95% CI 21-39) in the X-ray group and 49% (95% CI 39-59) in the CT group (p = .0004). 5-year OS was 35% (95% CI 26-44) in the X-ray group and 60% (95% CI 51-70) in the CT group (p = .004).

Conclusions: A follow-up strategy with chest CT leads to a higher rate of CR-2 and significantly improves PRS and OS in osteosarcoma, compared to chest X-ray.
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http://dx.doi.org/10.1186/s13569-017-0067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5307808PMC
February 2017

The role of FDG PET/CT in patients treated with neoadjuvant chemotherapy for localized bone sarcomas.

Eur J Nucl Med Mol Imaging 2017 Feb 20;44(2):215-223. Epub 2016 Sep 20.

Chemotherapy, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy.

Purpose: The histological response to neoadjuvant chemotherapy is an important prognostic factor in patients with osteosarcoma (OS) and Ewing sarcoma (EWS). The aim of this study was to assess baseline primary tumour FDG uptake on PET/CT, and serum values of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), to establish whether these factors are correlated with tumour necrosis and prognosis.

Methods: Patients treated between 2009 and 2014 for localized EWS and OS, who underwent FDG PET/CT as part of their staging work-up, were included. The relationships between primary tumour SUVmax at baseline (SUV1), SUVmax after induction chemotherapy (SUV2), metabolic response calculated as [(SUV1 - SUV2)/SUV1)] × 100, LDH and ALP and tumour response/survival were analysed. A good response (GR) was defined as tumour necrosis >90 % in patients with OS, and grade II-III Picci necrosis (persitence of microscopic foci only or no viable tumor) in patients with Ewing sarcoma.

Results: The study included 77 patients, 45 with EWS and 32 with OS. A good histological response was achieved in 53 % of EWS patients, and 41 % of OS patients. The 3-year event-free survival (EFS) was 57 % in EWS patients and 48 % OS patients. The median SUV1 was 5.6 (range 0 - 17) in EWS patients and 7.9 (range 0 - 24) in OS patients (p = 0.006). In EWS patients the GR rate was 30 % in those with a high SUV1 (≥6) and 72 % in those with a lower SUV1 (p = 0.0004), and in OS patients the GR rate was 29 % in those with SUV1 ≥6 and 64 % in those with a lower SUV1 (p = 0.05). In the univariate analysis the 3-year EFS was significantly better in patients with a low ALP level (59 %) than in those with a high ALP level (22 %, p = 0.02) and in patients with a low LDH level (62 %) than in those with a high LDH level (37 %, p = 0.004). In EWS patients the 3-year EFS was 37 % in those with a high SUV1 and 75 % in those with a low SUV1 (p = 0.004), and in OS patients the 3-year EFS was 32 % in those with a high SUV1 and 66 % in those with a low SUV1 (p = 0.1). Histology, age and gender were not associated with survival. In the multivariate analysis, SUV1 was the only independent pretreatment prognostic factor to retain statistical significance (p = 0.017). SUV2 was assessed in 25 EWS patients: the median SUV2 was 1.9 (range 1 - 8). The GR rate was 20 % in patients with a high SUV2, and 67 % in those with a low SUV2 (p = 0.02). A good metabolic response (SUV reduction of ≥55 %) was associated with a 3-year EFS of 80 % and a poor metabolic response with a 3-year EFS of 20 % (p = 0.05). In the OS patients the median SUV2 was 2.7 (range 0 - 4.5). Neither SUV2 nor the metabolic response was associated with outcome in OS patients.

Conclusion: FDG PET/CT is a useful and noninvasive tool for identifying patients who are more likely to be resistant to chemotherapy. If this finding is confirmed in a larger series, SUV1, SUV2 and metabolic response could be proposed as factors for stratifying EWS patients to identify those with high-grade localized bone EWS who would benefit from risk-adapted induction chemotherapy.
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http://dx.doi.org/10.1007/s00259-016-3509-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215266PMC
February 2017

Ewing sarcoma in patients over 40 years of age: a prospective analysis of 31 patients treated at a single institution.

Tumori 2016 Oct 18;102(5):481-487. Epub 2016 Jul 18.

 Chemotherapy Section, Rizzoli Orthopedic Institute, Bologna - Italy.

Purpose: Patients with Ewing sarcoma who are 40 years old or older are usually excluded from clinical trials. For this reason, information on this subset of patients is limited.

Methods: Clinical characteristics and treatment-related variables of patients aged 40 years or more, with a diagnosis of Ewing sarcoma, treated at the authors' institution had been prospectively collected since 1999.

Results: Thirty-one patients were identified, with ages ranging from 40 to 70 years (median 45 years). Twenty-six (84%) had localized disease, 4 patients presented with lung metastases, and 1 patient had multiple metastases (bone, lung, abdominal nodes, and bone marrow). The primary tumors were skeletal in 19 (61%) patients, while 12 (39%) had extraskeletal disease. All patients received chemotherapy according to regimens similar to those adopted in younger patients, based on doxorubicin, cyclophosphamide, etoposide, vincristine, dactinomycin, and ifosfamide. All patients experienced grade 4 leukopenia (100%); red blood cells or platelets transfusions were needed in 50% and 16% of patients, respectively. Toxicity-related dose reduction was required in 13 patients (43%). The 5-year overall survival (OS) was 54% for the whole group. In patients with complete remission, 5-year disease-free survival was 57%. Survival was different for patients with skeletal and extraskeletal Ewing sarcoma (5-year OS: 64% vs 40%, p = 0.2).

Conclusions: In older patients, the incidence of extraskeletal Ewing sarcoma is high. Intensive chemotherapy treatment can be recommended in this group. The high chemotherapy toxicity can be justified by expected results, similar to those of younger patients.
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http://dx.doi.org/10.5301/tj.5000534DOI Listing
October 2016

High-grade focal areas in low-grade central osteosarcoma: high-grade or still low-grade osteosarcoma?

Clin Sarcoma Res 2015 29;5:23. Epub 2015 Oct 29.

Department of Oncology, Rizzoli Institute, Bologna, Italy.

Background: High-grade foci (grade 3 according to Broder's grading system) are sometimes detected in low-grade (grade 1 and 2) central osteosarcoma. The aim of this study was to retrospectively evaluate the clinical outcome in patients upgraded to high grade (grade 3) after a first diagnosis of low-grade osteosarcoma, following the detection of high-grade areas (grade 3) in the resected specimen.

Methods: Of the 132 patients with a diagnosis of low-grade central osteosarcoma at surgical biopsy at our Institute, 33 patients were considered eligible for the study.

Results: Median age was 37 (range 13-58 years). Location was in an extremity in 29 patients (88 %). Post-operative chemotherapy was given in 22 (67 %) patients. Follow-up data were available for all patients, with a median observation time of 115 months (range 4-322 months). After histological revision, areas of high-grade (grade 3) osteosarcoma accounting for less than 50 % of the tumor were found in 20 (61 %) patients, whereas the majority of the tumor was composed of a high-grade (grade 3) component in 13 (39 %) patients. In the 20 cases of low-grade osteosarcoma with high-grade foci (grade 3) in less than 50 % of the tumor, 9 patients did not receive adjuvant chemotherapy; only one of them died, of unrelated causes. In the adjuvant chemotherapy group (11 out of 20 patients), one patient developed multiple lung metastases and died of disease 39 months after the first diagnosis. In the other 13 cases of low-grade osteosarcoma with high-grade foci (grade 3) in more than 50 % of the tumor, 12 patients received adjuvant chemotherapy: 2 had recurrence, 4 developed multiple lung metastases and 3 died of disease. The only patient who did not receive chemotherapy is alive without disease 232 months after complete surgical remission.

Conclusion: Our data indicate that patients with a diagnosis of low-grade osteosarcoma where the high-grade (grade 3) component is lower than 50 % of the resected specimen, may not require chemotherapy, achieving high survival rates by means of complete surgical resection only.
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http://dx.doi.org/10.1186/s13569-015-0038-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627618PMC
November 2015

Post-relapse survival in patients with Ewing sarcoma.

Pediatr Blood Cancer 2015 Jun 13;62(6):994-9. Epub 2015 Jan 13.

Department of Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.

Background: Post-relapse survival (PRS) was evaluated in patients with Ewing sarcoma (EWS) enrolled in chemotherapy protocols based on the use of high-dose chemotherapy with busulfan and melfalan (HDT) as a first-line consolidation treatment in high-risk patients.

Procedure: EWS patients enrolled in ISG/SSG III and IV trials who relapsed after complete remission were included in the analysis. At recurrence, chemotherapy based on high-dose ifosfamide was foreseen, and patients who responded but had not received HDT underwent consolidation therapy with HDT.

Results: Data from 107 EWS patients were included in the analysis. Median time to recurrence (RFI) was 18 months, and 45 (42%) patients had multiple sites of recurrence. Patients who had previously been treated with HDT had a significantly (P = 0.02) shorter RFI and were less likely to achieve a second complete remission (CR2). CR2 status was achieved by 42 (39%) patients. Fifty patients received high-dose IFO (20 went to consolidation HDT). The 5-year PRS was 19% (95% CI 11 to 27%). With CR2, the 5-year PRS was 48% (95% CI 31 to 64%). Without CR2, median time to death was six months (range 1-45 months). According to the multivariate analysis, patients younger than 15 years, recurrence to the lung only, and RFI longer than 24 months significantly influenced the probability of PRS.

Conclusions: Age, pattern of recurrence, RFI, and response to second-line chemotherapy influence post-relapse survival in patients with recurrent Ewing sarcoma. No survival advantage was observed from chemotherapy consolidation with HDT.
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http://dx.doi.org/10.1002/pbc.25388DOI Listing
June 2015

Emerging therapeutic targets for synovial sarcoma.

Expert Rev Anticancer Ther 2014 Jul 24;14(7):791-806. Epub 2014 Mar 24.

Chemotherapy, Musculoskeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.
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http://dx.doi.org/10.1586/14737140.2014.901155DOI Listing
July 2014

Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age.

J Chemother 2014 Feb 6;26(1):49-56. Epub 2013 Dec 6.

Influence of age and sex on chemotherapy-related toxicity was evaluated in children (3-9 years), adolescents (10-17 years), and adults (up to 40 years) with localized Ewing sarcoma (ES) enrolled in the ISG/SSG III protocol. Treatment was based on vincristine, doxorubicin, cyclophosphamide, ifosfamide, dactinomycin, and etoposide. High-dose chemotherapy with busulfan and melphalan was given in poor responder patients. The analysis was based on 2191 courses of standard chemotherapy and 230 patients. A lower risk of G4 leukopenia and thrombocytopenia, hospitalization, febrile neutropenia, and red blood cell (RBC) transfusions was observed in males. Use of granulocyte colony-stimulating factor (G-CSF) was more frequent in adults, while children more often received RBC transfusions. A significant correlation between sex and chemotherapy-related toxicity was observed in the study, whereas no significant differences in terms of bone marrow toxicity can be expected according to patient age. Further studies should analyse the role of pharmacokinetics, pharmacogenomics, and clinical characteristics.
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http://dx.doi.org/10.1179/1973947813Y.0000000103DOI Listing
February 2014

Analysis of risk factors for central venous catheter-related complications: a prospective observational study in pediatric patients with bone sarcomas.

Cancer Nurs 2014 Jul-Aug;37(4):292-8

Author Affiliations: Department of Chemotherapy (Dr Abate, Ms Boschi, Ms Raspanti, Dr Cesari, Dr Paioli, Dr Palmerini, Dr Ferrari), Radiology Section (Ms Loro), and Ultrasound Section (Dr Affinito), Istituto Ortopedico Rizzoli, Bologna, Italy; and Pediatric Oncology Unit (Dr Escobosa Sánchez), Carlos Haya Hospital, Málaga, Spain.

Background: The incidence of central venous catheter (CVC)-related complications reported in pediatric sarcoma patients is not established as reports in available literature are limited. The analysis of risk factors is part of the strategy to reduce the incidence of CVC complications.

Objective: The objective of this study was to determine the incidence of CVC complications in children with bone sarcomas and if defined clinical variables represent a risk factor.

Methods: During an 8-year period, 155 pediatric patients with bone sarcomas were prospectively followed up for CVC complications. Incidence and correlation with clinical features including gender, age, body mass index, histology, disease stage, and use of thromboprophylaxis with low-molecular-weight heparin were analyzed.

Results: Thirty-three CVC complications were recorded among 42 687 CVC-days (0.77 per 1000 CVC-days). No correlation between the specific clinical variables and the CVC complications was found. A high incidence of CVC-related sepsis secondary to gram-negative bacteria was observed.

Conclusions: The analysis of CVC complications and their potential risk factors in this sizable and relatively homogeneous pediatric population with bone sarcomas has led to the implementation of a multimodal approach by doctors and nurses to reduce the incidence and morbidity of the CVC-related infections, particularly those related to gram-negative bacteria.

Implications For Practice: As a result of this joint medical and nursing study, a multimodal approach that included equipping faucets with water filters, the reeducation of doctors and nurses, and the systematic review of CVC protocol was implemented.
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http://dx.doi.org/10.1097/NCC.0b013e31829627e7DOI Listing
December 2015

Primary angiosarcoma of bone: a retrospective analysis of 60 patients from 2 institutions.

Am J Clin Oncol 2014 Dec;37(6):528-34

Departments of *Chemotherapy ‡Orthopaedic Surgery §Surgical Pathology ¶Research Laboratory, Musculoskeletal Oncology Department, Istituto Ortopedico Rizzoli, Bologna, Italy Departments of †Medicine ∥Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.

Background: Angiosarcoma of bone is a rare high-grade malignant vascular tumor. The literature regarding treatment and outcome of patients with this tumor is limited.We performed a 2 institutional retrospective study to analyze treatment and survival of patients with angiosarcoma of bone.

Patients And Methods: We reviewed patients with the histologic diagnosis of primary angiosarcoma of bone treated from 1980 to 2009. Demographic details, histology, treatment, and survival were reviewed.

Results: A total of 38 men and 22 women (median age, 54 y) were recruited. Most lesions occurred in the femur and the pelvis. Metastatic disease at presentation was diagnosed in 24 patients (40%). Forty-three patients underwent surgery, with 30 of them achieving surgical complete remission (SCR). Radiotherapy was applied to 17 patients, and chemotherapy to 13/35 and 15/22 patients with localized and metastatic disease, respectively.The 5-year overall survival (OS) was 20%: 33% for patients with localized disease and 0% for metastatic patients. Higher 5-year OS was reported for patients who achieved SCR (46%) than for those who did not (0%). In nonmetastatic patients, a trend toward improved survival was observed after SCR and adjuvant chemotherapy based on cisplatin, doxorubicin, and ifosfamide.Fifteen patients received chemotherapy for metastases. Two RECIST partial responses of 13 evaluable patients were documented (paclitaxel [n=1] and doxorubicin [n=1]). Stable disease was observed in 2 patients.

Conclusions: Complete surgical resection is essential for outcome. Survival of patients with metastatic or unresectable disease is very poor. Activity of taxanes and anthracycline was observed in the metastatic setting and merits further evaluation.
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http://dx.doi.org/10.1097/COC.0b013e31827defa1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681918PMC
December 2014

Carboplatin and etoposide (CE) chemotherapy in patients with recurrent or progressive oligodendroglial tumors.

J Neurooncol 2006 Sep 28;79(3):299-305. Epub 2006 Apr 28.

Department of Medical Oncology, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy.

Background: Oligodendroglial tumors are rare and chemosensitive diseases; but the overall results with current chemotherapy regimens cannot be considered satisfactory and other active treatments are necessary. We decided to determine the efficacy and toxicity profile of the carboplatin and etoposide (CE) regimen in this setting.

Methods: In this phase II trial we evaluated the response rate of first or second line CE regimen (Carboplatin AUC 5 on day 1 and Etoposide 120 mg/m2 on days 1-3 every 28 days) in patients with recurrent/progressive oligodendroglial tumors.

Results: Thirty-two patients were enrolled. Median age was 42 years (range 22-66); median ECOG PS was 0 (range 0-2); 9 patients had oligodendroglioma, 3 patients had oligoastrocytoma, 11 patients had anaplastic oligodendroglioma, 9 patients had anaplastic oligoastrocytoma. CE regimen showed a response rate of 46.9% with 5 complete responses (15.6%) and 10 partial responses (31.3%). Eleven patients (34.4%) had stable disease. Median time to progression was 8 months, progression-free survivals at 6 and 12 months were 80% and 46.9%, respectively. Toxicity was mainly hematological, with grade 3-4 neutropenia in 5 (15.6%) patients.

Conclusions: In this trial CE regimen has shown relevant activity with a favourable safety profile.
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http://dx.doi.org/10.1007/s11060-006-9144-yDOI Listing
September 2006

Temozolomide-induced partial response in a patient with primary diffuse leptomeningeal gliomatosis.

J Neurooncol 2005 Jul;73(3):261-4

Department of Medical Oncology, Bellaria Hospital, Via Altura 3, Bologna, 40139, Italy.

Herein we describe the case of a patient with primary diffuse leptomeningeal gliomatosis (PDLG). After surgery and ventriculoperitoneal shunt placement, due to poor general conditions, the patient was not eligible for radiotherapy. For this reason we decided to start a systemic chemotherapy treatment with Temozolomide (150 mg/m2 per day for 5 days every 4 weeks). After three cycles a partial response was achieved with a clear improvement of general conditions. In our knowledge, this is the first time that PDLG treatment with Temozolomide has been described.
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http://dx.doi.org/10.1007/s11060-004-5672-5DOI Listing
July 2005
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