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Antoine Italiano,
Angela Cioffi,
Paola Coco,
Robert G Maki,
Patrick Schöffski,
Piotr Rutkowski,
Axel Le Cesne,
Florence Duffaud,
Antoine Adenis,
Nicolas Isambert,
Emmanuelle Bompas,
Jean-Yves Blay, Paolo Casali,
Mary Louise Keohan,
Maud Toulmonde,
Cristina R Antonescu,
Maria Debiec-Rychter,
Jean-Michel Coindre,
Binh Bui
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ABSTRACT: Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited.
Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed.
The three most frequent drugs used in the 3rd-line setting were: nilotinib n = 67 (29.5%), sorafenib n = 55 (24.5%), and imatinib n = 40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6 months [95% confidence interval (95% CI), 3.1-4.1] and 9.2 months (95% CI, 7.5-10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC.
In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.
Annals of Surgical Oncology 11/2011; 19(5):1551-9. · 4.17 Impact Factor
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Antoine Italiano,
Armelle Laurand,
Audrey Laroche, Paolo Casali,
Roberta Sanfilippo,
Axel Le Cesne,
Ian Judson,
Jean-Yves Blay,
Isabelle Ray-Coquard,
Binh Bui,
Jean-Michel Coindre,
Antonio Nieto,
Juan-Carlos Tercero,
Jose Jimeno,
Jacques Robert,
Philippe Pourquier
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ABSTRACT: The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS).
The authors analyzed excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross-complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate-use program. The 6-month progression-free rate (PFR), progression-free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log-rank tests.
High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine-to-cytosine (T→C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple-adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS.
In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS.
Cancer 02/2011; 117(15):3445-56. · 4.77 Impact Factor
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Roberta Frapolli,
Elena Tamborini,
Emanuela Virdis,
Ezia Bello,
Eva Tarantino,
Sergio Marchini,
Federica Grosso,
Roberta Sanfilippo,
Alessandro Gronchi,
Juan Carlos Tercero,
Gabriella Peloso, Paolo Casali,
Silvana Pilotti,
Maurizio D'Incalci
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ABSTRACT: Myxoid liposarcoma is a common subtype of liposarcoma. It is associated in more than 90% of cases with the chromosomal translocation t(12;16)(q13;p11) leading to the fusion FUS-CHOP gene that is responsible for the oncogenic transformation of preadipocytes. Recently the marine natural product trabectedin has shown highly selective activity for myxoid liposarcoma, even in the most aggressive round-cell subtype. Experimental
Fragments of 17 sarcomas were transplanted s.c. in female athymic NCr-nu/nu mice. Xenografts were established and characterized by morphology, fluorescence in situ hybridization analysis for the translocation and reverse transcriptase-PCR analysis for fusion transcripts. Trabectedin was injected i.v.
Seven of 17 tumors grew as continuous xenografts, five of them being myxoid liposarcoma of the round-cell subtype. The chromosomal rearrangement and fusion transcripts in different passages were the same as in the human tumors from which they were derived. The responsiveness to trabectedin in type II myxoid liposarcoma xenografts was as high as in patients. The pathologic response was associated with the presence of the FUS-CHOP fusion gene, indicating that the drug does not totally eradicate the disease. Type III myxoid liposarcoma xenografts seemed much less sensitive to trabectedin, confirming previous clinical observations.
This study reports for the first time the characterization of human myxoid liposarcoma xenografts that adequately mimic the biological and pharmacologic features of the human tumor. These models offer a useful tool for investigating the mechanism of selectivity of trabectedin, testing new combinations with this drug and evaluating novel therapies for myxoid liposarcoma.
Clinical Cancer Research 10/2010; 16(20):4958-67. · 7.74 Impact Factor
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Silvia Stacchiotti, Paolo Giovanni Casali,
Salvatore Lo Vullo,
Luigi Mariani,
Elena Palassini,
Mario Mercuri,
Marco Alberghini,
Silvana Pilotti,
Licciana Zanella,
Alessandro Gronchi,
Piero Picci
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ABSTRACT: Chordoma is a rare tumor, and its natural history is still not well known.
All patients affected by localized chordoma surgically treated at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, between 1980 and 2008 were reviewed. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out.
A total of 138 consecutive patients were identified (sacrum 78%, lumbar spine 15%, cervical-dorsal spine 7%). Of these, 130 underwent surgical resection. Median follow-up was 142 months. The 5- and 10-year OS, local relapse-free survival (LRFS), and distant relapse-free survival (DRFS) were, respectively, 78% and 54%, 52% and 33%, and 86% and 72%. Size was an independent prognostic factor for OS (P value < .001), LRFS (P value: .038), and DRFS (P value: .004), while surgical margins independently predicted LRFS (P value: .003) with a trend for OS. The 5- and 10-year OS, LRFS, and DRFS after the first local relapse were 50% and 26%, 47% and 31%, and 64% and 61%. The size of the recurrence and quality of surgical margins did not influence postrelapse OS. The 5-year OS after the second local relapse was 19%. 22% of patients developed distant metastases with a 5-year post-metastases OS of 33%.
Tumor size and surgical margins affected outcome only on initial presentation. However, wide surgery was feasible in a minority of cases. Most patients died of local-regional disease even when metastases occurred. Indeed, long-term prognosis was such that disease-free survival at 10 years was only 26%.
Annals of Surgical Oncology 10/2009; 17(1):211-9. · 4.17 Impact Factor
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ABSTRACT: Surgery is still the standard treatment for desmoid-type fibromatosis (DF). Recently, the Institut Gustave Roussy (IGR), Villejuif, France, reported a series of patients treated with a front-line conservative approach (no surgery and no radiotherapy). The disease remained stable in more than half of patients. This study was designed to evaluate this approach on the natural history of the disease in a larger series of patients.
A total of 142 patients presenting to the IGR or Istituto Nazionale Tumori (INT), Milan, Italy, were initially treated using a front-line deliberately conservative policy. Their progression-free survival (PFS) was observed and a multivariate analysis was performed for major clinical variables.
Seventy-four patients presented with primary tumor, 68 with recurrence. Eighty-three patients received a "wait & see" policy (W&S), whereas 59 were initially offered medical therapy (MT), mainly hormonal therapy and chemotherapy. A family history of sporadic colorectal cancer was present in 8% of patients. The 5-year PFS was 49.9% for the W&S group and 58.6% for the medically treated patients (P = 0.3196). Similar results emerged for primary and recurrent DF. Multivariate analysis identified no clinical variables as independent predictors of PFS. In the event of progression, all patients were subsequently managed safely.
A conservative policy could be a safe approach to primary and recurrent DF, which could avoid unnecessary morbidity from surgery and/or radiation therapy. Half of patients had medium-term stable disease after W&S or MT. A multidisciplinary, stepwise approach should be prospectively tested in DF.
Annals of Surgical Oncology 08/2009; 16(9):2587-93. · 4.17 Impact Factor
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Claudia Forni,
Mario Minuzzo,
Emanuela Virdis,
Elena Tamborini,
Matteo Simone,
Michele Tavecchio,
Eugenio Erba,
Federica Grosso,
Alessandro Gronchi,
Pierre Aman, Paolo Casali,
Maurizio D'Incalci,
Silvana Pilotti,
Roberto Mantovani
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ABSTRACT: Differentiation is a complex set of events that can be blocked by rearrangements of regulatory genes producing fusion proteins with altered properties. In the case of myxoid liposarcoma (MLS) tumors, the causative abnormality is a fusion between the CHOP transcription factor and the FUS or EWS genes. CHOP belongs to and is a negative regulator of the large CAAT/enhancer binding protein family whose alpha, beta, and delta members are master genes of adipogenesis. Recent clinical data indicate a peculiar sensitivity of these tumors to the natural marine compound trabectedin. One hypothesis is that the activity of trabectedin is related to the inactivation of the FUS-CHOP oncogene. We find that trabectedin causes detachment of the FUS-CHOP chimera from targeted promoters. Reverse transcription-PCR and chromatin immunoprecipitation analysis in a MLS line and surgical specimens of MLS patients in vivo show activation of the CAAT/enhancer binding protein-mediated transcriptional program that leads to morphologic changes of terminal adipogenesis. The activity is observed in cells with type 1 but not type 8 fusions. Hence, the drug induces maturation of MLS lipoblasts in vivo by targeting the FUS-CHOP-mediated transcriptional block. These data provide a rationale for the specific activity of trabectedin and open the perspective of combinatorial treatments with drugs acting on lipogenic pathways.
Molecular Cancer Therapeutics 03/2009; 8(2):449-57. · 5.23 Impact Factor
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ABSTRACT: Abdominal sarcomatosis (AS) is a rare condition characterized by soft tissue sarcoma spreading throughout the abdomen, in the absence of extra-abdominal dissemination. Retroperitoneal sarcomas, pelvic sarcomas, particularly uterine leiomyosarcoma, and gastrointestinal stromal tumors (GISTs) most frequently give rise to AS. Systemic chemotherapy is the standard of care for AS from non-GIST sarcomas, but with an essentially palliative aim and major limitations. Innovative targeted therapies has deeply affected the natural history of GIST, at least in prolonging significantly survival in responsive patients. In this context, the notion that abdominal spread in the lack of extra-peritoneal lesions may typically occur in a number of patients, along with the dismal prognosis generally carried by AS, has prompted a few centers to perform cytoreductive surgery and perioperative intraperitoneal chemotherapy. To date, the rarity of these presentations makes it difficult to evaluate the clinical results and the role of combined local-regional treatment is still a matter of debate. This article presents the results of a group of experts from around the World trying to achieve a consensus statement in AS comprehensive management. A questionnaire was placed on the website of the 5th International Workshop on Peritoneal Surface Malignancy and the experts voted via internet.
Journal of Surgical Oncology 10/2008; 98(4):291-4. · 2.10 Impact Factor
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George D Demetri,
Robert S Benjamin,
Charles D Blanke,
Jean-Yves Blay, Paolo Casali,
Haesun Choi,
Christopher L Corless,
Maria Debiec-Rychter,
Ronald P DeMatteo,
David S Ettinger, [......],
Michael Morse,
Alberto S Pappo,
Peter W T Pisters,
Chandrajit P Raut,
Peter Reichardt,
Douglas S Tyler,
Annick D Van den Abbeele,
Margaret von Mehren,
Jeffrey D Wayne,
John Zalcberg
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ABSTRACT: The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST.
Journal of the National Comprehensive Cancer Network: JNCCN 08/2007; 5 Suppl 2:S1-29; quiz S30. · 4.41 Impact Factor
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ABSTRACT: Diffuse malignant peritoneal mesothelioma (DMPM) is a subset of peritoneal mesothelioma with a poor clinical outcome. We performed a prognostic analysis in a cohort of DMPM patients treated homogeneously by cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP).
Forty-nine DMPM patients who underwent 52 consecutive procedures were enrolled onto the study. Cytoreductive surgery was performed according to the peritonectomy technique, and the IPHP was performed with cisplatin plus doxorubicin or cisplatin plus mitomycin C. We assessed the correlation of the clinicopathologic variables (previous surgical score, age, sex, performance status, previous systemic chemotherapy, carcinomatosis extension, completeness of cytoreduction, IPHP drug schedule, mitotic count [MC], nuclear grade, and biological markers [epidermal growth factor receptor, p16, matrix metalloproteinase 2 and matrix metalloproteinase 9]) with overall and progression-free survival.
The mean age was 52 years (range, 22-74 years). The mean follow-up was 20.3 months (range, 1-89 months). Regarding the biological markers, the rates of immunoreactivity of epidermal growth factor receptor, p16, matrix metalloproteinase 2, and matrix metalloproteinase 9 were 94%, 60%, 100%, and 85%, respectively. The strongest factors influencing overall survival were completeness of cytoreduction and MC, whereas those for progression-free survival were performance status and MC. No biological markers were shown to be of prognostic value.
Completeness of cytoreduction, performance status, and MC seem to be the best determinants of outcome. These data warrant confirmation by a further prospective formal trial. No biological markers presented a significant correlation with the outcome. The overexpression of epidermal growth factor receptor, matrix metalloproteinase 2, and matrix metalloproteinase 9 and absent or reduced expression of p16 might be related to the underlining tumor kinetics of DMPM and warrant further investigation with other methods.
Annals of Surgical Oncology 03/2006; 13(2):229-37. · 4.17 Impact Factor
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ABSTRACT: In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors.
Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS).
The patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24-73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0-160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance.
The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics.
Cancer 12/2005; 104(10):2181-8. · 4.77 Impact Factor
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Daisuke Nonaka M.D,
Shigeki Kusamura M.D,
Dario Baratti M.D,
Paolo Casali M.D,
Antonello Domenico Cabras M.D,
Rami Younan M.D,
Juan Rosai M.D,
Marcello Deraco M.D,
Daisuke Nonaka,
Shigeki Kusamura,
Dario Baratti, Paolo Casali,
Antonello Domenico Cabras,
Rami Younan,
Juan Rosai,
Marcello Deraco
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ABSTRACT: BACKGROUND
In the current study, the authors report the clinicopathologic features of patients with peritoneal diffuse malignant mesothelioma (DMM) who were treated in a uniform fashion at a single institution to assess prognostic factors.METHODS
Thirty-five patients were treated with cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). The tumors were classified into epithelial, sarcomatoid, and biphasic types. Immunohistochemistry stains were performed for calretinin, WT-1, pCEA, Ber-EP4, epidermal growth factor receptor (EGFR), p16, matrix metalloprotease-2 (MMP-2), and MMP-9. Statistical correlation was evaluated for age, gender, completeness of cytoreduction (CC), tumor histotype, mitotic count (MC), necrosis, nuclear grade (NG), and biologic markers with regard to overall survival (OS) and progression-free survival (PFS).RESULTSThe patient group was comprised of 15 men and 20 women with a median age of 52 years (range, 24–73 yrs). Twenty-five patients underwent optimal cytoreduction. There were 32 epithelial tumors and 3 biphasic tumors, and 3 patients had an NG of 1, 19 had an NG of 2, and 13 had an NG of 3. The mean MC was 14.1 (range, 0–160 per 50 high-power fields). Necrosis was present in 11 cases. All the tumors were found to be positive for calretinin and WT-1 and were negative for pCEA and Ber-EP4. The NG and MC were found to be significantly associated with OS (P = 0.02 and P = 0.01, respectively) whereas CC was found to be associated with both OS (P = 0.05) and PFS (P = 0.03). No biologic markers were found to be of prognostic significance.CONCLUSIONS
The results of the current study indicate that NG, MC, and CC may be useful prognostic factors in patients treated with CRS and IPHP. The expression of EGFR, MMP-2, and MMP-9 and absent and/or reduced expression of p16 in DMMs confirms the results of previous studies suggesting their role in tumor pathogenesis and kinetics. Cancer 2005. © 2005 American Cancer Society.
Cancer 11/2005; 104(10):2181 - 2188. · 4.77 Impact Factor
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ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. Most of them are thought to be sporadic, but some arise in the settings of neurofibromatosis type I (NF-1) and the Carney triad. The Carney triad is a syndrome of unknown etiology, occurring predominantly in young females, comprising gastrointestinal stromal tumors, pulmonary chondromas, and extra-adrenal paragangliomas. GISTs of the Carney triad involve predominantly the body and the antrum of the stomach, are generally multifocal, and have a better prognosis than sporadic GISTs. We describe the clinical and pathological features of a case of Carney triad that featured multiple gastric GISTs, mediastinal paraganglioma, and esophageal leiomyoma. Ten years after gastric resection, the patient developed liver and peritoneal metastasis and was treated with Imatinib mesylate for 6 months with no change in the lesions. The molecular analysis of the GIST, the first reported in a gastric tumor from the triad, showed a wild-type KIT and PDGFRA genes.
Human Pathlogy 02/2005; 36(1):112-6. · 2.88 Impact Factor
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ABSTRACT: Nature distributed medicine everywhere. - Pliny the Elder, circa AD 77
Purpose of review: The therapeutic pharmacologic armamentarium in sarcoma is limited, and patients with advanced disease have a dismal prognosis. The onset of metastatic disease yields to median survival of 1 year. The identification of new active agents against sarcoma is one of the most important challenges in cancer research.
Recent findings: ET-743 (Yondelis; trabectidin) is a marine-derived cytotoxic bearing an innovative mode of action. An extensive phase II program has confirmed activity and a therapeutic impact in the natural history of patients with advanced pretreated soft tissue sarcoma.
Summary: The results generated in heavily pretreated bone sarcoma warrant further studies in less pretreated cases, and the early data released in Ewing sarcoma warrant further developmental efforts. The ongoing phase I program in combination therapy is expected to bring new paradigmatic models to allow further investigations in sarcoma. The specific correlation between the DNA repair capability and the sensitivity and resistance to ET-743 in experimental models provide a solid foundation to investigate whether such correlates are confirmed at the clinical level to establish further customized therapies to improve the outcome of patients with sarcoma.
Current Opinion in Orthopaedics 11/2003; 14(6):419-428.
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ABSTRACT: Peritoneal mesothelioma (PM) is a rare disease, with a poor prognosis. We decided to prospectively evaluate the prognostic impact of aggressive surgery followed by intraperitoneal chemotherapy with local hyperthermia.
In this prospective study, 19 patients with PM were treated by cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP). Mean follow-up was 27 months (range: 1-65). Fifteen (68%) patients had malignant disease, two had well-differentiated papillary mesothelioma, and two had multicystic PM. Thirteen (65%) patients received preoperative chemotherapy. Fifteen cases (75%) underwent optimal cytoreduction (residual disease <2.5 mm). One patient underwent the procedure twice due to locoregional progression. IPHP was performed with closed abdomen technique, using a preheated polysaline perfusate (42.5 degrees C) containing cisplatin + mitomycin C or cisplatin + doxorubicin administered through a heart-lung pump for 60 or 90 min.
Three-year overall and progression-free survival was 69 and 66%, respectively. The operative morbidity (grade II/III), mortality, and overall toxicity (grade I-IV) rates were 25, 0, and 30%, respectively. Seventeen (94%) out of 18 patients had resolution of ascites.
This therapeutic strategy proved feasible and was well tolerated. Early results seem promising and consistent with a potentially major impact on survival in selected patients with PM.
Journal of Surgical Oncology 08/2003; 83(3):147-53. · 2.10 Impact Factor
