Publications by authors named "Gaetano Apice"

33 Publications

Crosstalk between Macrophages and Myxoid Liposarcoma Cells Increases Spreading and Invasiveness of Tumor Cells.

Cancers (Basel) 2021 Jun 30;13(13). Epub 2021 Jun 30.

Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', 80131 Naples, Italy.

Myxoid liposarcoma (MLPS) is the second most common subtype of liposarcoma and has tendency to metastasize to soft tissues. To date, the mechanisms of invasion and metastasis of MLPS remain unclear, and new therapeutic strategies that improve patients' outcomes are expected. In this study, we analyzed by immunohistochemistry the immune cellular components and microvessel density in tumor tissues from patients affected by MLPS. In order to evaluate the effects of primary human MLPS cells on macrophage polarization and, in turn, the ability of macrophages to influence invasiveness of MLPS cells, non-contact and 3D organotypic co-cultures were set up. High grade MLPS tissues were found heavily vascularized, exhibited a CD3, CD4, and CD8 positive T lymphocyte-poor phenotype and were massively infiltrated by CD163 positive M2-like macrophages. Conversely, low grade MLPS tissues were infiltrated by a discrete amount of CD3, CD4, and CD8 positive T lymphocytes and a scarce amount of CD163 positive macrophages. Kaplan-Meier analysis revealed a shorter Progression Free Survival in MLPS patients whose tumor tissues were highly vascularized and heavily infiltrated by CD163 positive macrophages, indicating a clear-cut link between M2-like macrophage abundance and poor prognosis in patients. Moreover, we documented that, in co-culture, soluble factors produced by primary human MLPS cells induce macrophage polarization toward an M2-like phenotype which, in turn, increases MLPS cell capability to spread into extracellular matrix and to cross endothelial monolayers. The identification of M2-like polarization factors secreted by MLPS cells may allow to develop novel targeted therapies counteracting MLPS progression.
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http://dx.doi.org/10.3390/cancers13133298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268435PMC
June 2021

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

Eur J Cancer 2021 Jul 11;151:150-158. Epub 2021 May 11.

Department of Orthopaedics and Orthopaedic Oncology, University of Padova, Padova, Italy.

Introduction: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study.

Materials And Methods: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models.

Results: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles.

Conclusions: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.
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http://dx.doi.org/10.1016/j.ejca.2021.04.017DOI Listing
July 2021

Inhibiting Monocyte Recruitment to Prevent the Pro-Tumoral Activity of Tumor-Associated Macrophages in Chondrosarcoma.

Cells 2020 04 24;9(4). Epub 2020 Apr 24.

Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS 'Fondazione G. Pascale', Naples 80131, Italy.

Chondrosarcomas (CHS) are malignant cartilaginous neoplasms with diverse morphological features, characterized by resistance to chemo- and radiation therapies. In this study, we investigated the role of tumor-associated macrophages (TAM)s in tumor tissues from CHS patients by immunohistochemistry. Three-dimensional organotypic co-cultures were set up in order to evaluate the contribution of primary human CHS cells in driving an M2-like phenotype in monocyte-derived primary macrophages, and the capability of macrophages to promote growth and/or invasiveness of CHS cells. Finally, with an in vivo model of primary CHS cells engrafted in nude mice, we tested the ability of a potent peptide inhibitor of cell migration (Ac-d-Tyr-d-Arg-Aib-d-Arg-NH, denoted RI-3) to reduce recruitment and infiltration of monocytes into CHS neoplastic lesions. We found a significant correlation between alternatively activated M2 macrophages and intratumor microvessel density in both conventional and dedifferentiated CHS human tissues, suggesting a link between TAM abundance and vascularization in CHS. In 3D and non-contact cu-culture models, soluble factors produced by CHS induced a M2-like phenotype in macrophages that, in turn, increased motility, invasion and matrix spreading of CHS cells. Finally, we present evidence that RI-3 successfully prevent both recruitment and infiltration of monocytes into CHS tissues, in nude mice.
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http://dx.doi.org/10.3390/cells9041062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226304PMC
April 2020

Sarcoma Spheroids and Organoids-Promising Tools in the Era of Personalized Medicine.

Int J Mol Sci 2018 02 21;19(2). Epub 2018 Feb 21.

Department of Biochemistry Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes. Their low incidence and high level of histopathological heterogeneity have greatly limited progress in their treatment, and trials of clinical sarcoma are less frequent than trials of other carcinomas. The main advantage of 3D cultures from tumor cells or biopsy is that they provide patient-specific models of solid tumors, and they overcome some limitations of traditional 2D monolayer cultures by reflecting cell heterogeneity, native histologic architectures, and cell-extracellular matrix interactions. Recent advances promise that these models can help bridge the gap between preclinical and clinical research by providing a relevant in vitro model of human cancer useful for drug testing and studying metastatic and dormancy mechanisms. However, additional improvements of 3D models are expected in the future, specifically the inclusion of tumor vasculature and the immune system, to enhance their full ability to capture the biological features of native tumors in high-throughput screening. Here, we summarize recent advances and future perspectives of spheroid and organoid in vitro models of rare sarcomas that can be used to investigate individual molecular biology and predict clinical responses. We also highlight how spheroid and organoid culture models could facilitate the personalization of sarcoma treatment, provide specific clinical scenarios, and discuss the relative strengths and limitations of these models.
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http://dx.doi.org/10.3390/ijms19020615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855837PMC
February 2018

Confirmed Activity and Tolerability of Weekly Paclitaxel in the Treatment of Advanced Angiosarcoma.

Sarcoma 2016 25;2016:6862090. Epub 2016 Feb 25.

Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Via Mariano Semmola, 80131 Napoli, Italy.

Background. In several prospective and retrospective studies, weekly paclitaxel showed promising activity in patients with angiosarcoma. Patients and Methods. Our study was originally designed as a prospective, phase II multicenter trial for patients younger than 75, with ECOG performance status 0-2, affected by locally advanced or metastatic angiosarcoma. Patients received paclitaxel 80 mg/m(2) intravenously, at days 1, 8, and 15 every 4 weeks, until disease progression or unacceptable toxicity. Primary endpoint was objective response. Results. Eight patients were enrolled but, due to very slow accrual, the trial was prematurely stopped and further 10 patients were retrospectively included in the analysis. Out of 17 evaluable patients, 6 patients obtained an objective response (5 partial, 1 complete), with an objective response rate of 35% (95% confidence interval 17%-59%). Of note, five responses were obtained in pretreated patients. In the paper, details of overall survival, progression-free survival, and tolerability are reported. Conclusions. In this small series of patients with locally advanced or metastatic angiosarcoma, weekly paclitaxel was confirmed to be well tolerated and active even in pretreated patients.
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http://dx.doi.org/10.1155/2016/6862090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785388PMC
March 2016

An unusual association of malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like) and Ewing sarcoma.

Pathol Res Pract 2015 Sep 17;211(9):688-92. Epub 2015 Jun 17.

Department of Pathology, University Hospital of Basel, Switzerland.

Very recently a new designation of "Malignant Neuroectodermal Gastrointestinal Tumor" has been proposed for an aggressive form of neuroectodermal tumor with features similar to that of Clear Cell Sarcoma of Soft Tissue, however without a melanocytic differentiation. Also known as "clear cell sarcoma-like tumors of the gastrointestinal tract", these tumors show some features strongly suggesting an origin from a gastrointestinal neuroectodermal precursor cell unable to differentiate along the melanocytic lineage. They occur mainly in young and middle-aged adults, and have a poor prognosis with a high rate of liver and lymphnode metastases. Histologically they are composed of epithelioid or oval-to spindle cells with a sheet-like or nested pattern of growth, strongly positive for neural markers (S-100, SOX10, and vimentin) and negative for the melanocytic ones. EWSR1 gene rearrangements including EWSR1-ATF1 or EWSR1-CREB1 GENE fusions are typically assessed in these tumors. Here we report a case of malignant neuroectodermal gastrointestinal tumor which immunophenotypically unusually expressed FLI-1, occurring in a 29-year-old man with a previous medical history of Ewing sarcoma. We finally suggest that this case might be a further evidence of a link between these two entities.
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http://dx.doi.org/10.1016/j.prp.2015.06.001DOI Listing
September 2015

Treatment of cutaneous angiosarcoma of the face: efficacy of combined chemotherapy and radiotherapy.

Tumori 2013 Sep-Oct;99(5):e211-5

Introduction: Cutaneous angiosarcoma (AS) is a rare form of soft tissue sarcoma. It is aggressive and has a poor prognosis. The aim of our report is to show that with combined chemotherapy and radiotherapy it is possible to obtain good results in terms of local control, complete response, and aesthetic outcome.

Case Report: We present the case of a 60-year-old man affected by AS covering the entire surface of the nose. Surgery, although indicated, was excluded because it was considered mutilating and would give a poor cosmetic result. The patient was treated with chemotherapy consisting of paclitaxel 80 mg/m2 for 6 cycles followed by radiotherapy at a dose of 50 Gy. Then 3 additional cycles of chemotherapy were administered according to the same scheme. A complete response was obtained. At 40 months after treatment, the patient did not show any signs of late toxicity, all lesions had disappeared, and all laboratory tests were negative.

Conclusions: Our experience shows that concomitant chemoradiotherapy can be delivered safely and can be tolerated with low toxicity and good results in terms of local control and complete response. We obtained an excellent aesthetic result with improvement of the patient's quality of life.
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http://dx.doi.org/10.1700/1377.15317DOI Listing
February 2014

Anthracycline-based chemotherapy in extraskeletal myxoid chondrosarcoma: a retrospective study.

Clin Sarcoma Res 2013 Dec 18;3(1):16. Epub 2013 Dec 18.

Adult Mesenchymal Tumor Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare subgroup within soft tissue sarcomas. Its sensitivity to chemotherapy is reported to be low.

Methods: We retrospectively reviewed a series of 11 EMC patients treated as from 2001 within the Italian Rare Cancer Network (RCN) with anthracycline-based chemotherapy. Pathologic diagnosis was centrally reviewed in all cases and confirmed by the presence of the specific chromosomal rearrangements, involving the NR4A3 gene locus on chromosome 9.

Results: Eleven patients treated with anthracycline-based chemotherapy were included (M/F: 9/2 - mean age: 52 years - site of primary: lower limb/other = 9/2 - metastatic = 11 - front line/ further line = 10/1 - anthracycline as single agent/ combined with ifosfamide = 1/10). Ten patients are evaluable for response. Overall, best response according to RECIST was: partial response (PR) = 4 (40 %), stable disease (SD) = 3, progressive disease (PD) = 3 cases. Median PFS was 8 (range 2-10) months.

Conclusions: By contrast to what reported so far, anthracycline-based chemotherapy is active in a distinct proportion of EMC patients.
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http://dx.doi.org/10.1186/2045-3329-3-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879193PMC
December 2013

Ex vivo behaviour of human bone tumor endothelial cells.

Cancers (Basel) 2013 Apr 11;5(2):404-17. Epub 2013 Apr 11.

SDN-Foundation, Institute of Diagnostic and Nuclear Development, IRCCS, 80143 Naples, Italy.

Cooperation between endothelial cells and bone in bone remodelling is well established. In contrast, bone microvasculature supporting the growth of primary tumors and metastasis is poorly understood. Several antiangiogenic agents have recently been undergoing trials, although an extensive body of clinical data and experimental research have proved that angiogenic pathways differ in each tumor type and stage. Here, for the first time, we characterize at the molecular and functional level tumor endothelial cells from human bone sarcomas at different stages of disease and with different histotypes. We selected a CD31+ subpopulation from biopsies that displayed the capability to grow as adherent cell lines without vascular endothelial growth factor (VEGF). Our findings show the existence in human primary bone sarcomas of highly proliferative endothelial cells expressing CD31, CD44, CD105, CD146 and CD90 markers. These cells are committed to develop capillary-like structures and colony formation units, and to produce nitric oxide. We believe that a better understanding of tumor vasculature could be a valid tool for the design of an efficacious antiangiogenic therapy as adjuvant treatment of sarcomas.
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http://dx.doi.org/10.3390/cancers5020404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730325PMC
April 2013

Hyperexpression of HOXC13, located in the 12q13 chromosomal region, in well‑differentiated and dedifferentiated human liposarcomas.

Oncol Rep 2013 Dec 1;30(6):2579-86. Epub 2013 Oct 1.

Division of Pathology, Istituto Nazionale Tumori 'Fondazione G. Pascale'-IRCCS, 80131 Naples, Italy.

Liposarcoma (LPS) is the most common soft tissue neoplasm in adults and is characterized by neoplastic adipocyte proliferation. Some subtypes of LPSs show aberrations involving the chromosome 12. The most frequent are t(12;16) (q13;p11) present in more than 90% of myxoid LPSs and 12q13-15 amplification in well-differentiated and dedifferentiated LPSs. In this region, there are important oncogenes such as CHOP (DDIT3), GLI, MDM2, CDK4, SAS, HMGA2, but also the HOXC locus, involved in development and tumor progression. In this study, we evaluated the expression of HOXC13, included in this chromosomal region, in a series of adipocytic tumors. We included 18 well-differentiated, 4 dedifferentiated, 11 myxoid and 6 pleomorphic LPSs as well as 13 lipomas in a tissue microarray. We evaluated the HOXC13 protein and gene expression by immunohistochemistry and quantitative PCR. Amplification/translocation of the 12q13-15 region was verified by FISH. Immunohistochemical HOXC13 overexpression was observed in all well-differentiated and dedifferentiated LPSs, all characterized by the chromosome 12q13-15 amplification, and confirmed by quantitative PCR analysis. In conclusion, our data show a deregulation of the HOXC13 marker in well‑differentiated and dedifferentiated LPSs, possibly related to 12q13-15 chromosomal amplification.
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http://dx.doi.org/10.3892/or.2013.2760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839951PMC
December 2013

Platelet gel in cutaneous radiation dermatitis.

Support Care Cancer 2013 Jan 13;21(1):287-93. Epub 2012 Nov 13.

Transfusion Service, Department of Haematology, Istituto Nazionale Tumori-Fondazione G. Pascale, Naples, Italy.

Introduction: Radiotherapy, alone or in combination with chemotherapy and/or surgery, is a fundamental and irreplaceable method of treating tumours. Nonetheless, although the technological advances made during recent years and the associated improvements in this type of treatment have reduced the incidence of complications, 5-15 % of patients still experience damage to the healthy tissues exposed to radiation. Cutaneous and mucosal lesions are severe collateral effects of radiotherapy that have an enormous impact on a patient's quality of life. Unfortunately, however, the efficacy of conventional treatments, while demonstrably useful in acute lesions, remains disputed in chronic cases. Nevertheless, numerous studies and clinical findings have demonstrated that topical, non-transfusional plasma-rich platelet gel is able to accelerate the regeneration and repair of tissues through the action of the various growth factors contained within the alpha granules of platelets. We therefore set out to evaluate the efficacy of autologous platelet gel, chosen for its limited cost and ease of preparation, in chronic cutaneous radiation dermatitis.

Methods: "Home-made" platelet gel was produced by treating platelets with autologous thrombin. The safety of the product was ensured by microbiological tests. The autologous platelet gel was applied topically once a week, for a mean duration of 35 days, to chronic third- and fourth-degree (European Pressure Ulcer Advisory Panel classification and Common Terminology Criteria for Adverse Events score) cutaneous radiation dermatitis in a group of ten patients previously treated for moderate-to-high grade (histology G2-G3) limb sarcoma by tumour excision and post-surgical radiotherapy (dose 50-64 Gy). The radiation dermatitis had appeared at different intervals after treatment and had all proved resistant to conventional treatments.

Results: The autologous platelet gel was found to be successful in seven out of the ten patients treated. The various phases of the healing process were observed in all cases. Platelet gel application was suspended in three patients: in one patient after one application due to tumour progression, in another patient after two applications due to development of distant metastases and in the third after six applications with only partial tissue response. At 5-year follow-up, six of the seven successfully treated patients remained free of both disease and lesion, while the remaining patient, the eldest, had passed away in the interim due to extraneous causes.

Conclusion: Platelet gel treatment could therefore be used to bring about healing in chronic cutaneous radiation dermatitis, lending itself to better patient compliance and a favourable cost/benefit ratio, due to a reduction in the number of medications and hospital visits required.
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http://dx.doi.org/10.1007/s00520-012-1635-0DOI Listing
January 2013

Fine-needle cytology of Kaposi's sarcoma in an intramammary lymphnode: report of one case.

Diagn Cytopathol 2012 Aug 27;40 Suppl 2:E149-52. Epub 2012 Mar 27.

S.S.D. di Citopatologia, A.F. di Anatomia Patologica e Citopatologia, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.

Kaposi's sarcoma (KS) is the most common human immunodeficiency virus (HIV) infection disease-associated malignancy. It consists of an angiosarcomatous change of the epithelial and mucous membrane-associated connective tissue not only in various sites, for example, skin, gastrointestinal system, lungs, and so on, but may also involve nonepithelial organs, such as lymphnodes. An unusual localization of KS to an intramammary lymphnode is reported here. The patient, an HIV-negative 69-year-old woman with a clinical history of rheumatoid arthritis treated with hydrocortisone, had an 8-month pathological history of biopsy-proven Kaposi sarcoma of the skin with visceral extension (stomach and duodenum). The appearance of a well-defined 23 × 20 mm(2) breast nodule during chemotherapy elicited fine-needle cytology to exclude breast carcinoma. Surgical excision confirmed the cytopathological diagnosis of Kaposis's sarcoma.
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http://dx.doi.org/10.1002/dc.21783DOI Listing
August 2012

YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma.

BMC Cancer 2011 Nov 2;11:472. Epub 2011 Nov 2.

Department of General Pathology, Division of Clinical Pathology and U.O.C. Immunohematology, Second University of Naples, 80138 Naples, Italy.

Background: The polycomb transcription factor Yin Yang 1 (YY1) overexpression can be causally implicated in experimental tumor growth and metastasization. To date, there is no clinical evidence of YY1 involvement in outcome of patients with osteosarcoma. Prognosis of osteosarcoma is still severe and only few patients survive beyond five years. We performed a prospective immunohistochemistry analysis to correlate YY1 immunostaining with metastatic development and survival in a selected homogeneous group of patients with osteosarcoma.

Methods: We studied 41 patients suffering from osteosarcoma (stage II-IVa). Multivariate analysis was performed using Cox proportional hazard regression to evaluate the correlation between YY1 expression and both metastasis development and mortality.

Results: YY1 protein is not usually present in normal bone; in contrast, a high number of patients (61%) showed a high score of YY1 positive cells (51-100%) and 39% had a low score (10-50% positive cells). No statistical difference was found in histology, anatomic sites, or response to chemotherapy between the two degrees of YY1 expression. Cox regression analysis demonstrated that the highest score of YY1 expression was predictive of both low metastasis-free survival (HR = 4.690, 95%CI = 1.079-20.396; p = 0.039) and poor overall survival (HR = 8.353, 95%CI = 1.863-37.451 p = 0.006) regardless of the effects of covariates such as age, gender, histology and chemonecrosis.

Conclusion: Overexpression of YY1 in primary site of osteosarcoma is associated with the occurrence of metastasis and poor clinical outcome.
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http://dx.doi.org/10.1186/1471-2407-11-472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240836PMC
November 2011

The use of veritas collagen matrix to reconstruct the posterior chest wall after costovertebrectomy.

Ann Thorac Surg 2011 Jul;92(1):e17-8

Department of Thoracic Surgery and Services of Neurosurgery, Orthopaedic and Plastic Surgery and Sarcoma Team, National Cancer Institute, Pascale Foundation, Naples, Italy.

Among the new materials introduced for chest wall reconstruction, the use of collagen matrix is gaining increasing favor for its biomechanical properties. We describe the reconstruction of the chest wall with Veritas (Synovis, St Paul, MN) collagen matrix of a posterior chest wall defect after costovertebrectomy for Ewing's sarcoma. En bloc resection was performed, including partial D7 through D9 vertebrectomy along with the posterolateral segments of corresponding ribs. The collagen matrix patch was sutured to the spine stabilizer and the surrounding rib segments and was covered by previously raised latissimus dorsi and trapezius muscle flaps. Excellent stabilization was obtained.
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http://dx.doi.org/10.1016/j.athoracsur.2011.02.080DOI Listing
July 2011

Involvement of the soluble urokinase receptor in chondrosarcoma cell mobilization.

Sarcoma 2011 30;2011:842842. Epub 2010 Dec 30.

Department of Experimental Oncology, National Cancer Institute of Naples, Via Mariano Semmola 1, 80131 Naples, Italy.

High levels of urokinase receptor (uPAR) in tissue and serum of patients with chondrosarcoma correlate with poor prognosis. First, we analyzed the uPAR levels in tissues and plasma of five patients affected by chondrosarcoma. Interestingly, very high levels of uPAR and its soluble forms (SuPAR) were found on tumor cell surfaces and plasma, respectively, of two patients with lung metastases. Therefore, to investigate the role of SuPAR in chondrosaromas, we generated a primary cell culture from a chondrosarcoma tissue overexpressing uPAR on cell surfaces. We found that chondrosarcoma-like primary culture cells release a large amount of SuPAR in the medium. In vitro, SuPAR elicits chondrosarcoma cell migration likely through its uPAR(88-92) sequence, since the DII(88-183) or DIIDIIR(88-284) uPAR domains retain motogen effect whereas DI(1-87) or DIII(184-284) domains, both lacking the uPAR(88-92) sequence, are ineffective. Chondrosarcoma cells cross matrigel in response to SuPAR, and their invasion capability is abrogated by RERF peptide which inhibits uPAR(88-92) signalling. These findings assign a role to uPAR in mobilizing chondrosarcoma cells and suggest that RERF peptide may be regarded as a prototype to generate new therapeutics for the chondrosarcoma treatment.
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http://dx.doi.org/10.1155/2011/842842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021884PMC
July 2011

Intracardiac metastasis originated from chondrosarcoma.

J Cardiovasc Med (Hagerstown) 2017 May;18(5):385-388

aCardiology Division Institute bDepartment of Colorectal Oncology, National Cancer Institute G. Pascale Foundation cDepartment of Public Health, Section of Pathology, Second University of Naples, Naples, Italy.

Primary cardiac tumors are extremely rare. By comparison, metastatic involvement of the heart is over 20 times more common and has been reported in autopsy series in up to one in five patients dying of cancer. Cardiac metastasis of chondrosarcoma is absolutely not frequent. In the recent literature, a cardiac metastasis from chondrosarcoma has never been described. We report the case of an 18-year-old man with a diagnosis of cardiac metastasis that originated from a left scapular chondrosarcoma. Chondrosarcoma is a skeletal tumor with various grades of malignancy, rapidly evolving, and with a strong tendency to metastasize, with low responsiveness to chemotherapy. The onset of characteristic systemic symptoms in the late stage of the disease led to the diagnosis of a mass localized in the right atrium. Management and differential diagnosis of infective heart lesions were also very complex in a rapidly evolving life-threatening condition.
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http://dx.doi.org/10.2459/JCM.0b013e32834165ebDOI Listing
May 2017

Axial chordoma and parachordoma (soft tissue chordoma): two of a kind: report of two cases with primary diagnosis on fine-needle cytology samples.

Diagn Cytopathol 2011 Jul 20;39(7):475-81. Epub 2010 Aug 20.

S.S.D. di Citopatologia, A.F. di Anatomia Patologica, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.

This report concerns one case of sacrococcygeal chordoma and one case of parachordoma (soft-tissue chordoma) that were primarily diagnosed on fine-needle cytology (FNC) samples. Both neoplasms consisted of medium-sized epithelioid cells with eccentric, nucleolated nuclei, displaying abundant cytoplasm filled with bubbly vacuoles with refractile borders (physaliphorous cells). The neoplastic cells were embedded in an abundant extracellular substance staining metachromatically with Diff-Quik™. Both neoplasms had a typical clinical and instrumental presentation (primary sacrococcygeal tumor in a 58-year-old man and primary soft tissue mass of the hand palm and wrist in a 31-year-old man). The cytopathological findings in both the neoplasms were so similar as to be almost indistinguishable, and this similarity included the immunocytochemical findings. The deep similarity between these neoplasms indicates that the only pathological differences in the described cases probably reside in their different anatomical location and, perhaps, in different cytogenetic changes.
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http://dx.doi.org/10.1002/dc.21412DOI Listing
July 2011

Primary giant clear cell sarcoma (soft tissue malignant melanoma) of the sternum.

Ann Thorac Surg 2009 Jun;87(6):1927-8

Department of Thoracic Surgery and Oncology, National Cancer Institute, Pascale Foundation, IRCCS, Naples, Italy.

One case of a primary clear cell sarcoma of the sternum (also called soft tissue melanoma) is reported. This neoplasm represents a rare occurrence, and as a rule, differential diagnosis with melanoma often requires detailed immunohistochemistry and cytogenetic analysis (ie, rearrangement of EWS gene localized on 22q12 chromosome). Because wide resection is recommended, chest wall reconstruction may pose challenging technical issues. In our patient, we elected not to proceed to clavicular stabilization. Nevertheless, acceptable shoulder girdle mobility was observed after surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2008.10.077DOI Listing
June 2009

Fine needle aspiration of metastatic epithelioid angiosarcoma: a report of 2 cases.

Acta Cytol 2008 Sep-Oct;52(5):612-8

Cytopathology Service, Section of Pathology, Department of Surgery, National Cancer Center, Fondazione G. Pascale, Naples.

Background: Epithelioid angiosarcomas (EAs) are uncommon mesenchymal tumors occurring in the thyroid, deep-seated soft tissues, parenchymal organs and, more rarely, superficial soft tissues of the head and neck. Due to their cytologic and immunocytochemical presentation on fine needle aspiration cytology (FNAC) samples, these neoplasms may closely mimic a number of different tumors, potentially causing an erroneous cytopathologic diagnosis unless immunophenotypical markers of vascular differentiation are sought in the cellular material.

Cases: A 68-year-old man with a 1-year history of total thyroidectomy for EA presented with a suspicious right neck node and underwent FNA. A 63-year-old woman with a history of recurring multiple scalp nodules diagnosed as EA ultimately developed small multiple, bilateral lymph nodes in the neck and underwent FNA. In both cases a cytopathologic diagnosis of metastatic EA was made.

Conclusion: The cytopathologic diagnosis of EA is a challenge. Knowledge of the clinical history is of great help in diagnosing metastatic lesions. The cytopathologicpicture of metastases is a useful way for cytopathologists to gain confidence with presentaton of this rare entity in primary sites on FNAC samples. Cytopathologic hints of vascular differentiation should be sought in the cytopathologic material when a diagnosis of EA is entertained.
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http://dx.doi.org/10.1159/000325607DOI Listing
November 2008

Cell invasiveness in sarcomas: a possibly useful clinical correlation.

Tumori 2008 Jul-Aug;94(4):505-10

Department of Experimental Oncology, National Cancer Institute of Naples, Naples, Italy.

Aims And Background: The prognosis of each individual patient affected by sarcoma, including those with low histopathologic grading, cannot be reliably predicted at the time of surgery. We have developed an in vitro cell invasion assay on early primary cell cultures derived from surgically removed sarcomas.

Methods: Primary cell cultures were subjected to in vitro cell invasion assays by using Boyden chambers, filters coated with matrigel and fetal bovine serum as a source of chemoattractant. For each primary cell culture, the sarcoma cell invasion index was determined in comparison with the percentage of human fibrosarcoma HT1080 cell invasion extent. The cell invasion index of 7 different sarcomas was evaluated in respect to the outcome of the disease, after a follow-up ranging from 14 to 48 months.

Results: Data evidenced that a low cell invasion index (39.7% +/- 8.9) was retained by tumor cells derived from patients with no progression of the disease and with a longer interval of disease-free survival (21 +/- 0.8 months). However, an increase in cell invasion index (61% +/- 5) was retained by tumor cells derived from patients with progression of the disease and with a shorter disease-free survival (9 +/- 3 months). Overall, although only 7 cases were analyzed, a statistically significant correlation was found between disease-free survival and cell invasion index (P = 0.003).

Conclusions: Our data support the possibility that cell invasion assays performed in vitro on cells derived from human sarcomas may be predictive of a more aggressive form of the disease.
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October 2008

Malignant glomus tumour: a case report and review of the literature.

Sarcoma 2003 ;7(2):87-91

Department of Pathology Istituto dei Tumori di Napoli ‘G. Pascale’ di Napoli Via M. Semmola Napoli 80131 Italy.

Purpose: Glomus tumours are characteristically benign solitary tumours. At our knowledge, about 23 reports are present in literature regarding the malignant counterpart, but only a minority developed metastases. We describe a locally aggressive glomus tumour with lymphnode metastasis.

Patient: The patient was a 40 year-old man presenting a 1.5-cm lesion on the right wrist incompletely excised and a recurrent tumour, 4 x 2 cm in size, removed after 9 months, for which he received radiotherapy. After 2 years he developed an axillary lymphnode metastasis.

Results: Histologically, both tumours (primary and metastasis) were similar. There were sheets and nests of uniform small cells with scant eosinophilic cytoplasm and round to polygonal nuclei; there was some degree of pleomorphism and the mitotic index was high (up to 18 m/10 HPF). The tumour cells were positive for vimentin and smooth muscle actin, but negative for desmin, NSE, Factor VIII, chromogranin, cytokeratin. Remarkably, in the primary, the cells strongly expressed p53 (70%) and MIB-1 (35%).

Discussions: In many reported malignant cases, the histology of the tumour cells suggested that they were malignant, yet the clinical course has been benign. Carefully reviewing the literature, it seems that actually we have enough histological criteria to identify the cases with biological adverse outcome. Those unfortunate cases behave as high grade sarcomas and therefore may deserve an aggressive therapeutic treatment.
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http://dx.doi.org/10.1080/1357714031000081207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395518PMC
July 2011

Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives.

Rev Recent Clin Trials 2006 Jan;1(1):35-42

Istituto Nazionale Tumori, Fondazione G. Pascale, Via M. Semmola, 80131 Napoli, Italy.

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.
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http://dx.doi.org/10.2174/157488706775246175DOI Listing
January 2006

Expression of transcription factor Yin Yang 1 in human osteosarcomas.

Eur J Cancer 2006 Oct 7;42(15):2420-4. Epub 2006 Sep 7.

Department of General Pathology, Division of Clinical Pathology, 1st School of Medicine, II University of Naples, Italy.

The transcription factor Yin Yang 1 (YY1) is known to be present in some human cancer cell lines and its expression correlates with immune-mediated apoptosis. By using Western blot analysis, we have shown that the YY1 protein is strongly expressed in human osteosarcoma cells and localised mainly in the nucleus. Moreover, by using immunohistochemistry and RT-PCR techniques, we have analysed the expression of YY1 protein in biopsies from human osteosarcomas. The YY1 protein was not detectable by immunohistochemistry in osteoid tissue. However, its expression was restricted to osteosarcoma tissues. These data were confirmed by densitometric analysis of RT-PCR for YY1 expression. Thus, YY1 gene activation appears to be an early event in the process of osteoblastic transformation and its detection may represent, together with the analysis of other established markers, a useful diagnostic tool in human osteosarcomas.
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http://dx.doi.org/10.1016/j.ejca.2006.06.008DOI Listing
October 2006

Adjuvant treatment of high-risk adult soft tissue sarcomas: a survey by the Italian Sarcoma Group.

Tumori 2006 Mar-Apr;92(2):92-7

Department of Medical Oncology, National Cancer Institute, Aviano.

Aims And Background: After the first adjuvant study on adult soft tissue sarcomas was concluded, the participating institutions continued to select and treat patients according to that protocol. The aim of this study was to test the protocol reproducibility when applied as a standard practice.

Methods: A call for retrospective data was launched in June 1999 (self-referral of consecutive unregistered patients); thereafter, a prospective follow-up was performed. The treatment regimen consisted of epirubicin (60 mg/m2 days 1 and 2), ifosfamide (3 g/m2/die for 3 days) and equimolar doses of 6-mercapto-ethansulfonate (MESNA), with 300 microg G-CSF administered subcutaneously from day +8 until recovery, every 3 weeks for a total of 5 cycles.

Results: From November 1996 to June 1999, 55 high-risk, adult patients were treated. The average median dose intensity was 89% of the planned program. Grade 3-4 toxicities were leukopenia (49%), thrombocytopenia (14%), transfusion requiring anemia in 7 patients (16%), and alopecia in all patients (100%). After a median follow-up of 70 months, 23 patients (41.8%) relapsed and 19 died. Median disease-free, local disease-free and overall survival rates have not yet been reached. The disease-free survival rates at 2 and 4 years were 73% and 57%, respectively; the corresponding overall survival rates were 91% and 70%, respectively.

Conclusions: The feasibility and reproducibility of the original protocol were confirmed, since disease-specific overall survival and disease-free survival rates at the same period of observation and with the same prolonged follow-up did not differ.
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June 2006

New emerging drugs in soft tissue sarcoma.

Crit Rev Oncol Hematol 2006 Jul 13;59(1):74-84. Epub 2006 Mar 13.

Istituto Nazionale Tumori, Fondazione G. Pascale, Via M. Semmola, 80131 Napoli, Italy.

Doxorubicin and ifosfamide are the two most active drugs in the treatment of patients with advanced, soft tissue sarcoma (STS) of most histologic subtypes, aside from gastrointestinal stromal tumor (GIST). However, after failure of these drugs, alone or in combination, patients with advanced STS have few therapeutic options and the search for new active drugs is well worth pursuing. ET-743, a DNA minor groove binder, which blocks cell cycle progression in G2/M phase through a p53-independent apoptotic process, represents the most promising among novel compounds in STS, since recently completed phase II trials have consistently shown high survival, in spite of the relatively low incidence of major objective responses. The potential for combination with other active compounds further increases the appeal of ET-743. Imatinib mesylate is being tested also in STS other than GIST, which can overexpress one or more of the tyrosine kinases inhibited by imatinib; however, negative data have recently been presented. Clinical studies with a number of other compounds are ongoing or planned. However, investigators involved in the management of patients with advanced STS are to be increasingly aware of the emergence of new molecular targets and genetic profiles in different histologic subtypes, according to which treatment strategies should be adapted.
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http://dx.doi.org/10.1016/j.critrevonc.2005.12.002DOI Listing
July 2006

Biological prognostic factors in adult soft tissue sarcomas.

Anticancer Res 2005 Nov-Dec;25(6C):4519-26

Division of Immunology, National Cancer Institute, G. Pascale Foundation, via Mariano Semmola, 80131, Naples, Italy.

Adult soft tissue sarcomas (STSs) are a rare group of highly heterogeneous neoplasms arising in different tissues. They are locally aggressive and can produce recurrence and distant metastasis. The most common metastatic sites are lung, lymph nodes, liver, bone and soft tissues. Staging for STSs has been based on some prognostic information: grade (low vs. intermediate/high grade), size (small vs. large tumors), depth of infiltration (superficial vs. deep neoplasms) and presence or not of distant metastasis. In the last 10 years, a plethora of new markers (proliferation markers and DNA alteration, P-gp, p53, TLS-CHOP, cyclins, survivin, TERT, PAX3-PAX7/FKHR, SYT-SSX1/2, VEGF, E-cadherin and beta-catenin, nm23, SKP-2, p27, CD40) has been studied with regard to their role in promoting progression (in a laboratory setting) and then determining prognosis and therapy (in a clinical setting). In the present survey, we focused on the role of new biological prognostic factors in STSs and also reported the quality of such studies with an ad hoc designed questionnaire.
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January 2006

Primary gastrointestinal stromal tumor of the liver with lung metastases successfully treated with STI-571 (imatinib mesylate).

Front Biosci 2006 Jan 1;11:498-501. Epub 2006 Jan 1.

UOC Pathology, Istituto dei Tumori G. Pascale, Naples, Italy.

We report a case of a primary malignant GIST of the liver metastatic to the lung in a 37 years-old man. The liver tumor showed histological feature of a GIST and expressed vimentin, and diffusely exhibited CD117. One year after the resection of the liver mass, the patient developed multiple small lung metastases which completely disappeared with STI-571 (imatinib mesylate--Gleevec) therapy. C.T. or PET did not show any mass in the abdomen. These findings suggest that the liver mass was a primary rather than a metastatic tumour. They also support the hypothesis that GIST could originate from undifferentiated mesenchymal cells capable to differentiate toward a pacemaker cell phenotype, which are present in sites other than the G.I. tract.
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http://dx.doi.org/10.2741/1813DOI Listing
January 2006

Prognostic value of CD40 in adult soft tissue sarcomas.

Clin Cancer Res 2004 Apr;10(8):2824-31

Division of Medical Oncology B, National Cancer Institute, Naples, Italy.

Purpose: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value.

Experimental Design: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with chi(2) test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases.

Results: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in <10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in >50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in >50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26-6.60) and 6.92 (95% confidence interval: 2.18-22.0), respectively.

Conclusions: These data suggest that expression of CD40 protein in >50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.
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http://dx.doi.org/10.1158/1078-0432.ccr-0139-03DOI Listing
April 2004

In vitro and in vivo expression of somatostatin receptors in intermediate and malignant soft tissue tumors.

Anticancer Res 2003 May-Jun;23(3B):2465-71

National Institute for Cancer Research, Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genova, Italy.

Background: Previous studies showed that the subtype 2 of somatostatin receptors (sstr2) is generally expressed by soft tissue sarcomas.

Materials And Methods: Using reverse transcription-polymerase chain reaction (RT-PCR), the present study evaluated the expression of sstr mRNA in 31 human intermediate and malignant soft tissue tumors. In 8 patients somatostatin receptor scintigraphy was performed to detect soft tissue tumor sites and visualize in vivo sstr expression.

Results: Somatostatin receptors were identified in 84% of the tumors analyzed by RT-PCR analysis. sstr1 and sstr2 were the receptors most frequently detected. Somatostatin receptor scintigraphy was able to identify primary and/or metastatic sites in 7 out of 8 patients, with an overall sensitivity per site of 87%. Concordant results were found between in vitro and in vivo techniques.

Conclusion: The wide expression of sstrs in soft tissue tumors suggest a relevant role for these receptors in diagnosis and may have therapeutic applications.
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August 2003
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