Publications (13)35.55 Total impact
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Article: Characterization of a New Human Cell Line (CH-3573) Derived from a Grade II Chondrosarcoma with Matrix Production.
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ABSTRACT: Chondrosarcomas are malignant cartilage-forming tumors that represent the third most common malignant solid tumor of bone. In patients with grades II and III, local recurrence, increasing tumor size and dedifferentiation have been associated with lower survival rates. These biologically poorly-understood neoplasms vary considerably in clinical presentation and biological behavior. Cytogenetic studies have shown that heterogeneity is related to karyotypic complexity; moreover, alterations in the 9p21 locus and TP53 gene are related to disease progression. Despite the relatively high frequency of chondrosarcoma only a limited number of cell lines exist in the scientific community, limiting the possibility to study hypothesis-derived research or primary drug interaction necessary for pre-clinical studies. We report a chondrosarcoma cell line, CH-3573, derived from a primary tumor that may serve as a useful tool for both in vitro and in vivo models to study the molecular pathogenesis. In addition, xenograft passages in nude mice were studied to characterize the genetic stability over the course of tumor progression. In contrary to other reported cell lines, an important feature of our established cell line was the retained matrix production, a characteristic feature of a conventional grade II chondrosarcoma. The cell line (CH-3573) was characterized by pathological, immunohistochemical and molecular genetic methods.Pathology & Oncology Research 02/2012; 18(4):793-802. · 1.37 Impact Factor -
Article: Superficial Ewing's sarcoma family of tumors: a clinicopathological study with differential diagnoses.
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ABSTRACT: Superficial/cutaneous Ewing's sarcoma family of tumors (ESFT) are rare and have a relatively favorable prognosis compared with deep-seated tumors. The aim of the present study is to describe the clinicopathological characteristics of six genetically confirmed ESFT presenting a superficial location. Clinical data, radiology, histopathology, immunohistochemistry, molecular study [reverse transcriptase-polymerase chain reaction (RT-PCR)/fluorescence in situ hybridization], treatment and follow-up data were retrieved. Locations included fingers (2), back (1), neck (1), thigh (1) and subcutaneous breast (1). Two tumors showed conventional morphology, one consisted of primitive neuroectodermal tumor and three tumors showed atypical vascular morphology with hemosiderin deposition and pigmentation. All cases showed CD99, FLI-1, HNK-1 and CAV-1 positivity. RT-PCR revealed the EWS/Fli1 gene fusion in all cases. Treatment was by wide excision in all cases; one received chemotherapy (CT) and one CT and radiotherapy. Available follow-up revealed the following: two patients with metastasis and death at 5 months and 2 years and one local recurrence at 18 years. Superficial ESFT appears to have a relatively favorable prognosis but further studies with additional series, a larger number of cases and more extensive follow-up are necessary to confirm this statement.Journal of Cutaneous Pathology 06/2011; 38(8):636-43. · 1.56 Impact Factor -
Article: Clinicopathological significance of cell cycle regulation markers in a large series of genetically confirmed Ewing's sarcoma family of tumors.
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ABSTRACT: More than 90% of all Ewing's Sarcoma Family of Tumors (ESFT) exhibit specific chromosomal rearrangements between the EWS gene on chromosome 22 and various members of the ETS gene family of transcription factors. The gene fusion type and other secondary genetic alterations, mainly involving cell cycle regulators, have been shown to be of prognostic relevance in ESFT. However, no conclusive results have been reported. We analyzed the clinicopathological significance of relevant cell cycle regulators in genetically confirmed ESFT. A total of 324 cases were analyzed for the immunohistochemical expression of p53, p21(Waf1/Cip1) , p27(Kip1) and Ki67 and the chromosomal alterations of the p53 and 9p21 locus by fluorescent in situ hybridization. We observed that expression of p53 (p = 0.025), p21(Waf1/Cip1) (p = 0.015) and p27(Kip1) (p = 0.013) was higher in disseminated than in localized disease. Furthermore, a cohort of 217 patients with localized disease was considered for studying the prognosis involvement of these factors on patient follow-up. The median follow-up was 39 months (range: 0.17-452) with an overall survival (OS) of 55%. Ki67 was expressed in 34% of cases and constituted an independent prognostic factor for progression free survival and OS independently of the type of treatment [hazard ratio of 2.0 (95% CI: 1.3-3.1; p = 0.003) and 1.9 (95% IC: 1.3-2.9; p = 0.007) for progression free survival and OS, respectively, being especially relevant in the group of patients which incorporated radiotherapy in their regimen schedules. In conclusion, this study demonstrates that Ki67 expression constitutes a valuable indicator of poor prognosis in localized ESFT.International Journal of Cancer 03/2011; 128(5):1139-50. · 5.44 Impact Factor -
Article: Evaluation of prognostic factors and their capacity to predict biological behavior in gastrointestinal stromal tumors.
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ABSTRACT: Gastrointestinal stromal tumors (GISTs) are c-KIT-signaling-driven mesenchymal tumors of the human digestive tract, many of which have c-KIT or PDGFRα activating mutations. The authors studied the immunohistochemical markers, c-KIT and PDGFRα mutations, in GISTs and their association with the clinicopathological and clinical follow-up in 145 GISTs. Tumors were located mainly in the stomach, the median tumor size being 7.5 cm. The mitotic index was ≤5 mitoses per 50 high-power fields in 61% of cases, 96% expressed CD117, and c-KIT or PDGFRα mutations were detected in 68% of cases. The median follow-up of the series was 52 months (range = 1 to 244.9 months). Tumor size, cell morphology, mitotic index, incomplete resection, Fletcher's risk classification, Ki-67 overexpression, and c-KIT mutations were associated with progression-free survival. Incomplete resection and mitotic activity also provide information about overall survival. In conclusion, complete clinicopathological, immunohistochemical, and genetic descriptions are necessary to characterize this disease and optimize its clinical management.International Journal of Surgical Pathology 03/2011; 19(4):448-61. · 1.00 Impact Factor -
Article: Clinical significance of tumor protein D52 immunostaining in a large series of Ewing's sarcoma family of tumors.
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ABSTRACT: Abstract.Pediatric and Developmental Pathology 02/2011; 14(3):255-6. · 0.99 Impact Factor -
Article: The epithelial mesenchymal transition process in wilms tumor: a study based on a xenograft model.
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ABSTRACT: Until now, only a few mouse-transplanted human tumors or experimental Wilms tumor (WT) cell lines have been described. The aim of this study was to show the biological behavior, including histology, immunohistochemistry (IHC), and molecular biology, of a WT including the original tumor and metastasis transferred into nude mice and followed for successive generations in xenografts. A WT metastasis was xenotransplanted into nude mice and the mice was monitored for 7 passages over a period of 29 months; the original neoplasm was comparatively studied. The morphology was evaluated by optical and electron microscopy. The protein expression was analyzed by immunohistochemistry in whole sections and in tissue microarray. The molecular studies were carried out by multiplex ligation-dependent probe amplification and polymerase chain reaction analysis. The histology changed markedly between the fourth and fifth transfer. The tumor exhibited an increased epithelial component (>40%) together with a slowing in the growth rate (8 mo). An epithelial-mesenchymal transition seemed to take place in the fourth passage and increased thereafter. The genetic studies also showed a WT5 deletion and a MYCN gain in all the tumor samples in passage 4 and beyond, but did not show E-cadherin, β-catenin, and APC mutations. An epithelial pattern was associated with slow tumor growth, whereas the predominance of mesenchymal spindle cells with striated muscle cell differentiation was related with a high growth rate. The in vivo reorganization of the tumor components (blastemal, epithelial, and mesenchymal) does not seem to be related with the Wnt and EMT pathways.Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 01/2011; 19(4):369-75. · 1.63 Impact Factor -
Article: The many faces of atypical Ewing's sarcoma. A true entity mimicking sarcomas, carcinomas and lymphomas.
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ABSTRACT: Ewing's sarcoma family of tumours (ESFT) comprises a group of small round cell tumours (SRCT) genetically defined by specific chromosomal translocations resulting in a fusion of the EWSR1 gene with a member of the ETS family of transcription factors. Atypical ESFT are the most challenging of the ESFT subtypes, and the differential diagnosis with other SRCT of bone and soft tissue is difficult since these subtypes can resemble other neoplasms. The present article describes nine cases of genetically confirmed, atypical ESFT, having unusual alterations at morphological and immunohistochemical (IHC) levels associated with atypical clinical presentation mimicking sarcomas, carcinomas and lymphomas. Present results demonstrate that ESFT showing overlapping morphological and immunohistochemical features with other SRCT of soft tissue and bone, or even with carcinomas or lymphoma, can be differentiated using molecular techniques. In SRCT with EWSR1 translocation demonstrated by FISH, the RT-PCR analysis of specific sarcoma-related gene fusion can offer important clues for the diagnosis of specific entities, especially in tumours with unusual histopathology and/or IHC findings. Thus, we confirm that the integration of clinical, histopathological, IHC and genetic data becomes decisive in the diagnosis of bone and soft tissue sarcomas.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2010; 458(3):281-90. · 2.49 Impact Factor -
Article: Mutational analysis of E-cadherin, β-catenin and APC genes in synovial sarcomas.
Histopathology 09/2010; 57(3):482-6. · 3.08 Impact Factor -
Article: Inflammatory fibroid polyp of the small bowel with a mutation in exon 12 of PDGFR alpha.
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ABSTRACT: Inflammatory fibroid polyp (IFP) is a benign reactive uncommon submucosal lesion of the gastrointestinal tract, the small intestine being the most common site of origin. Histologically, IFPs are characterized by spindle cells, a heavy inflammatory infiltrate including eosinophils and onion-sheet-like formation of lesional cells around blood vessels. We present a case report of an IFP harboring an activation mutation in the PDGFR alpha gene. The lesion was positive for CD34, PDGFR alpha, and p-PDGFR alpha immunostaining but was negative for c-KIT and desmin. After a sequencing analysis of KIT and PDGFR alpha, a mutation consisting of an in-frame deletion of codons 567-571 and a missense mutation in codon 566 (S566R) of PDGFR alpha was observed. This mutation could activate key cellular pathways with involvement in the pathogenesis of this entity. We concluded that more studies are necessary in order to clarify if this finding is a biologically distinct behavior or, on the contrary, represents a specific feature of the IFP.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2009; 454(3):327-31. · 2.49 Impact Factor -
Article: Inflammatory fibroid polyp of the small bowel with a mutation in exon 12 of PDGFRα
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ABSTRACT: Inflammatory fibroid polyp (IFP) is a benign reactive uncommon submucosal lesion of the gastrointestinal tract, the small intestine being the most common site of origin. Histologically, IFPs are characterized by spindle cells, a heavy inflammatory infiltrate including eosinophils and onion-sheet-like formation of lesional cells around blood vessels. We present a case report of an IFP harboring an activation mutation in the PDGFRα gene. The lesion was positive for CD34, PDGFRα, and p-PDGFRα immunostaining but was negative for c-KIT and desmin. After a sequencing analysis of KIT and PDGFRα, a mutation consisting of an in-frame deletion of codons 567-571 and a missense mutation in codon 566 (S566R) of PDGFRα was observed. This mutation could activate key cellular pathways with involvement in the pathogenesis of this entity. We concluded that more studies are necessary in order to clarify if this finding is a biologically distinct behavior or, on the contrary, represents a specific feature of the IFP.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2009; 454(3):327-331. · 2.49 Impact Factor -
Article: Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder.
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ABSTRACT: To evaluate the prognostic and predictive value of molecular and immunohistochemical markers related to cell-cycle control in terms of recurrence, progression, and survival in urothelial neoplasms of the bladder (UNB). Clinical and pathological findings of 84 patients with UNB were assessed. Homozygous deletion (HD) and promoter methylation of p14ARF, p15INK4B, p16INK4A, loss of heterozygosity of the locus 9p21, p53 mutations, and immunohistochemical expression of p53, p16, p14, p21, p27, pRb, Ki67, MDM2, and cyclin D1 proteins were evaluated in relation to overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). In the univariate analysis, RFS was shorter in cases with p14ARF (p=0.006), p15INK4B (p=0.003), p16INK4A (p=0.03) HD, low p14 immunoreactivity index (IRI) (p=0.01) and high Ki67 IRI (p=0.04); HD of the 9p21 locus genes and p14 IRI remained as independent prognostic factors for early UNB recurrence (p=0.006) whereas tumour stage (p=0.00001) and cyclin D1 IRI (p=0.049) were related to worse PFS in the multivariate analysis. In the univariate analysis, IRI for Ki67 (p=0.002), cyclin D1 (p=0.06), p53 (p=0.00008), p16 (p=0.02), p27 (p=0.0005) MDM2 (p=0.01) and p53 mutations (p=0.03) were related to poor OS, and only the Ki67 IRI retained their independent value in the multivariate analysis. 9p21 HD and p14 IRI constitute independent predictive factors for UNB recurrence and cyclin D1 IRI and tumour stage for progression. In addition, Ki67 IRI and tumour stage are independent prognostic factors for overall survival in UNB.European Urology 10/2006; 50(3):506-15; discussion 515. · 8.49 Impact Factor -
Article: Mutational analysis of the c-KIT AND PDGFRalpha in a series of molecularly well-characterized synovial sarcomas.
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ABSTRACT: The c-KIT and the platelet-derived growth factor receptor alpha (PDGFRalpha) have been shown to be important for tumor growth and progression in several soft-tissue sarcomas, including synovial sarcomas (SSs). It has been suggested that these c-KIT-positive cases might benefit from a tyrosine kinase inhibitor therapy. In this study, we analyze a series of SSs to investigate the presence of c-KIT and PDGFRalpha mutations with the aim of selecting those for a more adequate and appropriate therapy. We analyzed fresh-frozen tissues from 12 SSs (8 primary tumors and 4 nude mice xenotransplants from primary tumors). RNA was extracted to identify the presence of the SYT-SSX gene fusion to confirm the SS diagnosis. Mutational analysis of exons 9, 11, 13, and 17 of c-KIT and exons 12 and 18 of PDGFRalpha was performed by direct sequencing. Immunohistochemical analysis of c-KIT, PDGFRalpha, and p-PDGFRalpha was also performed. All analyzed cases showed the presence of SYT-SSX gene fusion transcripts confirming the diagnosis of SS, 10 carried the SYT-SSX1 fusion, and 2 the SYT-SSX2. Immunohistochemical analysis showed expression of c-KIT in 3 cases in which no molecular alterations were detected. For the PDGFRalpha, we observed an in-frame deletion of codons 554 and 555 in a case which also showed a strong immunopositivity for the phosphorylated form of PDGFRalpha. PDGFRalpha expression was observed in 8 cases. We suggest that a more exhaustive mutational analysis of the c-KIT and PDGFRalpha genes should be performed to ascertain which cases would really benefit from a tyrosine kinase inhibitor therapy in SS.Diagnostic Molecular Pathology 10/2005; 14(3):134-9. · 2.26 Impact Factor -
Article: Mutational Analysis of the c-KIT AND PDGFR[alpha] in a Series of Molecularly Well-Characterized Synovial Sarcomas
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ABSTRACT: The c-KIT and the platelet-derived growth factor receptor α (PDGFRα) have been shown to be important for tumor growth and progression in several soft-tissue sarcomas, including synovial sarcomas (SSs). It has been suggested that these c-KIT-positive cases might benefit from a tyrosine kinase inhibitor therapy. In this study, we analyze a series of SSs to investigate the presence of c-KIT and PDGFRα mutations with the aim of selecting those for a more adequate and appropriate therapy. We analyzed fresh-frozen tissues from 12 SSs (8 primary tumors and 4 nude mice xenotransplants from primary tumors). RNA was extracted to identify the presence of the SYT-SSX gene fusion to confirm the SS diagnosis. Mutational analysis of exons 9, 11, 13, and 17 of c-KIT and exons 12 and 18 of PDGFRα was performed by direct sequencing. Immunohistochemical analysis of c-KIT, PDGFRα, and p-PDGFRα was also performed. All analyzed cases showed the presence of SYT-SSX gene fusion transcripts confirming the diagnosis of SS, 10 carried the SYT-SSX1 fusion, and 2 the SYT-SSX2. Immunohistochemical analysis showed expression of c-KIT in 3 cases in which no molecular alterations were detected. For the PDGFRα, we observed an in-frame deletion of codons 554 and 555 in a case which also showed a strong immunopositivity for the phosphorylated form of PDGFRα. PDGFRα expression was observed in 8 cases. We suggest that a more exhaustive mutational analysis of the c-KIT and PDGFRα genes should be performed to ascertain which cases would really benefit from a tyrosine kinase inhibitor therapy in SS.Diagnostic Molecular Pathology 08/2005; 14(3):134-139. · 2.26 Impact Factor
Top co-authors
Top Journals
Institutions
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2009–2012
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University of Valencia
- Departamento de Patología
Valencia, Valencia, Spain
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2006
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National Academy of Medical Sciences of Ukraine
- Institute of Urology
Kiev, Misto Kyyiv, Ukraine
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