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Samuel Navarro

Publications and source records attributed to Samuel Navarro.

At least 19 recordsLinked to original sources
PubMed2007

Evaluation of genetic stability of the SYT gene rearrangement by break-apart FISH in primary and xenotransplanted synovial sarcomas.

Synovial sarcomas (SS) are infrequent and morphologically heterogeneous soft tissue sarcomas. The t(X;18)(p11.2;q11.2), which results in fusion of the SYT gene at 18q11 with the SSX1, SSX2, or (rarely) SSX4 gene is a primary genetic event in 90% of SS. To determine whether the t(X;18) present in the original tumor is maintained in its passages, a dual-color break-apart FISH assay for SYT gene disruption was performed in two tissue microarrays (TMA) comprising eight molecularly confirmed primary SSs and their xenografts, which were followed for several generations. A simplified scoring system was applied to the FISH results of the primary and xenotransplanted SS to classify the FISH data into distinct groups. SYT disruption was identified in all eight primary SS and in all their passages without any significant differences among them, despite wide variations in xenotransplantation time between the primary tumors and their xenografts. The TMA-based FISH assay demonstrated genetic stability related to SYT gene rearrangement in primary and xenografted SS.

Animals↗
PubMed2006

Tissue microarray profiling of primary and xenotransplanted synovial sarcomas demonstrates the immunophenotypic similarities existing between SYT-SSX fusion gene confirmed, biphasic, and monophasic fibrous variants.

This paper discusses the diversity of synovial sarcomas (SSs) [biphasic (BSS), monophasic fibrous (MFSS), and poorly differentiated (PDSS)] and tissue microarray (TMA) evaluation of the immunophenotypic and histological progression of SSs in nude mice using three TMAs comprising 11 primary SSs (8 MFSSs, 2 BSSs, and 1 PDSS) and their xenografts. BSS and MFSS progressively transformed to a similar undifferentiated phenotype with loss of glandular component in the xenografts. Epidermal growth factor receptor and SALL2 were expressed in primary tumors and xenografts. Enhanced bcl-2 and bax expression were noted in xenografts. Ki-67 overexpression in xenografts correlated with high mitotic index. Epithelial membrane antigen (EMA) and cytokeratin AE1/AE3 were detected in all original and xenografted SSs. Hierarchical clustering differentiated original MFSS and BSS, but their xenografts clustered together due to similar immunoexpression profile. Our study demonstrates definite phenotypic variability of BSS and MFSS in the xenografts. Differences in immunoexpression for various markers existed between primary tumor and xenografts but not between subtypes. Hierarchical clustering grouped TMA immunostaining data and confirmed immunophenotypic variability; however, it failed to reveal any immunophenotypic differences between SYT-SSX1 and SYT-SSX2 type tumors. Nonetheless, reverse-transcriptase-polymerase chain reaction detected SYT-SSX transcripts in all primary SSs and their xenografts, thereby demonstrating their genetic stability.

Animals↗
PubMed2006

Prognostic value of the International Neuroblastoma Pathology Classification in Neuroblastoma (Schwannian stroma-poor) and comparison with other prognostic factors: a study of 182 cases from the Spanish Neuroblastoma Registry.

In addition to clinical and biological factors, further valuable prognostic information in neuroblastoma (Schwannian stroma-poor) (NB) patients is provided by the histopathologic analysis and the application of the International Neuroblastoma Pathology Classification (INPC) system. The objective of this study was to assess the prognostic impact of the INPC classification in a series of NB (Schwannian stroma-poor) and its relation with other prognostic factors. One hundred eighty-two cases of NB were collected from the files of the Spanish Neuroblastoma Registry. Slides were reviewed, and NB cases were grouped into favorable and unfavorable categories according to INPC criteria, taking into account morphological features (mitosis-karyorrhexis index, histological subtype) and patient's age at diagnosis. Other pathological [presence of calcifications, tissular components, and number of mitotic cells per 10 high-power field (HPF)], immunohistochemical (P-glycoprotein and Ki-67 protein expression) and genetic (MYCN amplification and chromosome 1p deletion) features were also studied. Statistical analyses of overall survival with Kaplan-Meier curves and a multivariate study using Cox regression were performed (40.3% of NBs were considered favorable and 59.7% unfavorable). Unfavorable NB showed a mean survival time of 57 months compared with 89 months in favorable cases. Advanced stage, more than ten mitoses per 10 HPF, Ki-67 expression in more than 30% of tumor cells, MYCN oncogene amplification and chromosome 1p deletion were observed more frequently in unfavorable NB. The Cox regression analysis demonstrated that clinical stage (International Neuroblastoma Staging System stage 4) and histological subtype (undifferentiated NB) were the most important factors that influence the overall survival (p<0.001). INPC classification results are major prognostic indicators in NB and should be considered in the therapeutic stratification of NB patients.

Child↗
PubMed2006

HER2 amplification in recurrent breast cancer following breast-conserving therapy correlates with distant metastasis and poor survival.

The authors analyzed the HER2 status in early-stage nonrecurrent and recurrent breast cancer groups following breast-conserving treatment. Retrospective analyses of a group of 36 invasive early breast cancer (IBC) patients who developed a local recurrence as a first event and of a random control group of 69 IBC patients were made. HER2 status was assessed by the HercepTest and fluorescence in situ hybridization. The Kaplan-Meier proportional log-rank test was used to study the impact of the biological factors on the metastasis-free interval (MFI) and the overall survival (OS). The Cox proportional hazards model, using stepwise selection was performed to identify the independent predictors of poor outcome. The median time of follow-up was 156 months (range: 22-230) for the nonrecurrent group of patients and 119 months (range: 36-228) for the recurrent group. No significant differences between either group were observed in terms of either patient or tumor characteristics, or of HER2 expression. However, a higher proportion of HER2 amplified cases were found in the recurrent group, in contrast to a higher proportion of hormonal receptor positive cases in the nonrecurrent group. After univariate and multivariate analyses, HER2 amplification was found to be an independent predictive factor for distant metastasis (HR = 10.75; p = 0.00008) and for survival (HR = 4.22; p = 0.004). In conclusion, HER2 amplification constitutes an independent poor prognostic factor for the MFI and OS in patients with recurrent breast cancer. The clinical implications are discussed.

Adult↗
PubMed2006

Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol.

PURPOSE: To assess the prognostic value of clinical, biologic, and morphologic data in peripheral neuroblastic tumors, International Neuroblastoma Staging System (INSS) stages 2A and 2B MYCN nonamplified, a multinational protocol entitled Localized Neuroblastoma European Study Group trial 94.01, with a trial of surgery as the only treatment, was initiated in 1995. We present the prognostic value of the revised International Neuroblastoma Pathology Classification (INPC) applied to the patients included in this protocol until its closure in 1999. MATERIALS AND METHODS: A total of 120 neuroblastic tumors from trial patients were reviewed by the European International Society of Pediatric Oncology neuroblastoma pathology panel and assigned to a favorable or unfavorable prognostic category according to the INPC guidelines. Overall survival and relapse-free survival (RFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: A total of 115 of 120 patients were assessable and were assigned to the favorable (90 patients; 78.3%) or unfavorable (25 patients; 21.7%) category. The 60-month survival rate was 97.7% in favorable patients compared with 73.8% in unfavorable patients (P = .0002). RFS analysis showed a 60-month relapse rate of 13.4% and 32% in favorable and unfavorable patients (P < .025), respectively. Statistical analysis demonstrated a significant association of unfavorable INPC category and high lactate dehydrogenase level (P < .045). CONCLUSION: This European study shows for the first time that the INPC prognostic categorization has a significant impact on outcome prediction in INSS stage 2 localized peripheral neuroblastic tumors.

Disease-Free Survival↗
PubMed2006

Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.

In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.

Animals↗
PubMed2006

p16INK4A (CDKN2A) gene deletion is a frequent genetic event in synovial sarcomas.

We assessed the frequency of genomic deletion of p16INK4A (CDKN2A) in synovial sarcomas (SSs) and its possible association with immunoexpression of p16 and cyclin D1 and the Ki-67 proliferation index using dual-color fluorescence in situ hybridization (FISH) on tissue microarray sections of 41 histologically and molecularly confirmed SSs. A heterozygous p16INK4A gene deletion was identified in 28 (74%) of 38 cases, with 25 (89%) of them showing abnormal p16 protein expression (20 negative and 5 heterogeneous). Of 25 cases, 19 (76%) exhibiting increased cyclin D1expression also demonstrated heterozygous p16INK4A deletion. No significant association was observed between p16INK4A deletion and Ki-67 proliferation index, tumor grade, or histologic subtype. Our results demonstrate that p16INK4A (CDKN2A) gene deletion is a frequent genetic event in SS.

Biomarkers, Tumor↗
PubMed2005

Delayed motherhood decreases life expectancy of mouse offspring.

This study analyzes the long-term effects of delayed motherhood on reproductive fitness and life expectancy of offspring in the mouse. Hybrid (C57BL/6JIco x CBA/JIco) first-generation (F1) females, either at the age of 10 or 51 wk, were individually housed with a randomly selected 12- to 14-wk-old hybrid male following a breeding pen system until females reached the end of their reproductive life. Reproductive fitness of second-generation (F2) females was tested from the age of 25 wk until the end of their reproductive life. In F2 males, the testing period ranged from the age of 52 wk until their natural death. Delayed motherhood of hybrid F1 female mice was associated with a decreased percentage of male F3 offspring at birth and lower life expectancy and body weight during adulthood of F2 offspring. There was, however, no evident negative effect of delayed motherhood on several reproductive fitness variables in either male or female F2 offspring. This included between-parturition interval, litter size at birth and at weaning, body weight at weaning and preweaning mortality of F3 pups, percentage of F3 litters with at least one pup cannibalized, and time at which female and male F2 offspring ceased their reproductive life. These data clearly show that delayed motherhood in the mouse is associated with negative long-term effects on offspring survival.

Animals↗
PubMed2005

[Neuroblastoma].

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Forecasting↗
PubMed2005

Mutational analysis of the c-KIT AND PDGFRalpha in a series of molecularly well-characterized synovial sarcomas.

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.

Adolescent↗
PubMed2004

Prognostic value of morphometry in low grade papillary urothelial bladder neoplasms.

OBJECTIVE: To analyze the prognostic value of morphometry in low grade papillary urothelial bladder neoplasms (LGPUBNs). STUDY DESIGN: The primary (most common) and secondary (second most common) histologic grades were considered in accordance with the 1998 World Health Organization/International Society of Urological Pathology and the 1999 World Health Organization classifications. With the primary grade, 54 cases were papillary urothelial neoplasms of low malignant potential (PUNLMPs) and 66 low grade papillary urothelial carcinomas (LGPUCs), whereas the secondary grade consisted of 45 PUNLMPs and 75 LGPUCs. To assess the proliferative index, an immunohistochemical study was performed. Regarding nuclear morphometry, an image analysis system on Feulgen-stained sections was utilized in different tumor zones (Zs): Z 1, 100-150 cells from the outer layers of the papillae; Z 2, 100-150 cells from the inner layers; and Z 3, 10 largest nuclei. In univariate studies, a t test, and Mann-Whitney U test and Kaplan-Meier curves were applied, whereas a Cox regression model was used for multivariate study of the variables: size, multiplicity, maximum Ki-67 index, mean nuclear area (MNA) and SD, mean nuclear perimeter and SD, and roundness factor. RESULTS: All 120 cases were followed for a mean of 76.6 months (range, 36-168). In univariate studies, many variables showed a significant correlation (p < 0.05) with recurrence prediction, relapse-free interval and histologic grade regardless of adjuvant therapy. Otherwise, only the MNA of the 10 largest nuclei (threshold, 52 microm2) and the maximum proliferative index (threshold, 7.9%) appeared as independent prognostic markers in the multivariate study. CONCLUSION: In LGPUBNs, the independent prognostic value of MNA of the 10 largest nuclei as well as the maximum proliferative index indicates the importance of histologic grade assessment based on the secondary (second most common) grade.

Aged↗
PubMed2003

Cytokeratin expression patterns in low-grade papillary urothelial neoplasms of the urinary bladder.

BACKGROUND: The differential expression patterns of cytokeratin 20 (CK20) and 34betaE12 antigen in low-grade papillary urothelial tumors of the bladder are discussed. METHODS: A retrospective study of 120 patients with low-grade papillary bladder tumors (45 neoplasms of low malignant potential and 75 low-grade WHO G1 carcinomas) was performed. All tumors were graded in accordance with the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications. The mean follow-up was 76.6 months (range, 36-168 mos), considering for prognostic purposes the time to first recurrence, or relapse-free interval (RFI), and the total number of recurrent patients. Immunohistochemically, normal or abnormal CK20 and 34betaE12 antigen expression patterns were determined for each patient. CK20 (clone IT-Ks) and a high-molecular weight cytokeratin (clone 34betaE12) were the monoclonal antibodies used in the immunohistochemical study. RESULTS: Seventy-seven of 120 patients (64.2%) experienced a recurrence during follow-up. In recurrence prediction, the differential expression pattern of both cytokeratins showed a high sensitivity (76.6% for CK20 and 80.5% for 34betaE12 antigen) and a high positive predictive value (85.5% for CK20 and 75.6% for 34betaE12 antigen), although specificity was higher for CK20 (76.7%) than it was for 34betaE12 antigen (53.4%). Independent of adjuvant intravesical chemotherapy, these 2 markers showed a strong statistical correlation (p < 0.001) in univariate studies with both the prediction of disease recurrences and RFI. CONCLUSIONS: CK20 and 34betaE12 antigen have proved to be strong predictive markers of disease recurrences when considering different topographic expression profiles, and, in the authors' opinion, these profiles could be incorporated into follow-up clinicopathologic strategies.

Adult↗
PubMed2003

MYCN gain and MYCN amplification in a stage 4S neuroblastoma.

Stage 4S neuroblastoma is a disease associated with spontaneous regression and good survival. We present a patient whose evolution has shown the variety and complexity of this disease in infants. Biologic factors, such as ploidy, MYCN copy number, loss of 1p36, and other chromosomal gains and losses were determined. A complex pattern of genetic abnormalities, such as near-diploidy, MYCN gain (2-4 copies per haploid genome) and imbalance/deletion of 1p36 was seen in the diagnostic sample. An extensive disseminated disease after a latent period of 26 months was associated with a special genetic evolution, such a tetraploidy, MYCN amplification (2:100-500 copies), 1p36 deletion, and gain of 17q. Our results provide evidence that either the primary tumor was heterogeneous in terms of gene amplification or that amplification was acquired later on as a transition from MYCN gain. We suggest that near-di-/tetraploid 4S tumors with MYCN gain and/or deletion 1p could be progressing 4S tumors.

Adrenal Gland Neoplasms↗
PubMed2003

Subject realization and crosslinguistic interference in the bilingual acquisition of Spanish and English: what is the role of the input?

This study investigated whether crosslinguistic interference occurs in the domain of subject realization in Spanish in a bilingual acquisition context. We were also interested in exploring whether the source of the interference is due to child-internal crosslanguage contact between English and Spanish, as is commonly assumed, or due to the nature of the language input in a bilingual family, a factor which has not typically been considered in studies of crosslinguistic influence. The use of subjects in a null subject language like Spanish is a phenomenon linked to the pragmatics/syntax interface of the grammar, and thus, is a domain where crosslinguistic interference is predicted to be likely to occur in bilingual acquisition (Müller & Hulk, 2001). Using spontaneous language data available from CHILDES (www.childes.psy.cmu.edu), we examined the use of overt subjects in Spanish by two Spanish monolingual children (ages: 1;8-2;7 and 1;8-1;11) one Spanish-English bilingual child (age 1;9-2;6) and their parental interlocutors. We looked at the proportions of overt versus null subjects as well as the discourse-pragmatic contexts of overt subject use by the children in order to uncover bilingual/monolingual differences in the distributional properties and the functional determinants of subject realization. We also looked at identical variables in the speech of the children's parental interlocutors to investigate the potential influence of the input on the children's output. Our results suggest that the bilingual child showed patterns in her subject realizations in Spanish that could be interpreted as due to crosslinguistic effects from English; however, there is also evidence that these effects may have a source in the input, rather than resulting from internal crosslanguage contact. While our data do not permit us to distinguish conclusively between these two possible sources, they indicate that future research on crosslinguistic influence in bilingual acquisition should take input into account.

Child Language↗
PubMed2003

Establishment and characterization of a continuous human chondrosarcoma cell line, ch-2879: comparative histologic and genetic studies with its tumor of origin.

Chondrosarcomas are malignant cartilage-forming tumors that represent the second most common malignant solid tumor of bone. These biologically poorly understood neoplasms vary considerably in clinical presentation and biologic behavior. Chemotherapy and radiation therapy are generally ineffective. Here we describe the establishment and characterization of a new human chondrosarcoma cell line named ch-2879, and we compare the cell line with its tumor of origin. The cell line was established from a recurrent grade 3 chondrosarcoma of the chest wall and characterized by growth kinetics and morphologic studies. Immunocytochemistry and RT-PCR were performed to examine the expression of cartilage-specific phenotypes. Genetic characterization was performed using cytogenetics, fluorescence in situ hybridization, flow cytometry, and molecular techniques for analysis of the genes implicated in cell cycle control, amplification of MDM2, CDK4, and Cyclin D1, and mutations in the p53 gene. ch-2879 cells were subcultured for more than 80 passages. They expressed vimentin, HNK-1, HBA-71, Ki-67, cyclin D1, Fli-1, S-100, p21, p27, and p53 and were negative for cytokeratin, EMA, p14, p16, MDM2, Rb, and c-erb-b2 antigens. Cytogenetically the recurrent tumor showed a hyperhaploid karyotype with clonal numerical and structural abnormalities. The sole structural abnormality was a chromosome derivative of a t(1;21) translocation. The cell line at passage 3 showed two populations: the hyperhaploid and an exactly duplicated, hypotriploid population. After the 18th passage, only the hypotriploid population was present. The cells expressed collagen 2. Molecular comparison of the primary and recurrent tumor evidenced an in vivo molecular change consisting of a deletion of 9p21 genes in the recurrence, probably caused by a selection process. Because of its gene expression profile, including expression of genes implicated in chondrogenesis in uncoated plastic dishes, this cell line may prove useful for cellular and molecular studies as well as studies of chondrosarcoma characterization and treatment.

Bone Neoplasms↗
PubMed2002

CD99 immunoreactivity in atypical fibroxanthoma: a common feature of diagnostic value.

Atypical fibroxanthoma (AFX), a pleomorphic superficial cutaneous tumor of low-grade malignancy, shares many morphologic features with malignant melanoma (MM) and squamous cell carcinoma (SCC). Absence of S-100, keratin, and desmin immunoreactivity is the clue for this diagnosis. In a search for positive markers, we tested 26 cases of AFX with 2 antibodies: O13 (CD99) and protein gene product 9.5 (PGP9.5). We also included 10 cases of poorly differentiated SCC and 10 cases of MM in the study. In AFX, CD99 immunoreactivity was present in 19 cases (73%), whereas focal PGP9.5 immunoreactivity was found in only 9 cases (35%). None of the SCC cases showed CD99 immunostaining. No CD99 immunoreactivity was found in 9 of 10 cases of MM. To our knowledge, this is the first report of CD99 and PGP9.5 immunostaining in AFX. We believe, based on our results, that CD99 may be a helpful "positive" feature in the histopathologic diagnosis of AFX.

12E7 Antigen↗