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Biomedical subjects

S Pilotti

Publications and source records attributed to S Pilotti.

At least 55 records · Page 3Linked to original sources
PubMed2000

The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma.

Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12q13-15, whereas well differentiated liposarcomas (WDL) show supernumerary ring and giant marker chromosomes, known to contain amplified 12q sequences. The tight correlation between the presence of ring chromosomes and both amplification and overexpression of MDM2 and CDK4 genes suggests the exploration of the possibility that immunocytochemistry (ICC) might assist in the differential diagnosis of lipoma-like well differentiated liposarcomas (LL-WDL) and large deep-seated lipomas (LDSL). For this purpose, 21 cases of the former and 19 cases of the latter tumours were analysed by ICC and, according to the availability of material, by molecular and cytogenetic approaches. All lipomas displayed a null MDM2/CDK4 phenotype, whereas all LL-WDL showed MDM2/CDK4 or CDK4 phenotypes. Southern blot analysis performed on 16 suitable cases, complemented by fluorescence in situ hybridization and classical cytogenetic analysis in 11 cases, was consistent with, and further supported the immunophenotyping data. In conclusion, MDM2/CDK4 product-based immunophenotyping appears to represent a valuable method for the categorization of arguable LDSL.

Adult↗
PubMed2000

Breast cancer patients treated without axillary surgery: clinical implications and biologic analysis.

OBJECTIVE: To evaluate the impact of breast carcinoma (T1-2N0) surgery without axillary dissection on axillary and distant relapses, and to evaluate the usefulness of a panel of pathobiologic parameters determined from the primary tumor, independent of axillary nodal status, in planning adjuvant treatment. METHODS: In a prospective nonrandomized pilot study, 401 breast cancer patients who underwent breast surgery without axillary dissection were accrued from January 1986 to June 1994. At surgery, all patients were clinically node-negative and lacked evidence of distant metastases after clinical or radiologic examination. A precise 4-month clinical and radiologic follow-up was performed to detect axillary or distant metastases. Patients with clinical evidence of axillary nodal relapse were considered for surgery as salvage treatment. Biologic characteristics of primary carcinomas were investigated by immunohistochemistry, and four pathologic and biologic parameters (size, grading, laminin receptor, and c-erbB-2 receptor) were analyzed to determine a prognostic score. RESULTS: The 5-year follow-up of these patients revealed a low rate of nodal relapses (6.7%), particularly for T1a and T1b patients (2% and 1.7%, respectively), whereas T1c and T2 patients showed a 10% and 18% relapse rate, respectively. Surgery was a safe and feasible salvage treatment without technical problems in all 19 cases of progressive disease at the axillary level. The low rate of distant metastases in T1a and T1b groups (<6%) increased to 15% in T1c and 34% in T2 patients. Analyzing the primary tumor with respect to the panel of pathologic and biologic parameters was predictive of metastatic spread and therefore can replace nodal status information for planning adjuvant treatment. CONCLUSIONS: Middle-term follow-up shows that the rate of axillary relapse in this patient population is lower than expected, suggesting that only a minimal number of microembolic nodal metastases become clinically evident. Avoidance of axillary dissection has a negligible effect on the outcome of T1 patients, particularly in T1a and T1b tumors with no palpable nodes, because the rate of axillary node relapse is very low for both. In T1 breast carcinoma, postsurgical therapy should be considered on the basis of biologic characteristics rather than nodal involvement. The authors' prognostic score based on the primary tumor identified patients who required postsurgical treatment, providing a practical alternative to axillary status for deciding on adjuvant treatment. Conversely, in the T2 group, the high rate of salvage surgery for axillary relapses, which is expected in tumors larger than 2.5 cm or 3.0 cm, represents a limit for avoiding axillary dissection. Preoperative evaluation of axillary nodes for modification of surgical dissection in this subgroup would be more useful more than in T1 breast cancer because of the high risk. Complete dissection is feasible without technical problems if precise follow-up detects progressive axillary disease.

Aged↗
PubMed2000

TP53 mutations and mdm2 protein overexpression in cholangiocarcinomas.

Tumor suppressor protein p53 is a positive regulator of MDM2 gene expression and the mdm2 protein can bind to p53, preventing the transactivation of p53 responsive genes, thus mimicking TP53 mutation. The authors looked for alterations that could affect, directly and indirectly, p53 function in 13 patients with extrahepatic cholangiocarcinoma. Molecular analysis by single strand conformation polymorphism and DNA sequencing revealed that TP53 gene mutations occurred in only 2 of 13 cholangiocarcinomas. High levels of mdm2 protein were found, by immunohistochemical staining, in 61% of the cholangiocarcinomas and in almost all specimens (70%) displaying stabilized p53 protein in the absence and in the presence of TP53 mutations. The finding of co-overexpressed mdm2 and p53 proteins in cholangiocarcinomas indicates that they can upregulate the expression of mdm2 protein to a level sufficient for binding and accumulating p53 in a presumably inactive complexed form. The presence of TP53 mutations or upregulation of MDM2 gene expression in 9 of the 13 cholangiocarcinomas strongly supports that the impairment of the p53 pathway is an important and specific step in cholangiocarcinoma pathogenesis. At variance with other authors, no alteration of p16ink4/CDKN2 gene was observed in all 13 cholangiocarcinomas.

Aged↗
PubMed2000

Morphologic-cytogenetic analysis of dedifferentiated liposarcomas with an extensive misleading leiomyosarcomatous component.

This report describes two cases of recurrent retroperitoneal dedifferentiated liposarcoma characterized by an extensive leiomyomatous component that prevented the correct diagnosis before the last recurrence. Strong immunoreactivity with smooth muscle and desmin antibodies and ultrastructural features consistent with leiomyosarcoma were observed in the spindle-cell and/or myxoid-like components in all four recurrences in case 1, and in the spindle-cell component of the primary tumor and the first recurrence in case 2. In case 1, the correct diagnosis was suggested by the cytogenetic evidence of ring markers, a hallmark of well-differentiated/dedifferentiated liposarcoma. In case 2, tumor type was yielded mainly by the morphology of the second recurrence, which consisted entirely of a well-differentiated liposarcoma, a sclerosing inflammatory variant, as confirmed by the karyotype. Reevaluation of the first two surgical specimens of each case revealed small areas consistent with well-differentiated liposarcoma that had been previously overlooked. Despite the smooth-muscle antigen profile, both cases retained an mdm2+/p53+/cdk4+ immunophenotype consistent with the genotype.

Aged↗
PubMed2000

Gene product immunophenotyping of neuroendocrine lung tumors. No linking evidence between carcinoids and small-cell lung carcinomas suggested by multivariate statistical analysis.

Fifty-three neuroendocrine lung tumors (24 carcinoids, one atypical carcinoid, five large-cell neuroendocrine carcinomas, and 23 small-cell lung carcinomas) were investigated for immunocytochemical expression of several gene products, i.e., p53, Rb, bcl-2, c-kit, mdm-2, cdk-4, p21 proteins, and proliferation index as assessed by MIB-1. The goal of the study was to explore the relationships between histotypes in light of their own gene product-based immunophenotypical profiles. To this aim we applied the multiple correspondence analysis, which is an exploratory statistical multivariate technique that converts a data matrix into a particular type of graphic display in which the rows and columns are depicted as points. Such statistical analysis displayed that some categories of the gene product-based immunophenotyping variables are grouped in the plot identifying three groups: the first group related to carcinoids, the second to small-cell carcinomas, and the third to large-cell neuroendocrine carcinomas. These data support the evidence that carcinoids and small-cell carcinomas are two distinct, apparently immunogenotypically unrelated entities among neuroendocrine lung tumors and that atypical carcinoids and large-cell neuroendocrine carcinomas seem not to represent intermediate steps between them.

Antigens, Nuclear↗
PubMed2000

Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma.

UNLABELLED: The purposes of this study were to establish the diagnostic accuracy of FDG PET for lymph node metastases and to determine the smallest detectable volume of disease. METHODS: Using FDG PET, we preoperatively studied 56 lymph node basins in 38 patients with a clinical or instrumental diagnosis of lymph node metastases from melanoma. All lymph node basins underwent node dissection. The FDG PET results were compared with the postoperative histopathology results. PET images were obtained using a GE 4096 WB scanner, after injection of a mean activity of 496 MBq (range, 366-699 MBq) of FDG. RESULTS: The efficacy of FDG PET in the diagnosis of involved lymph node basins was good. Sensitivity was 95% (35/37); specificity, 84% (16/19); accuracy, 91% (51/56); positive predictive value, 92% (35/38); and negative predicative value, 89% (16/18). Metastases were shown histologically in 114 of 647 surgically removed lymph nodes. FDG PET detected 100% of metastases > or = 10 mm, 83% of metastases 6-10 mm, and 23% of metastases < or = 5 mm. Moreover, FDG PET had high sensitivity (> or = 93%) only for metastases with more than 50% lymph node involvement or with capsular infiltration. CONCLUSION: Our study shows that FDG PET has a reasonable sensitivity and specificity for detecting the presence or absence of lymph node metastases in patients with melanoma. However, even if able to detect small volumes of subclinical macroscopic disease, FDG PET cannot detect subclinical microscopic disease with acceptable sensitivity. The specificity of FDG PET is good, but some false-positive results may occur.

Adult↗
PubMed1999

Simultaneous phenotypically distinct but clonally identical mucosa-associated lymphoid tissue and follicular lymphoma in a patient with Sjögren's syndrome.

A 44-year-old woman with a 12-year history of Sjögren's syndrome (SS) developed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland. Two years later, she presented with generalized lymphadenopathy and hepatosplenomegaly and a follicular lymphoma was diagnosed. To investigate the relationship of the two histologically distinct lymphomas, we re-examined their histology and immunophenotype and studied the lymphomatous tissue from the parotid, cervical lymph node, and spleen using molecular genetic methods. Histologic and immunophenotypic studies confirmed the previous diagnoses and also identified a previously unnoticed focus of follicular lymphoma in the second parotid gland biopsy. Polymerase chain reaction (PCR) amplification of the rearranged Ig heavy-chain gene showed the same sized dominant product in the MALT lymphoma and the follicular lymphoma. Similarly, PCR analysis of the t(14:18) translocation yielded an identical sized band from both MALT and follicular lymphoma. Cloning and sequencing of the Ig PCR products showed an identical CDR3 sequence from each lesion, indicating a common clonal lineage. The follicular lymphoma of the parotid gland lymph node and the follicular lymphoma of the spleen showed an identical mutation signature to that of the salivary gland MALT lymphoma. We propose that follicular lymphoma in the parotid gland lymph node may have resulted from colonization of lymphoid follicles by MALT lymphoma cells, following which the tumor cells were induced to express a follicular lymphoma phenotype, due to Bcl-2 overexpression caused by t(14;18), leading to a change in clinical behavior resulting in rapid widespread dissemination of disease. These observations suggest that the distinct phenotypes of low-grade B-cell lymphomas may be the consequence of interplay between genetic and local microenvironmental factors.

Adult↗
PubMed1999

An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions.

It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-1(27-35)-specific CTL precursors (CTLp) were >/=1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO(+) memory T cell subset. In the remaining five patients, a low (<1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA(+) naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a "brisk" or "nonbrisk" CD3(+)CD8(+) T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.

Adult↗
PubMed1999

FHIT loss of function in human primary breast cancer correlates with advanced stage of the disease.

The FHIT gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a tumor suppressor gene involved in different tumor types. We have assessed 29 human primary breast carcinomas for both the presence of abnormal FHIT transcripts and the Fhit protein levels as compared with the normal breast epithelium of the same patients. In addition, we have also examined a second retrospective series of 156 consecutive breast carcinomas for the expression of the Fhit protein. In nine (31%) cases of the first series, FHIT transcripts were either aberrant or absent as determined by reverse transcription-PCR, and Fhit protein levels in tumors were low or absent as determined immunohistochemically. In 11 other cases (38%), only normal FHIT transcripts were detected by PCR, paralleled by the reduction or absence of Fhit protein. In the remaining nine cases (31%), the presence of the normal FHIT transcript corresponded to protein levels that were similar in tumor and normal breast epithelia. Thus, alterations in FHIT transcripts were detected in 31% of the patients, but reduction or absence of Fhit protein occurred in 69% of the breast carcinoma samples examined. These data suggest that alteration in Fhit expression in breast carcinomas is a frequent event. Analysis of correlation between Fhit expression and pathological, clinical, and biological parameters in these 29 tumors and in a second retrospective series of 156 consecutive primary breast carcinomas indicated that a decrease or an absence of Fhit protein expression is associated with high proliferation and large tumor size.

Acid Anhydride Hydrolases↗
PubMed1999

Absence of microsatellite instability in breast carcinomas with both p53 and c-erbB-2 alterations.

Based on a previous finding that amplification of the c-erbB-2 oncogene and alteration of p53 are strongly associated in most aggressive breast tumours, the present study investigated whether microsatellite instability (MI) might also be associated with this tumour phenotype. Nine polymorphic microsatellite markers, including six dinucleotide, one trinucleotide, and two tetranucleotide repeats, were amplified from paired normal and tumour DNA samples of 15 breast tumours that overexpressed both c-erbB-2 and p53 and of 15 control breast tumours that overexpressed neither protein. All 30 breast tumours analysed exhibited a replication error-negative phenotype, with only one sample showing MI in one of the nine loci. This suggests that the genetic events underlying MI, which are critical in colorectal and gastric tumours, are not involved in the pathogenesis of c-erbB-2/p53 double-altered breast tumours and do not play a central role in breast tumour formation.

Adult↗
PubMed1999

Unilateral aneuploid dedifferentiated acinic cell carcinoma associated with bilateral-low grade diploid acinic cell carcinoma of the parotid gland.

A dedifferentiated acinic cell carcinoma (AciCC) of the right parotid gland with lymph node metastases occurred in a 36-year-old woman. The tumour was associated with a bilateral well-differentiated AciCC. The two components of this tumour had different (high and low) proliferative activity measured by Mib-1 and different (aneuploid and diploid) DNA content. Despite the presence of a high-grade component, TP53 mutations, microsatellite instability (MSI) and/or loss of heterozygosity (LOH) at the p53 locus were not detected. Although the follow-up of the patient is very short, the aggressiveness of the tumour is shown by a recurrence in the right parotid within 4 months and by the rapid development of regional metastases.

Adult↗
PubMed1999

Fluctuation of HER2 expression in breast carcinomas during the menstrual cycle.

The hormonal milieu at time of tumor surgery seems to have a significant impact on survival in premenopausal breast cancer patients. Indeed, surgery performed during the follicular phase of the menstrual cycle was suggested to correlate with a poor prognosis. To investigate the relationship between prognosis and menstrual cycle at time of surgery, we analyzed the expression of some markers associated with tumor aggressiveness, such as the hormone receptors, HER2, p53, Bcl2, and cathepsin D in breast carcinomas obtained from 198 premenopausal women who underwent surgery during different phases of the menstrual cycle. HER2 overexpression was found to fluctuate in hormone receptor-positive tumors. In actual fact, 20% of the tumors removed during the follicular phase scored HER2-positive, versus 8% of those removed during the luteal phase. Similarly, a number of hormone receptor-positive tumor specimens, obtained from the same patients during follicular and luteal phases, were scored HER2-positive when the sample was removed during the follicular phase and HER2-negative when removed in the luteal phase. Southern blot analysis of the HER2 gene indicated that, in hormone receptor-positive cases, the overexpression of HER2 is often not associated with gene amplification. The finding that overexpression of the HER2 gene, associated with tumor aggressiveness, can fluctuate according to the hormonal milieu may explain the increased survival of patients operated during the luteal phase. It is also relevant to the selection and treatment of patients most likely to benefit from anti-HER2 antibody therapy.

Adult↗
PubMed1999

Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features.

Experimental evidence has shown, both in vitro and in animal models, that neoplastic growth and subsequent metastasis formation depend on the tumor's ability to induce an angiogenic switch. This requires a change in the balance of angiogenic stimulators and inhibitors. To assess the potential role of angiogenesis factors in human thyroid tumor growth and spread, we analyzed their expression by semiquantitative RT-PCR and immunohistochemistry in normal thyroid tissues, benign lesions, and different thyroid carcinomas. Compared to normal tissues, in thyroid neoplasias we observed a consistent increase in vascular endothelial growth factor (VEGF), VEGF-C, and angiopoietin-2 and in their tyrosine kinase receptors KDR, Flt-4, and Tek. In particular, we report the overexpression of angiopoietin-2 and VEGF in thyroid tumor progression from a prevascular to a vascular phase. In fact, we found a strong association between tumor size and high levels of VEGF and angiopoietin-2. Furthermore, our results show an increased expression of VEGF-C in lymph node invasive thyroid tumors and, on the other hand, a decrease of thrombospondin-1, an angioinhibitory factor, in thyroid malignancies capable of hematic spread. These results suggest that, in human thyroid tumors, angiogenesis factors seem involved in neoplastic growth and aggressiveness. Moreover, our findings are in keeping with a recent hypothesis that in the presence of VEGF, angiopoietin-2 may collaborate at the front of invading vascular sprouts, serving as an initial angiogenic signal that accompanies tumor growth.

Angiogenesis Inducing Agents↗
PubMed1999

Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors.

Many different pathological and biological variables which characterize breast carcinomas have been found to be associated. The aim of this work was to analyze the complex relationship among these parameters. The pathologic, biologic, and clinical characteristics of a series of primary breast carcinomas from 676 patients were retrospectively investigated. Multiple correspondence analysis of 13 factors revealed clustering of eight pathobiologic variables, that is histologic grade, necrosis, lymphoid infiltration, number of mitoses, c-erbB-2 overexpression, p53, progesterone receptor, and bcl2 expression. An index for each tumor calculated on the basis of these eight factors served to distinguish two different tumor phenotypes, designated A and B. Phenotype A is represented by tumors sharing most of the biologic features of normal breast tissues: indeed, these tumors are characterized by a relatively high degree of differentiation, low proliferation, no necrosis or leukocyte infiltration, and no gene alterations. By contrast, phenotype B is quite divergent from the normal tissue because of its poor differentiation, high proliferation, frequent gene alterations and evidence of a host immune reaction. As regards the disease progression, these two subsets showed marked differences: phenotype A tumors had a low recurrence rate per year that remained constant over time and affected more frequently elderly patients, whereas group B tumors showed high aggressivity in the first years after surgery followed by a low long-term recurrence rate and were more frequently seen in younger patients. These data suggest that breast carcinoma consists of two different subsets that can be identified on the basis of pathobiologic features.

Adult↗
PubMed1999

c-erbB2/neu gene and chromosome 17 analysis in breast cancer by FISH on archival cytological fine-needle aspirates.

The detection of specific genetic alterations in breast cancer is useful for diagnosing, predicting prognosis and planning preoperative treatment. c-erbB2/neu overexpression is usually detected by immunocytochemistry (ICC), although this technique is neither completely reproducible nor highly reliable, owing to specimen and methodologic variability and antibody sensitivity. Here, we combine two well-established techniques, fine-needle aspiration (FNA) and fluorescence in situ hybridization (FISH), to detect c-erbB2/neu amplification in patients candidate to primary chemotherapy and, in part, previously analysed for c-erbB2/neu overexpression. Sixty smears from FNA were used to simultaneously detect c-erbB2/neu and chromosome 17 centromere. FISH was successful in 58 cases and detected 24 amplified cases, three of which were negative by immunophenotyping, 28 negative cases, with evidence of two normal c-erbB2/neu/signals, two cases with deletion of c-erbB2/neu, and four cases with polysomy, thus providing more reliable and informative results than ICC. This study underlines the advantages offered by the FNA and FISH combination which are two rapid, reliable, simple and informative techniques, to analyse one of the most important genetic markers for predicting prognosis and chemotherapy planning for breast carcinoma in particular in the light of the recently proposed trials of primary chemotherapy.

Adult↗
PubMed1999

Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing's group.

Esthesioneuroblastoma (ENB) is a rare, site-specific, locally aggressive neuronal malignancy so far thought to belong to primitive peripheral neuroectodermal tumour-Ewing's tumour (pPNETs-ETs). Its anatomical location, in addition to morphologic, immunophenotypic and ultrastructural features, suggests its origin in the neuronal or neuroendocrine cells of the olfactory epithelium. However, the cytogenetic and molecular data currently available appear controversial on the presence of the typical translocation t(11;22)(q24;q12) and of trisomy 8, chromosomal changes that characterize the tumours belonging to the pPNETs-ETs. Herein we have analysed five ENB tumour specimens for trisomy 8 by fluorescence in situ hybridization (FISH), for the presence of EWS gene rearrangements by FISH, reverse transcription polymerase chain reaction and Southern blot analyses, as well as for the expression of the Ewing sarcoma-associated MIC2 antigen by immunohistochemistry. Neither EWS/FLI-I, EWS/ERG and EWS/FEV fusion genes nor MIC2 expression were found in any tumour, whereas trisomy 8 was found in one case only. Moreover, DNA from three cases analysed by Southern blot did not show EWS gene rearrangements. Our results support the evidence that ENB is not a member of the pPNETs-ETs.

Adult↗