Publications (12)46.46 Total impact
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Article: Classical lobular breast carcinoma consistently lacks topoisomerase-IIα gene amplification: implications for the tailored use of anthracycline-based chemotherapies.
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ABSTRACT: There is consistent lack of data focusing the topoisomerase-IIα gene status in lobular breast carcinoma, a subtype that usually shows poor responsiveness to chemotherapies including those using anthracycline drugs. Forty-six infiltrative lobular carcinomas, 13 with matched metastases, were used. Topoisomerase-IIα gene amplification was evaluated by chromogenic in situ hybridization (CISH) and fluorescence in situ hybridization (FISH). We also assessed Her2/neu status by CISH, FISH and silver in situ hybridization (SISH). HER2 immunoexpression was assessed by the HercepTest. Forty-four of 46 (95%) cases revealed no topoisomerase-IIα amplification, whereas two of 46 (5%) cases were amplified by all three techniques. Eleven of the 13 metastatic sites showed no amplification either in the primary or in the metastases (85%); the remaining two were amplified (15%). Her2/neu was not amplified in 44 of 46 (95%) cases nor was it amplified in 11 of 13 (95%) metastatic tissues. The two cases showing Her2/neu and topoisomerase-IIα amplification scored 3+; the remaining non-amplified cases scored 0 or 1+ in 40 and 2+ in four cases. In the era of personalized and tailored therapies, we suggest that patients affected by the classical lobular subtype of breast carcinoma constantly lack the ad hoc predictive rationale for receiving common chemotherapy that includes anthracyclines.Histopathology 12/2011; 60(3):482-8. · 3.08 Impact Factor -
Article: FISH scoring on paraffin sections versus single-cell suspension for chromophobe renal carcinoma and renal oncocytoma.
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ABSTRACT: Sectioning of the nuclei on tissue sections may give an overestimate of monosomy, a feature diagnostic of chromophobe renal cell carcinoma versus renal oncocytoma. The aim of the study was to assess whether or not nuclear sectioning may distort the results obtained from interphase fluorescence in situ hybridization (FISH) comparing the data obtained from analysis of isolated nuclei derived from formalin-fixed, paraffin-embedded sections with histological sections from the adjacent sections from the same tumors. Five chromophobe renal cell carcinomas and five renal oncocytomas were recruited. Sections of 5 μm and 30 μm were cut for FISH to investigate chromosomes 1, 2, 6 10 and 17. FISH of isolated nuclei from renal oncocytomas showed a mean increase of 3.0% for nuclei with two signals when compared to tissue sections. For chromosomes 2, 6, 10 and 17, isolated nuclei showed a mean increase of 4.9% of fluorescent signals over nuclei from tissue sections. FISH analysis of isolated nuclei from chromophobe renal cell carcinoma showed a similar counts. When a tumor section exhibits a borderline percentage of nuclei with single signals around the cut-off level on tissue sections, the test should be repeated on isolated nuclei to confirm chromosomal loss, diagnostic of chromophobe renal carcinoma.Anticancer research 10/2011; 31(10):3137-42. · 1.73 Impact Factor -
Article: Suitability of infiltrative lobular breast carcinoma for anti-human epidermal growth factor receptor 2 treatment after the ASCO/CAP and 2009 St Gallen International Expert Consensus meeting.
Histopathology 12/2010; 57(6):935-40. · 3.08 Impact Factor -
Article: Chromosome 3p alterations in pancreatic endocrine neoplasia.
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ABSTRACT: Pancreatic endocrine tumors (PET) are rare neoplasms classified as functioning (F-PET) or non-functioning (NF-PET) according to the presence of a clinical syndrome due to hormonal hypersecretion. PETs show variable degrees of clinical aggressiveness and loss of chromosome 3p has been suggested to be associated with an advanced stage of disease. We assessed chromosome 3p copy number in 113 primary PETs and 32 metastases by fluorescence in situ hybridization (FISH) using tissue microarrays. The series included 56 well-differentiated endocrine tumors (WDET), 62 well-differentiated endocrine carcinomas (WDEC), and 6 poorly differentiated endocrine carcinomas (PDEC). Chromosome 3p alterations were found in 23/113 (20%) primary tumors, with losses being predominant over gains (14% vs. 6%). Loss of 3p was found in 5/55 (9%) WDET, 11/52 (21%) WDEC, and never in PDEC. Gains of 3p were detected in 4/55 (7%) WDET, no WDEC, but notably in 3/6 (50%) PDEC (OR 23.6; P = 0.003). Metastases were more frequently monosomic for 3p compared to primary tumors (OR 3.6; P = 0.005). Monosomy was significantly associated with larger tumor size, more advanced tumor stage, and metastasis. No association was found with survival. Chromosome 3p copy number alterations are frequent events in advanced stage PET, with gains prevailing in PDEC while losses are more frequent in WDEC, supporting the view that a specific pattern of alterations are involved in these diverse disease subtypes.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2010; 458(1):39-45. · 2.49 Impact Factor -
Article: MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases.
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ABSTRACT: Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical-pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein-protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.Endocrine Related Cancer 09/2010; 17(3):771-83. · 4.36 Impact Factor -
Article: The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type.
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ABSTRACT: PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and their clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions presented in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise.Journal of Experimental & Clinical Cancer Research 01/2010; 29:32. · 2.15 Impact Factor -
Article: Diagnostic usefulness of fluorescent cytogenetics in differentiating chromophobe renal cell carcinoma from renal oncocytoma: a validation study combining metaphase and interphase analyses.
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ABSTRACT: We investigated the usefulness of interphase fluorescence in situ hybridization (FISH) analysis to differentiate between 11 chromophobe renal carcinomas and 12 renal oncocytomas, showing different clinical outcomes, when compared with conventional metaphase cytogenetics by karyotyping. Karyotypically, 3 chromophobe renal cell carcinomas showed losses of chromosomes, 3 were polyploid, 1 was normal, and 4 failed to grow. Of 12 oncocytomas, 5 showed a normal numeric karyotype and 6 additional structural rearrangements. FISH on chromophobe renal cell carcinomas showed a high percentage of cases (10/11 [91%]) with multiple numeric losses among chromosomes 1, 2, 6, 10, and 17; this interphase pattern was observed irrespective of the 3 different metaphase karyotypes. Of 12 oncocytomas, 11 (92%) revealed a normal numeric chromosomal status showing at least 2 chromosomes without aneusomy by interphase FISH. The study demonstrates that indeed FISH performed on formalin-fixed, paraffin-embedded tissue can provide clinically useful information more reliably than karyotyping of most of these tumors.American Journal of Clinical Pathology 01/2010; 133(1):116-26. · 2.60 Impact Factor -
Article: Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy.
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality for which novel gene therapy approaches relying on tumor-tropic adenoviruses are being tested. We obtained the global transcriptional profiling of primary PDAC using RNA from eight xenografted primary PDAC, three primary PDAC bulk tissues, three chronic pancreatitis and three normal pancreatic tissues. The Affymetrix GeneChip HG-U133A was used. The results of the expression profiles were validated applying immunohistochemical and western blot analysis on a set of 34 primary PDAC and 10 established PDAC cell lines. Permissivity to viral vectors used for gene therapy, Adenovirus 5 and Adeno-Associated Viruses 5 and 6, was assessed on PDAC cell lines. The analysis of the expression profiles allowed the identification of two clearly distinguishable phenotypes according to the expression of interferon-stimulated genes. The two phenotypes could be readily recognized by immunohistochemical detection of the Myxovirus-resistance A protein, whose expression reflects the activation of interferon dependent pathways. The two molecular phenotypes discovered in primary carcinomas were also observed among established pancreatic adenocarcinoma cell lines, suggesting that these phenotypes are an intrinsic characteristic of cancer cells independent of their interaction with the host's microenvironment. The two pancreatic cancer phenotypes are characterized by different permissivity to viral vectors used for gene therapy, as cell lines expressing interferon stimulated genes resisted to Adenovirus 5 mediated lysis in vitro. Similar results were observed when cells were transduced with Adeno-Associated Viruses 5 and 6. Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials.Journal of Translational Medicine 01/2010; 8:10. · 3.41 Impact Factor -
Article: Research The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type
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ABSTRACT: Background: PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. Methods: We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells.Journal of Experimental & Clinical Cancer Research. 01/2010; 29. -
Article: Genotypic intratumoral heterogeneity in breast carcinoma with HER2/neu amplification: evaluation according to ASCO/CAP criteria.
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ABSTRACT: We evaluated intratumoral heterogeneity of 30 ductal breast carcinomas with HER2/neu amplification, scored by the American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) criteria, and 3+ immunoexpression. High-grade (ratio > or =4.0) vs low-grade amplification (ratio >2.2 to <4.0) and chromosome 17 polysomy were also evaluated. On whole tissue sections, 20 tumors (67%) showed high-grade and 10 (33%) showed low-grade HER2/ neu amplification. Of 20 tumors with high-grade amplification, 14 (70%) showed no intratumoral genotypic heterogeneity; 6 (30%) showed at least 1 core with low-grade amplification. Of 10 cases with low-grade amplification, 6 (60%) showed no intratumoral heterogeneity; 4 (40%) showed chromosome 17 polysomy without gene amplification in 2 of 3 cores per case. Of 30 cases with gene amplification, 4 (13%) showed a "not-amplified pattern" in other parts of the tumor. The routine assessment of HER2/neu amplification using the ASCO/CAP criteria on whole tissue sections is not significantly confounded by intratumoral heterogeneity in breast cancer with high-grade amplification; however, genetic heterogeneity exists in a subset of breast carcinomas with low-grade amplification. The clinical relevance and impact on treatment outcome of intratumoral heterogeneity in breast cancer with low-grade HER2/neu amplification or chromosome 17 polysomy need further investigation.American Journal of Clinical Pathology 05/2009; 131(5):678-82. · 2.60 Impact Factor -
Article: HER-2/neu assessment in breast cancer using the original FDA and new ASCO/CAP guideline recommendations: impact on selecting patients for herceptin therapy.
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ABSTRACT: We evaluated HER-2/neu status in 100 consecutive ductal breast carcinomas by using the Food and Drug Administration (FDA) and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) scoring systems. With the FDA system, scores were 3+ in 23.0%, 2+ in 25.0%, and 0 or 1+ in 52.0% of cases. With the ASCO/CAP system, scores were 3+ in 16.0%, 2+ in 34.0%, and 0 or 1+ in 50.0%. With the FDA and ASCO/CAP systems, respectively, 3+ cases (n = 23 and 16, respectively) showed high-grade, granular HER-2/neu amplification in 15 (65%) and 14 (88%); low-grade, borderline amplification in 7 (30%) and 1 (6%); and chromosome 17 polysomy without amplification in 1 (4%) and 1 (6%). Concordance between schemes was higher for cases with high-grade, granular HER-2/neu amplification (concordance coefficient, 0.74). Cases with low-grade, borderline HER-2/neu amplification showed poor concordance (concordance coefficient, 0.20). The FDA and ASCO/CAP schemes for HER-2/neu evaluation select patients differently for trastuzumab therapy. Major discordance is present for low-grade, borderline HER-2/neu amplification. FDA low-grade, borderline tumors would be reclassified as without HER-2/neu amplification or as polysomic. The ASCO/CAP scheme has a great concordance coefficient between strong 3+ immunohistochemical cases and cases with high-grade, granular HER-2/neu amplification.American Journal of Clinical Pathology 07/2008; 129(6):907-11. · 2.60 Impact Factor -
Article: MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior.
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ABSTRACT: We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies. Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas. Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.Journal of Clinical Oncology 11/2006; 24(29):4677-84. · 18.37 Impact Factor
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Institutions
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2008–2009
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Università degli studi di Verona
- Department of Pathology
Verona, Veneto, Italy
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