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1.
Oncogene ; 31(1): 27-38, 2012 Jan 05.
Article in English | MEDLINE | ID: mdl-21643016

ABSTRACT

The expression of small, non-coding RNA or microRNAs (miR), is frequently deregulated in human cancer, but how these pathways affect disease progression is still largely elusive. Here, we report on a miR, miR-296, which is progressively lost during tumor progression and correlates with metastatic disease in colorectal, breast, lung, gastric, parathyroid, liver and bile ducts cancers. Functionally, miR-296 controls a global cell motility gene signature in epithelial cells by transcriptionally repressing the cell polarity-cell plasticity module, Scribble (Scrib). In turn, loss of miR-296 causes aberrantly increased and mislocalized Scrib in human tumors, resulting in exaggerated random cell migration and tumor cell invasiveness. Re-expression of miR-296 in MDA-MB231 cells inhibits tumor growth in vivo. Finally, miR-296 or Scrib levels predict tumor relapse in hepatocellular carcinoma patients. These data identify miR-296 as a global repressor of tumorigenicity and uncover a previously unexplored exploitation of Scrib in tumor progression in humans.


Subject(s)
Cell Polarity , MicroRNAs/physiology , Neoplasms/etiology , Animals , Cell Movement , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Membrane Proteins/genetics , Mice , Neoplasms/genetics , Neoplasms/pathology , Tumor Suppressor Proteins/genetics
2.
Oncogene ; 26(29): 4284-94, 2007 Jun 21.
Article in English | MEDLINE | ID: mdl-17297478

ABSTRACT

Gastric carcinoma is one of the major causes of cancer mortality worldwide. Early detection results in excellent prognosis for patients with early cancer (EGC), whereas the prognosis of advanced cancer (AGC) patients remains poor. It is not clear whether EGC and AGC are molecularly distinct, and whether they represent progressive stages of the same tumor or different entities ab initio. Gene expression profiles of EGC and AGC were determined by Affymetrix technology and quantitative polymerase chain reaction. Representative regulated genes were further analysed by in situ hybridization (ISH) on tissue microarrays. Expression analysis allowed the identification of a signature that differentiates AGC from EGC. In addition, comparison with normal gastric mucosa indicated that the majority of alterations associated with EGC are retained in AGC, and that further expression changes mark the transition from EGC to AGC. Finally, ISH analysis showed that representative genes, differentially expressed in the invasive areas of EGC and AGC, are not differentially expressed in the non-invasive areas of the same tumors. Our data are more directly compatible with a progression model of gastric carcinogenesis, whereby EGC and AGC may represent different molecular stages of the same tumor. Finally, the identification of an AGC-specific signature might help devising novel therapeutic strategies for advanced gastric cancer.


Subject(s)
Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Gene Expression Profiling , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Cell Differentiation/genetics , Cell Proliferation , Disease Progression , Follow-Up Studies , Humans , Oligonucleotide Array Sequence Analysis , Severity of Illness Index , Stomach Neoplasms/classification , Stomach Neoplasms/metabolism
3.
Pathologica ; 98(1): 37-40, 2006 Feb.
Article in Italian | MEDLINE | ID: mdl-16789684

ABSTRACT

Recently, many progresses have been recorded in the molecular and histogenetic characterization of the haematopoietic and lymphoid tumours, resulting in important classifying changes. As a consequence, the exact definition of lymphoma subtype requires an integration between traditional morphologic "expertise" and several bio-functional data obtained from advanced and complex ancillary techniques (immunohistochemistry, molecular biology and cytogenetics). At the same time, the data provided by gene expression profiling studies are going to deeply modify the therapies in haematological cancers. These studies are expected to allow the achievement of single-patient-tailored genic therapy; for this reason it is necessary to get biological samples of good quality. Indeed, while these progresses contribute to highlight the pathologist's diagnostic role, they should make us reflect on the state of the art of the Italian haemolymphopathology diagnostics and on its ability to cope up with the new challanges. The aim of this article is to outline a realistic picture of the present condition, and to explain the reasons for setting up, inside SIAPEC-IAP, the Haemolymphopathology Italian Group (H.I.G.). The purpose of H.I.G. will be twofold: first of all, scheduling of a series of projects so as to the haemolymphopathological diagnostic standardization; secondly, building a national network among all the pathologists involved in this exciting and complex field of the anatomic pathology.


Subject(s)
Hematologic Neoplasms/diagnosis , Hematology/organization & administration , Pathology, Clinical/organization & administration , Societies, Medical , Europe , Gene Expression Profiling , Genetic Therapy , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Hematology/methods , Humans , Immunophenotyping , Italy , Lymphoma/blood , Lymphoma/diagnosis , Lymphoma/pathology , Lymphoma/therapy , Medical Oncology/methods , Medical Oncology/organization & administration , Pathology, Clinical/methods , Societies, Medical/organization & administration
4.
J Thromb Haemost ; 3(4): 724-32, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15842357

ABSTRACT

BACKGROUND: Type I fibrinogen deficiencies (hypofibrinogenemia and afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antigen levels. Their genetic bases are represented by mutations within the three fibrinogen genes. Among the 11 reported missense mutations, a few have been characterized by expression studies and found to have an impaired fibrinogen assembly and/or secretion. Histopathological analyses were previously reported in two hypofibrinogenemic cases with discernible hepatic disease, revealing that both underlying mutations (gamma-Gly284Arg and gamma-Arg375Trp) were associated with hepatic fibrinogen endoplasmic reticulum storage disease (ERSD). OBJECTIVE: The objective of this study was to investigate the liver histology in an afibrinogenemic patient, homozygous for the Bbeta-Leu353Arg mutation, and to study the intracellular processing of the mutant protein. PATIENTS AND METHODS: Liver histology was evaluated by light microscopy, electron microscopy and immunocytochemistry. Intracellular processing of mutant fibrinogen was analyzed by pulse-chase labeling and immunoprecipitation experiments. Messenger RNA levels were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The histopathological characterization of the liver showed no signs of fibrinogen accumulation, a difference from the previously reported findings in two hypofibrinogenemic kindreds with ERSD. To evaluate whether the Bbeta-Leu353Arg mutation and the ERSD-associated gamma-Gly284Arg mutation affected intracellular fibrinogen trafficking differently, both mutant proteins were expressed in COS-1 cells. Bbeta-Leu353Arg led to a more severe secretion defect, but no differences that could explain phenotype-genotype correlation were found in the intracellular processing. Endoglycosidase-H analysis demonstrated a secretion block before translocation to the Golgi medial stacks. Real-time RT-PCR studies showed normal levels of the Bbeta mRNA in the patient's liver. CONCLUSIONS: The results confirm that Bbeta-Leu353Arg is associated with impaired fibrinogen secretion, but not with hepatic ERSD.


Subject(s)
Endoplasmic Reticulum/pathology , Fibrinogen/genetics , Liver Diseases/pathology , Liver/pathology , Metabolism, Inborn Errors/pathology , Mutation , Adolescent , Animals , Arginine/chemistry , COS Cells , DNA, Complementary/metabolism , Electrophoresis, Polyacrylamide Gel , Fibrinogen/chemistry , Genotype , Glycoside Hydrolases/metabolism , Humans , Immunohistochemistry , Immunoprecipitation , Leucine/chemistry , Liver/metabolism , Liver Diseases/genetics , Male , Metabolism, Inborn Errors/genetics , Microscopy, Electron , Mutation, Missense , Phenotype , RNA/metabolism , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transfection
6.
BMC Cancer ; 4: 46, 2004 Aug 09.
Article in English | MEDLINE | ID: mdl-15301691

ABSTRACT

BACKGROUND: We studied the expression of DMBT1 (deleted in malignant brain tumor 1), a putative tumor suppressor gene, in normal, proliferative, and malignant breast epithelium and its possible relation to cell cycle. METHODS: Sections from 17 benign lesions and 55 carcinomas were immunostained with anti DMBT1 antibody (DMBTh12) and sections from 36 samples, were double-stained also with anti MCM5, one of the 6 pre-replicative complex proteins with cell proliferation-licensing functions. DMBT1 gene expression at mRNA level was assessed by RT-PCR in frozen tissues samples from 39 patients. RESULTS: Normal glands and hyperplastic epithelium in benign lesions displayed a luminal polarized DMBTh12 immunoreactivity. Normal and hyperplastic epithelium adjacent to carcinomas showed a loss of polarization, with immunostaining present in basal and perinuclear cytoplasmic compartments. DMBT1 protein expression was down-regulated in the cancerous lesions compared to the normal and/or hyperplastic epithelium adjacent to carcinomas (3/55 positive carcinomas versus 33/42 positive normal/hyperplastic epithelia; p = 0.0001). In 72% of cases RT-PCR confirmed immunohistochemical results. Most of normal and hyperplastic mammary cells positive with DMBTh12 were also MCM5-positive. CONCLUSIONS: The redistribution and up-regulation of DMBT1 in normal and hyperplastic tissues flanking malignant tumours and its down-regulation in carcinomas suggests a potential role in breast cancer. Moreover, the concomitant expression of DMTB1 and MCM5 suggests its possible association with the cell-cycle regulation.


Subject(s)
Agglutinins/metabolism , Breast Neoplasms/genetics , Carcinoma/genetics , Receptors, Cell Surface/metabolism , Breast/pathology , Breast Neoplasms/pathology , Calcium-Binding Proteins , Carcinoma/pathology , Cell Cycle/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cytoplasm/metabolism , Cytoplasm/pathology , DNA-Binding Proteins , Down-Regulation , Epithelium/pathology , Humans , Hyperplasia/genetics , Hyperplasia/pathology , Immunohistochemistry , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins
7.
Int J Cancer ; 94(3): 383-9, 2001 Nov 01.
Article in English | MEDLINE | ID: mdl-11745418

ABSTRACT

Loss of heterozygosity (LOH) and microsatellite instability (MSI) have been shown to be mechanisms for tumor-suppressor gene inactivation in human oncogenesis. In our study, we examined LOH and MSI using 16 polymorphic markers of DNA for chromosomes 1, 3, 7, 8, 10 and 11. Microdissected tumor samples were isolated from 32 patients, representing 11 foci of incidentally discovered prostate cancer of the transitional zone (TZ), 12 prostate cancer of the peripheral zone (PZ) and 10 of high-grade PIN. We found loss of heterozygosity in the TZ group in 91% of informative cases (10/11) with al least 1 marker compared to 58% of cases (7/12) in PZ group and 70% of cases (7/10) in the HGPIN group. Chromosome 7 showed the highest rate of allelic loss in all 3 categories, with loss of 43% of loci in PIN, 37% in TZ tumors and 31% in PZ tumors. At chromosome 11, LOH was detected in 26% of loci in the TZ group, in 7% of loci in the PZ group and in 13% of loci in the PIN group. On chromosome 8, the PZ and HGPIN group showed allelic loss in 22% and 21% of loci, respectively, compared to 10% detected in the TZ group. The TZ group showed a significant higher rate of allelic instability compared to that observed in tumor samples from the peripheral zone: 73% of cases (8/11) showed genetic alterations (RER+ phenotype) in at least 4 loci analyzed compared to 8% and 10% in the PZ and HGPIN groups, respectively (p = 0.0006). These data suggest that transitional zone carcinoma and peripheral zone carcinoma display distinct and specific genetic alterations in different chromosomes. This diversity may help explain biologic and clinical differences between carcinomas arising in these distinct zones of the prostate. Also our results strongly suggest that the RER+ mutator phenotype could be linked to early development of transitional zone prostate carcinoma.


Subject(s)
Adenocarcinoma/genetics , Loss of Heterozygosity , Prostatic Neoplasms/genetics , Trinucleotide Repeat Expansion/genetics , Alleles , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 7 , Genetic Markers , Humans , Immunohistochemistry , Male , Mutation , Phenotype , Polymorphism, Genetic
8.
Am J Clin Pathol ; 116(5): 721-8, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11710690

ABSTRACT

We studied the presence of surfactant protein A (Sp-A) immunoreactivity and messenger RNA in 62 normal and abnormal breast samples. Sections were immunostained with polyclonal anti-Sp-A antibody. The association between Sp-A immunoreactivity and histologic grade of 32 invasive ductal carcinomas was assessed by 3 pathologists who scored the intensity of Sp-A immunoreactivity times the percentage of tumor immunostained; individual scores were averaged, and the final scores were correlated with tumor grade, proliferative index, and expression of estrogen and progesterone receptors. Strong Sp-A immunoreactivity was present at the luminal surface of ductal epithelial cells in normal breast samples and in benign lesions; carcinomas displayed variable immunoreactivity, inversely proportional to the degree of differentiation. Sp-A messenger RNA was detected by reverse transcriptase-polymerase chain reaction in 3 of 3 normal breast samples and 9 of 9 carcinomas. The significance of Sp-A expression in breast epithelium requires further study; possibly it has a role in native host defense or epithelial differentiation.


Subject(s)
Breast Neoplasms/metabolism , Breast/metabolism , Carcinoma, Intraductal, Noninfiltrating/metabolism , Proteolipids/biosynthesis , Pulmonary Surfactants/biosynthesis , Breast/anatomy & histology , Breast/chemistry , Breast/pathology , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/chemistry , Carcinoma, Intraductal, Noninfiltrating/secondary , Cell Division , DNA Primers/chemistry , Epithelium/chemistry , Epithelium/metabolism , Female , Humans , Immunoenzyme Techniques , Proteolipids/analysis , Proteolipids/genetics , Pulmonary Surfactant-Associated Protein A , Pulmonary Surfactant-Associated Proteins , Pulmonary Surfactants/analysis , Pulmonary Surfactants/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/analysis , Receptors, Estrogen/analysis , Receptors, Estrogen/metabolism , Receptors, Progesterone/analysis , Receptors, Progesterone/metabolism , Reverse Transcriptase Polymerase Chain Reaction
9.
Leuk Res ; 25(9): 735-9, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11489466

ABSTRACT

We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions.


Subject(s)
Chromosomes, Human, Pair 7 , Microsatellite Repeats/genetics , Monosomy , Myeloproliferative Disorders/genetics , Genes, Tumor Suppressor , Humans , Leukemia, Myeloid/genetics , Loss of Heterozygosity , Neural Tube Defects/genetics , Polymerase Chain Reaction
10.
J Clin Pathol ; 54(3): 236-7, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11253138

ABSTRACT

Whole mount sections of the prostate are widely used in many laboratories. Macrocryosections of the gland; that is, whole mount frozen sections of the prostate from radical prostatectomies represent a useful new research protocol. The technique is very simple and does not require expensive equipment.


Subject(s)
Cryoultramicrotomy/methods , Prostate/pathology , Cryoultramicrotomy/instrumentation , Humans , Male , Prostatectomy , Staining and Labeling
11.
Lab Invest ; 81(2): 241-7, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11232646

ABSTRACT

Alterations in proto-oncogenes and tumor suppressor genes play a role in the sequence from Barrett's metaplasia to esophageal adenocarcinoma. The present study aims to ascertain whether molecular abnormalities take place in Barrett's metaplasia and low-grade dysplasia and to correlate them with the histological features of the esophageal mucosa. Forty-one formalin-fixed, paraffin-embedded endoscopic esophageal biopsies were classified according to the type of metaplastic changes (noncolumnar fundic and cardial metaplasia; columnar metaplasia, with and without intestinal features). After microdissection samples were examined for loss of heterozygosity (LOH) using polymorphic markers on 5q (D5S82), corresponding to APC (adenomatous polyposis coli) gene, 13q (CA repeat in intron 2 position 14815 to 14998 of the retinoblastoma gene), 17p (D17S513) corresponding to p53 locus, and for p53 mutations. Molecular alterations including LOH, allelic imbalance, and microsatellite instability could be detected in all types of metaplastic changes and sporadically in the squamous epithelium adjacent to the metaplastic tissue. Molecular alterations involving microsatellites D5S82 and the CA repeat inside the retinoblastoma gene were more frequent in nonintestinal metaplasia whereas those involving the p53 locus took place in columnar intestinal metaplasia and in low-grade dysplasia. Clonal changes were demonstrated in different metaplastic areas in three patients. Genetic alterations comprising LOH and microsatellite instability characterize Barrett's mucosa and appear related to the type of metaplastic change. Some of them precede the development of intestinal metaplasia, suggesting that genetic alterations take place earlier than previously thought.


Subject(s)
Barrett Esophagus/genetics , Chromosomes, Human, Pair 13 , Chromosomes, Human, Pair 17 , Chromosomes, Human, Pair 5 , Loss of Heterozygosity , Barrett Esophagus/pathology , Biopsy , Chromosome Mapping , Dinucleotide Repeats , Dissection , Endoscopy , Genes, Retinoblastoma , Genes, p53 , Humans , Metaplasia , Microsatellite Repeats , Mutation , Polymerase Chain Reaction , Retrospective Studies
12.
Hepatology ; 32(5): 942-6, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11050043

ABSTRACT

The genetic profile of dysplastic hepatocellular nodules arising in cirrhosis is poorly understood. We assessed loss of heterozygosity (LOH) and microsatellite instability (MI) in 10 dysplastic nodules (4 low-grade and 6 high-grade) with surrounding cirrhosis and in 10 hepatocellular carcinomas (HCC). Six microsatellite loci were selected and investigated on microdissected needle biopsies. Twenty-four (24.4%) informative loci showed allelic loss, while MI was seen in 3 loci only (3%). The most involved sites were located on chromosomes 4q (54.5%) and 8p (50%). LOH was documented in 16.6%, cirrhotic, 50% low-grade dysplastic nodules (LGDN), 83% high-grade dysplastic nodules (HGDN), and 70% malignant nodules. LOH at multiple loci was increasingly seen from cirrhotic to HGDN, but not from the latter to HCC. The fractional allelic loss (FAL) was significantly increased in dysplastic and neoplastic nodules as compared with cirrhosis (P <.01). The progressive accumulation of genetic changes in cirrhotic, dysplastic, and malignant hepatocellular nodules is in keeping with a multistep process of carcinogenesis; within this spectrum, HGDN can be considered advanced precursors of HCC.


Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Diseases/genetics , Liver Neoplasms/genetics , Biopsy , Dissection , Female , Humans , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/genetics , Liver Diseases/complications , Loss of Heterozygosity , Male , Microsatellite Repeats , Middle Aged , Retrospective Studies
13.
Mol Cell Probes ; 14(3): 195-7, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10860718

ABSTRACT

Polymorphisms in the T-cell receptor genes can provide important information for the study of the immune response system, particularly for autoimmune diseases. This report characterizes a common T to C polymorphism in the promoter of the beta 2 constant chain of the T-cell receptor, which abolishes a recognition site for BglII restriction endonuclease.


Subject(s)
Bacterial Proteins , Genes, T-Cell Receptor beta/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Adult , Alleles , Deoxyribonucleases, Type II Site-Specific/metabolism , Female , Gene Frequency/genetics , Genotype , Humans , Male , Mutation/genetics , Polymorphism, Restriction Fragment Length , White People/genetics
14.
J Nephrol ; 13(2): 129-36, 2000.
Article in English | MEDLINE | ID: mdl-10858976

ABSTRACT

BACKGROUND: beta2-microglobulin (beta2m) is considered to be the amyloidogenic precursor in dialysis-related amyloidosis (DRA, Abeta2M amyloidosis). beta2m modified with advanced glycation end products (AGE) may be an important factor in the pathogenesis of DRA. The presence of AGE in beta2m-positive amyloid deposits and surrounding macrophages has been demonstrated by immunohistochemical techniques in light microscopy. METHODS: In order to better define the localization of beta2m and AGE in amyloid deposits and in cells, carpal tunnel connective tissues obtained from surgical specimens in six patients with DRA were studied by immunohistochemistry and electron microscopy, using the avidine-biotine complex and immunogold staining procedures, respectively. A polyclonal rabbit anti-human beta2m and two monoclonal mouse anti-AGE antibodies [AG-1 anti-imidazolone and AG-10 anti-N(epsilon)-carboxymethyl-lysine] enabled us to label their respective antigens at the optical and ultrastructural level. RESULTS: with both techniques, extracellular amyloid deposits strongly reacted with anti-beta2m and anti-AGE antibodies, although the immunoreactivity of beta2m was more intense. Macrophage-like synovial cells (CD-68 positive) surrounding amyloid deposits were also immunoreactive for beta2m and AGE, which were detected in lysosomes and in intracellular fibrillar material. Anti-AGE reactivity was also evident in collagenous structures in the absence of beta2m or amyloid deposits, supporting the proposal that AGE modification of collagen might have pathogenic relevance in the development of DRA. CONCLUSIONS: The co-localization of AGE and beta2m, both intra- and extra-cellularly, in amyloid fibrils was confirmed by immunoelectron microscopy; however, the positivity of collagen to anti-AGE antibodies and a different pattern of intracellular localization suggest that molecules other than beta2m may also be modified by AGE and may be involved in the pathogenesis of DRA.


Subject(s)
Amyloidosis/etiology , Glycation End Products, Advanced/metabolism , Renal Dialysis/adverse effects , Synovial Membrane/ultrastructure , Tendons/ultrastructure , beta 2-Microglobulin/metabolism , Animals , Carpal Tunnel Syndrome/etiology , Carpal Tunnel Syndrome/pathology , Glycation End Products, Advanced/analysis , Humans , Mice , Microscopy, Electron , Rabbits , Synovial Membrane/chemistry , Synovial Membrane/pathology , Tendons/chemistry , Tendons/pathology , beta 2-Microglobulin/analysis
15.
Virchows Arch ; 436(3): 289-95, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10782889

ABSTRACT

Peripheral papillary adenomas of the lung are uncommon neoplasms (only ten cases have been described so far in the English literature) composed predominantly of type-II pneumocytes and generally considered benign. We describe here two additional cases of this lung tumor. In both cases histological examination revealed an encapsulated papillary neoplasm with invasion of the capsule and, in one case, invasion of the adjacent alveoli and visceral pleura too. The proliferative index (Ki67) was less than 2% and the epithelial cells were positive for cytokeratins, surfactant apoproteins (SP), and nuclear thyroid transcription factor-1 (TTF- 1). Ultrastructurally, the epithelial cells showed the characteristic surface microvilli and cytoplasmic lamellar inclusions of type-II cells. Review of the literature has revealed two other cases of peripheral papillary adenoma of type-II pneumocytes with infiltrative features. Thus, we propose replacing the term peripheral papillary adenoma with peripheral papillary tumor of undetermined malignant potential.


Subject(s)
Adenoma/pathology , Lung Neoplasms/pathology , Adenoma/physiopathology , Adenoma/surgery , Adolescent , Adult , Humans , Lung/pathology , Lung/ultrastructure , Lung Neoplasms/physiopathology , Lung Neoplasms/surgery , Male , Microscopy, Electron
16.
Hepatology ; 31(4): 846-50, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10733538

ABSTRACT

Hepatocellular carcinoma (HCC) is usually preceded by cirrhosis whose genetic background is still poorly understood. The aim of this study was to evaluate, in non-end-stage cirrhosis, the fractional allelic loss (FAL) at loci mostly reported to be altered in HCC and the microsatellite instability (MSI). Twenty cases of cirrhosis were retrospectively selected. Eleven had developed an HCC during the follow-up (HCC-prone group), while 9 remained HCC-free (HCC-free group). Microdissected hepatocellular cirrhotic nodules from basal liver biopsies, were studied at 20 loci (on the chromosomal arms 1p and 1q, 3p, 4q, 6q, 7q, 8p, 13q, and 18q) and with the mononucleotide repeats BAT26 and TGFbIIR. Genetic changes were detected in both groups. Overall, the FAL index was statistically increased in the HCC-prone group (0.213) as compared to the HCC-free group (0.094; P =.044). Allelic loss at chromosomal arms 1p, 4q, 13q, 18q, and concurrent losses at more than 3 loci were confined to the HCC-prone group. In both groups, MSI was never ascertained using BAT26 and TGFbIIR. In conclusion, an increased FAL index and the lack of MSI characterize the non-end-stage cirrhosis of patients undergoing HCC during follow-up. These data emphasize the role of early clonal changes in chronic liver disease, and their potential predictive significance for clinical use.


Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Loss of Heterozygosity , Biopsy , Carcinoma, Hepatocellular/pathology , Female , Humans , Liver/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Male , Microsatellite Repeats , Middle Aged , Retrospective Studies
18.
Mol Cell Probes ; 13(5): 393-5, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10508562

ABSTRACT

TP53 gene plays a major role in the process of malignant transformation and tumour progression so that abnormalities such as point mutation or allelic loss of this gene are a common finding in different tumour types. Most of the mutations identified cover a conserved region of the gene, spanning from exon 4 to exon 9. The present report describes a novel polymorphism, 12 nucleotides downstream the splicing junction of exon/intron 9 identified in a cohort of 103 Italian healthy blood donors. The polymorphism results in the creation of a new restriction site for Ava I.


Subject(s)
Genes, p53/genetics , Blood Donors , DNA Restriction Enzymes/genetics , Exons , Female , Gene Frequency , Humans , Introns , Italy/epidemiology , Male , Point Mutation , Polymorphism, Genetic/genetics , Polymorphism, Restriction Fragment Length , Polymorphism, Single-Stranded Conformational
19.
Hepatology ; 30(5): 1174-8, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10534338

ABSTRACT

We investigated the angiogenic phenotype of regenerative and dysplastic hepatocellular nodules to assess whether these lesions have distinct vascular profiles compared with the adjacent nonneoplastic or malignant liver. Forty-three liver nodules surgically removed from 18 patients were classified into regenerative and dysplastic categories. Serial sections of each nodule, adjacent cirrhotic liver (16 patients), and associated hepatocellular carcinoma (HCC) (6 patients), have been immunostained against CD31 and alpha-smooth muscle actin (alphaSMA) to detect capillary and muscular vessels. The study included 20 large regenerative nodules (LRNs), 13 low-grade dysplastic nodules (LGDNs), and 10 high-grade dysplastic nodules (HGDNs). The number of both capillary units and unpaired arteries was significantly increased in HGDNs and malignant lesions over LGDNs, regenerative, and cirrhotic nodules (P <.01), which showed an overlapping vascular profile. In addition, the number of capillary units, but not that of unpaired arteries, was significantly increased in HCC compared with HGDNs (P <.01). These results show that certain angiogenic features segregate HGDNs from other nonmalignant nodules such as LRNs and LGDNs. The former group of lesions is similar to HCC whereas the latter group is undistinguishable from the adjacent cirrhosis as far as their vascular profile is concerned. The adopted investigative approach does not support the morphological distinction between LRNs and LGDNs although it suggests that HGDNs are likely advanced precursors of HCC. An abnormal number of capillary units and/or unpaired arteries in a nonmalignant hepatocellular nodule can be diagnostically helpful to identify a precancerous lesion.


Subject(s)
Carcinoma, Hepatocellular/pathology , Liver Cirrhosis/classification , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Liver/pathology , Actins/analysis , Capillaries/pathology , Carcinoma, Hepatocellular/blood supply , Female , Humans , Liver/blood supply , Liver Neoplasms/blood supply , Male , Middle Aged , Neovascularization, Pathologic/pathology , Platelet Endothelial Cell Adhesion Molecule-1/analysis
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