Biomedical subjects

A Vecchione

Publications and source records attributed to A Vecchione.

At least 19 recordsLinked to original sources

PubMed2001

FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis.

The FEZ1/LZTS1 gene maps to chromosome 8p22, a region that is frequently deleted in human tumors. Alterations in FEZ1/LZTS1 expression have been observed in esophageal, breast, and prostate cancers. Here, we show that introduction of FEZ1/LZTS1 into Fez1/Lzts1-negative cancer cells results in suppression of tumorigenicity and reduced cell growth with accumulation of cells at late S-G(2)/M stage of the cell cycle. Fez1/Lzts1 protein is hyperphosphorylated by cAMP-dependent kinase during cell-cycle progression. We found that Fez1/Lzts1 is associated with microtubule components and interacts with p34(cdc2) at late S-G(2)/M stage in vivo. Present data show that FEZ1/LZTS1 inhibits cancer cell growth through regulation of mitosis, and that its alterations result in abnormal cell growth.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Onset of natural killer cell lymphomas in transgenic mice carrying a truncated HMGI-C gene by the chronic stimulation of the IL-2 and IL-15 pathway.

Rearrangements of the high mobility group protein I-C (HMGI-C) gene, consisting in the loss of the carboxyl-terminal tail, have been frequently detected in benign human tumors of mesenchymal origin. We have previously demonstrated that transgenic (TG) mice carrying a truncated HMGI-C construct (HMGI-C/T) exhibit a giant phenotype together with a predominantly abdominal/pelvic lipomatosis. Here, we report that HMGI-C/T TG mice develop natural killer (NK)-T/NK cell lymphomas starting from 12 months of age. We found an increased expression of IL-2 and IL-15 proteins and their receptors in these lymphomas, and we demonstrate that HMGI-C/T protein positively regulates their expression in vitro. Therefore, the HMGI-C/T-mediated chronic stimulation of the IL-2/IL-15 pathway could be responsible for the onset of NK-T/NK cell lymphomas in HMGI-C/T TG mice.

Animals↗

PubMed2001

Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer.

The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered by deletion in a large fraction of human tumors, including pancreatic cancer. To evaluate the potential of FHIT gene therapy, we developed recombinant adenoviral and adenoassociated viral (AAV) FHIT vectors and tested these vectors in vitro and in vivo for activity against human pancreatic cancer cells. Our data show that viral FHIT gene delivery results in apoptosis by activation of the caspase pathway. Furthermore, Fhit overexpression enhances the susceptibility of pancreatic cancer cells to exogenous inducers of apoptosis. In vivo results show that FHIT gene transfer delays tumor growth and prolongs survival in a murine model mimicking human disease.

Acid Anhydride Hydrolases↗

PubMed2001

Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions.

BACKGROUND: Thyroid cancer is the most common endocrine malignant disease, but preoperative diagnosis remains a challenge. Fine-needle aspiration cytology has greatly improved the clinical management of thyroid nodules, but the preoperative characterisation of follicular lesions is very difficult. Many patients are thus referred to surgery more for diagnosis than for therapeutic necessity. We undertook an international multicentre study to assess the usefulness of immunohistocytochemical staining for two potential markers of malignant thyrocytes. METHODS: Expression of galectin-3 and CD44v6 was tested on 1009 thyroid lesions (tissue specimens and cytological cell-blocks) and 226 fresh cytological samples obtained preoperatively by ultrasound-guided fine-needle aspiration of thyroid nodules (prospective analysis). The test used monoclonal antibodies specific for CD44v6 and galectin-3, the indirect avidin-biotin complex immunoperoxidase method, and 3-amino-9-ethyl-carbazole as substrate. FINDINGS: The sensitivity, specificity, positive predictive value, and diagnostic accuracy of this test method (for coexpression of the two markers) in the prospective analysis were 88%, 98%, 91%, and 97%, respectively. The sensitivity and specificity of galectin-3 immunodetection alone in discriminating benign from malignant thyroid lesions were more than 99% and 98% respectively, and the positive predictive value and diagnostic accuracy were 92% and 99%. INTERPRETATION: The integration of galectin-3 immunostaining with conventional cytomorphological and clinical diagnostic procedures represents a sensitive and reliable diagnostic approach for preoperative identification of thyroid carcinomas. This test method improves the diagnostic accuracy of conventional cytology and provides the molecular basis for a new nosological assignation of the not yet classified thyroid neoplasms of indeterminate malignant behaviour.

Antigens, Differentiation↗

PubMed2001

FHIT gene therapy prevents tumor development in Fhit-deficient mice.

The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral or adenoassociated viral vectors expressing the human FHIT gene, in heterozygous Fhit(+/-) knockout mice, that are prone to tumor development after carcinogen exposure. We therefore suggest that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Acid Anhydride Hydrolases↗

PubMed2001

Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells.

Reintroduction of a tumor suppressor gene product in cancer cells is a promising strategy for cancer gene therapy. The fragile histidine triad (FHIT) gene has been identified in a region at chromosome 3p14.2, which is deleted in many tumors, including esophageal cancer. Previous studies have shown frequent biallelic alterations of the FHIT gene in numerous tumors, and have demonstrated a tumor suppressor function of Fhit. We have studied the biological effects of adenoviral-FHIT transduction in esophageal cancer cell lines. Results showed suppression of cell growth in vitro in three of seven esophageal cancer cell lines, all seven of which showed abundant expression of the transgene. Adenoviral-FHIT expression, but not control adenoviral infections, induced caspase-dependent apoptosis in two esophageal cancer cell lines, TE14 and TE4, which express no or very little Fhit, respectively. Treatment of TE14 cells with adenoviral-FHIT vectors resulted in abrogation of tumorigenicity in nude mice. A third esophageal cancer cell line, TE12, without detectable endogenous Fhit, showed accumulation of cells at S to G2-M and a small apoptotic cell fraction after adenoviral-FHIT transduction. Thus, adenoviral-FHIT expression can inhibit the growth of esophageal cancer cells, at least in part through caspase-dependent apoptosis, suggesting that adenoviral-FHIT infection should be explored as a therapeutic strategy.

Acid Anhydride Hydrolases↗

PubMed2001

E-cadherin and alpha-catenin expression during tumor progression of cervical carcinoma.

OBJECTIVE: The objective of this study was to determine whether a relationship between the E-caherin molecule and the E-cadherin-associated cytoplasmic molecule, alpha-catenin, could provide additional information in the neoplastic progression of cervical cancer. METHODS: In this study we investigated by immunohistochemistry E-cadherin (E-cad) and alpha-catenin (alpha-cat) expression in 57 cervical biopsy samples representative of normal exocervical epithelium, viral (human papillomavirus (HPV) infection) and dysplastic lesions (low- and high-grade lesions), and invasive squamous cell carcinoma. The presence of immunostaining and the pattern of distribution of these molecules were correlated with the histological diagnosis (normal cervical epithelium vs HPV, cervical intraepithelial neoplasia (CIN), and invasive carcinoma). RESULTS: The correlation between alpha-cat expression and the histological diagnosis was statistically significant (chi2 test, P < 0.0077); moreover, E-cad and alpha-cat distributions were significantly correlated with the histological classification (P < 0.0001 and P < 0.0043, respectively). CONCLUSION: These results suggest that not only E-cad but also alpha-cat are associated with the loss of differentiation in CIN and squamous cell carcinomas; thus the coexpression of E-cad and alpha-cat may represent a discriminant of malignant potential and could provide an additional criterion to define high-grade CIN.

Cadherins↗

PubMed2001

Gastric epithelial cell proliferation in patients with liver cirrhosis.

An increased risk for gastric cancer in patients with liver cirrhosis has recently been reported. This study was performed in order to determine gastric epithelial cell proliferation in cirrhotic patients and to evaluate the role of congestive gastropathy (CG) and Helicobacter pylori infection in this process. Thirty-six cirrhotic patients and 18 controls were enrolled in the study. All patients underwent endoscopy and three biopsies were performed in the antrum and three in the gastric body. The presence of H. pylori infection was assessed by a rapid urease test and histology. The antral biopsies were used for gastric cell proliferation assessment by an immunohistochemical analysis (Ki-67). There was no significant difference in epithelial cell proliferation between cirrhotics and controls. Gastric proliferation values were higher in patients with H. pylori infection compared with uninfected patients, both in cirrhotic (P = 0.003) and in control groups (P = 0.06). Among the cirrhotic group, we found a progressive increase in gastric cell proliferation values related to the degree of CG, the highest values being observed in cirrhotic patients with severe CG. Moreover, cirrhotics with both severe CG and H. pylori infection had the highest proliferation values when compared with all other subgroups. In conclusion, this study found that: (1) CG significantly affects epithelial cell proliferation in gastric mucosa in cirrhotic patients, (2) H. pylori infection plays a similar role in gastric cell proliferation in both cirrhotic and non-cirrhotic patients, and (3) CG and H. pylori could act synergistically in this process.

Adult↗

PubMed2001

Performance of cytology and colposcopy in diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-positive and HIV-negative women.

As part of an extensive multi-institutional DIANAIDS-HIV-HPV-SIL project run in Italy (co-ordinated by ISS), the present study compares the performance (sensitivity, specificity, agreement) of routine cervical smear cytology with that of colposcopy in the detection of histologically-confirmed CIN lesions in 37 HIV-positive and 21 HIV-negative women, belonging to the DIANAIDS cohort of 459 women. All women were subjected to a cervical smear, colposcopy and biopsy, making possible the pairwise comparison of these techniques. In the whole series of HIV-positive and HIV-negative women, cytology had a sensitivity of 86.9% and specificity of 83.3%, the sensitivity of grade 2 abnormality on colposcopy against histology being 82.6% and specificity, 33.3%. No statistically significant difference was observed in the performance of Pap smears between the HIV-positive and HIV-negative women. The sensitivity of cytology was 89.7% vs 82.4% and the specificity, 75% vs 100%. For colposcopy, the sensitivity was 79.3% vs 88.2% and the specificity, 75% vs 50%. These data suggest that cervical Pap smear cytology is a highly sensitive and specific diagnostic tool in the clinical monitoring of lower genital tract pathology in HIV-positive women. Colposcopy, on the other hand, proved to be a somewhat less accurate diagnostic tool in these women.

Adolescent↗

PubMed2001

Human herpesvirus 6 infection in neoplastic and normal brain tissue.

The presence and variant distribution of human herpesvirus 6 (HHV-6) was investigated by a nested polymerase chain reaction (PCR) in 118 biopsies from patients affected by nervous tissue tumor (115 primary tumors and 3 metastasis) and in 31 autopsy samples from the brain of healthy individuals. HHV-6 DNA sequences were detected in normal and neoplastic nervous tissue at a frequency of 32% and 37%, respectively. In both tissues, variant A was three times more frequent than the variant B. Peripheral blood lymphocytes (PBLs) derived from seven tumor affected patients contained the same variant as their respective brain sample, as judged by PCR. The expression of HHV-6 encoded immediate early protein p41 was detected by immunohistochemistry in neoplastic but not in normal brain. This may reflect viral reactivation from latency in immunocompromised patients. The seroepidemiological data indicated a frequency distribution of anti-HHV-6 antibodies in patients with brain tumors similar to that found in healthy donors.

Antibodies, Viral↗

PubMed2001

[Controversial categories in cytopathology of the uterine cervix. I. ASCUS: atypical squamous cells of undetermined significance].

ASCUS (Atypical Squamous Cells of Undetermined Significance) is a class for reporting cervical cytopathologic diagnoses. The Bethesda System (TBS) introduced ASCUS in 1988 and then defined this cytologic class further. Since the initial subclassification in probably reactive or probably neoplastic , TBS proposed different subgroups for a correct clinical management. At present, the subgroups are the following: ASCUS a) due to compromised specimen (poor processing or obscuring material); b) with mature intermediate-type cytoplasm; c) in postmenopausal women; d) atypical metaplasia; and e) with orangeophilic cytoplasm. Generally, clinical management of ASCUS presents 3 options: 1) cytologic follow-up (colposcopy only in a persistent diagnosis of ASCUS); 2) colposcopy; and 3) both Human papillomavirus testing and Pap-test. These options may be adopted in the ASCUS type b) and e) whereas in the type c) only in postmenopausal women receiving hormone replacement therapy. In the ASCUS type a), Pap-test should be immediately repeated (processing defects) or after therapy (excessive inflammation). In postmenopausal women not receiving hormone replacement therapy, the Pap-test has to be repeated after topical estrogen therapy. In ASCUS type d), a more aggressive follow-up is needed, such as colposcopy and eventual biopsy. Therefore, in the ASCUS diagnosis an effective communication between cytopathologist and clinician is needed for a correct clinical management.

Carcinoma, Squamous Cell↗

PubMed2001

[Controversial categories in cytopathology of the uterine cervix. II. AGUS: atypical glandular cells of undetermined significance].

AGUS (Atypical Glandular Cells of Undetermined Significance), or AGCUS, is a category for reporting doubtful or suspicious glandular changes of the uterine cervix. Glandular lesions are not well known by the cytopathologist and their cytologic criteria are not completely reproducible. Only with the introduction of The Bethesda System (TBS) in 1988, the presence of endocervical cells is considered essential to correctly evaluate a cervical specimen. The origin of atypical glandular cells, endometrial or endocervical, should be distinguished. Moreover, endocervical AGUS should be further qualified as favor reactive or favor neoplastic or Adeno-carcinoma in situ (AIS) . Recently, it has been proposed to classify endocervical AGUS in a) AIS; and b) AGUS that cannot rule out AIS when incomplete criteria of AIS are present. Moreover, the origin of AGUS is sometimes impossible to know. In these cases, the diagnosis is AGUS not otherwise specified (NOS). The clinical management of AGUS presents different options depending on its origin or its further qualification: cytologic follow-up, colposcopy and eventual biopsy, endocervical or endometrial curettage, hysteroscopy, human papillomavirus typing, etc. including conization and hysterectomy. In conclusion, an appropriate clinical management is needed to detect glandular or squamous lesions that can be frequently identified in the AGUS follow-up.

Female↗

PubMed2001

[The STF Project: Female Tumor Screening].

A pilot study has been carried out to evaluate women's compliance to a screening program for cervical cancer. The study, initiated in 1994, was performed in conjunction with the ACRO project of the CNR by the Italian National Health Institute, in collaboration with La Sapienza University of Rome and the National Institute for Cancer Research in Genoa. A preliminary telephone survey was carried out on a sample of 400 women (200 in Rome and 200 in Genoa) to assess, among other factors, their attitude towards the screening program. Afterwards, an ad hoc advertising campaign was launched and 21,827 women, randomly chosen from the register office's lists, were sent a personal invitation to participate in the screening. Most women showed interest in attending the screening program at the interview, but the percentages of participation were low (25.7% in Genoa and 27.3% in Rome). On the other hand, a high percentage of women who participated in the screening had already had a Pap test in the previous three years (Genoa, 73%; Rome, 76%). The recruiting techniques that were used in this study, and that are commonly used, do not seem to reach the core of the target population for cervical screening, i.e. women who have never had a Pap test or who had a Pap test more than 5 years earlier. New methods of recruiting aimed at categories at risk and based more on direct contacts need to be developed.

Adult↗

PubMed2001

Cervical dysplasia, ploidy, and human papillomavirus status correlate with loss of Fhit expression.

PURPOSE: The tumor suppressor gene, FHIT, has been cloned and mapped at chromosome region 3p14.2, one of the regions most frequently deleted in cervical carcinoma. In this report, we show that the expression of the Fhit protein in relation to human papillomavirus (HPV) subtype, the type of the intraepithelial lesion, HIV-induced immunodeficiency, and the DNA content (ploidy) correlates with the biological behavior of the lesions. EXPERIMENTAL DESIGN: To investigate involvement of the FHIT gene in squamous intraepithelial lesions of low and high grade (LGSILs and HGSILs, respectively) of the uterine cervix, we examined the Fhit protein expression by immunocytochemistry in 131 cervical smears of 96 HIV-seropositive patients (42 with LGSILs and 10 with HGSILs) and 35 HIV-seronegative (5 with LGSILs) persons. RESULTS: Fhit protein was detected in normal cells, whereas dysplastic cells (independently of HPV infection and HPV subtypes) showed reduced expression of Fhit (P = 0.00001). Lesions from 52 HIV-seropositive patients, 42 LGSILs and 10 HGSILs, showed diploid DNA content in 63.5%, aneuploid in 32.7%, and polyploid in 3.8%, but 90% of the HGSILs showed an aneuploid DNA content, and all were infected by HPV 16/18 subtypes. 23.8% of LGSIL cases were associated with HPV 16. CONCLUSIONS: These data clearly suggest that loss of Fhit expression occurs in the early stages of cervical carcinogenesis. Pap test represents one of the most convenient and rapid procedures available in identification of cellular changes; hence, Fhit staining might be used as an useful tool in larger population screening to detect early alteration in cellular behaviors.

Acid Anhydride Hydrolases↗

PubMed2001

Fez1/lzts1 alterations in gastric carcinoma.

PURPOSE: Loss of heterozygosity (LOH) involving the short arm of chromosome 8 (8p) is a common feature of the malignant progression of human tumors, including gastric cancer. We have cloned and mapped a candidate tumor suppressor gene, FEZ1/LZTS1, to 8p22. Here we have analyzed whether FEZ1/LZTS1 alterations play a role in the development and progression of gastric carcinoma. EXPERIMENTAL DESIGN: We examined Fez1/Lzts1 expression in 8 gastric carcinoma cell lines by Western blot, and in 88 primary gastric carcinomas by immunohistochemistry. Twenty-six of these 88 primary gastric carcinomas were also microdissected and tested for LOH at the FEZ1/LZTS1 locus and for mutation of the FEZ1/LZTS1 gene. Furthermore, we studied the FEZ1/LZTS1 gene regulation and transcriptional control and the methylation status of the 5' region of the gene in all 8 gastric carcinoma cell lines. RESULTS: Fez1/Lzts1 protein was barely detectable in all of the gastric cancer cell lines tested and was absent or significantly reduced in 39 of the 88 (44.3%) gastric carcinomas analyzed by immunohistochemistry, with a significant correlation (P < 0.001) to diffuse histotype. DNA allelotyping analysis showed allelic loss in 3 of 17 (18%) and microsatellite instability in 4 of 17 (23.5%) cases informative for D8S261 at the FEZ1/LZTS1 locus. When we compared the presence of LOH with Fez1/Lzts1 expression, we found loss of protein expression in all three of the tumors with allelic imbalance at D8S261. A missense mutation was detected in one case that did not express Fez1/Lzts1. Hypermethylation of the CpG island flanking the Fez1/Lzts1 promoter was evident in six of the eight cell lines examined as well as in the normal control. CONCLUSIONS: Our findings support FEZ1/LZTS1 as a candidate tumor suppressor gene at 8p in a subtype of gastric cancer and suggest that its inactivation is attributable to several factors including genomic deletion and methylation.

Adaptor Proteins, Signal Transducing↗

PubMed2001

[Genetics-based prognosis evaluation of patients surgically treated for sporadic colorectal cancer].

The basic assumption as rationale of this research was that DNA repair genes (MMR system) are at beginning of the genetic mutational cascade causing the induction of oncogenesis of sporadic colorectal cancers as well as their multiclonal heterogeneity. In a previous study the Authors randomly selected, from a series of 256 patients, 29 patients up to the age of 60 years who underwent surgery for colorectal carcinoma with radical intent. All selected cases were considered as sporadic cancers from a clinical point of view, since none of them fulfilled the Amsterdam criteria for HNPCC and familial adenomatous polyposis was included too. Mismatch repair gene proteins expression and, in particular, gene hMSH2 protein was investigated by immunohistochemistry analysis. In 12 cases (41.4%) hMSH2 exhibited strong expression in the tumoral cells as well as in the surrounding mucosa and at distant mucosa. In 14 cases (48.3%) loss of hMSH2 protein expression was observed in tumoral cells and low immunoreactivity was detected in peritumoral mucosa while strong hMSH2 expression was observed in distant mucosa. In a third small group of patients (10.3%) loss of hMSH2 protein expression was detected in tumoral, adjacent and at distance normal mucosa. After a five years follow up, 100% of twelve patients of first group are still alive vs 64.3% of fourteen patients of second group, while in the third group only one patient survives. These results support the hypothesis of an involvement of hMSH2 gene defect in development of a subset of sporadic colorectal cancer. For the patients with strong expression of hMSH2 in the tumoral cells as well as in the surrounding mucosa and at distant mucosa, this parameter could represent an independent criterion for a good prognostic value.

Colorectal Neoplasms↗

PubMed2001

[The significance of "atypical metaplasia" in the follow-up of patients operated for bladder cancer].

BACKGROUND: The aim of this study was to evaluate the clinical usefulness of urinary cytology in the follow-up of patients who under-went surgery for bladder cancer. Particularly, the positive predictive value of urinary cytology and time elapsed between a positive test and the diagnosis of a cystoscopically confirmed bladder tumor are analyzed. METHODS: This study was carried out at the Cytological Laboratory Department of Experimental Medicine and Pathology, University La Sapienza, Rome. Among 230 cases studied since 1996, 30 male patients over 50 were examined (25 with a previous bladder cancer and 5 with a previous prostate cancer) with long time follow-up, who underwent more than two cytological examinations on voided urine (2-12) at pre-fixed intervals. RESULTS: Nine (30%) of the patients suffered from recurrent disease. The cytological examinations was positive in 8 out of the 9 positive cases and negative in 17 out of the 21 negative cases. Absence of disease was confirmed in all the latter cases both by cystoscopic examination and clinical follow-up. One negative case showed clearly malignant cells in more than one specimen taken at different time intervals. This patient is actually under strict control. In 5 cases atypical metaplasia was present in the cytological specimen. In two of those cases cystoscopic examination 5 and 8 months later confirmed progressive disease. In the other three cases cystoscopy showed no evidence of disease. Two of the patients are well and alive after 2 and 14 months respectively. One is dead of prostatic cancer. CONCLUSIONS: Considering the cases of atypical metaplasi as positive the cytological examinations showed 100% sensibility, 81% specificity, a predictive negative value of 1 and a predictive positive value of 0.66.

Follow-Up Studies↗

PubMed2000

nm23-H1 protein expression in anal canal carcinoma: does it correlate with prognosis?

BACKGROUND AND OBJECTIVES: Anatomic extent is not the sole axis of classification of tumors and of tumor patients relevant to treatment planning and estimation of prognosis. This results in the need to demonstrate an improvement in prognostic assessment and choice of therapy achieved by consideration of factors other than TNM. nm23 protein does prevent tumor from metastasizing and may also play a role in the control of growth and development. The purpose of this study was to elucidate the clinical significance of nm23 expression in human anal canal carcinoma and to evaluate its influence on the outcome of patients after surgery or radiochemotherapy. METHODS: Twenty-two patients affected by anal canal carcinoma were evaluated. Each section was incubated with monoclonal antibody nm23 NDPK-A. Immunostaining was considered positive when at least 10% of the tumor cells were immunostained. RESULTS: nm23 immunoreactivity was detected in 6/22 (27.3%) tumors. No significant association was found between nm23 expression and prognosis. CONCLUSIONS: The mechanisms causing enhanced nm23-H1 expression in anal canal carcinoma are unknown. Although the level and expression were not correlated with prognosis, activation of nm23-H1 gene might be a prerequisite for oncogenesis in this type of tumor, while an alternate possibility is the modification of cellular characteristics in relation to proliferation and/or differentiation as a consequence of oncogenesis.

Aged↗