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Biomedical subjects

R Bertorelle

Publications and source records attributed to R Bertorelle.

At least 19 recordsLinked to original sources
PubMed2006

Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO).

The efficacy of temozolomide strongly depends on O(6)-alkylguanine DNA-alkyl transferase (AGAT), which repairs DNA damage caused by the drug itself. Low-dose protracted temozolomide administration can decrease AGAT activity. The main end point of the present study was therefore to test progression-free survival at 6 months (PFS-6) in glioblastoma patients following a prolonged temozolomide schedule. Chemonaïve glioblastoma patients with disease recurrence or progression after surgery and standard radiotherapy were considered eligible. Chemotherapy cycles consisted of temozolomide 75 mg/m(2)/daily for 21 days every 28 days until disease progression. O(6)-methyl-guanine-DNA-methyl-tranferase (MGMT) was determined in 22 patients (66.7%). A total of 33 patients (median age 57 years, range 31-71) with a median KPS of 90 (range 60-100) were accrued. The overall response rate was 9%, and PFS-6 30.3% (95% CI:18-51%). No correlation was found between the MGMT promoter methylation status of the tumours and the overall response rate, time to progression and survival. In 153 treatment cycles delivered, the most common grade 3/4 event was lymphopoenia. The prolonged temozolomide schedule considered in the present study is followed by a high PFS-6 rate; toxicity is acceptable. Further randomised trials should therefore be conducted to confirm the efficacy of this regimen.

Adult↗
PubMed2006

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Adenocarcinoma↗
PubMed2005

Microsatellite instability and gastric non-invasive neoplasia in a high risk population in Cesena, Italy.

BACKGROUND/AIMS: In the natural history of gastric cancer, non-invasive neoplasia (NiN) precedes invasive carcinoma. A histological classification of gastric NiN has recently been proposed by a World Health Organisation international panel of experts. Genetic instability is known to be among the molecular pathways involved in gastric oncogenesis. In this retrospective cross sectional study, microsatellite instability (MSI) was analysed in a consecutive series of NiN and NiN related histological alterations from a northern Italian region at high risk for gastric cancer. PATIENTS/METHODS: Fifty five consecutive cases (indefinite for NiN, 29 cases; low grade NiN, 17 cases; high grade NiN, nine cases) were analysed by radioactive polymerase chain reaction and electrophoresis for microsatellite alterations at six loci (BAT25, BAT26, D2S123, D5S346, D17S250, and D3S1317). MSI was defined according to the Bethesda criteria distinguishing: (1) no instability in the analysed loci; (2) low frequency MSI (MSI-L); and (3) high frequency MSI (MSI-H). Immunohistochemical expression of MLH1 and MSH2 proteins was also analysed in all cases. RESULTS: Overall, MSI was found in 11 of 55 cases (indefinite for NiN, five of 29 (MSI-L, four; MSI-H, one); low grade NiN, three of 17 (MSI-L, one; MSI-H, two); high grade NiN, three of nine (MSI-L, one; MSI-H, two). CONCLUSIONS: In an Italian high risk area for gastric cancer, MSI is part of the spectrum of genetic alterations in gastric non-invasive neoplasia. In European populations at high risk of gastric cancer, DNA repair system alterations are thought to be among the early molecular events in gastric carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Fas ligand is up-regulated during the colorectal adenoma-carcinoma sequence.

AIMS: Fas ligand (FasL) expression by cancer cells may mediate tumour immune privilege. The purpose of the present study was to investigate the timing and significance of FasL expression during the colorectal adenoma-carcinoma sequence. METHODS: FasL expression was studied by immunohistochemistry in 170 formalin-fixed tissue sections representing the entire colorectal adenoma-carcinoma sequence. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to search for FasL mRNA. Analysis of survival was performed in patients with carcinomas. RESULTS: A significant positive linear correlation was found between FasL expression and tumour progression throughout the colorectal adenoma-carcinoma sequence (r(s)=0.677 P<0.001). A pattern of high FasL expression was detected in 19% of high grade adenomas, 40% of stage I-II, 67% of stage III and 70% of stage IV carcinomas. No significant differences were observed between FasL expression in the primary tumours and that in the corresponding liver metastases. The specificity of FasL expression was confirmed at RT-PCR. For stage I-II carcinomas, the 5 year survival was 90% in patients without, or with moderate, tumoural FasL expression compared with 60% in those with high tumoural FasL expression (P<0.05). CONCLUSIONS: Our findings suggest that FasL expression may be involved in the development of colorectal cancer and its progression.

Adenocarcinoma↗
PubMed2001

Polymorphisms in the CCR5 promoter region influence disease progression in perinatally human immunodeficiency virus type 1-infected children.

The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression.

Adolescent↗
PubMed2001

Genital human papillomavirus types in immunocompetent and immunodepressed women in northeast Italy: prevalence and cytomorphological correlations.

OBJECTIVE: We evaluated the prevalence of genital human papillomavirus (HPV) types in correlation with cytomorphological findings in patients at different risk for cervical intraepithelial neoplasia living in northeast Italy. METHODS: Exfoliated cervicovaginal cells from 943 women, who were divided into three groups, were analyzed by polymerase chain reaction. RESULTS: Overall, HPV prevalence rates were 7%, 38%, and 52%, respectively. The single most frequent type was HPV 16 (18%), followed by types 6, 31, 53, 58, 61, and novel/unidentified (5-7%); other types had a frequency <5%. Infection with multiple types was present in 12%. In HIV-infected women, HPV infection was correlated with lower CD4 level and higher viral load; HGSILs were correlated only with a lower CD4 count, and no correlations were found for LGSILs. CONCLUSIONS: HGSILs were associated with high-risk types, mainly HPV 16 (40%). LGSILs, instead, were associated with a broad spectrum of low-risk and high-risk types.

Journal Article↗
PubMed2000

Vulvar carcinoma in a 12-year-old girl with vertically acquired human immunodeficiency virus infection.

We report the first case of a girl with vertically acquired human immunodeficiency virus (HIV) infection, who developed invasive squamous cell carcinoma of the vulva at 12 years of age. Lesions resembling bowenoid papulosis covered the perianal area as well. She underwent a nonmutilating surgical excision of the infiltrating lesion. More than 3 years later, her clinical condition is excellent, although dysplastic, noninfiltrating multifocal lesions persist. This case highlights the need to perform careful periodic genital examinations in all HIV-infected children and adolescents born to HIV-positive mothers.

CD4 Lymphocyte Count↗
PubMed2000

Colposcopy, cytology and HPV-DNA testing in HIV-positive and HIV-negative women.

In this study we examined the incidence of colposcopic-colpocytologic findings and analyzed Human Papilloma Virus (HPV)-DNA testing by Polymerase Chain Reaction (PCR) in 104 Human Immunodeficiency Virus (HIV) serous positive women (Group 1) and 218 HIV-negative women (control Groups 2 and 3). The aim of the study was to evaluate the most appropriate and efficacious diagnostic methods for screening programs for cervical cancer in HIV-positive women. For Group 1 we also considered the value of CD4+ T-lymphocytes and morphologic and molecular follow-up from 3 to 6 months. The results showed that the abnormal transformation zone (ANTZ) was present in 66.3% of the cases in Group 1 compared with 31.4% in control-Group 2 (p<0.001), and with 58.93% of the cases in control-Group 3 (p=0.257); intraepithelial squamous lesions (SIL) were found in 50% vs 5.66% (p<0.001) and vs 56.25% of the cases (p=0.433), respectively. In 28.85% of the HIV-positive patients the first cytological screening exam was not evaluable due to inflammation but in 56.67% of the cases colposcopy revealed ANTZ. The subsequent colpocytological checkup after therapy showed 10 cases (30%) of low risk squamous intraepithelial lesions (LSIL) and two cases (6.6%) of high risk squamous intraepithelial lesions (HSIL). HPV-DNA testing by PCR was positive in 53.8% of the cases in Group 1, in 6.6% in control-Group 2 and in 42% in control-Group 3. In HIV-positive patients multiple HPV genotypes were simultaneously present in 21.43% of the cases and high risk genotypes were present in 70% of the cases of HSIL. In Group 1, 36.61% of the cases had lesions of the lower genital tract. The value of CD4+ T-lympocytes was <200 cells/ml in 30% of the cases of HSIL. Our data, like those of other Authors, confirm a high incidence of HSIL, abnormal colposcopic findings, and HPV infections in HIV-positive women with respect to control-Group 2, while there was not much difference between Group 1 and control-Group 3. Such frequency again suggests that an integrated morphological diagnostic approach with colposcopy-colpocytology in the screening of immunosuppressed subjects would be worthwhile.

Adult↗
PubMed1999

Mutator phenotype in human hematopoietic neoplasms and its association with deletions disabling DNA repair genes and bcl-2 rearrangements.

As mice carrying mutations of the DNA mismatch repair genes MSH2 and MSH6 often develop lymphoid neoplasms, we addressed the prevalence of the replication error (RER(+)) phenotype, a manifestation of an underlying defect of DNA mismatch repair genes, in human lymphoid tumors. We compared microsatellite instability (MSI) at 10 loci in 37 lymphoid tumors, including 16 acute lymphoid leukemias (ALL) and 21 non-Hodgkin's lymphomas (NHL), and in 29 acute myeloid leukemias (AML). Significant differences in MSI prevalence between AMLs and ALLs emerged, and MSI occurrence was more frequent in the NHLs versus AMLs. Indeed, only 3 of 29 (10%) AMLs exhibited MSI, thus confirming its paucity in myeloid tumors, while 10 of 37 (27%) lymphoid tumors, 6 ALLs and 4 NHLs, disclosed an RER(+) phenotype. In 1 ALL patient, the same molecular alterations were observed in correspondence with a relapse, but were not detected during remission over a 14-month follow-up; in another ALL patient, findings correlated with impending clinical relapse. These results suggest that the study of MSI in lymphoid tumors might provide a useful molecular tool to monitor disease progression in a subset of ALLs. To correlate MSI with other known genetic abnormalities, we investigated the status of the proto-oncogene, bcl-2, in the lymphoma patients and found that 4 of 4 NHL patients with MSI carried bcl-2 rearrangements, thus linking genomic instability to enhanced cell survival in NHL; moreover, no p53 mutations were found in these patients. Finally, we addressed the putative cause of MSI in hematopoietic tumors by searching for both mutations and deletions affecting DNA repair genes. A limited genetic analysis did not show any tumor-specific mutation in MLH1 exons 9 and 16 and in MSH2 exons 5 and 13. However, loss of heterozygosity (LOH) of markers closely linked to mismatch repair genes MLH1, MSH2, and PMS2 was demonstrated in 4 of 6 ALLs and 1 of 3 AMLs with MSI. These observations indicate that chromosomal deletions might represent a mechanism of inactivation of DNA repair genes in acute leukemia.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Hepatitis C virus infection associated with human hepatocellular carcinoma: lack of correlation with p53 abnormalities in Caucasian patients.

BACKGROUND: Several lines of evidence indicate that there is a close association between hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC). However, the role of the virus itself in the development of the disease is not yet well understood. METHODS: In liver samples from 15 anti-HCV positive Caucasian patients with HCC, the authors searched for the presence and genomic characteristics of the infecting virus, and also analyzed the p53 gene by single strand conformation polymorphism and sequencing of abnormal bands. RESULTS: In all cases but one, HCV RNA was detected in nonneoplastic liver tissue, whereas in neoplastic tissue, viral sequences were detected in 6 of 6 samples containing moderately differentiated HCC (Edmondson grades I-II) and in 2 of 9 containing poorly differentiated HCC (Edmondson grade III) (P=0.007). Seventy-three percent of the cases were infected by genotype 1 and 20% by genotype 2, whereas the liver cells of 1 patient with a previous history of hepatitis B infection were HCV RNA negative. p53 mutations, observed in 2 patients, consisted of a G-to-A transition at codon 176 of exon 5 in 1 patient and a G-to-T transversion at codon 287 of exon 8 in the other. CONCLUSIONS: The results of this study indicate that HCV may contribute to liver tumor development during the early stages of carcinogenesis, whereas p53 gene mutations were detected only in 2 of 15 patients in this cohort.

Adenine↗
PubMed1998

Nuclear p53 protein expression in resected hepatic metastases from colorectal cancer: an independent prognostic factor of survival.

An association has been reported between nuclear p53 protein expression in tumour cells and a poor outcome in patients with colorectal cancer (CRC). In this study we investigated the prognostic significance of nuclear p53 protein expression in CRC liver metastases after curative hepatic resection. The study population consisted of 69 consecutive patients who underwent curative hepatic resection for metastases from CRC at our Institution between February 1987 and October 1993. Immunohistochemical expression of p53 protein was evaluated in formalin-fixed paraffin-embedded sections of CRC liver metastases using the monoclonal antibodies (MAbs) D01 and Pab 1801. The Cox proportional hazards model was used in forward stepwise regression to assess the relative influence of different prognostic factors. Forty-four (63.8%) CRC liver metastases were p53-positive. Kaplan-Meier survival curves demonstrated that patients with p53-positive metastases had a median survival of 27 months versus 93 months for patients with p53-negative metastases (P < 0.01). The 3 and 5 years survival rates were 31.5 and 21.0% in patients with p53-positive metastases and 71.8 and 53.1% in patients with p53-negative metastases. At multivariate analysis p53 protein status was the single best predictor of survival (P = 0.0079); the odds ratio of death among patients with p53-positive tumours was 2.53. Nuclear p53 protein expression in hepatic metastases from CRC is an independent prognostic factor of survival following liver resection. These findings may be of clinical importance in the selection of patients more likely to benefit from liver resection and could be used as criteria for stratification in trials on adjuvant therapy.

Adult↗
PubMed1996

p53 gene alterations and protein accumulation in colorectal cancer.

Aim-To correlate immunohistochemical staining with single strand conformation polymorphism (SSCP) analysis of the p53 gene in colorectal cancer in order to understand how the findings provided by the two techniques complement each other in defining p53 functional status.Methods-Frozen tumour tissue from 94 patients with colorectal cancer was studied for p53 protein accumulation and gene mutations. Accumulation of p53 protein was detected by immunohistochemistry using PAb1801 and BP53-12-1 monoclonal antibodies. The findings were then compared with SSCP analysis of exons 5 to 8 of the p53 gene. All cases with a positive result by SSCP analysis were confirmed by sequencing.Results-Nuclear staining was observed in 51 (54.2%) cases. SSCP analysis of the DNA amplified by PCR revealed that the electrophoretic pattern had shifted in 30 cases; sequence analysis confirmed the occurrence of a mutation in 29 cases and of a polymorphism in one. In 27 cases both assays gave a positive result, and in 40 both were negative; therefore, concordance between PCR-SSCP and immunohistochemistry was seen in 72% of cases.Conclusion-The data indicate that positive immunostaining corresponds with the presence of a mutation in most, but not all, cases studied; other mechanisms could be responsible for stabilisation and accumulation of p53 protein in the nucleus. Nonsense mutations which do not confer stability on the protein will not be detected by immunohistochemistry and false negative results can also occur with SSCP analysis.

Journal Article↗
PubMed1995

Association of p53 gene and protein alterations with metastases in colorectal cancer.

Using monoclonal antibody PAb 1801, p53 protein was detected in the neoplastic cells of 39 (46.9%) of 83 colorectal carcinomas studied. Patients with p53+ tumors showed a higher incidence of lymph node and liver metastases (p = 0.035); in patients whose tumors were located in the rectosigmoid, p53 expression also correlated with a more advanced stage according to Dukes' classification (p = 0.015) as well as nodal (p = 0.006) and liver (p = 0.019) metastases. Following amplification of exons 5 to 8 of the p53 gene by means of the polymerase chain reaction technique, single-strand conformation polymorphism analysis disclosed an anomalous migration pattern in 23 of the 39 p53+ tumors and in four of the 35 p53- tumors analyzed. Sequence analysis showed G:C-->A:T transitions in 63.6%, G:C-->T:A and G:C-->C:G transversions in 18.2%, deletions and insertions in 13.6%, and A:T-->G:C transitions in 4.6% of the cases. Loss of heterozygosity was studied in the DNA of 79 patients; allelic loss was found in 29 (49.1%) of the 59 informative patients. Loss of heterozygosity was correlated with p53 overexpression (p = 0.0002) as well as with the presence of mutations as detected by single strand conformation polymorphism analysis (p = 0.0024).

Adenocarcinoma↗
PubMed1994

A CD30-positive T cell line established from an aggressive anaplastic large cell lymphoma, originally diagnosed as Hodgkin's disease.

Ten months following the diagnosis of Hodgkin's disease (HD), a 46-year-old woman presented cutaneous and leukemic involvement by CD30+ anaplastic large cells, from which a continuously growing, exogenous growth factor-independent T cell line was established. The cultured cells are phenotypically and genotypically T cell in type, negative for EBV, HTLV-I and HTLV-II viral sequences, and release soluble CD30 into the supernatant. Karyotype analysis disclosed several chromosomal abnormalities, but none on chromosome 5q. The involvement of the short arm of chromosome 17 prompted us to investigate the TP53 gene by means of the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, but no alterations were found in exons 5-8.

DNA, Viral↗