27 research outputs found
Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators
The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM2-P14ARF system. The incidence of such changes has to date not been analysed in non-tumourous livers showing regenerative proliferation. In the present study, 24 cirrhotic livers of alcohol-, autoimmue disorder- or HCV-caused genesis were screened for MDM2-P14ARF alterations at the level of protein, DNA and mRNA. Using confocal laser scanning microscopy, the absence of MDM2 and P14ARF expression was detected in all samples except three HCV-infected livers (four livers) which contained hepatocytes overexpressing MDM2 (P14ARF) protein. In two of the samples lacking P14ARF expression, laser microdissection and PCR demonstrated deletion of the P14ARF gene. The P14ARF gene amplified from other specimens did not carry mutations. MDM2 splicing variants were present in tissues from alcohol- and autoimmune disorder-induced cirrhoses. Sequencing of full-size mRNA revealed a MDM2 mis-sense mutation in an alcohol-induced cirrhosis. One sample contained regenerative nodules with genetic instability occurring at MDM2 locus D12S83 according to the data of automatic PCR fragment analysis. In summary, this study gives first evidence for different types of MDM2 and P14ARF alterations in cirrhotic livers. We suggest that the changes impair the regulatory MDM2-P14ARF system, thus possibly favouring regenerative proliferation and transformation
Correlation of enhanced cell turnover with prognosis of gastrointestinal stromal tumors of the stomach: Relevance of cellularity and p27 Kip1
Estrogen receptor beta 2 is inversely correlated with Ki-67 in hyperplastic and noninvasive neoplastic breast lesions
The prognosis in spindle-cell sarcoma depends on the expression of cyclin-dependent kinase inhibitor p27Kip1 and cyclin E
Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: a phase I/II study conducted by the Hellenic Cooperative Oncology Group
Paclitaxel (lTaxol(R)) and carboplatin are an effective combination
regimen for treating advanced breast cancer. Gefitinib (IRESSA) is the
first epidermal growth factor receptor tyrosine kinase inhibitor to be
approved for cancer treatment. This multicenter phase II trial treated
68 patients with advanced breast cancer with paclitaxel ( 175 mg/ m 2
over 3 h) and 3-weekly carboplatin ( area under the curve of 6) for six
cycles, and 250 mg/ day gefitinib orally. Median age was 57 ( range 35 -
77) years, patients had performance status 0 (69.1%), 1 (27.9%) 2
(2.9%), 82.4% of patients had visceral metastases and 63.2% had
received adjuvant chemotherapy. Forty-eight (70.6%) patients completed
six cycles of chemotherapy and 20 (29.4%) patients discontinued
treatment ( seven [10.3%] due to disease progression, seven [
10.3%] due to toxicity,five [7.4%] withdrew consent and one
[1.5%] died after the first cycle). Sixty-three (92.7%) patients
were evaluable for response; nine (13.2%) had complete responses, 30
(44.1%) had partial responses, 21 (30.9%) had stable disease and three
(4.4%) had disease progression. Grade 3/4 adverse events in >= 5% of
patients except of alopecia, included neutropenia (17.7%), anemia (
10.3%), diarrhea ( 7.4%), thrombocytopenia (5.9%) and peripheral
neuropathy ( 5.9%). Of those tumor biopsies available for
immunohistochemical analysis ( n= 60), 5.0% were positive and 35.0%
negative for expression of all HER-family receptors. Comparable numbers
of tumor biopsies were nuclear p27(kipl) positive and negative (39.7 and
42.7%, respectively), with the majority (72.1%) negative for
cytoplasmic p27(kipl). The observed efficacy data in this study were
similar to those reported for the combination of paclitaxel and
carboplatin alone