Expression of bcl-2, p53 and Ki-67 in arsenical skin cancers

To investigate the regulation of apoptosis and proliferation in arsenic-induced skin cancers, we examined the expression of bcl-2, p53, and Ki-67 using immunohistochemical staining. Thirty patients with Bowen's disease (BD), ten with basal cell carcinoma (BCC), eight with squamous cell carcinoma (SCC) and eleven of perilesional normal skin (PLN) of the non-sun exposure sites from endemic area were examined. The results showed that: 1) bcl-2 was expressed in all of the BCC homogeneously, in none of the SCC, and in 12/30 of the BD focally or homogeneously; 2) p53 was expressed in all of the arsenical skin cancers with a labelling index of 75 +/- 14% of BD, 50 +/- 17% of BCC, 61 +/- 15% of SCC, and also in all of the perilesional normal skin with a labelling index of 55 +/- 24%; 3) Ki-67 was expressed in all of the skin cancers with labelling index of 58 +/- 17% of BD, 12 +/- 7% of BCC, 47 +/- 21% of SCC, and in 9/11 of PLN with a labelling index of 41 +/- 24%. Expression of bcl-2 in BCC or BD is related to the phenotype of germinative basal cell. The constant expression of bcl-2 i early dysplastic cells of BD and the earliest expression of P53 in the basal cells of perilesional normal skin indicate that the initial step of arsenic-induced carcinogenesis is from the basal germinative cells. There is no mutual relationship between bcl-2, p53 or Ki-67 expression in any type of the arsenical skin cancers, but there is a positive correlation between p53 and Ki-67 expression identified in perilesional normal skin. BD had the highest labelling index of p53 and Ki-67.     

Locally recurrent prostate tumors following either radiation therapy or radical prostatectomy have changes in Ki-67 labeling index, p53 and bcl-2 immunoreactivity

Mast cells participate in the host defense against parasites. Mast cells release leukotrienes (LTs), potent 5-lipoxygenase (LO) products of arachidonic acid well-known to be involved in the inflammatory process. After incubation with Toxoplasma gondii, mast cells were found to degranulate and release LTB4; this interaction damages the tachyzoites. This mast cell activity against the tachyzoites was inhibited by the 5-LO inhibitor A-63162 and the 5-LO-activating protein inhibitor MK-886 but not by the cyclooxygenase inhibitor indomethacin. Reactive oxygen species were not implicated in the mast cell-mediated toxoplasmacidal activity. The generation of LTs is important for mast cell secretion, and LTB4 released by mast cells and other inflammatory cells may be a key factor in the host defense against T. gondii.     

Ki-67 and p53 in T2 laryngeal cancer

OBJECTIVE: To study the relationship between the proliferative capacity, represented by the immunohistochemical labeling index (LI) of proliferation marker Ki-67, and the p53 status, as in theory an intact p53 cell cycle checkpoint system should result in a lower proliferative capacity. STUDY DESIGN: From a group of 128 patients with a T2 laryngeal carcinoma, presented from 1989 to 1993 at the University Hospital Utrecht, 20 patients with recurrent disease and 16 patients without recurrent disease were randomly selected. All patients received primary irradiation. METHODS: Denaturing gradient gel electrophoresis and immunohistochemistry determined the p53 status. MIB-1 staining was used to determine the Ki-67 LI. RESULTS: In 36% of specimens we found a p53 mutation with overexpression (LI, 31%). In 8% a p53 mutation without p53 overexpression was found (LI, 18%). Forty-two percent showed no mutation but, nevertheless, overexpression (LI, 35%). Neither mutation nor overexpression was found in 14% (LI, 38%). No correlation exists between p53 status and proliferative capacity of tumors (analysis of variance [ANOVA]; P = .104). The proliferation rate as established with Ki-67 LI positively correlates with response to radiotherapy (P = .006). CONCLUSIONS: 1. Overexpression of wild-type p53 protein does not result in cell cycle arrest measurable by a lower Ki-67 LI in comparison with cases overexpressing mutant type p53 protein. 2. A high Ki-67 LI correlates with a favorable response to radiotherapy.     

Prognostic significance of Ki-67 and p53 antigen expression in carcinomas of bile duct and gallbladder

Ki-67 and p53 protein expression was evaluated immunohistochemically in 32 patients with intrahepatic, extrahepatic bile duct and gallbladder carcinomas, who underwent surgery at First Department of Surgery, The University of Tokushima School of Medicine. p53 expression was found more in the well differentiated group than poorly differentiated group (p = 0.007). MIB1 labelling index (MIB1 LI) was higher in EHC than in GBC (p = 0.0061). MIB1 LI (T), (MIB1 LI in tumor) was higher in cases with lymph node metastasis than in those without lymph node metastasis (p = 0.0189). Moreover, MIB1 LI (L) (MIB1 LI in metastasized lymph node) was higher in poorly differentiated than in well differentiated carcinoma (p = 0.0404). Prognostically, patients with high MIB1 LI (T) (> 56.93) had a worse prognosis after surgery than those with low MIB1 LI (T) (p < 0.05). There was no association between p53 positive tumors and MIB1 expression. These results suggest that cancer cell proliferative activity was markedly increased in cases with EHC compared to those with GBC and the poorly differentiated and lymph node metastasis group. MIB1 LI in tumor was found to be a good prognostic indicator whereas there was no association of p53 positive tumor with MIB1 expression and prognosis of the patients.     

Immunohistochemical expression of p53, MDM2, Ki-67 and PCNA in central giant cell granuloma and giant cell tumor

Central giant cell granuloma (CGCG) is a reactive bone lesion that occurs mainly in the jaws. The giant cell tumour (GCT) is a benign locally aggressive neoplasm located near the articular end of tubular bones. Both lesions are characterised histologically by multinucleated giant cells in a background of ovoid to spindle-shaped mesenchymal cells. There is a basic question whether both lesions are separate entities or variants of the same disease. The study of cell cycle-associated proteins may give insights into clarifying such question. The expression of these proteins is also important to determine the cell cycle regulation in both tumours. The purpose of this study was to evaluate the immunohistochemical expression of p53, MDM2, Ki-67 and PCNA in CGCG and GCT. The results demonstrated that, despite the lack of p53 immunoreactivity, all the samples showed wide expression of MDM2. The percentage of Ki-67- and PCNA-positive cells in CGCG was statistically higher than that of GCT Our findings show that CGCG has a higher proliferative activity compared with that of the GCT. Our results also suggest that p53 inactivation by MDM2 expression may be involved in the pathogenesis of giant cell lesions of the jaws and long bones.     

Primary central nervous system lymphomas in immunocompetent individuals: histology, Epstein-Barr virus genome, Ki-67 proliferation index, p53 and bcl-2 gene expression

We investigated the effects of potassium channel inhibitors on electrical activity, membrane ionic currents, intracellular calcium concentration ([Ca2+]i) and hormone release in GH3/B6 cells (a line of pituitary origin). Patch-clamp recordings show a two-component after hyperpolarization (AHP) following each action potential (current clamp) or a two-component tail current (voltage-clamp). Both components can be blocked by inhibiting Ca2+ influx. Application of D-tubocurarine (dTc) (20-500 microM) reversibly suppressed the slowly decaying Ca2+-activated K+ tail current (I AHPs) in a concentration-dependent manner. On the other hand, low doses of tetraethylammonium ions (TEA+) only blocked the rapidly decaying voltage- and Ca2+-activated K+ tail current (I AHPf). Therefore, GH3/B6 cells exhibit at least two quite distinct Ca2+-dependent K+ currents, which differ in size, voltage- and Ca2+-sensitivity, kinetics and pharmacology. These two currents also play quite separate roles in shaping the action potential. d-tubocurarine increased spontaneous Ca2+ action potential firing, whereas TEA increased action potential duration. Thus, both agents stimulated Ca2+ entry. I AHPs is activated by a transient increase in [Ca2+]i such as a thyrotrophin releasing hormone-induced Ca2+ mobilization. All the K+ channel inhibitors we tested: TEA, apamin, dTC and charybdotoxin, stimulated prolactin and growth hormone release in GH3/B6 cells. Our results show that I AHPs is a good sensor for subplasmalemmal Ca2+ and that dTc is a good pharmacological tool for studying this current.     

bcl-2, p53 immunophenotypes and apoptosis in squamous cell carcinoma of the oesophagus

To establish baseline information on neopterin concentrations in livestock, companion and laboratory animals and identify the factors that may influence these concentrations, blood samples were taken from normal dairy cattle, horses, llamas, dogs, cats and rats of varying ages and sexes. In addition, neopterin concentrations in normal, adult equines were compared with those found in racing Thoroughbreds. There were no differences due to sex, sexual maturity, pregnancy, castration, or age. For all ages and sexes combined, mean neopterin concentrations were significantly lower in llamas (2.27+/-0.33 nmol litre(-1)) and rats (2.13+/-0.21 nmol litre(-1)) when compared with the other species tested. Racing Thoroughbreds demonstrated higher neopterin values than adult equines not in training (3.54+/-0.64 vs 3.13+/-1.02 nmol litre(-1)).     

Apoptotic death of tumor cells correlates with chemosensitivity, independent of p53 or bcl-2

p53 has been implicated as a determinant of chemosensitivity and radiosensitivity. We measured chemosensitivity of human tumor cell lines (n = 11), with or without wild-type p53, following exposure to clinically useful chemotherapeutic drugs (n = 4). Chemosensitivity and apoptosis induction were correlated independently of p53 status or Bcl-2 protein levels in vitro. Wild-type p53 correlated with chemosensitivity in ovarian carcinoma and some Burkitt's lymphoma cells, but not in leukemia or lung cancer. Bcl-2 levels correlated with chemoresistance only in Burkitt's lymphoma. p53-dependent p21(WAF1/CIP1) induction and cell cycle arrest occurred at sublethal doses of chemotherapy, whereas at lethal doses of chemotherapy apoptotic death was observed, consistent with models proposing a relationship between the level of DNA damage versus survival or death. Loss of apoptosis induction was observed in drug-resistant ML-1 and HL-60 leukemia cells, without changes in p53 or Bcl-2. Targeted loss of p53 protein in H460 lung cancer cells using HPV-16 E6 inhibited the etoposide-induced G1 checkpoint but did not decrease chemosensitivity. Our studies suggest that the simple measurement of apoptosis induction may be a useful predictor of chemosensitivity, at least in vitro, and confirm that p53 status and Bcl-2 expression may be useful predictors of chemosensitivity in certain cell types.     

膀胱癌组织中MMP-2与TIMP-2 mRNA的表达及临床意义

Objective:The aim of the study was to investigate the expressions of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of MMP-2 (TIMP-2) mRNA in transitional cell carcinomas of bladder and discuss their clinical significances.Methods:Using RT-PCR and real time quantitative PCR (RQ-PCR) technique, the expressions of MMP-2 and TIMP-2 mRNA of 45 cases of bladder carcinoma (tumor group) and 10 cases of normal bladder tissue (control group) were analyzed. Results:MMP-2 and TIMP-2 were not expressed in control group. MMP-2 was expressed in 30 cases tumor samples and TIMP2 was expressed in 26 cases. The expression of MMP-2 mRNA in non-muscle invasive bladder cancers and grade I cancers significant (P < 0.05). The expression of MMP-2 in recurrent patients was higher than that in incipient patients. TIMP-2 mRNA expression decreased with grades and stage. The expression of TIMP-2 in non-muscle invasive bladder cancers and statistical difference between two groups (P < 0.05). TIMP-2 expression in incipient patients was higher than that in recurrent patients, but the difference was not significant (P > 0.05). Conclusion:These results suggest that MMP-2 and TIMP-2 play an important role in the invasion step of transitional cell carcinoma of bladder. MMP-2 may become a new approach to the diagnosis of bladder carcinoma.     

Clinical relevance of p53 index and expression of proliferating cell nuclear antigen and Ki-67 in gastric cancer

To improve the therapeutic outcome for inoperable non-small-cell lung cancer, we applied definitive thoracic radiotherapy combined with concurrent administration of carboplatin and etoposide. We retrospectively analyzed 55 eligible patients with Stage III disease. The one-year rate of overall survival (OAS) and distant metastasis-free survival (DMFS) of the total group were 46.1% and 36.1%, respectively. Twenty-nine patients developed thoracic failures (52.7%) and 23 (41.8%) distant failures. Using univariate and multivariate analyses, radiation dose, performance status and LDH were revealed as significant prognostic factors of OAS, and LDH had a strong adverse effect on DMFS. Leucopenia of Grade 3 or higher was noted in 75.9%, anemia in 55.6%, thrombocytopenia in 59.3%, esophagitis in 20.4%, and lung injury in 10.9%. Sufficient gain was not obtained by our strategy, and higher morbidity, especially of lung, was noted than was expected. It was suspected that simultaneous use of oral etoposide might increase radiation pneumonitis, so one should take special care of unexpected toxicity in concurrent chemoradiotherapy. Both the hyperfractionated technique of radiotherapy and the time-dose modification of anti-tumor drugs should be considered in further steps.     

p53 is a persistent and predictive marker in advanced ovarian carcinomas: multivariate analysis including comparison with Ki67 immunoreactivity

p53 mutation and p53 protein overexpression are common findings in ovarian carcinomas. In order to evaluate the prognostic significance of the p53 status and its role in metastasis, we examined 104 ovarian carcinomas, among them 83 cases with follow-up data, and 40 pairs of primary tumors and metastases, by p53 immunohistochemistry and temperature-gradient gel electrophoresis. Comparison of primary tumors and their metastases revealed identical results in 88%-90% of the cases, indicating that, in most cases, mutant p53 occurs prior to metastatic spread and remains clonally conserved. With respect to all tumors, moderate/high p53 expression was significantly more prevalent in serous-papillary types, carcinomas with high grade, and high Ki67 scores, but was not associated with age, stage, or hormone receptor status. Kaplan-Meier analysis of 83 cases, followed-up for 9-96 months, demonstrated that moderate/high p53 overexpression in the group of 66 stage T3/M1 tumors was associated significantly (P = 0.0028 and P = 0.0105) with shorter overall and recurrence-free survival. Multivariate analysis revealed that advanced clinical stage and p53 positivity were the only independent predictive variables. No significance was seen in regard to second-look results and outcome of 50 patients receiving platinum-based chemotherapy. These observations show that p52 immunohistochemistry is an independent prognostic indicator at the given cut-off level, but does not reliably predict chemotherapy response.     

Molecular screening of multifocal transitional cell carcinoma of the bladder using p53 mutations as biomarkers

Thirteen of 28 patients (46%) with grade 2-3 multifocal transitional cell carcinoma (TCC) of the bladder were found to have p53 mutations using DNA sequence analysis. These were subsequently utilized as tumor-specific biomarkers. Analysis of 17 episodes of recurrence from five of the patients revealed that all but one carried the identical mutation to the primary tumor. Thirty urine samples were collected, at initial diagnosis and during follow-up screening, from eight patients with mutations over a period of 24 months. Sequence analysis of PCR products generated from DNA extracted from the urine sediments was carried out. The p53 mutation seen in the primary tumors was detectable in 24 of 30 urine samples. The remaining six cases coincided with a negative cystoscopic examination. Interestingly, 6 of the 24 urine samples in which mutations were detectable also coincided with negative cystoscopy. The results are consistent with: (a) monoclonality of multifocal TCC; (b) the spread of TCC through a seeding mechanism; and (c) the long-term persistence of tumor cell clones (up to 97 months) within the bladder, even in the absence of obvious tumor growth.     

Gene mutations and increased levels of p53 protein in human squamous cell carcinomas and their cell lines

Using immunocytochemical and Western blotting techniques we have demonstrated the presence of abnormally high levels of p53 protein in 8/24 (33%) of human squamous cell carcinomas (SCC) and 9/18 (50%) of SCC cell lines. There was a correlation between the immunocytochemical results obtained with eight SCC samples and their corresponding cell lines. Direct sequencing of PCR-amplified, reverse transcribed, p53 mRNA confirmed the expression of point mutations in six of the positive cell lines and detected in-frame deletions in two others. We also detected two stop mutations and three out-of-frame deletions in five lines which did not express elevated levels of p53 protein. Several of the mutations found in SCC of the tongue (3/7) were in a region (codons 144-166) previously identified as being a p53 mutational hot spot in non-small cell lung tumours (Mitsudomi et al., 1992). In 11/13 cases only the mutant alleles were expressed suggesting loss or reduced expression of the wild type alleles in these cases. Six of the mutations were also detected in the SCCs from which the lines were derived, strongly suggesting that the mutations occurred, and were selected, in vivo. The 12th mutation GTG-->GGG (valine-->glycine) at codon 216 was expressed in line SCC-12 clone B along with an apparently normal p53 allele and is to our knowledge a novel mutation. Line BICR-19 also expressed a normal p53 allele in addition to one where exon 10 was deleted. Additionally 15 of the SCC lines (including all of those which did not show elevated p53 protein levels) were screened for the presence of human papillomavirus types 16 and 18 and were found to be negative. These results are discussed in relation to the pathogenesis of SCC and the immortalisation of human keratinocytes in vitro.     

Detection and clinical pathological significance of the expression of P21, P185, p53 proteins and mutation of ras, p53 genes in transitional cell carcinoma of the bladder

OBJECTIVE: In order to observe the effects of inhaling nitric oxide (NO) on acute lung injury (ALI). METHODS: 24 rabbits divided into 4 groups. Six rabbits injured with intravenous E. Coli endotoxin, then followed by treatment of inhaling 80 ppm NO in inspired gas. Before and after the infusion of endotoxin, the mean pulmonary arterial pressure (mPAP), mean systemic arterial pressure (mPSA) and the PaO2 were examined. The venous methemoglobin (MHb) was measured by using spectrophometer colorimitry. The extravasculur lung water was evaluated with rate of dried to wet lung weight at the end of study. RESULTS: The rabbits injured with endotoxin inhaling 80 ppm NO could rapidly reduce the mPAP, increase the PaO2 and without inducing significant change of mPSA, MHb and extravasculur lung water. CONCLUSIONS: Inhalation of 80 ppm NO can selectively cause pulmonary artery dilatation, reduce mPAP, improve pulmonary gas exchange, without producing system vasodilation and toxic effects to the rabbits.     

DNA ploidy and MYC DNA amplification in ovarian carcinomas. Correlation with p53 and bcl-2 expression, proliferative activity and prognosis

There is increasing evidence that DNA ploidy is a prognostic factor in ovarian carcinomas, but it is uncertain whether MYC DNA amplification is an epiphenomenon of DNA nondiploidy or a distinct biological change with an impact on the clinical course of the disease. To clarify these issues we analysed DNA ploidy by flow and image cytometry and MYC copy number by polymerase chain reaction in archival material from ovarian carcinomas with known follow up. The results were compared with proliferative activity (Ki67 index) and p53 and bcl-2 expression. DNA cytometry revealed nondiploidy in 84 of 144 cases (58.3%). Nondiploidy was statistically significantly correlated with histological tumour type, histological grade, Ki67 index > 10%, FIGO stage, presence of residual tumour after debulking surgery and adverse postoperative outcome. Furthermore, DNA nondiploidy was associated with p53 accumulation. We found that 84.9% of the p53-positive cases were nondiploid. This points to the paramount importance of wild type p53 for the maintenance of genome integrity in this tumour type. MYC DNA amplification was seen in 33.8% (26/77 cases) of ovarian carcinoma. There was no correlation between MYC DNA amplification and histological tumour type, histological grade, FIGO stage, DNA ploidy, proliferative activity or prognosis. However, when p53 and bcl-2 expression was taken into account, a statistically significant correlation between gene alteration or expression patterns and histological tumour type was revealed. The group of mucinous carcinomas demonstrated both MYC DNA amplification and strong bcl-2 expression in 50% and contained the largest fraction of cases without aberration (37.5%). Endometrioid carcinomas were characterized by strong bcl-2 expression in 85%, whereas serous and undifferentiated carcinomas predominantly exhibited p53 alterations, frequently accompanied by bcl-2 overexpression or MYC DNA amplification. Thus, in interaction with other genes MYC DNA amplification may play a role in the determination of the varying differentiation patterns of ovarian carcinomas.     

Spindle cell carcinoma of the breast: a case report and an immunohistochemical study including p53 and Ki-67 expression

A rare case of spindle cell carcinoma (SpCC) of the breast occurring in a 51-year-old Japanese woman is reported. A firm and well-circumscribed tumor, measuring 9 x 8.5 x 8.5 cm, was located on the upper lateral region of the right breast. Microscopically, the tumor consisted of sheets of both malignant spindle cells and poorly differentiated ductal carcinoma containing squamoid islands with gradual transition to the spindle cell component. The immunocytochemical expression of epithelial markers was recognized in the spindle cells, as well as in the carcinomatous cells. Moreover, the spindle cell component expressed vimentin, alpha-smooth muscle actin and S-100 protein. Ultrastructurally, in addition to the features of adenocarcinoma, squamous or myoepithelial differentiation was confirmed in the spindle cell component. These findings thus suggest an epithelial origin with squamous differentiation and myoepithelial participation in the genesis of SpCC. In a comparative study, the expression of p53 protein and Ki-67 as a proliferation marker in each component of this tumor was also investigated. The mean p53 labeling index (LI) in both the carcinomatous and spindle cell area was similar, however the mean MIB-1 LI in the spindle cell area was significantly higher than that in the carcinomatous area. The results indicate that p53 overexpression is involved in the tumorigenesis of both components in the SpCC, and the spindle cell component shows a higher degree of proliferative activity than the carcinomatous component.     

Expression of topoisomerase II, bcl-2, and p53 in three human brain tumor cell lines and their possible relationship to intrinsic resistance to etoposide

We characterized three human brain tumor cell lines (D54, HBT-20, and HBT-28) with respect to resistance to etoposide (VP-16), a topoisomerase II-reactive drug. All three cell lines were inherently resistant to VP-16 when compared to other human cell lines, with D54 showing the greatest resistance using colony formation assays. Resistance to VP-16 has been attributed to decreased drug uptake and changes in topoisomerase II; however, drug uptake and topoisomerase II protein levels (immunoblot) were no lower in D54 than in HBT-20 and HBT-28, cell lines relatively more sensitive to VP-16. More to the point, measurement of topoisomerase II-mediated DNA cleavage of cellular DNA after treatment with VP-16 showed that the topoisomerase II in these cells was active. These data indicate mechanisms other than those attributable to decreased drug uptake or altered topoisomerase II exist for clinical resistance to VP-16. VP-16-induced DNA cleavage has been associated with apoptosis in some cell lines; however, neither DNA laddering nor morphological changes characteristic of apoptosis were detected in these cell lines after treatment with VP-16. Bcl-2 and mutant p53 were present in these cells. Either of these conditions can prevent apoptosis and could explain a dissociation between the proximal mediator of VP-16-induced cytotoxicity (topoisomerase II-DNA complex formation) and cellular death.     

Distinction of basaloid carcinoma of the prostate from benign basal cell lesions by using immunohistochemistry for bcl-2 and Ki-67

The distinction of rare basaloid carcinomas (BC) of the prostate from more common basal cell hyperplasia may be difficult, because basal cell hyperplasia (BCH) may have prominent nucleoli and may appear infiltrative. Using immunohistochemistry, we studied bcl-2 and p53 expression and Ki-67 proliferation index in eight cases of typical BCH, eight cases of BCH with nucleoli, and six cases of BC. Bcl-2 expression (P < .0001) and Ki-67 index (P=.005) were elevated in BC compared with typical BCH or BCH with nucleoli, whereas there was no significant difference between typical BCH and BCH with nucleoli. P53 was not discriminative in separating benign from malignant basal cell lesions of the prostate. Bcl-2 may play a role in the pathogenesis of basal cell lesions of the prostate. Elevated expression of bcl-2 and higher Ki-67 index may aid in the diagnosis of basal cell proliferative lesions of the prostate.     

Intratumor pO2, S-phase fraction and p53 status in cervix carcinomas

PURPOSE: Investigation whether tumor tissue oxygenation is influenced by proliferation or p53-status in cervical cancers. MATERIAL AND METHODS: From April 1995 through December 1996, 28 patients with locally advanced cervical cancers (age 36 to 78 years; FIGO stages: 10 patients IIB, 16 patients IIIB, 2 patients IVA) underwent intratumoral measurement of pO2 prior to definitive radiotherapy. The histological specimens were examined for grading and quantitative immunohistological expression of the MIB-antigen and p53-protein. Proliferation was estimated by measuring the S-phase fraction with flow cytometry. RESULTS: The median pO2-values showed a broad variation from 2.2 through 60.4 mm Hg, median 19.7 mm Hg. The S-phase fraction varied from 4.2 through 34.2% (median 11.6%), MIB-positive cells from 20 through 100% (median 74%), and immunohistologically p53-positive cells from 0 through 95% (median 2%). The patients were divided in 2 groups according to the pretreatment pO2. Tumors with a pO2 above the median had a lower S-phase fraction than tumors with a pO2 below the median, 10.4 +/- 3.8% versus 16.3 +/- 5.5%, p < 0.02. MIB and p53 were not different in both groups (MIB: 68.1 +/- 27.7% versus 75.0 +/- 18.4%, p = 0.1; p53: 26.4 +/- 38.5% versus 18.1 +/- 19.8%, n. s.). Grade of differentiation and FIGO stage had no impact on pO2. CONCLUSION: Locally advanced cervical cancers with a poor oxygenation have a higher proliferative activity. Tumor proliferation may play a causative role for the development of hypoxia as suspected from radiobiological theories.     

bcl-2 and p53 immunophenotypes in pre-invasive, early and advanced oesophageal squamous cancer

AIMS: An inverse correlation between bcl-2 and p53 expression has been reported in several types of epithelial tumour. The role of bcl-2 and p53 in the development of oesophageal squamous carcinoma has yet to be established. The expression of bcl-2 and p53 proteins has been evaluated in the multistage oesophageal tumorigenesis, which progresses from normal mucosa to dysplasia (squamous intraepithelial lesion, SIL), to invasive early and advanced oesophageal squamous cancer. METHODS AND RESULTS: Sixty-four cases of squamous oesophageal cancer, coexisting with SIL in 18 cases, were immunohistochemically analysed for any overexpression of bcl-2 and p53 proteins. Any association of bcl-2 and p53 protein expression with patient survival was also analysed. We observed bcl-2 expression that decreased significantly during the progression of oesophageal carcinogenesis. A decreasing frequency in the expression of bcl-2 in advanced oesophageal squamous cancer coincided with frequent p53 overexpression. bcl-2 expression was correlated with patient survival by univariate analysis. The association disappeared after adjusting for tumour stage, p53 overexpression showed no association with patient survival by either univariate or multivariate analysis. CONCLUSIONS: The down-regulation of bcl-2 and upregulation of p53 in advanced oesophageal squamous cancer suggest that bcl-2 and p53 proteins may interact in the progression of oesophageal squamous cancer.