Relationship of tumor angiogenesis and nuclear p53 accumulation in invasive bladder cancer

The purpose of this investigation was to evaluate the relationship between tumor angiogenesis and nuclear p53 accumulation in invasive bladder cancer. We studied 161 patients with invasive transitional cell carcinoma of the bladder who had previously undergone radical cystectomy. Analysis was performed to determine the presence of p53 nuclear accumulation and extent of tumor-associated angiogenesis. p53 status identified a group of patients at high risk for tumor progression (p53-altered tumors), and microvessel density determinations added additional prognostic information by identifying a subset of aggressive tumors within the wild-type p53 subgroup. At 5 years, patients with tumors exhibiting no evidence of p53 alterations and low microvessel counts demonstrated 3% recurrence and 88% survival, compared to 43% recurrence and 59% overall survival for patients with intermediate vessel counts and 61% recurrence and 43% overall survival for patients with the highest vessel counts (P < 0.001 and P = 0.003, respectively). Angiogenesis also provides additional prognostic information to patients with tumors that demonstrate p53 alterations. An association between angiogenesis and p53 status did exist (P = 0. 05); however, 27% of the tumors that showed no evidence of p53 alterations exhibited high microvessel counts, and 26% of tumors with evidence of p53 alterations had low microvessel counts. Tumor-associated angiogenesis adds additional useful prognostic information to that which is obtained from p53 status in patients with invasive transitional cell carcinoma of the bladder. Although an association between p53 status and the degree of angiogenesis was identified, other factors appear to play a role in the regulation of tumor-induced neovasularization.     

Effect of ramipril on heart rate variability in digitalis-treated patients with chronic heart failure

Bilharzial-related bladder carcinoma (BBC) is the most common malignant neoplasm in Egypt, also occurring with a high incidence in other regions of the Middle East and East Africa. The clinical and pathological features of BBC are different than those described for the conventional transitional cell carcinoma of the bladder, including the high incidence of squamous cell carcinoma reported in BBC and the fact that over 90% of BBC cases at presentation are advanced-stage tumors (P3 and P4). This study was conducted to better define the phenotypic alterations associated with BBC affecting the p53 cell cycle control pathway, including altered patterns of expression of downstream effector proteins such as mdm2 and p21/WAF1. A well-characterized cohort of 125 patients affected with bilharzial-related bladder tumors was studied. Tumors were classified as squamous carcinomas (n = 68), transitional cell carcinomas (n = 55), or adenocarcinomas (n = 2). The products encoded by TP53, mdm2, and p21/WAF1 genes were analyzed by immunohistochemistry. Furthermore, the patterns of expression of these molecules were correlated with the Ki67 proliferative index. In addition, the microanatomical distribution of programmed cell death was assessed in a subset of tumors, using the so-called terminal deoxynucleotidyl transferase-mediated nick end labeling method. p53 nuclear overexpression was identified in 25 (20%) of 125 cases. Nuclear overexpression of mdm2 was detected in 74 (59.2%) of 125 cases. There was a statistically significant association between coexpression of both p53 and mdm2 and detection of lymph node metastases (P = 0.04). p21/WAF1 expression was detected in 87 (72%) of 121 evaluable cases. A high Ki67 proliferative index was observed in 99 (86%) of 115 evaluable cases. There was a statistically significant association between high Ki67 proliferative index and mdm2-positive phenotype (P = 0.005) and deep muscle invasion (P3b; P = 0.026) as well as lymph node metastases (P = 0.039). Apoptosis was observed in terminally differentiated tumor cells identified in the superficial layers of well-differentiated squamous carcinoma or exfoliating cells in transitional lesions. However, only rare apoptotic tumor cells were found in basal or suprabasal layers as well as in the invasive elements of the neoplasms studied. These results suggest that the frequency of p53 nuclear overexpression in BBC is lower than that reported for conventional transitional cell carcinoma. Nevertheless, tumors with p53 alterations have a greater propensity to progress. The prominent number of cases displaying an mdm2-positive phenotype suggests that this may be an early incident in BBC and should be regarded as a potential oncogenic phenomenon. This is supported by the significant correlation between high Ki67 proliferative index and mdm2 overexpression. The association of an aggressive clinical course with the coexpression of both p53 and mdm2 products might be viewed as a cooperative effect that develops in tumor progression.     

Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53

Rb protein (pRb) expression was evaluated in 185 cases of transitional cell carcinoma of the bladder from patients that underwent radical cystectomy. Tumors were stratified into three categories based on the percentage of nuclei expressing pRb: (a) 0, 0% of tumor cells showing nuclear reactivity; (b) 1+, 1-50% of tumor cells showing nuclear reactivity; and (c) 2+, >50% of tumor cells showing nuclear reactivity. Cases with undetectable (pRb 0) and high (pRb 2+) pRb reactivity had identical rates of recurrence. These cases had significantly higher recurrence (P = 0.0001) and lower survival rates (P = 0.0002) compared to cases with moderate (pRb 1+) pRb reactivity, indicating that high levels of pRb expression may reflect a dysfunctional (altered) Rb pathway. The tumors were also examined for alterations in p53 expression; patients with tumors altered in both p53 and pRb had significantly increased rates of recurrence (P < 0.0001) and survival (P < 0.0001) compared to patients with no alterations in either p53 or pRb; patients with alterations in only one of these proteins had intermediate rates of recurrence and survival. These results suggest that: (a) bladder cancers with high pRb expression do not show the tumor suppressor effects of the protein; and (b) alteration in both p53 and pRb may act in cooperative or synergistic ways to promote tumor progression.     

Circadian food anticipation persists in capsaicin deafferented rats

Accumulation of p53 and C-Myc overexpression are frequently found in advanced urothelial carcinomas. The prevalence and predictive value of both molecular alterations was investigated in 61 patients with superficial urothelial tumors. Distinct patterns of p53 accumulation and C-Myc overexpression were observed in superficial urothelial carcinoma of different stages. For instance, 67% of carcinomata in situ displayed accumulation of p53, but only 44% showed C-Myc overexpression, whereas in pT1 tumors the corresponding percentages were 25 and 75%. Similarly, while p53 accumulation was significantly (p = 0.02) associated with tumor grade, C-Myc overexpression did not correlate with grade. In multivariate analysis, p53 accumulation was found to be an independent predictor of tumor progression (p = 0.0096), whereas C-Myc overexpression did not correlate with the course of disease. Alterations in both markers together predicted neither tumor recurrence nor tumor progression better than p53 accumulation on its own. Sufficient expression of C-Myc may be a general requirement for proliferative competence in urothelial tumors, barring its use as a predictive marker. The predictive value of p53 accumulation for tumor progression was further underlined by the finding that in a distinct group of 52 patients with progressive urothelial carcinoma 73% of the recurrent tumors displayed p53 accumulation.     

Apoptosis loss and bcl-2 expression: key determinants of lymph node metastases in T1 breast cancer

The Bcl-2 proto-oncogene extends cell survival but does not confer any proliferative advantage to cells that express it. Thus, the loss of apoptosis may have a role in progression allowing the acquisition of additional mutations. To determine whether apoptosis loss at diagnosis is associated with the metastatic advantage of ductal breast carcinomas and to examine the relationship between Bcl-2 expression, p53, and tumor cell death status, we examined tumor samples from 116 patients diagnosed with T1 (2 cm or less) breast cancer with (n = 49) or without (n = 67) lymph node metastases. Apoptosis loss in histological sections was considered when <1% of tumor nuclei were stained with terminal deoxynucleotidyl transferase labeled with biotin. We studied the expression of Bcl-2 and p53 by immunohistochemistry and in 37 p53 mutations by single-strand conformational polymorphism analysis and cycle sequencing. Multivariate logistic regression modeling was used to estimate prevalence odds ratios (pORs) for apoptosis loss and presence of lymph node metastases. Patients with marked apoptosis loss in their tumor cells were about 5 times more likely to present lymph node metastases than those with no apoptosis loss in their tumor cells (adjusted pOR, 4.7; 95% confidence interval, 1.4-15.6; trend test, P = 0.008). Bcl-2 expression was strongly associated with both apoptosis loss (pOR, 6.9; trend test, P < 0.0001) and presence of lymph node metastases (pOR, 5.7; trend test, P = 0.002). These associations were more evident in histological grade I and II tumors than in poorly differentiated histological grade III tumors and in p53-negative tumors than in p53-positive tumors. This study demonstrates for the first time that the lymphatic progression of T1 human breast cancer is strongly related to apoptosis loss.     

c-myc copy number gains in bladder cancer detected by fluorescence in situ hybridization

Amplification and overexpression of c-myc have been suggested as prognostic markers in human cancer. To assess the role of c-myc gene copy number alterations in bladder cancer, 87 bladder tumors were examined for c-myc aberrations by fluorescence in situ hybridization. Dual labeling hybridization with a repetitive pericentromeric probe specific for chromosome 8 and a probe for the c-myc locus (at 8q24) was performed to analyze c-myc copy number in relation to chromosome 8 copy number on a cell by cell basis. A clear-cut c-myc amplification (up to 40 to 150 copies per cell) was found in 3 tumors. There was a low level c-myc copy number increase in 32 of the remaining 84 tumors. There was no association of low level c-myc copy number increase with c-myc protein overexpression. This suggests that a c-myc gene copy number gain as detected by fluorescence in situ hybridization does not necessarily reflect a disturbed c-myc gene function but may indicate a structural chromosome 8 abnormality including gain of distal 8q. The strong association of low level c-myc (8q) gains with tumor grade (P < 0.0001), stage (P < 0.0001), chromosome polysomy (P < 0.0001), p53 protein expression (P = 0.0019), p53 deletion (P = 0.0403), and tumor cell proliferation (Ki67 labeling index; P = 0.0021) is consistent with a role of chromosome 8 alterations in bladder cancer progression.     

Rb and p16INK4a expression in resected non-small cell lung tumors

Inactivation of the cyclin-dependent kinase inhibitor p16INK4a (CDKN2/MTS1) is documented in a wide variety of cancer cell lines and tumors. We have shown that loss of p16INK4a protein expression is a common event in early stage non-small cell lung cancer (NSCLC), correlates with a significantly worse survival, and is more common in higher stage disease. One hundred NSCLC tumors from patients undergoing definitive thoracotomies at a single institution were examined for p16INK4a and retinoblastoma protein (pRB) expression. Abnormal pRB staining was identified in 15% of the tumors, whereas 51% possessed aberrant p16INK4a protein expression. Tumors with aberrant expression of p16INK4a by immunohistochemistry were associated with a significantly worse survival (P=0.04). Additionally, the inverse correlation of pRB and p16INK4a expression previously noted in lung cancer cell lines and tumors was confirmed in this large cohort of patients, with 65% of the tumors demonstrating inverse expression of pRB and p16INK4a (p=0.00019). A statistically significant increase in aberrant p16INK4a expression, as well as inverse expression of p16INK4a and pRB, was seen with increasing pathological stage of disease. These findings establish the prognostic significance (of the absence of p16INK4, in resected NSCLC and confirm the critical importance of disrupting the pathway of cyclin-dependent kinase-mediated phosphorylation of pRB in the molecular oncogenesis and progression of NSCLC.     

Abdominal complications after heart surgery interventions]

Transitional cell carcinoma of the bladder is heterogeneous and unpredictable. Tumor with similar clinicopathological parameters display different progression patterns. There is a need for a better management of these lesions, adapting the therapeutic load to tumor aggressiveness. Among various molecular abnormalities associated with tumor progression, analysis of p53 gene and/or p53 gene product, appears as a critical event. p53 mutation is observed in 34% of cases. Nuclear overexpression of p53 protein by mean of immunohistochemistry on tissue specimens and p53 gene mutations detectable on bladder washings may in the future implement histopathological and cytological analysis on routine preparations. Methods of standardisation and comparison between markers, are necessary in order to plan prospectives studies. These data strongly suggest that p53 gene and gene product alterations may be used as a clinically relevant tumor marker for bladder cancer.     

Expression of p53 protein in colorectal cancer and its relationship to cell proliferative activity and prognosis

The expression of p53 protein in 66 cases of colorectal cancer and its relationship to cell proliferative activity, lymph node metastasis as well as prognosis were investigated by means of AB-PAP immunohistochemical technique. The results showed that 62.1% of colorectal cancer was positive. The cell proliferative activity and the frequency of lymph node metastasis in p53-positive cases were significantly higher than those of p53-negative cases (P < 0.05). The survival rate in patients with p53-positive tumors was significantly shorter than those with p53-negative tumors (P < 0.05). Our results suggest that the abnormal expression of p53 and cell proliferation associated with mutations are involved in both human carcinogenesis and lymph node metastasis of colorectal cancer. Examination of p53 expression is of value in understanding the degree of malignancy, and evaluating prognosis of the disease.     

Uterine papillary serous carcinoma evolves via a p53-driven pathway

Uterine papillary serous carcinoma (UPSC) is a highly aggressive type of endometrial cancer that occurs in the absence of hyperestrogenism and endometrial hyperplasia. Biologically, UPSC belongs to a distinct group of aggressive neoplasms of the extended Müllerian epithelium that are characterized by hypoestrogenism, advanced disease at diagnosis, a serous papillary histotype, and a dismal prognosis. There is mounting evidence that loss of p53 function is critical for the molecular genetic cause of all tumors in this group. To further assess the role of p53 alterations in UPSC, we studied 40 patients using immunohistochemical expression analysis. Thirty-four tumors (85%) showed intense nuclear overexpression of p53, whereas six tumors (15%) were p53 negative. Thirteen p53-positive tumors had multiple samplings from distinct anatomic sites, and all showed complete concordance in p53 staining, suggesting that p53 alterations occur early in UPSC carcinogenesis. p53 positivity was associated with loss of hormone receptors. Thirty-nine cases were concomitantly analyzed for estrogen or progesterone receptor expression. Among those, 31 tumors were p53 positive but hormone receptor negative throughout, in contrast to only two tumors that were diffusely p53 positive and focally hormone receptor positive. Patients whose tumors overexpressed p53 had a statistically significant shorter survival than those whose tumors did not at 24 and 48 months (P = .03). This study represents one of the two largest analyses published to date that confirm the strong association between UPSC and p53 overexpression. Furthermore, we suggest that the concept of UPSC be broadened: UPSC is a p53-driven neoplasm that biologically is a kin to other serous papillary malignancies of the ovaries and peritoneum. This group of tumors bypasses the slow hormone-dependent pathway of tumorigenesis but instead undergoes early p53 alterations that lead to rapid tumor development.     

Loss of p53 gene mutation after irradiation is associated with increased aggressiveness in recurring head and neck cancer

The p53 gene plays a pivotal role in the control of a checkpoint during G1 and in the apoptotic program. It has been postulated that alterations of p53 may influence radio-sensitivity and prognosis in several malignancies. We studied the p53 gene status of 35 consecutive head and neck cancer patients who failed primary radiotherapy (RT) in preirradiated and postirradiated tumor samples using DNA single-strand conformational polymorphism analysis. Sixteen of 35 (46%) preirradiated samples presented with band shifts suggestive of point mutations in one or two exons. Eleven of these tumors (69%) showed the same shift even in the postirradiated samples. Exons 5 and 8 were prevalently affected in this group. Five tumors (31%) lost the mutation following RT. The missed mutations clustered in exon 7. All mutations were confirmed by sequencing. Actuarial analysis demonstrated increased survival in patients with tumors bearing a p53 gene mutation in both preirradiated and postirradiated samples (P = 0.05 and P = 0.01, respectively). We also found that loss of p53 gene mutation in postirradiated cancers is associated with a significantly shorter disease-free interval (P < 0.02) and a worse prognosis (P < 0.05). A possible explanation in such cases is clonal selection by RT of more aggressive and radioresistant cell subpopulations, which are wild-type for the p53 gene. Taken together, our data suggest that not only p53 gene status but also the pattern of mutations could modulate the response of tumor cell to RT in vivo.     

p53 alterations are associated with improved prognosis in distal colonic carcinomas

Alterations of the p53 gene and the p53 protein are common in a wide spectrum of human malignancies. In several tumor types, p53 gene mutation and/or p53 protein overexpression correlate with a more clinically aggressive phenotype as judged by worse patient survival. This has not been clearly demonstrated to be the case in colorectal cancer. Herein, we report results of the prognostic significance of p53 protein accumulation and gene mutation in a large series of colorectal cancers (n = 541) with long patient follow-up (mean, 87 months). The large majority of patients (95%) received no postoperative systemic adjuvant therapy. The incidence of p53 accumulation detected by immunohistochemistry with the monoclonal antibody DO-7 was 30%, whereas the incidence of p53 gene mutation in exons 5-8 detected using PCR-single strand conformation polymorphism was 36%. Accumulation of p53 protein was associated with improved patient survival independent of tumor stage or grade (hazard ratio, 0.66; 95% confidence interval, 0.47-0.93; P = 0.017). A marked difference was observed depending on the location of the tumor: tumors originating in the distal colon showed a strong association between the presence of p53 accumulation and improved patient survival (P = 0.003), but this was not the case for those located in the proximal colon. Dukes' stage C tumors, but not stage B, also showed an association between p53 accumulation and better outcome (P = 0.013). Mutation of the p53 gene was associated with a trend toward improved survival, particularly in the distal tumors. Our results demonstrate that in some tumor types, the presence of p53 abnormalities can correlate with better prognosis.     

The prognostic significance of accumulation of p53 protein in stage III non-small cell lung cancer treated by radiotherapy

In the present study the prognostic significance of accumulation of nuclear p53 protein on survival and freedom from local progression was investigated. Formalin-fixed, paraffin-embedded sections obtained by bronchoscopy or mediastinoscopy were used to examine the expression of nuclear p53 protein using immunohistochemistry. In 37 cases (57%), overexpression of the p53 protein was detected. No relation was found between p53 expression and other pretreatment variables. Response to radiotherapy was found in 11 p53-negative cases (65%) versus 10 p53-positive cases (42%). Freedom from local progression was significantly better in the p53-negative cases as compared with the p53-positive cases. The p53-negative cases who responded to radiotherapy showed an excellent freedom from local progression rate after 2 years of 100%, whereas all p53-positive cases without response to radiotherapy showed local progression within 24 months. Overall survival between p53-negative and -positive cases did not differ, however the disease-specific survival was found to be worse in the p53-positive cases as compared to the negative cases (median survival 8.4 vs. 14.4 months (P < 0.05)). No correlation was found between p53 expression and the frequency of distant metastases. In conclusion, the results of this study suggest that p53 protein expression may be of prognostic value on freedom from local progression in non-small cell lung carcinoma.     

p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site

We initiated a retrospective study to determine whether p53 status and thymidylate synthase (TS) protein expression in primary colon tumors influence recurrence and survival for patients with stage II colon cancer. Tumor specimens from 45 consecutive untreated patients with stage II colon cancer were examined for p53 and TS protein expression using immunohistochemistry. The median follow-up was 5.1 years. Eighteen patients had left-sided tumors, and 27 had right-sided tumors. Fourteen of 45 patients (31%) developed recurrence. p53 overexpression was detected in the tumors of 18 patients (40%); 10 patients (55%) with p53 overexpression recurred; and 4 of 27 (15%) without evidence of p53 overexpression recurred (P = 0.002). High TS expression was detected in the tumors of 16 patients (36%): 8 patients (50%) with high TS expression recurred, and 6 patients (21%) with low TS expression recurred (P = 0.027). Patients with p53 overexpression had a significantly poorer survival than did those patients without p53 overexpression (P < 0.001). High TS expression was associated with poor survival (P = 0.004). p53 overexpression and high TS expression were significantly associated with left-sided tumors (P = 0.003 and P = 0.022). Thirteen of 16 patients (81%) with high TS expression also overexpressed p53, and 24 of 29 patients (81%) with low TS expression did not manifest p53 overexpression (P < 0.001). p53 and TS expression in primary stage II colon cancer are associated and appear to influence recurrence and survival. In this pilot study, left-sided tumors demonstrate significantly more p53 overexpression and significantly higher TS expression than do right-sided tumors, which may explain the significantly poorer survival for patients with left-sided tumors.     

Circulating antibodies against p53 protein in patients with ovarian carcinoma. Correlation with clinicopathologic features and survival

BACKGROUND: Genetic alterations of the p53 tumor suppressor protein are the most frequent molecular events in human carcinogenesis. For as yet unknown reasons, mutant p53 often acts as an immunogen for autoantibody generation. These autoantibodies can be detected in the serum of cancer patients. The presence of such antibodies has been identified in a subset of patients with ovarian carcinoma, but their clinical significance has not been investigated. METHODS: Serum samples from patients with ovarian carcinoma were quantitatively analyzed for the presence of p53 autoantibodies with a time-resolved immunofluorometric procedure. Tumor p53 overexpression was assessed by immunohistochemical analysis of tissue sections. Kaplan-Meier survival curves were calculated for p53 antibody positive and negative patients, and the Cox model was used to evaluate the strength of the associations between the presence of serum p53 antibodies and cancer relapse or death, and also between the presence of such antibodies and other clinicopathologic features. RESULTS: p53 antibodies were detected in the serum of 41 of 174 patients with ovarian carcinoma (24%). Antibody levels ranged from a few hundred to 9 x 10(6) arbitrary Units/L, and fluctuated during the course of the disease. p53 antibody positive patients tended to have tumors overexpressing p53, but the association between the two parameters was not statistically significant (P = 0.13). There was also no association between the presence of p53 antibodies and clinical stage, tumor histologic type, or overall patient survival. However, these antibodies were more frequently present in patients older than 50 years (P = 0.001), in patients with moderately or poorly differentiated tumors (P = 0.001), and in patients who received chemotherapy (P = 0.015), and who suffered relapse after surgery (P = 0.018). In univariate analysis, p53 antibody positive patients were at an increased risk for relapse but not death. In multivariate analysis, the differences in disease free and overall survival between patients who were p53 antibody positive or negative were not statistically significant. CONCLUSIONS: p53 autoantibodies are found frequently in the serum of patients with ovarian carcinoma. The presence of such autoantibodies was associated with older patient age, more aggressive tumors, and reduced patient disease free survival. In multivariate analysis the prognostic value of p53 autoantibodies was not statistically significant.     

Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis

Routinely processed pathological specimens from 119 patients with stage I and II adenocarcinomas or squamous cell carcinomas were examined by immunohistochemical analysis for altered retinoblastoma (RB) and/or p53 protein expression. Absent RB nuclear staining (RB-) indicating loss of RB function occurred in 19 (16%) of the cases studied, whereas expression of a putative mutant p53 nuclear protein (p53(+)) was found in 54 (45%) of the tumors. The median survival was 39 versus 12 months for patients with RB+ and RB- tumors, respectively (P = 0.05 by log rank analysis). Similarly, the median survival was 41 months for patients whose tumors had no expression of mutant p53 (p53(-)) compared with 24 months for individuals with p53 (+) tumors (P = 0.01). These differences in survival, however, were not statistically significant by multivariate analysis. Nevertheless, individuals with RB-/p53(+) tumors had a significantly shorter median survival (12 months) than those with RB+/p53(-) tumors (41 months), as determined by both log rank and multivariate analyses (P = 0.005 and 0.03, respectively). In addition, 66 large cell carcinomas from all stages were examined. Again, a more significant difference in survival (48 versus 8 months) was found between patients with RB+/p53(-) versus RB-/p53(+) tumors (P = 0. 006). These results suggest that RB and p53 status might be used synergistically as prognostic factors in a subset of non-small cell lung carcinomas.     

Reporting of medication regimen in applied studies of persons with mental retardation and ADHD

Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes which, when activated, become dominant events characterized by the gain of function, and tumor suppressor genes which become recessive events characterized by the loss of function. Alterations in proto-oncogenes and tumor suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. Proto-oncogenes are activated mainly by point mutations; however, amplification and translocation events are also common. Tumor suppressor genes are inactivated by an allelic loss followed by a point mutation of the remaining allele. The prototype suppressor genes are the retinoblastoma (RB) gene and the TP53 (also known as p53) genes. Recent studies have shown that inactivation of TP53 and RB occur in bladder tumors that have a more aggressive clinical outcome and poor prognosis. We will review the molecular abnormalities associated with both oncogenes and tumor suppressor genes in bladder tumors, and also discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance our ability to assess tumor biological activities and to design effective treatment regimes.     

Selective activation of rolipram-sensitive, cAMP-specific phosphodiesterase isoforms by phosphatidic acid

BACKGROUND: Regulatory coupling of cell proliferation and apoptosis is suggested by recent findings with regard to certain tumors, such as the finding of tumor resistance to anticancer therapy caused by inhibition of apoptosis. The processes leading to apoptosis appear to be regulated by a variety of oncogenes and tumor suppressor genes. In the current study, the relation between apoptosis and expression of retinoblastoma protein (pRB) was assessed in 50 primary anaplastic astrocytomas (AAs) and 46 recurrent tumors in the same patients as the primary tumors after macroscopic total surgical resection and chemoradiotherapy. METHODS: Apoptotic cells were identified by the in situ 3'-end labeling technique. Proliferative potential, pRB expression, and p53 expression were evaluated immunohistochemically using anti-Ki-67 (MIB-1), anti-pRB, and anti-p53 antibodies, respectively. The prognostic value of these biologic markers in AA patients undergoing treatment was also evaluated. RESULTS: The mean apoptotic index (AI) was 0.91 +/- 0.70% for specimens obtained at the initial surgery and 2.32 +/- 1.71% for those obtained at recurrence. There was no apparent correlation between the AI and the MIB-1 staining index (MI) in primary AAs, whereas significantly higher AI and MI were observed in recurrent pRB negative cases than in their pRB positive counterparts. The survival of patients with AAs showing a high MI and negative pRB immunostaining was significantly shorter than in the other cases. Neither the size of the apoptotic fraction nor the p53 expression in primary tumor correlated with the overall survival. CONCLUSIONS: The clinical outcome of patients with AA may be associated with aberrant pRB function and increased proliferative activity rather than an inability of tumor cells to undergo apoptosis.     

Analysis of p21WAF1/CIP1 in primary bladder tumors

The p21WAF1/CIP1 gene is regulated by p53 and encodes a cyclin-dependent kinase (Cdk)-inhibitor involved in senescence and cell quiescence. The role of p21 as a negative regulator of cell proliferation suggests that it may function as a tumor suppressor gene. However, only a few mutations of the p21WAF1/CIP1 gene have been reported to date. In order to assess potential p21WAF1/CIP1 gene alterations in human bladder cancer, we have examined this gene and its encoded product in a well-characterized cohort of 27 primary bladder tumors. Mobility shifts by single-strand conformation polymorphism in the p21WAF1/CIP1 gene were identified in 2 cases. Sequencing analyses revealed that one of these cases had point mutations in the 3' untranslated region, while the other case had a frame shift mutation at positions 322 (C to A) and a deletion of 8 nucleotides (323-->331; CCG-->ACG, codon 81 Arg-->Thr) that produced a stop signal at codon 83 (Gly--Stop). This tumor had a p21-negative phenotype by immunohistochemistry, but did not lose any allele. We further characterized these cases by the study of TP53 mutations using single-strand conformation polymorphism (PCR-SSCP) and sequencing, as well as immunohistochemical assays. Seven mobility shifts were identified and seven cases showed p53 nuclear accumulation. The two cases displaying mutated p21WAF1/CIP1 had wild-type TP53. It is concluded that p21WAF1/CIP1 gene aberrations are infrequent in bladder carcinoma but may be occasionally identified in primary bladder tumors.     

Clinical evaluation of grade 3 superficial bladder cancer

PURPOSE: To evaluate the treatment of grade 3 superficial bladder tumor, retrospective analysis of superficial bladder tumors was performed with special references to tumor progression and prognostic factors. MATERIALS AND METHODS: From 1976 to 1994, 247 cases with pTa-pT1 superficial bladder tumor were treated. Mean duration of follow up 77.3 months. These patients were divided into pTa (196), pT1 (52), grade 1 (61), grade 2 (196) and grade 3 (62). The prognostic factors were calculated with multivariate and univariate analysis. Tumor progression was defined as muscle invasion or distant metastasis. RESULTS: G3 tumor showed poor prognosis and was more frequent in tumor progression compared with G1 and G2 tumors (19.4% vs 0% and 1.6%). According to multivariate analysis, significant variables for actual survival rate were patient age and tumor grade. Tumor grade, recurrence and tumor configuration were also significant risk factor for cause-specific survival rate. By univariate analysis, patient age, tumor configuration, tumor size, multiplicity and concomitant CIS in G3 group were different from the other two G groups. In the G3 group, only recurrence was the predictable factor for progression. Analysis of prognosis and therapeutic modality revealed that G1 and G2 tumors were sufficiently controlled by endoscopic treatment. On the other hand, 21 cases (33.9%) of G3 tumor required total cystectomy after all. 11 cases of G3 group died of bladder cancer. Lymphatic involvement was detected in some cases of G3 tumor even if superficial. This factor showed a little relevance to poor prognosis of G3 tumor. CONCLUSION: Tumor grade was thought to be the most important risk factor of superficial bladder tumor. These results suggested that total cystectomy should be considered for the treatment of superficial G3 bladder cancer when recurrence occurs or conservative treatment is though to be failed.