Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers

PURPOSE: To investigate the prognostic and predictive value of c-erbB-2 overexpression in breast cancer in relation to other prognostic markers. PATIENTS AND METHODS: Paraffin-embedded tumors from 315 consecutive primary breast cancer patients were screened for c-erbB-2 protein (p185) overexpression by immunohistochemistry using the monoclonal antibody CB11. RESULTS: c-erbB-2 protein overexpression was detected in 19% of tumors and was associated with shorter 5-year overall survival (OAS) rate compared with c-erbB-2-negative cases in the total patient material (58% and 77%, respectively; P = .004) and in the 96 node-positive patients (31% and 61%, respectively; P = .02), but not in node-negative patients. For 47 node-positive patients treated with adjuvant tamoxifen and radiotherapy, the 5-year OAS was 13% for c-erbB-2 overexpression and 75% for c-erbB-2-negative patients (P = .00004). The frequency of c-erbB-2 overexpression decreased with age at diagnosis. The prognostic value of c-erbB-2 on OAS was independent of age, node status, tumor size, histopathologic grade, hormone receptor status, S phase, p53 status, and adjuvant treatment. c-erbB-2 status added prognostic information to p53-negative and low S-phase cases, but not to p53-positive and high S-phase cases. Correspondingly, these only added information to c-erbB-2-negative cases. CONCLUSION: c-erbB-2 protein overexpression may have a predictive value with regard to adjuvant therapy in node-positive patients, for whom adjuvant tamoxifen with radiotherapy appears insufficient in the presence of c-erbB-2 overexpression. Combination of conventional and newer tumor markers may identify patients with a worse prognosis within groups with a generally favorable prognosis.     

Immunohistochemical expression of p53 and c-erbB-2 in breast carcinoma: relation with epidemiologic factors, histologic features and prognosis

We have performed immunohistochemical staining for p53 and c-erbB-2 on formaldehyde-fixed, paraffin-embedded primary invasive ductal carcinomas from 112 patients, with a minimal follow-up time of 60 months. All of them had received postoperative chemoradiation therapy. We have analyzed the association of these factors with epidemiologic risk factors, histopathologic features and hormonal receptor status and the influence on prognosis. Our results indicate that the expression of c-erbB-2 protein defines a group of node-negative patients with poor prognosis. The overexpression of c-erbB-2 has shown a significant association with estrogen receptor status (those tumors expressing c-erbB-2 are usually estrogen receptor negative), presence of fibrosis and lymphoplasmacytoid infiltrates. P53 expression has shown no relation either with prognosis or with any other histopathologic or clinical feature. The only factors with prognostic influence in our series have been tumor size, the presence of node metastases, TNM stage and the prognostic morphometric index (Baak's index), apart from c-erbB-2 in node-negative patients. However, only the TNM stage showed an independent association with prognosis after a multivariate analysis. In summary, in our experience the expression of p53 protein has no prognostic influence on breast carcinoma, and TNM stage remains to be as the most powerful prognostic factor in these patients.     

p53 gene mutations and HPV infection in primary head and neck squamous cell carcinomas do not correlate with overall survival: a long-term follow-up study

We analyzed specimens of head and neck squamous cell carcinomas (HNSCC) from 110 patients for p53 gene mutations, and 92 of them for human papillomavirus (HPV) infection, in order to evaluate the prognostic significance of these factors by comparison with clinical follow-up data. Mutations within the exons 5 to 8 of the p53 gene were found in 48 tumors (44%). Sequencing revealed in most cases mis-sense mutations (16/21). Frequency of p53 gene mutations was not related to the tumor stage or the presence of lymph node metastases. Of the 46 tumors that were analyzed by immunohistochemistry, 26 stained positively (56%). The number of positively stained nuclei increased slightly with decreasing differentiation of the tumors, whereas no correlation was found between tumor stage and immunoreactivity. An infection with the high-risk HPV types 16 and 18 could be detected in 39/92 tumor specimens (42%). Follow-up data were obtained from 99 patients within a range of 2 to 112 months. No dependence of overall survival on the presence of p53 gene mutations or HPV infection could be observed. The absence of statistically significant correlations between p53 gene mutation and progressive disease, however, does not deny its putative relevance in early phases of tumor development.     

Osmolyte contents of cultured astrocytes grown in hypoosmotic medium

The prognostic value of p53 protein overexpression was investigated in a large series of early stage endometrial carcinomas with long follow-up (n=179, median follow-up 147 months). P53 overexpression was detected in 10 cases (5.6%). At the end of the study period, 30% (3/10) of patients with p53 protein overexpression had died of their disease compared to 6.5% (11/169) of those without overexpression. Multivariate analysis revealed that only myometrial invasion (RR 2. 1; 95% CI=1.2-3.6; P=0.001) and p53 overexpression (RR 9.5; 95% CI=2. 5-36.8; P=0.007) were independent predictors of survival. These results suggest that immunohistochemical evaluation of p53 protein overexpression provides strong prognostic information for the outcome of endometrial carcinoma patients with early stage disease.     

Heart rate variability in insomniacs and matched normal sleepers

BACKGROUND: Heat shock proteins have been associated with the mutant form of the tumor suppressor gene, TP53, and with resistance to cancer chemotherapy. METHODS: Archival tissues from 50 patients with head and neck squamous cell carcinoma who received primary surgical resection were examined for p53, HSP27, and HSP70 by immunohistochemistry and correlated with tumor stage, grade, and 5-year survival (alive or deceased). RESULTS: Both heat shock proteins were strongly expressed in normal mucosa and in small (T1 and T2) tumors. Thirty (60%) of tumors were positive for p53, 43 (86%) for HSP27, and 34 (68%) for HSP70, with no association between p53 and heat shock protein expression. Twenty-five patients were alive (4 with disease), and 25 patients were deceased (9 from other causes). p53 Protein overexpression correlated with low-grade tumors. Only primary tumor site (i.e., oral cavity > larynx > oropharynx/base of tongue) and N stage were significantly associated with survival. CONCLUSIONS: Heat shock proteins are expressed in normal upper respiratory tract squamous mucosa, and their role in carcinoma remains unclear. None of the markers, p53, HSP27, or HSP70, demonstrated prognostic significance for 5-year survival. We confirm the recognized association of cervical lymph node metastases with decreased survival.     

Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma

The bcl-2 proto-oncogene encodes a Mr 25,000 protein that has been shown to prevent apoptosis or programmed cell death. The bcl-2 protein is detectable in basal cells of normal colonic epithelium, and an altered topographic distribution of this protein is found in colonic neoplasms. However, the clinical significance of abnormal bcl-2 expression in colon carcinomas remains unknown. We examined the prognostic value of the bcl-2 protein in TNM stage II colon carcinomas and its relationship to DNA ploidy, cell proliferation indices, p53 expression, and clinicopathological features. We analyzed 119 resected and otherwise untreated, paraffin-embedded stage II colon carcinomas for bcl-2 and p53 protein expression using immunohistochemistry. DNA ploidy and proliferative index (% S-phase + % G2-M) were determined by flow cytometry, and tumor grade and vascular microinvasion were assessed on histological sections. Cytoplasmic expression of the bcl-2 protein was detected in 72 (66%) of 110 carcinomas, and a high level of expression was significantly correlated with diploid DNA content (P = 0.02) and low proliferative activity (P = 0.005). bcl-2 was not associated with nuclear p53 expression. In a univariate analysis, a higher fraction of bcl-2-positive tumor cells was associated with better relapse-free survival (P = 0.02) and overall survival (P = 0.05) rates. Moreover, a high level of bcl-2 expression was an independent predictor of better relapse-free survival (P = 0.04), but not overall survival (P = 0.14), after adjustment for other variables, including proliferative index, DNA ploidy, and race. In conclusion, bcl-2 overexpression is associated with favorable prognostic features and may predict clinical outcome in stage II colon carcinomas.     

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.     

P53 overexpression in head and neck carcinoma and radiotherapy results

PURPOSE: P53 gene mutations are the common genetic changes encountered in human cancers, and there is extensive evidence that the P53 status may determine tumor response to therapy. This study was carried out to investigate whether there is any correlation between accumulation (overexpression) of P53 protein and poor prognosis in patients with head and neck carcinomas treated with radical radiotherapy. METHODS AND MATERIALS: Seventy-nine patients with head and neck carcinomas who were diagnosed and treated in 1989-90 with curative radiotherapy were studied retrospectively. Paraffin sections from archival material were studied using immunohistochemical staining (IHC) with mouse monoclonal antibodies (D0-7) to human P53 protein. Univariate and multivariate analysis of loco-regional tumor control and patient survival were performed on possible prognostic factors. RESULTS: Forty-two (53%) patients showed positive IHC staining in their tumors. Fifty-three percent of the laryngeal, 64% of the oropharyngeal, and 43% of the oral cavity carcinomas showed P53 overexpression. All tumor specimens with vascular, lymphatic, and/or sarcolemmal invasion showed P53 overexpression. The proportion of tumor-stained nuclei was higher in the poorly differentiated than in the well and moderately differentiated tumors (p < 0.05), but there was no correlation with the patient overall or disease-free 5-year actuarial survival. There was no difference in the 5-year actuarial survival and disease-free survival between patients with P53 immunostaining in their tumors and those with no immunostaining (59% vs. 65% and 57% vs. 51%, respectively). The TNM tumor stage was the most significant prognostic factor with 5-year actuarial survival of 87% for early and 14% for late stages (p < 0.0001). There was a significant correlation between immunostaining and history of smoking (p = 0.02). CONCLUSION: The data demonstrate that the P53 accumulation as detected by immunohistochemical staining in a group of head and neck carcinomas was not predictive of patient's poor survival or disease-free survival. Multivariate statistical analysis showed that the TNM tumor stage was the only significant prognostic factor. There was a significant association between P53 accumulation and smoking.     

p53 protein overexpression and K-ras codon 12 mutation in pancreatic ductal carcinoma: correlation with histologic factors

The correlation of p53 protein overexpression and the K-ras codon 12 mutation with histologic type, grade of cytologic atypia, depth of invasion and other histologic prognostic factors was studied in paraffin sections from 43 ductectatic- and 70 solid-type pancreatic ductal carcinomas. Overexpression of p53 was found in 23.3% (10/43) of ductectatic carcinomas (17.2% of intraductal and 35.7% of invasive carcinomas) and in 61.4% (43/70) of solid carcinomas. In ductectatic cancers, p53 overexpression was detected in 14.8% (4/27) of carcinomas with low-grade atypia (CAL), 50.0% (5/10) of carcinomas with high-grade atypia (CAH) and in 16.7% (1/6) of mixed low- and high-grade cancers. In the last group, expression was restricted to an area of CAH. In solid cancers, p53 overexpression did not differ by histologic type or grade. Overexpression of p53 and K-ras mutations did not correlate with histologic prognostic factors (lymphatic, venous and perineural invasion, and lymph node metastasis) in ductectatic and solid cancers or depth of invasion of solid carcinomas. Our data suggest that p53 alteration occurs at an early intraductal stage of solid carcinoma, irrespective of cellular atypia, but is low in ductectatic CAL and becomes higher in ductectatic CAH. K-ras mutation, present in a high percentage of tumors of all groups and not correlating with the factors above, showed no changes in frequency with tumor progression.     

p53 nuclear protein overexpression in colorectal cancer: a dominant predictor of survival in patients with advanced hepatic metastases

PURPOSE: To determine whether p53 protein expression is similar within primary colorectal cancer (CRC) and synchronous regional and distant metastases and to assess whether p53 nuclear protein expression could predict outcome in patients with synchronous unresectable liver metastases treated by hepatic artery infusional (HAI) chemotherapy. MATERIALS AND METHODS: Paraffin sections from tumor and corresponding normal mucosa representative of 50 consecutive advanced CRC cases were examined for p53 nuclear protein expression by immunohistochemistry using the monoclonal antibody PAb 1801. Patterns of p53 nuclear expression were correlated with standard clinicopathologic variables and outcome, including response to HAI and survival. In a subset analysis, the pattern of nuclear p53 immunoreactivity was compared between primary CRC and lymph node and liver metastases. RESULTS: Positive nuclear immunoreactivity for p53 protein was found in 72% of cases. The pattern of p53 protein expression in lymph node and liver metastases was identical to that of the primary tumor. The median survival time was 21.0 months in patients with p53-positive tumors and 53.2 months in patients with p53-negative tumors (Wilcoxon test P = .038). Two-year survival rates were 41.7% and 78.6%, respectively (P < .01). No significant difference was found in the response rates to HAI chemotherapy between the two groups. By multivariate analysis, p53 protein status was the single best predictor of survival, with a relative risk of 6.312. CONCLUSION: Our results indicate that nuclear p53 protein status in primary CRC is similar to that in metastatic sites and may be the dominant predictor of survival in patients with advanced hepatic metastases.     

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.     

p53 and p21(WAF1/CIP1/SDI1) gene products in Barrett esophagus and adenocarcinoma of the esophagus and esophagogastric junction

The WAF1 (CIP1/SDI1) gene encodes a cyclin-dependent kinase inhibitor which is induced by wild-type, but not mutated, p53 gene product. WAF1 immunohistochemistry has been suggested to clarify the phenotype of overexpressed p53 gene product. We evaluated both p53 and WAF1 gene products by immunohistochemistry in 98 esophagectomy specimens with Barrett esophagus and/or adenocarcinoma of the esophagus and esophagogastric junction. Diffuse positive p53 staining was found in 40 of 88 adenocarcinomas (45%) and in dysplastic Barrett epithelium in 20 of 65 cases (31%), but not in Barrett mucosa without dysplasia (n = 36, P = .0004). Eighty-eight percent of cancers exhibited WAF1 expression, but there was no association with p53 and WAF1 staining. WAF1 protein was also identified in Barrett epithelium and in esophageal squamous and gastric epithelium. In contrast to carcinomas, a unique pattern of mutually exclusive p53 and WAF1 expression was found in five cases of dysplastic Barrett epithelium; a missense mutation at codon 175 of p53 was identified in one. p53 staining of adenocarcinoma was associated with shorter patient survival but was not independent of stage; WAF1 status added no prognostic information. Our findings show that WAF1 immunohistochemistry complements p53 immunohistochemistry in some cases of Barrett dysplasia but not in adenocarcinomas. Positive p53 immunostaining can serve to confirm a neoplastic process in Barrett mucosa. Positive staining of adenocarcinomas may be an indication of advanced stage.     

Antenatal glucocorticoid therapy suppresses angiotensin-converting enzyme activity in rats with nitrofen-induced congenital diaphragmatic hernia

BACKGROUND: Carcinoma of the true vocal cord represents the earliest clinically recognizable invasive malignancy in the head and neck region and provides a unique model for studying possible prognostic genetic markers. The aim of this study was to determine whether p53 overexpression correlated with tumor recurrence in a homogenous population of patients with early stage glottic carcinoma treated with radiotherapy alone. METHODS: One hundred and fourteen patients with T1N0M0 squamous cell carcinoma of the glottis were treated with curative radiotherapy between 1976 and 1990. With a median follow-up of 6 years, actuarial local control was 80% with 23 local recurrences. Laryngeal biopsy specimens obtained prior to radiation therapy were analyzed retrospectively in 22 patients. Forty-five patients with local control were used as a control group. p53 overexpression indicating a mutated p53 gene was analyzed by immunohistochemistry using the mouse monoclonal antibody D0-7. RESULTS: Approximately 82% of carcinomas that recurred locally expressed p53 compared with only 29% of those with local control (P < 0.001). No significant relation was noted between p53 expression and histologic grade. Intensity of staining did not predict tumor recurrence. CONCLUSIONS: The authors believe that this case-controlled study demonstrated the role of p53 as an independent prognostic factor in patients with early stage glottic carcinoma.     

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.     

Novel attributes of an androgenic steroid-mediated increase in cardiac end diastolic stiffness in rats

The expression of ras was investigated by using immunohistochemistry in 245 primary colorectal adenocarcinomas and 49 corresponding metastases in the lymph nodes. One hundred and forty-four (59%) of the primary tumours presented as ras positive and 37 (76%) were positive in metastases. The ras expression was positively related to cell proliferation (p=0.01) and significantly increased in tumours with aneuploidy (68%) compared to tumours with diploidy (51%) and tetraploidy (53%, p=0.01). The frequency of ras expression was increased from Dukes' stage A to stages B-D (41% vs 62%, p=0.01). ras expression was compared in 40 paired primary tumours and their corresponding metastases, and the difference in expression did not reach statistical significance (73% vs 83%, p=0.32). In survival analyses, ras overexpression predicted a poor prognosis independent of Dukes' stage, DNA ploidy and S-phase fraction (p=0.049). We did not find any significant relationship between ras expression and patients' sex, age, tumour location, growth pattern, differentiation, p53 expression or heat shock protein. The results indicate that the alteration of ras expression may be involved in the instability of DNA and cellular overproliferation, but not in the progression to advanced stage and the development of metastases. The expression of ras was an important biological marker for evaluating the prognosis in patients with colorectal adenocarcinoma.     

Overexpression of epithelial macrophage colony-stimulating factor (CSF-1) and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer, contrasted with a protective effect of stromal CSF-1

Markedly elevated levels of macrophage colony-stimulating factor (CSF-1) in the serum and ascites of epithelial ovarian cancer patients have been previously associated with a poor prognosis. However, measurements of circulating CSF-1 cannot separate CSF-1 originating in the cancer cell from that originating in stromal macrophage or fibroblast. To study the prognosis related to expression of CSF-1 and its receptor in primary and metastatic ovarian cancers and to compare the significance of epithelial versus stromal CSF-1 expression, an immunohistochemical study of 130 ovarian carcinomas was performed. Twenty-two stage I and II and 108 stage III and IV primary tumors were studied. Metastatic lesions were also studied in 96 of these 130 cases, 90 of which came from those cases with advanced-stage disease. The intensity and extent of staining for CSF-1 in epithelium and stroma and for epithelial CSF-1 receptor was scored. Kaplan-Meier curves of survival were compared with the log-rank test. The Cox regression model was used for multivariate analysis. In the primary tumors, there was strong expression of CSF-1 receptor in 65%, epithelial CSF-1 in 36%, and stromal CSF-1 in 22%. In the metastases, there was strong staining for CSF-1 receptor in 65%, epithelial CSF-1 in 41%, and stromal CSF-1 in 15%; strong staining for both CSF-1 receptor and epithelial CSF-1 was noted in 26% of the cases. When the metastases expressed both CSF-1 receptor and epithelial CSF-1 strongly, a significant decrease in disease-free survival in stage III invasive ovarian cancers was observe (P = 0.043), which was found to be an independent prognostic factor (P = 0.007), with an increased relative risk of recurrence of 2.3-fold. Although strong staining for stromal CSF-1 in the primary tumor was not found to have prognostic value, for all stages and for the subsets of stages III and IV and for stage III alone, the finding of any degree of stromal CSF-1 expression in the ovary was a favorable prognostic factor for disease-free (P = 0.046) and overall (P = 0.015) survival. This finding was associated with younger patients (P = 0.007) and low-grade tumors (P = 0.033) and was not an independent prognostic factor on multivariate analysis. Among the primary tumors, there was a significant association (P = 0.022) between stromal CSF-1 staining and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1; 67 of 94 cases shared these features in the primary tumors. In the metastases of invasive stage III cases, strong staining for stromal CSF-1 was a favorable prognostic factor for overall survival in the absence of strong CSF-1 receptor staining (P = 0.033) and was associated with low-grade tumors (P = 0.0002). We report that strong expression of epithelial CSF-1 along with its receptor in the metastases of ovarian cancer patients appears to be a strong independent poor prognostic factor for outcome. We find that expression of the same cytokine (CSF-1) in the stroma of the primary tumors is associated with low-grade tumors and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1, leading to an improved long-term outcome. This study may help explain the previous observations that elevated levels of CSF-1 in serum and ascites are associated with a worse prognosis in advanced ovarian cancer patients; the results suggest that the source of secreted CSF-1 may largely be the epithelium. The results of this study suggest that paracrine effects of stromal CSF-1 on tumor behavior contrast with those demonstrated when the tumor cell is capable of autocrine intracellular or extracellular interactions between CSF-1 and its receptor.     

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 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.     

Mucin carbohydrate antigens (T, Tn, and sialyl-Tn) in human ovarian carcinomas: relationship with histopathology and prognosis

Altered glycosylation of mucins leading to the expression of T, Tn, and sialyl-Tn antigens has been shown in ovarian carcinoma, but its relationship with prognosis is still unclear. We investigated immunohistochemically the expression of these antigens in 38 (17 serous and 21 mucinous) ovarian carcinomas to assess their potential prognostic value as compared with stage of disease, histopathology of tumors, and survival time of patients. Eight benign ovarian tumors (four serous and four mucinous), and four normal ovarian tissues also were studied. Of the 38 carcinomas, 25 (66%) expressed T, 27 (71%) expressed Tn, and 33 (87%) expressed sialyl-Tn antigens. Most cases (83%) expressed two or all of the three types of antigens simultaneously. Normal ovarian epithelia showed no staining for these antigens, and benign ovarian tumors were either negative or occasionally expressed weak staining in less than 25% of epithelial cell areas. Statistical analyses showed strong associations between Tn and sialyl-Tn antigen expressions and disease stage as well as histological grade. In 19 ovarian carcinoma patients with available survival data, the overall survival times of patients with high Tn or sialyl-Tn antigen expression were significantly worse than those of the patients with negative and low expression (P < .05 and P < .01). In multivariate stepwise regression analysis, disease stage (P = .000) and Tn antigen expression (P = .02) were found to be significant independent parameters associated with the overall survival time. These findings suggest that, with exception of T antigen expression, the expression of Tn and sialyl-Tn antigens in ovarian carcinomas may provide additional prognostic information on patient outcome.     

Expression of p53 protein has no independent prognostic value in breast cancer

A series of 392 female breast carcinomas was analysed immunohistochemically for expression of p53 protein with special emphasis on the role of p53 as an independent prognostic factor. Altogether, 54.8 per cent of the carcinomas expressed p53 protein, with the mean [standard error (SE)] fraction of positive nuclei being 17.1 per cent (1.2 per cent). Expression of p53 protein was independent of tumour metastasis at diagnosis, axillary lymph node status, tumour diameter, histological type, tubule formation, proportion of intraductal growth, margin formation, necrosis, DNA ploidy, and S-phase fraction. A high fraction of p53-positive nuclei was significantly related to patient age under 70 years, high grade, severe nuclear pleomorphism, dense infiltration of tumour by lymphocytes, high mitotic index, and high apoptotic index (for all, P < 0.05). Impaired survival probability in the entire cohort (P = 0.05) and in the axillary lymph node-positive (ANP) tumours (P = 0.015) was associated with a fraction of p53-positive nuclei less than 25 per cent, while in the axillary lymph node-negative (ANN) tumours, expression of p53 had no prognostic value. In multivariate analysis, independent prognostic predictors included axillary lymph node status, tumour diameter, and mitotic index. In the ANN tumours, tumour diameter, fraction of p53-positive nuclei, and tumour grade were independent prognostic factors, whereas in the ANP tumours, diameter and mitotic index were the two independent prognostic factors. The results suggest that abnormal expression of p53 protein is only a weak independent prognostic factor in female breast cancer.