Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma

CONCLUSION: This study could not attribute survival differences to the coincident acquisition of two common genetic alterations, K-ras mutation and p53 overexpression in pancreatic adenocarcinoma patients. Additionally, our data indicate the converse to be true: Those patients lacking both K-ras mutation and aberrant p53 expression showed the shortest survival when compared with cases showing either alteration or both. This study also showed the negative effect of K-ras mutation and p53 expression on pancreas cancer patients' survival after treatment with either radiation therapy or chemotherapy. BACKGROUND: Mutations of the oncogene K-ras at codon 12 are reported to be the most common genetic alteration in pancreatic carcinoma, whereas either overexpression or mutation of the tumor suppressor p53 gene is considered the most common genetic alteration in neoplasia of all types. p53 overexpression has been attributed to survival differences in pancreatic carcinoma, but such association is still controversial. No studies have fully documented the combined incidence of K-ras and p53 alterations in pancreatic adenocarcinoma, or their combined effect on patient survival in a large case series. The influence of radiation or chemotherapy in groups showing both, either, or neither mutation is also undocumented. METHODS: Paraffin-embedded tissue sections from 76 cases of pancreatic adenocarcinoma were cut for DNA extraction for K-ras analysis and immunohistochemical staining for aberrant p53 expression. K-ras mutation was determined by single-strand conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product p53 expression was scored on the basis of percent nuclear staining with the MAb DO7. RESULTS: Sixty-four of 76 cases (84%) showed K-ras mutation, p53 expression, or both, K-ras was mutated in 55 of 76 cases (72%). p53 was expressed in 33 of 76 cases (43%). Twenty-four of 76 cases (31%) showed both K-ras mutation and p53 expression. The presence of both alterations was not related to significant differences in tumor grade, stage, or survival compared to either alteration alone. A sizable subset (16% of cases) lacked either alteration, and surprisingly, this group showed the shortest median survival compared to those with K-ras mutation, p53 expression, or both (p = 0.024). Patients whose tumors were K-ras-negative showed the greatest difference in median survival with radiation therapy (median survival 30.8 mo vs 7.8 mo with no radiation, p = 0.005).     

Comparison of p53 gene mutation and protein overexpression in colorectal carcinomas

Immunocytochemistry (ICC) has been used routinely to stain for p53 overexpression in a range of human tumours. The underlying assumption has been that positive staining indicates a mutation in the p53 coding sequence. Recently, however, discordancy has been observed and the accuracy of ICC as a marker of p53 gene mutation has been questioned. In this study of 109 colorectal adenocarcinomas, we compared ICC staining with p53 gene mutations detected by single-strand conformation polymorphism (SSCP) analysis. Concordancy between the two techniques was found in 69% of tumours. ICC-positive/SSCP-negative cases accounted for 20% of tumours and ICC-negative/SSCP-positive cases for the remaining 11%. These results caution against the assumption that p53 protein overexpression is always associated with a gene mutation. Epigenetic phenomena may account for a significant proportion of ICC-positive tumours.     

Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features

Missense mutations in p53 frequently occur at 'hotspot' amino acids which are highly conserved and represent regions of structural or functional importance. Using the p53 mutation database and the p53 DNA sequences for 11 species, we more precisely defined the relationships among conservation, mutation frequency and protein structure. We aligned the p53 sequences codon-by-codon and determined the degree of substitution among them. As a whole, p53 is evolving at an average rate for a mammalian protein-coding gene. As expected, the DNA binding domain is evolving more slowly than the carboxy and amino termini. A detailed map of evolutionary conservation shows that within the DNA binding domain there are repeating peaks and valleys of higher and lower evolutionary constraint. Mutation hotspots were identified by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Seventy-three hotspots were identified; these 19% of codons account for 88% of all reported p53 mutations. Both high evolutionary constraint and mutation hotspots are noted at amino acids close to the protein-DNA interface and at others more distant from DNA, often buried within the core of the folded protein but sometimes on its surface. The results indicate that targeting highly conserved regions for mutational and functional analysis may be efficient strategies for the study of cancer-related genes.     

APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis

The pancreatitis-associated proteins (PAPs) are major pancreatic secretory proteins during acute pancreatitis. However, mechanisms of regulation of PAP gene expression are poorly understood, and there is a lack of information regarding mouse PAP gene expression. Herein, we employed Northern blotting and RNase protection assays to measure mouse PAP-I mRNA levels in the normal pancreas and intestine, and in the pancreas during caerulein-induced acute pancreatitis. Unexpectedly, we found that mouse PAP-I mRNA levels are constitutively high in the adult pancreas, as well as in the small intestine. Furthermore, mouse pancreatic PAP-I mRNA levels are rapidly and dramatically down-regulated (3 h) after the initiation of caerulein injections, but slowly return to high levels by 72 h. Interestingly, we found that pancreatic PAP-I mRNA levels are also transiently and dramatically down-regulated after L-buthionine-[S,R]-sulfoximine administration. Thus, a correlation between PAP-I mRNA levels and glutathione levels in the mouse pancreas was demonstrated.     

Usefulness of K-ras gene mutation at codon 12 in bile for diagnosing biliary strictures

Point mutations of the K-ras gene at codon 12 are often detected in the pancreatic juice of patients with pancreatic cancer. Detection of these mutations may, thus, have diagnostic implications. K-ras mutations may also have diagnostic potential for other biliary tumors. We sought to detect K-ras mutations in DNA obtained from bile in patients with biliary tract cancers, pancreatic cancer and benign biliary disease but who had obstructive jaundice. In 35 patients, bile was collected during percutaneous transhepatic choledocal drainage (PTCD) catheters. K-ras gene mutations at codon 12 in the samples were examined using mutant-allele-specific-amplification (MASA). We compared these results with cytological analyses of bile. K-ras mutations at codon 12 in bile were detected in 11 of 14 (79%) of the patients with biliary duct cancer, 3 of 9 (33%) with pancreatic cancer but not in patients with gallbladder cancer (n=3), papilla of Vater's cancer (n=3) or benign biliary diseases (n=6). In the patients, where cytological evaluation did not reveal malignant cells, K-ras mutations in bile were detected in 5 of 7 (71%) patients with biliary duct cancer and 2 of 5 (40%) with pancreatic cancer. This approach, when used in conjunction with bile cytology, may improve the yield in diagnosing suspected malignant tumors of the pancreatic-biliary system.     

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.     

Flow cytometric DNA analysis and p53 protein expression show a good correlation with histologic findings in patients with Barrett's esophagus

BACKGROUND: There is a considerable degree of subjectivity and, therefore, substantial interobserver and intraobserver disagreement in the diagnosis and grading of dysplastic lesions in Barrett's esophagus (BE). The aim of this study was to evaluate the usefulness of DNA flow cytometry and immunohistochemical staining for p53 protein as objective methods to complement the conventional histologic diagnosis of dysplasia in patients with this disease. The most common problems and the possible advantages of using these procedures are analyzed briefly in this article. METHODS: Formalin fixed, paraffin embedded tissue from 55 patients diagnosed with BE were processed for flow cytometric measurements (ploidy and proliferation index) and p53 immunostaining. RESULTS: Both the cytometric data and the positivity of staining for p53 revealed a statistically significant increase throughout the following sequence: no dysplasia --> indefinite for dysplasia --> low grade dysplasia --> high grade dysplasia --> adenocarcinoma. There was also a highly significant correlation between the results of the cytometric study and the positivity of staining for p53. CONCLUSIONS: In the future, the use of this procedure could play an important role in the evaluation of patients with BE. Considering that staining for p53 is technically simple, economical, and quick, and the materials required are available to most pathology laboratories, this method appears to be a firm candidate for application as a biomarker in BE. The authors have shown that it is possible to obtain adequate results for cytometric analysis with small formalin fixed, paraffin embedded biopsies if a strict protocol for the acceptance of tissue samples and/or histograms is observed.     

p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis

PURPOSE: The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS: Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS: The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION: The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.     

Loss of heterozygosity and overexpression of the p53 gene in ovarian carcinoma

Eight anticonvulsant drugs-including clonazepam, diazepam and phenobarbital-were tested for their effects on GABA-stimulated chloride uptake in rat cerebral cortical microsacs (unfiltered synaptoneurosomes). "Mid" and "high" therapeutic concentrations were screened, and, if significant enhancement was found, full concentration-response tests were done. In the initial screens, enhancement of GABA-stimulated uptake was found only with phenobarbital, clonazepam and diazepam. In subsequent concentration-response tests, the effects of phenobarbital were found to occur throughout the range of normal, anticonvulsant concentrations, whereas the effects of clonazepam and diazepam were observed only above the concentrations normally used for the chronic control of seizures or anxiety. These data suggest that phenobarbital's anticonvulsant effects are mediated via the GABAA receptor complex, but that the low-dose effects of the benzodiazepines may be mediated via some other mechanism.     

Microvessel density, p53 overexpression, and apoptosis in invasive breast carcinoma

AIM: To investigate the possibility of a correlation among microvessel density, p53 overexpression, and apoptosis in invasive breast carcinoma. METHODS: Microvessel density was analysed in 105 cases of invasive breast carcinoma by immunohistology using antifactor VIII related antibody. The results were correlated with the immunohistochemical expression of p53 and the apoptotic index, detected using the in situ end labelling of fragmented DNA method (TUNEL). Assessment was made with a CAS 200 image analyser. All these studies were performed on formalin fixed, paraffin wax embedded tissue sections of tumour samples. RESULTS: The mean (SD) microvessel count was 47.2 (51.1), with a range from 7 to 250. Thirty five (33%) carcinomas showed overexpression of p53 protein. The apoptotic index of tumours ranged from 0.0 to 28.0, with a mean (SD) of 1.7 (3.2). The results showed that there was a significant inverse correlation between microvessel density and p53 expression (p = 0.04; odds ratio, 0.37). In contrast, no correlation was identified between the microvessel density and apoptotic index. CONCLUSIONS: These results suggest that in invasive breast carcinoma the p53 overexpression phenotype downregulates tumour neoangiogenesis, as does the wild-type of p53 protein. In addition, they suggest that apoptosis and neoangiogenesis in these tumours are independent processes.     

Overexpression of p53 protein and histologic grades of dysplasia in colorectal adenomas

PURPOSE: To clarify the relation between tumor-suppressor gene p53 expression and histologic grades of dysplasia in colorectal adenomas, we performed immunohistochemical analysis in a series of 59 colorectal polyps and 40 advanced carcinomas. METHODS: Adenomatous polyps were stained by hematoxylin and eosin and classified into mild, moderate, and severe dysplasia (intramucosal carcinoma), according to the World Health Organization's classification. RESULTS: p53 was positive in 7.1 percent (2/28) of mild, 29.4 percent (5/17) of moderate, and 62.5 percent (5/8) of severe dysplasia. In submucosal and advanced carcinomas, positivity rates were 75 percent (3/4) and 47.5 percent (19/40), respectively. Different staining patterns were found, according to grades of dysplasia. In the adenomas with mild or moderate dysplasia, a few focal crypts showed localized p53-positive staining. Adenomas with severe dysplasia had two different staining types. One was a focal staining type as shown in mild or moderate dysplasia; the other was a diffuse staining type, in which glands with mild or moderate dysplasia, surrounding severe dysplasia area, were also stained. Submucosal and advanced carcinomas showed a strong positive staining in cancer cells only. CONCLUSIONS: Overexpression of p53 protein in adenomas with mild or moderate dysplasia and existence of two types of expression in adenomas with severe dysplasia were observed. These facts suggested the possible existence of different pathways in the adenoma to carcinoma progression.     

K-ras and p53 mutations in stage I gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct

BACKGROUND: An anomalous junction of the pancreaticobiliary duct (AJPBD) was thought to be an important risk factor for gallbladder carcinoma in Japan. In this report, we compared K-ras and p53 mutations in Stage I gallbladder carcinomas (GC) of patients with AJPBD with those in patients without AJPBD: METHODS: We examined 6 GC of patients with AJPBD and 20 GC of patients without AJPBD: Immunohistochemistry was performed for p53 protein. K-ras and p53 mutations were examined using genomic DNA extracted from the cancer regions. The methods of polymerase chain reaction (PCR) single strand conformation polymorphism analysis were performed for mutations in exons 5-8 of p53. The methods of PCR restriction fragment length polymorphism were performed for mutation in codon 12 of K-ras. RESULTS: p53 positivity was 67% in GC of patients with AJPBD and 65% in GC of patients without AJPBD: p53 mutations were found in exons 7 and 8 in GC of patients with AJPBD and in exons 5, 6, and 7 in GC of patients without AJPBD: The incidence of K-ras mutation in GC of patients with AJPBD (50%) was greater than that in patients without AJPBD (6%) (P < 0.05). CONCLUSIONS: These results suggest that K-ras mutation may be important in the early stage of carcinogenesis of the gallbladder mucosa with AJPBD, and that p53 mutations may also contribute to the early stage of carcinogenesis of the gallbladder mucosa, regardless of AJPBD:     

MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas

The endothelium is one of the largest cellular compartments of the human body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradiction, data on growth and angiogenesis control mechanisms of angiosarcomas are scarce. In this study of 19 angiosarcomas and 10 benign vascular control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2 proto-oncogene, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factors, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exhibited clear nuclear p53 protein accumulation. Two of these cases revealed mutations in the sequence-specific DNA binding domain of the p53 gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 protein. Elevated expression of p53 and MDM-2 protein correlated with increased VEGF expression, which was found in nearly 80% of the angiosarcoma cases. Negative or clearly lower immunostaining was obtained in cases from the benign control collective. Only one case of a juvenile hemangioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression. Our data suggest that the p53/ MDM-2 pathway is impaired in about two-thirds (14/ 19) of the angiosarcomas. This may be a key event in the pathogenesis of human angiosarcomas. The increased VEGF expression observed supports this hypothesis.     

Detection of p53 protein overexpression and DNA ploidy analysis in colon cancer

BACKGROUND/AIMS: This study was designed to demonstrate the accumulation of the mutant p53 protein in human neoplasms. The correlation of flow cytometric DNA ploidy pattern with p53 expression using the immunoblotting technique was also investigated. METHODOLOGY: In this study, the occurrence of p53 overexpression was analyzed in 34 cases of adenocarcinoma of the colon by western immunoblotting technique, using an anti-human p53 monoclonal antibody (Do-7). The nuclear protein extract from human colon tumor specimens was immunoblotted relative to protein standards of known molecular weight. Flow cytometric analysis was used to study the DNA ploidy pattern of the tumor cells. RESULTS: Monoclonal antibody p53-Do 7 detected a single band of 53 KDa in 70.5% (24 of 34) of the tumor specimens examined. Whereas, no bands were detected in the normal colon mucosa. The relation between p53 overexpression and the clinicopathological variable (Dukes' staging) was studied and no significant difference in p53 overexpression between Dukes' stages B and C was found. Flow cytometric analysis revealed a higher incidence of DNA aneuploidy in 75% (15 of 20) of p53 positive cases compared with 64.3% (9 of 14) in the diploid tumors. CONCLUSION: The immunoblotting technique can successfully detect the mutant p53 and is therefore expected to provide valuable information on the role of p53 in the process of carcinogenesis.     

Detection of K-ras gene mutations at codon 12 in the pancreatic juice of patients with intraductal papillary mucinous tumors of the pancreas

BACKGROUND: The authors previously found specific mutations of the K-ras gene at codon 12 in the pancreatic juice of 67% of patients (6 of 9) with pancreatic ductal carcinoma, and the detection of these mutations was useful for diagnosis. This study was performed to detect and evaluate K-ras mutations in pancreatic juice from patients with intraductal papillary mucinous tumor of the pancreas, which is considered a low grade malignancy. The results were interpreted from the viewpoint of clinical significance. METHODS: K-ras mutations were examined using seminested polymerase chain reaction analysis combined with restriction enzyme digestion, followed by nonradioisotopic single strand DNA conformation polymorphism. RESULTS: Twelve of thirteen cases (92%) of intraductal papillary mucinous tumor of the pancreas, confirmed histologically (9 adenomas and 4 carcinomas), and 26 of 43 cases (60%) of ductal carcinoma showed specific K-ras gene mutations in the pancreatic juice. Furthermore, 4 of 22 patients (18%) with chronic pancreatitis, followed for more than 1 year without a sign of pancreatic tumor, showed K-ras mutations. In contrast, no mutations of the K-ras gene were detected in the pancreatic juice from 28 normal controls. CONCLUSIONS: K-ras mutations were found in the pancreatic juice of all but one patient with intraductal papillary mucinous tumor of the pancreas, but they were not useful for distinguishing carcinoma from adenoma. The authors concluded that K-ras mutations are not a specific marker for pancreatic neoplasms because similar mutations were detected in the pancreatic juice from patients with chronic pancreatitis. At the present time, the detection of K-ras mutations in pancreatic juice should be used clinically as an adjunct diagnostic modality for pancreatic diseases.     

Detection of K-ras point mutations at codon 12 in pancreatic juice for the diagnosis of pancreatic cancer by hybridization protection assay: a simple method for the determination of the types of point mutation

The present study was undertaken to detect K-ras oncogene point mutations at codon 12 in pure pancreatic juice (PPJ) by the hybridization protection assay (HPA) method for the diagnosis of pancreatic cancer (PC). This assay can be carried out within 30 min and can determine not only the presence of a mutation, but also the mutational type of K-ras at codon 12. The minimal ratio of mutant DNA detectable by the HPA was 5-10% of the total DNA. PPJ was collected through a cannula under duodenal fiberscope control from 20 patients with PC and 20 patients with chronic pancreatitis (CP). Analysis of PPJ by the HPA revealed that the incidence of K-ras point mutations at codon 12 was 55% (11/20) in patients with PC and 0% (0/20) in those with CP. Mutational types of K-ras at codon 12 in PC were aspartic acid (Asp) in nine cases, both Asp and cysteine in one case, and arginine in one case. Analysis of K-ras point mutations at codon 12 in PPJ using the HPA method seems promising as a new genetic test for the diagnosis of PC, because the HPA method is simple, and can easily determine the mutational type.     

Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma

In the biology of a cell, the central role of p53 in controlling functions such as G1/S transition (check point) and DNA damage repair, and as a trigger of apoptosis, is well established. Somatic mutations or other changes in P53 have been reported in numerous tumor types, and in some of these, they are associated with poor prognosis. In this study, we examined 237 cytogenetically characterized B-cell non-Hodgkin's lymphomas (B-NHLs) for somatic changes in P53 by Southern blot analysis, by single-strand conformation polymorphism analysis (SSCP) of exon 5 through 9, and by direct sequencing of SSCP variants to determine the frequency and types of mutations and their clinical significance. In a portion of these (173 tumors), we also studied p53 expression by immunostaining. On Southern blots, no gross change was identified in P53 and no mutation was identified in exon 9. In exons 5 through 8, 27 different mutations were identified in 25 patients (23 single-base substitutions, 3 deletions, 1 duplication). Mutations in P53 were identified in 25 of 237 tumors (10.5%), which included 1 of 45 small lymphocytic lymphomas (SLLs), 2 of 38 follicular small cleaved-cell lymphomas (FSCCs), 2 of 35 follicular mixed small cleaved-cell and large-cell lymphomas (FMxs), 1 of 4 follicular large-cell lymphomas (FLCs), 1 of 14 diffuse small cleaved-cell lymphomas (DSCCs), 2 of 17 diffuse mixed small- and large-cell lymphomas (DMxs), and 16 of 84 diffuse large-cell lymphomas (DLCCs); the difference between the histologic groups was significant (P < .01). Among mantle-cell lymphoma (MC) patients, 3 of 10 had mutations. In 16 patients, the mutation was identified in specimens obtained at diagnosis. Mutation of transition type and transversion type occurred at a relative frequency of 2:1. Thirty percent occurred at CpG dinucleotide sequences and the codon for arginine was most frequently affected. Nineteen of 99 tumors with complex cytogenetic abnormalities, but none of 69 tumors with simple cytogenetic abnormalities, had mutations (P < .001). Similarly, 11 of 25 tumors with an abnormality of 17p and 8 of 143 tumors with apparently normal 17p had mutations (P < .0001). Positive correlations were found between a mutation and p53 expression (P < .001), between missense type mutations and p53 expression (P < .005), and between 17p abnormalities and p53 expression (P < .05). Twenty-two of 49 patients without mutation and 14 of 17 patients with mutations died (P < .05), but there was no significant difference in median survival. Similarly, 21 of 26 p53 positive patients died, whereas only 1 of 24 p53-negative patients died on-study (P < .001). Among p53-negative patients, mutation (P < .01) was positively associated with a fatal outcome. These findings indicate that in B-NHL, somatic changes in P53 were present in diagnostic specimens of all histologic types, but at a higher frequency in DLC and MC tumors. P53 mutation and/or expression has a negative influence on survival, and therefore can serve as prognostic indicators. Immunostaining for p53 is an effective way to screen for P53 changes in these tumors.     

Serum p53 antibodies in patients with oral lesions: correlation with p53/HSP70 complexes

In order to evaluate the role of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) in the maintenance of blood Hb concentration in infants, we studied the serum concentrations of IGF-I and IGFBP-3 in relation to blood hemoglobin values in 25 healthy term infants at birth and two months of age. The mean concentration of IGF-I was 18.6+/-7.1 ng/ml and IGFBP-3 was 1240+/-498 ng/ml at birth. Positive correlation was observed between the blood Hb concentrations and both IGF-I (r = 0.56, p = 0.004) and IGFBP-3 levels (r = 0.38, p = 0.04) at the first examination. Our results show that blood Hb is positively correlated to serum IGF-I levels indicating indirectly the involvement of mediators of growth hormone in the regulation of physiologic Hb concentrations at birth. As no relationship was found between IGF-I, IGFBP-3 and Hb levels at the second examination, the same association could not be demonstrated at two months of age.