Tissue expression and serum levels of the oncoprotein HER-2/neu in 157 primary breast tumours.

BACKGROUND: We studied HER-2 expression in paired serum and tissue samples, in 157 selected cases from 701 consecutive primary breast cancer patients with pre-treatment HER-2 extracellular domain (ECD) > or = 10 ng/ml, or < 10 ng/ml but showing a HER-2 ECD lead time before first metastasis. PATIENTS AND METHODS: HER-2 ECD was measured by the Immuno 1 automated ELISA (Bayer). Tumour tissue was analysed by immunohistochemistry (IHC) with Dako A 0485 and CB 11 antibodies and scored with the Dako scoring system. RESULTS: Mean HER-2 ECD was 12.48+/-7.08 ng/ml and 21/157 (13.4%) sera were > or = 15 ng/ml (cut-off). Forty tumours (25.48%) showed both invasive and intraductal components, 3 (1.91%) were pure in situ carcinomas and 114 (72.61%) were pure invasive tumours. Elevated HER-2 ECD concentration was related only to pT (p=0.0008), histological grade (p=0.0465), presence of comedonecrosis (p=0.0123) or comedo-type carcinoma (p=0.041) and was unrelated to the presence of an intraductal component. HER-2 ECD was > or = 15 ng/ml in 48% of Dako 3+ and 60% of CB 11 2+ and 3+ tumours. By logistic regression analysis, the significant parameters associated with HER-2 ECD concentration were pT (p=0.0038) and Dako 3+ scores (p=0.0005). In Dako 3+ or CB 11 2+3+ tumours, elevated mean HER-2 ECD concentrations were observed only when pT exceeded 28-30 mm (p=0.0062 and p=0.0036, respectively). CONCLUSION: In breast tumours, a threshold in size and HER-2 overexpression is necessary to observe elevated concentrations of HER-2 ECD at diagnosis. This information may be useful when the primary tumour is not available for IHC.

Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen.

PURPOSE: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen. PATIENTS AND METHODS: Five hundred sixty-two estrogen receptor-positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu. RESULTS: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P =.008), clinical benefit (CB; 57% v 45%; P =.016), time to progression (TTP; median, 12.2 v 8.5 months; P =.0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P =.0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P =.45) or CB (33% v 26%; P =.31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P =.0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P =.0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP. CONCLUSION: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.

Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.

ErbB-2 protein in sera and tumors of breast cancer patients.

We compared levels of erbB-2 oncoprotein among three groups: Group I included 60 asymptomatic women; Group II had 51 women with benign breast biopsies; and Group III had 67 women with node-negative breast cancer. Serological levels of erbB-2 protein were measured in all participants; tumor levels were measured for Groups II and III. Forty-three percent of usable tumors (25/58), including three of seven lobular tumors, were erbB-2 positive. Tumor and blood oncoprotein levels were unrelated. Blood levels, however, were positively related to tumor volume, but only when the tumor had both a ductal carcinoma in situ (DCIS) component and an invasive component, suggesting a role for erbB-2 protein in progression of DCIS to invasive carcinoma. In Groups I and II serological levels of erbB-2 protein were directly related to age, and inversely related to having had a live birth. Therefore, a model that determined the threshold levels of serological erbB-2 positivity in Group III included age and nulliparity as independent variables. Only three of the 67 women (4.5%) in Group III were positive for serological erbB-2. In a multivariate model, with serological erbB-2 as the dependent variable, and in which the independent variables included Study Group, there was a statistical trend for younger women, in which Group III had the highest serological levels of erbB-2, followed by Group II, and then Group I. In women who were over the age of 50 years the trend was reversed; i.e., levels of erbB-2 tended to be lowest in Group III, followed by Group II, and finally Group I.

Molecular epidemiology of p53 protein mutations in workers exposed to vinyl chloride.

The production of mutations in cellular tumor suppressor genes such as p53 is involved in the development of many human cancers. These mutations result in the expression of mutant forms of the encoded p53 protein which can potentially serve as a biomarker for this carcinogenic process. Workers exposed to vinyl chloride who are at risk for the development of the sentinel neoplasm angiosarcoma of the liver represent a model population for the study of such a mutant p53 biomarker, since vinyl chloride is known to cause specific p53 mutations in persons with angiosarcoma of the liver. To determine the relation between vinyl chloride exposure and this p53 biomarker, the authors examined serum samples collected between 1987 and 1992 from a cohort of 225 French vinyl chloride workers and 111 unexposed controls (matched according to age, sex, race, smoking, and alcohol drinking) for the presence of mutant p53 protein, using an enzyme-linked immunosorbent assay. Stratification of the exposed workers by quartile of vinyl chloride exposure (in estimated ppm-years) yielded a statistically significant trend of increasing odds ratios for p53 biomarker seropositivity with increasing exposure. These results suggest that this serum biomarker for mutant p53 protein is related to vinyl chloride exposure and may be an early indicator of carcinogenic risk in exposed individuals.

Bcl-2 expression and DNA fragmentation in breast carcinoma, pathologic and steroid hormone receptors correlates.

B-cell leukemia/lymphoma (bcl-2) expression can override the apoptosis development in lymphoid and hormonally regulated tissue-like breast. The presence of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) have revealed in breast carcinomas, but they have not been correlated to the bcl-2 protein expression and DNA fragmentation markers. We evaluated the immunohistochemical expression of bcl-2 protein and hormonal receptors (ER, PR, AR) and differentiation grade in 37 infiltrating ductal carcinomas of the breast for which frozen tissues were available for DNA extraction. The immunohistochemical reaction for bcl-2 was considered positive if more than 50% of neoplastic cells had intense cytoplasmic staining, whereas for steroid receptor evaluation Battifora's criteria were used. The DNA was extracted according to the phenol-chloroform procedure and used for bcl-2 gene rearrangement study of the major breakpoint region (Southern blot) and for membrane-based end-labeling using digoxigenin-labeled nucleotides and E. coli DNA polymerase I (Klenow fragment). The results were quantified by three different observers. Low-grade carcinomas were positive for bcl-2 protein (27/28, 96.4%) and ER (15/28, 53.6%), whereas the remaining neoplasms were negative for bcl-2 (9/9, 100.0%) and ER (8/9, 53.6%) (p < 0.001). No statistically significant differences were revealed at the bcl-2, PR and AR comparisons. The Southern blot analysis for bcl-2 major breakpoint region showed neither rearrangement nor genetic amplification (densitometric study). Only the membrane-based end-labeling of DNA fragments showed correlation with bcl-2 protein and ER expressions: all except one bcl-2-negative tumor and two bcl-2-positive tumors had positive labeling using 7 pg of DNA at dot blot analysis (p < 0.002). The bcl-2 protein expression would allow both proliferation and cell progression by blocking apoptosis in well-differentiated, ER-positive breast carcinomas. In these neoplasms, DNA fragmentation as a molecular marker of apoptosis was prevented by bcl-2 expression.

Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein.

PURPOSE: Overexpression of the HER-2/c-neu/c-erbB2 proto-oncogene is associated with a worse prognosis in patients with breast cancer, perhaps due to an association of the HER-2 proto-oncogene protein with resistance to hormone and/or chemotherapy. Circulating levels of the extracellular domain (ECD) of the HER-2/c-neu-related protein (NRP) are elevated in 20% to 40% of patients with metastatic breast cancer. We investigated whether pretreatment levels of NRP predict response to hormone therapy (HT). MATERIALS AND METHODS: Circulating NRP levels were determined in 94 patients who participated in a randomized trial of three different doses of the antiestrogen, droloxifene (DRO), as first-line HT for metastatic breast cancer. RESULTS: NRP levels were elevated (> or = 5,000 U/mL) in 32 of 94 patients (34%). Only three of 32 patients (9%) with elevated NRP levels responded to DRO, compared with 35 of 62 (56%) with nonelevated NRP levels (P = .00001). Low pretreatment NRP level was the most powerful predictor of response to DRO (odds ratio of response, 22.4; P = .0001). Elevated pretreatment NRP levels were also associated with a shorter time to progression (TTP) and survival duration. CONCLUSION: Pretreatment circulating NRP levels predict a low likelihood of benefit from HT, specifically DRO, in patients with estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive or receptor-unknown metastatic breast cancer, even when adjusted for other known predictive factors, such as ER and/or PgR levels, site of disease, disease-free interval from primary treatment to recurrence, and prior adjuvant chemotherapy. These data suggest that pretreatment NRP levels may be useful in deciding whether to treat a patient who otherwise appears to be likely to respond to HT.

Epitopic characterization of the human wild-type and mutant ras proteins using membrane-bound peptides.

Overlapping octapeptides encompassing the entire sequences of the human oncogene products Ha-ras, K-ras and N-ras protein were synthesized as spots on polypropylene membrane sheets. The binding of anti-ras protein monoclonal antibodies (mAbs) to the membrane-bound peptides was assessed using an enzyme-linked immunosorbent assay. Epitopes of 10 of 18 mAbs to the human ras proteins were mapped and identified by this procedure. The epitopes of nine of the mAbs are within residues 28-39 in the constant domain common to the three ras proteins, whereas the epitope of the tenth (mAb 21) spans residues 136-144 in Ha-ras. The minimal lengths of epitopes of all ten of the mAbs were further precisely mapped using peptides of varying length, and the tolerance for mAb binding of mutated epitopes was determined by systematically replacing each residue in the epitope with each of the 20 common amino acids. The results show that most of these mAbs have essentially the same binding specificity, namely for the sequence YDPT (residues 32-35) or for slightly longer sequences containing these residues. This site is in the switch 1 region (residues 32-38) in the ras effector loop, indicating that some of the same residues important for the interaction of ras with other proteins (GTPase-activating protein, neurofibromin or raf) are highly antigenic. In addition, we investigated epitopes and specificity of five mAbs against the activated human ras proteins by the same procedure. The information gained from this study should be useful both for study of the complicated functions of ras proteins and clinical detection of ras oncogenes in human tumor cells.

Conformational effects in the p53 protein of mutations induced during chemical carcinogenesis: molecular dynamic and immunologic analyses.

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Vinyl chloride, a known human carcinogen that induces the rare sentinel neoplasm angiosarcoma of the liver, has been associated with specific A-->T transversions at the first base of codons 249 and 255 of the p53 gene. These mutations result in an Arg-->Trp amino acid substitution at residue 249 and an Ile-->Phe amino acid substitution at residue 255 in a highly conserved region in the DNA-binding core domain of the p53 protein. To determine the effects of these substitutions on the three-dimensional structure of the p53 protein, we have performed molecular dynamics calculations on this core domain of the wild-type and the Trp-249 and Phe-255 mutants to compute the average structures of each of the three forms. Comparisons of the computed average structures show that both mutants differ substantially from the wild-type structure in certain common, discrete regions. One of these regions (residues 204-217) contains the epitope for the monoclonal antibody PAb240, which is concealed in the wild-type structure but accessible in both mutant structures. In order to confirm this conformational shift, tumor tissue and serum from vinyl chloride-exposed individuals with angiosarcomas of the liver were examined by immunohistochemistry and enzyme-linked immunosorbent assay. Individuals with tumors that contained the p53 mutations were found to have detectable mutant p53 protein in their tumor tissue and serum, whereas individuals with tumors without mutations and normal controls did not.

Percutaneous revascularization of complex iliac artery stenoses and occlusions with use of Wallstents: three-year experience.

PURPOSE: To assess the outcome of percutaneous placement of Wallstents for treatment of hemodynamically significant diffuse stenoses (> 3 cm in length), chronic occlusions, failed angioplasty procedures, and flow-limiting dissection in the iliac arteries. MATERIALS AND METHODS: Lesions in 94 iliac limbs were treated in 66 patients. Indications for stent placement included claudication in 49 limbs and limb-threatening ischemia in 45. Forty-two limbs were treated for diffuse disease, 39 for chronic occlusion, nine for failed angioplasty, and four for flow-limiting dissection. RESULTS: Technical success was achieved in 86 of 94 limbs (91%), with major complications in 9% of patients. One death occurred within 30 days (not procedure-related). Ankle-brachial indexes improved from 0.51 +/- 0.24 to 0.76 +/- 0.22 (P < .001). Eighty-five percent demonstrated improvement under Rutherford criteria. Follow-up was obtained up to 38 months (mean, 14 months +/- 8). Cumulative primary patency rates were 78% at 1 year and 53% at 2 and 3 years (standard error 10%). Secondary patency rates were 86% at 1 year and 82% up to 32 months (standard error > 10% after 32 months). No significant decrease in mean ankle-brachial index was observed during follow up. No difference in primary patency was observed based on lesion type, symptom severity, lesion location, or runoff status. The limb salvage rate for patients with limb-threatening ischemia was 98% at a mean follow-up of 14 months +/- 7. CONCLUSIONS: Technical success and complication rates for percutaneous iliac artery revascularization with use of Wallstents are favorable, symptoms improved in the majority of patients, and excellent secondary patency can be achieved. With use of Wallstents, most patients with iliac artery insufficiency as a result of long-segment disease or chronic occlusions can be treated percutaneously.

ErbB-2 protein levels in healthy, asymptomatic women.

Abstract Recently, a number of studies have found a relationship between having breast cancer and elevated serological levels of the extracellular domain (ECD) of the erbB-2 protein. This study focuses on healthy, asymptomatic women, and evaluates the relationship between serological concentration of the ECD of erbB-2 protein and the following parameters: age, ethnicity, smoking status, age at menarche, age at first live birth, menopausal status, whether surgery had been performed within the prior year, history of breast cancer, history of any other cancer, family history of breast cancer, history of other cancers in first degree relatives, and number of prior benign breast biopsies. Blood samples were stored at -70°C and analysed within 3 weeks of phlebotomy. Statistical analysis indicates that in healthy women, the level of erbB-2 protein in the blood is directly related to age (p = 0.0002) and inversely related to having had a live birth (p = 0.018). The relationship to age is independent of the association between the oncoprotein level and menopausal status. The data indicate that rather than having only one threshold value for serological erbB-2 positivity, it may be necessary to have values that reflect age and nulliparity status.

Serum oncoproteins in asbestosis patients.

Using ELISAs, we determined the concentrations of transforming growth factor alpha (TGF-alpha), the extracellular domain of the erbB-2 receptor (erbB-2 ECD), and mutant p53 protein in stored serum samples of asbestosis patients with and without cancer and control subjects (without asbestosis or cancer). The percentage of individuals in these three groups with increased serum concentrations of TGF-alpha, erbB-2 ECD, and mutant p53, respectively, were: asbestosis patients with cancer, 36%, 16%, 19%; asbestosis patients without cancer, 38%, 19%, 6%; control subjects, 0%, 5%, 10%. Although differences in serum positivity for these oncoproteins were apparent among these groups, the differences did not achieve statistical significance (P > 0.05). In several of the cancer cases, increased concentrations of TGF-alpha, erbB-2 ECD, and mutant p53 were also detected in the stored serum samples collected years before the clinical diagnosis of disease.

Parasitized erythrocyte membrane antigens of Plasmodium brasilianum: relationships with the ring-infected erythrocyte surface antigen of Plasmodium falciparum.

An antigen, designated here as the parasitized erythrocyte membrane antigen (PEMA), is present in the erythrocyte membrane surrounding all intraerythrocytic stages of Plasmodium brasilianum. An antibody specific for PEMA appeared in 21 (50%) of 42 antisera from Saimiri sciureus monkeys naturally infected with P. brasilianum. Of these 42 sera, nine (21.4%) contained antibody to the ring-infected erythrocyte membrane antigen (RESA); of these nine sera, six did not react with PEMA. Sera of humans infected with P. malariae reacted with PEMA and RESA in a similar pattern; i.e., of 83 antisera, 71 (85.5%) reacted with PEMA and 30 (36%) reacted with RESA. Only one of these latter 30 sera were not reactive with PEMA. Of 167 sera from humans infected with P. falciparum but not P. malariae, 133 (79.6%) reacted with RESA; of these, 43 (25.7% of the total) reacted with PEMA but not RESA. Although PEMA was demonstrated with P. brasilianum and RESA with P. falciparum, neither PEMA or RESA could be demonstrated with P. malariae. Interactions of PEMA and RESA and the corresponding antibodies offer a method whereby the two morphologically similar quartan species, P. malariae and P. brasilianum, can be readily distinguished from each other and may furnish clues to genetic separation of the two and the mechanisms of interaction of quartan malaria and P. falciparum where they are coendemic.

Detection of p21ras mutations in colorectal adenomas and carcinomas by enzyme-linked immunosorbent assay.

BACKGROUND: Point mutations of the ras protooncogene, primarily within codons 12 and 13, are commonly identified in colorectal carcinomas and large adenomas. Despite data suggesting that ras genotyping may have clinical significance with respect to colorectal cancer screening and prognosis, more widespread use has been limited because of the lack of a suitable assay system. The principal objective of this study was to assess the feasibility and validity of a qualitative enzyme-linked immunosorbent assay (ELISA) for detecting the four most common ras mutations in human colorectal tumors at the protein (p21ras) level. METHODS: Tissue homogenates (11-121 micrograms) from endoscopically or surgically resected colorectal adenomas, carcinomas, and normal mucosae were evaluated by a commercially available ELISA (Oncogene Science, Inc. Cambridge, MA) for mutant p21ras containing arginine position 12 (arg12), valine position 12 (val12), aspartate position 12 (asp12), and aspartate position 13 (asp13) amino acid substitutions. Portions of the same tissue from an initial series of 27 specimens also were subjected to mutant-enriched polymerase chain reaction (PCR) and/or PCR amplification with subsequent DNA sequence analysis to validate the ELISA data. RESULTS: Forty-seven adenomas, 9 carcinomas, and 14 normal mucosae were assayed. Mutations were identified in 16 (34%) of the adenomas (7-asp12, 7-val12, 2-asp13), 3 (33%) of the carcinomas (1-asp12, 1-arg12, 1-asp13), and none of the normal mucosae by ELISA: Polymerase Chain Reaction and DNA sequencing analyses demonstrated identical results for 21 of the 23 (91%) and 14 of 16 (88%) homogenates tested, respectively. The ELISA demonstrated an overall sensitivity of 80-86%, specificity of 90-92%, positive predictive value of 86-100%, and negative predictive value of 86-91%. CONCLUSIONS: The ELISA is a feasible and valid approach for identifying p21ras mutations in human colorectal adenomas and carcinomas.

Levels of p53 antigen in the plasma of patients with adenomas and carcinomas of the colon.

Plasma levels of p53 protein were examined by an enzyme linked immunosorbent assay in 184 patients enrolled in a colonoscopy study. The mean levels among 47 individuals with normal colonoscopic examinations and no prior history of colonic neoplasia (0.12 ng/ml) and among 61 individuals with normal colonoscopic examinations and a prior history of colonic neoplasia (0.09 ng/ml) were similar. However, the mean levels among 54 individuals with newly diagnosed colonic adenomas (0.44 ng/ml) and 22 individuals with newly diagnosed colonic carcinomas (0.55 ng/ml) were statistically significantly elevated compared to the normal controls (P < 0.02). Among these tumor patients, the plasma levels tended to increase with increasing adenoma size and with increasing carcinoma stage, although these trends were not statistically significant. Defining a significant positive plasma level as any value greater than ten times background, the percentage of positive samples increased from 4% in the controls to 20% in the adenoma cases to 32% in the carcinoma cases. These results demonstrate that plasma p53 protein levels are elevated in a subgroup of individuals with colonic neoplasia.

Comparison of basilic vein and polytetrafluoroethylene for brachial arteriovenous fistula.

PURPOSE: The aim of this study was to compare patency and complication rates between basilic vein and polytetrafluoroethylene (PTFE) for brachial arteriovenous fistulas (AVF) for long-term hemodialysis. METHODS: All basilic vein and PTFE brachial AVF constructed between March 1988 and April 1993 were retrospectively reviewed. After construction of life-tables, log-rank testing was used to compare the primary patency rate of basilic vein AVF (n = 59) with the primary and secondary patency rates of PTFE AVF (n = 47). Complication rates were calculated for each type of fistula and compared by use of chi-squared testing. RESULTS: The primary patency rate for basilic vein AVF (90%) was superior to that of PTFE AVF (70%) at 1 year (p < 0.01), and at 2 years (86% vs 49%, p < 0.001). Complications occurred two and a half times more frequently in the PTFE group than in the basilic vein group (p < 0.05). CONCLUSIONS: Basilic vein AVF provided superior patency rates and lower complication rates compared with PTFE AVF. Prospective randomized trials comparing the two fistula types is required to firmly establish the basilic vein AVF as the alternative access procedure of choice after a failed or unconstructable radiocephalic fistula.

The detection of increased amounts of the extracellular domain of the epidermal growth factor receptor in serum during carcinogenesis in asbestosis patients.

Overexpression of the epidermal growth factor receptor (EGFr) has been implicated in the pathogenesis of a wide variety of human malignancies and may be related to asbestos-induced carcinogenesis. Overexpression of the EGFr can be detected immunologically by quantitation of the extracellular domain (ECD) in the extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the EGFr ECD was used to examine banked serum samples of 38 asbestosis patients who subsequently developed cancer, 72 age-sex-race-smoking-asbestos exposure matched asbestosis controls without cancer, and 20 age-sex-race-smoking matched nonasbestosis noncancer controls. The mean serum level for the EGFr ECD in the cancer cases (636 +/- 299 fmol/ml) was statistically significantly elevated (P < 0.05) in comparison to the mean level in the asbestosis controls (546 +/- 147 fmol/ml) or the nonasbestosis controls (336 +/- 228 fmol/ml). Defining a positive elevation of the serum EGFr ECD as any value more than 2 standard deviations above the nonasbestosis control mean, 7 (18%) of the cancer cases were positive compared to 4 (6%) of the asbestosis controls and one (5%) of the nonasbestosis controls. In addition, all of these cancer cases had positive serum samples prior to the time of disease diagnosis (average = 5.1 years). These results suggest that serum EGFr ECD may be elevated at an early stage of carcinogenesis in some asbestosis patients and that further prospective study of the utility of this biomarker is warranted.

Correlations of chronic hepatitis B virus infection and cigarette smoking with elevated expression of neu oncoprotein in the development of hepatocellular carcinoma.

To investigate the potential role of neu oncogene expression in hepatocarcinogenesis, a nested case-control study was conducted within a cohort of 9691 male adults in Taiwan. Blood samples of study subjects were collected during 1984-1986 and frozen at -30 degrees C until subsequent analysis. The neu oncoprotein level in the stored serum was measured by an enzyme-linked immunosorbent assay for 27 cases of newly developed hepatocellular carcinoma (HCC), 12 liver cirrhosis cases, and 40 healthy controls. The mean level of neu oncoprotein was significantly higher in HCC and liver cirrhosis cases than in controls. The risk of HCC increased significantly with increasing serum level of neu oncoprotein (trend test, P = 0.02). The proportion of subjects having an elevated serum level of neu oncoprotein, defined as a level greater than the mean level of all controls, was significantly higher among asymptomatic HBsAg carriers than noncarriers (P = 0.05), showing a multivariate-adjusted odds ratio of 4.0. Among HCC cases, a strong association was observed between cigarette smoking and elevated prediagnostic serum level of neu oncoprotein. The association remained highly significant (P = 0.017) even when adjustment was made for potential confounders. The multivariate-adjusted odds ratio of having an elevated serum level of neu oncoprotein, defined as a level greater than the mean plus 1 SD of control levels, for HCC cases who smoked more than 10 cigarettes a day was as high as 386.5 compared with the cases who smoked less than 10 cigarettes a day or nonsmoking cases. The results suggest that both HBsAg carrier status and cigarette smoking are related to the increased expression of neu oncogene, and cigarette smoking seems to play a significant role in the latter stages of hepatocarcinogenesis. There was no association between alcohol drinking and serum neu oncoprotein level.