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Vascular endothelial growth factor plays a pivotal role in the progression of atherosclerotic lesions and causes instability of atherosclerotic plaques by inducing neoangiogenesis inside the current plaque. The pro-inflammatory cytokine interleukin (IL-) 6 induces vascular endothelial growth factor in smooth muscle cells (SMC). HMG-CoA reductase inhibitors (statins), display beside their lipid-lowering potency various pleiotropic effects. Such pleiotropic effects include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. In this study we investigate the influence of statin treatment on the serum levels of VEGF in hypercholesterolemic patients. One hundred and seven hypercholesterolemic patients were treated with 20 (n = 52) or 40 mg (n = 55) simvastatin daily. Six weeks of treatment resulted in a significant decrease of VEGF from 1017.1 +/- 297.8 pg/mL at baseline to 543.5 +/- 317.4 pg/mL after 6 weeks (-47.7%) and to 211.8 +/- 155.3 pg/mL after 6 months (-79.7%; all P < 0.001). IL-6 induced the expression of vascular endothelial growth factor in human SMC as analyzed by rt-PCR and flow cytometry. Statins decreased the stimulatory effect of IL-6 on mRNA and protein levels. This effect could be inhibited by co-incubation with mevalonate acid. This study contributes in understanding the pleiotropic effects of statins particularly with regard to their use in treatment and prevention of cardiovascular disease.

Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin(R)) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p = 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR = 8.0, p = 0.021 and OR = 8.0, p = 0.021) and clinical benefit (OR = 5.47, p = 0.041 and OR = 6.22, p = 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR = 0.21, p = 0.01 and RR = 0.45, p = 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR = 0.17, p = 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy.

Objective.—Polymerase chain reaction (PCR) and indirect in situ hybridization were combined to detect human papillomavirus (HPV) DNA on Papanicolaou (PAP)-stained cervical smears. To our knowledge, this is the first report of an experiment using indirect in situ PCR (IS-PCR) on PAP-stained cervical smears. Design.—We collected native cell specimens from cervicovaginal lavage of 162 patients with squamous intraepithelial lesions. Solution-phase PCR (SP-PCR) was performed as the reference method in the detection of HPV DNA. Indirect IS-PCR was carried out for the same patients to detect the HPV DNA types 6/11 and 16/18 after the PAP-stained smears had been decolorized. Low-risk and high-risk HPV DNA types were also detected by both SP-PCR and indirect IS-PCR. Results.—In the evaluation by indirect IS-PCR, 48 of 81 PAP-stained cell smears of low-grade squamous intraepithelial lesions were positive for HPV DNA, as compared to 40 positive cell smears determined by indirect SP-PCR (sensitivity of indirect IS-PCR compared to SP-PCR, 98.1%). Forty-two of 42 high-grade squamous intraepithelial lesion samples were positive for HPV DNA, as determined by both methods (sensitivity of IS-PCR, 100%). Cell lines investigated in this study as positive or negative controls for HPV DNA were confirmed by indirect IS-PCR and SP-PCR. Conclusions.—Our data show that in comparison to SP-PCR, indirect IS-PCR is a highly sensitive method to detect HPV DNA in cell smears from the uterine cervix. The advantages of indirect IS-PCR are (a) low numbers of cells needed, (b) the possibility of using PAP-stained specimens, and (c) cytologic details of smears can be preserved.

The aim of this study was to detect activated c-K-ras by gene point mutation and to find c-erbB-2 gene amplification with p185 expression in association with the c-K-ras gene product p21 in the human endometrium. Specimens obtained from 25 normal, 31 hyperplastic and 72 malignant samples of the human endometrium were examined for point mutation in codons 12, 13 and 61 of the c-K-ras by direct sequencing and c-erbB-2 gene amplification with p185 and p21 expression by differential polymerase chain reaction (DPCR) and immunohistochemistry. Neither the normal endometrium nor endometrial hyperplasias were found to have mutations in the c-K-ras gene, although a double mutation of codons 12 and 13 as a single-point mutation was observed in one case of endometrioid carcinoma (2.8%). In each of two other cases of endometrioid carcinoma (2/72), two single-point mutations of codon 13 (5.6%) were shown. Using DPCR, we found c-erbB-2 to be amplified in 15 premalignant (48%) and 45 malignant (63%) samples. We noticed that nonamplification of the c-erbB-2 gene was associated with the absence of immunoreactivity. Our data indicate that, while c-erbB-2 plays a role in the early development of endometrioid carcinomas, c-K-ras gene activation by point mutation does not.

Purpose: The objective of our study was to demonstrate differences in relapse rates, total survival times, and complication rates between inguinofemoral radiation and its absence in cases of invasive vulvar carcinoma without lymph node involvement (FIG0 Stages Tl, NO-l). Methods and Materials: From 1974 to 1990, 135 patients with invasive vulvar carcinoma in Stage Tl without clinical evidence of inguinal lymph node involvement underwent simple vulvectomy performed by hot-knife resection without lymphadenectomy. Although 65 patients (Group 1) received postoperative inguinofemoral radiation therapy, 70 patients (Group 2) did not, and none received local vulva irradiation. Results: The S-year survival rates were 93.7% in Group 1 and 91.4% in Group 2 (p = NS). Although clitoris involvement was significantly more prevalent in the irradiation group (p = 0.04), inguinal relapse was found less frequently in Group 1 (4.6% or 3 out of 65 patients) than in group 2 (10% or 7 out of 70 patients) (p = 0.32). The complication rates were, 7.7% in Group 1 and 2.9% in Group 2,2.7% for vaginal stenosis (two patients in each group), 1.5% for inguinal pain (one patient in Group 1), 1.5% for rectovaginal fistula (one patient in Group 1)) 1.5% for vulvar infection (one patient in Group 1). Conclusion: No statistically significant differences in the relapse rates and survival times were found. Risk factors were equally distributed in both study groups except for clitoris involvement. The 5.year survival rates in both groups were similar to those reported in the literature for radical vulvectomy and inguinal lymph-node dissection (83-96% ). Morbidity in our study was low. Although our data showed similar results in both groups, we are not recommending at this time to omit groin radiation in general, but it may be justified in low-risk cases. 0 1997 Elsevier Science Inc.

The presence of hepatitis C virus (HCV) in normal cervical smears (CS) obtained from 22 HCV-seropositive and 50 HCV-seronegative patients was assessed by reverse-transcriptase-polymerase chain reaction (RT-PCR). The presence of HCV in serum was established by use of enzyme-linked immunosorbent assay, Western blot test, and RT-PCR. HCV was detected in 36.4% (n = 8) of CS cells recovered from 22 HCV-seropositive patients, but not in CS samples obtained from 50 HCV-seronegative patients. Furthermore, cells from the CS of 2 seropositive/smear-positive patients and 1 seropositive/smear-negative patient were isolated; HCV RNA was detectable in the cervical lymphocytes of the 2 smear-positive patients, but not in epithelial cells or granulocytes. HCV RNA is detectable in the CS of some HCV-seropositive women. The clinical importance of these data requires further study.