Gerald Wolf

A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk

A common 936 C/T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels. In our case‐control study, we investigated the role of this polymorphism for breast cancer risk. VEGF genotype was determined in 500 women with breast cancer and 500 sex‐ and age‐matched healthy control subjects. Carriers of a 936T‐allele were more frequent among controls (29.4%) than among patients (17.6%; p = 0.000014). The odds ratio for carriers of a 936T‐allele for breast cancer was 0.51 (95% confidence interval 0.38–0.70). Additionally, VEGF plasma levels were determined in 21 nonsmoking post‐menopausal controls; carriers of a 936T allele had significantly lower levels (median 23 pg/ml; range 6–50 pg/ml) than noncarriers (37; 21–387; p = 0.034). We conclude that carriers of a VEGF 936T‐allele are at decreased risk for breast cancer, this, however, requiring further confirmation in a larger study.

The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk

Transforming growth factor-beta 1 (TGF-beta1) is a potent inhibitor of proliferation of epithelial, endothelial and hematopoietic cells and acts as a tumor suppressor. The gene for TGF-beta1, TGFB1, carries a common T/C variation of nucleotide 29, resulting in a leucine (L) to proline (P) polymorphism at codon 10 (TGFB1 L10P). The less common 10P allele has repeatedly been linked to higher TGF-beta1 levels and in at least one study to a lower incidence of breast cancer. To further analyze the role of this polymorphism for breast cancer risk, 500 patients with histologically confirmed breast cancer and 500 sex-and age-matched healthy control subjects were genotyped for the TGFB1 L10P polymorphism by an allele-specific polymerase chain reaction assay. TGFB1 LL, LP and PP genotype frequencies were not significantly different for patients (39.6, 44.2, 16.2%) and controls (36.5, 45.9, 17.6%). We conclude that the TGFB1 L10P polymorphism is not associated with breast cancer risk.

The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk.

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68–1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.

The 870G>A Polymorphism of the Cyclin D1 Gene is not Associated with Breast Cancer

A common 870G > A polymorphism in the gene for cyclin D1, CCND1, has been linked to alternative splicing and cancer susceptibility. To analyze its role for breast cancer, we determined the CCND1 genotype in 500 breast cancer patients and 500 controls. CCND1 genotype frequencies were similar among patients and controls. The CCND1 genotype was furthermore not associated with tumor characteristics. We conclude that the CCND1 870G > A polymorphism is not associated with breast cancer.

Endolacrimal laser assisted lacrimal surgery

AIMS To utilise the improved optical qualities of newly developed lacrimal endoscopes and newly miniaturised laser fibres for diagnostic visualisation and laser surgery of the lacrimal system. METHODS A KTP laser (wavelength 532 nm, 10 W energy) was used for laser assisted dacryocystorhinostomy (DCR) with endolacrimal visualisation in 26 patients. Bicanalicular silicone intubation was placed in all patients for at least 3 months. RESULTS After 3–9 months of follow up, the silicone tube in all 21 patients who underwent KTP laser DCR are still patent, three patients have eye watering in extremely cold weather and two required a conventional DCR. CONCLUSIONS The KTP laser generates enough power to open the bony window in DCR surgery. Precise endolacrimal visualisation via a specially designed miniendoscope is essential for surgical success.

Genetic polymorphisms in the vascular endothelial growth factor gene and breast cancer risk. The Austrian “tumor of breast tissue: incidence, genetics, and environmental risk factors” study

PurposeVascular endothelial growth factor (VEGF) is a key regulator of tumor-induced angiogenesis and is required for growth of tumors. We tested the hypothesis that VEGF gene polymorphisms may be associated with breast cancer.Experimental designWe performed a case–control study including 804 female incident breast cancer patients and 804 female age-matched healthy control subjects. We selected seven VEGF candidate polymorphisms and determined genotypes by 5′-nuclease (TaqMan) assays. Furthermore, VEGF plasma levels and genotypes were analyzed in a group of 81 healthy volunteers (64 men and 17 women).ResultsHaplotype analysis showed two separate blocks of high-linkage disequilibrium, formed by five polymorphisms upstream of the coding sequence (promoter and 5′ untranslated region) and two polymorphisms downstream of the coding sequence. None of the single polymorphisms or haplotypes was significantly associated with the presence of breast cancer. After Bonferroni correction for multiple testing, only one statistical signifcant association between VEGF genotypes and haplotypes and tumor characteristics was observed (-634C allele and small tumor size; pxa0<xa00.001). In a multivariate regression analysis including sex, age, VEGF genotypes, and haplotypes as covariates and VEGF plasma level as dependent variable, none of the VEGF polymorphism or haplotypes was a significant predictor of VEGF plasma levels.ConclusionsOur findings do not support the hypothesis that VEGF polymorphisms are associated with breast cancer risk. The association of the VEGF -634C allele with small tumor size is in clear contrast to a previous publication and should be interpreted with caution until replicated by additional studies.

Genetic Variants of the Sulfotransferase 1A1 and Breast Cancer Risk

Sulfotransferase 1A1 (SULT1A1), also designated as phenol-preferring sulfotransferase, is involved in the bioactivation and detoxification of a variety of potential carcinogens, including iodothyronines, hydroxylated aromatic amines, and phenolic xenobiotics. A common arginine (R) to histidine (H) polymorphism at amino acid position 213 influences SULT1A1 activity and has been suggested as risk factor for a different types of cancers. To investigate the role of this polymorphism for breast cancer risk, SULT1A1 genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. Frequencies of heterozygous (controls: 42.5% patients: 50.2%) or homozygous (controls: 12.6%; patients: 9.4%) carriers of the 213H variant were not significantly different between groups.ficantly different between groups. The SULT1A1 genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. The SULT1A1 213H variant was associated with the presence of lymph node metastases (p = 0.002). We conclude that the SULT1A1 R213H polymorphism is not a general risk factor for breast cancer, but may be involved in lymph node metastazing in breast cancer patients.

The 936C>T polymorphism of the gene for vascular endothelial growth factor is associated with 18F-fluorodeoxyglucose uptake

Background: Positron emission tomography (PET) is a an important technology for detection and staging of breast cancer. The method is based upon assessment of glucose metabolism using the 18F-fluorodeoxyglucose (18F-FDG) as glucose analog. A strong variability of 18F-FDG uptake by breast cancer tissue has been reported, the reason for which is not fully understood but may involve vascular density and integrity. A 936C>T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels and breast cancer risk.Methods: To analyze the role of this polymorphism for 18F-FDG uptake in breast cancer patients, we determined the VEGF genotype in 37 patients in whom PET was performed for detection of metastases. An 18F-FDG uptake score of 1 (low uptake), 2 (medium uptake) or 3 (high uptake) was assigned to each patient.Results: VEGF CC, CT and TT genotypes were found in 28, 8 and 1 patient. Uptake score of 1 was found in three patients, score 2 in 12 patients and score 3 in 22 patients. VEGF genotype was significantly associated with FDG uptake score (χ2 test, p=0.007). The number of 936-T alleles correlated with a lower 18F-FDG uptake score (Spearman correlation test, p=0.032).Conclusion: In the present study the common VEGF 936C>T polymorphisms had a major impact on 18F-FDG uptake in breast cancer patients. If this result can be confirmed in following studies, it might have strong relevance for the use of PET as diagnostic tool.

Analysis of common germline polymorphisms as prognostic factors in patients with lymph node-positive breast cancer.

PurposeWomen with breast cancer that initially involves local lymph nodes have a higher risk for local recurrence or developing metastases. Recent data suggest that germline polymorphism is a significant, previously unrecognized factor in breast cancer progression and metastasis. We assessed the influence of 16 selected common germline polymorphisms in disease-free survival and overall survival among 216 women diagnosed with lymph node-positive breast cancer.ResultsThe rare allele of FAS 1377G>A was significantly associated with prolonged disease-free survival (Pxa0=xa00.012, risk ratio of recurrence (RR)xa0=xa00.557, 95% confidence interval (CI)xa0=xa00.353–0.878) in univariate analysis. After adjusting for known breast cancer prognostic factors the association remained significant (Pxa0=xa00.050, RRxa0=xa00.500, CIxa0=xa00.309–0.809). In overall survival analysis we found a significant association of the FAS 1377G>A (Pxa0=xa00.040, RRxa0=xa00.451, CIxa0=xa00.496–1.188) and IL10 592C>A polymorphisms (Pxa0=xa00.020, RRxa0=xa01.707, CIxa0=xa01.087–2.680) in the univariate Cox regression. The effect remained statistically significant in the multivariate analysis for the IL10 592C>A polymorphism (Pxa0=xa00.013, RR 1.841, CI 1.140–2.973). No association was found for MTHFR 677C>T, VEGF 936C>T, CCND1 870G>A, TGFB1 29T>C, FASLG 844C>T, FAS 670A>G, GPB3 825C>T, ITGA2 807C>T, ITGA2 1648G>A, ITGB3 176T>C, MMP1 -1607 1G/2G, MMP3 5A/6A, PTGS2 8473T>C, IL10 592C>A and SULT1A1 638G>A polymorphisms and disease-free survival or overall survival.ConclusionsOur data suggest that the FAS 1377G>A and IL10 592C>A polymorphisms could modify disease-free and overall survival in women with lymph node-positive breast cancer.

Die Wirkung topischer Kortikosteroide und topischer Antihistaminika auf das Flimmerepithel humaner Nasenschleimhaut in vitro

ZusammenfassungFür eine ungestörte mucociliäre Clearence der Nase und Nasennebenhöhlen ist ein koordinierter Flimmerschlag zilientragender Zellen der Nasenschleimhaut notwendig. Untersucht wurde die Wirkung topischer Kortikosteroide und topischer Antihistaminika auf die Flimmerschlagfrequenz humaner Nasenschleimhaut in vitro. Die 4 getesteten Nasensprays enthielten als Wirksubstanz die Kortikosteroide Budesonid und Fluticasonpropionat bzw. die Antihistaminika Levocabastin und Azelastin. Die Experimente wurden unter konstanten und standardisierten Bedingungen an humanen Zellkulturen durchgeführt; 3 der 4 untersuchten Nasensprays enthielten Benzalkoniumchlorid als Konservierungsmittel. Die Messungen ergaben einen irreversiblen Stillstand der Zilien durch Benzalkoniumchlorid haltige Nasensprays in einer Verdünnung 1:1 mit Tyrodelösung. Der Budesonid enthaltende Nasenspray, der als einziger der 4 getesteten Nasensprays Benzalkoniumchlorid frei ist, führte nur zu geringer, nach 20xa0min voll reversibler Beeinflußung des Flimmerschlags. Da Benzalkoniumchlorid in vitro den Flimmerschlag bis zum irreversiblen Stillstand hemmen kann, sollte die Substanz nicht mehr als Konservierungsmittel in Lokalthera-peutika für die Nase verwendet werden.SummaryA normal ciliary beat frequency of ciliated cells is necessary for the mucociliary clearance of the nose and paranasal sinuses. An in vitro investigation was performed to eval-uate the influence of topical corticosteroids and antihistamines on the ciliary beat frequency of human nasal mucosa. The nasal sprays examined contained the corticosteroids budesonide or fluticasone propionate and the topical antihistamines azelastine or levocabastine. All tests were performed on cell cultures of human nasal mucosa during constant conditions. Three of the four nasal sprays tested contained benzalkonium chloride as preservative. An irreversible cessation of ciliary movement was observed in all cells exposed to nasal sprays containing benzalkonium chloride in a 50 per cent solution. The nasal spray containing budesonide was benzalkonium chloride-free and caused minor but fully reversible decreases in ciliary beat frequency after 20xa0min. As benzalkonium chloride can cause complete standstill of ciliary beat frequency in vitro in human nasal mucosa, we recommend that this preservative should not be used anymore in topical nasal medications.