Biomedical subjects

Lukas A Hefler

Publications and source records attributed to Lukas A Hefler.

At least 19 recordsLinked to original sources

PubMed2007

An estrogen metabolism-related polymorphism of the 17-alpha HSD gene is associated with perimenopausal body mass index.

In a cross-sectional study of 2,802 perimenopausal caucasian women, carriage of at least one mutated allele of the 17-alpha-hydroxysteroid dehydrogenase type 1 (17-alpha HSD) vlV A-->C single nucleotide polymorphism (SNP) was associated with a significantly increased body mass index (mean 24.3 +/- 4.4 kg/m(2) vs. 23.5 +/- 4.2 kg/m(2); P<.001), and obesity was more frequent among mutant allele carriers (P=.06; odds ratio 1.38; 95% confidence interval 0.97-1.95), providing evidence of 17-alpha HSD as a candidate gene of perimenopausal obesity.

Body Mass Index↗

PubMed2007

The lack of laminin-5 as a prognostic marker in low-grade cervical squamous intraepithelial lesions: correlation with clinical follow-up data.

Low-grade cervical squamous intraepithelial lesions have a high rate of spontaneous regression but may undergo surgical treatment (cone biopsy) in case of persistence of the lesion or discrepancy between Pap-smear diagnosis and biopsy diagnosis. This may sometimes lead to surgical complications and/or adverse effects on fertility. Thus, the present study was designed to investigate the potential of laminin-5 as a sensitive molecular marker identifying cervical intraepithelial neoplastic lesions (CIN), which are likely to regress and ultimately spare women unnecessary surgical procedures. Cervical punch biopsy samples from 65 women with either a CIN I or a CIN II were evaluated for the expression of laminin-5 by immunohistochemistry. All study subjects agreed to a conservative clinical management and were frequently followed-up (median follow-up time 237 days) to evaluate for changes in the dysplastic lesion. Laminin-5 staining results were correlated with patient's characteristics as well as clinical follow-up data. Laminin-5 expression was detected in 16 of 40 CIN I (40%) lesions, 2 of 21 CIN II (9.5%) lesions and none of 4 reclassified CIN III lesions. Within positive cases, laminin-5 expression was localized to the cytoplasm of the dysplastic cells. The laminin-5 expression was significantly associated with the grade of CIN lesion (p < 0.005). Correlations with patient's characteristics were not statistically significant except for education and ectocervical smear diagnosis. No significant associations were noted between laminin-5 expression and either regression, persistence or progression of the CIN lesions. These data indicate that laminin-5 is not a useful diagnostic adjunct in histopathology for the identification of CIN lesions with progressive capacity.

Adolescent↗

PubMed2006

Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer.

OBJECTIVE: Serum vascular endothelial growth factor (VEGF) levels have been shown to be associated with an adverse outcome in patients with ovarian cancer. We studied the clinical value of serum VEGF as an independent prognostic parameter. METHODS: In the present study, we ascertained preoperative serum VEGF in a series of 314 patients with ovarian cancer: 45 new cases and 269 from four previously published studies. Serum VEGF was evaluated prior to primary surgery, results were correlated with clinical data. RESULTS: Median serum VEGF was 407 (238-746) pg/mL. In a univariate Kaplan-Meier analysis, FIGO stage, residual tumor mass, tumor grade, patients' age, serum CA 125, and preoperative serum VEGF were associated with overall survival. In a multivariate Cox regression model, higher FIGO stage, presence of residual tumor mass after primary surgery, and higher serum VEGF were independently associated with a shortened overall survival. Planned subgroup analysis was performed for patients with ovarian cancer FIGO stage I. In a multivariate Cox regression model, higher tumor grade and higher serum VEGF were the only independent prognosticators for overall survival. Patients with FIGO stage I ovarian cancer and a serum VEGF > or = 380 pg/mL had an 8-fold increased risk for experiencing cancer-related death. CONCLUSION: Serum VEGF is an independent prognostic parameter in patients with all stages of ovarian cancer.

CA-125 Antigen↗

PubMed2006

Polymorphisms of the endothelial nitric oxide synthase gene in breast cancer.

Nitric oxide (NO) is known to be critically involved in breast carcinogenesis. Genetic polymorphisms of the gene encoding for endothelial nitric oxide synthase (Nos3), the enzyme catalyzing the production of the NO, are known to predispose to malignant disease. Whether these polymorphisms also influence breast cancer risk is unknown. In the present case-control study, we ascertained 2 polymorphisms of the Nos3 gene cluster (Nos3 exon 7 Glu298Asp and a 27-base pair repeat in intron 4 of Nos3) in 269 Caucasian patients with breast cancer and 244 healthy controls using pyrosequencing and PCR, respectively. Presence of the exon 7 Nos3 polymorphism predisposed women to breast cancer (p=0.03, Odds ratio [95% Confidence Intervals]=1.9 [1.1-3.6]), but was not associated with any clinico-pathological parameters. No significant associations were ascertained with respect to the intron 4 Nos3 polymorphism. In our series, presence of the mutant exon7 Nos3 polymorphism was associated with an increased risk for breast cancer in Caucasian women.

Breast Neoplasms↗

PubMed2006

A model for predicting age at menopause in white women.

OBJECTIVE: To develop a model to predict the age at natural menopause and the risk for premenopausal hysterectomy. DESIGN: Cross-sectional study. SETTING: Multicenter study. PATIENT(S): A total of 1,345 white women. INTERVENTION(S): Ten single nucleotide polymorphisms (SNPs) of seven estrogen (E)-metabolizing genes (i.e., catechol-O-methyltransferase, 17-beta-hydroxysteroid dehydrogenase type 1, cytochrome P-450 [CYP] 17, CYP1A1, CYP1B1, CYP19, and E receptor [ER] alpha) were analyzed by sequencing-on-chip-technology. MAIN OUTCOME MEASURE(S): Patients' reproductive and medical histories were ascertained and correlated to genotypes. RESULT(S): The model incorporates the number of full term pregnancies, the body mass index (BMI), a history of breast surgery, and the presence of CYP17 and CYP1B1-4 polymorphisms as well as the BMI to predict age at natural menopause and the risk for undergoing premenopausal hysterectomy. CONCLUSION(S): We present the first model to date, which can predict age at natural menopause and the risk for undergoing premenopausal hysterectomy based on genotype information and personal history.

Aging↗

PubMed2006

How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer?

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased in recent years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of estradiol and xenobiotics metabolisms as well as genes involved in cell-cycle control have been described as significant contributors to breast cancer susceptibility, with variations depending on ethnic background and co-factors such as smoking and family history of breast cancer. In sum, the highest level of evidence to date linking SNPs and breast cancer comes from nested case-control studies within the prospective Nurses' Health Study. These data establish seven SNPs - hPRB +331G/A, AR CAG repeat, CYP19 (TTTA)10, CYP1A1 MspI, VDR FOK1, XRCC1 Arg194Trp and XRCC2 Arg188His - as small but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature establishes the TGFBR1*6A, HRAS1, GSTP Ile105Val and GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer. The clinical consequences of such a risk elevation may be detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of body mass index, physical exercise, avoidance of alcohol and long-term hormone replacement therapy, and participation in a breast cancer screening program between the ages of 50 and 70 years. Specific surgical or drug interventions such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen are not indicated based on SNP analysis at this time.

Breast Neoplasms↗

PubMed2006

Multilocus genotypes spanning estrogen metabolism associated with breast cancer and fibroadenoma.

We investigated inherited polymorphic variation in genes spanning estrogen metabolism (10 SNPs [single nucleotide polymorphism]) to distinguish multilocus genotypes associated with breast cancer (n = 393), benign breast lesions (n = 154), and low risk (n = 1936). Three latent classification GoM extreme type groups represented the data: (a) fibroadenoma, and infrequent SRD5A2 and VDR alleles; (b) postmenopausal breast cancer, and infrequent CYP1A1-1 and CYP1A1-2 alleles (both over-represented infrequent alleles for CYP17, CYP19-3, and COMT); and (c) women at intrinsically low risk. Carriage of the respective multilocus genotypes increased risk 25-fold. We conclude that GoM latent classification may be useful to identify genetic risk sets and estimate risk for individuals.

Aged↗

PubMed2005

A common polymorphism within the steroid 5-alpha-reductase type 2 gene and timing of menopause in Caucasian women.

OBJECTIVE: Androgens are thought to play an important role in various reproductive functions. We evaluated the association between a common polymorphism of the steroid 5-alpha-reductase type 2 gene (SRD5A2) involved in androgen metabolism and the timing of menopause. STUDY DESIGN: Three hundred and twenty-three consecutive women were included in this cross-sectional study. The common exon 1 Valine/Leucin polymorphism of the SRD5A2 gene was analyzed using a microarray-based system. RESULTS: No significant association between the SRD5A2 polymorphism and age (years) at natural menopause was ascertained. There were no significant differences in the background characteristics of the subjects among SDR5A2 genotypes including the number of full term pregnancies, age at first delivery, BMI, personal or family history of breast cancer, smoking status and personal history of recurrent abortion. A multivariate regression analysis showed that the number of full term pregnancies, but not smoking, an increased body mass index, or a history of breast cancer significantly influenced timing of natural menopause. CONCLUSION: In the present study the number of full term pregnancies, but not the common V89L SRD5A2 polymorphism, is the only significant predictor for the timing of natural menopause in Caucasian women.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2005

A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the prognosis of patients with ovarian cancer.

OBJECTIVE: The enzyme matrix metalloproteinase (MMP)-1 is involved in ovarian carcinogenesis. A common guanine insertion-deletion promoter polymorphism within the gene encoding MMP-1 (MMP1) has been suggested to be a candidate gene for ovarian cancer. We investigated whether this common polymorphism can also serve as independent prognostic parameter in a large series of affected women. METHODS: The MMP1 promoter polymorphism was examined in 151 Caucasian patients with epithelial ovarian cancer using polymerase chain reaction. Results were correlated with clinical data. RESULTS: No associations were ascertained between the MMP1 polymorphism and tumor stage (P = 1.0, odds ratio [OR] 1.08), lymph node involvement (P = 1.0, OR 0.8), tumor grading (P = 0.2, OR 0.5), and patient's age at diagnosis (P = 1.0, OR 1.04). Besides the clinically established prognosticators, tumor stage and histological grade, presence of the MMP1 polymorphism was associated with a shortened disease-free and overall survival in a univariate Kaplan-Meier analysis (P = 0.01) and a multivariate Cox regression model (P = 0.04). CONCLUSION: Presence of the MMP1 gene promoter polymorphisms was found to be a negative prognostic parameter in patients with ovarian cancer.

Female↗

PubMed2005

A common interleukin-6 promoter polymorphism in patients with vulvar cancer.

OBJECTIVE: Besides its important role in immune response and inflammatory processes the cytokine interleukin-6 (IL-6) is crucially involved in carcinogenesis. A common polymorphism within the gene encoding IL-6 (IL6) is known to alter IL-6 protein expression and has been associated with patients' prognosis in various malignancies. No data are available with respect to vulvar cancer. Therefore, we determined the prognostic potential of the common -174(G-->C) single nucleotide polymorphism in the promoter region of IL6 in a series of patients with this disease. METHODS: The IL6 promoter polymorphism was investigated in 81 Caucasian patients with surgically treated squamous cell vulvar cancer using pyrosequencing. Results were correlated with clinical data. RESULTS: No association was ascertained between the IL6 promoter polymorphism and the investigated clinicopathologic parameters, ie, tumor stage, lymph node involvement, tumor grade, and patient's age at diagnosis. In an univariate analysis, lymph node involvement and patients' age at diagnosis were associated with patient prognosis. In a multivariate analysis, including tumor stage and lymph node involvement as established prognostic factors and the IL6 promoter polymorphism, lymph node involvement, and the presence of at least one mutant allele, but not tumor stage, were associated with increased disease-free and overall survival. CONCLUSION: Our data suggest that the IL6 -174(G-->C) promoter polymorphism might serve as an additional prognostic parameter in patients with vulvar cancer.

Aged↗

PubMed2005

The cyclooxygenase-2 inhibitor rofecoxib (Vioxx) in the treatment of cervical dysplasia grade II-III A phase II trial.

OBJECTIVE: To determine whether the cyclooxygenase (COX)-2 inhibitor rofecoxib increases the regression rates of cervical intraepithelial neoplasia (CIN) grade II and III. STUDY DESIGN: A prospective, randomized, placebo-controlled, double-blind study with rofecoxib 25 mg daily for 6 [corrected] months as active treatment for patients with CIN II and III was started in May 2004 [corrected] and was halted after rofecoxib withdrawal in October 2004 [corrected] RESULTS: A total of 16 patients with CIN II (n=9) and CIN III (n=7) were included in our study. Eight and eight patients received rofecoxib and placebo, respectively. Regression rates in the rofecoxib and placebo arm were statistically not significant (25% versus 12.5%) after a mean of 87 (46.3) days of treatment. No severe side effects were noted during the therapy; no dropouts were recorded. CONCLUSION: A conservative treatment of CIN II and III is feasible. Inhibitors of COX, especially COX-2, were seen as candidates for cancer chemoprevention. Our study was halted after rofecoxib was withdrawn. The results obtained should be added to those already published for planning future studies on medical therapies for high grade CIN.

Adult↗

PubMed2005

A polymorphism of the plasminogen activator inhibitor-1 gene promoter and the polycystic ovary syndrome.

OBJECTIVE: To investigate the association of a common 5G/4G polymorphism of the plasminogen activator inhibitor-1 gene (PAI1) with occurrence and clinical characteristics of the polycystic ovary syndrome (PCOS). STUDY DESIGN: In a case-control study, we evaluated a series of 106 Caucasian women with PCOS and 102 healthy controls. Women completed a detailed questionnaire and underwent a peripheral venous puncture, ultrasonography, and a standardized oral glucose tolerance test (OGTT). The PAI1 gene promoter polymorphism was evaluated using PCR. RESULTS: Allele and genotype frequencies were not significantly different among women with PCOS and controls (P=0.3 and 0.6, respectively). In women with PCOS, presence of the 5G/4G polymorphism of PAI1 was not associated with changes in serum hormone levels or with clinical characteristics. CONCLUSIONS: The 5G/4G polymorphism of the PAI1 promoter is not associated with occurrence and phenotype of the PCOS.

Adult↗

PubMed2005

Interleukin-1 and interleukin-6 gene polymorphisms and the risk of breast cancer in caucasian women.

PURPOSE: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. EXPERIMENTAL DESIGN: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [-889 C/T polymorphism of the IL1alpha gene (IL1A), -511 C/T polymorphism of the IL1beta promoter (IL1B promoter), a polymorphism of IL1beta exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the -174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. RESULTS: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. CONCLUSIONS: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the -174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.

Aged↗

PubMed2005

The influence of a Vitamin D receptor gene polymorphism on the timing of female reproductive functions in humans.

OBJECTIVE: To evaluate the association between a common polymorphism of the Vitamin D receptor gene (VDR) and the timing of female reproductive functions in humans. METHODS: One thousand fifty-eight consecutive women were included in this cross-sectional study. We analyzed the intron 8 Bsm I restriction fragment length polymorphism (RFLP) of VDR on chromosome 12q using a microarray-based system. RESULTS: The presence of the VDR polymorphism did not influence the timing of menarche and natural menopause and was not associated with the number of spontaneous abortions, full term pregnancies (FTP) as well as the total number of pregnancies. Of note, women with at least one mutant allele of VDR were at a significantly decreased risk for experiencing surgical menopause (odds ratio [OR] 0.65, 95% confidence interval [CI], 0.46-0.92, P = 0.02). Smoking and a body mass index (BMI) > 25 were associated with an earlier natural menopause and an increased risk for surgical menopause, respectively. CONCLUSIONS: While no association of a common polymorphism of VDR with the timing of menarche and menopause was ascertained, we found the presence of at least one mutant allele of VDR to be associated with a decreased risk of experiencing surgical menopause, i.e., premenopausal hysterectomy, in a large series of Caucasian women.

Adult↗

PubMed2005

Ultrasound criteria for ductal invasive breast cancer are modified by age, tumor size, and axillary lymph node status.

PURPOSE: To evaluate the influence of distinct clinicopathological parameters on ultrasound criteria for ductal invasive breast cancer. PATIENTS AND METHODS: The hardcopy prints of 337 ductal invasive breast cancers were analyzed. Ten ultrasound criteria (shape, orientation, echogenicity, echo pattern, calcifications, margin, margin contour, lesion boundary, surrounding tissue, and posterior acoustic features) were defined and correlated to age, tumor size, axillary lymph node status, and histological grading in a multivariate analysis. RESULTS: Tumors in women < or = 50 years displayed more often an indistinct margin (p = 0.003) and an enhanced/indifferent posterior ultrasound transmission (p = 0.008). Tumors in an advanced T-stage showed more frequently an irregular shape ( p = 0.006), an orientation parallel to the skin ( p = 0.01), hypoechogenicity ( p < 0.0001), and less often calcifications ( p = 0.002). A positive axillary lymph node status was significantly correlated to oval/round shape ( p = 0.004), hyper-/isoechogenicity ( p = 0.001), and a homogeneous echo pattern ( p = 0.002). Grading showed no correlation to the examined ultrasound criteria. CONCLUSION: Breast ultrasound criteria, which are used to differentiate benign from malignant breast lesions, are influenced by age, size and lymph node status. These clinical conditions should be considered in the ultrasound diagnosis of breast lesions.

Adult↗

PubMed2005

A polymorphism in the matrix metalloproteinase-1 gene promoter is associated with the presence of polycystic ovary syndrome in Caucasian women.

A common -1607 GG/G polymorphism of the matrix metalloproteinase-1 (MMP1) gene promoter was investigated in a series of Caucasian women with polycystic ovary syndrome (PCOS) and controls, by direct sequencing. In this prospective case-control study, the odds for women with at least one mutant GG allele of the MMP1 promoter to be diagnosed with PCOS was 2.7.

Adult↗

PubMed2005

Role of the vaginally administered aromatase inhibitor anastrozole in women with rectovaginal endometriosis: a pilot study.

In the present nonrandomized pilot study we determined the role of the vaginally administered aromatase inhibitor anastrozole (0.25 mg anastrozole/d for 6 months) in the treatment of women with histologically proven rectovaginal endometriosis. In a series of 10 patients, dysmenorrhea, physical and social functioning, but not chronic pelvic pain and dyspareunia, improved during therapy.

Administration, Intravaginal↗

PubMed2005

Ultrasound morphology of invasive lobular breast cancer is different compared with other types of breast cancer.

The aim of this study was to evaluate the ultrasound (US) morphology of invasive lobular breast carcinomas (ILC) in comparison to that of invasive tumors of other histologic differentiation (TOD). Images of 406 breast lesions were included in this retrospective study. A total of 10 US criteria (shape, orientation, echogenicity, echo pattern, calcifications, margin, margin contour, lesion boundary, surrounding tissue and posterior acoustic features) were defined and determined. Tumors were stratified into ILC (n = 69) vs. TOD (n = 337). The correlation between the sonographically and pathologically measured size of the tumors was analyzed. Irregular shape was found in 88% of ILC vs. 67% of TOD (p < 0.001). Margins were indistinct in 94% of ILC compared to 76% of TOD (p = 0.001). Posterior shadowing was observed in 84% of ILC and 58% of TOD (p = 0.001). Irregular margin contour, hyper- or isoechoic pattern and architectural distortion were more frequent in ILC. Underestimation of tumor size by US was significantly more frequent in ILC (5.4 +/- 12.2 mm) than in TOD (1.4 +/- 12.0 mm) (p = 0.015). In summary, we found that histologic differentiation significantly influences ultrasonographic appearance of breast cancer. The underestimation of tumor size of ILC might compromise the operative strategy.

Breast Neoplasms↗