C Marth

University of Innsbruck, Innsbruck, Tyrol, Austria

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Publications (412)1750.43 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer. In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed. GGT serum levels were associated with FIGO stage (p<0.0001) and age (r=0.2, p<0.0001) but not with lymph node involvement (p=0.85), and histological type (p=0.98). High-risk GGT group affiliation (p=0.01 and p<0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox-regression model (p=0.59 and p=0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer. High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer.
    Gynecologic Oncology 06/2011; 122(3):590-4. · 3.93 Impact Factor
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    ABSTRACT: Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition. Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen. BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.
    Journal of Clinical Oncology 05/2011; 29(19):2653-9. · 18.04 Impact Factor
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    ABSTRACT: There is now a greater understanding of the molecular pathways in ovarian cancer, and using this knowledge, a large number of new therapeutic agents can be tested. The success of these drugs will depend on selecting drugs that target known key dysfunctional molecular pathways. To make best use of these compounds, prognostic and predictive biomarkers need to be identified. Novel methods of assessment such as functional imaging need to be developed as additional biological end points to evaluate these therapies. Promising antitumor activity has been observed with some drugs, and careful consideration is needed to determine in what circumstances new agents, such as antiangiogenic compounds, could be considered as a standard therapy. These areas were discussed at the 4th Ovarian Cancer Consensus Conference.
    International Journal of Gynecological Cancer 05/2011; 21(4):763-70. · 1.94 Impact Factor
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    ABSTRACT: 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer. This report provides the outcomes from the Fourth Ovarian Cancer Consensus Conference.
    International Journal of Gynecological Cancer 05/2011; 21(4):750-5. · 1.94 Impact Factor
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    ABSTRACT: Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (ρ=0.349, P=0.0001) and residual disease (ρ=0.254, P=0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P=0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P=0.013; OS: hazards ratio 4.651 (1.189-15.572), P=0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.
    Oncogene 04/2011; 30(38):4038-49. · 8.56 Impact Factor
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    ABSTRACT: Efficiency and efficacy of organised mammography screening programs have been proven in large randomised trials. But every local implementation of mammography screening has to check whether the well established quality standards are met. Therefore it was the aim of this study to analyse the most common quality indices after introducing organised mammography screening in Tyrol, Austria, in a smooth transition from the existing system of opportunistic screening. In June 2007, the system of opportunistic mammography screening in Tyrol was changed to an organised system by introducing a personal invitation system, a training program, a quality assurance program and by setting up a screening database. All procedures are noted in a written protocol. Most EU recommendations for organised mammography screening were followed, except double reading. All women living in Tyrol and covered by social insurance are now invited for a mammography, in age group 40-59 annually and in age group 60-69 biannually. Screening mammography is offered mainly by radiologists in private practice. We report on the results of the first year of piloting organised mammography screening in two counties in Tyrol. 56,432 women were invited. Estimated participation rate was 34.5% at one year of follow-up (and 55.5% at the second year of follow-up); 3.4% of screened women were recalled for further assessment or intermediate screening within six months. Per 1000 mammograms nine biopsies were performed and four breast cancer cases detected (N = 68). Of invasive breast cancer cases 34.4% were ≤ 10 mm in size and 65.6% were node-negative. In total, six interval cancer cases were detected during one year of follow-up; this is 19% of the background incidence rate. In the Tyrolean breast cancer screening program, a smooth transition from a spontaneous to an organised mammography screening system was achieved in a short time and with minimal additional resources. One year after introduction of the screening program, most of the quality indicators recommended by the European guidelines had been reached.However, it will be necessary to introduce double reading, to change the rule for BI-RADS 3, and to concentrate on actions toward improving the participation rate.
    BMC Public Health 02/2011; 11:91. · 2.08 Impact Factor
  • Oncology (Williston Park, N.Y.) 02/2011; 25(2):170, 173-4. · 3.19 Impact Factor
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    ABSTRACT: The present study was undertaken to analyze the impact of epigenetic alterations with a main focus on nuclear area, aneuploidy, hyperploidy, and proliferation in 70 ovarian cancer specimens. Morphometric changes and somatic chromosomal ploidy status were assessed by Feulgen spectrophotometry. DNA-hypomethylation of LINE1 repeats was analyzed by means of MethyLight PCR, and methylation levels of satellite 2 (Sat2) and satellite alpha (Satα) DNA sequences in chromosome 1 were measured by Southern blot analysis. These parameters were analyzed with regard to correlations as well as to recurrence and survival. We identified a significant association between LINE1 DNA-hypomethylation and patient age (p=0.029). Furthermore, LINE1 DNA-hypomethylation was positively correlated with the nuclear area (r=0.47; p<0.001) and the proliferation index (r=0.36; p<0.001). Univariate survival analysis showed that the nuclear area and LINE1 DNA-hypomethylation were prognostic factors for overall (p=0.015 and =0.006, respectively) and progression-free survival (p=0.020 and p=0.001 respectively), the percentage of aneuploidy only for overall survival (p=0.031). Subgroup survival analyses revealed that the prognostic value of these factors is strictly confined to mucinous cancers. In serous cancers no prognostic value could be pointed out for any analyzed parameter. Multivariate analysis of the entire cohort showed that the percentage of hyperploidy was an independent prognostic parameter for overall survival (p=0.003) and LINE1 DNA-hypomethylation for progression-free survival (p=0.03). In mucinous cancers nuclear area and LINE1 DNA-hypomethylation were found to be independent predictors of progression-free and overall survival. In this study we identified the correlations between early cancer-associated genome DNA-hypomethylation, nuclear morphometric changes, somatic chromosomal ploidy status and the proliferation index. Prognostic relevance of nuclear area and LINE1 DNA-hypomethylation was revealed exclusively in mucinous ovarian cancers.
    Gynecologic Oncology 01/2011; 121(1):24-31. · 3.93 Impact Factor
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    ABSTRACT: Free circulating DNA is increased in the serum/plasma of cancer patients, and methylation of certain genes has been found to be characteristic for malignancy. Therefore, we investigated the prognostic value of two promising genes, PITX2 and RASSF1A, in peripheral blood-plasma (PB-P) and bone marrow plasma (BM-P) of breast cancer patients. Peripheral blood and bone marrow samples from patients with primary breast cancer were prospectively collected during primary surgery at the Department of Obstetrics and Gynecology in Innsbruck (n = 428) from June 2000 to December 2006. The study has been approved by the ethical committee of the Medical University of Innsbruck. Methylation analysis was performed using MethyLight, a methylation-specific quantitative PCR-method. In univariate survival analysis, methylated PITX2 in PB-P was found to be a significant indicator for poor overall survival (OAS) and distant disease-free survival (DDFS) (P = 0.001 and P = 0.023). Methylated RASSF1A in PB-P was also an indicator for poor OAS and DDFS (P = 0.001 and P = 0.004). RASSF1A had also significant prognostic potential when determined in BM-P (P = 0.016). In multivariate survival analysis methylated PITX2 and RASSF1A in PB-P remained as therapy-independent prognostic factors for OAS (P = 0.021, P < 0.001). For DDFS only RASSF1A in PB-P showed prognostic significance (P = 0.002). Methylated RASSF1A and PITX2 in PB-P appear to have promising potential as prognostic markers in clinical use.
    Breast Cancer Research and Treatment 01/2011; 130(1):109-17. · 4.47 Impact Factor
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    ABSTRACT: Well-documented cases of untreated cervical intra-epithelial dysplasia resulting in fatal progression of invasive cervical cancer are scarce because of a long pre-invasive state, the availability of cervical cytology screening programs, and the efficacy of the treatment of both pre-invasive and early-stage invasive lesions. We present a well-documented case of a 29-year-old Caucasian woman who was found, through routine conventional cervical cytology screening, to have pathologic Papanicolaou (Pap) grade III D lesions (squamous cell abnormalities). She subsequently died as a result of human papillomavirus type 18-associated cervical cancer after she refused all recommended curative therapeutic procedures over a period of 13 years. This case clearly demonstrates a caveat against the promotion and use of complementary alternative medicine as pseudo-immunologic approaches outside evidence-based medicine paths. It also demonstrates the impact of the individualized demands in diagnosis, treatment and palliative care of patients with advanced cancer express their will to refuse evidence-based treatment recommendations.
    Journal of Medical Case Reports 01/2011; 5:316.
  • European Journal of Cancer - EUR J CANCER. 01/2011; 47.
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    ABSTRACT: The identification of sensitive biomarkers for the detection of ovarian cancer is of high clinical relevance for early detection and/or monitoring of disease recurrence. We developed a systematic multi-step biomarker discovery and verification strategy to identify candidate DNA methylation markers for the blood-based detection of ovarian cancer. We used the Illumina Infinium platform to analyze the DNA methylation status of 27,578 CpG sites in 41 ovarian tumors. We employed a marker selection strategy that emphasized sensitivity by requiring consistency of methylation across tumors, while achieving specificity by excluding markers with methylation in control leukocyte or serum DNA. Our verification strategy involved testing the ability of identified markers to monitor disease burden in serially collected serum samples from ovarian cancer patients who had undergone surgical tumor resection compared to CA-125 levels. We identified one marker, IFFO1 promoter methylation (IFFO1-M), that is frequently methylated in ovarian tumors and that is rarely detected in the blood of normal controls. When tested in 127 serially collected sera from ovarian cancer patients, IFFO1-M showed post-resection kinetics significantly correlated with serum CA-125 measurements in six out of 16 patients. We implemented an effective marker screening and verification strategy, leading to the identification of IFFO1-M as a blood-based candidate marker for sensitive detection of ovarian cancer. Serum levels of IFFO1-M displayed post-resection kinetics consistent with a reflection of disease burden. We anticipate that IFFO1-M and other candidate markers emerging from this marker development pipeline may provide disease detection capabilities that complement existing biomarkers.
    PLoS ONE 01/2011; 6(12):e28141. · 3.53 Impact Factor
  • Breast. 01/2011; 20.
  • Breast. 01/2011; 20.
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    ABSTRACT: To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), Australia/New Zealand (ANZ), Europe (E), and North America (NAm). A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey. A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation [SD] 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002). Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
    International journal of radiation oncology, biology, physics 12/2010; 82(1):250-5. · 4.59 Impact Factor
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    ABSTRACT: The main objective of the present investigation was to study the urinary neopterin excretion in the context of the activation of the adaptive cellular immune system at the tumor site. For this purpose, we compared pre-treatment urinary neopterin levels measured in 92 ovarian cancer patients, with intratumoral levels of mRNA transcripts from factors either involved in the adaptive antitumor immune defense (CD3, IFN-γ, IRF-1, IRF-2, SOCS1 and iNOS) or immune tolerance (FoxP3). This study did not reveal an association between urinary neopterin and one of these investigated "on tumor site transcripts". From all the factors reflecting the magnitude of the local adaptive antitumor response, intratumoral IRF-1 expression above the edge of the 25th percentile was found to predict most reliably favorable progression-free (median 34 months vs. 10 months; p < 0.001) and overall (median 52 months vs. 16 months; p < 0.001) survival. In contrast, pre-treatment urinary neopterin excretion above 275 μmol/mol creatinine, which indicates an unspecific activation of the innate immune system, was associated with a very poor overall survival with a median of only 11 months when compared with a median overall survival of 40 months in patients with lower urinary neopterin excretion (p = 0.021). Interestingly, the considerable survival benefit in patients with high IRF-1-expressing cancers was completely abrogated as well for progression-free as for overall survival when urinary neopterin concentrations were found to be concomitantly elevated. These findings demonstrate that in ovarian carcinomas the unspecific "cancer-related inflammation" contributes to a significant subversion of the adaptive antitumor immune defense mounted at the tumor site.
    Cancer Immunology and Immunotherapy 12/2010; 59(12):1813-23. · 3.64 Impact Factor
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    ABSTRACT: The Calypso trial showed an improved progression-free survival with PEG-liposomal doxorubicin (PLD) and carboplatin (P) as compared with the standard regimen paclitaxel (PCLTX) and P in the second- or third-line treatment of platinum-sensitive epithelial ovarian cancer [1]. A panel of Austrian gynecologic oncologists discussed the clinical consequences of the data from the Calypso study for the routine practice. PLD + P had a significantly lower rate of alopecia and neuropathy than the taxane regimen, both toxicities which compromise the quality of life. Due to possible significant thrombocytopenia, the blood counts of patients undergoing PLD + P therapy should be monitored weekly. Patients receiving PLD/P are at higher risk of nausea and vomiting. Palmoplantar erythrodysesthesia (hand-foot syndrome) is a significant toxicity of PLD + P most prevalent after the third or fourth cycle. Prophylaxis consists of avoiding pressure on feet and hands and other parts of the body. Similarly, prophylaxis of mucositis seems important and includes avoiding consumption of hot, spicy and salty foods and drinks. Mouth dryness should be avoided. Premedication with antiemetics and dexamethasone dissolved in 5% glucose is done to prevent hypersensitivity to PLD. In conclusion, the therapeutic index is more favorable for PLD + P than for PCTX + P.
    Wiener klinische Wochenschrift 11/2010; 122(21-22):649-52. · 0.81 Impact Factor
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    ABSTRACT: Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin(®)), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted.
    Wiener Medizinische Wochenschrift 10/2010; 160(19-20):506-12.
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    ABSTRACT: To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration. In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting. The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues. The clinical trials discussed spanned the spectrum of ovarian cancer from initial diagnosis, staging, and cytoreductive surgery to consolidation chemotherapy, and treatment of recurrent disease. Ongoing and effective collaboration with industry, government, and patients aims to ensure that the most important scientific questions can be answered rapidly. We encourage women with ovarian cancer and their oncologists to consider participation in the academic clinical trials conducted by the member groups of the Gynecologic Cancer Intergroup.
    International Journal of Gynecological Cancer 10/2010; 20(7):1290-8. · 1.94 Impact Factor
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    ABSTRACT: We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.
    Journal of Clinical Oncology 09/2010; 28(27):4111-9. · 18.04 Impact Factor

Publication Stats

7k Citations
1,750.43 Total Impact Points

Institutions

  • 1984–2014
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2009–2013
    • Medical University of Vienna
      • Department of Obstetrics and Gynecology
      Vienna, Vienna, Austria
  • 1987–2013
    • Medizinische Universität Innsbruck
      • • Univ.-Klinik für Gynäkologie und Geburtshilfe
      • • Department für Medizinische Statistik, Informatik und Gesundheitsökonomie
      • • Univ.-Klinik für Innere Medizin V (Hämatologie und Onkologie)
      Innsbruck, Tyrol, Austria
  • 2004–2011
    • University of Southern California
      • Department of Urology
      Los Angeles, California, United States
  • 2010
    • Kaplan Medical Center
      Kefar Yavne, Central District, Israel
  • 2007–2010
    • University College London
      • Institute for Women's Health
      London, ENG, United Kingdom
  • 2006–2010
    • Medical University of Graz
      Gratz, Styria, Austria
  • 2000
    • Robert-Bosch Krankenhaus
      Stuttgart, Baden-Württemberg, Germany
  • 1990
    • Austrian Academy of Sciences
      Wien, Vienna, Austria
  • 1983
    • Innsbruck Economics
      Absam, Tyrol, Austria