Michael Marberger’s research while affiliated with Medical University of Vienna and other places

Background The purpose of these clinical studies was to validate a Tissue Change Monitoring (TCM) algorithm in vivo. TCM is a quantitative tool for the real-time assessment of HIFU dose. TCM provides quantitative analysis of the backscatter pulse echo signals (pre and immediately post HIFU) for each individual ablative site, using ultrasonic tissue characterization as a surrogate for monitoring tissue temperature. Real-time analysis generates an energy difference parameter (ΔE in dB) that is proportional to tissue temperature. Methods Post in vitro studies, two clinical studies were conducted to validate the TCM algorithm on the Sonablate® device. Studies enrolled histologically confirmed, organ confined prostate cancer patients. The first clinical study was conducted in two phases for whole gland ablation. First eight patients’ data were used to measure the algorithm performance followed by 89 additional patients for long term outcome. The second clinical study enrolled five patients; four patients with focal cancer had hemi-ablation only and one had whole gland ablation. Four 3 Fr. needles containing three thermocouples each were placed transperineally in the prostate to record tissue temperatures in the focal zone, posterior to the focal zone and on the lateral gland where no HIFU was applied. Tissue temperatures from the focal zone were correlated to the ΔE parameter. Results In the first clinical study, the average TCM rate was 86%. Pre and 6 months post HIFU, median PSA was 7.64 and 0.025 ng/ml respectively and 97% patients had negative biopsy. For the second clinical study, the measured prostate tissue temperatures (Average, Max, and Min) in the ablation zones were 84°, 114° and 60 °C and the corresponding ΔE (dB/10) parameters were 1.05, 2.6 and 0.4 resulting in 83% of temperatures in the range of 75°-100 °C and 17% in the 60°-74 °C range. Outside the focal zone, the average temperature was 50 °C and in the lateral lobe where no HIFU was applied, peak temperature was 40.7 °C. Conclusions The TCM algorithm is able to estimate tissue changes reliably during the HIFU procedure for prostate tissue ablation in real-time and can be used as a guide for HIFU dose delivery and tissue ablation control.

Objective: This study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine. Methods: Consecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n=789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test. Results: High diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903-0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p=0.58) but was statistically associated with tumour size (p=0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p=0.7) and controls (p=0.2). Conclusions: Our GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC.

Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future. © 2015 S. Karger AG, Basel.

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.

Objective: To explore explanations for the numerical imbalance of biopsy-detected Gleason 8-10 prostate cancers (PCa) diagnosed in years 3-4 in the dutasteride and placebo groups of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. Methods: REDUCE was a 4-year, randomized, double-blind, placebo-controlled trial of dutasteride (0.5 mg/d) vs placebo for PCa risk reduction. We modeled the incidence of Gleason 8-10 cancer and used logistic regression analysis to evaluate the effects of baseline predictors of PCa, as well as post-baseline prostate volume at the time of biopsy, on PCa diagnosis. We compared needle biopsy Gleason scores with corresponding surgery Gleason scores. All statistical tests conducted were 2-sided. Results: Had there been a scheduled biopsy occurring only at year 4, we estimated a similar incidence of Gleason 8-10 PCa in the dutasteride (n = 45) and placebo (n = 46) groups. Two biopsy Gleason 7 cancers in the placebo group (n = 150) were upgraded to Gleason 8-10 cancer on prostatectomy, and no patients in the dutasteride group (n = 111) were upgraded. Logistic regression analysis demonstrated the effect of prostate volume on Gleason 8-10 cancer diagnosis. Conclusion: Although modeling of REDUCE data showed a similar incidence of Gleason 8-10 cancer in the dutasteride and placebo groups at year 4, an association between dutasteride and Gleason 8-10 cancer cannot be definitely excluded. It is likely that several biases, notably study design and prostate size at the time of biopsy, contributed to the numerical imbalance in Gleason 8-10 cancers observed between the treatment groups in years 3-4.

A high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make diagnosis and therapy of prostate cancer a special challenge for urologists. Effective prevention of the disease may help to resolve some of the problems mentioned above. Two randomised, controlled studies prove that effective chemoprevention of prostate cancer is possible using 5-α reductase inhibitors (finasteride, dutasteride) (LoE 1) both in individuals at low and those at high risk developing prostate cancer. Furthermore, there is evidence that other compounds, e.g. selective estrogen receptor modulators (SERMs), non-steroidal anti-inflammatory drugs (NSAIDs) and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economic aspects. The authors conclude that chemoprevention in a high risk cohort using 5-α reductase inhibitors is a viable option and may even be cost effective. In consequence, the options of chemoprevention in prostate cancer should be further explored in an open and unbiased way.

Objective To explore explanations for the numerical imbalance of biopsy-detected Gleason 8-10 prostate cancers (PCa) diagnosed in years 3-4 in the dutasteride and placebo groups of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. Methods REDUCE was a 4-year, randomized, double-blind, placebo-controlled trial of dutasteride (0.5 mg/d) vs placebo for PCa risk reduction. We modeled the incidence of Gleason 8-10 cancer and used logistic regression analysis to evaluate the effects of baseline predictors of PCa, as well as post-baseline prostate volume at the time of biopsy, on PCa diagnosis. We compared needle biopsy Gleason scores with corresponding surgery Gleason scores. All statistical tests conducted were 2-sided. Results Had there been a scheduled biopsy occurring only at year 4, we estimated a similar incidence of Gleason 8-10 PCa in the dutasteride (n = 45) and placebo (n = 46) groups. Two biopsy Gleason 7 cancers in the placebo group (n = 150) were upgraded to Gleason 8-10 cancer on prostatectomy, and no patients in the dutasteride group (n = 111) were upgraded. Logistic regression analysis demonstrated the effect of prostate volume on Gleason 8-10 cancer diagnosis. Conclusion Although modeling of REDUCE data showed a similar incidence of Gleason 8-10 cancer in the dutasteride and placebo groups at year 4, an association between dutasteride and Gleason 8-10 cancer cannot be definitely excluded. It is likely that several biases, notably study design and prostate size at the time of biopsy, contributed to the numerical imbalance in Gleason 8-10 cancers observed between the treatment groups in years 3-4.

To establish a consensus on the utility of multiparametric magnetic resonance imaging (mpMRI) to identify patients for focal therapy. Topics specifically not included staging of prostate cancer (PCa), but rather identifying the optimal requirements for performing MRI, and the current status of optimally performed mpMRI to a) determine focality of prostate cancer (i.e. localizing small target lesions of 0.5 cm3 and greater), b) to monitor and assess the outcome of focal ablation therapies, and c) to indentify the diagnostic advantages of new MRI methods. In addition, the need for transperineal template saturation biopsies in selecting patients for focal therapy was discussed, if a high quality mpMRI is available. In other words, can mpMRI replace the role of transperineal saturation biopsies in patient selection for focal therapy? Urological surgeons, radiologists, and basic researchers, from Europe and North America participated in a consensus meeting about the use of mpMRI in focal therapy of prostate cancer. The consensus process was face-to-face and specific clinical issues were raised and discussed with agreement sought when possible. All participants are listed among the authors. Consensus was reached on most key aspects of the meeting, however on definition of the optimal requirements for mpMRI, there was 1 dissenting voice. mpMRI is the optimum approach to achieve the objectives needed for focal therapy, if made on a high quality machine (3T with/without endorectal coil or 1.5 with endorectal coil) and judged by an experienced radiologist. Structured and standardized reporting of prostate MRI is paramount. State of the art mpMRI is capable to localize small tumors for focal therapy. State of the art mpMRI is the technique of choice for follow up of focal ablation. The present evidence for MRI in focal therapy is limited. mpMRI is not accurate enough to consistently grade tumor aggressiveness. Template guided saturation biopsies are no longer necessary when a high quality state of the art mpMRI is available, however, suspicious lesion should always be confirmed by (targeted) biopsy.

Objective To define the role of multiparametric MRI (mpMRI) for treatment planning, guidance and follow-up in focal therapy for prostate cancer based on a multidisciplinary Delphi consensus project. Materials and Methods An online consensus process based on a questionnaire was circulated according to the Delphi method. Discussion points were identified by literature research and were sent to the panel via an online questionnaire in three rounds. A face-to-face consensus meeting followed the three rounds of questions that were sent to a 48-participant expert panel consisting of urologists, radiologists and engineers. Participants were presented with the results of the previous rounds. Conclusions formulated from the results of the questionnaire were discussed in the final face-to-face meeting. ResultsConsensus was reached in 41% of all key items. Patients selected for focal therapy should have biopsy-proven prostate cancer. Biopsies should ideally be performed after mpMRI of the prostate. Standardization of imaging protocols is essential and mpMRIs should be read by an experienced radiologist. In the follow-up after focal therapy, mpMRI should be performed after 6 months, followed by a yearly mpMRI. mpMRI findings should be confirmed by targeted biopsies before re-treatment. No consensus was reached on whether mpMRI could replace transperineal template saturation biopsies to exclude significant lesions outside the target lesion. Conclusions Consensus was reached on a number of areas related to the conduct, interpretation and reporting of mpMRI for use in treatment planning, guidance and follow-up of focal therapy for prostate cancer. Future studies, comparing mpMRI with transperineal saturation mapping biopsies, will confirm the importance of mpMRI for a variety of purposes in focal therapy for prostate cancer.