Tillmann Loch

Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer

PURPOSE To report the 8-year outcome of local dose escalation using high-dose-rate conformal brachytherapy combined with elective irradiation of the pelvic lymphatics for localized prostate cancer. METHODS AND MATERIALS One hundred forty-four consecutively treated men (1986-1992) were recorded prospectively. Twenty-nine (20.14%) patients had T1b-2a tumors, and 115 (79.86%) patients had T2b-3 tumors according to, respectively, American Joint Committee on Cancer/Union Internationale Contre le Cancer 1992. All patients had a negative nodal status, proven by CT or MRI. The mean initial PSA value was 25.61 ng/mL (Initial value for 41.66% of patients was <10 ng/mL, for 21.52% was 10-20 ng/mL, and for 32.63% was >20 ng/mL). The total dose applied by external beam radiotherapy was 50 Gy in the pelvis and 40 Gy in the prostate. The high-dose-rate brachytherapy was delivered in two fractions, which were incorporated into the external beam treatment (after 20-Gy and 40-Gy external beam radiotherapy dose). The dose per fraction was 15 Gy for the PTV1 (peripheral prostate zone) and 9 Gy for the PTV2 (entire prostatic gland). Any patient free of clinical or biochemical evidence of disease was termed bNED. Actuarial rates of outcome were calculated by Kaplan-Meier and compared using the log-rank. Cox regression models were used to establish prognostic factors of the various measures of outcome. RESULTS The median follow-up was 8 years (range 60-171 months). The overall survival rate was 71.5%, and the disease-free survival rate was 82.6%. The bNED survival rate was 72.9%. Freedom from local recurrence for T3 stage was 91.3%, whereas for G3 lesions it was 88.23%. Freedom from distant recurrence for T3 stage was 82.6% and for G3 lesions 70.59%. Univariate survival analyses revealed that low stage (T1-2), low grade (G1-2), no hormonal therapy, initial PSA value less than 40 ng/mL, and PSA normalization <1.0 ng/mL after irradiation were associated with long survival. In multivariate analyses, initial PSA value, PSA kinetics after radiation therapy, and no adjuvant hormonal treatment were independent prognostic factors. Grade 3 late radiation toxicity (according to RTOG/EORTC scoring scheme) was 2.3% for the genitourinary system in terms of cystitis and 4.10% for the gastrointestinal system in terms of proctitis. Grades 4 and 5 genitourinary/gastrointestinal morbidity was not observed. A history of transurethral resection of the prostate with a median interval of less than 6 months from radiotherapy was associated with a high risk of genitourinary toxicity. CONCLUSION The 8-year results confirm the feasibility and effectiveness of combined elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for cure of localized and especially high-risk prostate cancer.

Artificial neural network analysis (ANNA) of prostatic transrectal ultrasound

Our purpose was to determine the diagnostic potential of a new, computerized method of interpreting transrectal ultrasound (TRUS) information by artificial neural network analysis (ANNA). This method was developed to resolve the current dilemma of visual differentiation between benign and malignant tissue on TRUS. To train and objectively evaluate ANNA, a new precise method of computerized virtual correlation of preoperative ultrasound findings and radical prostatectomy histopathology was devised. After training with this pathologically confirmed digitized TRUS information, ANNA was tested in a blinded study.

Prostate preservation by combined external beam and HDR brachytherapy in nodal negative prostate cancer

PurposeThe combined external beam- and high-dose rate brachytherapy (HDR-BT) of localized prostate cancer was introduced at Kiel University in 1986. The aim of this intermediate analysis was to judge the Kiel method of localized prostate cancer radiation treatment after ten years experience.Patients and MethodsIn the past ten years 174 patients with histological proven localized prostate cancer were subjected to combined tele-/HDR-brachytherapy. Local staging in all of the cases by transrectal ultrasound, nodal staging in the majority of the cases by CT or MRI. Average age of the patients was 68.2 years (44–84). According to AJCC/UICC staging T1B, T2, T3 was found in 2, 113 and 59 cases, respectively. Highly differentiated tumors (G1) were found in 27, moderately differentited (G2) in 87, poorly differentiated (G3) in 60 cases. The mean follow-up was 47.1 months with the median of 51.7 months. Total prescribed dose 50 Gy on the small pelvis and 70 Gy on the prostate capsule due to the integration of two, 15 Gy each, HDR-brachytherapy fractions in 6 weeks.ResultsTen patients died of prostate cancer and 18 of intercurrent diseases resulting in a 5 years overall survival rate of 83% and tumor specific survival rate of 94%. Twenty-one patients showed a clinical progression, of these 14 systemic, 5 local and 2 both systemic and local. Additional 16 patients had PSA elevation only. The 5-years biochemical and/or clinical progression-free survival in the cohort was 79% and 73% for the T3 tumors. Side effects were 27 cases of proctitis/colitis and 20 cases of dysuria/cystitis.ConclusionThe integrated HDR-BT combined with external beam radiation treatment is a method with excellent tumor control rates at five years superior to those of external beam treatment alone or external beam combined with iodine-125 implants. This form of radiotherapy would appear to be particularly well-suited to treatment of advanced localized (T3) tumors.

Cytokeratin–20 Reverse–Transcriptase Polymerase Chain Reaction as a New Tool for the Detection of Circulating Tumor Cells in Peripheral Blood and Bone Marrow of Bladder Cancer Patients

Objectives: Systemic progression is the prevalent form of bladder tumor recurrence after radical cystectomy. The ability to detect circulating tumor cells in peripheral blood or bone marrow could be of prognostic value for the disease with the consequence of early adjuvant chemotherapy. We established a sensitive and specific method using a double cytokeratin–20 (CK–20) reverse–transcriptase polymerase chain reaction (RT–PCR) to detect circulating bladder cancer cells in venous blood and bone marrow Material and Methods: The sensitivity of the detection method was determined by a serial dilution of bladder cancer cells from the cell line HT1376 in whole blood. Bone marrow from 20 bladder cancer patients was drawn prior to radical cystectomy and CK–20 cDNA was amplified by RT–PCR. Additionally, pre– and postoperative venous blood samples from 11 of these patients with bone marrow aspirates and 9 patients undergoing only transurethral resection of the bladder as well as blood samples of 25 healthy volunteers were investigated by CK–20 RT–PCR. Results: The detection limit of the method was 2 bladder cancer cells/ml whole blood containing one million peripheral blood mononuclear cells. The positive detection rate in bone marrow was 7 of 20 (35%) for bladder cancer patients of all stages. However, investigation of the preoperatively collected venous blood samples from 20 patients revealed onyl 2 positive findings, belonging to advanced tumor stages pT4pN0M0 and pT3pN2M0. In contrast, CK–20 was detected in 3 of 20 postoperatively collected venous blood samples from patients with low tumor stages (pTaNXM0 and pT1NXM0) as well as from 1 patient with pelvic lymph node metastases (pT3apN2M0). All venous blood samples of the control group (n = 25) were negative for CK–20. Conclusion: The detection of circulating bladder tumor cells in venous blood and bone marrow by the CK–20 RT–PCR is a promising approach that could improve risk assessment and the identification of bladder cancer patients who would benefit from adjuvant chemotherapy.

Computerized transrectal ultrasound of the prostate in a multicenter setup (C-TRUS-MS): detection of cancer after multiple negative systematic random and in primary biopsies

ObjectiveTo improve prostate cancer diagnostic imaging, a computer-based analysis of the transrectal ultrasound signal (C-TRUS) was developed. Until recently, the C-TRUS existed only as a stand-alone device. Now, C-TRUS was developed into a network-compatible module (C-TRUS-MS). This new technology allows users to transmit C-TRUS images from any internet platform to C-TRUS-MS investigation. After analysis, the cancer-suspicious marked images are then retransmitted via internet. Targeted biopsies can then be taken at the urologists’ office remotely.Materials and methodsThis prospective study investigates whether the rates of prostate cancer detection with C-TRUS-MS “multicenter online” are comparable with those achieved by the stand-alone unit. In addition to patients with a history of multiple systematic random biopsies, a group of patients who had not undergone systematic random biopsies were analyzed.ResultsA total of 1,545 digital images (2–23 per patient, median 6) from 57 urologists were transmitted to the analysis center. After analysis, the color-coded images were sent back electronically and utilized for a maximum of six targeted biopsies. C-TRUS-MS was able to detect prostate cancer in 91 patients.In addition, we evaluated 75 patients without any previous random biopsies. In this group, C-TRUS-MS was able to detect prostate cancer in 31 out of 75 patients (41%).ConclusionThe results indicate that C-TRUS-MS “online” achieves similar results as the stand-alone system, independent of the user even with little experience in the method. Furthermore, C-TRUS-MS for the first time is able to detect carcinomas in patients without prior biopsies in a high number by taking only six targeted biopsies.

Urologic imaging for localized prostate cancer in 2007

Increasing numbers of systematic random biopsies have virtually replaced urologic imaging as a detection and staging tool in prostate cancer. TRUS as the most commonly utilized urologic imaging is now mainly utilized to guide the biopsy needle into the correct anatomical or topographic region of the prostate. But even multiple systematic random biopsies have been shown to overlook a large number of clinically significant carcinoma. This fact has led to a dramatic increase in the number of biopsies taken in the detection of localized prostate cancer. There are some centers where 6, 10, 12, even up to 143 biopsies are taken in one sitting. This increasingly invasive and heterogeneous strategy underlines the need for an improvement in diagnostic imaging. New modalities and innovative techniques are currently being investigated in order to identify prostate cancer more accurately. The purpose of this paper is to review innovative urologic imaging techniques to identify emerging modalities that may be beneficial in the management of prostate cancer. Enhanced transrectal ultrasonography modalities, including ultrasound contrast agents, color and power doppler, elastography and computerized (C)-TRUS with artificial neural network analysis (ANNA) promise benefits in comparison to standard gray-scale ultrasonography to accurately target and diagnose prostate cancer.

Weiterentwicklung des transrektalen Ultraschalls Artifizielle neuronale Netzwerkanalyse (ANNA) in der Erkennung und Stadieneinteilung des Prostatakarzinoms

ZusammenfassungDas prostataspezifische Antigen (PSA) ist heutzutage der meistgenutzte Marker in der Diagnostik des Prostatakarzinoms. Hieraus resultiert eine vermehrte Anzahl von asymptomatischen Männern, die allein durch eine PSA-Werterhöhung Kandidaten für eine weiterführende Prostatadiagnostik werden. Ein deutlich erhöhter PSA-Serumwert (>20 ng/ml) lässt mit hoher Wahrscheinlichkeit auf das Vorhandensein eines Prostatakarzinoms schließen. Im sog. Graubereich zwischen 4 und 10 ng/ml ist der Gewebemarker PSA meist durch gutartige Veränderungen beeinflusst, so dass eine Unterscheidung zwischen maligner und benigner Ursache aufgrund des PSA-Wertes allein nicht möglich ist [1–4]. Darüber hinaus findet man Karzinome bei Patienten, die ein PSA unter dem Normwert von 4 ng/ml aufweisen.Die Methoden, die bislang für die Früherkennung oder Erkennung des Prostatakarzinoms zur Verfügung standen (Tastbefund und Ultraschall) sind unzureichend. So sind ca. 70% der palpablen Tumoren nicht mehr organbegrenzt [5, 6]. Das klassische Problem der visuellen Ultraschallbeurteilung ist die mangelnde Spezifität, insbesondere bei geringer Erfahrung mit der Methode [7–11].Um die diagnostischen Möglichkeiten des transrektalen Ultraschalls (TRUS) in der Prostatakarzinom-Früherkennung und -Stadieneinteilung zu erhöhen, wird in der hier vorgestellten Studie eine Artifizielle Neuronale Netzwerkanalyse (ANNA) eingesetzt, die zusätzliche subvisuelle, graustufendifferente Informationen des TRUS erfassen und auswerten kann [12–14]. Dieser Ansatz erscheint vielversprechend, da Artifizielle Neuronale Netzwerke die im Ultraschallbild vorhandenen komplexen Datenformationen erkennen können, sie gleichsam “lernen” und diese dann bei noch nicht gesehenen Datenformationen wiedererkennen und korrekt klassifizieren können [15].AbstractAs a result of the enhanced clinical application of prostate specific antigen (PSA), an increasing number of men are becoming candidates for prostate cancer work-up. A high PSA value over 20 ng/ml is a good indicator of the presence of prostate cancer, but within the range of 4–10 ng/ml, it is rather unreliable. Even more alarming is the fact that prostate cancer has been found in 12–37% of patients with a “normal” PSA value of under 4 ng/ml (Hybritech). While PSA is capable of indicating a statistical risk of prostate cancer in a defined patient population, it is not able to localize cancer within the prostate gland or guide a biopsy needle to a suspicious area. This necessitates an additional effective diagnostic technique that is able to localize or rule out a malignant growth within the prostate. The methods available for the detection of these prostate cancers are digital rectal examination (DRE) and Transrectal ultasound (TRUS). DRE is not suitable for early detection, as about 70% of the palpable malignancies have already spread beyond the prostate. The classic problem of visual interpretation of TRUS images is that hypoechoic areas suspicious for cancer may be either normal or cancerous histologically. Moreover, about 25% of all cancers have been found to be isoechoic and therefore not distinguishable from normal-appearing areas. None of the current biobsy or imaging techniques are able to cope with this dilemma. Artificial neural networks (ANN) are complex nonlinear computational models, designed much like the neuronal organization of a brain. These networks are able to model complicated biologic relationships without making assumptions based on conventional statistical distributions. Applications in Medicine and Urology have been promising. One example of such an application will be discussed in detail: A new method of Artificial Neural Network Analysis (ANNA) was employed in an attempt to obtain existing subvisual information, other than the gray scale, from conventional TRUS and to improve the accuracy of prostate cancer identification.

Computer-aided image analysis in transrectal ultrasound of the prostate

SummaryTo objectify the interpretation of prostate, ultrasound images were processed by a computer-based image analysis system (IAS). The IAS “tissue descriptors” are not dependent on the gray scale. Transrectal ultrasound (TRUS) images, results of the IAS and pathologic whole mounts (PWM), were correlated in an attempt to define the efficiency of the IAS in differentiating carcinoma from normal tissue of the prostate. Using the closely correlated TRUS and PWM slices, a restrictive setting (high specificity) of the IAS yielded rates of 90% (true positive), 10% (false negative) and 5% (false positive). Using a less restrictive setting (higher sensitivity), rates of 100% (true positive), 10% (false negative) and 12% (false positive) were noted. These encouraging results were obtained from the peripheral zone of the prostate. However, the clinical false-positive and false-negative rates for IAS have not yet been determined.

The European Association of Urology (EAU) Guidelines Methodology: A Critical Evaluation

OBJECTIVES Guidelines can be produced and written in numerous ways. The aim of the present article is to describe and evaluate the method currently used to produce the European Association of Urology (EAU) guidelines. DESIGN, SETTING, AND PARTICIPANTS The methodology is described in detail, compared to other urologic guidelines by members of the EAU Guidelines Office Board. MEASUREMENTS The new methodology is evaluated by the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. RESULTS AND LIMITATIONS The currently used methodology is adapted to the aims and objectives as established by the EAU for their guidelines; wide coverage (essentially all fields of urology) and useful to urologists all over Europe. The frequent updates are easily accessible in a printed and electronic format. The AGREE instrument supports these strong points, but also identifies potentially weak points, such as no patient involvement, no formal validation of the guidelines texts prior to publication, and lack of discussion of organisational barriers and cost implications. CONCLUSION The currently used methodology for the production of EAU guidelines fulfils the associations main objectives related to their guidelines, but the texts will benefit from the inclusion of country-specific cost and organisational data. For the practising clinician, these guidelines will help to take science into clinical practice.

Urinary Leakage of Tubular Enzymes after Shock Wave Lithotripsy

Objectives: Urinary loss of tubular marker enzymes following shock wave lithotripsy (SWL) suggests corresponding morphological changes in the kidney. To date, the morphological correlate of enzymuria and its dependence on the energy applied remains unclear. Methods: In an animal study, the acute morphological changes occurring in the tubulus cells as the basis of enzymuria were investigated. It was evaluated whether SWL-induced enzymuria correlates with the extent of renal damage. Results: Acute morphological changes in the tubulus cells were demonstrated beneath isolated tubulus necrosis. The mechanically induced lesions of the cell organelles included fragmentation of the lysosomes and severe alterations of the cell membrane. The tubulus damage can be quantified. With the help of histochemical N-acetyl-β-D-glucosaminidase (NAG) staining and electron microscopic observations, a significant correlation was found between the shock wave parameters number of impulses and intensity and the tubular damage. The intensity of NAG enzymuria reflected the severity of the tubular damage. Conclusions: In this animal model, NAG proved to be a suitable marker enzyme for estimation of the degree of SWL-induced tubular damage.