Why we should not routinely apply irreversible electroporation as an alternative curative treatment modality for localized prostate cancer at this stage.

Irreversible electroporation (IRE), a new tissue ablation procedure available since 2007, could meet the requirements for ideal focal therapy of prostate cancer with its postulated features, especially the absence of a thermal ablation effect. Thus far, there is not enough evidence of its effectiveness or adverse effects to justify its use as a definitive treatment option for localized prostate cancer. Moreover, neither optimal nor individual treatment parameters nor uniform endpoints have been defined thus far. No advantages over established treatment procedures have as yet been demonstrated. Nevertheless, IRE is now being increasingly applied for primary prostate cancer therapy outside clinical trials, not least through active advertising in the lay press. This review reflects the previous relevant literature on IRE of the prostate or prostate cancer and shows why we should not adopt IRE as a routine treatment modality at this stage.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

[Results of the randomised phase III study of the German Testicular Cancer Study Group. Retroperitoneal lymphadenectomy versus one cycle BEP as adjuvant therapy for non-seminomatous testicular tumours in clinical stage I]. / Ergebnisse der randomisierten Phase-III-Studie der "German Testicular Cancer Study Group". Retroperitoneale Lymphadenektomie vs. 1 Zyklus PEB als adjuvante Therapie beim nichtseminomatösen Hodentumor im klinischen Stadium I.

OBJECTIVE: As 30% of non-seminomas in clinical stage I will progress during active surveillance, alternative adjuvant strategies of 2 cycles of bleomycin, etoposid, cisplatin (BEP) or nerve sparing retroperitoneal lymphadenectomy (RPLND) can be offered. The risk of relapse is reduced to 2% and 10%, respectively. Without prognostic markers and with lowered toxicity it is postulated that only one cycle of BEP could significantly reduce the recurrence rate in comparison to RPLND. MATERIALS AND METHODS: Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n=191) or 1 cycle of BEP (n=191). In accordance with the protocol, 174 patients were treated with 1 cycle of BEP and 173 underwent RPLND. The primary study end-point was a reduction of recurrence from 10% after RPLND to a maximum of 3% after 1 cycle of BEP. RESULTS: After a mean follow-up of 4.7 years, there were 2 and 13 recurrences in the according-to-protocol population with chemotherapy and surgery, respectively. The difference between chemotherapy (1.15%) and surgery (7.5%) was statistically significant (p=0.0033). The tumor-specific survival was 100%. CONCLUSION: This largest randomized trial investigating treatment strategies in clinical stage I non-seminomas (AUO AH 01/94) showed the superiority of one cycle BEP over RPLND. The data obtained represent the basis for a reduced chemotherapy.

[The future of ESWL]. / Die Zukunft der ESWL.

With the introduction of the Dornier HM3 lithotripter, the successful history of extracorporeal shock wave lithotripsy (ESWL) for noninvasive treatment of urinary stones began about 25 years ago. The development of newer lithotripters has not been able to improve clinical efficacy because the shock wave parameters specifically responsible for stone disintegration or tissue trauma and pain induction have not yet been identified. Actual research in lithotripter technology deals with modification of the focal point. The evolution of endoscopic procedures, ureterorenoscopy, and percutaneous nephrolithotomy took longer but was more successful in terms of clinical efficacy. Nowadays, ESWL or an endoscopic procedure is offered as a reasonable option for most urinary stone cases. Therefore, economic aspects and the surgeon's expertise will become greater factors when a procedure is chosen. ESWL, with or without anaesthesia, will be an inherent part of future treatment modalities for urinary stones.

[New guidelines for urinary stone treatment. Controversy or development?]. / Neue Leitlinien zur Harnsteintherapie. Widerspruch oder Weiterentwicklung?

The new guidelines of the European (EAU), American (AUA), German, and Austrian associations of urology are based on thorough and consistent research and analysis of the published literature. However, the methodology is very diverse. In the case of the EAU-AUA guidelines on ureteral stones, the evidence was generated by a laborious meta-analysis of the entire available published literature on the subject. These guidelines represent the 1A level of evidence. The traditional European guidelines evaluate each statement separately and assign a level of evidence to each. The following aspects are new: the even greater effort to formulate guidelines accompanied by the initiation of international cooperative projects, clarity of presentation and evaluation of the individual statements (including levels of evidence), information on medication-based treatment to facilitate spontaneous passage of ureteral stones as well as stone fragments after extracorporeal shock wave lithotripsy (ESWL), a shift in the value of ESWL and ureterorenoscopy for ureteral stones, retrograde intrarenal surgery for small kidney stones refractory to ESWL or in settings unsuitable for ESWL, the use of laparoscopy in those rare cases that represent an indication for open surgery, and the additional value given to metaphylaxis in diagnosis and therapy. All of the new guidelines take these developments into account, although they differ slightly in the importance they assign to the individual items. The modifications represent the developments secondary to electronic data processing and preparation on the one hand and the rapid development of medical instruments on the other. Although ESWL is still the most important procedure for treating urinary stones, advances in flexible endoscopes, intracorporeal lithotripsy, and extraction instruments have led to a shift in the range of indications. These developments are fully accommodated in the new guidelines.

[Focal therapy of prostate cancer]. / Fokale Therapie des Prostatakarzinoms.

The target of focal therapy (FT) in prostate cancer (PC) is partial treatment of the prostate aiming at preserving surrounding anatomical structures. The intention is to minimize typical side effects of radical treatment options combined with local tumor control. Numerous established and new technologies are used. Results of published studies showed a good safety profile, few side effects and good preservation of functional results. Oncologic long-term data are lacking so far. Photodynamic therapy (PDT) is the only technology that has been studied in a published prospective randomized trial. The FT is challenged by the multifocality of PC; therefore, the quality of prostate biopsy, histopathological assessment as well as imaging are of paramount importance. Multiparametric magnetic resonance imaging (MRI) has gained increasing importance. The FT is experimental and should only be offered within clinical trials.

[MRI/TRUS fusion-guided prostate biopsy : Value in the context of focal therapy]. / MRT/TRUS-fusionierte Biopsiesysteme : Stellenwert bei der fokalen Therapie des Prostatakarzinoms.

BACKGROUND: Several systems for MRI/TRUS fusion-guided biopsy of the prostate are commercially available. Many studies have shown superiority of fusion systems for tumor detection and diagnostic quality compared to random biopsy. The benefit of fusion systems in focal therapy of prostate cancer (PC) is less clear. OBJECTIVES: Critical considerations of fusion systems for planning and monitoring of focal therapy of PC were investigated. MATERIALS AND METHODS: A systematic literature review of available fusion systems for the period 2013-5/2016 was performed. A checklist of technical details, suitability for special anatomic situations and suitability for focal therapy was established by the German working group for focal therapy (Arbeitskreis fokale und Mikrotherapie). RESULTS: Eight fusion systems were considered (Artemis™, BioJet, BiopSee®, iSR´obot™ Mona Lisa, Hitachi HI-RVS, UroNav and Urostation®). Differences were found for biopsy mode (transrectal, perineal, both), fusion mode (elastic or rigid), navigation (image-based, electromagnetic sensor-based or mechanical sensor-based) and space requirements. DISCUSSION: Several consensus groups recommend fusion systems for focal therapy. Useful features are "needle tracking" and compatibility between fusion system and treatment device (available for Artemis™, BiopSee® and Urostation® with Focal One®; BiopSee®, Hitachi HI-RVS with NanoKnife®; BioJet, BiopSee® with cryoablation, brachytherapy). CONCLUSIONS: There are a few studies for treatment planning. However, studies on treatment monitoring after focal therapy are missing.

[Focal therapy for small renal masses : Observation, ablation or surgery]. / Fokale Therapie von kleinen Nierentumoren : Beobachtung, Ablation oder Operation.

BACKGROUND: The rising incidence of renal cell carcinoma, its more frequent early detection (stage T1a) and the increasing prevalence of chronic renal failure with higher morbidity and shorter life expectancy underscore the need for multimodal focal nephron-sparing therapy. DISCUSSION: During the past decade, the gold standard shifted from radical to partial nephrectomy. Depending on the surgeon's experience, the patient's constitution and the tumor's location, the intervention can be performed laparoscopically with the corresponding advantages of lower invasiveness. A treatment alternative can be advantageous for selected patients with high morbidity and/or an increased risk of complications associated with anesthesia or surgery. Corresponding risk stratification necessitates previous confirmation of the small renal mass (cT1a) by histological examination of biopsy samples. Active surveillance represents a controlled delay in the initiation of treatment. RESULTS: Percutaneous radiofrequency ablation (RFA) and laparoscopic cryoablation are currently the most common treatment alternatives, although there are limitations particularly for renal tumors located centrally near the hilum. More recent ablation procedures such as high intensity focused ultrasound (HIFU), irreversible electroporation, microwave ablation, percutaneous stereotactic ablative radiotherapy and high-dose brachytherapy have high potential in some cases but are currently regarded as experimental for the treatment of renal cell carcinoma.

[Cancer control in focus insights and future perspectives for the focal treatment of prostate cancer]. / Krebskontrolle im Fokus - Einblicke und Ausblicke rund um die fokale Therapie des Prostatakrebses.

Faced with the dilemma of choosing between the extremes of standard whole gland therapy and active surveillance, those affected by prostate cancer have recently been on the lookout for less invasive alternatives. Particularly the question of whether it would be possible in low risk cancer to treat only the tumour itself while sparing the organ has long been considered. This article discusses the pros and cons of focal treatment and elucidates the latest innovative technologies. High overtreatment rates in low-risk patients submitted to standard therapy and considerable technological advances in diagnosis (particularly multiparametric MRI) and therapy are regarded by the authors as key arguments for abandoning complete tumour eradication with its side effects in favour of sufficient local cancer control by focal treatment with better preserved quality of life in suitable cases.

[Irreversible electroporation. Current value for focal treatment of prostate cancer]. / Irreversible Elektroporation. Aktueller Stellenwert in der fokalen Therapie des Prostatakarzinoms.

BACKGROUND: Irreversible electroporation (IRE), a new tissue ablation procedure available since 2007, could meet the requirements for ideal focal therapy (FT) with its postulated features, especially the absence of a thermal ablative effect. Thus far, there is no adequate tumor-entity-specific proof of its effectiveness, and its clinical application has hitherto been confined to very small patient cohorts. This also holds true for prostate cancer (PCA). Nevertheless, it is now being increasingly applied outside clinical trials-to a certain extent due to active advertising in the lay press. AIM OF THE STUDY: In this study, current discrepancies between the clinical application and study situation and the approval and market implementation of the procedure are described. The media portrayal of IRE is discussed from different perspectives, particularly with reference to the FT of PCA. This is followed by a final clinical assessment of IRE using the NanoKnife® system. DISCUSSION: Strict requirements govern new drug approvals. According to the German Drug Act (AMG), evidence of additional benefit over existing therapy must be provided through comparative clinical trials. For medicotechnical treatment procedures, on the other hand, such trial-based proof is not required according to the Medical Devices Act (MPG). The use of IRE even outside clinical trials has been actively promoted since the NanoKnife® system was put on the market. This has led to an increase in the number of uncontrolled IRE treatments of PCA in the last 2 years. The patients have to cover the high treatment costs themselves in these cases. If articles in the lay press advertise the procedure with promising but unverified contents, false hopes are raised in those concerned. This is disastrous if it delays the use of truly effective treatment options. CONCLUSION: IRE basically still has high potential for the treatment of malignancies; however, whether it can really be used for FT remains unclear due to the lack of data. This also holds true for the treatment of PCA. Only carefully conducted scientific research studies can clarify the unresolved issues regarding IRE of PCA. The urgently needed development of universally valid treatment standards for IRE is unnecessarily hampered by the flow commercially driven patients.

Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma.

Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil.

Histomorphologic and ultrastructural findings of shockwave-induced lesions in the isolated perfused kidney of the pig.

The aim of this investigation was the development of an easily reproducible model with which to evaluate shockwave-induced renal tissue damage using light and electron microscopy. Kidneys (n = 45) from freshly slaughtered pigs were perfused under physiologic conditions and treated with shockwaves at different doses (2-250 shockwaves; 12-20 kV) on the Modulith SL 20 lithotripter. The dose-dependent alterations in tissue structure were characterized by disintegration of tubular cells leading to circumscribed gap-like defects resulting from reticular fiber disruptions. Even after low shockwave doses, cellular and subcellular alterations could be observed. Our findings in this ex vivo model verify the development of considerable strictly localized, dose-dependent shockwave-induced damage of the renal parenchyma. On morphologic grounds, we cannot confirm a primary lesion or rupture of blood vessel walls as the cause of the shockwave lesions. The destruction of tubular cells in combination with disruption of peritubular and pericapillary reticular fiber coats results in capillarotubular leaks, which can explain even severe transitory macrohematuria after clinical shockwave lithotripsy without renal hematoma formation.

Antegrade-retrograde urethrotomy for treatment of severe strictures of the urethra: experience and literature review.

In cases of urethral stricture that are nonpassable when using conventional internal urethrotomy, open urethroplasty can be avoided by performing combined antegrade-retrograde urethrotomy (ARUT). A rigid cystoscope is guided through a dilated suprapubic cystostomy channel toward the stricture in the membranous or bulbar urethra. A urethrotome is inserted in retrograde fashion, and the "cut to the light" procedure is performed. Using the ARUT method, realignment was achieved in nine patients; four of whom had strictures induced by trauma or urethritis and five of which were the result of previous transurethral management. Recurrent stricture in four of seven cases necessitated further urethrotomy. There was no recurrence in five of seven patients for at least 5 months subsequent to the last treatment. All patients were spared open surgery. The antegrade-retrograde technique was described in 1978, but to date, only 70 cases have been reported in the literature. The primary success rate is 25%. Successful retreatment following recurrence was observed in 65%. We recommend ARUT as a first-choice treatment for severe strictures of the bulbar and membranous urethra.

In vitro and in vivo experiences with ureterorenoscope by Gelet.

Using ureterorenoscopes with unidirectional flow, the urologist faces a conflict between a good view on one hand and high pressure in the ureter and the pelvic collecting system of the kidney on the other hand. The ureterorenoscope designed by Gelet, which has continuous (bidirectional) flow and separate irrigation and working channels, was compared with the instrument by Pérez-Castro, which has a common irrigation and working access. The features investigated were optical quality, flow-irrigation characteristics, and handling. The latest generation of ureterorenoscopes provides small total diameters because of minimized working channels and fiberoptic image and light transmission. These semirigid instruments combine the features of flexible endoscopes and traditional ureterorenoscopes. The Gelet instrument offers continuous flow, achieved by separation of the irrigation and working channel, and provides a good view even when working instruments are inserted. The additional outlet channel prevents high pressure in the ureter and renal pelvis and offers another access for instrumentation, if necessary, which means maximum safety for the patient. Because the connection of camera and light source on a flexible system is separated from the instrument, ureterorenoscopy is a more convenient procedure for the urologist.

Rotoresect: new technique for resection of the prostate: experimental phase.

We developed a new resection device-the Rotoresect -with the aim of reducing morbidity during transurethral resection of the prostate (TURP). During rotoresection, a rotating ablator electrode enables simultaneous tissue coagulation by high-frequency current and mechanical tissue ablation. The tissue ablation rate and the extent of bleeding were quantified ex vivo using a blood-perfused porcine kidney (N = 30) and then compared with loop resection and electrovaporization (grooved roller/Rollerball). Additionally, transurethral rotoresection of the prostate and open partial resection of the liver were carried out in five dogs. With the blood-perfused porcine kidney, we demonstrated that the tissue ablation rate increases with increasing of the coagulation current and rotation speed of the ablator electrode. The Rotoresect achieved a tissue ablation rate comparable to that of the resection loop (5.5-6.0 g/min), which was more than twice the rate achieved by electrovaporization (1.7-2.0 g/min). The extent of bleeding during standard loop resection was many times higher (16.5-18.0 g/min) than that induced by rotoresection and electrovaporization (< 2.3 g/min). In our in vivo canine trials, we performed transurethral prostate resection and open segmental liver resection with minimal bleeding. The Rotoresect is a promising instrument for ablation of parenchymal organs during transurethral, laparoscopic, and open surgical procedures.

Durability of laser probes in interstitial thermotherapy: investigations on an ex vivo model of effect of carbonization.

BACKGROUND AND PURPOSE: Interstitial laser application is successful for clinical tissue ablation in various organs. One great drawback of this method is the high costs caused by the vulnerability of the probes. Our objective was to investigate whether the prevention of carbonization deposits on laser probes averts reduced transmission after the application of high laser energy. MATERIALS AND METHODS: Interstitial laser probes were used to pierce an in vitro kidney model, and 9900 J of energy (Nd:YAG laser) was applied. The transmission of the laser probe was determined and compared with that of a reference probe. RESULTS: The application of laser energy, up to a total of 49,500 J, did not reduce transmission. The deviation of the transmission comparing working probes and the reference probe was between 2% and 7%. The application of high energy (40 W) over a longer period (>20 seconds) led to carbonization and consequent distinct reduction of transmission. CONCLUSIONS: The durability of laser probes can be prolonged by preventing carbonization. The economic effect achieved is the repeated use of the probes at less expense.

The isolated perfused kidney of the pig: new model to evaluate shock wave-induced lesions.

Little is known about the mechanisms and determining factors of shock wave-induced kidney trauma. After classification of the renal lesion in a canine model, we attempted to establish an ex vivo model using the isolated kidney of the pig perfused by Tyrode's solution under physiologic conditions. After shock wave application on the Modulith SL 20, vessel lesions were evaluated by microangiography to determine the size and frequency of dye extravasation in the different areas of the organ. Variation of the focus localization caused different patterns of lesions that characterized the pathway of the shock wave. In particular, constant petechial extravasation in the cortex was observed. The generator voltage correlated with the diameter and the frequency of the lesion area. The number of shock waves primarily affected the incidence of vessel rupture in the regions adjacent to the focal zone. Light microscopy revealed dose-dependent necrosis of tubular cells up to gap-like parenchymal defects. Even after application of the minimal shock wave doses, electron microscopy demonstrated vacuolization of tubular cells in the shock wave focus. Traumatic junctions between capillaries and the tubulur system can explain clinically observed macrohematuria without renal hematomas. With this model, it was possible to evaluate localization and dose dependence of shock wave-induced kidney trauma with high sensitivity and reproducibility. Further advantages of the model were easy availability and the fact that studies on living animals were not necessary. Therefore, standardization and comparison of different lithotripters becomes possible.

[Parameters influencing the incidence of recurrent urinary calculus after ESWL]. / Einflussparameter für die Häufigkeit des Harnsteinrezidivs nach ESWL.

With extracorporeal shock wave lithotripsy, stone fragmentation and the potential creation of residual stones has become an integral part of the treatment strategy. Therefore, true recurrence, regrowth and pseudo-recurrence determine the rate of new stone formation. In nonselected series the overall recurrence rate after ESWL varies between 6% after 1 year and 20% after 4 years. The comparison between recurrence rate after ESWL and the natural recurrence rate reveals that the results of ESWL are better than expected. Lithotripsy has no specific effect on true stone recurrence, and even the pseudo-recurrence is of minor clinical significance. Nevertheless, metaphylaxis keeps its place in treatment of recurrent urolithiasis.

[Control parameters for high-intensity focused ultrasound (HIFU) for tissue ablation in the ex-vivo kidney]. / Steuerparameter des hochenergetischen fokussierten Ultraschalls (HIFU) zur Gewebeablation an der Ex-vivo-Niere.

PURPOSE: Therapeutic application of contactless thermoablation by high-intensity focused ultrasound (HIFU) demands precise physical definition of focal size and determination of control parameters. Our objective was to define the focal expansion of a new ultrasound generator and to evaluate the extent of tissue ablation under variable generator parameters in an ex vivo model. MATERIALS AND METHODS: Axial and transversal distribution of ultrasound intensity in the area of the focal point was calculated by needle hydrophone. The extent of tissue necrosis after focused ultrasound was assessed in an ex vivo porcine kidney model applying generator power up to 400 Watt and pulse duration up to 8 s. RESULTS: The measurement of field distribution revealed a physical focal size of 32 x 4 mm. Sharp demarcation between coagulation necrosis and intact tissue was observed in our tissue model. Lesion size was kept under control by variation of both generator power and impulse duration. At a constant impulse duration of 2 s, generator power of 100 W remained below the threshold doses for induction of a reproducible lesion. An increase in power up to 200 W and 400 W, respectively, induced lesions with diameters up to 11.2 x 3 mm. Constant total energy (generator power x impulse duration) led to a larger lesion size under higher generator power. CONCLUSION: It is possible to induce sharply demarcated, reproducible thermonecrosis, which can be regulated by generator power and impulse duration, by means of a cylindrical piezo element with a paraboloid reflector at a focal distance of 10 cm. The variation of generator power was an especially suitable control parameter for the inducement of a defined lesion size.

[Minimally-invasive therapy of urinary stones]. / Interventionelle Therapie von Harnsteinen.

Open surgery was the standard therapy for urinary calculi up to about 30 years ago. This changed upon introduction of extracorporeal shockwave lithotripsy (ESWL) in 1980, a procedure that is now the primary therapy for 70 % of the patients in western countries. Simultaneously, endourological procedures like ureterorenoscopy (URS) and percutaneous nephrolithotripsy (PCNL) have been improved, and now, modern small diameter and highly efficient instruments offer an ideal alternative to shockwave lithotripsy. Today, minimally-invasive stone treatment has replaced open stone surgery almost completely. This article introduces ESWL, URS and PCNL and discusses indications, outcomes and limitations.