The HELENA study: Hexvix®-TURB vs. white-light TURB followed by intravesical adjuvant chemotherapy-a prospective randomized controlled open-label multicenter non-inferiority study.

PURPOSE: Photodynamic diagnosis and white-light TURB with adjuvant intravesical chemotherapy (ICT) is widely used in treatment of bladder cancer. This non-inferiority trial is designed to demonstrate non-inferiority regarding recurrence-free survival (RFS) of Hexvix® TURB followed by immediate instillation compared to white-light TURB with immediate instillation followed by maintenance ICT. METHODS: Between 07/2010 and 12/2016, 129 patients with EORTC intermediate risk non-muscle invasive bladder cancer treated with TURB were included in this multicentre phase III study. Patients were randomized and received either white-light TURB with immediate ICT followed by maintenance ICT (n = 62, 20 mg Mitomycin weekly for 6 weeks as induction phase, afterwards 20 mg/month for 6 months) or Hexvix® TURB with immediate ICT only (n = 67, 40 mg Mitomycin). Primary study endpoint was RFS after 12 months. Hexvix® TURB was counted as non-inferior to white light alone if the upper limit of the one-sided 95% confidence interval of hazard ratio was lower than 1.676. Due to the non-inferiority design, the per-protocol population was used as the primary analysis population (n = 113) RESULTS: Median follow-up was 1.81 years. Hexvix® group showed more events (recurrence or death) than white-light group (19 vs. 10) resulting in a HR of 1.29 (upper limit of one-sided 95%-CI = 2.45; pnon-inferiority = 0.249). The ITT population yielded similar results (HR = 1.67); 3.18], pnon-inferiority = 0.493). There was no significant difference in overall survival between both groups (p = 0.257). CONCLUSION: Non-inferiority of Hexvix® TURB relative to white-light TURB with maintenance Mitomycin instillation in intermediate risk urothelial carcinoma of the bladder was not proven. Hence a higher effect of maintenance ICT is to assume compared to a Hexvix®-improved TURB only, confirming its important role in patient treatment.

[Current and established diagnostic modalities for bladder cancer]. / Aktuelle und etablierte Diagnoseverfahren beim Harnblasenkarzinom.

INTRODUCTION: In this paper, current guidelines regarding diagnostic and staging modalities of urothelial cancer of the bladder are summarized and an overview of endoscopic, imaging, and molecular methods currently being tested are outlined. METHODS: Relevant passages from current guidelines and recent literature as well as to a certain extent our own research are examined. RESULTS: Over the last decade, imaging mainly in the form of photodynamic diagnosis (PDD) has undergone further development and found its way into several guidelines. PDD-based transurethral resection of the bladder (TURB) proved to have a long-term effect regarding recurrence rate, progression and reduction of cystectomy in some patients. More light-filtering techniques and improvements in the screen resolution are currently being clinically tested. Molecular substaging using combinations of immunohistochemical biomarkers has the potential to change the clinical management of advanced urothelial cancer. CONCLUSION: New visualization techniques are likely to improve recurrence intervals and prognosis of bladder cancer. Molecular substaging will revolutionize prognostic assessment and therapeutic strategies of urothelial cancer.

[Active surveillance of low risk prostate cancer]. / Aktive Überwachung beim Niedrigrisikoprostatakarzinom.

In Europe prostate cancer is one of the most common cancers among men. The diagnostics always include a control of the prostate-specific antigen (PSA) level and examination of a representative tissue sample from the prostate. With these findings it is possible to evaluate the degree of progression of the cancer and its prognosis. Several treatment options for localized prostate cancer are given by national and international guidelines including radical prostatectomy, percutaneous radiation therapy, or brachytherapy and surveillance of the cancer with optional treatment at a later stage. For the latter treatment option, known as active surveillance, strict criteria have to be met. The advantage of active surveillance is that only patients with progressive cancer are subjected to radical therapy. Patients with very slow or non-progressing cancer do not have to undergo therapy and thus do not have to suffer from the side effects. The basic idea behind active surveillance is that some cancers will not progress to a stage that requires treatment within the lifetime of the patient and therefore do not require treatment at all. Unfortunately the criteria for active surveillance are not definitive enough at the current time leading only to a delay in effective treatment for many patients. The surveillance strategy has without doubt a high significance among the treatment options for prostate cancer; however, at the current time it lacks reliable indicators for a certain prognosis. Therefore, patients must be informed in detail about the advantages and disadvantages of active surveillance.

[Photodynamic diagnostics of the bladder: current study results]. / Die photodynamische Diagnostik der Harnblase : Aktuelle Studienergebnisse.

The diagnosis and follow-up of bladder cancer is based on the so-called golden standard of urine cytology and white light endoscopy. In recent years fluorescence endoscopy, also known as photodynamic diagnosis (PDD), of the urinary bladder has become more and more popular. The rising interest in this procedure becomes clear when looking at the current literature. Nowadays, there are studies on PDD from all over Europe and the USA. This article gives an up to date review of these new studies and shows new developments in the outpatient use of PDD.

[Diagnostic procedure for bladder cancer. Standards and current developments]. / Diagnostische Verfahren beim Harnblasenkarzinom. Standards und aktuelle Entwicklungen.

Urinary cytology and white light endoscopy have been the gold standard for initial diagnosis of bladder cancer for decades. Furthermore the use of imaging techniques, such as ultrasound or CT scanning can be necessary in certain cases. This article gives an overview on standard diagnostic techniques and introduces new optical diagnostic technologies, such as Raman spectroscopy, optical coherence tomography, narrow band imaging and confocal laser microscopy, which could play a role in the diagnosis of bladder cancer in the future. Furthermore the current indications for photodynamic diagnoses are discussed.

Minimizing complications during retropubic radical prostatectomy - Is ureteral stenting necessary?

OBJECTIVES AND AIMS: To avoid damage to the ureters during bladder neck preparation in radical prostatectomy for prostate cancer, it may be helpful to insert ureteral stents temporarily or to intravenously administer indigo carmine dye for enhanced visualisation of ureteric orifices. We evaluated our bladder neck preserving technique at radical prostatectomy with regard to ureteric injuries. PATIENTS AND METHODS: We analysed 369 consecutive radical prostatectomies operated in our clinic in a bladder neck preserving technique. The following parameters were assessed in this retrospective study: number of prophylactic ureteric stent insertions, application of indigo carmine dye, observed injuries of the ureters by the surgeon, postoperative increase of serum creatinine and postoperative status of kidney ultrasound. RESULTS: In 7/369 prostatectomies (1.90%) a ureteric stent insertion was performed, indigo carmine was not applied to any patient at all, yet no intraoperative injury of a ureter was observed by a surgeon. No revision was necessary due to a ureteral injury within the observation period of one year after surgery. In 17 patients with preoperative normal creatinine value a pathological value was observed on the first postoperative day (mean 1.4 mg/dl). In these patients no consecutive postrenal acute renal failure was observed, no hydronephrosis was monitored by ultrasound and no further intervention was necessary. CONCLUSIONS: Bladder neck preserving operation technique does not implicate the need of prophylactic ureteric stent insertions and has no higher incidence of ureteric injuries.

[Precancerous lesions of the urothelium. From Feulgen staining to single cell CGH]. / Präkanzerosen des Urothels. Von der Feulgen-Färbung bis zur Einzelzell-CGH.

Feulgen staining represents a staining method to quantitatively document the DNA content of a nucleus. Thus it is an excellent and straightforward method to reflect the irregular increase in DNA content of a malignant cell as a sign of genetic instability. Genetic instability of the tumour cell is the key feature of the 2004 WHO classification of bladder tumours, in which flat and papillary neoplasia are grouped into low- and high-grade lesions. "High grade" represents the tumor with genetic instability and consequently a higher likelihood of progression. Concomitant distinct genetic aberrations other than the numeric ones are increasingly identified as discriminators and help group the entities. The current status of genetic investigations, especially those in precancerous lesions, will be outlined in this review in the context of morphology (histology and cytology) as well as clinical situation.

[Photodynamic diagnostics in the urinary tract. Consensus paper of the Working Group for Oncology of the German Society for Urology]. / Photodynamische Diagnostik im Harntrakt. Konsensusempfehlungen des Arbeitskreises Onkologie der Deutschen Gesellschaft für Urologie.

Because of the frequency of occurrence and the long protracted course, bladder carcinoma is the most expensive solid tumor in terms of costs, from diagnosis to death of the patient. The most important cost factor within the total cost is the treatment of recurrent, non-muscle invasive bladder carcinoma. Photodynamic diagnosis (PDD) improves the early detection rate of non-muscle invasive bladder cancer, especially the detection of carcinoma in situ and severe dysplasia. PDD also reduces the number of residual tumors after TUR-B compared to white-light guided TUR-B and also the early recurrence rate although long-term outcome with hexylaminolaevulinic acid with regards to the general course of bladder cancer is still lacking. PDD has been used mainly for detection of bladder cancer and specifically carcinoma in situ in conjunction with diagnostic and therapeutic transurethral resection of the bladder. In 2006 hexylaminolaevulinic acid (HAL) was approved in the EU (EMEA) as a photosensitizer for the use in photodynamic diagnosis of the bladder. Several guidelines have incorporated PDD as optional form of diagnosis during endoscopy in proven or suspected bladder cancer, but no specific recommendations regarding indication and application of PDD exist. The German group of urologic oncology (AKO) invited urologists and biologists involved in the development of hexylaminolaevulinic acid as well its clinical use to participate in evaluating the data for HAL and its predecessor delta-aminolaevulinic acid (5-ALA). A consensus with regards to the indications, contraindications, technique, pre-clinical data, comparison of HAL and 5-ALA, current results, costs and follow-up was reached and are presented in this paper.

[Diagnosis of urothelial carcinoma]. / Diagnostik des Harnblasenkarzinoms.

Bladder cancer represents the fifth most common malignancy in the US. In Germany we face 25,000 new incidences of urothelial cancers every year. At present a variety of different techniques is available for the diagnosis of bladder cancer. On the one hand techniques are needed that show the possible presence of a tumour and on the other hand procedures that can confirm a lesion to be a tumour, like in most cases histology does. The following article gives an overview of the currently used standards in the diagnosis of urothelial cancer. Also new techniques for diagnosis and surveillance of urothelial cancer are discussed. The combination of white light endoscopy and urine cytology is currently considered the gold standard for diagnosis. Transurethral biopsies or TUR-BT subsequently follow in the case of positive findings. To optimize the sensitivity and lower the recurrence rate as well as the residual tumour rate, fluorescence endoscopy can be used as an additional approach. Also urine-based markers play an important role in the diagnosis and surveillance of urothelial carcinomas, but cannot yet be recommended as a single procedure in the routine diagnosis of bladder tumour.

[Fluorescence cystoscopy at bladder cancer: present trials]. / Die Fluoreszenzzystoskopie beim Harnblasenkarzinom : Aktueller Stellenwert.

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of not-muscle-infiltrating bladder cancer are now well established, significant challenges remain, which influence patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity and increase quality of life and survival. Fluorescence cystoscopy, often referred to as "photodynamic diagnosis" (PDD) with intravesical application of photosensitizing agents has been developed in order to enhance the early detection of bladder cancer. Since March 2005 the hexyl-ALA ester (Hexvix) has been approved for the diagnosis of bladder cancer in 27 EU/EEA countries through the European Mutual Recognition Procedure. There is growing evidence that PDD enhances the detection of bladder cancer, particularly of high-grade flat lesions. Furthermore, transurethral resection of bladder tumor under fluorescence guidance has been shown to reduce the risk of recurrent tumors. Nevertheless, a resulting relatively decreased number of recurrences have still to be verified in prospective randomized trials.

[Fluorescence cytology. Improvement of urinary cytology]. / Die Fluoreszenzzytologie. Eine Weiterentwicklung der Urinzytologie.

Urothelial cancer of the bladder is a frequent disease, and urinary cytology often is used as a routine diagnostic tool. But this technique has an impaired sensitivity in low-grade tumours, and as a subjective method it is highly dependent on the experience of the cytologist. Here we present the technique of fluorescence cytology as an improvement of conventional cytology. This method is potentially able to compensate for the disadvantages of urinary cytology as it is an automated process that uses the principles of 5-Ala-induced photodynamic diagnosis (PDD).

[Urine cytology and urine markers. Significance for clinical practice]. / Urinzytologie und Urinmarker. Bedeutung für die Praxis.

Urothelial carcinoma of the bladder is a frequent disease that can be identified timely by screening patients at high risk. Due to the high rate of disease recurrence, frequent follow-up procedures are necessary. For this purpose, cystoscopy is the standard procedure, and supplementary non-invasive procedures such as cytology or tumor marker tests are used. These tests have different advantages and disadvantages in terms of their sensitivities and specificities. Thus, they provide additional information, but are not able to replace cystoscopy as the standard instrument in the diagnosis of bladder cancer.

[Painless enlargement of the scrotum]. / Schmerzlose Schwellungen des Hodensacks immer abklären: Odem, Bruch oder Tumor?

Painless swelling of the scrotum may be due either to an increase in bulk of the scrotal contents or to changes affecting the skin of the scrotum. The reliable and rapid differentiation of harmless from serious conditions such as cancer of the testicles, is essential.

[Urinary cytology. Possibilities, limitations and the future]. / Die Urinzytologie. Möglichkeiten, Grenzen und Zukunft.

Even now, 60 years after the fundamental studies on oncological urinary cytology carried out by Papanicolaou and Marschall and the subsequent integration of the test they devised into the diagnostic investigations applied in the diagnosis of urothelial carcinoma, urinary cytology still maintains its place in the diagnosis of primary and recurrent tumours of the urinary tract. Newer diagnostic techniques involving urine-bound tumour markers have not so far achieved such high levels of acceptance as their method. It is possible, certainly, that a combination of these newer methods with cytological testing, or with other innovative diagnostic methods, such as photodynamic techniques, could prove very promising in the future and might overcome the limitations of urinary cytology.

[Noninvasive and invasive bladder cancer: diagnostics and treatment]. / Nichtinvasives und invasives Harnblasenkarzinom: Diagnostik und Therapie.

Therapy of superficial bladder tumors is transurethral resection (TUR), and in cases of pT1 or high-grade tumors a re-TUR is indicated. Patients with carcinoma in situ receive intravesical chemotherapy or BCG for at least 3 months. Persistent carcinoma in situ may be treated by radical cystectomy. With the provision of a functionally adequate urinary diversion, cystectomy represents an effective treatment for patients with muscle-invasive bladder cancer without metastatic spread. Regional lymph node metastases can be found in up to 15% of stage T1 disease and are present in 33% of stage T3/4 lesions. Thus, lymphadenectomy gains diagnostic and possibly also therapeutic importance. For selected patients, who cannot be treated by radical cystectomy, multimodal concepts aiming to preserve the bladder are discussed. After or prior to cystectomy systemic chemotherapy may become necessary for some patients to positively affect the course of the disease in cases of locally advanced or metastatic lesions.

[Urinary bladder tumours. The new 2004 WHO classification]. / Harnblasentumoren Die neue WHO-Klassifikation 2004.

Increasing knowledge in molecular genetic research on urinary bladder carcinoma has allowed us to classify the morphological picture on the basis of a better understanding. But this new knowledge will only be ground-breaking if it can be correlated with the clinical outcome of urinary bladder tumours and with histopathological findings. The use of the new 2004 WHO classification results in a standardized diagnosis of urothelial tumours by means of an exact definition of the subgroups. In the future, trials can thus be compared worldwide and risk profiles can be stratified. Further research in molecular genetics and correlation with the current classification together with molecular biological techniques may allow refinement of this scheme, e.g. by immunohistochemical subclassifications, enabling identification of potentially genetically unstable tumours. In this paper we present the new 2004 WHO classification of urinary bladder tumours emphasizing the changes in relation to the former classifications focusing on histological typing, grading and molecular characterization. Until the new classification is finally validated, and those working in the field have become familiar with it, the WHO classification of 1973 should be mentioned additionally in the histopathological report.

Fluorescence diagnosis: a novel method to guide radical inguinal lymph node dissection in penile cancer.

In penile cancer there is still a diagnostic dilemma between over treatment of lymph node-negative patients and the missing of occult metastases by watchful waiting. In the current study the value of fluorescence diagnosis during radical inguinal lymph node dissection was evaluated. Five patients with penile cancer were elected to undergo groin dissection. All patients received 5-aminolevulinic acid (5-ALA) orally before the operation for fluorescence diagnosis. Intraoperatively, fluorescence detection of the lymph nodes was performed by visual detection and spectroscopy. Two of the five patients had positive inguinal lymph nodes. Fluorescence in tumor-bearing tissue was detectable in the exposed lymph nodes. Protoporphyrin IX (PPIX) is accumulated in tumor-positive lymph nodes, making fluorescence diagnosis in penile cancer possible. More studies with higher patient numbers are necessary to evaluate optimal dosage and excitation conditions to detect tumor-bearing nodes in vivo.

[Precancerous conditions in the urothelium. Early detection and molecular understanding through endoscopic fluorescence diagnosis]. / Präkanzerosen des Urothels. Früherkennung und molekulares Verständnis durch endoskopische Fluoreszenzdiagnostik.

Fluorescence diagnosis after application of 5-aminolevulinic acid (ALA) detects red-fluorescing preneoplastic and neoplastic lesions using light excitation. The principle of the method is the relative tumor-selective accumulation of the metabolite protoporphyrin IX (PPIX), which is built intracellularly out of exogenously applied ALA. The early detection of tumors and especially preneoplasias is an ideal prerequisite for genetic analysis of these lesions. With this approach, methods such as fluorescence in situ hybridization and loss of heterozygosity analysis for deletion mapping as well as gene sequencing data could be compared. New data are presented on deletions, numeric chromosomal aberrations, and oligoclonality of tumors found in about 30% of cases. The phenomenon of tumor-selective fluorescence was further investigated by parallel biochemical analysis, which showed marked differences in heme metabolism. The analysis of gene and protein expression may aid in identifying tumor-specific molecules associated with heme metabolism.