M. Retz

Mucin 7 and Cytokeratin 20 as New Diagnostic Urinary Markers for Bladder Tumor

PURPOSEnWe determine the sensitivity and specificity of cytokeratin 20 (CK-20) and mucin 7 (MUC7) gene expression in voided urine samples taken from patients with bladder tumor and from control groups to investigate putative, noninvasive urinary markers for bladder tumor detection and monitoring.nnnMATERIALS AND METHODSnVoided urine samples were collected from 50 patients with histologically proven bladder neoplasms (pTaN0M0G1-3 in 19 and pTisN0M0G3-pT4pN1M1G3 in 31), 20 patients with urolithiasis, 20 patients with urinary tract infection, 20 patients with other urological neoplasms and 20 healthy volunteers. Total RNA was extracted from exfoliated cells collected from 200 ml. voided urine. All RNA samples were investigated by a specific CK-20 and MUC7 nested reverse transcriptase polymerase chain reaction.nnnRESULTSnThe overall sensitivity of CK-20 gene expression in voided urine samples for the detection of bladder neoplasms was 78%. In contrast, voided urine samples from control patients and healthy volunteers showed a high rate of false-positive CK-20 detection resulting in a low specificity of 36%. The overall sensitivity of the MUC7 test for all bladder tumor cases was 66%. The sensitivity for papillary urothelial neoplasms (pTaN0M0G1-3) was 42% whereas analysis of the carcinoma in situ and invasive bladder cancer group (pTisN0M0G3-pT4pN1M1G3) yielded a sensitivity of 81%. The overall specificity of the MUC7 nested reverse transcriptase polymerase chain reaction method in the control groups was 80%.nnnCONCLUSIONSnA high positive CK-20 detection rate was found not only in voided urine samples from patients with bladder tumor, but also in urine specimens from control groups. Therefore, CK-20 is not a reliable urinary tumor marker for bladder neoplasms. In contrast to CK-20, analysis of MUC7 demonstrated a high sensitivity and high specificity for carcinoma in situ and invasive bladder cancer, thus fulfilling the criteria of a urinary tumor marker.

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.

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.

Long term follow-up of combined radiochemotherapy for locally advanced bladder carcinoma

The 5‐ and 10‐year survival rates and the toxicity of combined radiochemotherapy for 53 consecutive patients with locally advanced bladder carcinoma were studied in a noncomparative trial.

A HYPOECHOIC LESION FOUND ON TESTICULAR ULTRASOUND AFTER TESTICULAR PIERCING

A 33-year-old white man presented with a painless palpable mass of the right testicle without signs of acute inflammation. Medical history was uneventful and physical examination revealed no other abnormal findings. Standard laboratory values and serum tumor markers a-fetoprotein and b-human chorionic gonadotropin were normal. Scrotal ultrasound showed an intratesticular homogeneous hypodensity of the right testicle measuring 8 3 7 x 9 mm. arousing high suspicion of testicular malignancy (see figure). 1 The left testis was normal on palpation and ultrasound. Initially, the patient denied any relevant history leading to this condition. However, when surgical exploration of the testicular mass was suggested he admitted an attempt to pierce both of the testicles with a 9 cm. long titanium needle about 5 months earlier, intending autoerotic stimulation. After pulling out the needle from both testicles he noticed tenderness and swelling of the right testis that resolved during the following days, while the left testis was unaffected. To rule out a testicular tumor the patient underwent exploration of the right testis by an inguinal incision. Intraoperative frozen sections of an incisional biopsy of the lesion demonstrated no testicular cancer. After excision of the lesion the tunica albuginea was closed and right orchiopexy was performed. Pathological examination was consistent with chronic orchitis and periorchitis with lymphocytic infiltration, plasma cells and capillary tissues. Standard microbiological culture of the lesion demonstrated no causative pathogen. DISCUSSION

Nachsorge des Harnblasenkarzinoms

ZusammenfassungIm vorliegenden Beitrag wird ein Leitfaden zur Nachsorge von Harnblasenkarzinompatienten angeboten. Die Empfehlungen basieren dabei auf der Grundlage der Leitlinien der Deutschen Gesellschaft für Urologie und der European Association of Urology. Die Nachsorge richtet sich stets nach dem Rezidiv- und Progressionsrisiko des Primärtumors und nach dem Umfang seiner Therapie. So steht nach transurethraler Resektion des oberflächlichen Harnblasenkarzinoms die Kontrollzystoskopie im Mittelpunkt der Nachsorge. Nach radikaler Zystektomie des muskelinvasiven und lokal fortgeschrittenen Karzinoms sollten umfangreichere Untersuchungen inkl. Computer- bzw. Kernspintomographie des Beckens und Abdomens erfolgen. Zusätzlich müssen die unterschiedlichen Harnableitungsformen nach Zystektomie mit ihren spezifischen Spätkomplikationen in die Nachsorge miteinbezogen werden. Darüber hinaus darf die psychologische Bedeutung der Nachsorgeuntersuchungen nicht vernachlässigt werden.AbstractThe present article offers an introduction to the aftercare of patients with carcinoma of the urinary bladder. These recommendations are based on the guidelines of the German Association of Urology and the European Association of Urology. Aftercare always depends on the risk of recurrence and progression of the primary tumor and the extent of the therapy applied. Thus, after transurethral resection of a superficial carcinoma of the urinary bladder, aftercare focuses on follow-up cystoscopy. Radical cystectomy of the muscle-invading and locally advanced carcinoma should be followed by extensive examinations, including computed tomography of the pelvis and the abdomen. In addition, the various forms of urinary diversion after cystectomy with its specific late complications should be included in the aftercare. Moreover, the psychological significance of the follow-up examinations should not be neglected.

Gemcitabine in advanced bladder cancer

ZusammenfassungSeit 1985 konnte sich die Kombinationschemotherapie mit MVAC bzw. MVEC (Methotrexat, Vinblastin, Doxorubicin/Epirubicin, Cisplatin) in der systemischen Behandlung des fortgeschrittenen Urothelkarzinoms als Gold-Standard durchsetzen. In einer von 1996 bis 1998 durchgeführten multinationalen Studie zeigte sich eine vergleichbare Effektivität von Gemcitabin/Cisplatin gegenüber MVAC (statistisch nicht signifikant) bei gleichzeitig besserer Verträglichkeit. Die Wirksamkeit von Gemcitabin in der Behandlung des fortgeschrittenen Urothelkarzinoms wurde bereits seit Anfang der 1990er Jahre in verschiedenen Phase-II-Studien als Monotherapie oder in Kombination mit anderen Chemotherapeutika beobachtet. Dabei liegen die Tumorremissionsraten für das fortgeschrittene Urothelkarzinom mit der Gemcitabinmonotherapie zwischen 11% und 28%, in der Kombination mit Cisplatin bei 50% und in der Dreifachtherapie u.xa0a. mit Cisplatin und Paclitaxel bei über 75%.Zuletzt konnten im Rahmen einer bundesdeutschen Phase-II-Studie zur Gemcitabin/Cisplatin Therapie im 3-Wochen-Schema niedrigere Toxizitätsraten bei ähnlichen Tumoransprechraten im Vergleich zur 4-wöchigen Applikation in der multinationalen Phase-III-Studie beobachtet werden.AbstractMVAC (methotrexate, vinblastine, doxorubicin, cisplatin) has been the standard treatment for patients with advanced urothelial cancer for more than 15xa0years. Combination chemotherapy including gemcitabine/cisplatin showed similar tumor response and survival rates with a more tolerable toxicity profile in a recent multinational phase III study when compared to MVAC. Effectivity of gemcitabine as a single agent or in combination with other cytotoxic agents had been investigated before in several phase II studies treating patients with advanced urothelial cancers. The tumor response rate for single agent gemcitabine in advanced urothelial cancers is between 11% and 28%. Tumor response rates rise to 50% when combining gemcitabine with cisplatin, and median survival times between 12 and 15xa0months can be expected. Triplet therapy schedules including gemcitabine may yield response rates in up to 80% of patients, particularly when used sequentially with other regimens. Further improvement of tolerability during systemic gemcitabine/cisplatin combination therapy without compromising effectivity was recently demonstrated by a German phase II study when the 4-week schedule was reduced to a 3-week schedule with gemcitabine given on days 1 and 8.