Frank Oberpenning

De novo reconstitution of a functional mammalian urinary bladder by tissue engineering.

Human organ replacement is limited by a donor shortage, problems with tissue compatibility, and rejection. Creation of an organ with autologous tissue would be advantageous. In this study, transplantable urinary bladder neo–organs were reproducibly created in vitro from urothelial and smooth muscle cells grown in culture from canine native bladder biopsies and seeded onto preformed bladder–shaped polymers. The native bladders were subsequently excised from canine donors and replaced with the tissue–engineered neo–organs. In functional evaluations for up to 11 months, the bladder neo–organs demonstrated a normal capacity to retain urine, normal elastic properties, and histologic architecture. This study demonstrates, for the first time, that successful reconstitution of an autonomous hollow organ is possible using tissue–engineering methods.

Bladder augmentation using allogenic bladder submucosa seeded with cells

OBJECTIVES The search for a suitable material to reconstruct the genitourinary tract has been a challenging task. Bowel has been widely used for urinary tract reconstruction, despite its subsequent complications. We investigated the possibility of using allogenic bladder submucosa, a tissue consisting of nonimmunogenic acellular collagen, either with or without cells, as a material for bladder augmentation. METHODS Partial cystectomies were performed in 10 beagle dogs. Both urothelial and smooth muscle cells were harvested and expanded separately in 5 animals. The allogenic bladder submucosa obtained from sacrificed dogs was seeded with muscle cells on one side and urothelial cells on the opposite side. All beagles underwent cruciate cystotomies on the bladder dome. Augmentation cystoplasty was performed with the allogenic bladder submucosa seeded with cells in 5 animals and with the allogenic bladder submucosa without cells in 5. The augmented bladders were retrieved 2 and 3 months after augmentation. RESULTS Bladders augmented with the allogenic bladder submucosa seeded with cells showed a 99% increase in capacity compared with bladders augmented with the cell-free allogenic bladder submucosa, which showed only a 30% increase in capacity. All dogs showed a normal bladder compliance, as evidenced by urodynamic studies. Histologically, all retrieved bladders contained a normal cellular organization consisting of a urothelial lined lumen surrounded by submucosal tissue and smooth muscle. Immunocytochemical analyses confirmed the urothelial and muscle cell phenotype and showed the presence of nerve fibers. CONCLUSIONS These results show that allogenic bladder submucosa seeded with cells appears to be an excellent option as a biomaterial for bladder augmentation.

Discordance of assay methods creates pitfalls for the interpretation of prostate-specific antigen values

The availability of numerous different assays for the determination of prostate‐specific antigen (PSA) has created substantial problems in the interpretation of PSA concentrations. Currently over 60 assays are commercially offered on the European market. The majority of the recently marketed assays are based on the commonly used reference range (<4 ng/ml), although this rarely has been verified. Some manufacturers avoid specifying the range altogether, while others derive the data from very small collectives. Reference ranges established with sera of young males or even with an unspecified proportion of sera of females are not suitable for assessing the specificity of PSA assays for detecting prostate cancer among males older than age 50 years. Most manufacturers recommend that their assays not be used for diagnostic purposes but only for following up patients previously diagnosed with prostate cancer. Usually the physician remains unaware of this warning as well as of the name of the assay used. Since PSA concentrations may vary in identical samples by a factor of two depending on the assay used, the clinician in charge of interpreting the results needs to be aware of the method used and must have detailed information on the assay‐specific reference range.

LONG-TERM RESULTS OF TRIGONE-PRESERVING ORTHOTOPIC SUBSTITUTION ENTEROCYSTOPLASTY FOR INTERSTITIAL CYSTITIS

PURPOSE Interstitial cystitis is a chronic debilitating condition mainly affecting women. Conservative treatment often produces unsatisfactory results and the identification of the best surgical treatment modality is difficult. We evaluate retrospectively the long-term results of trigone-preserving cystectomy followed by orthotopic substitution enteroplasty for women suffering from interstitial cystitis. MATERIALS AND METHODS The study comprised 18 women with a mean age of 55.9 years. All surgical interventions were performed by 1 surgeon. All patients completed a voiding log and were interviewed about symptoms. Renal ultrasonography was done to evaluate the upper urinary tract. Followup data also comprised blood chemistry studies, including vitamin B12 blood levels and blood gas analysis. Pain and lower urinary tract problems were measured using a validated self-assessment symptom index. RESULTS Ileocoecal augmentation was performed in 10 women and ileal substitute was done in 8. After a mean followup of 57 months 14 patients are completely pain-free, 12 void spontaneously and 15 report complete resolution of dysuria. Three patients perform intermittent self-catheterization and 1 woman prefers a suprapubic catheter for control of urinary hypercontinence. These 4 patients underwent ileoplasty. Surgery failed to relieve symptoms in 2 of the 18 patients. Surgery achieved a statistically highly significant improvement of diurnal and nocturnal voiding frequencies, functional bladder capacity and symptom index score. CONCLUSIONS Substitution enterocystoplasty is a valuable and safe therapeutic option for patients with intractable interstitial cystitis resistant to conservative therapy. In our series use of the ileocecal bowel segment showed better functional results.

Impact of free prostate-specific antigen on discordant measurement results of assays for total prostate-specific antigen

OBJECTIVES To determine why various assays for total PSA (t-PSA) produce discordant results in identical serum samples. METHODS A total of 84 sera from 40 patients with histologically confirmed benign prostatic hyperplasia and from 44 patients with untreated prostate cancer were analyzed with seven assays for t-PSA and the Hybritech research assay for free prostate-specific antigen (f-PSA). Comparison between assays was performed by linear regression of the t-PSA concentrations as well as between the t-PSA concentrations and the f/t-PSA ratios. RESULTS The coefficients of correlation for the investigated assays versus Hybritech Tandem-E range from 0.96 to 0.99. Nevertheless average PSA concentrations differed significantly from the Tandem-E assay in all assays. Despite a good correlation, some assays showed a regression line with a slope notably different from 1. In these assays, elevated concentrations were observed in sera with a high proportion of f-PSA. CONCLUSIONS The study illustrates a significant and clinically relevant discordance between reported t-PSA concentrations for identical samples, depending on the assay used and on the contents of f-PSA in the sample. The interpretation of t-PSA concentrations requires awareness of the applied assay as well as the establishment of an assay-specific reference range in order to avoid inappropriate clinical consequences, such as unnecessary biopsies. Respective details must be contained in the laboratory reports. A change of assays without specifically reassessing previously valid reference ranges or the uncritical use of a customarily applied limit of < 4 ng/mL will otherwise be harmful to the patient.

A new modification of the Chiron ACS assay for total prostate-specific antigen achieves equimolar response characteristics and improves the detection of prostate cancer.

Abstract Nonequimolar-response assays for prostate-specific antigen (PSA) are criticized for overestimating total PSA in some men without prostate cancer (PCA), and underestimating total PSA in some men with PCA. We recently studied three nonequimolar-response PSA assays that had undergone modifications. While two of the studied assays achieved equimolar-response characteristics with improved areas under receiver operating characteristic (ROC) curves (AUC), the modification of the Chiron ACS PSA assay (ACS PSA2, Chiron) failed to achieve this. Recently, the ACS assay underwent another modification (ACS PSA, Bayer), which we investigated. Sera from 305 men (155 without and 150 with PCA, PSA ≥2 and ≤30 μg/l, Tandem-E) were measured using both modifications of the ACS assay and equimolar-response reference methods (Tandem-R free and Tandem- E, Hybritech). Molar response relative to the reference method and clinical performance (comparison of AUCs) between the previous and new ACS assay modifications were studied. The new modification of the ACS assay (ACS PSA, Bayer) achieved equimolar-response characteristics but reported lower values (average 10%) than the Tandem-E assay. Compared to the previous modification (ACS PSA2, Chiron), a 3% improvement in AUC (p = 0.01) was found. Using results of the redesigned equimolar-response assay (ACS PSA, Bayer), we calculated that 6 of 155 men without PCA in this sample set could be spared unnecessary biopsy compared with the previous nonequimolar-response assay (ACS PSA2, Chiron) without missing additional PCA (90% sensitivity). These data provide additional evidence for clinical advantages of equimolar-response over nonequimolar-response PSA assay formats.

Diagnostik der interstitiellen Zystitis

ZusammenfassungDie interstitielle Zystitis (IC) ist eine seltene, komplexe Form der Harnblasenentzündung, deren Diagnostik Probleme bereiten kann. Die für Forschungszwecke festgelegten strengen NIH-Kriterien zur IC-Diagnostik sind in der Routine ungeeignet, da ein Großteil von IC-Patienten übersehen wird. Bei IC-Verdacht wird nach Anamnese und körperlicher Untersuchung ein mehrtägiges Miktionsprotokoll gefordert. Größere Miktionsvolumina (funktionelle Blasenkapazität >250 ml) oder längere Miktionsintervalle (>2 h), fehlende Nykturie oder symptomfreie Phasen sprechen gegen eine IC.Die weiterführende Ausschlussdiagnostik umfasst Urinuntersuchungen (Infekt), Zytologie (Carcinoma in situ), Harntraktsonographie (Steine, Raumforderungen, Anomalien) und in Sonderfällen Urodynamik. Blasenkapazitätsbestimmungen in Sedoanalgesie sind ungeeignet, da funktionell kleine Blasen mechanisch dehnbar sein können.Standardverfahren der IC-Diagnostik ist die Zystoskopie in Narkose, bei der 90% der IC-Patienten nach Blasendistension charakteristische Schleimhautglomerulationen entwickeln. Blasenbiopsien zum Malignitätsausschluss sind empfehlenswert.Kaliuminstillationstests haben bei der Routinediagnostik wegen geringer Spezifität keinen Stellenwert. Gleichermaßen sind aufwendige Bestimmugen neuartiger IC-Marker (Histamin, Tryptase, Zytokine, Wachstumsfaktoren, Substanz-P, Stickoxid) Forschungszentren vorbehalten und ohne Relevanz im Klinikalltag.AbstractInterstitial cystitis (IC) represents a rare and complex inflammatory bladder condition in which diagnostics can be challenging. Strict NIH criteria for its diagnosis were designed for research purposes. Their routine application would miss large proportions of IC patients. When IC is suspected, history and physical exam are followed by an evaluation of long-term voiding diaries. Large voided volumes (functional capacity >250 cc) or longer micturition intervals (>2 h.), absence of nocturia or symptom-free periods reduce the likelihood of IC. Further exclusion diagnostics include urine tests (infection), cytology (in-situ carcinoma), ultrasound (calculi, bulks, anomalies) and urodynamics in selected cases. Bladder capacity measurements under sedoanalgesia are of limited value, since functional low-volume bladders can be mechanically extendable. Cystoscopy under general anesthesia represents the diagnostic standard procedure for IC during which 90% of IC-patients present with characteristic mucosal glomerulations after bladder distension. Biopsies are recommended for exclusion of malignancy. Potassium-leak testing plays no relevant role in routine diagnostics due to its poor sensitivity. Similarly, complex determinations of novel IC markers (histamine, tryptase, cytokines, growth factors, substance P, nitric oxide) are of no relevance in clinical settings and should be restricted to research projects.

Offen-chirurgische Therapie der interstitiellen Zystitis

ZusammenfassungDie Behandlung der interstitiellen Zystitis (IC) stellt eine der schwierigsten therapeutischen Herausforderungen in der Urologie dar. Zahlreiche Urologen sind der Ansicht, dass ein konservativer Therapieansatz bei den leidenden Patienten nicht länger hinausgezögert werden sollte, da effektive chirurgische Alternativen zur Verfügung stehen, die eine schnelle und anhaltende Linderung zu erzielen vermögen.Die angewandten operativen Techniken – supratrigonale Zystektomie, subtrigonale Zystektomie unter Belassung des Blasenhalses und radikale Zystektomie mit Urethrektomie – werden nach wie vor hinsichtlich ihrer Vor- und Nachteile diskutiert. Gemeinsam ist diesen Techniken, dass das entfernte Blasengewebe durch ausgeschaltete Darmanteile ersetzt wird.AbstractTreatment of IC is one of the most difficult therapeutic challenges in urology, frequently resulting in frustration for both patient and therapist. Many urologists believe that conservative treatment should not be unnecessarily prolonged in severe cases with low bladder capacity, since cystectomy may provide immediate and permanent relief for the suffering patient.However, it remains unclear which surgical approach and technique is the most suitable. Generally three different techniques are performed: supratrigonal cystectomy; radical cystectomy, saving only the bladder neck; and, finally, radical cystectomy combined with excision of the urethra. All three techniques require substitution of the excised bladder tissue with bowel segments.