[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany]. / Gemcitabin/Cisplatin vs. MVAC. 5-Jahres-Ergebnisse der Phase-III-Studie zur Chemotherapie des fortgeschrittenen Urothelkarzinoms in Deutschland.

Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.

PSCA expression is regulated by phorbol ester and cell adhesion in the bladder carcinoma cell line RT112.

The expression of the surface protein prostate stem cell antigen (PSCA) in prostate carcinoma increases in parallel with the progression of the tumor. In contrast, we have recently shown that PSCA expression is reduced or undetectable in other types of undifferentiated tumors. To elucidate the cellular mechanisms that underlie this complex pattern of expression, we studied regulatory parameters for PSCA expression in the bladder carcinoma cell line RT112 by Northern analysis. PSCA gene expression was stimulated by a culture dish surface that caused aggregation of cells, suggesting that its expression is regulated by mechanisms related to the adhesion of epithelial cells. Phorbol ester markedly stimulated PSCA gene expression in a cycloheximide- and actinomycin-inhibitable manner after a lag phase of 10 h, indicating that transcription of the PSCA gene is regulated by protein kinase C and a newly synthesized protein. In contrast, epidermal growth factor, platelet-derived growth factor (PDGF)-BB, tumor necrosis factor-alpha, interferon-gamma or a slightly lowered pH failed to increase PSCA mRNA levels. Consistent with the variable expression of PSCA in different tumors, our analysis in RT112 cells shows that its expression is controlled by a strongly inducible promoter that is specifically regulated by extracellular signals.

Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early?

PURPOSE: We evaluated the prognostic significance of a second transurethral resection in patients with moderately and poorly differentiated T1 bladder cancer. MATERIALS AND METHODS: A total of 47 patients with primary T1 bladder cancer were evaluated. A second transurethral resection was performed in 42 patients in case of moderately or poorly differentiated T1 bladder tumor or concomitant carcinoma in situ in the first resection. Five patients underwent immediate cystectomy due to large, multifocal and moderately or poorly differentiated pT1 disease. RESULTS: Of the 42 patients who underwent repeat resection 15 (36%) had no tumors. Up staging and change of treatment strategy due to the result of the second resection occurred in 10 (24%) cases. Mean followup was 60 months. An R0 second resection correlated with a 33% recurrence rate at followup compared with 57%, 75% and 87.5% in patients with pTa, Tis and T1 residual tumor, respectively, in the second resection. The rate of organ preservation was also related to the result of the second resection with 100% organ preservation in patients with no tumor in the second procedure. After immediate radical cystectomy 3 of 5 patients died during followup due to disease progression. Of this group 2 patients survived without clinical or radiological signs of disease progression. CONCLUSIONS: To our knowledge residual tumor after the first transurethral resection is a fact in bladder cancer treatment. The second transurethral resection offers the possibility to preserve the bladder. Furthermore, residual disease can be detected and removed in due time. In case of up staging to muscle infiltrating tumor, cystectomy is the next therapeutic step.

Magnetic resonance urography enhanced by gadolinium and diuretics: a comparison with conventional urography in diagnosing the cause of ureteric obstruction.

OBJECTIVE: To compare the ability of magnetic resonance urography (MRU), enhanced using gadolinium and frusemide diuresis, and conventional intravenous urography (IVU) to diagnose the cause of ureteric obstruction. PATIENTS AND METHODS: The study included 82 patients in whom IVU showed or suggested obstruction and who also underwent MRU. The images from both methods were interpreted by various investigators independently; two evaluated the IVU and two others the MRU, the latter being unaware of the diagnosis after IVU. If the diagnosis remained unclear, further investigations (e.g. computed tomography, retrograde pyelography or ureteroscopy) were conducted. RESULTS: The diagnoses were ureteric calculi in 72 patients, ureteric tumours in eight and extra-ureteric tumours in two. In those with urolithiasis, the diagnosis was correct with IVU in 49 patients and with MRU in 64. The diagnosis in this group was incorrect with MRU in only two patients. The main reason for the failure of IVU was absent contrast medium excretion. Three of eight patients with ureteric tumours were correctly diagnosed by IVU but in three patients the diagnosis was incorrect. MRU correctly diagnosed seven of the eight patients in this group, with no false diagnosis. CONCLUSION: IVU is currently likely to remain the standard procedure for imaging the upper urinary tract, but this study shows the potential of MRU when enhanced with gadolinium and frusemide. MRU may be helpful if there is a dilated system with no excretory function, in pregnant women, in children and in those with contrast medium allergy.

Cytochrome P450 isoenzyme mRNA expression pattern in human urinary bladder malignancies and normal urothelium.

This study was designed to analyze the cytochrome P450 isoenzyme mRNA expression pattern of transitional cell carcinomas of the bladder (N = 19) and normal urothelium (N = 10). In addition, biopsies from normal urothelium (N = 32) taken at the time of transurethral resection of bladder cancer in eight patients from surrounding histologically normal urothelium also were characterized concerning their specific cytochrome P450 mRNA expression pattern. A total of 13 of 19 of the analyzed tumor specimens (68%) revealed expression of cytochrome P450 1B1. Cytochrome P450 4B1 and 1A1 mRNA expression were detected in 79% (15 of 19) and 53% (10 of 19) of the tumor specimens, with no correlation between tumor stage and grade of the neoplasm. Biopsies from macroscopically and histologically normal urothelium from tumor-invaded bladders also showed expression of cytochrome P450 1B1 in 75% (24 of 32), 4B1 in 62.5% (20 of 32), and 1A1 in 50% (16 of 32). Furthermore, a 75% homology concerning cytochrome P450 1B1 and 4B1 mRNA expression was observed between the bladder tumor and the biopsies from this bladder. The polymerase chain reaction analysis of normal urothelium from normal bladders that do not harbor a neoplasm revealed CYP450 mRNA expression for CYP450 1A1 in 6 of 10; 1B1 in 5 of 10; 4B1 in 6 of 10; 2D6 in 2 of 10; and 2E1 in 2 of 10. According to our data, CYP450 1B1 mRNA expression is not tumor-specific. The present findings are the first to compare CYP450 expression in bladder cancer with biopsies from the same tumor-bearing bladder, and they indicate that, from the enzymatic point of view, bladder cancer also is a panurothelial field disease present in even normal urothelium.

Epidemiology and biology of human urinary bladder cancer.

The bladder constitutes the most frequent localization of malignant tumors in the urinary tract. Further prognostic factors are molecular and cytogenetic alterations, which have been identified as key mechanisms in the carcinogenetic pathway of bladder cancer. Structural or numerical chromosomal alterations lead to the activation of a variety of cancer-inducing oncogenes as well as to the inactivation of various distinct antiproliferative tumor-suppressor genes. With regard to the biological heterogeneity in transitional cell carcinoma, which is also reflected in epidemiological data, the differing clinical course and the limited value of established prognosticators, the analysis of new molecular parameters has become of interest in predicting the prognosis of bladder cancer patients. In addition, the definition of high-risk patient groups that are at at risk of progression and recurrence is a further objective of urological research in this field.

Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors.

Prostate stem cell antigen (PSCA) is a member of the LY-6 family of surface proteins that is overexpressed in prostate cancer. Using serial analysis of gene expression (SAGE), we identified PSCA as one of the most abundant transcripts in a differentiated urothelial tumor. As assessed by Northern blotting, PSCA is highly expressed in normal urothelium and noninvasive urothelial tumors. In contrast to the previously reported overexpression of PSCA in progressive and invasive forms of prostate cancer, we found a markedly reduced expression in undifferentiated bladder carcinoma. In addition, several aberrant splicing products derived from the PSCA gene were found in urothelial tumors. Furthermore, PSCA mRNA was highly abundant in normal esophagus and stomach, but was undetectable in esophageal or gastric tumors. The PSCA expression appeared to depend on cell contact, since mRNA levels were increased when RT112 bladder carcinoma cells were grown to confluence. Our data suggest that PSCA could serve as a potential marker for the early carcinogenesis in urothelial and gastric tissues and that its expression is specific for epithelial cells.

GLUT8, a novel member of the sugar transport facilitator family with glucose transport activity.

GLUT8 is a novel glucose transporter-like protein that exhibits significant sequence similarity with the members of the sugar transport facilitator family (29.4% of amino acids identical with GLUT1). Human and mouse sequence (86.2% identical amino acids) comprise 12 putative membrane-spanning helices and several conserved motifs (sugar transporter signatures), which have previously been shown to be essential for transport activity, e.g. GRK in loop 2, PETPR in loop 6, QQLSGVN in helix 7, DRAGRR in loop 8, GWGPIPW in helix 10, and PETKG in the C-terminal tail. An expressed sequence tag (STS A005N15) corresponding with the 3'-untranslated region of GLUT8 has previously been mapped to human chromosome 9. COS-7 cells transfected with GLUT8 cDNA expressed a 42-kDa protein exhibiting specific, glucose-inhibitable cytochalasin B binding (K(D) = 56.6 +/- 18 nm) and reconstitutable glucose transport activity (8.1 +/- 1. 4 nmol/(mg protein x 10 s) versus 1.1 +/- 0.1 in control transfections). In human tissues, a 2.4-kilobase pair transcript was predominantly found in testis, but not in testicular carcinoma. Lower amounts of the mRNA were detected in most other tissues including skeletal muscle, heart, small intestine, and brain. GLUT8 mRNA was found in testis from adult, but not from prepubertal rats; its expression in human testis was suppressed by estrogen treatment. It is concluded that GLUT8 is a sugar transport facilitator with glucose transport activity and a hormonally regulated testicular function.

[In vitro analysis and animal experiment study of surface modified biodegradable polylactide ureteral stents]. / In-vitro-Analytik und tierexperimentelle Untersuchung oberflächenmodifizierter biodegradierbarer Polylactidureterstents.

With the objective of developing a biodegradable ureteric stent, various polylactides were analyzed and grafted with a clinically adapted surface. Stent moulding was performed by CESP technology (Controlled Expansion of Saturated Polymers), which is not based on high temperature but gas-loading under high pressure which induces a foamy bulk structure. The hydrolytically biodegradable, synthetic homo- and copolymers poly(D,L-lactide) (PDLLA), poly(D,L-lactide-co-trimethylene-carbonate) (PDLLA-co-TMC), poly(D,L-lactide-co-glycolide) (PDLLA-co-Gly) as derivatives of lactic acid or glycolic acid and surface modifications with hydroxyethylene-methacrylate (HEMA) and oligoethyleneoxidemonomethacrylate (OEOMA) were analyzed with regard to cytotoxicity and cell adhesion. Methacrylates have minimized protein and cell adhesion and degradation of non-toxic products. All polymers exhibited a high degree of biocompatibility and cell adhesion was markedly reduced following HEMA grafting. A 3 cm and 7 Charrière prototype of the stent was moulded from PDLLA-co-TMC by CESP-technology, and grafted with HEMA by means of plasma-induced polymerization. Finally, the stents were implanted into female sheep, following unilateral ureterotomy. Regular blood and urine analysis as well as ultrasound and the final autopsy revealed no pathological findings. Histopathological analysis exhibited a regular epithelium without any changes being determined by contact to the stent, and a good regeneration of all layers in the area of anastomosis.

Tumor-adopted diagnosis of bladder cancer.

70% of our patients suffering from bladder cancer present themselves initially with a superficial tumor (Tis, Ta, T1) and only 30% are initially seen with a muscle-invasive carcinoma (T2, T3-4, N+, M+). Clinical history, physical examination, urine cytology, IVP and cystoscopy in combination with adequate tissue harvest by transurethral resection are the basis of our diagnostic procedures. Bimanual palpation, systematic biopsies, sonography, computed tomography, bone scan and further procedures are not to be considered as routine examinations and are only used in special situations. Only exactly defined diagnostic algorithms permit the development and use of valid prognostic parameters. They further allow to perform a tumor-orientated therapy and to compare patient groups which have been treated in different institutions according to similar or different therapeutic regimens. This includes the importance of a TNM-oriented therapy. It has to be stressed though that the prevalence of distinct pathological changes, such as bone metastases in T1 tumors, as well as financial resources, have to be taken into account. Further, definite therapeutic intention such as a curative vs. palliative regimen is a decisive criterium for the amount of performed diagnostic procedures. It also is of importance that new diagnostic modalities, if introduced into the clinical routine, have to be investigated concerning their validity in relevant and large patient cohorts and their rationale in our diagnostic algorithm has to be defined. This is predominantly not the case in radiological imaging techniques and thus a large amount of resources are wasted.

Cytokeratin markers in patients with prostatic diseases.

OBJECTIVES: Recently tissue polypeptide specific antigen (TPS), a cytokeratin 18 marker, was described to be discriminative between cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Cyfra 8/18, a marker which recognizes both cytokeratin 8 and 18 fragments, is thought to improve sensitivity and specificity of TPS. In our study we investigated the ability of the TPS and cyfra 8/18 serum concentration to discriminate between patients with clinically localized CaP and BPH. METHODS: Serum levels of TPS and Cyfra 8/18 were determined in patients with untreated CaP (pT1-3pNoMo: n = 11) and BPH (n = 22). The TPS and the Cyfra 8/18 concentrations were correlated to the prostate specific antigen (PSA) serum concentration. RESULTS: Median TPS concentration was 45.3 U/L in CaP-patients and 54.8 U/L in BPH-patients. This difference is statistically not significant (p = 0.2). Median Cyfra 8/18 level was 0.64 ng/mL in CaP-patients and 0.57 ng/mL in BPH-patients. This difference is statistically not significant (p = 0.91). Furthermore no correlation with PSA levels could be established (TPS: r = -0.13; Cyfra 8/18: r = 0.17). CONCLUSION: In contrast to recent reports we found both cytokeratin markers, TPS as well as Cyfra 8/18, to be non-discriminative parameters in CaP and BPH.

Cytogenetic analysis of 11 renal oncocytomas: further evidence of structural rearrangements of 11q13 as a characteristic chromosomal anomaly.

We carried out cytogenetic analysis on 11 renal oncotytomas by using G-banding and DAPI-banding techniques. Four of our tumors exhibited structural rearrangements affecting chromosome 11 at band q13. Together with another case previously described by us, our tumors constitute the largest series of renal oncocytomas displaying translocations involving 11q13. A review of the literature disclosed only 6 similar oncocytomas, 1 tumor with a t(9;11)(p23;q12), 2 tumors with a nearly identical t(9;11)(p23;q13), and 3 tumors with a t(5;11)(q35;q13). Therefore, our findings provide further cytogenetic evidence that genes located on 11q12-13 may be involved in the tumorigenesis of renal oncocytomas.

Efficacy of skeletal alkaline phosphatase and prostate-specific antigen in the diagnosis of bone metastasis in cancer of the prostate.

PURPOSE: To study the efficacy of prostate-specific antigen (PSA) and skeletal alkaline phosphatase (SAP) as staging markers in discriminating patients with cancer of the prostate (CaP) with (M+) and without bone metastases (M0). MATERIAL AND METHODS: 73 patients with untreated CaP entered the study. After staging the patients were divided into 3 groups: group I, patients with CaP and bone metastases (n = 21); group II, patients with locally advanced CaP without bone metastases (n = 26), and group III, patients with clinically localized CaP without bone metastases (n = 26). RESULTS: None of the M0 patients but 71% of the M+ patients exhibited an increased SAP. A corresponding cutoff point of 100 ng/ml for PSA showed that 19% of M0 patients and 71% of the M+ patients exhibited a value of >100 ng/ml. This resulted in a sensitivity and specificity of 71 and 100% of SAP and 71 and 81% for PSA, respectively. CONCLUSION: SAP could become a useful marker in the evaluation of patients with newly diagnosed CaP as it provides additional information concerning the skeletal status of these patients.

Cytokeratin 8/18 levels in patients with prostate cancer and benign prostatic hyperplasia.

OBJECTIVES: Recently, tissue polypeptide-specific antigen (TPS), a cytokeratin 18 marker, was described to be discriminative between cancer of the prostate (CaP) and benign prostatic hyperplasia (BPH). Cyfra 8/18, a marker which recognizes both cytokeratin 8 and 18 fragments, is discussed to improve sensitivity and specificity of TPS. We investigated whether Cyfra 8/18 serum concentration discriminates between patients with clinically localized CaP and BPH. METHODS: Serum Cyfra 8/18 levels were determined in patients with untreated CaP before radical prostatectomy (pT1-3pNoMo; n = 11) and with histologically confirmed BPH (n = 22). Cyfra 8/18 concentration was correlated to the prostate-specific antigen (PSA) concentration. RESULTS: Median Cyfra 8/18 level was 0.64 ng/ml in CaP patients and 0.57 ng/ml in BPH patients. This difference is statistically not significant (p = 0.91). Furthermore, no correlation to PSA levels could be established (CaP: r = 0.036; BPH: r = 0.09). CONCLUSION: In contrast to a recent report we found the Cyfra 8/18 serum concentration to be a nondiscriminative parameter between CaP and BPH.

Biocompatibility, cell adhesion, and degradation of surface-modified biodegradable polymers designed for the upper urinary tract.

OBJECTIVES: The aim of this study was to develop a short bioresorbable ureteric stent and to characterize polymers and their surface modifications with respect to biocompatibility, degradation kinetics, cell adhesion properties, and incorporation of biologically active substances. Poly(D,L-lactide) PDLLA, poly(D,L-lactide-co-glycolide) PDLLA-co-GLY, and poly(D,L-lactide-co-trimethylenecarbonate) PDLLA-co-TMC were chosen as basic polymers. Surface modification was performed by plasma-induced graft polymerization and included grafting with hydroxyethylmethacrylate (HEMA), oligo(ethyleneoxide)-monomethacrylate (OEOMA), and acrylic acid (AAC). Biocompatibility of the polymers was assessed in vitro applying parameters of cell morphology, proliferative activity, and cell adhesion. All polymers were biocompatible and exerted no toxic effect on urothelial cell lines and on primary human urothelial cell cultures. A markedly reduced cell adhesion could be achieved in polymers grafted with HEMA, OEOMA, and AAC. Our results indicate that surface modification of bioresorbable polymers by grafting with HEMA, OEOMA, or AAC is an efficient approach to improve surface properties with respect to biocompatibility and cell adhesion properties.

Computed tomography characterization of renal cell tumors in correlation with histopathology.

RATIONALE AND OBJECTIVES: The authors distinguish the histomorphologic subtypes of renal cell tumors (RCTs) by computed tomography (CT). METHODS: In a consensus conference between radiologists, pathologists, and urologists, the CT criteria of the various subtypes of RCTs (clear cell, chromophilic cell, chromophobic cell renal carcinoma and oncocytoma) were established. Computed tomography scans of 65 resected RCTs were reevaluated independently by seven radiologists. Using a numerical scoring system, they first attempted to differentiate clear cell from nonclear cell RCTs. A further attempt then was made to classify each tumor into one of the four categories. RESULTS: The sensitivity for the diagnosis of clear cell RCT was 72.5% (213 of 294 true-positive findings) and 82% (132 of 161 true-positive findings) for the nonclear cell group. For tumors more than 3 cm in diameter the sensitivities were 80.25% for the clear cell group and 80.7% for the nonclear cell group. Specific differentiation into the four subtypes was not possible. Oncocytomas were classified correctly in only 6 of 49 observations (12.2%). CONCLUSIONS: Small clear cell tumors often fail to show the CT characteristics that would permit an accurate classification. In tumors measuring 3 cm or more, differentiation between clear cell and nonclear cell types by means of CT criteria is possible. Nevertheless, as RCTs show a great variation in appearance, a differentiation into subtypes of the nonclear cell RCTs cannot be accomplished by CT. Using a uniform examination protocol and spiral scanning technique, the sensitivity of CT in the diagnosis of the subtypes of RCTs may be able to be further increased. Some tumors, especially oncocytomas, undoubtedly will remain diagnostic dilemmas.

Inflammatory pseudotumor of the epididymis.

We report the case of a 73-year-old patient who presented clinically with a palpable left scrotal mass after a 3-month history of therapy-resistant epidiymitis. He underwent epidiymectomy, and the following histopathologic and immunohistochemical evaluation revealed an inflammatory pseudotumor. We present the second case of an inflammatory pseudotumor of the epididymis being reported in the literature and give a brief review of the literature concerning this very rare neoplastic entity.

Seizures associated with cisplatin administration.

A 50-year-old patient with a diagnosis of a primary extragonadal germ cell tumor received cisplatin-containing polychemotherapy and developed seizures after the first course of drug administration. We discuss this very rare toxic side effect of cisplatin and present a review of the literature concerning the experience with neurotoxic effects exerted by this agent.