G. Jakse

Guidelines on Bladder Cancer

OBJECTIVES On behalf of the European Association of Urology (EAU) guidelines for diagnosis, therapy and follow-up of bladder cancer patients were established. Criteria for recommendations were evidence based, and included aspects of cost-effectiveness and clinical feasibility. METHOD A systematic literature research using Medline Services was conducted. References were weighted by a panel of experts. RESULTS TNM 1997 classification and WHO grading 1998 are recommended. Recommendations are developed for diagnosis for bladder cancer in general, treatment of superficial and infiltrative bladder cancer, and follow-up after different types of treatment modalities, such as intravesical instillations, radical cystectomy, urinary diversions, radiotherapy and chemotherapy.

The updated EAU guidelines on muscle-invasive and metastatic bladder cancer.

CONTEXT New data regarding diagnosis and treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. OBJECTIVE To review the new EAU guidelines for MiM-BC. EVIDENCE ACQUISITION A comprehensive workup of the literature obtained from Medline, the Cochrane central register of systematic reviews, and reference lists in publications and review articles was developed and screened by a group of urologists, oncologists, and radiologist appointed by the EAU Guideline Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SYNTHESIS The diagnosis of muscle-invasive bladder cancer (BCa) is made by transurethral resection (TUR) and following histopathologic evaluation. Patients with confirmed muscle-invasive BCa should be staged by computed tomography (CT) scans of the chest, abdomen, and pelvis, if available. Adjuvant chemotherapy is currently only advised within clinical trials. Radical cystectomy (RC) is the treatment of choice for both sexes, and lymph node dissection should be an integral part of cystectomy. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for clinical or personal reasons. An appropriate schedule for disease monitoring should be based on (1) natural timing of recurrence, (2) probability of disease recurrence, (3) functional deterioration at particular sites, and (4) consideration of treatment of a recurrence. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin is cisplatin-containing combination chemotherapy. Presently, there is no standard second-line chemotherapy. CONCLUSIONS These EAU guidelines are a short, comprehensive overview of the updated guidelines of (MiM-BC) as recently published in the EAU guidelines and also available in the National Guideline Clearinghouse.

Metabolic Imaging of Untreated Prostate Cancer by Positron Emission Tomography with sup 18 Fluorine-Labeled Deoxyglucose

PURPOSE We evaluated positron emission tomograph (PET) with 18fluorine (18F)-labeled deoxyglucose for metabolic grading of untreated primary prostate cancer, and differentiation of benign and malignant prostatic disease. MATERIALS AND METHODS A total of 48 patients with untreated prostate cancer of different stages and 16 with histologically confirmed benign prostatic hyperplasia (BPH) underwent static PET after intravenous injection of 150 to 300 MBq. 18F-deoxyglucose. 18F-deoxyglucose accumulation was quantitated by calculating differential uptake ratios and prostate-to-skeletal muscle ratios. RESULTS Low 18F-deoxyglucose uptake was noted in the majority of primary tumors (81%). 18F-deoxyglucose accumulation did not correlate with increasing tumor grade or stage. There was a significant overlap in uptake values in BPH and malignant prostatic disease. A trend towards statistical significance was noted with lower prostate-to-skeletal muscle ratios in patients with BPH (p < 0.07). Increased 18F-deoxyglucose accumulation was detected in some patients with BPH and malignant prostatic disease, as well as in those with lymph node and bone metastases of prostate cancer. CONCLUSIONS 18F-deoxyglucose PET does not allow for metabolic labeling in the majority of untreated primary prostate cancers. BPH and primary prostate cancer cannot be reliably differentiated on the basis of PET. Increased 18F-deoxyglucose accumulation occurs in some primary prostate tumors and in metastatic deposits of prostate cancer.

Does positron emission tomography using 18-fluoro-2-deoxyglucose improve clinical staging of testicular cancer?— results of a study in 50 patients

OBJECTIVES To compare positron emission tomography (PET) using 18-fluoro-2-deoxyglucose (FDG) with conventional clinical staging in unselected patients with germ cell cancer. METHODS Fifty patients underwent PET scans of the abdomen (n = 50) and chest (n = 41 ) after the initial diagnosis. PET images were evaluated qualitatively and quantitatively using standardized uptake values (SUVs). The results were compared with computed tomography (CT) results and tumor markers (human chorionic gonadotropin, alpha-fetoprotein, and lactate dehydrogenase). Retroperitoneal lymphadenectomy in 12 patients and clinical staging, including follow-up data in all patients, were taken as a reference standard. RESULTS PET detected metastases in 13 (87%) of 15 patients and excluded metastases in 33 (94%) of 35 patients. A sensitivity of 73% and a specificity of 94% were obtained using CT. The respective values for tumor marker determination were 67% and 100%. Retroperitoneal metastases were detected in 2 patients by PET only and in 1 patient by CT only. In the latter patient, surgery of a residual mass after chemotherapy revealed a well-differentiated teratoma. False-negative findings with PET and CT occurred in 2 patients with retroperitoneal metastases approximately 10 mm in size. False-positive findings were due to sarcoidosis or to muscular activity of the neck. Quantitative FDG uptake was very heterogeneous, with an SUV ranging from 1.8 to 17.3. CONCLUSIONS FDG PET has the potential to improve clinical staging of testicular cancer. However, PET, as well as CT, is limited in the detection of small retroperitoneal lymph node metastases.

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.

Is Prostate-Specific Antigen a Reliable Marker of Bone Metastasis in Patients with Newly Diagnosed Cancer of the Prostate?

Objective: Staging in patients with newly diagnosed cancer of the prostate has significant ramifications in the management of the disease. At present, measurement of serum prostate-specific antigen (PSA) concentration and radionuclide bone scintigraphy are two important procedures in the metastatic workup of these patients. We evaluated the efficacy of PSA as a staging marker to discriminate prostate cancer patients with and without bone metastases. Methods: In a retrospective study, 359 prostate cancer patients with (n = 40) and without (n = 319) bone metastases were analyzed. In all patients the initial PSA measurement as well as the radionuclide bone scan were evaluated. Results: Patients without bone metastases demonstrated a median serum PSA concentration of 12 ng/ml, whereas those with bone metastases revealed a median serum PSA concentration of 59 ng/ml, with 7 patients demonstrating a serum PSA concentration of <10 ng/ml. This resulted in a negative predictive value of 96%. In addition, only 40% of these patients with bone metastases demonstrated a serum PSA concentration of >100 ng/ml, which resulted in a positive predictive value of 50%. Conclusion: The serum PSA concentration seems only to provide limited information with regard to the presence of bone metastasis in patients with newly diagnosed cancer of the prostate. We therefore question whether a staging radionuclide bone scan may be omitted in patients with a serum PSA value of <10 ng/ml.

Serum Proteomic Profiling in Patients with Bladder Cancer

BACKGROUND Despite continuing research for accurate bladder cancer biomarkers, the analytes suffer from lack of sensitivity and specificity. OBJECTIVE To search for discriminating protein patterns in serum, we used magnetic bead-based separation followed by matrix-assisted laser desorption ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) to identify patients with bladder cancer. DESIGN, SETTING AND PARTICIPANTS In total, serum samples from 105 patients with bladder cancer, 98 healthy controls, and 45 prostate cancer patients were included in this study. MEASUREMENTS Serum samples were fractionated by means of surface-activated magnetic beads and were subsequently analyzed with MALDI-TOF MS. Multidimensional data analysis was done to generate algorithms capable of distinguishing between cancer patients and healthy individuals. The algorithms were trained using a training set of 41 bladder cancer patients and 39 healthy controls and were validated with an independent test set of 64 bladder cancer patients and 59 healthy controls. Additionally, 45 prostate cancer samples were used as a third test set. RESULTS AND LIMITATIONS In the training set, patients with bladder cancer could be identified with an overall sensitivity of 94.1% and specificity of 89.2%. Similar results could be achieved for the test set, showing 96.4% sensitivity and 86.5% specificity. Even the presence of low-stage tumors could be predicted with 96% sensitivity and could be distinguished from higher stage or grade tumors with a sensitivity of 77.3%. Distinction between other tumor stages, however, resulted in lower sensitivity values. CONCLUSIONS These findings demonstrate that screening for serum protein patterns using MALDI-TOF MS shows high sensitivity and specificity in identifying patients with bladder cancer, regardless of tumor stage. Due to high-throughput capability, the identified differential protein panel may improve the detection of bladder cancer.

Visualization of the Basement Membrane Zone of the Bladder by Optical Coherence Tomography: Feasibility of Noninvasive Evaluation of Tumor Invasion

OBJECTIVES Imaging techniques with high resolution are evolving rapidly for medical applications and may substitute invasive diagnostic techniques. The use of ultrahigh resolution optical coherence tomography (UHR-OCT) to image healthy and morphologically altered bladder tissue with virtual histology is evaluated ex vivo to define parameters necessary for future, diagnostically relevant in vivo systems. Here, special focus is on the visualization of the basement membrane zone. METHODS Optical coherence tomography examinations were performed by using a modified commercial OCT system comprising a Ti:sapphire femtosecond laser to support an enhanced resolution of 3 microm axial x 10 microm lateral. Tomograms of 142 fresh human bladder tissue samples from cystectomies, radical prostatectomies, and transurethral tumor resections were recorded and referenced to histologic sections using standard hematoxylin and eosin staining. RESULTS OCT of normal bladder mucosa allows for a clear differentiation of urothelium and lamina propria. The basement membrane zone is identified as a narrow, low-scattering band between these layers. This allows for reliable exclusion of invasion. Healthy urothelial tissue, carcinoma in situ, and transitional cell carcinoma can be differentiated using this imaging technique. Sensitivity of UHR-OCT for malignant bladder tissue could be determined to be 83.8%, and specificity to be 78.1%. CONCLUSIONS UHR-OCT is considered promising in the attempt to strive for fluorescence cystoscopy-guided virtual histology as a means of supporting therapeutic decisions for bladder neoplasia.

The human urothelium consists of multiple clonal units, each maintained by a stem cell

Little is known about the clonal architecture of human urothelium. It is likely that urothelial stem cells reside within the basal epithelial layer, yet lineage tracing from a single stem cell as a means to show the presence of a urothelial stem cell has never been performed. Here, we identify clonally related cell areas within human bladder mucosa in order to visualize epithelial fields maintained by a single founder/stem cell. Sixteen frozen cystectomy specimens were serially sectioned. Patches of cells deficient for the mitochondrially encoded enzyme cytochrome c oxidase (CCO) were identified using dual‐colour enzyme histochemistry. To show that these patches represent clonal proliferations, small CCO‐proficient and ‐deficient areas were individually laser‐capture microdissected and the entire mitochondrial genome (mtDNA) in each area was PCR amplified and sequenced to identify mtDNA mutations. Immunohistochemistry was performed for the different cell layers of the urothelium and adjacent mesenchyme. CCO‐deficient patches could be observed in normal urothelium of all cystectomy specimens. The two‐dimensional length of these negative patches varied from 2–3 cells (about 30 µm) to 4.7 mm. Each cell area within a CCO‐deficient patch contained an identical somatic mtDNA mutation, indicating that the patch was a clonal unit. Patches contained all the mature cell differentiation stages present in the urothelium, suggesting the presence of a stem cell. Our results demonstrate that the normal mucosa of human bladder contains stem cell‐derived clonal units that actively replenish the urothelium during ageing. The size of the clonal unit attributable to each stem cell was broadly distributed, suggesting replacement of one stem cell clone by another. Copyright

Computed tomography for detection and staging of transitional cell carcinoma of the upper urinary tract

A total of 91 patients were treated for upper tract urothelial tumors between 1981 and 1991. Preoperative computed tomography (CT) scans and nephroureterectomy for treatment of transitional cell carcinoma were performed in 26 patients. At pathological examination, 28 tumors were diagnosed of which 19 were in the renal pelvis and 7 were in the ureter. Intravenous pyelogram, retrograde and antegrade pyelogram detected 26 of 28 tumors (93%). CT detected 24 of 28 tumors (86%). However, CT is still the best current method for staging of upper urinary tract urothelial tumors, although staging was correct in only 5 of 9 T3 and T4 tumors.