Correlation of pathological and cytological-cytometric grading of transitional cell carcinoma of the urinary tract.

INTRODUCTION: Cystoscopy and cytology are standard procedures for diagnosis and follow-up of patients with bladder cancer. Urinary cytodiagnosis is a descriptive method for tumor characterization. We correlated histopathologic diagnosis of noninvasive urothelial carcinomas with cytological evaluation and, furthermore, we validated cytology by cytometric analysis. PATIENTS AND METHODS: 94 patients with a history of bladder cancer were included in the study. 25 patients were negative for tumors, 22 showed pTa G1 carcinomas, 25 had pTaG2 and 22 patients had G3 carcinomas. All patients underwent cytological and cytometric evaluation. Nuclear diameter and circumference were measured for 15 representative nuclei per specimen. Statistical evaluation was performed using Graph Pad Software. RESULTS: Cytology showed excellent tumor detection for G2 and G3 carcinomas, with a sensitivity of 100% combined with a specificity of 100%. Using cytometry, we can significantly distinguish between unsuspicious patients and G1 carcinomas on the one hand and high-grade carcinomas on the other. Furthermore, in 6 of 25 patients (24%) with noninvasive G2 carcinomas, but G3 cytological evaluation, tumor progression occurred. CONCLUSIONS: Urinary cytology is an excellent instrument for detection of clinically relevant high-grade bladder cancer. Descriptive alterations of the cytopathology can be validated by objective data using cytometric analysis.

The f/t-PSA ratio in diagnosis of in-patients and out-patients: a unitary cutoff value is not useful!

PURPOSE: In the prostate specific antigen (PSA) range of 4-10 ng/ml after a negative digital rectal examination, the PSA value indicates a lack of specificity with a carcinoma detection rate of roughly 20%. To improve the biopsy/carcinoma ratio, the interdisciplinary consensus recommends free PSA (fPSA) measurement. This does not take into account the pre-analysis when the cutoff value is established for biopsy indication. METHODS: In the present study, an in-patient cohort whose blood samples were immediately analysed was compared with an out-patient cohort whose sample processing was delayed by between 24 and 48 h. RESULTS: The in-patient cohort comprises 382 patients with 99 prostate carcinomas, the out-patient cohort 987 patients with 235 carcinomas. In the in-patient cohort a sensitivity of 90% with a cutoff value of 25% for the f/t-PSA ratios is achieved with the theoretical possibility of reducing the number of punch biopsies by 34.6%. A sensitivity of 90% in the out-patient cohort necessitates a cutoff value of 18% for the f/t-PSA ratios. The specificity is 35.3% with a possible biopsy reduction of 29.1%. CONCLUSIONS: The cutoff values from cohorts with an immediate fPSA measurement cannot be adopted for a typical out-patient cohort whose analyses are delayed. On the contrary, an individual adjustment is necessary which corresponds to the pre-analysis.

[Value of targeted therapy for prostate cancer]. / Der Stellenwert der Targeted-Therapie beim Prostatakarzinom.

Prostate cancer is the most frequent malignancy of the male population. Every year in Germany approximately 12,000 patients die of their hormone-refractory prostate cancer even though early detection is able to find more curable prostate cancers. In a hormone-refractory stage we only have limited options for treatment. Although docetaxel is currently the standard of care in most hormone-refractory prostate cancers, it is not the magic therapy that will dramatically change the patient's poor survival. This drug provides an overall survival advantage of 2 months. During recent years, significant progress has been made in the field of molecular therapy in urologic oncology. Targeted therapy leads to an inhibition of angiogenesis and proliferation in malignant tumors. Even if there is a great theoretical potential, mono- and combination therapies with target substances are not relevant in the clinical routine.

[Targeted therapy for metastatic bladder cancer]. / Targeted-Therapie des metastasierten Urothelkarzinoms.

The current therapy concept for metastatic bladder cancer is chemotherapy with gemcitabine and cisplatin as the first line protocol. Within the last 20 years no real progress could be achieved; the median survival is 14 months, though many different protocols have been tested. Expression analyses of growth factor receptors in human tumor tissue showed that expression of certain receptors is correlated with a severe clinical course.For many of these growth factor receptors pharmacological inhibitors are available in order to perform targeted therapy. The following review gives a survey of current studies on targeted therapy of metastatic bladder carcinoma.

[From marker expression to individual therapy of patients with bladder cancer]. / Von der Markerexpression zur individuellen Prognoseabschätzung urothelialer Neoplasien.

Urothelial carcinoma of the bladder is a tumor entity with a heterogenous clinical course. At one end of the spectrum, patients are treated for low-grade carcinomas, which are likely to reccur but show low rates of tumor progression. At the other end, patients suffer from noninvasive or early invasive high-grade carcinomas. In these cases, risk-adapted treatment decisions are more complicated. The following article gives an overview of research activities on bladder cancer with the aim to individualize treatment of patients with bladder cancer.

[Palliative therapy concepts for patients with urothelial cancer of the urinary bladder]. / Palliative Therapiekonzepte bei Patienten mit Urothelkarzinom der Harnblase.

Urothelial carcinoma usually occurs in older patients. At initial diagnosis, about 30% of all patients show muscle invasive tumor growth or metastases. Due to their advanced clinical stage, palliative therapy concepts become more and more interesting. Gross and intractable hematuria can be treated with special bladder irrigation or selective arterial embolization. Hydronephrosis can be treated in the long-term with self-expanding memotherm stents. Palliative pelvic radiation is still controversial.

[The management of cutaneous metastases]. / Management kutaner Metastasen.

Cutaneous metastases are rare and usually signify a poor prognosis. The manifestation of cutaneous metastases is variable; crucial to their diagnosis is their inclusion in the differential diagnosis. The therapy occurs mostly with palliative intention. The quality of life of the patient should take first priority. A combination chemotherapy is usually carried out because of systemic progress. For local tumor control and wound care, metastasis surgery and radiotherapy are used.

[Is there an indication for adjuvant or neoadjuvant systemic therapy in prostate cancer?]. / Gibt es eine Indikation für eine adjuvante oder neoadjuvante Systemtherapie beim Prostatakarzinom?

In the meantime prostate cancer has become the most common malignancy in the male population. Due to the shift in age at the time of first diagnosis in favour of younger men with a high life expectancy and a maximum of physical and sexual activity it would be desirable to have neoadjuvant or adjuvant therapy concepts at hand which lead to an improvement of therapeutic success. So far the results of studies for adjuvant and neoadjuvant hormonal ablation therapy concepts have not led to a clear therapeutic reference. Only before radiation therapy is neoadjuvant hormonal ablation a standard part of therapy at most centres. Existing data for chemotherapeutic concepts are limited to androgen-independent advanced prostate cancer. An international study using docetaxel as an adjuvant drug is currently being performed, but the results are not yet available.

[Use of silicon chip technology to detect protein-based tumor markers in bladder cancer]. / Einsatz der Siliziumchiptechnologie zur Detektion von Tumormarkern auf Proteinbasis beim Harnblasenkarzinom.

The protein structure of human tumor tissue has a significant influence on the molecular attributes. It was demonstrated that the individual prognosis of tumor patients is among other things dependent on molecular tumor tissue characteristics.A promising marker is E-cadherin, an adhesion glycoprotein which plays a central role in the mediation of cell-cell contacts. Aberrant E-cadherin expressions were described in several tumors such as in bladder cancer. This was also found to be correlated with tumor invasion and survival. There are hardly any fast, quantitative and easily automated protein assays in everyday practice which can analyze several markers at the same time. With silicon chip technology we have a new detection and measurement method which makes it possible to give a quantitative analysis of numerous different proteins in tissue, urine, or serum in a few minutes.

[Immunotherapy of metastatic renal cell carcinoma with interleukin-2, interferon-alpha2a and erythropoietin-beta]. / Immuntherapie des metastasierten Nierenzellkarzinoms mit Interleukin-2, Interferon-alpha2a und Erythropoetin-beta.

BACKGROUND: The combination of interferon-alpha2a (IFN-alpha2a) and interleukin-2 (IL-2) induces objective responses in patients with metastatic renal cell carcinoma (MRCC). Anaemia is associated with poor cancer control and reduced quality of life. The aim of the study was to investigate response rate and quality of life in patients with MRCC receiving the combination of Erythropoetin, IFN-alpha2a and IL-2. MATERIAL AND METHOD: Patients with MRCC received epoetin beta (150 IU/kg and haemoglobin <130 g/l or 75 IU/kg and haemoglobin >or=130 g/l) three times weekly, from 14 days before and continuing throughout immunotherapy. In weeks 3-6 the patients received IFN-alpha2a 6 x 10(6) IU/m2 and IL-2 4.5 x 10(6) IU/m2 three times weekly on days 1, 3 and 5. The treatment was repeated two times and in the case of success a third cycle was added. The quality of life was assessed with the FACT questionnaire for fatigue, before, during and after therapy. RESULTS: A total of 21 patients were treated, 19 of whom could be evaluated concerning response, toxicity and quality of life. We observed 1 complete remission, 2 partial remissions, 5 cases of stable disease and 11 with progressive disease. The overall response rate was 16%. Toxicity was mild to moderate; there were no WHO grade III or IV toxicity. The quality of life increased in ten patients, nine of whom exhibited an increase in their haemoglobin during therapy. Five of the nine patients with decreased quality of life also experienced a decrease in their haemoglobin. The correlation of increased haemoglobin and quality of life was significant (p<0.05). CONCLUSION: The combination of IFN-alpha2a, IL-2 and epoetin beta resulted in objective remissions with mild to moderate toxicity. The quality of life correlates significantly with increasing haemoglobin.

[Comparison of perioperative methylene blue-stained and permanent Papanicolaou-stained urine cytology to detect patients with high-grade urothelial cancer or the urinary bladder. Part 1]. / Sofort-Zytologie vs.Papanicolaougefärbte Zytologie in der Diagnostik von Urothelkarzinomen. Teil 1.

INTRODUCTION: The aim of the study was to investigate whether intraoperative methylene blue-stained and permanent Papanicolaou-stained urine cytologies show comparable accuracy in detection of high-grade urothelial carcinoma. PATIENTS AND METHODS: The study included 130 patients; 50 patients were without malignancy (25 follow-up, 25 with hematuria). In 80 patients transurethral resection due to urothelial carcinoma was performed. Per patient two cytology specimens were prepared: one immediate methylene blue-stained specimen, which was evaluated by the surgeon, and one Papanicolaou-stained permanent cytology slide, which was blinded and evaluated by one urologist. RESULTS: Cytology results of all patients without malignancy were unsuspicious irrespective of the staining method. Of 80 patients with urothelial carcinoma, 50 showed a low-grade tumor. Sensitivity of tumor detection was 20 and 30% for methylene blue/Papanicolaou-stained slides, respectively. Among 30 patients with high-grade carcinoma, 10 were detected by methylene blue cytology and 30 by Papanicolaou-stained slides, corresponding to a sensitivity of 40 and 100%, respectively. CONCLUSIONS: The results of standard Papanicolaou-stained urine cytology in the detection of clinically relevant high-grade urothelial carcinoma are excellent. The quality of cytological tumor detection by methylene blue-stained cytology made by different evaluators is insufficient in our opinion.

[Proapoptotic antibodies as new therapeutic agents for tumor treatment]. / Proapoptotische Antikörper als neue Tumortherapeutika.

To convert the concept already successful in mice into clinical practice and commercialize it, a human anti-CD95-antibody must be produced. In a second step experiments must be performed on various normal healthy cells and tissues to determine whether these human anti-CD95-antibodies administered in very low doses have any effect on human cells (particularly hepatocytes) or at least cause only minimal side effects. If these studies yield positive results, then clinical trials can be conducted in which increasing doses are given to exclude an acute hepatotoxic effect and then the effect exerted by the antibody in combination with irradiation on tumor growth can be investigated.The advantage of this concept lies in the fact that systemic stimulus (low doses of anti-CD95-antibodies) is highly intensified by local radiotherapy and only then initiates cell death. Since the anti-CD95-antibodies trigger apoptosis primarily in tumor endothelia, this approach could be employed not only for prostate cancer and melanomas, which have already been tested, but also for many other tumors.

[Therapeutic options for hormone-refractory prostate cancer]. / Therapieoptionen beim hormonrefraktären Prostatakarzinom.

For a long time, hormone-refractory prostate cancer was regarded as a chemoresistant tumor. The introduction of taxanes has prompted a change in this opinion. For the first time treatment with 75 mg/m(2) docetaxel every 3 weeks has evidenced a survival benefit in a phase III trial (median survival of 18.9 months versus 16.5 months with mitoxantrone). Further advantages were improved pain reduction and quality of life. Neutropenia was foremost among the side effects. Docetaxel is currently the standard treatment for hormone-refractory prostate cancer. The morbidity of metastatic hormone-refractory prostate cancer is influenced by bone metastases. Pain is a prominent feature. Skeletal complications are frequent. Therapy with 4 mg zoledronic acid reduced skeletal complications significantly in comparison to placebo. The most pronounced effect is the reduction of pathological fractures. Side effects include flu-like symptoms, muscle pain, and edemas. Zoledronic acid also belongs to the standard treatment of hormone-refractory prostate cancer with bone metastases.

[Treatment costs of localized prostate cancer in Germany : Economic results from the HAROW observational study]. / Behandlungskosten des lokal begrenzten Prostatakarzinoms in Deutschland : Ökonomische Ergebnisse der HAROW-Beobachtungsstudie.

BACKGROUND: Prostate cancer (PCa) is the most common cancer in men. For medical treatment of PCa, a number of therapies are available. The economic consequences associated with these individual treatment options in routine care in Germany are unclear so far. METHODS: The present analysis was based on the Germany-wide HAROW observational study, which was conducted from 2008-2013. During this study, all participating physicians and involved patients reported and documented individual health care resource consumption. These data were evaluated in monetary terms stratified by treatment regime (hormone therapy, HT; active surveillance, AS; radiotherapy, RT; radical prostatectomy, RP; watchful waiting, WW). RESULTS: Overall, the data of 2672 patients were available for analysis. Based on the observational study design, the included patient groups were heterogeneous in their baseline characteristics. The annual total costs from the societal perspective were the largest for patient undergoing RP (9254 €; 95 % CI 8353-10,154), mainly driven by the costs for the initial hospital stay for surgery. HT, AS, RT, and WW seem to be comparable in terms of direct costs, ranging from 805 € (95 % CI 154-1455) for WW up to 1115 € (95 % CI 826-1405) for RT. The highest indirect costs were observed for patients receiving RT (3928 €; 95 % CI 0-10,675), which can be justified by the frequent incapacity to work in this patient group. CONCLUSION: The treatment of prostate cancer can lead to significant economic follow-up costs which vary greatly depending on the type of treatment. The analysis indicates a need for the implementation of a long-term health economic study in the future, which will be more suitable to show treatment-specific differences in the temporal occurrence of costs.

[Inhaled immunotherapy for pulmonary metastases of renal cell cancer]. / Inhalative Immuntherapie beim pulmonal metastasierten Nierenzellkarzinom.

Studies on immunotherapy with inhaled interleukin-2 (IL-2) for the treatment of pulmonary metastases in renal cell carcinoma patients have indicated objective response rates of 11%. The aim of the present study was to evaluate efficacy, toxicity, and quality of life during inhaled immunotherapy with IL-2. Patients with pulmonary metastases of renal cell carcinoma were treated with interferon-alpha (IFN-alpha) 3 x 10(6) IU/m(2) s.c. on days 1, 3, and 5 and inhaled twice a day 9 x 10(6) IU IL-2 on days 1-5. Treatment continued for 4 weeks and after a 2-week rest a second cycle was given. Patients who responded received two additional cycles. Quality of life was assessed according a self-administered quality of life questionnaire (QLQ-C30) before, during, and after therapy. Of 23 treated patients, 21 could be evaluated concerning response rate and toxicity [16 men, 5 women; median age: 60 years (38-72 years)]. Sixteen patients had pulmonary metastases only and five patients additionally had bone or liver metastasis or local recurrence. One patient (5%) developed a partial remission for 4 months and ten patients (47.5%) showed a stable disease for a median time of 6 months (2-24 months). The median follow-up was 9 months (3-26 months). Ten patients (47.5%) developed progressive disease. Maximal toxicity was mild and grade III-IV toxicity (WHO) was not observed. The patients' quality of life did not change significantly at any time during therapy. Inhaled immunotherapy is a treatment option with little toxicity, but achieved only a few objective responses. Whether or not it influences overall survival could not be answered in this study.

[Transforming growth factor ß in prostate cancer: cellular effects and basic molecular mechanisms]. / "Transforming growth factor ß" im Prostatakarzinom : Zelluläre Wirkungen und molekulare Grundlagen.

The multifunctional cytokine transforming growth factor ß (TGFß) plays a dual role in prostate cancer (PCa), cell growth and tumorigenesis, reflected by its opposing properties of anti-oncogenic (e.g. growth inhibition and apoptosis) and pro-oncogenic effects (e.g. proliferation, cell motility and remodelling of the microenvironment). In the later stages of PCa, TGFß loses anti-proliferative and thereby tumor-suppressive functions and shifts to a tumorigenic phenotype, mainly initiated by cross-talk between TGFß signalling and other proliferation signal transduction pathways, such as mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signalling. Although TGFß plays an important role in tumor progression little is known about the underlying effects of TGFß in the molecular pathology of PCa.

[Second line therapy for castration-resistant prostate cancer (CRPC)]. / Zweitlinientherapie beim kastrationsresistenten Prostatakarzinom (CRPC).

Every year in Germany approximately 12,000 men die of castration-resistant prostate cancer even though early detection using PSA-based diagnostics allows more patients to be diagnosed with a curable cancer. An established first line therapy at this stadium is docetaxel chemotherapy, given in a 3-week regimen, providing an overall survival advantage of 2 months. In 6-9 months, the patients treated primarily with docetaxel will progress to a docetaxel-insensitive phase which requires a secondary systemic therapy. Increasing understanding of molecular signal transduction has permitted a growing variety of promising modern drugs, including cabazitaxel, sipuleucel-T and abiraterone. More prospective clinical data will provide a large variety of different therapy combinations, sequence therapies or other therapy regimens particularly for selected subgroups of patients with castration-resistant prostate cancer.

[Parameters to improve the specificity of the prostate-specific antigen. Early detection of prostate cancer]. / Parameter zur Verbesserung der Spezifität des prostataspezifischen Antigens. Früherkennung des Prostatakarzinoms.

PURPOSE: The aim of the study was to improve the case detection rate of prostate cancer for patients who had unremarkable palpation findings and a PSA value in the range of 4 to 10 ng/ml by combination of the parameters total PSA (tPSA), f/tPSA ratio, prostate volume, PSA density, patient's age and transrectal ultrasound findings. METHODS: Sextant biopsy of the prostate was performed for 619 patients aged 45-75 years who had unremarkable palpation findings and PSA values in the range of 4 to 10 ng/ml. The f/tPSA ratio was determined, transrectal ultrasound examination was performed, the prostate volume was measured and the PSA density calculated. The relationship between the various test variables - and their combination - and the histology results was investigated using logistic regression. RESULTS: Prostate cancer was detected in 131 of 619 patients. Analysis of the aforementioned test variables by means of logistic regression revealed that the combination of the parameters f/tPSA ratio, PSA density and patient's age can significantly increase the sensitivity and specificity of PSA in predicting prostate cancer compared with the use of these parameters on an individual basis. With an assumed limit value of 5% for performance of punch biopsy, 31% of biopsies could be avoided in practice. In such a case, only 3% of instances of prostate cancer would have gone undetected. CONCLUSION: The combined use of f/tPSA ratio, PSA density and patient's age can significantly enhance the case detection sensitivity for the PSA range of 4 to 10 ng/ml.

[Early detection of prostate cancer: is serum PSA testing alone sufficient?]. / Früherkennung von Prostatakarzinomen : Ist die Untersuchung des Serum-PSA alleine ausreichend?

The euphoria over PSA as an optimal marker for prostate cancer is gone. Measuring PSA levels has several deficiencies in detecting prostate cancer. First results of the randomized studies ERSPC and PLCO were not able to conclusively prove the value of PSA-based screening. Many attempts have been made to optimize early detection of prostate cancer like using modern imaging techniques or new biomarkers. This review deals with PSA isoforms und emerging biomarkers for the diagnosis of prostate cancer. Despite the inadequacies of PSA it is still the most important marker for the early detection of prostate cancer. Modern biomarkers with the ability to reliably predict aggressive prostate cancer are still missing.