[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.

[PSA--Quo vadis?]. / PSA--Quo vadis?

Prostate cancer is the most frequent cancer in males. Because of the high cure rates, early detection of prostate cancer should identify organ-confined prostate cancers. An early detection examination should be performed annually starting at the age of 50 years and ending when life expectancy is less than 10 years. Digital rectal examination is supplemented by determination of prostate-specific antigen (PSA). Before the first PSA test, the patient must be informed of possible consequences such as biopsy recommendation and treatment options. A threshold of 4 ng/ml is defined as the indication for prostate biopsy. Imaging methods do not play a major role in early detection of prostate cancer today. Early detection identifies many latent prostate cancers, and patients may receive overtreatment. A possible solution is to change the early detection paradigm from detection of all prostate cancers to identification of aggressive ones. In this article, early detection is discussed based on the recent literature.

[Informed consent for patients on early recognition of prostate carcinoma is insufficient]. / Die Patientenaufklärung zur Prostatakarzinomfrüherkennung ist unzureichend.

Men that undergo an early detection investigation should be informed of the advantages and disadvantages as well as of the therapeutic consequences. In this study the quality of information was checked using the state of scientific knowledge of the patients.An informative consultation was carried out before the early detection investigation using a clarification brochure and an examination by a urologist. A questionnaire was also filled out after the investigation. A total of 1,536 men were questioned. Although 47% of the men had previously undertaken a PSA at least once, only 55% knew their own test result. Subjectively 82% of men felt well informed. In contrast one-third did not know the significance of an increased PSA level. In the field of patient clarification for the early detection for prostate cancer there are considerable deficits but the information received was considered adequate by the participants. However, more than one-third did not understand the significance of the PSA level.

[Free/total PSA ratio in clinical and ambulatory application. Are different cutoffs justified?]. / Der Quotient f/t-PSA in klinischer und ambulanter Anwendung. Sind unterschiedliche Grenzwerte gerechtfertigt?

Especially in the setting of total prostate-specific antigen (PSA) in the intermediate range of 4-10 ng/ml and a negative digital rectal examination, the use of the free/total (F/T) PSA ratio has proved to be an effective tool in prostate cancer screening. Whole blood should be analyzed as soon as possible after venipuncture to ensure optimal effectiveness of the F/T PSA ratio. If an immediate serum analysis is not possible, the serum should be frozen or stored at a maximum of 4 degrees C for a short period. Otherwise, when applying the F/T PSA cutoffs as recommended in the literature to a cohort with delayed analysis, a lack of specificity arises, and the initial advantage of reducing biopsies is minimized. To prevent loss of quality in a setting with delayed F/T PSA measurement, we recommend that physicians compare their own data critically with presented results and eventually adapt the cutoffs individually.

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.

[Early detection of prostate cancer in Germany. A study of a representative random sample of the population]. / Prostatakarzinomfrüherkennung in Deutschland. Untersuchung einer repräsentativen Bevölkerungsstichprobe.

The goals of our study were to assess the prevalence of prostate cancer screening (PCS) among German men in terms of regularity of use and to analyze predictors of PCS use. A representative sample of 10,659 men aged 45-70 (mean=55.2) were surveyed to self-assess regularity of DRE and PSA tests; sociodemographic variables (age, income, education, marital status and health insurance status), family history of cancer, physician recommendation and medical checkups were assessed as well.Two thirds of the sample report ever undergoing a DRE; 48% had ever had a PSA test. In contrast, the rates of men who undergo PCS regularly are lower (44% DRE, 33% PSA). PCS increases with age; socioeconomic variables (such as education or income), however, are less important predictors. Family history of cancer is associated with PCS use, but not with regularity of use. The most important predictors are having medical checkups and physician recommendation.

Systematic development of a guideline for early detection of prostate cancer: the German way in the evidence gap.

OBJECTIVE: To develop an evidence-based guideline, helping physcians make prudent decisions about diagnostic care for men wishing to undergo examination for early detection of prostate cancer. METHODS: A guideline development group, comprised of twenty healthcare professionals, including urologists, clinical chemists, pathologists, geriatricians, epidemiologists, technicians and a member of a patient self-help group, systematically gathered, evaluated, and discussed the most recent research available on early detection of prostate cancer. Nominal group technique (NGT) was employed to facilitate the decision-making process. RESULTS: The NGT was sufficient to find a consensus among different medical disciplines in a timely fashion. A standardized guideline, containing a short version for physicians and a standardized patient information booklet, for nation-wide use was developed. CONCLUSIONS: Population-based screening is not favoured, instead information should be given to men in their 50-70s, to enable shared decision-making between physician and patient for or against PSA-based early detection of prostate cancer.

Clinical usefulness of free PSA in early detection of prostate cancer.

OBJECTIVE: Measurement of serum prostate-specific antigen (PSA) is widely used as an aid in early detection of prostate cancer. Most patients with prostate cancer and a PSA level less than 10.0 ng/ml have early-stage disease. Thus, the detection of prostate cancer in its potentially curable stages requires the use of low PSA cutoffs, inevitably leading to many unnecessary biopsies. The combined use of free PSA and total PSA increases specificity of early detection. To develop risk assessment guidelines and a cutoff value of ratio of free (f) to total (t) PSA with a high predictive value for prostate cancer in men to whom the test would be applied in real life practice, a multicenter early detection trial was initiated. PATIENTS AND METHODS: In one week in November 1997, 963 urologists prospectively examined 11,644 men between 45 and 75 years by digital rectal examination (DRE) and prostate-specific antigen with 4.0 ng/ml as cutoff. Data of physical examination were collected by questionnaire. At this time participants were not aware of their PSA values. Suspicious findings were further investigated with sextant biopsy. Prostate volume was determined with transrectal ultrasound (TRUS). Different cutoff levels were correlated to age and detection rate. RESULTS: From1,115 biopsied men, the data of 633 men fulfilled the criteria DRE-negative, TRUS-estimated volume, and PSA 4.0-10.0 ng/ml. In that cohort 91 cancers were detected. Percentage of fPSA was significantly more predictive of cancer than tPSA (p < 0.001). The area under the ROC curve was 0.72 for percent fPSA (% fPSA) and 0.62 for total PSA. The cancer risk nearly doubled using a cutoff of 10% fPSA, the median %PSA level of the detected cancers. A better discrimination of cancer and noncancer especially in the age group above 70 years is possible. Using a cutoff of 16% fPSA increases positive predictive value (PPV) to 25% missing only 4% of cancers. Nearly 45% of the biopsies could be avoided. In the age group 45-69 years, a cutoff of 20% fPSA leads to PPV of 15%, missing 6% of cancers. Unnecessary biopsies could be avoided in 12%. CONCLUSIONS: Using % fPSA in early detection of prostate cancer reduces the number of unnecessary biopsies, especially in men with negative rectal examination in the PSA range of 4.0-10.0 ng/ml. In order to diminish biopsy rate in men 70 years or older a cutoff of 16% fPSA should be used. A cutoff of 20% fPSA in men younger than 70 years is recommended to increase sensitivity in that age group.

A multicenter clinical trial on the use of alpha1-antichymotrypsin-prostate-specific antigen in prostate cancer diagnosis.

BACKGROUND: The aim was to evaluate the clinical performance of alpha(1)-antichymotrypsin prostate-specific antigen (PSA-ACT) for early diagnosis of prostate cancer (PCa) in a multicenter trial. METHODS: Three hundred sixty-seven white men with PCa and 290 with benign prostatic hyperplasia (BPH) with tPSA concentrations between 2 and 20 microg/L were analyzed. The Elecsys system 2010 (Roche Diagnostics, Germany) was used for determination of total PSA (tPSA) and free PSA (fPSA). The PSA-ACT test was a prototype assay used on the ES system (Roche Diagnostics). RESULTS: The median concentrations of tPSA (PCa: 8.43 microg/L vs. BPH: 6.60 microg/L) and PSA-ACT (8.30 microg/L vs. 6.46 microg/L) were significantly different, respectively. The median ratios of fPSA/tPSA (PCa: 12% vs. BPH: 16%) and PSA-ACT/tPSA (98% vs. 95%) were significantly different. Receiver operating characteristics (ROC) analysis for discrimination between PCa and BPH (tPSA between 2 and 20 microg/L) was performed with 252 matched pairs and showed that the area under the curve (AUC) of the ratio fPSA/tPSA (0.66) was significantly different from tPSA (0.50) and PSA-ACT (0.52). PSA-ACT alone or the ratio PSA-ACT/tPSA (0.56) were not significantly different from tPSA. For tPSA between 4 and 10 microg/L (n = 145 pairs), the AUC of the ratio fPSA/tPSA (0.65) was significantly higher than tPSA (0.50) and PSA-ACT (0.54). Significant differences between tPSA and PSA-ACT or PSA-ACT/tPSA (0.56) were not found. CONCLUSIONS: The determination of PSA-ACT as well as the PSA-ACT/tPSA ratio did not improve the diagnostic impact in patients undergoing evaluation for PCa compared to fPSA/tPSA ratio.

Early detection of prostate cancer in Germany: a study using digital rectal examination and 4.0 ng/ml prostate-specific antigen as cutoff.

OBJECTIVE: While international screening studies for prostate cancer are by now almost reaching the estimated number of recruitments mandatory for the necessary power to investigate an effect on mortality of prostate cancer, no statistical figures on the detection of prostate cancer in Germany - apart from historical data before the use of prostate-specific antigen (PSA) are available. In order to generate a database and to investigate the diagnostic efficacy of the primarily practice-based urological care system, a case finding study designed as a nationwide longitudinal early detection trial was initiated. METHODS: In one week in November 1997, 963 urologists prospectively examined 11,644 men between 45 and 75 years of age by digital rectal examination (DRE) and PSA with 4.0 ng/ml as cutoff. Data of family history and physical examination were collected by questionnaire. At this time participants were not aware of their PSA value. PSA was determined in the study center. Indication for sextant biopsy was a PSA value above 4.0 ng/ml or a suspicious lesion on DRE. Any indicated biopsy not performed had to be clarified. In a second questionnaire results of prostate biopsy, treatment and tumor status were documented. RESULTS: The mean age of the study population was 62 years (median 62). The PSA median was 1.4 ng/ml with 82.8% presenting with < 4.0 ng/ml, 12.8% with 4-10 ng/ml and 4.4% with >10 ng/ml. From 1,115 men (47.7%) biopsied, 262 cancers were detected resulting in a detection rate of 23.5%. While 399 men refused biopsy, further investigation was not recommended in 387 men by their urologist, because prostatitis or benign hyperplasia was thought to be the cause for elevated PSA. From the 143 patients undergoing radical prostatectomy, 93 (65%) cancers were organ confined. T(1c) cancers with elevated PSA > 10 ng/ml could be treated with curative intent in 44% only. The positive predictive value (PPV) was estimated to be 16% for DRE alone (14/90), 17% for PSA alone (143/819) and 51% for the combination of both (105/206). In that cohort, use of age-adjusted PSA values and PSA density increased the PPV of PSA testing nonsignificantly. CONCLUSIONS: Significant higher PPV indicated that utilizing a combination of both DRE and PSA is most effective in the early detection of prostate cancer. Unnecessary biopsies can be avoided using either age-adjusted PSA value or PSA density, but the PPV is not significantly changed and potentially curable cancer is missed in up to 25%. Given the substantial variability of the diagnostic approach despite the study design, uniform guidelines are necessary to ensure countrywide sufficient screening.

[Early detection of prostatic carcinoma in urologic practice with digital rectal examination and prostate-specific antigen. Early Detection Project Group]. / Früherkennung des Prostatakarzinoms in der urologischen Praxis mit digitaler rektaler Untersuchung und prostataspezifischem Antigen. Projektgruppe Früherkennung.

For the early detection of prostate cancer, a patient should undergo digital rectal examination (DRE) and PSA investigation. Follow-up of increased PSA levels detects nearly 80% of cancers. Positive predictive value of suspicious DRE and PSA is about 50%. Whereas in the first evaluation of this case-finding trial about 70% of the patients had organ-confined cancers, nearly all of the detected cancers in the follow-up investigation were organ confined. The increased number of organ-confined cancers detected in early periodical examinations can lead to a reduction of mortality and morbidity from prostate cancer.

Prognostic factors for carcinoma of the prostate.

Prognostic factors for prostatic carcinoma should be significant, independent and clinically important. They should be of practical use, and their determination should be affordable in everyday practice. Prognostic factors may be grouped into patient-related, tumor-related and treatment-related. They should meet certain requirements, such as possession of a clear biological significance, an adequate sample size (possibly more than 150 patients), no patient population bias, an adequate statistical test, such as Cox regression analysis, as well as optimized cut-off values and reproducibility. From a pathologist's view, prognostic factors with established values are grade, margin involvement, capsular penetration, seminal vesical involvement, metastases and invasion of fat in needle biopsies. In contrast to this, factors with little value are, among others, zone location or nuclear shape. If these guidelines for assessment of prognostic factors are not met, the prognostic factors grow exponentially, as an individual patient can only belong to one prognostic group. If one considers all three categories of prognostic factors together, the clinical stage matters most despite all uncertainties. The same holds true for grading; particularly, the well-differentiated grades on biopsy cores have the drawback of being reflected in the specimen only infrequently. The use of biomarkers to give a better prognostic information is also disappointing, as only PSA and PAP have a reliable value among 28 biomarkers. It is of note that new biomarkers are continuously being discovered and examined, such as cyclin A or D. Due to these deficiencies in all three categories of prognostic factors for prostatic carcinoma, prognostic indices in the form of nomograms were constructed. But, if these indices are employed to answer the most important question at the time of diagnosis, i.e., 'is this man a candidate for surveillance?', neoadjuvant treatment plus irradiation, neoadjuvant treatment plus radical prostatectomy, perineal radical prostatectomy, because of a low probability of extracapsular extension or positive lymph nodes, adjuvant therapy after local treatment with curative intent as opposed to progression-based treatment or immediate systemic treatment, let alone intermittent endocrine manipulation, are not reliably possible. The outcomes of the few available studies based on prognostic factors should be studied carefully. If considered, a valuable new way of estimating artificial neural networks is a possibility to come to practical terms.

[Early recognition of prostate carcinoma. Initial results of a prospective multicenter study in Germany. Project Group for Early Detection DGU-BDU Laboratory diagnosis Professional Circle]. / Früherkennung des Prostatakarzinoms. Erste Ergebnisse einer prospektiven multizentrischen Studie in Deutschland. Projektgrouppe Früherkennung DGU-BDU-Arbeitskreis Labordiagnostik.

To compare the efficacy of digital rectal examination (DRE) and serum prostate specific antigen (PSA) in early detection of prostate cancer, we initiated a prospective multicenter screening trial. In 12,542 men choosen at random with a mean age of 62 (+/- 7.5) a suspect DRE or a PSA level > 4.0 ng/ml was found in 2343 (20%). Of the presently performed 744 biopsies, 157 revealed diagnosis of prostate cancer. Although further biopsies as well as the follow up of the 12,542 men are still missing, combination of DRE and PSA value > 4.0 ng/ml appears to be superior to DRE alone with a positive predictive value of 50% versus 19% in early detection of prostate cancer.

[Secondary erectile dysfunction. Is oral medication in the diagnostic phase indicated?]. / Sekundäre erektile Dysfunktion. Ist eine orale Medikation in der diagnostischen Phase indiziert?

For patients with erectile dysfunction oral medication seems to be the most comfortable form of application. This can also be seen in the expectations looking forward to Sildenafil and other drugs in development. We present a prospective examination with the oral medication of 100 mg acecarbamol, 30 mg extract of cortex quebracho and 33 mg tocopherol acetate (Afrodor) in 100 patients complaining secondary erectile dysfunction. The patients were treated unselected with 3 x 1 tablet/day during the diagnostic schedule. 14% of the patients were able to perform satisfying sexual intercourse after 4 weeks of medication and another 15% showed an increased libido. Therefore we suggest, that the application of an oral medication, might be useful, especially during the time of diagnostics. Especially for those patients who gain without invasive diagnostic tools as intracavernous injection.

Genetic instability of 3p12-p21-specific microsatellite sequences in renal cell carcinoma.

OBJECTIVE: To determine the role of structural alterations of human chromosome region 3p12-p21 in the possible inactivation of one or more tumour-suppressor genes in the pathogenesis of renal cell carcinoma (RCC), lung cancer and other neoplasms. MATERIALS AND METHODS: As microsatellite instability (MI), in particular MI with loss of heterozygosity (LOH), may indicate putative tumour-suppressor gene loci, 20 kidney tumours, including 14 clear cell carcinomas and six non-clear cell neoplasms, were investigated with 10 polymorphic simple sequence-repeat markers spanning 3p12-p21. Six of these markers map to the region of deletion flanked by markers D3S1285 and D3S1295 bracketing the t(3;8) translocation break-point in 3p14.2 of hereditary RCC. RESULTS: Twelve of 14 clear cell RCCs displayed MI for at least one locus, as opposed to none of the non-clear cell tumours (P = 0.001). Locus D3S1274 in 3p13 located in the region deleted in lung cancer line U2020 and loci D3S1313 and D3S1300 in 3p14.3 characterized common regions of instability and LOH. Two patients with RCC who also had lung cancer and colon cancer, respectively, showed LOH at D3S1313 or D3S1300 as the only alterations of their kidney tumours. CONCLUSIONS: These results suggest that human chromosome region 3p14.3 distal to the hereditary t(3;8) translocation breakpoint and the region deleted in the U2020 lung cancer cell line might be involved in the tumorigenesis or progression of clear cell RCC.

Selective loss of human leukocyte antigen class I allele expression in advanced renal cell carcinoma.

The expression of human leukocyte antigen (HLA) class I alleles was analyzed in 65 renal cell carcinomas using one-dimensional isoelectric focusing. Normal organ tissue and peripheral blood lymphocytes were used as controls. The patients were serologically typed using the standard microcytotoxicity test. Forty-two patients were staged as pT1 or pT2, and 23 patients had advanced tumor stages (pT3/pT4). In all cases the HLA-A,B phenotypes were confirmed using one-dimensional isoelectric focusing. The expression of HLA expression was reduced in two tumors [1 x HLA-A1(pT2); 1 x HLA-A28 (pT2)]. In three carcinomas the expression of HLA-A1 was lost. One tumor showed a combined loss of HLA-A2 and HLA-B38. These selective losses occurred in tumor stage pT3 (n = 1) or pT4 (n = 3; P = 0.013, Fisher's exact test). This leads to the conclusion that the loss of HLA expression is predominantly present in advanced tumor stages.

[Cytokine therapy of metastatic renal cell carcinoma]. / Zytokintherapie des metastasierten Nierenzellkarzinoms.

Cytokine therapy of metastatic renal cell carcinoma reveals a remission rate of about 25% regarding to the different patients selection criteria, i.e. age, performance status, site of metastasis, tumour load. Remission is not correlated to patient's survival. Adjuvant or neoadjuvant immunotherapy is not a treatment option. Nephrectomy has no influence on distant metastases and should be limited to symptomatic primary tumours. In conclusion, cytokine therapy is not a standard treatment. Its value has to be evaluated in randomized trials.