German S3 Evidence-Based Guidelines on Focal Therapy in Localized Prostate Cancer: The First Evidence-Based Guidelines on Focal Therapy.

BACKGROUND: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensus-based German S3 guidelines for a possible international use. SUMMARY: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. KEY MESSAGE: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and follow-up diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

Re: Results of a randomized trial of treatment modalities in patients with low or early­intermediate risk prostate cancer (PREFERE trial).

The authors of this "Letter to the Editors" express their major concern about selective and biased reporting in this paper.

[Advanced prostate cancer: sequence of androgen receptor-targeted substances and chemotherapy determines long-term survival]. / Fortgeschrittenes Prostatakarzinom: Sequenz aus androgenrezeptorgerichteten Substanzen und Chemotherapie entscheidet über das Langzeitüberleben.

The treatment of advanced prostate cancer is changing. New study data and the resulting new therapeutic options have led to increasingly differentiated treatment decisions. Despite the changing therapy landscape, taxane-based chemotherapy-being a life-prolonging treatment-remains an indispensable therapeutic component for chemotherapy-fit patients in the metastatic setting. The current results of the randomized study CARD show that cabazitaxel has a higher oncological effectiveness, including a significant survival benefit and no negative impact on quality of life parameters, compared to a second androgen receptor targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after treatment with docetaxel and an androgen receptor-targeted agent (ARTA). In mCNPC the combination therapies of ADT (androgen deprivation therapy) plus docetaxel or of ADT plus ARTA have been established. In addition, three ARTAs tested in recent phase III studies in a clinical setting for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) showed that their use significantly prolongs metastasis-free survival and overall survival. The potential early use of ARTAs also has implications for the treatment of mCNPC. The aim of this publication is to provide guidance for clinical routine and to develop criteria for individual therapy decisions with a special focus on the use of chemotherapy.

Effects of a 15-Month Supervised Exercise Program on Physical and Psychological Outcomes in Prostate Cancer Patients Following Prostatectomy: The ProRehab Study.

PURPOSE: Despite advanced medical treatment options, many prostate cancer patients are still confronted with unfavorable physical and psychological burdens. Physical exercise has proven to be beneficial for prostate cancer patients, yet specific exercise offers are rare. The ProRehab Study aimed to evaluate the exercise program offered in rehabilitative prostate cancer sports groups in Germany and determine whether it is beneficial for patients following prostatectomy. METHODS: Eighty-five prostate cancer patients were recruited for a multicenter, 2-armed, nonrandomized controlled trial 6 to 12 weeks after prostatectomy. The intervention group (n = 56) took part in a 15-month supervised multimodal exercise program. Exercise sessions took place once a week for 60 minutes at a moderate intensity (3.84-4.84 MET-hour). The control group (n = 29) received no intervention. Outcomes included aerobic fitness, activity levels, quality of life, disease- and treatment-related adverse effects, such as urinary incontinence and erectile dysfunction, and relapse-relevant blood values. Intention-to-treat analysis was performed. RESULTS: A significant between-group difference was observed in the urinary symptom score (P = .027). Physical fitness, urinary incontinence, physical, role, emotional, and social functioning, as well as further disease- and treatment-related side effects (dyspnea, urinary, and bowel symptoms) significantly improved within the intervention group. Erectile dysfunction and physical activity levels improved similarly in both groups. CONCLUSIONS: The presented data hint at the potential of rehabilitative sports groups for prostate cancer patients. However, according to the current state of the art, exercise intensity and volume may need to be increased to enhance the effects. A number of shorter studies (8-24 weeks) have proven significant between-group differences in quality of life, incontinence, and fitness outcomes when patients exercised 2 to 3 times per week. This is the first exercise intervention study with prostate cancer patients that was conducted over 15 months. Further studies are necessary to investigate whether prostate cancer patients recover sooner when receiving a supervised exercise program.

Segmental dosimetry, toxicity and long-term outcome in patients with prostate cancer treated with permanent seed implants.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The development of side effects characteristic for the different treatment methods with impact on the patients' quality of life plays a growing role for individual patients with early stage prostate cancer. Using permanent brachytherapy a high dose to the prostate can be applied with a steep dose gradient to the normal tissue. However, small partial volumes of normal tissue may be exposed to high doses inducing special side effects including lower urinary tract symptoms and/or erectile dysfunction. In the literature there are only few publications so far regarding segmental dosimetry and its influence on side effects and the results are conflicting. We could not identify any dosimetric parameter in segmental dosimetry that may have an influence at certain time intervals on the development of side effects such as lower urinary tract symptoms or erectile dysfunction. However, we could state clearly that the preoperative situation is the most important factor for postoperative outcome. OBJECTIVE: To report on the side effects of patients with low to low-intermediate risk prostate cancer treated with permanent interstitial brachytherapy with special emphasis on segmental dosimetry. PATIENTS AND METHODS: A series of 186 consecutive patients treated for early stage prostate cancer receiving definitive I-125 brachytherapy (permanent seed implantation) between November 2001 and April 2005 at our institution were examined for the development of side effects. Morbidity was assessed prospectively using the International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF-5) in a mean follow-up interval of 30 months. The scores were correlated with segmental dosimetry performed 6 weeks after the implantation. RESULTS: The mean postoperative dose to 90% of the prostate volume (D90) was 180.2 Gy, the mean preoperative IPSS 7.2 and the mean IIEF-5 14.35, with all scores showing a maximum deterioration after 6 weeks with normalization after 24 months. After correlating the segmental dosimetry and the scores at different time intervals, only the baseline scores remained statistically significant in multivariate regression analysis at all time intervals (P < 0.00). CONCLUSIONS: We could not demonstrate a correlation of segmental dosimetry with induction of side effects. There is no relationship between dose exposure of partial volumes and the development of radiation-induced toxicities. The preoperative situation regarding lower urinary tract symptoms and erectile function are the most important factors for postoperative outcome.

Apoptosis gene polymorphisms and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy.

BACKGROUND AND OBJECTIVES: Prostate cancer has a genetic component, and single nucleotide polymorphisms (SNPs) can contribute to the risk. We aimed to investigate the role of polymorphisms in 10 candidate genes with a key function in apoptosis. METHODS AND MATERIALS: Eight coding SNPs were chosen in ATM (Ser49Cys), BID (Ser56Cys), CASP8 (Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1 (Ser133Ala), TP53 (Arg72Pro), and TP53AIP1 (Ala7Val), and two non-coding SNPs were selected in BCL2 (-938C/A) and HDM2 (SNP309). A hospital-based case-control series of 510 prostate cancer patients and 490 healthy males from Northern Germany were genotyped for these polymorphisms. RESULTS: SNP rs4644 in LGALS3 showed evidence for a protective effect of the minor allele, encoding the His64 variant (OR 0.82, 95% CI 0.69;0.99, P = 0.04). Carriers were underrepresented among cases under a dominant model (OR 0.71; 95% CI 0.54;0.92; P = 0.01), and the effect appeared more pronounced in patients diagnosed before the age of 60 years (OR 0.52; 95% CI 0.31;0.85, P = 0.01). The other nine polymorphisms did not vary significantly between cases and controls, though subtle trends were noted for BCL2 (P = 0.07) and CASP10 (P = 0.08). The Asp302His variant of CASP8 tended to associate with a protective effect in the group with higher Gleason score under a dominant model (P = 0.03). Carriers of either the CASP8 or the CASP10 variants were underrepresented in the prostate cancer series (P = 0.02). CONCLUSIONS: These results provide first evidence to implicate the functional Pro64His variant of galectin-3 (LGALS3) in the genetic susceptibility towards prostate cancer. The potential role of polymorphisms in BCL2, CASP8, and CASP10 merits further investigation.

Implementation and scientific evaluation of rehabilitative sports groups for prostate cancer patients: study protocol of the ProRehab Study.

BACKGROUND: Although treatment regimen have improved in the last few years, prostate cancer patients following a radical prostatectomy still experience severe disease- and treatment-related side effects, including urinary incontinence, erectile dysfunction and psychological issues. Despite high incidence rates and the common adverse effects there is a lack of supportive measures for male patients and specific physical exercise recommendations for prostate cancer patients during rehabilitation or in the aftercare are still missing. METHODS/DESIGN: The ProRehab Project aims to establish rehabilitative sports groups particularly for prostate cancer patients and to evaluate the effects of the offered exercise program. Starting 8-12 weeks after prostatectomy or combination therapy, prostate cancer patients will exercise for 15 months within a patient preference randomized controlled trial. One exercise session will be conducted within a pre-established rehabilitative sports group, while the other will be completed independently. Patients in the control group will not participate in the intervention. The main outcomes of the study include aerobic fitness, quality of life, incontinence and erectile dysfunction. DISCUSSION: By combining science, practice, and public relations the first rehabilitative sports groups for prostate cancer patients in Germany have been set up and thus contribute to the care structure for prostate cancer patients. By offering a 15-month physical exercise intervention that is conducted in supervised group sessions, long-term lifestyle changes and therefore improvements in quality of life in prostate cancer patients can be expected. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004184.

Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer.

What's known on the subject? and What does the study add? Whole gland brachytherapy has been used to successfully treat prostate cancer but the protocol for focal therapy has not previously been established. The consensus findings provide guidance on patient selection for focal brachytherapy as well as recommendations for conducting therapy and patient follow-up. Low dose rate prostate brachytherapy is an effective treatment for localized prostate cancer. Recently, it has been considered for use in a focused manner whereby treatment is targeted only to areas of prostate cancer. The objective of focal brachytherapy is to provide effective cancer control for low-risk disease but with reduced genitourinary and rectal side-effects in a cost-effective way. We report on the outputs of a consensus meeting of international experts in brachytherapy and focal therapy convened to consider the feasibility and potential development of focal brachytherapy. A number of factors were considered for focal brachytherapy including optimal patient selection, disease characterization and localization, treatment protocols and outcome measures. The consensus meeting also addressed the design of a clinical trial that would assess the oncological outcomes and side-effect profiles resulting from focal brachytherapy.

Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.

What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.

Association of chromosomal locus 8q24 and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy.

BACKGROUND: Genetic susceptibility contributes to the risk of prostate cancer but the underlying genes are largely unknown. Polymorphic loci on chromosome 8q24 have emerged as possible risk factors for breast and prostate cancer from genome-wide association studies. OBJECTIVE: We aimed to define the risks associated with two single nucleotide polymorphisms, rs1447295 and rs13281615, in a hospital-based series of prostate cancer patients treated with brachytherapy. MATERIAL AND METHODS: We analyzed genomic DNA samples of 488 prostate cancer cases undergoing brachytherapy at Hannover Medical School, and of 462 male controls from the same location. Genotyping was performed using 5'-exonuclease allelic discrimination assays, and results were evaluated with chi(2) tests and logistic regression analyses. RESULTS: We investigated whether rs1447295 and rs13281615 are associated with disease risk in a hospital-based prostate cancer case-control series from Northern Germany. The rare allele of rs1447295 was observed at higher frequency among cases than among hospital-based controls (13.9% vs. 10.2%, P = 0.01), and there was a dose-dependent trend towards a higher prevalence of heterozygous and homozygous carriers among the prostate cancer patients (per allele OR 1.42, 95% CI 1.07; 1.87, P = 0.02). By contrast, the rare allele of rs13281615 did not predispose to prostate cancer (per allele OR 0.84, 95% CI 0.70; 1.00, P = 0.05). The distribution of combined 8q24 genotypes was significantly different between cases and controls (P = 0.01). CONCLUSION: Our results corroborate previous reports of 8q24 as a prostate cancer susceptibility locus and provide evidence for rs1447295 as a potentially important genetic marker. Further studies are required to confirm whether the adjacent breast cancer-associated variant rs13281615 may be inversely associated with prostate cancer risk.

TGFB1 gene polymorphism Leu10Pro (c.29T>C), prostate cancer incidence and quality of life in patients treated with brachytherapy.

OBJECTIVES: Transforming growth factor beta1 gene (TGFB1) variant Leu10Pro (L10P) has previously been implicated in prostate cancer risk and radiation-induced side-effects. We investigated whether prevalence of this polymorphism is increased in prostate cancer patients and whether carriers are at increased risk for treatment-related side effects. METHODS: A series of 445 consecutive patients treated for early-stage prostate cancer receiving definitive I-125 brachytherapy (permanent seed implantation) between 10/2000 and 10/2007 at our institution and a comparison group of 457 healthy male control individuals were screened for TGFB1 L10P (869T>C) polymorphism. Morbidity was assessed prospectively and compared between carriers versus non-carriers using International Prostate Symptom Score (IPSS), disease-specific Quality-of-Life single question added to the IPSS and International Index of Erectile Function with its subgroups. RESULTS: The Leu/Leu genotype was found in 150 patients (34%) versus 180 controls (39%), the Pro/Pro genotype in 75 patients (17%) versus 65 controls (14%) and the Leu/Pro genotype in 220 patients (49%) versus 212 controls (46%) without any statistically significant differences between the two groups. There was a trend towards an increased prevalence of the L10P substitution among patients with a per allele odds ratio of 1.19 (95% CI 0.99-1.44; P = 0.08). After a median follow-up of 18 months (range 1-60 months) there were no statistically significant differences regarding morbidity. CONCLUSIONS: TGFB1 polymorphism L10P is not strongly associated with prostate cancer risk. After 18 months, there was no evidence for increased adverse radiotherapy responses in heterozygote or rare homozygote carriers. Longer follow-up may be necessary to detect a statistically significant difference.

RASSF1A protein expression and correlation with clinicopathological parameters in renal cell carcinoma.

BACKGROUND: Epigenetic silencing of RAS association family 1A (RASSF1A) tumor suppressor gene occurs in various histological subtypes of renal cell carcinoma (RCC) but RASSF1A protein expression in clear cell RCC as well as a possible correlation with clinicopathological parameters of patients has not been analyzed at yet. METHODS: 318 primary clear cell carcinomas were analyzed using tissue microarray analysis and immunohistochemistry. Survival analysis was carried out for 187 patients considering a follow-up period of 2-240 month. RESULTS: Expression of RASSF1A was found to be significantly decreased in tumoral cells when compared to normal tubular epithelial cells. RASSF1A immunopositivity was significantly associated with pT stage, group stage and histological grade of tumors and showed a tendency for impaired survival in Kaplan-Meier analysis. CONCLUSION: While most tumors demonstrate a loss of RASSF1A protein, a subset of tumors was identified to exhibit substantial RASSF1A protein expression and show increased tumor progression. Thus RCC tumorigenesis without depletion of RASSF1A may be associated with an adverse clinical outcome.

RASSF1A promoter methylation and expression analysis in normal and neoplastic kidney indicates a role in early tumorigenesis.

BACKGROUND: Epigenetic silencing of the RAS association domain family 1A (RASSF1A) tumor suppressor gene promoter has been demonstrated in renal cell carcinoma (RCC) as a result of promoter hypermethylation. Contradictory results have been reported for RASSF1A methylation in normal kidney, thus it is not clear whether a significant difference between RASSF1A methylation in normal and tumor cells of the kidney exists. Moreover, RASSF1A expression has not been characterized in tumors or normal tissue as yet. RESULTS: Using combined bisulfite restriction analysis (COBRA) we compared RASSF1A methylation in 90 paired tissue samples obtained from primary kidney tumors and corresponding normal tissue. Bisulfite sequence analysis was carried out using both pooled amplicons from the tumor and normal tissue groups and subclones obtained from a single tissue pair. Expression of RASSF1A was analyzed by the use of tissue arrays and immunohistochemistry. We found significantly increased methylation in tumor samples (mean methylation, 20%) compared to corresponding normal tissues (mean methylation, 11%; P < 0.001). Densely methylated sequences were found both in pooled and individual sequences of normal tissue. Immunohistochemical analysis revealed a significant reduced expression of RASSF1A in most of the tumor samples. Heterogeneous expression patterns of RASSF1A were detected in a subgroup of histologically normal tubular epithelia. CONCLUSION: Our methylation and expression data support the hypothesis that RASSF1A is involved in early tumorigenesis of renal cell carcinoma.

Efficacy and safety of TachoSil as haemostatic treatment versus standard suturing in kidney tumour resection: a randomised prospective study.

OBJECTIVE: Elective nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) has gained general acceptance as an alternative to radical nephrectomy. To achieve haemostasis without risk of local ischaemia and necrosis of kidney parenchyma after standard haemostatic suturing, we investigated TachoSil's efficacy and safety as atraumatic haemostatic treatment after kidney tumour resection. METHODS: A total of 185 patients scheduled for NSS for small, superficial kidney tumours were included in an open, randomised, prospective, multicentre, parallel-group trial. Primary objectives were to test haemostatic efficacy and safety of TachoSil versus standard suturing. Efficacy was tested by comparing intraoperative time to haemostasis (primary end point). Secondary objectives included proportion of subjects with haemostasis after 10 min of trial treatment, occurrence of haematoma on day 2 after surgery, volume and haemoglobin concentration of postoperative drainage fluid, and surgeon's rating of usefulness of trial treatments. Safety was evaluated by occurrence of adverse events. RESULTS: In the intent-to-treat population, time to haemostasis was significantly shorter with TachoSil versus standard suturing (mean: 5.3 vs. 9.5 min [p<0.0001]). Haemostasis was obtained within 10 min in 92% of patients in the TachoSil group and in 67% in the standard treatment group (p<0.0001). Differences in other secondary end points were not statistically significant. Both treatments were well tolerated. Surgeons rated TachoSil higher in terms of convenience to prepare and apply, and impression of efficacy. CONCLUSION: TachoSil was superior to standard suturing in obtaining intraoperative control of haemorrhage and was as well tolerated as standard haemostatic treatment during NSS.

ATM missense variant P1054R predisposes to prostate cancer.

BACKGROUND: Prostate cancer is associated with defective DNA strand break repair after DNA damage leading to genetic instability and prostate cancer progression. The ATM (ataxia-telangiectasia mutated) gene product is known to play an important role in cell cycle regulation and maintenance of genomic integrity. We investigated whether the prevalence of the ATM missense substitution P1054R is increased in a hospital-based series of prostate cancer patients and whether carriers are at increased risk for treatment-related side effects. MATERIALS AND METHODS: A consecutive series of 261 patients treated for early-stage prostate cancer with I-125 brachytherapy (permanent seed implantation) between 10/2000 and 04/2006 at our institution and a comparison group of 460 male control individuals were screened for the presence of the P1054R variant. Outcome of therapy regarding morbidity was assessed prospectively and compared between carriers vs. non-carriers with the International Prostate Symptom Score (IPSS), a Quality-of-Life-index (QoL) and the International Index of Erectile Function (IIEF-15) with its subgroups (IIEF-5 and EF). RESULTS: The proportion of carriers of the P1054R variant was significantly higher among prostate cancer patients than in the general population (25 out of 261 vs. 22 out of 460; OR 2.1; 95% CI 1.2-3.8, p<0.01). A subgroup of the carriers additionally harboured the ATM missense variant F858L that was associated with a similar risk (OR=2.2; 95% CI 1.1-4.6; p=0.03). After a mean follow-up of 18 months there were no statistically significant differences regarding IPSS (p=0.48), QoL (p=0.61), IIEF-15 score (p=0.78), IIEF-5 score (p=0.83), and EF score (p=0.80), respectively. CONCLUSIONS: The ATM missense variant P1054R confers an about twofold increased risk for prostate cancer in our series. The subgroup of patients with the second-site variant F858L is not at significantly higher risk. After 18 months, there was no evidence for an increased adverse radiotherapy response in P1054R carriers.

Prospective diagnostic efficiency of biopsy washing DNA GSTP1 island hypermethylation for detection of adenocarcinoma of the prostate.

BACKGROUND: The prospective diagnostic efficiency of quantitative glutathione S transferase (GSTP1) promoter hypermethylation analysis in biopsy washing samples has not been determined so far. METHODS: Biopsies were obtained prospectively from 86 patients suspicious for prostate cancer (CaP). After isolation of DNA from biopsy washings and bisulfite conversion methylated and unmethylated GSTP1 sequences were specifically quantitated by real-time fluorescence PCR. Relative degrees of methylation were compared to results of histopathological examination. RESULTS: Increased relative methylation was found for the CaP group (mean 28.1%) compared to biopsies without histological evidence for malignancy (5.2%; P < 0.001). A sensitivity and specificity of 92% and 86% and positive and negative predictive values of 82% and 94% were obtained. Receiver operating characteristic (ROC) analysis demonstrated a value of 0.90 (95% CI 0.82-0.98) for the area under curve (AUC). CONCLUSIONS: Biopsy washing DNA GSTP1 hypermethylation analysis demonstrates a high diagnostic efficacy which is comparable to the retrospective analysis of biopsy tissue specimens. Moreover it is compatible with routine biopsy examination thus permitting further prospective evaluation in CaP diagnosis.

p16INK4a expression and clinicopathologic parameters in renal cell carcinoma.

OBJECTIVES: The tumour suppressor gene p16INK4a is a cyclin-dependent kinase inhibitor, for which inactivation attributable to promoter hypermethylation or homozygous deletion has been described in malignancies. Little is known about p16INK4a protein levels in renal cell carcinoma (RCC) and its association with clinicopathologic parameters or disease progression. METHODS: The expression of the p16INK4a gene was analysed with the use of immunohistochemistry and tissue microarrays (TMA). Tissue cores were obtained from the primary tumour itself, the tumoural invasion front, and histologically benign peritumoural tissue of 397 nephrectomies. For statistical analysis, sections were classified into four groups according to the relative amount of positively stained cells: negative (0%), low (1-10%), intermediate (11-50%), and high positivity (>50%). Follow-up data were analyzed for 198 patients (follow-up period: 2-240 mo; median: 138 mo). RESULTS: Absent or low expression of p16INK4a was observed in 82% of tumour samples. No statistically significant association was found between protein levels detected in tumour, invasion front, or normal renal tissues and any of the clinicopathologic variables. Survival analysis by Kaplan-Meier revealed a significant association between high expression (>50%) of p16INK4a in tumours and better disease-specific survival (p=0.03, log-rank test). Cox regression analysis showed that p16INK4a expression is an independent covariate in disease-specific survival (p<0.01). CONCLUSIONS: The absence of p16INK4a expression in most tumour cells indicates that p16INK4a could be involved in the tumourigenesis of RCC. Immunohistochemically detected positivity for p16INK4a is a positive prognosticator for specific survival in both uni- and multivariate analyses.

Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer.

Permanent interstitial brachytherapy represents the most conformal form of radiation therapy of the prostate and the number of patients with prostate cancers treated with permanent radioactive implants is increasing world wide. In the meanwhile long-term data on tumor control and treatment morbidity become available. Biochemical and clinical tumor control appears to be as effective as after radical prostatectomy or external beam radiation therapy in early prostate cancer. The risk of postreatment urinary incontinence and bowel dysfunction is low and erectile function can be preserved in the majority of patients. However, prostate brachytherapy requires a careful selection of patients as pretreatment factors predict for long-term outcome. The need for combined modality approaches in intermediate and high-risk patients remains controversely discussed. The continous refinement of intraoperative planning techniques and the elucidation of the etiology of urinary, sexual, and bowel dysfunction should result in further improvements in biochemical outcomes and decreased morbidity. Improved and standardized postimplantation evaluation will make outcome data more reliable and comparable.

Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patients.

Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients.