Inhibition of neurogenic and thromboxane A2 -induced human prostate smooth muscle contraction by the integrin α2ß1 inhibitor BTT-3033 and the integrin-linked kinase inhibitor Cpd22.

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.

Papillary vs clear cell renal cell carcinoma. Differentiation and grading by iodine concentration using DECT-correlation with microvascular density.

OBJECTIVES: Various imaging methods have been evaluated regarding non-invasive differentiation of renal cell carcinoma (RCC) subtypes. Dual-energy computed tomography (DECT) allows iodine concentration (IC) analysis as a correlate of tissue perfusion. Microvascular density (MVD) in histopathology specimens is evaluated to determine intratumoral vascularization. The objective of this study was to assess the potential of IC and MVD regarding the differentiation between papillary and clear cell RCC and between well- and dedifferentiated tumors. Further, we aimed to investigate a possible correlation between these parameters. METHODS: DECT imaging series of 53 patients with clear cell RCC (ccRCC) and 15 with papillary RCC (pRCC) were analyzed regarding IC. Histology samples were stained using CD31/CD34 monoclonal antibodies; MVD was evaluated digitally. Statistical analysis included performance of Mann-Whitney U test, ROC analysis, and Spearman rank correlation. RESULTS: Analysis of IC demonstrated significant differences between ccRCC and pRCC (p < 0.001). A cutoff value of ≤ 3.1 mg/ml at IC analysis allowed identification of pRCC with an accuracy of 86.8%. Within the ccRCC subgroup, G1/G2 tumors could significantly be differentiated from G3/G4 carcinomas (p = 0.045). A significant positive correlation between IC and MVD could be determined for the entire RCC cohort and the ccRCC subgroup. Limitations include the small percentage of pRCCs. CONCLUSIONS: IC analysis is a useful method to differentiate pRCC from ccRCC. The significant positive correlation between IC and MVD indicates valid representation of tumor perfusion by DECT. KEY POINTS: • Analysis of iodine concentration using DECT imaging could reliably distinguish papillary from clear cell subtypes of renal cell cancer (RCC). • A cutoff value of 3.1 mg/ml allowed a distinction between papillary and clear cell RCCs with an accuracy of 86.8%. • The positive correlation with microvascular density in tumor specimens indicates correct display of perfusion by iodine concentration analysis.

Adjuvant therapy in renal cell carcinoma: the perspective of urologists.

BACKGROUND: Until recently, there was no approved adjuvant therapy (AT) for renal cell carcinoma (RCC) unless sunitinib was approved in the US. We evaluated clinical opinion and estimated use regarding different treatment options and patient selection of AT in RCC patients based on current scientific data and individual experience in Germany. METHODS: We conducted an anonymous survey during a national urology conference in 01/2017. Answers of 157 urologists treating RCC patients could be included. Questions were related to practice setting, treatment of RCC, follow-up strategy, physicians' personal opinion and individually different important parameters regarding S-TRAC and ASSURE-trial. RESULTS: 82% were office based. 67% were located in larger cities. 83% reported that nephron-sparing surgery (NSS) was performed in tumors with diameter < 4 cm. Follow-up was done mainly in concordance with guideline recommendations. 68% treated an average of 2.9 patients/year with systemic therapy. Therapy was predominantly advocated using sunitinib (94%). Urologists were informed about S-TRAC and ASSURE-trial. For 47%, reported hazard ratio is the most important parameter to understand trial results followed by overall survival (OS) in 46%, disease-free survival in 38%, and results of other trials in 34%. The most convincing parameter to decide on AT is OS (69%). 62% placed their confidence in ASSURE over STRAC-trial. 44% would use AT for 12 months. Nodal involvement was the most common denominator for use of AT. 82% favor sunitinib as AT. CONCLUSIONS: A minority of urologists would use AT and are more confident in ASSURE-trial. Reluctance of prescribing AT mainly is based on lack of OS data and conflicting trial results.

Dynamic contrast-enhanced CT-derived blood flow measurements enable early prediction of long term outcome in metastatic renal cell cancer patients on antiangiogenic treatment.

PURPOSE: To evaluate the role of dynamic contrast-enhanced CT (DCE-CT) as an independent non-invasive biomarker in predicting long term outcome in patients with metastatic renal cell carcinoma (mRCC) on antiangiogenic treatment. MATERIAL AND METHODS: Eighty two mRCC patients were prospectively enrolled from 09/2011 to 04/2015, out of which 71 were included in the final data analysis; the population was observed until 12/2020 to obtain complete overall survival data. DCE-CT imaging was performed at baseline and 10 to 12 weeks after start of treatment with targeted therapy. DCE-CT included a dynamic acquisition after injection of 50 ml of nonionic contrast agent at 6 ml/s using a 4D spiral mode (10 cm z-axis coverage, acquisition time 43 sec, 100 kVp (abdomen), 80 kVp (chest), 80-100 mAs) on a dual source scanner (Definition FLASH, Siemens). Blood flow (BF) was calculated for target tumor volumes using a deconvolution model. Progression free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier statistics (SPSS version 24). RESULTS: Patients were treated with either sunitinib, pazopanib, sorafenib, tivozanib, axitinib, or cabozantinib. A cut-off value of 50% blood flow reduction at follow-up allowed for identification of patients with favorable long-term outcome: Median OS in n = 42 patients with an average blood flow reduction of >50% (mean, 79%) was 34 (range, 14-54) months, while n = 21 patients with an average reduction of less than 50% (mean, 28%) showed a median OS of 12 (range, 6-18) months, and n = 8 patients with an increase in blood flow survived for a median of 7 (range, 3-11) months. CONCLUSION: Blood flow in metastases measured with DCE-CT at first follow-up is a strong predictor of overall survival in mRCC patients on antiangiogenic treatment.

Propensity Score-Matched Analysis of Single Fraction Robotic Radiosurgery Versus Open Partial Nephrectomy in Renal Cell Carcinoma: Oncological Outcomes.

Introduction High-dose local stereotactic robotic radiosurgery (RRS) is a non-invasive alternative to surgery in renal masses and selected patients. We have, so far, limited its use to the elderly and patients at high risk from surgery. In this study, we matched patients with renal tumors who were treated with single fraction RRS to patients who underwent open partial nephrectomy (OPN). Methods Between January 2009 and December 2017, we included 571 consecutive patients undergoing OPN and 99 patients who underwent RRS in this retrospective analysis. Patients had to have a follow-up of at least six months and we were able to match 35 with a propensity score. Matching criteria were Eastern Cooperative Oncology Group (ECOG) status, age, clinical tumor, nodes, and metastases (TNM), and tumor diameter. Tumor response, renal function, survival, and adverse events were evaluated every three months until progression or death. Results Median age was 65 years for RRS (range 58-75) and 71 (range 56-76) for OPN (p=0.131). Median diameter of renal tumors was 2.8 cm (range 2.4-3.9) for RRS and 3.5 cm (2.8-4.5) for OPN, p=0.104. Median follow-up was 28.1 months (range 6.0-78.3 months). Local tumor control nine months after RRS and OPN was 98% (95% CI: 89-99%). Renal function remained stable with a median creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) at baseline of 76.8mlmin/1.73m2 (range 25.3-126.3) and 70.3ml/min/1.73m2 (range 18.6-127.3) at follow-up (p=0.89). Median overall survival was not reached. No difference in overall survival (OS) was seen in RRS compared to OPN (p=0.459). Conclusions Single fraction RRS is an alternative to OPN in patients unfit for surgery. Oncological and functional results are comparable to those of OPN. Further studies are needed to determine long-term results and limits of RRS in this setting and in younger patients.

Radical vaginal trachelectomy (RVT) combined with laparoscopic lymphadenectomy: prospective study of 225 patients with early-stage cervical cancer.

OBJECTIVE: The aim of the study was to prove the surgical and oncological safety of radical vaginal trachelectomy (RVT) and laparoscopic lymphadenectomy for patients with early-stage cervical cancer who are seeking parenthood. METHODS: A database of 225 patients with early-stage cervical cancer and intention to treat by RVT after laparoscopic lymphadenectomy was prospectively maintained. A total of 212 patients were treated according to the protocol. The procedure was preformed in a standardized manner, and life table analysis was applied. RESULTS: In the cohort of patients treated according to protocol, 8 recurrences occurred and 4 patients died from recurrence. The median follow-up time was 37 months (range, 0-171 months). The 5-year recurrence-free and overall survival was 94.4% and 97.4%, respectively. Perioperative and short-term postoperative complications were rare (2.8% and 7.5%, respectively). No severe long-term complications occurred. CONCLUSIONS: Radical vaginal trachelectomy combined with laparoscopic lymphadenectomy is a safe method for treatment of patients with early-stage cervical cancer who are seeking parenthood.

Purinergic smooth muscle contractions in the human prostate: estimation of relevance and characterization of different agonists.

Non-adrenergic prostate smooth muscle contractions may account for the limited effectiveness of α1-adrenoceptor antagonists, which are the first-line option for medical treatment of voiding symptoms suggestive of benign prostatic hyperplasia. In non-human prostates, purinergic agonists induce contractions reaching similar magnitudes as α1-adrenergic contractions. However, evidence for the human prostate is highly limited, and pointed to much weaker purinergic contractions. Here, we examined contractions of different purinergic agonists in human prostate tissues. Tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, and expression of purinergic receptors was studied by RT-PCR. Electric field stimulation (EFS)-induced contractions amounted to 104% of KCl-induced contractions (95% CI: 84-124%). From all tested agonists, only ATP induced concentration-dependent contractions, reaching an average maximum of 18% (12-24%) of KCl. Maximum tensions following application of other agonists averaged to 7.1% of KCl for α,ß-methylene-ATP (1.8-12.4%), 3.9% for ß,γ-methylene-ATP (2.0-5.4%), 3.1% for 2-methylthio-ATP (- 0.1-6.3%), and 5.1% for ATPγS (1.0-9.2%). Responses were not affected by the P2X antagonist NF023 or the P2Y antagonist PPADS. mRNA expression of P2X1-4 correlated with expression of a marker for catecholaminergic nerves, although neither ATP, NF023, nor PPADS changed EFS-induced contractions. Correlation between expression of receptors and the smooth muscle marker calponin was not observed. Our findings point to a low relevance of purinergic contractions in the human prostate, compared to other contractile stimuli in the human prostate and compared to purinergic contractions in non-human prostates. Purinergic contractions in the human prostate are not sensitive to NF023 or PPADS.

Can we define reliable risk factors for anastomotic strictures following radical prostatectomy?

BACKGROUND: To identify risk factors for anastomotic strictures in patients after radical prostatectomy. METHODS: In all, 140 prostate cancer patients with one or more postoperative anastomotic strictures after radical prostatectomy were included. All patients underwent transurethral anastomotic resection at the University Hospital of Munich between January 2009 and May 2016. Clinical data and follow-up information were retrieved from patients' records. Statistical analysis was done using Kaplan-Meier curves and log rank-test with time to first transurethral anastomotic resection as endpoint, Chi-square-test, and Mann-Whitney-U test. RESULTS: In all, 140 patients with a median age of 67 years (IQR: 61-71 years) underwent radical prostatectomy. Median age at time of transurethral anastomotic resection was 68 years (IQR: 62-72). Patients needed 2 surgical interventions in median (range: 1-15). Median time from radical prostatectomy to transurethral anastomotic resection was 6 months (IQR: 3.9-17.4). Median duration of catheterization after radical prostatectomy was 10 days (IQR: 8-13). In all, 26% (36/140) received additional radiotherapy. Regarding time to first transurethral anastomotic resection, age and longer duration of catheterization after radical prostatectomy with a cutoff of 7 days showed no statistically significant differences (p = 0.392 and p = 0.141, respectively). Tumor stage was no predictor for development of anastomotic strictures (p = 0.892), and neither was prior adjuvant radiation (p = 0.162). Potential risk factors were compared between patients with up to 2 strictures (low-risk) and patients developing > 2 strictures (high-risk): high-risk patients had more often injection of cortisone during surgery (14% vs 0%, p < 0.001) and more frequently advanced tumor stage pT > 2 (54% vs 38%, p = 0.055), respectively. Other risk factors did not show any significant difference compared to number of prior transurethral anastomotic strictures. CONCLUSIONS: We could not identify a reliable risk factor to predict development of anastomotic strictures following radical prostatectomy.

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766.

INTRODUCTION: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or ß3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues. METHODS: Female and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath. RESULTS: Electric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged Emax values. EHT1864 reduced carbachol-induced contractions, resulting in reduced Emax values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864. CONCLUSIONS: NSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A2-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS.

Sequential Treatment Based on Sunitinib and Sorafenib in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVES: The aim of our study was to evaluate the outcome of alternative sequences of sunitinib followed by sorafenib versus sorafenib followed by sunitinib therapies in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: This single-center study analyzed patients with mRCC on systemic therapy between January 2005 and August 2011. Patients were treated with the recommended first-line therapy (sunitinib, sorafenib, pazopanib, or immunotherapy) until progression or intolerable toxicity and afterward switched to another guideline-recommended systemic therapy. Only patients starting first-line therapy on either sorafenib or sunitinib and switching to the other of these drugs were included in this analysis. RESULTS: Out of 266 patients (females: 85, males: 181) with a median age of 57.1 years (30 - 76 years), 57 patients with a sequence of sunitinib and sorafenib were identified. First-line sorafenib therapy was followed by sunitinib (So-Su) in 32 patients; sunitinib was followed by sorafenib (Su-So) in 25 patients. Progression-free survival (PFS) for patients with first-line sorafenib was 11.6 months and was 8.7 months for sunitinib. Overall survival (OS) rates for Su-So was 118.8 months and 83.3 months with So-Su (p = 0.82). No new safety signals were detected. CONCLUSION: None of the therapeutic first-line approaches was superior to the other. Sequencing tyrosine kinase inhibitor (TKI) therapy seems to be effective in mRCC and superior to single-line therapy. Further studies should focus on the efficacy of single treatment lines rather than treatment sequences to estimate more potent drugs based on PFS rather than overall survival (OS).

Partial Nephrectomy in pT3a Tumors Less Than 7 cm in Diameter Has a Superior Overall Survival Compared to Radical Nephrectomy.

Objectives We conducted this study to analyze the survival rates of patients with advanced renal tumors <7 cm in diameter treated surgically by partial nephrectomy (PN) compared to those who received radical nephrectomy (RN). Material and methods We retrospectively analyzed clinical data from 55 consecutive patients from our institutional database with T3a renal cell carcinoma of <7 cm treated surgically either by PN (n = 38) or RN (n = 17) in the Department of Urology of Ludwig Maximilians University from January 2006 to August 2014. The overall survival (OS) rates were calculated according to Kaplan-Meier estimation. Results The median age of the population was 67.9 years (range: 39.4 to 87.9 years). The median blood loss was 164.1 ml (range: 0 to 1200 ml), and the median clamping time was 8.85 minutes (range: 0 to 38 minutes). On average, the surgery lasted for 118 minutes (range: 40 to 210 minutes). The median serum creatinine level measured was 1.2 mg/dl (range: 0.7 to 2.3 mg/dl) preoperatively, and 1.4 mg/dl (range: 0.7 to 4.3 mg/dl) postoperatively. The median creatinine serum level measured during follow up was 1.4 ng/ml in individuals with a PN (range: 0.7 to 3.2 ng/ml), and 1.5 ng/ml in those with an RN (range: 0.9 to 4.3 ng/ml). Patients with an RN had a median OS of 38.6 months (range: 0 to 63.3 months). The median OS for patients with a PN was not reached after a follow-up of 80 months. The difference in OS in patients with PN and RN was statistically significant (P < 0.005). Conclusion Performing a PN in T3a tumors leads to better survival rates compared to an RN. In tumors <7cm, cT3a does not seem to be a contraindication for a PN. Further data should be analyzed to prove this survival benefit in a larger, multi-institutional cohort.

Emphysematous pyelonephritis: Case report and literature overview.

INTRODUCTION: Emphysematous pyelonephritis is a rare necrotizing infection of the kidney with a poor prognosis. If it occurs in patients with a reduced general condition, this infection is life threatening. Early diagnosis is made by computed tomography. Treatment options are drainage and intensive care or immediate nephrectomy in severe cases. CASE DESCRIPTION: A 73-year-old woman in a poor general condition presented with a fulminant urosepsis. Computed tomography revealed an impressive abscess formation of the right kidney with free air retro and intraperitoneal. The diagnosis of emphysematous pyelonephritis was made. Besides septicemia, she had a multiorgan failure including kidney and liver function deterioration. Nephrectomy was performed immediately. The postoperative course was successful with a complete stabilization of the kidney and liver function and reconvalescence of the patient. DISCUSSION: The widespread availability of imaging techniques leads to early diagnosis and a reduction of mortality of renal and periphrenic abscesses and even of emphysematous pyelonephritis. However, severe cases have a poor outcome and require aggressive and immediate therapy. Besides systemic antibiotic therapy and percutaneous and surgical drainage, radical nephrectomy is a viable therapy option and should be performed immediately in patients with several risk factors, poor prognosis, and extensive findings. CONCLUSION: Radical nephrectomy being performed immediately seems to be the optimal management in patients with acute emphysematous nephritis and urosepsis.

Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance-A systematic review.

OBJECTIVE: To systematically evaluate evidence on prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance. METHODS: Systematic literature search conducted of Medline, Web of Science, Cochrane Library, and the conference proceedings of the ASCO, AUA, and EAU meetings (last search: October 2016), according to our prospectively registered protocol (PROSPERO registration number CRD42014009434). Identified records were reviewed according to the Cochrane Method Group of Prognosis Reviews recommendations and the PRISMA reporting guideline. Study quality was appraised with the Quality in Prognosis Studies (QUIPS) tool. RESULTS: Nineteen studies reporting on 26 potential prognostic factors were included in our analysis. Among the most frequently reported factors, tumor size (continuous or dichotomized) was significantly associated with relapse in 10/14 studies with a hazard ratio (HR) ranging from 1.33 (95% confidence interval [CI]: 1.14-1.56) to 3.17 (95% CI: 1.08-9.26). Rete testis invasion was significantly associated with relapse in only 4/13 studies with a HR ranging from 1.18 (95% CI: 0.92-1.51) to 1.36 (95% CI: 0.81-2.28). Lymphovascular invasion, young age, and preoperative HCG level had no association with relapse. Our findings are limited by heterogeneity of study designs, potential reporting bias, and moderate-to-poor study quality. CONCLUSION: In stage I seminoma, tumor size is the most valuable prognostic factor on which to base relapse risk and to counsel patients about adjuvant treatment. Large tumor size was defined quite inhomogenously among the included studies, so no distinct cutoff value for tumor size can be recommended. Other potential prognostic factors including rete testis invasion play a minor role in stage I seminoma.

[PSA screening]. / PSA zur Früherkennung des Prostatakarzinoms.

Screening for prostate cancer should help to detect malignancy at an early and potentially treatable stage. Serum psa has been used as a test for prostate cancer for over 20 years, but its practise is still very controversial worldwide. Studies can demostrate good aspects for screening with psa: the overall mortality and especially the metastases at stage of primary diagnosis can be reduced. A relevant factor is measuring the serum psa in younger men aged 40-50 for a baseline to evaluate the individual risk of prostate cancer. Furthermore, it is important not to exclude patients because of their age of measuring the psa. The individual life expectancy should help to decide about its usefulness. This aspect is especially important in the face of an increasing life expectancy and fitness level at old age. Further studies are needed to publish a recommendation for psa-screening. In Germany, the PROBASE is a current study to research this topic.

Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance--protocol for a systematic review.

BACKGROUND: Testicular cancer is primarily treated with the surgical removal of the affected testis. About 50% of testicular cancer patients present with a stage I seminoma. If no chemo- or radiotherapy as adjuvant treatment is initiated after orchiectomy, 15-20% of these patients will develop metastases. Although adjuvant treatment is effective in reducing the relapse risk, there is rising concern about overtreatment of these patients. Prognostic factors at primary diagnosis might have the potential to identify patients at higher risk of tumor relapse, allowing to guide individual therapy and to avoid overtreatment. Therefore, we aim to synthesize the available evidence on tumor or patient characteristics as possible prognostic factors for cancer recurrence in patients with clinical stage I seminoma. METHODS/DESIGN: We will conduct a broad systematic review to analyze what prognostic factors predict cancer recurrence in patients with a first time diagnosis of clinical stage I seminoma, who received no adjuvant chemo- or radiotherapy after orchiectomy. The literature search will comprise MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), and the conference proceedings of the American Society of Clinical Oncology (ASCO), American Urologic Association (AUA), and European Urologic Association (EAU) Annual Meetings. Prospective and retrospective longitudinal studies reporting on prognostic factors for cancer recurrence will be considered. We will consider the wealth of any candidate clinical or pathological prognostic factor reported in the literature. Our outcome of interest will be tumor recurrence at a minimum of 2 years follow-up. Study screening, data extraction, and quality assessment will be done by two reviewers independently. Hazard ratios will be used to measure the relationship between the potential prognostic factor and tumor recurrence. Meta-analyses will be conducted with sufficiently homogeneous studies and separately with respect to study design, by using the random-effects generic inverse variance model. DISCUSSION: Limitations and strengths will be discussed in our review, and the results will be put into context with other studies in this field. Our results will help to guide evidence-based decision-making on patients with clinical stage I seminoma, allowing a better adjustment of therapies with regard to the individual patient's risk. Our findings will furthermore help to formulate recommendations for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009434.