Search

Objective To systematically evaluate evidence on prognostic factors for tumor recurrence in clinical stage I nonseminoma patients other than lymphovascular invasion (LVI). Methods We performed a systematic literature search in the biomedical databases Medline (via Ovid) and Cochrane Central Register of Controlled Trials (search period January 2010 to February 2021) for full text publications in English and German language, reporting on retro- or prospectively assessed prognostic factors for tumor recurrence in patients with stage I nonseminomatous germ cell tumors. Results Our literature search yielded eleven studies reporting on 20 potential prognostic factors. Results are based on cohort studies of mostly moderate to low quality. Five out of eight studies found a significant association of embryonal carcinoma (EC) in the primary tumor with relapse. Among the different risk definitions of embryonal carcinoma (presence, predominance, pure), presence of EC alone seems to be sufficient for prognostification. Interesting results were found for rete testis invasion, predominant yolk sac tumor, T-stage and history of cryptorchidism, but the sparse data situation does not justify their clinical use. Conclusions No additional factors that meet the prognostic value of LVI, especially when determined by immunohistochemistry, could be identified through our systematic search. The presence of EC might serve as a second, subordinate prognostic factor for clinical use as the data situation is less abundant than the one of LVI. Further efforts are necessary to optimize the use of these two prognostic factors and to evaluate and validate further potential factors with promising preliminary data.

Purpose In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors. Methods This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety. Results Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success. Conclusions Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.

PDF file - 209KB, Positivity for SALL4, OCT3/4, keratins, EpCAM and Cellsearch(registered trademark) assay in control cell lines. A, Double fluorescence staining for SALL4 (green) / keratins (orange) and OCT3/4 (green) / EpCAM (orange) counterstained with DAPI (blue) to visualize cells' nuclei in 4 different germ cell tumor cell lines (magnification: 400x). Scale bar, 50 microm. B, Representation of the staining of tumor cells from 4 different germ cell tumor cell lines spiked into blood of healthy donors using the Cellsearch(registered trademark) assay. C, Representative images of primary testicular germ cell tumor samples positive for SALL4, OCT3/4, keratins and EpCAM immunohistochemical staining counterstained with Hematoxylin to visualize cells' nuclei (magnification - 400x, scale bar - 50 microm). (CK, cytokeratin. PE, phycoerythrin. APC, allophycocyanin. DAPI, 4′,6-diamidino-2-phenylindole). D, Dot-like pattern keratin (orange) staining in TCam-2 and NT2 cell lines, counterstained with DAPI (blue) to visualize cells' nuclei (magnification: 1000x). Scale bar, 20 microm.

PDF file - 65KB, Characterization of relapsed, treatment-refractory germ cell tumor patients.

Purpose: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell–specific markers, and results were correlated with disease stage, histology, and serum tumor markers.Experimental Design: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell–specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system.Results: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), β-human chorionic gonadotropin (βHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood.Conclusions: The inclusion of germ cell tumor–specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery. Clin Cancer Res; 20(14); 3830–41. ©2014 AACR.

Purpose The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients. Methods Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR). Results The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH p = 0.012) and 32% vs. 59% (p ≤ 0.001), respectively. Conclusions LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.

Purpose To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT). Methods A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables. Results The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the “poor prognosis” group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3–4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy. Conclusion In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors.

Die Surveillance ist die haufigste Therapieform bei Hodentumorpatienten im nicht-metastasierten klinischen Stadium I (cSI). Die Indikationen fur die Surveillance sowie der individuellen Aufklarung und Grenzen der Surveillance werden dargestellt. Der Beitrag gibt einen Uberblick uber den aktuellen Stand der Literatur unter Einbeziehung von Grundlagenarbeiten, systemischen Ubersichtsarbeiten, Expertenempfehlungen und Fallbeispielen. Das Progressionsrisiko unter Surveillance liegt fur die Seminome bei 5–30 % und fur die Nichtseminome bei 15–50 %. Die Surveillance ist die bevorzugte Therapieoption beim Seminom und beim Niedrig-Risiko-Nichtseminom ohne Vorliegen einer Lymphgefasinvasion. Die Patientenaufklarung sollte das individuelle Progressionsrisiko, die Moglichkeiten einer adjuvanten Therapie, potenzielle Nebenwirkungen der adjuvanten Therapie, die Art der Therapie im Falle eines Progresses sowie die Heilungswahrscheinlichkeit beinhalten. Ein hohes Progressionsrisiko, psychologische Aspekte und Malcompliance sind wichtige Limitationen fur die Surveillance. Unter Beachtung der wesentlichen Limitationen der Surveillance konnen Hodentumorpatienten im cSI mittels Surveillance sicher behandelt werden.

Purpose Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. Methods Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher’s exact and Chi-square test. Results Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. Conclusion Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Im Mai 2019 ist die erste deutsche S3-Leitlinie zur Diagnostik, Therapie und Nachsorge der Keimzelltumoren des Hodens erschienen. Grundlage war eine ausgiebige Literaturrecherche durch UroEvidence, auf Basis derer entsprechende Empfehlungen formuliert werden konnten. Die fur die Praxis wesentlichen Aspekte der Leitlinie werden in diesem Beitrag zusammengefasst.

Purpose The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options. Methods A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed. Results Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%–21.1% for RT and of 0%–14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities. Conclusions RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.

Purpose One of the main issues in testicular germ cell tumors (TGCTs) management is to reduce the necessary amount of treatment to achieve cure. Excess treatment burden may arise from late diagnosis of the primary as well as from false positive or negative staging results. Correct imaging is of paramount importance for successful management of TGCT. The aim of this review is to point out the current state of the art as well as innovative developments in TGCT imaging on the basis of three common challenging clinical situations. Methods A selective literature search was performed in PubMed, Medline as well as in recent conference proceedings. Results Regarding small testicular lesions, recent studies using elastography, contrast-enhanced ultrasound or magnetic resonance imaging (MRI) showed promising data for differentiation between benign and malignant histology. For borderline enlarged lymph nodes FDG-PET-CT performance is unsatisfactory, promising new techniques as lymphotropic nanoparticle-enhanced MRI is the subject of research in this field. Regarding the assessment of postchemotherapeutic residual masses, the use of conventional computerized tomography (CT) together with serum tumor markers is still the standard of care. To avoid overtreatment in this setting, new imaging modalities like diffusion-weighted MRI and radiomics are currently under investigation. For follow-up of clinical stage I TGCTs, the use of MRI is non-inferior to CT while omitting radiation exposure. Conclusion Further efforts should be made to refine imaging for TGCT patients, which is of high relevance for the guidance of treatment decisions as well as the associated treatment burdens and oncological outcomes.

Purpose Follow-up protocols for patients with testicular cancer (TC) have significantly reduced the number of cross-sectional imaging studies to reduce radiation exposure. At present, it is unclear whether magnetic resonance imaging (MRI) could replace conventional computerized tomography (CT) imaging. The objective of this study is to summarize the scientific evidence on this topic and to review guideline recommendations with regard to the use of MRI. Methods A systematic literature review was performed searching Medline and Cochrane databases for prospective studies on patients with TC in the follow-up care (last search in February 2021). Additionally, guideline recommendations for TC were screened. Data extraction and quality assessment of included studies were performed and used for a descriptive presentation of results. Results A total of four studies including two ongoing trials were identified. Overall, the scientific evidence of prospective comparative studies is based on 102 patients. Data suggest that abdominal imaging with MRI can replace conventional CT for detection of lymph node metastasis of the retroperitoneum to spare radiation exposure and contrast media application. However, experienced radiologists are needed. Clinical guidelines are aware of the risk of diagnosis-induced secondary malignancy due to CT imaging and some have adapted their recommendations accordingly. Results of the two ongoing trials on 738 patients are expected soon to provide more reliable results on this topic. Conclusions There is growing evidence that abdominopelvic MRI imaging can replace CT imaging during follow-up of patients with TC in order to reduce radiation exposure and diagnosis-induced secondary malignancy.

Surveillance is the most frequently used treatment option in testicular germ cell tumour (TGCT) patients in nonmetastasised clinical stage I (cSI).Presentation of indications for surveillance, the process of individual patient's advice and the limitations of surveillance.An overview of the current literature is given, including basic research, systemic reviews and expert recommendations. Basic principles are illustrated by case reports.The risk of progression for cSI TGCT patients under surveillance is 5-30% for seminomas and 15-50% for nonseminomas. Surveillance is the preferred treatment option in seminoma and low-risk nonseminoma without lymphovascular invasion. Patients should be informed concerning the individual risk of progression, the possibilities of adjuvant therapy, side effects of adjuvant therapy, the kind of therapy in case of progression and the cure rate. A high risk of progression, psychological issues and malcompliance are important limitations of surveillance.By thoroughly considering the limitations of surveillance, cSI TGCT patients can be safely treated with surveillance.HINTERGRUND: Die Surveillance ist die häufigste Therapieform bei Hodentumorpatienten im nicht-metastasierten klinischen Stadium I (cSI).Die Indikationen für die Surveillance sowie der individuellen Aufklärung und Grenzen der Surveillance werden dargestellt.Der Beitrag gibt einen Überblick über den aktuellen Stand der Literatur unter Einbeziehung von Grundlagenarbeiten, systemischen Übersichtsarbeiten, Expertenempfehlungen und Fallbeispielen.Das Progressionsrisiko unter Surveillance liegt für die Seminome bei 5–30 % und für die Nichtseminome bei 15–50 %. Die Surveillance ist die bevorzugte Therapieoption beim Seminom und beim Niedrig-Risiko-Nichtseminom ohne Vorliegen einer Lymphgefäßinvasion. Die Patientenaufklärung sollte das individuelle Progressionsrisiko, die Möglichkeiten einer adjuvanten Therapie, potenzielle Nebenwirkungen der adjuvanten Therapie, die Art der Therapie im Falle eines Progresses sowie die Heilungswahrscheinlichkeit beinhalten. Ein hohes Progressionsrisiko, psychologische Aspekte und Malcompliance sind wichtige Limitationen für die Surveillance.Unter Beachtung der wesentlichen Limitationen der Surveillance können Hodentumorpatienten im cSI mittels Surveillance sicher behandelt werden.

Objectives: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. Materials and Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. Results: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. Conclusion: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.

Introduction: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic’s background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. Results: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. Conclusion: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.

Background Post-chemotherapy retroperitoneal lymph node dissection (pc-RPLND) is one cornerstone in the clinical management of patients with nonseminomatous testicular germ cell tumours (GCT). A wide range of complication rates in this type of surgery is reported so far. We retrospectively evaluated the frequency of major complications by using the Clavien-Dindo classification and analysed the influence of various clinical factors on complication rates in pc-RPLND. Methods We retrospectively analysed 146 GCT patients undergoing pc-RPLND. Complications of grade III–V according to the Clavien-Dindo classification occurring within 30 days after surgery were registered along with the following clinical factors: age, body mass index (BMI), duration of surgery, number of anatomic fields resected, side of primary tumour, histology of surgical specimen, histology of primary tumour, and total dose of cisplatin applied prior to surgery. For comparison, we also evaluated 35 chemotherapy-naïve patients with primary RPLND and 19 with laparoscopic RPLND. We analysed types and frequencies of the various complications as well as associations with clinical factors using descriptive statistical methods. Results A total of 14.4% grade III–IV complications were observed in pc-RPLND, and 8.6% and 5.3% in primary and in laparoscopic RPLND, respectively. There was no perioperative mortality. Lymphocele was the most frequent adverse event (16% of grade III–IV complications). Operation time > 270 min (p = 0.001) and vital cancer in the resected specimen (p = 0.02) were significantly associated with higher complication rates. Left-sided resection fields involved two-fold higher complication rates, barely missing statistical significance (p = 0.06). Conclusions Pc-RPLND involves a grade III–V complication rate of 14.4%. Prolonged operation time and vital cancer in the residual mass are significantly associated with higher complication rates. The Clavien-Dindo classification system may allow inter-observer variation in rating complication grades, which may represent one reason for the wide range of reported RPLND complication rates. RPLND represents major surgery and surgeons active in this field must be competent to manage adverse events.

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.

Background Excellent uniform training of urology residents is crucial to secure both high-quality patient care and the future of our specialty. Residency training has come under scrutiny following the demands of subspecialized care, economical aspects, and working hour regulations. Objective To comprehensively assess the surgical training, research opportunities, and working conditions among urology residents in Germany. Design, setting, and participants We sent a 29-item online survey via email to 721 members of the German Society of Residents in Urology. Outcome measurements and statistical analysis Descriptive analyses were conducted to describe the surveys' four domains: (1) baseline characteristics, (2) surgical training (cumulative completed case volume for all minor-, medium-, and major-complexity surgeries), (3) research opportunities, and (4) working conditions. Results and limitations Four hundred and seventy-two residents completed the online survey (response rate 65%). Surgical training: the median number of cumulative completed cases for postgraduate yr (PGY)-5 residents was 113 (interquartile range: 76–178). Minor surgeries comprised 57% of all surgeries and were performed by residents in all PGYs. Medium-complexity surgeries comprised 39% of all surgeries and were mostly performed by residents in PGYs 2–5. Major surgeries comprised 4% of all surgeries and were occasionally performed by residents in PGYs 3–5. Research opportunities: some 44% have attained a medical thesis ( Dr. med. ), and 39% are currently pursuing research. Working conditions: psychosocial work-related stress was high and for 82% of residents their effort exceeded their rewards. Some 44% were satisfied, 32% were undecided, and 24% were dissatisfied with their current working situation. Limitations include self-reported survey answers and a lack of validated assessment tools. Conclusions Surgical exposure among German urology residents is low and comprises minor and medium-complex surgeries. Psychosocial work-related stress is high for the vast majority of residents indicating the need for structural improvements in German urology residency training. Patient summary In this study, we evaluated the surgical training, research opportunities, and working conditions among urology residents in Germany. We found low surgical exposure and high rates for psychosocial work-related stress, indicating the need for structural improvements in German urology residency training.

Previous randomized trials have not provided conclusive evidence about dose escalations and associated toxicities for salvage radiotherapy (SRT) in prostate cancer. Here, we retrospectively analyzed whether dose escalations influenced progression-free survival in 554 patients that received salvage radiotherapy for relapses or persistently elevated prostate cancer antigen (PSA) after a radical prostatectomy. Patients received SRT between 1997 and 2017 at two University Hospitals in Germany. We compared patient groups that received radiation doses

// Manuela A. Hoffmann 1, 2, 3 , Matthias Miederer 2 , Helmut J. Wieler 3 , Christian Ruf 4 , Frank M. Jakobs 5 and Mathias Schreckenberger 2 1 Supervisory Center for Medical Radiation Protection, Bundeswehr Medical Service Headquarters, Koblenz, Germany 2 Department of Nuclear Medicine, Johannes Gutenberg-University, Mainz, Germany 3 Department of Nuclear Medicine, Bundeswehr Central Hospital, Koblenz, Germany 4 Department of Urology, Bundeswehr Central Hospital, Koblenz, Germany 5 Department of Epidemiology, German Air Force Center for Aerospace Medicine, Furstenfeldbruck, Germany Correspondence to: Manuela A. Hoffmann, email: manuhoffmann@web.de Keywords: prostate cancer; positron emission tomography/computed tomography; prostate-specific membrane antigen; choline; detection of significant cancer Received: August 16, 2017 Accepted: October 27, 2017 Published: November 14, 2017 ABSTRACT Background : Radiolabeled prostate-specific membrane antigen (PSMA) has proven to be a highly accurate method to detect recurrence and metastases of prostate cancer, but only sparse data is available about its performance in the diagnosis of clinically significant primary prostate cancer. Methods : We compared 68 Ga-PSMA-11 PET/CT in 25 patients with 18 FEC PET/CT in 40 patients with suspected prostate carcinoma based on an increased PSA level. The PET/CT results were compared with the histopathologic Gleason Score (GS) of biopsies. Results : The 68 Ga-PSMA-11 PET/CT revealed highly suspect prostatic lesions (maximum standardized uptake value/SUV max >2.5) in 21/25 patients (84%), associated with GS≥6 (low-grade/high-grade carcinoma). Two histopathologic non-malignancy-relevant cases (GS 12.0 which further increased with rising GS. There were 2 false positives and no false negative findings for high-grade prostate cancer using a cut off-level for SUV max of 2.5. In contrast, the 18 FEC PET/CT showed suspected malignant lesions in 38/40 patients (95%), which included 3 lesions with GS

Background: The prognostic role of human chorionic gonadotropin (hCG) and lactate dehydrogenase (LDH) serum levels in seminoma patients remains uncertain. This observational study evaluates the prognostic impact of tumour marker levels, and other clinicopathological findings, in hCG-positive seminoma patients. Methods: Seminoma patients with serum hCG levels above normal at first diagnosis were eligible for recruitment. Statistical analysis, including multivariate regression, was performed to identify risk factors. Primary end-points were overall survival (OS) and recurrence-free survival (RFS). Results: We recruited 1031 hCG-positive patients (stage I: n = 586; stage II + III: n = 427) diagnosed between 1981 and 2018. In metastatic disease, LDH levels >= 3 above upper normal limit (UNL) pre- (n = 109) or post-orchiectomy (n = 73) and patients aged >= 40 years (n = 187) were associated with poor prognosis: 5-year OS rates of 84% (LDH >= 3 UNL pre-orchiectomy) versus 92% (= 3 UNL post-orchiectomy) versus 92% (= 40 years) versus 91% (= 2000 IU/l pre-orchiectomy (n = 17) exhibited a poor prognosis, with 5-year OS rates of 73% (>= 2000 IU/ l) versus 94% (= 2000 IU/l, may represent a separate prognostic subgroup associated with impaired survival rates. (C) 2020 Elsevier Ltd. All rights reserved.

Melatonin receptors are highly relevant for the hepatoprotective effects of the pineal hormone melatonin after experimental hemorrhagic shock in rats. In this study, we sought to determine the spatial expression pattern and a putative regulation of two melatonin receptors, membrane bound type 1 and 2 (MT1 and MT2), in the liver of rats. In a male rat model (Sprague Dawley) of hemorrhage and resuscitation, we investigated the gene expression and protein of MT1 and MT2 in rat liver by utilizing real-time quantitative polymerase chain reaction, a western blot analysis, and immunohistochemistry. Plasma melatonin content was measured by an enzyme-linked immunosorbent assay. Male rats underwent hemorrhage and were resuscitated with shed blood and a Ringer&rsquo, s solution (n = 8 per group). After 90 min of hemorrhage, animals were given vehicle, melatonin, or ramelteon (each 1.0 mg/kg intravenously). Sham-operated controls did not undergo hemorrhage but were treated likewise. Plasma melatonin was significantly increased in all groups treated with melatonin and also after hemorrhagic shock. Only MT1, but not the MT2 messenger ribonucleic acid (mRNA) and protein, was detected in the rat liver. The MT1 protein was located in pericentral fields of liver lobules in sham-operated animals. After hemorrhagic shock and treatment with melatonin or ramelteon, the hepatic MT1 protein amount was significantly attenuated in all groups compared to sham controls (50% reduction, p &lt, 0.001). With respect to MT1 mRNA, no significant changes were observed between groups (p = 0.264). Our results indicate that both endogenous melatonin exposure from hemorrhagic shock, as well as exogenous melatonin and ramelteon exposure, may attenuate melatonin receptors in rat hepatocytes, possibly by means of desensitization.

Leydig-cell tumours (LCT) of the testis are poorly understood clinically. The aim of this report is to analyse the clinical characteristics of LCT in a large patient sample and to compare these findings with corresponding data of germ-cell tumours (GCT). In a sample of 208 patients treated during 1995–2017 in 33 institutions, the following characteristics were registered: age, presenting symptoms, primary tumour size, testis-sparing surgery (TSS) or orchiectomy, malignancy, laterality, medical history, and outcome. Data analysis included descriptive statistical methods and logistic regression analysis. The ratio LCT:GCT is 1:23 (4.4%). The findings are as follows: median age 41 years, undescended testis 8%, bilateral LCTs 3%, malignant LCT 2.5%, contralateral GCT 2.5%, incidental detection 28%, scrotal symptoms 43%, infertility 18%, elevated estradiol levels 29%. TSS was performed in 56% with no local relapse. Of the patients with malignant LCT, one was cured through surgery. LCT is rare, with a relative frequency (relative to GCT) of 1:23. Malignancy is found in 2.5%. LCT and GCT share a number of clinical features, e.g. bilaterality, history of undescended testis, and presenting age. TSS is safe in benign LCT. Surgery is the treatment of choice in malignant LCT.

Zur Sicherung ihres wissenschaftlichen und klinischen Fortschritts braucht die deutsche Urologie gut ausgebildete Nachwuchswissenschaftler. Vor der Initiierung oder Fortfuhrung von qualitatssteigernden Masnahmen fur die urologische (Nachwuchs-)Forschung ist eine Analyse der Ist-Situation zur Standortbestimmung erforderlich. Die Forschungsvoraussetzungen, -skills und -leistungen urologischer Nachwuchswissenschaftler in Deutschland zu erfassen. Es wurde ein Online-Fragebogen mit 16 Fragen an 95 urologische Nachwuchswissenschaftler des Forschernetzwerks GeSRU Academics versandt. Hauptzielgrosen waren zeitliche Forschungsvoraussetzungen, Forschungsskills und deren Lernquellen sowie Forschungsleistungen als Peer-reviewed-Publikationen. An der Umfrage nahmen 78 Nachwuchswissenschaftler teil (82 % Rucklaufquote). Davon forschen 45 % ausschlieslich in der Freizeit. Die Selbsteinschatzung der Forschungsskills variiert von gut (systematische Literaturrecherche) bis ausreichend (Drittmittelgenerierung). Haufigste Quelle zum Erlernen aller Forschungsskills ist das Eigenstudium, gefolgt von Mentor, der eigenen Abteilung, Kursen und Netzwerken. 81 % der Nachwuchswissenschaftler weisen Peer-reviewed-Publikationen (Median 4) auf. Die Gruppen der wahrend der Arbeitszeit forschenden und mit guten Skills ausgestatteten sowie durch Mentoren/Netzwerke geforderten Nachwuchswissenschaftler haben hohere Forschungsleistungen als die jeweiligen Vergleichsgruppen. Urologische Nachwuchswissenschaftler in Deutschland werden vom zeitlichen Aspekt mit schwierigen Rahmenbedingungen konfrontiert und weisen variierende – vornehmlich durch Eigenstudium erworbene – Forschungsskills und erste messbare Forschungsleistungen auf.

5052 Background: Testicular germ cell tumors (TGCT) in clinical stage I (CSI) are tumors confined to the testis without evidence of metastasis. Around 50% of all TGCT patients present with elevated serum tumor markers (TM) such as alpha-feto protein (AFP), beta-humanochoriongonadotropin (ß-HCG) and lactate-dehydrogenase (LDH). After ablatio testis, TMs usually return to normal according to half-life kinetics, however, in clinical stage IS (CSIS) TMs remain elevated or increase after surgery. Follow-up data on CSIS is scarce and our study aims to assess clinical characteristics and oncologic outcomes in a large TGCT cohort. Methods: In this multicenter study we collected data from 5 tertiary referring hospitals in Germany, included patients with CSIS and evaluated TM levels, treatment and the primary outcome relapse-free survival. False CSIS was defined as documented CSIS but TMs that returned to normal after respective half-life kinetics. Differences between predefined groups (chemotherapy, TM, true/false CSIS) was analyzed with fisher’s exact and chi-square test. Results: Overall, 2616 patient data files were analyzed. Forty-three patients (1.6%) were documented as CSIS of which 27 (63%) were true and 16 (37%) false CSIS. Six (14%) had seminomas and 37 (86%) non-seminomas. In the true CSIS group AFP, ß-HCG, AFP plus ß-HCG and LDH were elevated in 13, 6, 3 and 2 cases. Four true CSIS patients received surveillance, 21 had 3x or 2x courses of BEP (bleomycin, etoposide and cisplatin) and 2 carboplatin. Within the false CSIS group, 2 patients were treated with surveillance, 10 received 3x BEP, one 3x PEI (cisplatin, etoposide and ifosfamid) and 3 had carboplatin. Chi-Square test revealed no difference between true or false CSIS classification in respect to application of chemotherapy (any chemotherapy, p = 0.83). Relapse-free survival after 5 and 10 years was 88.9% and 77.8%, respectively. Three patients in the true CSIS group relapsed (2 seminomas had carboplatin, 1 non-seminoma had surveillance). All relapses were treated with 3 courses of BEP with no documented death in the CSIS population. Conclusions: Overall, less than 2% of all TGCT were documented CSIS of which 37% were falsely classified. We report a high proportion of relapse-free survival in CSIS treated with surveillance or BEP with a high heterogeneity in treatment patterns. Correct classification of CSIS remains of critical importance to avoid toxicity for patients that could be safely treated with surveillance.

PURPOSE Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT. PATIENTS AND METHODS In a prospective, multicentric study, serum samples of 616 patients with testicular GCTs and 258 male controls were examined for serum levels of miRNA-371a-3p (miR levels) by quantitative polymerase chain reaction. The GCT population encompassed 359 patients with seminoma and 257 with nonseminoma; 371 had clinical stage I disease, 201 had systemic disease, and 46 had relapses. Paired measurements before and after orchiectomy were performed in 424 patients; 118 with systemic disease had serial measurements during treatment. miR levels were compared with those of β-human chorionic gonadotropin, α-fetoprotein, and lactate dehydrogenase. RESULTS For the primary diagnosis of GCT, the M371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.966 upon receiver operating characteristic analysis, and a positive predictive value of 97.2%. α-Fetoprotein, β-human chorionic gonadotropin, and lactate dehydrogenase had sensitivities of less than 50% in seminoma and slightly higher sensitivities in nonseminomas. miR levels were significantly associated with clinical stage, primary tumor size, and response to treatment. Relapses had elevated miR levels that subsequently dropped to normal upon remission. Teratoma did not express miR-371a-3p. CONCLUSION The M371 test outperforms the classic markers of GCT with both a sensitivity and a specificity greater than 90%. All histologic subgroups, except teratoma, express this marker. The test could be considered for clinical implementation after further validation.

Clinical stage (CS) 1 testicular seminoma is cured in almost 100% of cases following either retroperitoneal radiotherapy, carboplatin monotherapy, or surveillance strategies. Little is known about potential long-term effects of carboplatin. We, therefore, examined late sequelae of this drug in seminoma patients. We retrospectively identified 451 patients with CS1 testicular seminoma treated between 1994 and 2014, of whom 243 underwent carboplatin therapy [median follow-up (F/U) 96 months], 81 received radiotherapy (median F/U 142 months), and 127 underwent surveillance (median F/U 40 months). Satisfaction regarding management, as well as the following events during F/U, were analysed by questionnaire: subsequent malignant neoplasms (SMNs), cardiovascular events, arterial hypertension, peptic ulcer, tinnitus, peripheral neuropathy, hypogonadism, and infertility. The relative frequencies of the events were analysed using descriptive statistics. The frequency of observed SMNs was compared with the expected number. Patients receiving carboplatin tolerated the treatment less well (71.2%) than those under surveillance (81.9%). After carboplatin, 12 SMNs (5.0%) were noted vis-a-vis 5.0 expected. There were three cases of prostatic cancer and 3 melanomas among the SMNs. Half of these SMNs occurred early after treatment. Among the other health events, only reported hypogonadism (13.2%) appeared to be marginally increased in frequency. This study found a 2.4-fold higher than expected rate of SMN—and a slightly increased rate of hypogonadism—in the long-term period following carboplatin treatment. Although further studies are needed to confirm these preliminary findings, these results are probably informative for clinicians caring for seminoma patients.

This work addresses the factor of degraded automation reliability of machine based aerial reconnaissance in a manned-unmanned teaming approach. An army transport helicopter is accompanied by three unmanned aerial vehicles for reconnaissance purposes, guided by the helicopters crew. Automated capabilities onboard the UAVs offer high automated, task-based guidance as well as manual operation. We designed and implemented an assistance system in our helicopter flight simulator, that supports the commander in gaining relevant reconnaissance information on flight routes for the helicopter to follow. Due to imperfection in automated reconnaissance performed by machine algorithms, we explicitly regarded the aspect of degrading reliability by utilizing the paradigm of “Levels of Automation”. The automation system produces reconnaissance results, thereby considering differing automation reliability. Several data representation modes were applied to display preprocessed results in the helicopters multi-function displays. We conducted an extensive human-in-the-loop campaign with army helicopter crews in full mission scenarios, in which system-triggered changes between the automation levels occurred and the cooperative human-machine relationship changed online. This paper presents questionnaire-gathered results of our investigation during mission execution, shedding light on human factors, user acceptance and system design aspects.