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Purpose Lymphovascular invasion (LV1) and presence of > 50% embryonal carcinoma (> 50% EC) represent risk factors for progression in patients with clinical stage 1 (CS1) nonseminomatous (NS) testicular germ cell tumours. As serum levels of microRNA-371a-3p (M371) are capable of detecting small amounts of GCT, we evaluated if LV1 and > 50% EC are associated with M371 levels. Methods M371 serum levels were measured postoperatively in 153 NS CS1 patients and both pre- and postoperatively in 131 patients. We registered the following factors: age, tumour size, LV status, > 50% EC, teratoma in primary, preoperative elevation of classical tumour markers. M371 expression was compared among subgroups. The ability of M371 to predict LV1 was calculated by receiver operating characteristics (ROC) curves. Multiple regression analysis was used to look for associations of M371 levels with other factors. Results Postoperatively elevated M371 levels were found in 29.4% of the patients, but were neither associated with LV status nor with > 50% EC. Likewise, relative decrease of M371 was not associated. ROC analysis of postoperative M371 levels revealed an AUC of 0.5 for the ability to predict LV1 while preoperative M371 had an AUC of 0.732. Multiple regression analysis revealed significant associations of preoperative M371 levels with LV status (p = 0.003), tumour size (p = 0.001), > 50% EC (p = 0.004), and teratoma component (p = 0.045). Conclusion Postoperatively elevated M371 levels are not associated with risk factors for progression in NS CS1 patients. However, the significant association of preoperative M371 expression with LV1 deserves further evaluation.

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen UBC® Rapid Test for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high-risk of primary BC. Patients and methods: Data from 1,787 patients from 13 participating centers tested between 2012 and 2020, including 763 patients with BC, were analyzed. Urine samples were analyzed with the UBC® Rapid Test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid Test was evaluated using receiver operating characteristics analysis. Brier scores and calibration curves were chosen for validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC® Rapid Test were 46.4%, 75.5%, and 0.61 (95% CI: 0.58–0.64) for low-grade (LG-) BC, and 70.5%, 75.5%, and 0.73 (95% CI: 0.70–0.76) for high-grade (HG-) BC, respectively. Age, UBC® Rapid Test results, smoking status, and hematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in an area under the curve of 0.79 (95% CI: 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) in predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid Test alone for low and medium risk levels in decision curve analysis. An R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC® Rapid Test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status, and hematuria provides a fast, highly accurate, and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen UBC® Rapid Test for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high-risk of primary BC. Patients and methods: Data from 1,787 patients from 13 participating centers tested between 2012 and 2020, including 763 patients with BC, were analyzed. Urine samples were analyzed with the UBC® Rapid Test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid Test was evaluated using receiver operating characteristics analysis. Brier scores and calibration curves were chosen for validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC® Rapid Test were 46.4%, 75.5%, and 0.61 (95% CI: 0.58–0.64) for low-grade (LG-) BC, and 70.5%, 75.5%, and 0.73 (95% CI: 0.70–0.76) for high-grade (HG-) BC, respectively. Age, UBC® Rapid Test results, smoking status, and hematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in an area under the curve of 0.79 (95% CI: 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) in predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid Test alone for low and medium risk levels in decision curve analysis. An R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC® Rapid Test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status, and hematuria provides a fast, highly accurate, and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen UBC® Rapid Test for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high-risk of primary BC. Patients and methods: Data from 1,787 patients from 13 participating centers tested between 2012 and 2020, including 763 patients with BC, were analyzed. Urine samples were analyzed with the UBC® Rapid Test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid Test was evaluated using receiver operating characteristics analysis. Brier scores and calibration curves were chosen for validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC® Rapid Test were 46.4%, 75.5%, and 0.61 (95% CI: 0.58–0.64) for low-grade (LG-) BC, and 70.5%, 75.5%, and 0.73 (95% CI: 0.70–0.76) for high-grade (HG-) BC, respectively. Age, UBC® Rapid Test results, smoking status, and hematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in an area under the curve of 0.79 (95% CI: 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) in predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid Test alone for low and medium risk levels in decision curve analysis. An R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC® Rapid Test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status, and hematuria provides a fast, highly accurate, and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Objectives To evaluate the clinical utility of the urinary bladder cancer antigen test UBC (R) Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. Patients and Methods Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC (R) Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC (R) Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results The sensitivity, specificity, and area under the curve for the UBC (R) Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC (R) Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC (R) Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index. net. Conclusion The UBC (R) Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Introduction: Clinical stage 1 (CS1) nonseminomatous (NS) germ cell tumors involve a 30% probability of relapse upon surveillance. Adjuvant chemotherapy with one course of bleomycin, etoposide, and cisplatin (1xBEP) can reduce this risk to <5%. However, 1xBEP results are based solely on five controlled trials from high-volume centers. We analyzed the outcome in a real-life population. Patients and Methods: In a multicentric international study, 423 NS CS1 patients receiving 1xBEP were retrospectively evaluated. Median follow-up was 37 (range, 6-89) months. Primary end points were relapse-free and overall survival evaluated after 5 years. We also looked at associations of relapse with clinico-pathological factors using stratified Kaplan-Meier methods and Cox regression models. Treatment modality and outcome of recurrences were analyzed descriptively. Results: The 5-year relapse-free survival rate was 96.2%. Thirteen patients (3.1%; 95% confidence interval, 1.65-5.04%) relapsed after a median time of 13 months, of which 10 were salvaged (77%). Relapses were mostly confined to retroperitoneal nodes. Three patients succumbed, two to disease progression and one to toxicity of chemotherapy. Pathological stage >pT2 was significantly associated with relapse rate. Conclusion: The relapse rate of 3.1% found in this population of NS CS1 patients treated with 1xBEP at the routine care level was not inferior to the median rate of 2.3% reported from a meta-analysis of controlled trials. Also, the cure rate of relapses of 77% is consistent with the previously reported rate of 80%. This study clearly shows that the 1xBEP regimen represents a safe treatment for NS CS1 patients.

Purpose Lymphovascular invasion (LV1) and presence of > 50% embryonal carcinoma (> 50% EC) represent risk factors for progression in patients with clinical stage 1 (CS1) nonseminomatous (NS) testicular germ cell tumours. As serum levels of microRNA-371a-3p (M371) are capable of detecting small amounts of GCT, we evaluated if LV1 and > 50% EC are associated with M371 levels. Methods M371 serum levels were measured postoperatively in 153 NS CS1 patients and both pre- and postoperatively in 131 patients. We registered the following factors: age, tumour size, LV status, > 50% EC, teratoma in primary, preoperative elevation of classical tumour markers. M371 expression was compared among subgroups. The ability of M371 to predict LV1 was calculated by receiver operating characteristics (ROC) curves. Multiple regression analysis was used to look for associations of M371 levels with other factors. Results Postoperatively elevated M371 levels were found in 29.4% of the patients, but were neither associated with LV status nor with > 50% EC. Likewise, relative decrease of M371 was not associated. ROC analysis of postoperative M371 levels revealed an AUC of 0.5 for the ability to predict LV1 while preoperative M371 had an AUC of 0.732. Multiple regression analysis revealed significant associations of preoperative M371 levels with LV status (p = 0.003), tumour size (p = 0.001), > 50% EC (p = 0.004), and teratoma component (p = 0.045). Conclusion Postoperatively elevated M371 levels are not associated with risk factors for progression in NS CS1 patients. However, the significant association of preoperative M371 expression with LV1 deserves further evaluation.

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen UBC® Rapid Test for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high-risk of primary BC. Patients and methods: Data from 1,787 patients from 13 participating centers tested between 2012 and 2020, including 763 patients with BC, were analyzed. Urine samples were analyzed with the UBC® Rapid Test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid Test was evaluated using receiver operating characteristics analysis. Brier scores and calibration curves were chosen for validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC® Rapid Test were 46.4%, 75.5%, and 0.61 (95% CI: 0.58–0.64) for low-grade (LG-) BC, and 70.5%, 75.5%, and 0.73 (95% CI: 0.70–0.76) for high-grade (HG-) BC, respectively. Age, UBC® Rapid Test results, smoking status, and hematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in an area under the curve of 0.79 (95% CI: 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) in predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid Test alone for low and medium risk levels in decision curve analysis. An R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC® Rapid Test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status, and hematuria provides a fast, highly accurate, and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Objectives: To evaluate the clinical utility of the urinary bladder cancer antigen UBC® Rapid Test for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high-risk of primary BC. Patients and methods: Data from 1,787 patients from 13 participating centers tested between 2012 and 2020, including 763 patients with BC, were analyzed. Urine samples were analyzed with the UBC® Rapid Test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid Test was evaluated using receiver operating characteristics analysis. Brier scores and calibration curves were chosen for validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results: The sensitivity, specificity, and area under the curve for the UBC® Rapid Test were 46.4%, 75.5%, and 0.61 (95% CI: 0.58–0.64) for low-grade (LG-) BC, and 70.5%, 75.5%, and 0.73 (95% CI: 0.70–0.76) for high-grade (HG-) BC, respectively. Age, UBC® Rapid Test results, smoking status, and hematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in an area under the curve of 0.79 (95% CI: 0.72–0.87) and 0.95 (95% CI: 0.92–0.98) in predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid Test alone for low and medium risk levels in decision curve analysis. An R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. Conclusion: The UBC® Rapid Test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status, and hematuria provides a fast, highly accurate, and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

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 classific

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

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 the recommendations 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

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 the recommendations 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

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 classific

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 beta-human chorionic gonadotropin, alpha-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%. alpha-Fetoprotein, beta-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. (C) 2019 by American Society of Clinical Oncology

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 beta-human chorionic gonadotropin, alpha-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%. alpha-Fetoprotein, beta-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. (C) 2019 by American Society of Clinical Oncology

Obwohl die intravesikale Bacillus-Calmette Guérin (BCG) Therapie immer noch die wirksamste Immuntherapie beim sogenannten high-risk, nicht-muskelinvasiven Urothelkarzinom der Blase ist, zeigen ungefähr 30% aller Patienten kein Ansprechen im Sinne eines BCG Versagens. Neue Biomarker sind klinisch von großer Bedeutung, um jene Patienten zu stratifizieren, welche am meisten von einer “blasenerhaltenden Strategie” mit BCG oder von einer sofortigen radikalen Zystektomie profitieren würde. In einer retrospektiven Studie quantifizierten wir die lokale Dichte von verschiedenen Immunzell-Subpopulationen in formalin-fixiertem, paraffin-eingebettetem Blasentumorgewebe mittels Immunhistochemie. Zehn verschiedene monoklonale Antikörper wurden zur Detektion von tumor-assoziierten Makrophagen (TAMs; CD68, CD163), B-Lymphozyten (CD20) und T- Lymphozyten Subpopulationen (CD3, CD4, CD8, GATA3, T-bet, FOXP3 und CD25) verwendet. Die Zelldichte wurde in der Lamina propria, in der Invasionsfront, im papillären Tumorstroma und im neoplastischen Urothel bestimmt. 29 (72.5%) Patienten zeigten ein BCG Ansprechen bei einem durchschnittlichen Follow-up von 35.3 Monaten. Wir zeigten eine signifikante Assoziation zwischen BCG Versagen und einer geringen Zelldichte von CD4+ und GATA3+ T Zellen, sowie eine erhöhte Dichte von FOXP3+ und CD25+ regulatorischen T Zellen, CD68+ und CD163+ TAMs. Somit scheint eine generelle Th2 Prädisposition auf Ebene von Transkriptionsfaktoren (GATA3>T-bet) das therapeutische BCG Outcome zu beeinflussen. Das Ziel der prospektiven Folgestudie war es, den Zusammenhang zwischen einer solchen bestätigten Th2 Prädisposition und dem aktuellen, funktionalen Phänotyp vor, während und nach BCG Therapie als möglichen Biomarker zur Vorhersage des therapeutischen Ansprechens zu prüfen. Th1 (Neopterin, Tryptophan, Kynurenin, Kynurenine-Tryptophan Ratio (KTR), IL-12, IFN-, löslicher TNF-R75 und IL-2R) und Th2 (IL-4, IL-10) Biomarker sowie die CD4 Expression in T Helfer (Th), Effekt, Although intravesical Bacillus Calmette-Guérin (BCG) is still the most successful immunotherapy for high-risk, non-muscle invasive bladder cancer, approximately 30% of patients are unresponsive to treatment. Novel biomarkers are important to identify patients who will benefit most from bladder preservation with BCG or early radical cystectomy. In a retrospective study, local immune cell subsets were measured on formalin-fixed, paraffin-embedded tissue sections of bladder cancer by immunohistochemistry, using ten monoclonal antibodies against tumor-associated macrophages (TAMs; CD68, CD163), B-lymphocytes (CD20) and T-lymphocyte subsets (CD3, CD4, CD8, GATA3, T-bet, FOXP3 and CD25). The cell density in the lamina propria, at the invasive front if present, in the papillary tumor stroma, and in the neoplastic urothelium was calculated. Twenty-nine (72.5%) of 40 patients were classified as BCG responders after a mean follow-up of 35.3 months. We showed a significant association for BCG failure with low density of CD4+ and GATA3+ T cells, and increased expression of FOXP3+ and CD25+ regulatory T cells as well as CD68+ and CD163+ TAMs. Thus, a general Th2 predisposition at the level of transcription factors (GATA3>T-bet) seems to influence the therapeutic response to BCG. The aim of the prospective follow-up study was to examine the relation between such a Th2 predisposition and the actual functional phenotype at baseline, during and after BCG as a potential biomarker of therapeutic response. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-, soluble TNF-R75 and IL-2R) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined in 23 patients undergoing BCG therapy. BCG responders showed significantly higher levels of urinary (p=0.003) and serum neopterin (p=0.012), kynurenine (p=0.015), KTR (p=0.005), IFN- (p=0.005) and IL-12 (p=0.003) during therapy, whereas levels o, Renate Pichler, MD, FEBU, Kumulative Dissertation aus zwei Artikeln, Abweichender Titel laut Übersetzung der Verfasserin/des Verfassers, Zusammenfassung in deutscher Sprache, Medical University Innsbruck, Dissertation, 2017, OeBB, (VLID)1713478

In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment.

In recent years, considerable advances concerning therapeutic strategies in patients with metastatic cancer have been achieved. Particularly in renal cell cancer (RCC) and advanced stage non-small cell lung cancer (NSCLC), immune-activating and antiangiogenic (AA) drugs (i.e., checkpoint antibodies and vascular endothelial growth factor (VEGF)/VEGF receptors (VEGFR) targeting compounds, respectively) have been successfully developed. As immune-effector cells have to enter the tumor, it is tempting to speculate that the combination of immunotherapy with AA treatment may induce synergistic effects. In this short review, we explore the theoretical background and the therapeutic potential of this novel treatment option for patients with advanced RCC or NSCLC. We discuss the growing body of evidence that pro-angiogenic factors negatively modulate the T-cell-mediated immune response and examine the preclinical evidence for testing combined immune-activating and AA therapy concepts in clinical practice. Particular attention will also be paid to potential novel treatment-related adverse events induced by combination treatment.