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Thomas Wagner,1,2 Jakob Lauritsen,1 Mikkel Bandak,1 Linda Aagaard Rasmussen,3 Johannes Bakker,4 Hanna Birkbak Hovaldt,4 Heidi Larsson,4 Ib Jarle Christensen,1 Birgitte Grønkær Toft,2 Mads Agerbæk,5 Lars Dysager,6 Michael Kreiberg,1 Josephine Julie Rosenvilde,1 Birte Engvad,7 Daniel M Berney,8 Gedske Daugaard1 1Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3Research Unit for General Practice, Aarhus, Denmark; 4The Danish Clinical Quality Program – National Clinical Registries (RKKP), Aarhus, Odense and Copenhagen, Denmark; 5Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Oncology, Odense University Hospital, Odense, Denmark; 7Department of Pathology, Odense University Hospital, Odense, Denmark; 8Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UKCorrespondence: Thomas Wagner, Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, Denmark, Tel +45 35459682, Email thomas.wagner.nielsen@regionh.dkPurpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer.Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record i

Testicular cancer is predominantly curable, but the long-term side effects of chemotherapy have a severe impact on life quality. In this research study, we focus on hearing loss as a part of overall chemotherapy-induced ototoxicity. This is a unique approach where we combine clinical data from the acclaimed nationwide Danish Testicular Cancer (DaTeCa)-Late database. Clinical and genetic data on 433 patients were collected from hospital files in October 2014. Hearing loss was classified according to the FACT/GOG-Ntx-11 version 4 self-reported Ntx6. Machine learning models combining a genome-wide association study within a nested cross-validated logistic regression were applied to identify patients at high risk of hearing loss. The model comprising clinical and genetic data identified 67% of the patients with hearing loss; however, this was with a false discovery rate of 49%. For the non-affected patients, the model identified 66% of the patients with a false omission rate of 19%. An area under the receiver operating characteristic (ROC-AUC) curve of 0.73 (95% CI, 0.71–0.74) was obtained, and the model suggests genes SOD2 and MGST3 as important in improving prediction over the clinical-only model with a ROC-AUC of 0.66 (95% CI, 0.65–0.66). Such prediction models may be used to allow earlier detection and prevention of hearing loss. We suggest a possible biological mechanism for cisplatin-induced hearing loss development. On confirmation in larger studies, such models can help balance treatment in clinical practice.

Purpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2– 99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7– 100), a specificity of 98.9% (95% CI: 98.2– 99.6), and a positive predictive value of 95.9% (95% CI: 93.4– 98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, Purpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2–99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7–100), a specificity of 98.9% (95% CI: 98.2–99.6), and a positive predictive value of 95.9% (95% CI: 93.4–98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease tim

We investigated the impact of smoking on overall survival (OS) in testicular germ cell cancer (TC) patients receiving first-line combination chemotherapy (bleomycin-etoposide-cisplatin [BEP]). Patients who received BEP for metastatic TC were identified in the Danish Testicular Cancer database. Information on smoking status at the time of diagnosis was obtained by medical record review. OS and cause of death were compared between current smokers and never-smokers. Of 1883 eligible patients, information on smoking status was available in 1156 patients, of whom 602 were current smokers. The 10-year OS was 92% in never-smokers compared with 83% in current smokers (P < .001) (hazard ratio for death = 1.85, 95% confidence interval = 1.29 to 2.66, P = .001). A higher proportion of current smokers died of TC compared with nonsmokers (P < .01). Smoking negatively affects survival after BEP in patients with disseminated TC. Vigorous smoking cessation programs are advocated in TC patients., We investigated the impact of smoking on overall survival (OS) in testicular germ cell cancer (TC) patients receiving first-line combination chemotherapy (bleomycin-etoposide-cisplatin [BEP]). Patients who received BEP for metastatic TC were identified in the Danish Testicular Cancer database. Information on smoking status at the time of diagnosis was obtained by medical record review. OS and cause of death were compared between current smokers and never-smokers. Of 1883 eligible patients, information on smoking status was available in 1156 patients, of whom 602 were current smokers. The 10-year OS was 92% in never-smokers compared with 83% in current smokers (P < .001) (hazard ratio for death = 1.85, 95% confidence interval = 1.29 to 2.66, P = .001). A higher proportion of current smokers died of TC compared with nonsmokers (P < .01). Smoking negatively affects survival after BEP in patients with disseminated TC. Vigorous smoking cessation programs are advocated in TC patients.

Background: Testicular germ cell cancer (TC) incidence peaks during reproductive age, but knowledge on fertility after treatment is insufficient. The aim was to evaluate paternity after today's TC treatment. Methods: Clinical data were extracted from the Danish Testicular Cancer database, and patients were divided into 4 groups: 1) surveillance; 2) bleomycin, etoposide, and cisplatin (BEP); 3) BEP + postchemotherapy retroperitoneal surgery (BEP + surgery); and 4) abdominal radiotherapy. For each patient, 10 men matched on date of birth were randomly sampled from the normal population. Paternity was defined as date of birth of first child after TC treatment with or without the use of assisted reproductive technology and was assessed by linkage to the Danish Medical Birth Register and the Danish in vitro fertilization register. Results: We included 4846 unilateral TC patients and 48 456 men from the normal population. The 20-year predicted chance of obtaining fatherhood for a 30-year-old man was 39.7% in TC patients compared with 42.5% in the normal population. The chance of obtaining fatherhood was statistically significantly decreased after BEP (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.78 to 0.97) and BEP + surgery (HR = 0.74, 95% CI = 0.63 to 0.87), but not after radiotherapy (HR = 0.89, 95% CI = 0.75 to 1.06) or surveillance (HR = 0.95, 95% CI = 0.89 to 1.02). The risk of needing assisted reproductive technology to obtain fatherhood was increased after all treatment modalities. Conclusions: The chance of obtaining fatherhood after TC treatment was substantially higher than previously reported. Patients followed on a surveillance program had a similar chance of obtaining fatherhood as noncancerous men.

Background: Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combination with borderline low testosterone, is unknown. To clarify if TRT improves symptoms of depression and anxiety, sexual function, fatigue, and quality of life in TC survivors with mild Leydig cell insufficiency. Materials and Methods: In total, 69 men aged between 18 and 65 years with mild Leydig cell insufficiency after TC treatment were randomized 1:1 to 12 months daily transdermal testosterone (maximum dose 40 mg/daily) vs. placebo. Patient reported anxiety, depression, sexual function, fatigue, and overall quality of life were assessed at baseline, after 6- and 12 months treatment, and 3 months post-treatment using validated questionnaires. Results: After 12 months of treatment, median luteinizing hormone and median free testosterone were normalized in the testosterone group. Compared to placebo, TRT was not associated with statistically significant improvement of symptoms of anxiety and depression, sexual function, fatigue, and overall quality of life. Testosterone replacement therapy did not improve anxiety, depression, sexual function, fatigue, or overall quality of life in patients with mild Leydig cell insufficiency compared to placebo. Conclusion: Routine TRT in TC survivors with mild Leydig cell insufficiency to improve sexual function and quality of life cannot be generally recommended. The findings should preferably be validated in a larger cohort.

Background: Cisplatin-based chemotherapy may induce nephrotoxicity. This study presents a random forest predictive model that identifies testicular cancer patients at risk of nephrotoxicity before treatment. Methods: Clinical data and DNA from saliva samples were collected for 433 patients. These were genotyped on Illumina HumanOmniExpressExome-8 v1.2 (964 193 markers). Clinical and genomics-based random forest models generated a risk score for each individual to develop nephrotoxicity defined as a 20% drop in isotopic glomerular filtration rate during chemotherapy. The area under the receiver operating characteristic curve was the primary measure to evaluate models. Sensitivity, specificity, and positive and negative predictive values were used to discuss model clinical utility. Results: Of 433 patients assessed in this study, 26.8% developed nephrotoxicity after bleomycin-etoposide-cisplatin treatment. Genomic markers found to be associated with nephrotoxicity were located at NAT1, NAT2, and the intergenic region of CNTN6 and CNTN4. These, in addition to previously associated markers located at ERCC1, ERCC2, and SLC22A2, were found to improve predictions in a clinical feature-Trained random forest model. Using only clinical data for training the model, an area under the receiver operating characteristic curve of 0.635 (95% confidence interval [CI] 0.629 to 0.640) was obtained. Retraining the classifier by adding genomics markers increased performance to 0.731 (95% CI 0.726 to 0.736) and 0.692 (95% CI 0.688 to 0.696) on the holdout set. Conclusions: A clinical and genomics-based machine learning algorithm improved the ability to identify patients at risk of nephrotoxicity compared with using clinical variables alone. Novel genetics associations with cisplatin-induced nephrotoxicity were found for NAT1, NAT2, CNTN6, and CNTN4 that require replication in larger studies before application to clinical practice.

PURPOSE To analyze the risk of cardiovascular disease (CVD) after treatment of male germ cell cancer (GCC). METHODS Clinical data were extracted from the Danish Testicular Cancer database. For each patient, 10 men matched on date of birth were identified in the Danish normal population by risk-set sampling. Cardiovascular risk factors, CVD, and associated deaths were identified in Danish registries. The association between treatment and outcomes was analyzed by separate Cox models for each outcome. Cancer treatment was included as a time-varying covariate. RESULTS We included 5,185 patients with GCC and 51,850 men in the normal population. Median follow-up was 15.8 years. Treatment with bleomycin-etoposide-cisplatin (BEP; n = 1,819) was associated with increased risks of hypertension and hypercholesterolemia. Hazard ratios (HRs) of CVD<1 year after initiation of BEP treatment were as follows: Myocardial infarction (HR, 6.3; 95% CI, 2.9 to 13.9), cerebrovascular accident (HR, 6.0; 95% CI, 2.6 to 14.1), and venous thromboembolism (HR, 24.7; 95% CI, 14.0 to 43.6). One year after BEP treatment, the risk of CVD decreased to normal levels, but after 10 years, increasing risks were found for myocardial infarction (HR, 1.4; 95% CI, 1.0 to 2.0) and cardiovascular death (HR, 1.6; 95% CI, 1.0 to 2.5). Radiotherapy (n = 780) increased the risk of diabetes at long-term follow-up (HR, 1.4; 95% CI, 1.0 to 2.0) but not that of other outcomes. With surveillance (n = 3,332), cardiovascular risk factors, CVD, and cardiovascular death data were comparable to that of the normal population. CONCLUSION Treatment with BEP was associated with highly increased risks of CVD<1 year after treatment start and mildly increased risks after 10 years of follow-up. Radiotherapy increased the risk of diabetes but not incident CVD. The risk of CVD in patients followed in a surveillance program was comparable to that of the normal population.

PURPOSE: Long-term cancer survivors may develop psychological late effects. The aim of the present study was to determine prevalence of high level of stress in testicular cancer survivors (TCS) compared with the general population and prevalence of high level of stress among TCS stratified by type of treatment (surveillance, bleomycin, etoposide and cisplatin (BEP), or abdominal radiotherapy (RT)).METHODS: In this large, nationwide and population-based, cross-sectional study, a total of 2252 TCS filled in a questionnaire between 2014-2016 covering psychological stress (Perceived Stress Scale (PSS)), sociodemographic factors, and physical health variables. Results were compared with a reference population. The reference population consisted of 61,927 men without prior or present cancer and sampled at random from the central population. High level of stress was defined as a PSS score ≥ 16, equivalent to the highest scoring quintile in the reference population. Logistic regression models adjusted for relevant covariates were used to estimate prevalence ratios of high level of stress.RESULTS: Distribution of TCS was: surveillance, n = 1134; BEP, n = 807; and RT, n = 311 (median time since diagnosis was 19 years). TCS were more likely to have high level of stress compared to the reference population with a prevalence ratio of 1.56 (95% CI, 1.40-1.73). Individually, surveillance, BEP and RT groups had higher level of stress compared to the reference population.CONCLUSIONS: TCS are more likely to have high level of stress. Screening programs for psychological stress should be considered as part of the follow-up program.IMPLICATIONS FOR CANCER SURVIVORS: A higher level of stress is observed in TCS irrespective of treatment.

Introduction Approximately one-fourth of patients with clinical stage I testicular germ cell cancer will relapse within 5 years of follow-up. Certain histopathological features in the primary tumour have been associated with an increased risk of relapse. The available evidence on the prognostic value of the risk factors, however, is hampered by heterogeneity of the study populations included and variable reporting of the histopathological features. The aim of this study is to identify pathological risk factors for relapse in an unselected large nationwide cohort of patients with stage I disease. Methods and analysis All incident cases of stage I testicular germ cell cancer diagnosed in Denmark between 2013 and 2018 will be identified using the nationwide prospective Danish Testicular Cancer (DaTeCa) database. Archived microscopic slides from the orchiectomy specimens will be retrieved through linkage to the Danish Pathology Data Bank and reviewed blinded to the clinical outcome. The DaTeCa database includes 960 stage I seminoma patients with expected 185 relapses and 480 patients with stage I non-seminoma with expected 150 relapses. A minimum follow-up period of 3 years of all patients will be ensured. Predefined prognostic variables will be investigated with regard to relapse in univariable and multivariable analysis using the Cox proportional hazards model. Ethics and dissemination This study protocol has been approved by the Regional Ethics Committee (Region Zealand, Denmark) and the Danish Data Protection Agency. All data will be managed confidentially according to legislation. Study results will be presented at international conferences and published in peer-review journals.

The cohort was set up in order to analyze late effects in long-term testicular cancer survivors (TCS) and to contribute to the design of future follow-up programs addressing and potentially preventing late effects. Data for this cross-sectional study were collected between January 1, 2014, and December 31, 2016, among living Danish TCS and 60% agreed to participate in the cohort (N = 2,572). Mean time since testicular cancer (TC) diagnosis was 18 years (range 7-33) and mean age of participants was 53 years (range 25-95). Data consist of results of a questionnaire with patient reported outcomes which covers a broad range of items on late-effects. The study also included data obtained through linkages to Danish registries, a biobank, and clinical data from hospital files and pathology reports originating from the Danish Testicular Cancer Database (DaTeCa). The treatment during the observation period has been nearly the same for all stages of TC and is in agreement with today's standard treatment, this allows for interesting analysis with a wide timespan. We have extensive data on non-responders and are able to validate our study findings. Data from a Danish reference population (N = 162,283) allow us to compare our findings with a Danish background population. The cohort can easily be extended to access more outcomes, or include new TCS. A limitation of the present study is the cross-sectional design and despite the large sample size, The Danish Testicular Cancer Late Treatment Effects Cohort (DaTeCa-LATE) lacks statistical power to study very rare late effects. Since it was voluntary to participate in the study we have some selection bias, for instance, we lack responders who were not in a paired relationship, but we would still argue that this cohort of TCSs is representative for TCSs in Denmark.Collaboration and data access: Researches interested in collaboration with the DaTeCa-LATE study group please contact Professor Gedske Daugaard kirsten.gedske.daug