Oncological outcome and complications of post-chemotherapy retroperitoneal surgery in non-seminomatous germ cell tumours - a systematic review.

INTRODUCTION: Post-chemotherapy surgery constitutes an integral part of the management of patients with non-seminomatous germ-cell tumours with a residual mass in the retroperitoneum. Published data on recurrence rates and complications to bilateral retroperitoneal lymph node dissection (RPLND), unilateral template RPLND, and resection of residual mass only according to different surgical techniques (open, laparoscopic, and robotic surgery) were reviewed. MATERIAL AND METHODS: PubMed/Medline, Embase, and the Cochrane databases were searched systematically. The risk of bias was assessed with the Newcastle Ottawa Scale. RESULTS: In total, 28 studies were included. Eight studies reported on open surgery with the bilateral template, seven on the unilateral template, and three on resection of mass only. Median follow-up was 39, 39, and 70 months, respectively. Recurrences were found in 11, 12, and 14%, respectively. Major complications (Clavien-Dindo III or more) were observed in 18, 8, and 17%, respectively. Two studies reported on laparoscopic bilateral surgery, eight on unilateral, and two on residual mass only. A total of Median follow-up was 52, 29, and 55 months, respectively. Recurrences were found in 0, 1, and 9%, respectively. Major complications were not documented for bilateral but were observed in 4% for unilateral and 0% for resection of tumour only. Four studies on robotic bilateral surgery, three on unilateral and two on resection of tumour only were included. Follow-up was 18, 35, and 30 months, respectively. Recurrences were found in 0, 0, and 2%, respectively. Major complications were observed in 0, 10. and 2%, respectively. CONCLUSIONS: When patient selection is made, recurrence rates for the open unilateral template are comparable to the bilateral template. The risk of complications is highest after an open bilateral template. Laparoscopic and robotic surgery should not be used as a standard procedure. More studies are required with larger patient populations and longer follow-up.

Adverse health behaviours in long-term testicular cancer survivors: a Danish nationwide study.

BACKGROUND: Treatment for disseminated testicular cancer increases the risk of secondary malignancy and cardiovascular disease. The risk of developing these serious adverse effects may be positively affected by healthy living. The purpose of this study was to identify health behaviours with possible influence on late effects that could be targets for intervention. MATERIAL AND METHODS: In this cross-sectional study, testicular cancer survivors diagnosed in the period 1984-2007 from the Danish Testicular Cancer database completed a questionnaire on health behaviours (2014-2016). We estimated prevalence of smoking, alcohol consumption, sedentary lifestyle and overweight. Prevalence ratios described with 95% confidence intervals of adverse health behaviours were stratified by treatment modalities and compared to a reference population by means of logistic regression with adjustment for sociodemographic confounders. RESULTS: In total, 2395 testicular cancer survivors (surveillance, 1175; chemotherapy, 897; radiotherapy, 323), median time since diagnosis 19 years, and 65,289 noncancer males were included, questionnaire response rates were 60% and 54%, respectively. There were more current smokers (prevalence ratio; 1.14, 95% confidence interval (CI): 1.03-1.26) and patients with body mass index above 25 kg/m2 (prevalence ratio; 1.10, 95% CI: 1.01-1.20) among testicular cancer survivors than in the reference population. Testicular cancer survivors reported less sedentary lifestyle (prevalence ratio; 95% CI: 0.74, 0.64-0.85) and everyday drinkers were fewer (prevalence ratio; 0.79, 95% CI: 0.68-0.92) than in the reference population. CONCLUSION: We identified smoking cessation as primary target for intervention studies in testicular cancer survivors. The effect of smoking cessation interventions as part of treatment should be investigated. Whether drug-based intervention is effective in minimising the risk of exposure to conventional risk factors for cardiovascular disease is also of interest.

Beta2 -adrenoceptor agonist salbutamol increases protein turnover rates and alters signalling in skeletal muscle after resistance exercise in young men.

KEY POINTS: Animal models have shown that beta2 -adrenoceptor stimulation increases protein synthesis and attenuates breakdown processes in skeletal muscle. Thus, the beta2 -adrenoceptor is a potential target in the treatment of disuse-, disease- and age-related muscle atrophy. In the present study, we show that a few days of oral treatment with the commonly prescribed beta2 -adrenoceptor agonist, salbutamol, increased skeletal muscle protein synthesis and breakdown during the first 5 h after resistance exercise in young men. Salbutamol also counteracted a negative net protein balance in skeletal muscle after resistance exercise. Changes in protein turnover rates induced by salbutamol were associated with protein kinase A-signalling, activation of Akt2 and modulation of mRNA levels of growth-regulating proteins in skeletal muscle. These findings indicate that protein turnover rates can be augmented by beta2 -adrenoceptor agonist treatment during recovery from resistance exercise in humans. ABSTRACT: The effect of beta2 -adrenoceptor stimulation on skeletal muscle protein turnover and intracellular signalling is insufficiently explored in humans, particularly in association with exercise. In a randomized, placebo-controlled, cross-over study investigating 12 trained men, the effects of beta2 -agonist (6 × 4 mg oral salbutamol) on protein turnover rates, intracellular signalling and mRNA response in skeletal muscle were investigated 0.5-5 h after quadriceps resistance exercise. Each trial was preceded by a 4-day lead-in treatment period. Leg protein turnover rates were assessed by infusion of [13 C6 ]-phenylalanine and sampling of arterial and venous blood, as well as vastus lateralis muscle biopsies 0.5 and 5 h after exercise. Furthermore, myofibrillar fractional synthesis rate, intracellular signalling and mRNA response were measured in muscle biopsies. The mean (95% confidence interval) myofibrillar fractional synthesis rate was higher for salbutamol than placebo [0.079 (95% CI, 0.064 to 0.093) vs. 0.066 (95% CI, 0.056 to 0.075%) × h-1 ] (P < 0.05). Mean net leg phenylalanine balance 0.5-5 h after exercise was higher for salbutamol than placebo [3.6 (95% CI, 1.0 to 6.2 nmol) × min-1  × 100 gLeg Lean Mass-1 ] (P < 0.01). Phosphorylation of Akt2, cAMP response element binding protein and PKA substrate 0.5 and 5 h after exercise, as well as phosphorylation of eEF2 5 h after exercise, was higher (P < 0.05) for salbutamol than placebo. Calpain-1, Forkhead box protein O1, myostatin and Smad3 mRNA content was higher (P < 0.01) for salbutamol than placebo 0.5 h after exercise, as well as Forkhead box protein O1 and myostatin mRNA content 5 h after exercise, whereas ActivinRIIB mRNA content was lower (P < 0.01) for salbutamol 5 h after exercise. These observations suggest that beta2 -agonist increases protein turnover rates in skeletal muscle after resistance exercise in humans, with concomitant cAMP/PKA and Akt2 signalling, as well as modulation of mRNA response of growth-regulating proteins.

Sexual Function in a Nationwide Cohort of 2,260 Survivors of Testicular Cancer after 17 Years of Followup.

PURPOSE: Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer. MATERIALS AND METHODS: We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent. RESULTS: The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p <0.05), bleomycin, etoposide and cisplatin with post-chemotherapy surgery (OR 2.1, 95% CI 1.4-3.4, p <0.005), radiotherapy (OR 1.7, 95% CI 1.1-2.5, p <0.05) and more than 1 line of treatment (OR 3.2, 95% CI 1.6-6.3, p <0.005). Orgasmic dysfunction was associated with radiotherapy, bleomycin, etoposide and cisplatin with post-chemotherapy surgery and more than 1 line of treatment. CONCLUSIONS: Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

A randomized double-blind study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

BACKGROUND: Elevated serum levels of luteinizing hormone and slightly decreased serum levels of testosterone (mild Leydig cell insufficiency) is a common hormonal disturbance in testicular cancer (TC) survivors. A number of studies have shown that low serum levels of testosterone is associated with low grade inflammation and increased risk of metabolic syndrome. However, so far, no studies have evaluated whether testosterone substitution improves metabolic dysfunction in TC survivors with mild Leydig cell insufficiency. METHODS/DESIGN: This is a single-center, randomized, double-blind, placebo-controlled study, designed to evaluate the effect of testosterone replacement therapy in TC survivors with mild Leydig cell insufficiency. Seventy subjects will be randomized to receive either testosterone replacement therapy or placebo. The subjects will be invited for an information meeting where informed consent will be obtained. Afterwards, a 52-weeks treatment period begins in which study participants will receive a daily dose of transdermal testosterone or placebo. Dose adjustment will be made three times during the initial 8 weeks of the study to a maximal daily dose of 40 mg of testosterone in the intervention arm. Evaluation of primary and secondary endpoints will be performed at baseline, 26 weeks post-randomization, at the end of treatment (52 weeks) and 3 months after completion of treatment (week 64). DISCUSSION: This study is the first to investigate the effect of testosterone substitution in testicular cancer survivors with mild Leydig cell insufficiency. If positive, it may change the clinical handling of testicular cancer survivors with borderline low levels of testosterone. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02991209 (November 25, 2016).

Beta2-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men.

PURPOSE: ß2-Agonists have been proposed as weight-loss treatment, because they elevate energy expenditure. However, it is unknown what effect ß2-agonists have on energy expenditure in overweight individuals. Furthermore, the influence of ß2-agonist R- and S-enantiomer ratio for the increased energy expenditure is insufficiently explored. METHODS: Nineteen males were included in the study of which 14 completed. Subjects were 31.6 (±3.5) years [mean (±95% CI)] and had a fat percentage of 22.7 (±2.1)%. On separate days, subjects received either placebo or inhaled racemic (rac-) formoterol (2 × 27 µg). After an overnight fast, energy expenditure and substrate oxidation were estimated by indirect calorimetry at rest and during submaximal exercise. Plasma (R,R)- and (S,S)-formoterol enantiomer levels were measured by ultra-performance liquid chromatograph-mass spectrometry. RESULTS: At rest, energy expenditure and fat oxidation were 12% (P ≤ 0.001) and 38% (P = 0.006) higher for rac-formoterol than placebo. Systemic (R,R):(S,S) formoterol ratio was correlated with change in energy expenditure at rest in response to rac-formoterol (r = 0.63, P = 0.028), whereas no association was observed between fat percentage and rac-formoterol-induced change in energy expenditure. During exercise, energy expenditure was not different between treatments, although carbohydrate oxidation was 15% higher (P = 0.021) for rac-formoterol than placebo. Rac-formoterol-induced shift in substrate choice from rest to exercise was related to plasma ln-rac-formoterol concentrations (r = 0.75, P = 0.005). CONCLUSION: Selective ß2-adrenoceptor agonism effectively increases metabolic rate and fat oxidation in overweight individuals. The potential for weight loss induced by ß2-agonists may be greater for R-enantiopure formulations.

Relapse and Mortality Risk of Stage I Testicular Cancer.

OBJECTIVES: - To assess the medical insurance risk for patients with stage I testicular cancer (TC), by calculating the overall mortality risk with and without relapse, and compare it to men from the Danish population. BACKGROUND: - Testicular cancer is the most common malignancy in young males. Outcomes of a Danish cohort of 3366 patients with stage I TC (1366 non-seminomas (NSTC) and 2000 Seminomas (STC)), were analyzed. METHOD: - The data were analyzed by the "illness-death" model. For the analysis of the transitions between diagnosis, relapse and death we adopted a parametric approach, where the relationship between the intensities and the effect of covariates were specified by Poisson regression models for NSTC and STC individually. RESULTS: - In the NSTC group, 422 patients relapsed. Six relapses (1.4%) occurred after 5 years of follow-up. In the STC group, 389 relapsed. The relapse rate after 5 years was 4.1%. The overall mortality analyses showed that the standardized mortality ratio (SMR) for men with NSTC without relapse, was slightly lower than in the matched general population of Danish men (SMR = 0.9). In STC patients without relapse, SMR was 0.80. Relapse raised the overall mortality by a factor 2.0 for NSTC and 1.5 for STC. CONCLUSIONS: - The fact that few relapses occur 5 years after diagnosis is an important finding for risk assessment in life insurance. It makes it possible to insure men diagnosed with stage I TC, who have not experienced relapse 5 years after diagnosis, on normal terms.

Insulin-like Factor 3, Basal and Human Chorionic Gonadotropin-Stimulated Testosterone as Biomarkers to Predict the Effect of Testosterone Replacement in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency.

INTRODUCTION: Mild Leydig cell insufficiency affects a substantial proportion of testicular cancer survivors. Previous studies have not shown a beneficial effect of testosterone replacement therapy, however, with a pronounced interindividual effect. Thus, biomarkers identifying the subgroups that might benefit are wanted. We aimed to determine if insulin-like factor 3 (INSL3), basal and human chorionic gonadotropin (hCG)-stimulated testosterone can predict the effect of testosterone replacement therapy in testicular cancer survivors with mild Leydig cell insufficiency. PATIENTS AND METHODS: We randomized adult testicular cancer survivors with mild Leydig cell insufficiency 1:1 to 12 months of transdermal testosterone replacement therapy (Tostran gel 2%) or placebo. INSL3, basal, and hCG-stimulated testosterone were measured at baseline. Outcomes (glucose, insulin, HbA1C, lipids, blood pressure, and body composition) were measured at baseline, 6 and 12 months. We applied a linear mixed-effect model comparing patients receiving testosterone with placebo in subgroups by biomarker. RESULTS: We included and randomized 69 patients between October 2016 and February 2018. Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had a -1.7 kg (95% CI: -3.1, -0.4) and -2.0 kg (95% CI: -3.5, -0.6) change in fat mass after 12 months of testosterone replacement therapy compared with placebo. This was not the case in patients with INSL3 and hCG-stimulated testosterone above the median. We did not find any effect of these biomarkers on glucose, insulin, HbA1c, or lipids. CONCLUSION: Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had decreased fat mass after 12 months of testosterone replacement therapy compared with placebo. It should be evaluated in larger trials if these biomarkers can be used as predictive markers identifying testicular cancer patients with mild Leydig cell insufficiency who might benefit from testosterone substitution.

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study.

PURPOSE: Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review. METHODS: Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis. RESULTS: Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of ß-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70. CONCLUSION: The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.

Prognostic factors for relapse in patients with clinical stage I testicular non-seminoma: A nationwide, population-based cohort study.

BACKGROUND: Approximately 30% of patients with clinical stage I non-seminoma (CSI-NS) relapse. Current risk stratification is based on lymphovascular invasion (LVI) alone. The extent to which additional tumor characteristics can improve risk prediction remains unclear. OBJECTIVE: To determine the most important prognostic factors for relapse in CSI-NS patients. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study including all patients with CSI-NS diagnosed in Denmark between 2013 and 2018 with follow-up until 2022. Patients were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histological slides from the orchiectomy specimens were retrieved. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histological slides were reviewed blinded to the clinical outcome. Clinical data were obtained from medical records. The association between prespecified potential prognostic factors and relapse was assessed using Cox regression analysis. Model performance was evaluated by discrimination (Harrell's C-index) and calibration. RESULTS: Of 453 patients included, 139 patients (30.6%) relapsed during a median follow-up of 6.3 years. Tumor invasion into the hilar soft tissue of the testicular hilum, tumor size, LVI and embryonal carcinoma were independent predictors of relapse. The estimated 5-year risk of relapse ranged from < 5% to > 85%, depending on the number of risk factors. After internal model validation, the model had an overall concordance statistic of 0.75. Model calibration was excellent. CONCLUSION AND RELEVANCE: The identified prognostic factors provide a much more accurate risk stratification than current clinical practice, potentially aiding clinical decision-making.

Smoking as a prognostic factor for survival in patients with disseminated germ cell cancer.

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.

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer.

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 time-consuming medical record review and contribute to important future clinical research.

Paternity After Treatment for Testicular Germ Cell Cancer: A Danish Nationwide Population-Based Cohort Study.

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.

Effect of Testosterone Replacement Therapy on Quality of Life and Sexual Function in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency: Results From a Randomized Double-blind Trial.

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.

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

INTRODUCTION: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. PATIENTS AND METHODS: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. CLINICALTRIAL: gov (NCT02991209) and ended June 2019. RESULTS: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). CONCLUSION: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.

ß2-Adrenergic agonist salbutamol augments hypertrophy in MHCIIa fibers and sprint mean power output but not muscle force during 11 weeks of resistance training in young men.

In this study, we examined the effect of ß2-agonist salbutamol at oral doses during a period of resistance training on sprint performance, quadriceps contractile function, skeletal muscle hypertrophy, fiber type composition, maximal activity of enzymes of importance for anaerobic energy turnover, and sarcoplasmic reticulum Ca2+ handling in young men. Twenty-six men (23 ± 2 yr; means ± SD) were randomized to daily intake of oral salbutamol (16 mg/day; RES+SAL) or placebo (RES) during 11 wk of full-body resistance training 3 times/wk. Mean power output during 10-s maximal cycling increased more (P = 0.027) in RES+SAL (+12%) than in RES (+7%), whereas peak power output increased similarly (RES+SAL: +8%; RES: +7%; P = 0.400). Quadriceps dynamic peak torque and maximal voluntary isometric torque increased by 13 and 14% (P ≤ 0.001) in RES+SAL and 13 and 13% (P ≤ 0.001) in RES, respectively. Myosin heavy-chain (MHC) isoform distribution transitioned from MHCI and MHCIIx toward MHCIIa in RES+SAL (P = 0.002), but not in RES (P = 0.323). MHCIIa cross-sectional-area increased more (P = 0.040) in RES+SAL (+35%) than RES (+21%). Sarcoplasmic reticulum Ca2+ release rate increased in both groups (RES+SAL: +9%, P = 0.048; RES: +13%, P = 0.008), whereas Ca2+-uptake rate increased only in RES (+12%, P = 0.022) but was not different from the nonsignificant change in RES+SAL (+2%, P = 0.484). Maximal activity of lactate dehydrogenase increased only in RES+SAL (+13%, P = 0.008). Muscle content of the dihydropyridine receptor, ryanodine receptor 1, and sarcoplasmic reticulum Ca2+-ATPase isoform 1 and 2 did not change with the intervention in either group (P ≥ 0.100). These observations indicate that the enhancement of sprint mean power output induced by salbutamol is at least partly attributed to greater hypertrophy of MHCIIa fibers and transition toward the MHCIIa isoform.NEW & NOTEWORTHY Here, we show that daily oral treatment with selective ß2-agonist salbutamol induces muscle fiber isoform transition from myosin-heavy-chain (MHC)-I toward MHCIIa and augments hypertrophy of MHCIIa fibers during a period of resistance training. Compared with placebo, salbutamol enhanced sprint mean power output, whereas peak power output and measures of muscle strength increased similarly during the resistance training period despite augmented hypertrophy with salbutamol. Thus, salbutamol is a muscle anabolic drug that can enhance sprint ability adaptations to resistance training.

Long-term neurotoxicity and quality of life in testicular cancer survivors-a nationwide cohort study.

PURPOSE: To evaluate neurotoxicity in testicular cancer survivors (TCSs) years after treatment and secondly the influence of neurotoxicity on quality-of-life (QoL). METHODS: We identified 2234 TCSs who completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity questionnaire. QoL was evaluated with the European Organization for Research and Treatment of Cancer QLQ-C30. Patients were grouped according to treatment strategy: surveillance (N = 1113), infradiaphragmatic radiotherapy (N = 301), cisplatin-etoposide-bleomycin (BEP) (N = 759), and more than one line of treatment (MTOL) (N = 61). Association of treatment modality with long-term neurotoxicity was analyzed with ordinal logistic regression. Secondly, associations between neurotoxicity and QoL were analyzed in BEP-treated patients. Analyses were age-adjusted and repeated with additional adjustment for comorbidity, smoking, and alcohol consumption. RESULTS: After a median follow-up of 18.4 years, treatment with BEP and MTOL was associated with overall increased risk of neurotoxicity (odds ratio 2.4-4.7 depending on treatment intensity, P < 0.001) as well as subscales (peripheral neuropathy, ototoxicity, and dysfunction associated with neuropathy, all P < 0.001). Radiotherapy and surveillance were not associated with neurotoxicity. In patients treated with BEP, neurotoxicity was highly associated with all indicators of worse QoL outcomes (P-trend: 1.5 × 10-17 to 1.1 × 10-28) after almost 20 years of follow-up. CONCLUSIONS: Treatment with BEP was associated with long-term neurotoxicity, which was highly associated with decreased QoL. Strategies to ameliorate or prevent neurotoxicity should be investigated. IMPLICATIONS FOR CANCER SURVIVORS: Treatment with chemotherapy for testicular cancer induces long-term neuro- and ototoxicity which may have severe influence on quality-of-life years after treatment cessation.

Late adverse effects and quality of life in survivors of testicular germ cell tumour.

Currently, ~95% of patients with testicular germ cell tumour (TGCT) are cured, resulting in an increasing number of TGCT survivors. Although cured, these men face potential late adverse effects and reduced quality of life. Survivors face a twofold increased risk of second malignant neoplasms after chemotherapy and radiotherapy, with evidence of dose-dependent associations. For survivors managed with surveillance or treated with radiotherapy, the risk of cardiovascular disease (CVD) is comparable to the risk in the general population, whereas treatment with chemotherapy increases the risk of life-threatening CVD, especially during treatment and after 10 years of follow-up. Other adverse effects are organ-related toxicities such as neuropathy and ototoxicity. Pulmonary and renal impairment in patients with TGCT treated with chemotherapy is limited. Survivors of TGCT might experience psychosocial distress including anxiety disorders, fear of cancer recurrence and TGCT-specific issues, such as sexual dysfunction. Late adverse effects can be avoided in most patients with stage I disease if followed on a surveillance programme. However, patients with disseminated disease can experience toxicities associated with radiotherapy and chemotherapy, and/or adverse effects related to surgery for residual disease. The severity of adverse effects increases with dose of both chemotherapy and radiotherapy. This Review discusses the most recent data concerning the late adverse effects of today's standard treatments for TGCT.

Sexual Function and Quality of Life in a National Cohort of Survivors of Bilateral Testicular Cancer.

BACKGROUND: Sexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). OBJECTIVE: To investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC+GCNIS] or bilateral TC [BTC]). DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12-23). Results for survivors of TC+GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. RESULTS AND LIMITATIONS: The age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1-2.8; p=0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC+GCNIS (ß=0.067, 95% CI 0.0013-0.13; p=0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. CONCLUSIONS: Survivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. PATIENT SUMMARY: We evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer.

Psychological stress in long-term testicular cancer survivors: a Danish nationwide cohort study.

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.