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The imperative need for sensitive and precise tools is underscored in cancer diagnostics, with biomarkers playing a pivotal role in facilitating early detection and tumor diagnosis. Despite their classical pathological classification, testicular tumors lack valuable markers, emphasizing the necessity to identify and apply serum tumor markers in clinical management. Unfortunately, existing biomarkers exhibit limited sensitivities and specificities. Recent years have witnessed the discovery of novel RNA molecules, presenting a potential breakthrough as diagnostic tools and promising biomarkers. This report presents compelling evidence supporting the detection of early testicular cancer by applying a set of nine microRNAs (miRNAs), establishing them as valuable serum biomarkers for diagnosis. We developed a standardized serum-based measurement protocol and conducted comprehensive statistical analyses on the dataset to underscore the diagnostic accuracy of the miRNA pool. Notably, with a sensitivity exceeding 93%, miR-21, miR-29a, and miR-106b surpass classical serum tumor markers in the context of testicular cancer. Specifically, these miRNAs are poised to enhance clinical decision-making in testicular cancer detection and hold the potential for assessing tumor growth in monitoring chemotherapy outcomes., (© 2024. The Author(s).)

Purpose: To evaluate the association between serum alpha-fetoprotein (AFP) half-life (HL) and prognosis in prepubertal children with elevated AFP values 3 to 4 weeks after surgery for testicular yolk sac tumors (YST)., Methods: Prepubertal patients with testicular YST treated with radical orchiectomy between January 2016 and December 2022 were retrospectively reviewed. Negative outcomes were defined as relapse, metastasis or death. Univariate and multivariate logistic regression analyses were conducted to select risk factors for negative outcomes., Results: A total of 42 patients were eventually enrolled into the study. Patients were divided into non-negative and negative outcomes groups, consisting of 35 and 7 patients, respectively. Thirty-five patients were stage I, two cases were stage II, and five cases were stage IV, according to the Children's Oncology Group staging system. The overall survival (OS) rate was 100%. Average AFP values significantly decreased after resection (P < 0.001). A significant positive correlation was shown between pre- and postoperative AFP values (r = 0.60, P < 0.001). Long AFP HL was considered as an independent risk factor for negative outcomes in YST patients underwent radical orchiectomy (P = 0.04). The cut-off value for AFP HL was 5.78 days, regardless of age division., Conclusion: Testicular YST is a relatively rare disease in children with an OS of 100%, and salvage chemotherapy is effective even in grade IV patients. The postoperative AFP HL was significantly associated with prognosis in prepubertal patients with testicular YST. The cut-off value for AFP HL is 5.78 days regardless of the effect of physiological AFP elevation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Approximately 30% of seminoma (SEM) patients present with moderately elevated human chorionic gonadotropin (hCG) levels at first diagnosis. In case of high hCG serum levels, the presence of a non-SEM component, i.e. choriocarcinoma (CC), may be assumed. To characterize cases described as pure seminoma with high serum hCG levels, tissue samples and DNA were analyzed. Patient files from an international registry were screened for patients with SEM and extraordinarily high hCG serum levels. IHC and qRT-PCR analysis was performed for markers of SEM, embryonal carcinoma (EC) and CC/trophoblast cells. The cell lines TCam-2 (SEM), 2102EP, NCCIT, NT2/D1 (EC) and JAR, JEG3 and BeWo (CC) were included for comparison. Of 1031 SEM patients screened, 39 patients (3.7%) showed hCG serum levels > 1000 U/l. Of these, tumor material for IHC and RNA for qRT-PCR was available from n = 7 patients and n = 3 patients, respectively. Median pre-orchiectomy serum hCG level was 5356 U/l (range: 1224-40909 U/L). Histopathologically, all investigated samples were classified as SEM with syncytiotrophoblast sub-populations. SEM cells were SALL4 + / OCT3/4 + / D2-40 + , while syncytiotrophoblast cells were hCG + / GATA3 + / p63 + and SOX2 - /CDX2 - . qRT-PCR analysis detected trophoblast stem cell markers CDX2, EOMES and TFAP2C as well as the trophectoderm-specifier TEAD4, but not GATA3. Additionally, SOX17 and PRAME, but not SOX2, were detected, confirming the pure SEM-like gene expression signature of the analyzed samples. In conclusion, excessively increased hCG serum levels can appear in patients with pure SEM. To explain detectable hCG serum levels, it is important to diagnose the subtype of a SEM with syncytiotrophoblasts., (© 2023. The Author(s).)

Background: Testicular microlithiasis (TM) is thought to be associated with testicular tumors and impaired spermatogenesis; however, its etiology remains unclear., Objectives: To identify factors, other than testicular function, that are associated with testicular microlithiasis., Materials and Methods: We enrolled males who underwent ultrasound examination of the scrotum at Tokyo Dental College Ichikawa General Hospital. The patients were categorized into two groups: those with or those without testicular microlithiasis. Background and blood test data were compared between the groups., Results: Testicular microlithiasis was observed in 72 of the 828 (8.7%) patients enrolled. Ages ranged from 15 to 87 years (mean age, 40.0 years). A history of germ cell tumor was significantly more prevalent in patients with testicular microlithiasis than in those without (1.3 vs. 16.7%; p < 0.001). Blood test data showed that, patients with testicular microlithiasis had significantly higher serum creatinine levels (0.91 vs. 1.04 mg/dL; p = 0.046) and lower calcium levels (9.4 vs. 9.3 mg/dL; p = 0.031) than those without. Serum creatinine levels (> 1.00 mg/dL) and germ cell tumors were significantly associated with testicular microlithiasis in both univariate and multivariate analyses. The prevalence of testicular microlithiasis increased in patients older than 50 years. Age (> 50 years) was associated with testicular microlithiasis in univariate analysis. The mean body weight tended to be heavier (70.7 vs. 72.2 kg; p = 0.051) and epididymitis was observed more frequently (3.2 vs. 8.3%; p = 0.056) in patients with testicular microlithiasis than in those without., Discussion and Conclusion: A history of testicular tumors and elevated serum creatinine levels were associated with testicular microlithiasis. Testicular microlithiasis was observed across all age groups, with a tendency to increase in patients older than 50 years. Patients with testicular microlithiasis were slightly heavier and had a higher prevalence of epididymitis than those without. Our findings suggest that, in addition to testicular dysgenesis, other factors are involved in the development of testicular microlithiasis., (© 2023 American Society of Andrology and European Academy of Andrology.)

Purpose: We aimed to evaluate the diagnostic sensitivity and specificity of the miRNA-371a-3p for the primary diagnosis of germ cell tumors (GCT) and to investigate its relationship with pathological factors and clinical stage in the Turkish population., Materials and Methods: In this prospective study, a total of 60 patients with GCTs, and 40 healthy male controls were examined for serum levels of miRNA-371a-3p before orchiectomy and again two weeks after surgery. The miRNA-371a-3p, alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (bHCG) levels in the preoperative and postoperative periods were compared at different clinical stages. Receiver operating characteristics curve analyses were performed to determine the sensitivity and specificity of miRNA-371a-3p. Clinical and pathological factors such as clinical stage (CS), tumor size, histology, rete testis invasion, and lymphovascular invasion, potentially impacting miRNA-371a-3p expression levels (relative quantity, RQ), were evaluated statistically., Results: The sensitivity of miR-371a-3p in GCT patients was 98.3%, and the specificity was 95% (AUC = 0.997 [95%Cl:0.99-1], p < .001). miR-371a-3p expression was not detected in two patients with teratoma. The median miR-371a-3p RQ was 489 times in GCT and 2.2 times in the Control group (p < .001). In the postoperative period, there was a significant decrease in AFP and bHCG levels in all CS-1 (p = .01) and 30% of the other CS (p = .3). Throughout this time there was a decrease of 19 times at the miR-371a-3p RQ in CS-1(p < .001) and 1.6 times in the other CS (p < .001). The miR-371a-3p RQs were correlated with tumor size and CS., Conclusion: The miR-371a-3p seems to have higher diagnostic accuracy than classical serum tumor markers in GCT.

Introduction: In testicular cancer, the positive effect of early diagnosis on survival has been known for many years. In this study, we aimed to determine the diagnostic features of testicular cancer patients, to examine the effect of duration of diagnosis delay (DD) on tumor size, tumor stage, and serum tumor markers, and to reveal the possible benefits of early diagnosis., Methods: A total of 71 patients who underwent inguinal orchiectomy due to suspicion of testicular cancer and whose pathology was found to be the germ cell tumor were included in the study. The relationship between the duration of diagnosis delay and tumor size, level of tumor markers, TNM stage, presence of LAP, and presence of metastasis were examined., Results: Seminoma was detected in 39 (54.9%) patients and non-seminoma tumor was detected in 32 (45.1%) patients. In the correlation analysis between the markers, a significant and positive correlation was found between DD and radiological tumor size, pathological tumor size, retroperitoneal LAP detection rate, LDH and AFP levels, and N stage (respectively; r=0.345 p=0.003, r=0.324 p=0.006, r=0.244 p=0.041, r=0.286 p=0.015, r=0.244 p=0.040, r=0.238 p=0.046). It was determined that a 1-day increase in DD caused an increase of 0.431mm in the pathological size of the tumor., Conclusion: Duration of diagnosis delay is an issue that still keeps its importance for testicular tumors. Delay in diagnosis not only leads to an increase in tumor size but also negatively affects tumor stage and prognostic factors., (Copyright © 2023 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Background: In childhood (CCS) and testicular cancer (TCS) survivors, low-grade inflammation may represent a link between testosterone deficiency (hypogonadism) and risk of metabolic syndrome. We aimed to study levels of inflammatory markers in CCS and TCS and the association with hypogonadism and future cardio-metabolic risk factors., Methods: Serum levels of inflammatory markers and testosterone were analyzed in CCS (n = 90), and TCS (n = 64, median time from diagnosis: 20 and 2.0 years, respectively), and in controls (n = 44). Differences in levels between patients and controls were calculated using univariate analysis of variance. T-test and logistic regression were applied to compare levels of cardio-metabolic risk factors and odds ratio (OR) of hypogonadism and metabolic syndrome in low and high inflammatory marker groups after 4-12 years of follow up. Adjustment for age, smoking, and active cancer was made., Results: TCS and CCS, as compared to controls, had 1.44 (95%CI 1.06-1.96) and 1.25 (95 CI 1.02-1.53) times higher levels of IL-8, respectively. High IL-6 levels were associated with hypogonadism at baseline (OR 2.83, 95%CI 1.25-6.43) and the association was stronger for high IL-6 combined with low IL-10 levels (OR 3.10, 95%CI 1.37-7.01). High IL-6 levels were also associated with higher BMI, waist circumference, insulin, and HbA1c at follow up. High TNF-α was associated with higher diastolic blood pressure. No individual inflammatory marker was significantly associated with risk of metabolic syndrome at follow up. High IL-6 combined with low IL-10 levels were associated with risk of metabolic syndrome (OR 3.83, 95%CI 1.07-13.75), however not statistically significantly after adjustment., Conclusion: TCS and CCS present with low-grade inflammation. High IL-6 levels were associated with hypogonadism and cardio-metabolic risk factors. Low IL-10 levels might reinforce the IL-6 mediated risk of developing metabolic syndrome., (© 2022. The Author(s).)

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., (© 2021. The Author(s).)

Context: Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done., Objective: We aimed to define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART., Methods: Using liquid chromatography-tandem mass spectrometry, steroids were measured in left (n = 7) and right (n = 4) spermatic vein and simultaneously drawn peripheral blood (n = 7) samples from 7 men with 21OHD and TART. For comparison, we also measured the peripheral steroid concentrations in 5 adrenalectomized patients and 12 age- and BMI-matched controls. Additionally, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation., Results: Compared with peripheral blood from 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11β-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11β-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone and lower levels of A4 and 11OHA4 after ACTH stimulation compared with adrenal cells, indicating ACTH-induced production of testosterone in TART., Conclusion: In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic vs peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Persistent alpha-fetoprotein elevation in a patient following orchiectomy and chemotherapy for non-seminomatous testicular germ cell tumor is a rare condition when persistence of the tumor and false positivity of tumor marker elevation has to be differentiated. This situation often leads to over-treatment and potential toxicity with adverse events which can be severe., Case: A case of a patient with the abovementioned disease and course of treatment is presented. As no radiological signs of the disease were present and the level of alpha-fetoprotein was mild and stable, the tumor marker elevation was evaluated as false positive. Possible causes of the tumor marker elevation were identified as other serious diseases are known to cause such a false positivity. The level of alpha-fetoprotein remained unchanged despite alcohol abstinence and hepatoprotective treatment by silymarin. Hepatitis B and C serological tests were negative, and no other malignant tumor was identified. Finding of terminal ileum circular wall thickening and stratification with a reaction of surrounding visceral fat and lymph nodes persisting in CT scans suggests the presence of inflammatory bowel disease, possibly explaining the alpha-fetoprotein elevation. The patient has no evidence of the disease more than 14 months after the end of chemotherapy treatment with no change in the elevation of alpha-fetoprotein., Conclusion: After the treatment, when no other indication of testicular cancer than an elevated alpha-fetoprotein level is present, the patient should be managed by ongoing surveillance.

Objective: To describe the incidence, clinical and demographic factors, and treatment patterns associated with discordant elevated alpha-fetoprotein (AFP) findings in patients with pure seminomatous histology., Methods: We queried the National Cancer Database to identify patients with testicular germ cell tumors (GCT) diagnosed in 2011-2015. Patients were grouped based on histologic diagnosis and pre-operative serum AFP level., Results: Of 18,616 patients diagnosed with testicular GCT, 53% (N = 9,849) had pure seminomatous histology, of whom 8.3% (N = 821) had an elevated serum AFP pre-operatively. Non-white patients with seminoma were more likely to have a pre-op elevated AFP (OR 1.42; 95% CI: 1.10-1.83); patients treated at higher volume centers were less likely to have a pre-op elevated AFP (0.66, 95% CI: 0.53-0.83). Patients with seminoma with elevated AFP received adjuvant radiation more frequently than those with NSGCT (Stage I: 15% vs 0.2%, P <.01; Stage II: 21.9% vs 0.1%, P <.01) and less frequently underwent retroperitoneal lymph node dissection (RPLND) (Stage 1: 1.9% vs 11.1% P <.01; Stage II: 8.8% vs 17.4%, P <.01)., Conclusion: The detection of elevated serum alpha-fetoprotein (AFP) in patients with pure seminomatous testicular germ cell tumors (GCT) is a discordant finding that implies the presence of occult non-seminomatous GCT (NSGCT) elements. 8% of patients with pure seminomatous GCTs had diagnostically discordant elevated pre-operative AFP levels. Despite recommendations to manage these patients as NSGCT, patients with seminoma and elevated AFP were managed in a fashion comparable to those with seminoma and normal AFP levels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of our study was to analyze the potential relationship between tumor markers and 18 F-fluorodoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) results in patients affected by seminoma., Material and Methods: 65 18 F-FDG PET/CT scans of 41 patients with diagnosis of seminoma were analyzed and compared to alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG). PET/CT studies were analyzed qualitatively and measuring the maximum and mean standardized uptake value body weight max (SUVbwmax, SUVbwmean), maximum SUV lean body mass (SUVlbm), maximum SUV body surface area (SUVbsa), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of hypermetabolic lesions. All values were compared with serum markers., Results: 31 PET/CT studies were true negative, 28 true positive, 6 false positive and 0 false negative with sensitivity of 100%, specificity of 84%, negative predictive value of 100%, positive predictive value of 82% and accuracy of 91%. No correlation between PET results and tumor marker levels was found and also between AFP and PET/CT semiquantitive parameters. All semiquantitative PET parameters were significantly related to hCG level., Conclusions: 18 F-FDG PET/CT has good accuracy in evaluating patients with relapsed seminoma. HCG levels were significantly correlated with metabolic PET/CT parameters., (Copyright © 2020 Sociedad Española de Medicina Nuclear e Imagen Molecular. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: Previous research has indicated cognitive decline (CD) among testicular cancer patients (TCPs), even in the absence of chemotherapy, but little is known about the underlying pathophysiology. The present study assessed changes in cognitive functions and structural brain connectomes in TCPs and explored the associations between cognitive changes and endocrine status and hypothesized risk genotypes., Methods: Thirty-eight newly orchiectomized TCPs and 21 healthy controls (HCs) comparable to TCPs in terms of age and years of education underwent neuropsychological testing, structural MRI, and a biological assessment at baseline and 6 months later. Cognitive change was assessed with a neuropsychological test battery and determined using a standardized regression-based approach, with substantial change defined as z-scores ≤-1.64 or ≥1.64. MRI scans and graph theory were used to evaluate changes in structural brain connectomes. The associations of cognitive changes with testosterone levels, androgen receptor gene (AR) CAG repeat length, and genotypes (APOE, COMT, and BDNF) were explored., Results: Compared with HCs, TCPs showed higher rates of substantial decline on processing speed and visuospatial ability and higher rates of substantial improvement on verbal recall and visuospatial learning (p < 0.05; OR = 8.15-15.84). Brain network analysis indicated bilateral thalamic changes in node degree in HCs, but not in TCPs (p < 0.01). In TCPs, higher baseline testosterone levels predicted decline in verbal memory (p < 0.05). No effects were found for AR CAG repeat length, APOE, COMT, or BDNF., Conclusions: The present study confirms previous findings of domain-specific CD in TCPs following orchiectomy, but also points to domain-specific improvements. The results do not indicate changes in brain connectomes or endocrine status to be the main drivers of CD. Further studies evaluating the mechanisms underlying CD in TCPs, including the possible role of the dynamics of the hypothalamic-pituitary-gonadal axis, are warranted., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients., Methods: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR)., Results: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively., Conclusions: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification., (© 2021. The Author(s).)

MicroRNA-371a-3p (miR371) has been suggested as a sensitive biomarker in testicular germ cell cancer (TGCC). We aimed to compare miR371 with the classical biomarkers α-fetoprotein (AFP) and β-human chorionic gonadotropin (hCG β ). Overall, 180 patients were prospectively enrolled in the study, with serum samples collected before and after orchiectomy. We compared the use of digital droplet PCR (RT-ddPCR) with the quantitative PCR used by others for detection of miR371. The novel RT-ddPCR protocol showed high performance in detection of miR371 in serum samples. In the study cohort, miR371 was measured using RT-ddPCR. MiR371 detected CS1 of the seminoma and the non-seminoma sub-types with a sensitivity of 87% and 89%, respectively. The total sensitivity was 89%. After orchiectomy, miR371 levels declined in 154 of 159 TGCC cases. The ratio of miR371 pre- and post-orchiectomy was 20.5 in CS1 compared to 6.5 in systemic disease. AFP and hCG β had sensitivities of 52% and 51% in the non-seminomas. MiR371 is a sensitive marker that performs better than the classical markers in all sub-types and clinical stages. Especially for the seminomas CS1, the high sensitivity of miR371 in detecting TGCC cells may have clinical implications., (© 2021. The Author(s).)

Objective: To report our findings in patients with determination of testicular tumor markers from the vena spermatica during inguinal orchiectomy., Methods: In a retrospective setting, data of patients who underwent inguinal orchiectomy between January 2004 and December 2014 were analyzed. Cubital and testicular vein tumor markers were assessed and correlated to histology, clinical stage and outcome., Results: A total of 90 patients (seminomatous: n = 53, non-seminomatous: n = 37) with a median age of 37 years were included. The mean follow-up was 109 months. Overall, 60% (n = 54) of patients had one or more positive tumor marker level in the cubital vein vs 88.9% (n = 80) in the testicular vein. Median tumor marker levels of hCGβ in cubital and testicular vein were 1.9 U/l and 30.8U/l; the respective values for AFP were 2.9ng/ml and 2.4ng/ml and for hPLAP 49.9 mU/l and 418.9 mU/l. Differences in cubital vs testicular vein positivity were stage dependant and highest for pT1. Patients with seminomatous tumors had peripheral positivity of 59.3% vs 88.9% in the testicular vein (P = 0.003); in non-seminomatous patients the respective values were 61.1% and 88.9% (P = 0.02). All recurrent cancer patients under active surveillance (n = 5) were positive in the testicular vein., Conclusion: Virtually all testicular cancers shed tumor markers in the circulation. Differences in marker positivity (testicular vs testicular vein) were stage dependent (greatest in pT1), largely independent of histology and highest for hCGβ. The prognostic value of testicular vein sampling remains speculative., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To determine whether utilisation of a serum microRNA (miRNA) test could improve treatment appropriateness and cost-effectiveness for patients with Stage I non-seminomatous germ cell tumours (NSGCTs)., Patients and Methods: A decision tree model was built to investigate treatment course, clinical and cost outcomes for patients with Stage IA (T1N0M0S0) and IB (T2-4N0M0S0) NSGCT. The model compared outcomes and cost of standard approach using histopathology, conventional serum tumour markers and radiographic staging (standard model) to a miRNA-based approach using the standard model + post-orchidectomy serum miR-371a-3p (marker model). Probabilities of expected treatment and outcomes were based on presence/absence of cancer upon entering into the model. Overtreatment was defined as adjuvant chemotherapy or primary retroperitoneal lymph node dissection in a patient without cancer. Undertreatment was defined as initial surveillance for a patient with cancer., Results: Utilising the miRNA marker-based approach, 26% of patients avoid overtreatment and 8% avoid undertreatment in Stage IA NSGCT; 27% avoid overtreatment and 23% avoid undertreatment in Stage IB disease. Appropriate treatment decision-making increased from 65% to 94% and 50% to 92% for Stage IA and IB, respectively. The miRNA-based approach remained cost-effective over a wide range of performance characteristics with savings of ~$1400 (American dollars)/patient for both Stage IA and IB disease., Conclusion: A miRNA-based approach may potentially select patients with Stage I NSGCT for correct treatment in a cost-effective manner. Identification of residual teratoma-only remains an issue. Prospective studies are necessary to validate these findings., (© 2020 The Authors BJU International © 2020 BJU International.)

Purpose: Men with nonseminomatous germ cell tumors of the testicle without evidence of residual disease after radical orchiectomy (clinical stage I) are increasingly managed with active surveillance. The guideline-recommended cornerstones of surveillance are conventional serum tumor markers and computerized tomography. The reliability of serum tumor markers as a tool to diagnose early recurrence of clinical stage I nonseminomatous germ cell tumors is unclear. The study objective was to conduct a systematic review of the currently available evidence assessing the reliability of serum tumor markers as a test to diagnose recurrence in patients with clinical stage I nonseminomatous germ cell tumors under active surveillance., Materials and Methods: A systematic review was conducted in accordance with PRISMA guidelines, with no language or date restrictions. Studies were included that readily identified the tumor marker status of patients with clinical stage I nonseminomatous germ cell tumors who had a recurrence on active surveillance. The primary outcome was marker positivity at the time of recurrence. Risk of bias assessment was undertaken., Results: A total of 2,157 studies were identified and independently screened by 2 reviewers, with 37 studies ultimately being included. A relatively high risk of bias was identified among the studies, with the vast majority being retrospective series. The total population for the included studies was 8,545 patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, and 2,254 ultimately relapsed. Serum tumor markers were elevated in 28% to 75% of patients at the time of recurrence and were the only indication of recurrence in 4% to 39%. The unavailability of patient-level data is the major limitation to the present findings., Conclusions: In patients with clinical stage I nonseminomatous germ cell tumors managed by active surveillance, the use of serum tumor markers cannot obviate the need for computerized tomography. More reliable serum markers are needed in order to limit radiation exposure for these patients.

Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.

Purpose: Serum levels of microRNA-371a-3p (M371) have been shown to be a highly sensitive and specific biomarker for testicular germ cell tumours (TGCT). Little information exists on the expression of this marker in testicular neoplasms deriving from the gonadal stroma or other structures of the gonad. This study presents an expression analysis of the novel TGCT-biomarker M371 in a large cohort of testicular non-germ cell tumours., Methods: The M371 expression was measured by quantitative real time PCR in serum of 99 patients with testicular tumours of non-germ cell origin, thereof 30 patients with malignant testicular lymphomas and 61 patients with gonadal stroma tumours such as Leydig cell tumours, Sertoli cell tumours and 8 cases with miscellaneous benign testicular tumours. Their M371 levels were compared to those of 20 patients with TGCT and to 37 tumour-free male controls., Results: The median expression levels of benign testicular tumours and testicular lymphoma are close to zero, thus, identical with those of controls and significantly lower than those of TGCT. In summary, this study provides further evidence for the notion that M371 is exclusively expressed by germ cell tumours and not by testicular neoplasms of the non-germ cell subtypes., Conclusion: Clinically, the test might be of value in preoperative characterization of benign testicular tumours eligible for conservative surgery.

Gynecomastia is a frequent sign that may be physiological or caused by various benign or malignant diseases. In rare cases, it may be caused by testicular tumors. We describe a case of progressive gynecomastia at age 20 due to a Leydig cell tumor of the right testicle in a patient with a previous history of left-sided cryptorchidism. The patient underwent orchidectomy and testicular prosthesis placement, with subsequent improvement of gynecomastia and normalization of estrogen. Our case, in addition to demonstrating that gynecomastia may regress if the underlying cause is treated in a timely manner, shows that cryptorchidism may be related with the development of Leydig cell tumors in the same way as it is in other testicular tumors.

Purpose: The aim of this study was to compare the prognostic value of pretreatment inflammation-based scoring systems in terms of overall survival (OS) and progression-free survival (PFS) in patients with germ cell tumors (GCTs) receiving bleomycin, etoposide, and cisplatin (BEP) chemotherapy., Materials and Methods: We evaluated 63 patients with GCTs retrospectively. The Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio, prognostic index, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index, and albumin-to-globulin ratio (AGR) were measured in all patients before chemotherapy. To assess the predictive ability of each scoring system, areas under the receiver operating characteristic curve were calculated, and multivariate analysis was performed to identify associations between the predictive scores and OS., Results: Of all the inflammation-based scoring systems, the GPS had the greatest area under the curve (0.847) for predicting OS, followed by the PNI (0.829) and AGR (0.810). Kaplan-Meier analyses revealed that the GPS, PNI, and AGR were significantly associated with OS, whereas the GPS, PLR, and PNI were significantly associated with PFS. In the multivariate analysis, the GPS was an independent predictor of OS and PFS., Conclusions: We demonstrated that the GPS was the most valuable biomarker of OS and PFS in patients with GCTs., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Introduction: β-HCG has been the only tumor marker evaluated in testicular vein (VT) blood until now., Objective: To evaluate the correlation between the tumor markers β-HCG, AFP, PLAP, and LDH from the VT and peripheral blood as well as their significance in predicting tumor recurrence and tumor stage., Methods: Patients with testicular cancer undergoing orchiectomy were studied retrospectively over a period of 20 years. Tumor stage, tumor histology, time to tumor recurrence, and tumor markers from VT and peripheral blood were analyzed. Minimal follow-up was 2 years. Statistical analysis was performed by means of Cox- and logistic regression models and Spearman rank correlation coefficients., Results: A total of 172 patients with an average follow-up of 9.9 years were investigated. The overall recurrence rate was 18% (seminoma patients 20.8%, nonseminoma patients 14.5%). Marker values measured from VT blood were higher than in peripheral blood and correlated strongly with the peripherally measured values. AFP obtained from peripheral blood was the only tumor marker allowing a statement on the recurrence probability. Tumor markers from VT blood showed no correlation with tumor stage., Discussion/conclusion: Tumor markers from VT blood are significantly higher than in peripheral blood. Tumor markers obtained from VT blood do not provide clinical advantage in terms of assessing tumor stage and recurrence probability., (© 2020 S. Karger AG, Basel.)

Purpose: Current serum tumor markers for testicular germ cell tumor are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) germ cell tumor management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable germ cell tumor among patients undergoing partial or radical orchiectomy., Materials and Methods: Serum samples were collected from 69 consecutive patients before orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional serum tumor markers (⍺-fetoprotein / β-human chorionic gonadotropin / lactate dehydrogenase) between patients with viable germ cell tumor and those without viable germ cell tumor on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. The Kruskal-Wallis test and linear and ordinal regression models were used for analysis., Results: For detecting viable germ cell tumor, combined conventional serum tumor markers had a specificity of 100%, sensitivity of 58% and AUC of 0.79. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93% and AUC of 0.978. Median relative expression of miR-371a-3p in viable germ cell tumor cases was more than 6,800-fold higher than in those lacking viable germ cell tumor. miR-371a-3p levels correlated with composite stage (p=0.006) and, among composite stage I cases, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p <0.0001). Six patients underwent orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable germ cell tumor by the miR-371a-3p test., Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional serum tumor markers to aid clinical decision making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation.

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: In recent years, the incidence of testicular cancer has increased, but mortality rates have decreased thanks to the improvements in treatment. Although primary tumor characteristics and serum tumor markers are associated with metastasis and relapse, their predictive value is not reliable. Therefore, there is a need for new biomarkers that predict prognosis. In this study, we aimed to investigate the role of preoperative albumin to globulin ratio (AGR) in predicting retroperitoneal lymph node (RPLN) involvement, distant metastasis and prognosis in testicular cancer., Material and Methods: We retrospectively analyzed the medical records of all patients that underwent radical inguinal orchiectomy at our hospital between 2007 and 2018. AGR was calculated using the equation: AGR=serum albumin/(serum total protein-serum albumin). The predictive value of AGR for RPLN involvement and distant metastasis was evaluated using receiver operating characteristic analysis and its prognostic value was evaluated using Kaplan-Meier survival analysis., Results: A total of 115 patients with a mean age of 33.4±7.7years were included in the study. In multivariate analysis, AGR less than 1.47 and the presence of lymphovascular invasion were detected as the factors predicting RPLN involvement and distant metastasis. The AGR of patients who had died was significantly lower than AGR of those who were alive, 1±0.2 versus 1.6±0.3 (P=.001). In Kaplan-Meier survival analysis, the mean survival of patients with higher AGR (>1.47) was found longer than patients with lower AGR (<1.47)., Conclusions: Preoperative AGR is a biomarker that may be used in predicting RPLN involvement, distant metastasis and prognosis in testicular cancer., (Copyright © 2020 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The activities of tumor-infiltrating immune cells (TIICs) play an important role in the outcomes of many types of cancers. Here, we sought to describe the landscape of TIICs in testicular germ cell tumors (TGCT) and to develop a prognostic model based on this information., Methods: The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of 22 types of TIICs in a TGCT dataset (n = 74). Univariate and multivariate Cox regression analysis were used to develop an immune risk score (IRS) based on the association between TIICs and disease-free survival (DFS). The predictive accuracy of the IRS was evaluated using receiver operating characteristic curves, and the predictive accuracy of a prognostic nomogram was assessed using C-index and calibration curves. The biological functions of IRS-associated genes were evaluated by gene set enrichment analysis., Results: The relative abundances of three TIICs (plasma cells, M2 macrophages, and resting mast cells) were significantly associated with DFS in TGCT patients. In receiver operating characteristic curve analysis, the resulting IRS had areas under the curve of 0.70, 0.793, and 0.827, for predicting 1-, 2-, and 3-year DFS, respectively. Kaplan-Meier analysis confirmed that DFS was shorter for patients with high IRS compared with low IRS. IRS was an independent predictor of disease recurrence (hazard ratio 1.306, 95% confidence interval 1.022-1.668; P = 0.033). The C-index for the nomogram was 0.733. Genes involved in cancer-associated and immunity-associated pathways were enriched in TGCT samples from patients in the high- and low-risk groups, respectively, and expression of four immune checkpoint regulators was significantly lower in the high IRS group compared with the low IRS group., Conclusions: A TIIC-based IRS may have utility as a complementary tool to predict relapse in patients with TGCT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Choriocarcinoma germ cell tumors are rare and usually present with significantly elevated human chorionic gonadotropin (hCG) levels. When curable, it is felt to be largely a result of chemotherapy. We sought to determine the histologic characteristics for those undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) and compare them with metastatic nonseminomatous germ cell tumor (NSGCT) patients with similarly elevated hCG levels., Methods: We reviewed medical records of men undergoing PC-RPLND between 1988 and 2017 with postorchiectomy, preinduction chemotherapy hCG levels greater than 50,000 mIU/ml. They were stratified by primary tumor histology: Pure choriocarcinoma and mixed NSGCT. Clinical, pathologic, and serologic data were reported and logistic regression was used to assess for predictors of necrosis in the PC-RPLND specimen., Results: Our cohort consisted of 108 men. The mixed group (n = 91) had a median hCG of 165,177 mIU/ml, a postchemotherapy node size of 4.7 cm, of whom 19.8% also received salvage chemotherapy prior to RPLND. The pure choriocarcinoma group (n = 17) had a median hCG of 170,267 mIU/ml, a node size of 5.1 cm, of whom 17.6% received salvage chemotherapy. 88.2% of patients with choriocarcinoma had necrosis in the PC-RPLND specimen compared with 29.7% of the mixed NSGCT group (P = <0.0001). Controlling for salvage chemotherapy use, prechemotherapy hCG, node size and marker status, choriocarcinoma patients were 20 fold more likely to have necrosis on RPLND specimen (Odds ratio 20.68 [95% confidence interval 5.279-81.114])., Conclusion: While PC-RPLND is appropriate in patients with residual masses after chemotherapy, patients with pure choriocarcinoma presenting with significantly elevated hCG levels represent a unique patient population where necrosis is found more often than anticipated., (Published by Elsevier Inc.)

Background: It is important to assess the prevalence of hypogonadism and to identify the correlation between hypogonadism and cancer treatment with quality of life (QoL) in germ cell tumor (GCT) survivors., Methods: This is a single-center, non-randomized, prospective observational study in GCT survivors 18-50 years of age previously treated with surgery and chemotherapy (S+C) or surgery alone (S). Patients completed a validated QoL questionnaire at baseline, 3, and 6 months. Patients received supplemental testosterone as clinically indicated. Mean QoL scores were compared between two treatment groups (S+C vs. S) and within each group between survivors with hypogonadism (serum testosterone level < 300 ng/dL) versus without. A two-sided independent-groups t test was used to compare means., Results: We evaluated 199 GCT survivors. At baseline, the prevalence of biochemical hypogonadism was 48% overall, 51% in S+C group, and 45% in S group (p = .4). Overall, there was no statistically significant difference in QoL scores between S+C and C groups, except the S+C group exhibited greater modified Aging Male Symptoms (AMS) at baseline and 6 months. Patients with hypogonadism reported more fatigue, poor sleep quality, and worse general health at baseline. There were no statistical differences in mean QOL scores between patients with testosterone < 300 ng/dL who received testosterone supplementation and who did not., Conclusion: A significant proportion of GCT survivors have low testosterone levels after platinum-based chemotherapy and surgery as well as with just surgery alone. GCT survivors treated with platinum-based chemotherapy exhibited more symptoms related to male aging compared with survivors treated with surgery alone.

Objective: We aimed to investigate the possible association between testicular cancer prognosis and De Ritis ratio (AST/ALT)., Methods: The medical records of all patients who underwent radical inguinal orchiectomy at a single tertiary in Istanbul, Turkey between 2006 and 2017 were retrospectively analyzed. Investigated parameters included patients' demographics, complete blood count and blood biochemistry results, pathology results, treatment schemes, imaging results, and survival. De Ritis ratio was calculated as follows: AST/ALT., Results: A total of 171 patients with a mean age of 32.6 ± 10.1 years were included in the study. 73 patients had T1, 83 had T2, 13 had T3 and 2 had T4 disease. Rete testis invasion was detected in 74 patients (43.3 %) as well as lymphovascular invasion in 93 (54.4 %) and tunica albuginea invasion in 80 (46.8 %) patients. The cut-off value for AST/ALT was set at 1.35 [Area Under Curve (AUC): 0.791 with a sensitivity of 80 % and specificity of 73 %]. No statistically significance was observed between patients with and without elevated AST/ALT according to rete testis invasion, lymphovascular invasion, tunica albuginea invasion, and tunica vaginalis invasion (p = .25, p = .63, p = 1.0 and p = 1.0, respectively). 28.2 % of patients with seminoma had AST/ALT > 1.35 however 41.9 % of patients with non-seminoma pathology had AST/ALT > 1.35 (p = .078). Mean estimated survival time of patients with AST/ALT > 1.35 was higher than those with AST/ALT < 1.35, 91.8 versus 70.4 months, p < .001). As seen in Kaplan-Meier analysis elevated AST/ALT is associated with early-term mortality., Conclusion: De Ritis ratio was shown to be significantly associated with unfavorable prognosis. De Ritis ratio might serve as a prognostic biomarker in testicular tumor besides well-known tumor markers such as beta-human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH)., Competing Interests: The authors declare there are no conflicts of interest – financial or otherwise – related to the material presented herein., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose of Review: Although testicular cancer remains a highly curable malignancy, challenges and uncertainty still remain in certain aspects of management. Residual disease after chemotherapy in patients with germ cell tumors (GCT) remains one of these challenges. We aim to highlight the recent literature on the management of residual disease after chemotherapy in GCT and the emerging innovations that may provide further guidance into this area., Recent Findings: A subset of patients with GCT will have residual disease after chemotherapy, and management of these patients involves highly skilled multidisciplinary experts including medical oncologists, surgeons, radiologists, and pathologists. Management options depend on histologic subtype, either seminoma or nonseminoma, and involve size criteria, possible further imaging modalities, and tumor markers. Even with these tools at highly specialized expert centers, uncertainty in management remains, and recent literature has explored the use of newer biomarkers to aid in these cases., Summary: Postchemotherapy residual masses in GCT can prove to be complicated cases to manage. Balancing survival with quality of life outcomes is important and requires a multidisciplinary team experienced in treating GCT.

Testicular carcinoma recurrences represent a rare finding (1-6% in non-seminomatous germ cell tumours). However, cases of recurrence have been described many years later. We report a case of late recurrence of embryonic testicular carcinoma, after 26 years, with pulmonary metastases. Following evidence of increase of alpha-fetoprotein (AFP), the patient underwent a total body computed tomography scan that exhibited two pulmonary nodules, one in upper left lobe and other in left hilar region with multiple mediastinal and retrocrural lymph node enlargements All consolidations showed increased sugar uptake value at PET CT. Biopsies of lung consolidations confirmed diagnosis of recurrence of testicular carcinoma.

Objectives: To evaluate the potential prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in testicular cancer., Materials and Methods: 80 patients with testicular cancer treated at our institution from 2005 to 2018 were retrospectively reviewed. Age, tumor markers, stage and histotype at final pathology, eventual medical treatment, tumor recurrence and follow-up data were extracted. The NLR was retrospectively calculated from blood tests. Data were analyzed by medians comparison, linear correlation, univariate and multivariate Cox regression and survival curve analysis., Results: Population's median age was 33 years and median follow-up was 40.5 months. Overall, the median NLR was significantly reduced after orchiectomy (2.2 [1.55-3.09] vs. 1.77 [1.34-2.46], M-W P<0.001). Post-orchiectomy NLR was higher in patients who had disease recurrence (2.51;IQ 1.84-3.74 vs 1.59; IQ 1.10-2.24; M-W P=0.001), regardless of disease's stage: HR=1,85 (95%CI 0,99-3,46) and HR=1,91 (95%CI 0,96-3,78) for stage disease I or stage II, respectively. After stratification of patients by post-orchiectomy NLR (optimal cut-off: 2.255), patients with lower NLR had significantly longer recurrence-free survival (107.7 months [95%CI 97,7-119,2] vs. 57.65 months [95%CI 48,2-81,1], P<0.001). Univariable and multivariable Cox proportional hazard analyses, showed post-orchiectomy NLR, histotype at final pathology and disseminated disease at diagnosis as predictors of recurrence., Conclusion: NLR is a simple and wildly available biomarker. Higher post-orchiectomy NLR was found independently correlated to higher risk of recurrence, regardless of disease stage, which could potentially lead to a worse prognosis., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: We evaluated possible factors predicting testicular cancer in patients undergoing testis sparing surgery., Materials and Methods: We retrospectively analyzed the records of all patients who underwent testis sparing surgery for a small testicular mass at a total of 5 centers. All patients with 1 solitary lesion 2 cm or less on preoperative ultrasound were enrolled in the study. Testis sparing surgery consisted of tumor enucleation for frozen section examination. Immediate radical orchiectomy was performed in all cases of malignancy at frozen section examination but otherwise the testes were spared. Univariate and multivariate analysis were performed and ROC curves were produced to evaluate preoperative factors predicting testicular cancer., Results: Overall 147 patients were included in the study. No patient had elevated serum tumor markers. Overall 21 of the 147 men (14%) presented with testicular cancer. On multivariate analysis the preoperative ultrasound diameter of the lesion was a predictor of malignancy (OR 6.62, 95% CI 2.26-19.39, p=0.01). On ROC analysis lesion diameter had an AUC of 0.75 (95% CI 0.63-0.86, p=0.01) to predict testicular cancer. At the best cutoff of 0.85 the diameter of the lesion had 81% sensitivity, 58% specificity, 24% positive predictive value and 95% negative predictive value., Conclusions: Our study confirms that small testicular masses are often benign and do not always require radical orchiectomy. Preoperative ultrasound can assess lesion size and the smaller the nodule, the less likely that it is malignant. Therefore, we suggest a stepwise approach to small testicular masses, including tumorectomy, frozen section examination and radical orchiectomy or testis sparing surgery according to frozen section examination results.

Purpose of Review: miRNAs 371 and 302/367 clusters are abundantly secreted in the blood of patients with active germ cell malignancy (aGCM), both seminoma and nonseminoma. The serum concentration of those micro-RNAs correlates with tumor burden and to the activity of specific treatments; therefore, representing attractive biomarkers for the diagnosis and follow-up of patients with germ cell tumors. This review summarizes the most relevant evidence supporting their clinical validity in germ cell tumors., Recent Findings: Several retrospective studies have reported high sensitivity and specificity of those micro-RNAs in identifying aGCM prior to the orchiectomy or in patients with metastatic germ cell tumor prior to or during chemotherapy. Most recently, few prospective studies have confirmed their clinical validity during the follow-up of patients after surgery and/or chemotherapy. Large studies are panned across the spectrum of germ cell tumors to assess their clinical utility and several efforts to identify biomarkers of teratoma are underway., Summary: The integration of those micro-RNAs in the management of germ cell tumors has the potential to refine the therapeutic decision, especially in some clinical situations characterized by high uncertainty, such as clinical stage I, clinical stage IIA with normal tumor markers and residual disease postchemotherapy.

Purpose: To determine the utility of preoperative complete blood count (CBC) based systemic inflammatory markers in the prediction of testicular cancer and its prognosis., Material and Methods: Between 2008-2017 the data of all testicular tumor patients undergoing radical orchiectomy were retrospectively analyzed. Patient baseseline characteristics (age, tumor stage, tumor markers, etc.) and results of routine preoperative blood tests including mean platelet volume (MPV), red cell distribution width (RDW), lymphocyte ratio (LR) and neutrophil ratio (NR) were retrieved. In addition, neutrophil to lymphocyte ratio (NLR) was calculated., Results: Mean age of the tumor and control group was 36.0±15 and 30.50±11 years, respectively. Mean RDW, NR and NLR were significantly higher in the tumor group with p values<0.001; whereas LR and MPV were signifi cantly higher in the control group (p<0.001). Receiver Operating Characteristic (ROC) analyses of LR, NR, RDW, MPV, and NLR are shown in Table-3. The cut off values for RDW and NR were found as 13,7 (Area under the curve (AUC): 0.687, sensitivity = 42.2%, specifi city = 84.8%) and 55.3 (AUC:0.693, sensitivity 72.2%, specifi city 62%), respectively. Area under the curve for NLR in tumor group was 0.711, with a threshold value of 1.78 and sensitivity=81.8% and specifi city=55.4% (AUC:0.711/sig<0.001) that together with RDW exhibited the best differential diagnosis potential which could be used as an adjuvant tool in the prediction of testicular tumor and its prognosis., Conclusion: Several systemic inflammatory markers, which are obtained by routinely performed cost-effective blood tests, could demonstrate incremental predictive and prognostic information adjuvant to preoperativly achieved testiscular tumor markers., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Clinical practice guidelines for the management of germ cell tumors recommend the measurements of human chorionic gonadotropin (hCG) and/or free hCGβ subunit for earlier diagnosis/recognition of the residual disease, for the prognostic evaluation and for the post-chemotherapy surveillance. However, the marketed hCG assays are validated and approved only for pregnancy purposes, with the sole exception of the Elecsys 'hCG+β' assay (Roche Diagnostics), cleared in Europe for oncological application. Theoretically, the hCG assay design for oncological purposes should fulfil the recommendations of the International Society of Oncology and Biomarkers requiring the use of antibodies displaying an equimolar recognition of both intact hCG and hCGβ monomer. Further analytical requirements should also be considered, such as optimal analytical sensitivity to allow an early tumor detection and low cross-reactivity for luteinizing hormone (LH). For the Elecsys assay, the detection limit (0.2 U/L) and the reported cross-reactivity for LH (0.12%) may be considered adequate if compared with the recommended requirements. Another issue is the definition of decision limits for oncologic purposes. After 3 years of clinical experience using the Elecsys assay in the oncology setting, we were able to define limits partitioned by sex and age as follows: males <50 years, 0.3 U/L; males >50 years, 2.3 U/L; female <50 years, 2.1 U/L; female >50 years, 5.6 U/L. There is an urgent need to disseminate appropriate educational information and to boost the clinical use of selective, highly sensitive and precise assays, specifically manufactured for cancer application.

Purpose: To assess the relationship between testicular germ cell tumors (TGCT) and neutrophil to lymphocyte ratio (NLR) and to determine whether this ratio can be used as a serum tumor marker., Material and Methods: Sixty-one patients with testicular germ cell tumors were included into the study. Patients were grouped as localized and non-localized. Histologically patients were categorized as seminoma and nonseminomatous germ cell tumors. Complete blood cell count was measured the day before surgery and at the postoperative 1st month. Preoperative and postoperative mean NLR values were compared., Results: Thirty-six patients (59%) had seminomas and 25 patients (41%) had nonseminomatous testicular cancer. Forty-five patients (73.8%) had localized and 16 patients (26.2%) had non-localized testicular cancer. There was a statistically significant difference between preoperative and postoperative mean NLR of the localized patients (p=0.001) but no such difference was detected for non-localized patients (p=0.576). Nineteen patients with localized seminomas had normal preoperative serum tumor markers. There was a significant difference between preoperative and postoperative mean NLR in this group of patients (p=0.010). Twenty-six patients with localized tumors had preoperative increased serum tumor markers which normalized after orchiectomy. Mean NLR of these patients significantly decreased from 3.10 ± 2.13 to 1.62 ± 0.59 postoperatively (p=0.010)., Conclusions: NLR appears to be a useful marker for TGCT. It is successful in predicting localized and non-localized disease in early postoperative period., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Purpose: Our objective was to evaluate operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumor., Patients and Methods: One hundred eleven male patients with a history of or newly diagnosed germ cell tumors were evaluable. Biospecimens obtained before confirmed clinical events were analyzed for miR371 expression with blinding of providers and laboratory personnel to analytic results or clinical status, respectively. Cases (patients with clinically confirmed active germ cell malignancy [aGCM]) and controls (patients with no clinically confirmed aGCM) were assigned over the course of the management. Patients were assigned risk status (high, low, or moderate) based on the composite clinical picture at time points in management., Results: Considering all cases and controls and results of prospectively obtained biosamples analyzed for miR371 expression, 46 (35%) of 132 samples had clinically confirmed aGCM over the course of management; 44 (96%) of these 46 patients had plasma miR371 expression (true positives) with no false positives. Two (4%) of 46 patients had no miRNA expression despite pathologic confirmation of aGCM (false negatives). Plasma miR371 expression in confirmed aGCM had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively. Interpretation of sensitivity and negative predictive value is limited by modest follow-up. Specificity and sensitivity were 100% and 98%, 100% and 92%, and 100% and 97% in the low-, moderate-, and high-risk groups, respectively, with a median follow-up time of 15 months., Conclusion: Plasma miR371 expression predicts aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 await longer follow-up for more complete definition, the findings of a highly specific liquid biopsy strongly support moving forward with large-scale, real-world clinical trials to further define full operating characteristics and to identify clinical utility and areas of patient benefit.

Background: Germ cell tumor patients with intermediate prognosis (IPGCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification represent a heterogeneous group with different clinical features. This analysis was performed to investigate the prognostic impact of different tumor marker levels prior to first line chemotherapy within IPGCT., Methods: For this study an international registry for IPGCT was established. Eligibility criteria were intermediate prognosis according to IGCCCG criteria, nonseminomatous histology, male sex, and age ≥ 16 years. Uni- and multivariate analysis were conducted to identify characteristics associated with survival outcomes. Receiver-Operating-Characteristic curve analysis was applied to find cut-off parameters. Five-year overall survival (OS) rate was the primary and 5-year progression-free survival rate the secondary endpoint., Results: This database included 634 IPGCT with a median follow-up of 9.0 years (interquartile range: 14.35). Patients received first line treatment with platinum based chemotherapy, associated with a 5-year OS rate of 87%. The stratification of patients according to AFP levels revealed a correlation between AFP levels and outcome, associated with 5-year OS rates of 88% for AFP levels <1,000 IU/ml (n = 303), 89% for 1,000 to 2,000 IU/ml (n = 82), 87% for >2,000 to 6,000 IU/ml (n = 121), and 82% for >6,000 IU/ml (n = 57) prior first course of chemotherapy, respectively (P= 0.013). LDH levels prior fist course of chemotherapy also correlated with outcome associated with 5-year OS rates of 92% for <2 UNL (n = 271), 89% for ≥2 to 3 UNL (n = 85), 78% for >3 to 4 UNL (n = 34), and 77% for >4 UNL (n = 79), respectively (P= 0.03). Different HCG levels prior chemotherapy were not associated with outcome. In multivariable analysis AFP levels >6,000 IU/ml (P= 0.023; hazard ratio HR 2.263) or >1,982 IU/ml (P= 0.031; HR 1.722), and LDH levels >3 UNL (P< 0.001; HR 2.616) were independent prognosticators for OS., Conclusions: Prognostication according to LDH and AFP levels prior chemotherapy could offer a new approach to stratify patients within the intermediate prognosis cohort. According to our findings, patients with AFP values above 6,000 IU/ml or/and LDH > 3 UNL represent an independent high risk cohort. Our results need to be confirmed in the upcoming IGCCCG reclassification., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aim: FGF-2, HGF, MIF and PTN have been suggested as biomarkers for testicular germ cell cancer patients in earlier studies. Our study was designed to validate these potential novel tumor markers., Materials and Methods: Serum FGF-2, HGF, MIF and PTN levels were analysed using an ELISA technique in a screening cohort of 20 testicular germ cell cancer patients and 10 healthy men. MIF levels were measured in a validation cohort of 84 patients with testicular cancer, 24 with non-malignant testicular tumors and 64 healthy men., Results: Serum FGF-2, HGF and PTN levels did not differ in cancer patients and healthy males within the screening cohort, whereas MIF was significantly increased among cancer patients. Within the validation cohort, a modest but insignificant increase of serum MIF was observed in TGCT patients compared to healthy men. MIF levels were not correlated with adverse clinical-pathological parameters., Conclusion: FGF-2, HGF, MIF and PTN are not suitable as non-invasive biomarkers for testicular germ cell cancer patients., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: LDH (lactate dehydrogenase), AFP (alpha-fetoprotein) and β-HCG (human chorionic gonadotropin) are used in diagnosis and follow-up of testicular germ cell cancer (TGCC) patients. Our aim was to investigate the association between levels of miR-371a-3p, miR-373-3p and miR-367-3p and clinical features in metastatic TGCC., Methods: relative levels of miR-371a-3p, miR-373-3p and miR-367-3p were evaluated in serum of metastatic TGCC patients. A prospectively included and a retrospectively selected cohort were studied (total patient number = 109). Blood samples were drawn at start of chemotherapy and during follow-up. Serum microRNA (miR) levels were determined using the ampTSmiR test., Results: at start of chemotherapy, miR-371a-3p, miR-373-3p and miR-367-3p levels were positively correlated to LDH. The median level of these miRs was higher in patients who developed a relapse after complete biochemical remission ( n = 34) than in those who had complete durable remission ( n = 60). Higher levels of miR-367-3p were found in patients with refractory disease ( n = 15) compared to those who had complete response. miR levels decreased during the first week of chemotherapy in patients with complete response and stayed below threshold after one year of treatment., Conclusion: high miR levels at start of chemotherapy are associated with worse clinical outcome and can assist in early diagnosing of relapses.

Purpose: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or β-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series., Materials and Methods: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment., Results: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, β-human chorionic gonadotropin in 14%, and α-fetoprotein and β-human chorionic gonadotropin in 38%. Median α-fetoprotein and β-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85 % , respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy., Conclusions: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels., Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m 2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model., Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10 -3 ). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10 -3 ). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted OR high/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted OR high/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 ( P = 4.6 × 10 -8 , a SNP intronic to MYH14 )., Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels., (©2019 American Association for Cancer Research.)