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Background: In cases of advanced seminoma, up to 30% of patients may manifest cisplatin resistance, necessitating aggressive salvage therapy, with a consequent 50% risk of mortality attributable to cancer. Nevertheless, beyond chemotherapy and radiotherapy, no further therapeutic modalities have been implemented for these patients., Methods: The study commenced with the identification of differentially expressed immune-related genes, which were subsequently subjected to clustering using WGCNA. Prognostic signature construction ensued through the execution of univariable Cox regression, lasso regression, and multivariable Cox regression analyses. To validate the prognostic signature, the TCGA-TGCT and GSE99420 cohorts were employed, with assessments conducted via PFS, C-index, DCA, and ROC analyses. Subsequent exploration of the immune landscape and potential immunotherapeutic applications was undertaken through Cibersort and TIDE analyses. Molecular docking and dynamics simulation techniques were then employed for screening potential molecular compounds. Validation of these findings was pursued through in vitro and vivo assays., Results: CTLA4, SNX17, and TMX1 were selected to construct the signature. Patients in the high-risk group exhibited diminished progression-free survival rates. The AUC for predicting survival at 1, 3, and 5 years was 0.802, 0.899, and 0.943, respectively, surpassing those of other risk factors, such as lymphovascular invasion and T stage. The C-index for the risk score was 0.838. Decision curve analysis (DCA) suggests that incorporating lymphovascular invasion and the risk score yields the most favorable decision-making outcomes for patients. Moreover, individuals classified as high-risk may derive greater benefit from immunotherapy. Molecular compounds including Rutin, ICG-001, and Doxorubicin can selectively target CTLA4, SNX17, and TMX1, respectively, thereby inhibiting the proliferation and invasive capabilities of seminoma tumor cells in vitro and vivo., Conclusion: The signature initially constructed based on immune-related genes shows promise for predicting outcomes and assessing the efficacy of immunotherapy in seminoma patients. Rutin, ICG-001, and Doxorubicin have demonstrated potential to target these signature genes and inhibit tumor cell viability., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the medical ethics committee of The Jinling Hospital (DZGZRDW240021; 2024DZGJJ-021) and conducted in accordance with the Declaration of Helsinki. All patients included in this study provided informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Platinum-based antineoplastic drugs are widely used in the treatment of solid tumors. Carboplatin is a safe and efficacious adjuvant treatment for stage I seminoma following a risk-adapted treatment strategy. It consists in the administration of one or two courses for patients with one or both of rete testis involvement or tumor size more than 4 cm. Carboplatin is used with the purpose of minimizing nephrotoxicity and ototoxicity caused by cisplatin while achieving excellent results. We present a case of carboplatin-induced hematuria that led to an acute kidney injury as a rare complication., Case Presentation: A 48 year-old Caucasian man with no medical history and no history of renal disease presented with a painless testicular mass. He underwent an orchiectomy for stage I testicular seminoma and received one course of adjuvant carboplatin (area under the curve of 7); 2 days later, he developed frank hematuria associated with back pain. The physical examination revealed mild suprapubic tenderness and Goldflam's sign was positive bilaterally. Blood tests did not reveal anemia, his platelet count was normal, and creatinine levels were in range. Due to persisting hematuria requiring continuous bladder irrigation, he was hospitalized to monitor renal function and was initially managed conservatively with intravenous analgesics and adequate hydration. The following day, he developed an acute kidney injury (serum creatinine 1.90 mg/dL, glomerular filtration rate 41 mL/min/m 2 ). Transurethral cystoscopy showed a blood clot on the left urinary meatus, which was irrigated and removed, revealing a clear ureteral jet. With no further measures, creatinine started declining and back pain improved. His acute kidney injury resolved in the following 72 hours. Computed tomography urogram showed a left ureteral ectasia with an enhanced urothelium within the upper and middle ureter, suggesting ureteral obstruction. The patient improved completely and was discharged successfully. On further follow-up 2 months later, a computed tomography urogram showed a complete resolution of obstructive changes., Conclusions: Hematuria and acute kidney injury are rare but clinically relevant adverse events associated with the administration of carboplatin, regardless of the administered and accumulated dose. It is crucial to recognize this event and start adequate hydration promptly to prevent further kidney damage and the need for more aggressive measures, such as ureteral stenting or percutaneous nephrostomy., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Purpose: Novel techniques and advances in radiation therapy (RT) have been explored to treat testicular seminoma, a highly radiosensitive and curable histology. We evaluated the historical and current indications for radiation therapy (RT) in testicular seminoma., Methods: A narrative literature review was performed. Studies of RT for testicular seminoma were included. Additionally, recent trials testing the use of combination or surgical therapies for clinical stage (CS) II were included. Search parameters included radiation therapy, testicular seminoma, surgery, and chemoradiation. Parameters and outcomes assessed were progression-free survival (PFS), overall survival (OS), acute toxicities, long-term sequelae, and rates of secondary malignancies., Results: Practice defining and changing studies in the use or omission of radiation therapy for testicular seminoma were identified along with resultant changes in National Comprehensive Cancer Network (NCCN) and European guidelines. Recent trials in combined chemoradiation and upfront surgical approaches to CS II disease were reviewed., Conclusion: RT has historically been used as adjuvant treatment for CS I disease and is highly effective at treating CS II (A/B) testicular seminoma. The drive to maintain therapeutic efficacy and reduce acute and long-term side effects, namely secondary malignancies, is being tested using new radiation technologies, combined modality therapy in the form of chemoradiation and with upfront surgical approaches. Also, as guidelines now "strongly prefer" surveillance instead of adjuvant RT for CS I disease, the current CS II population comprises patients presenting with CS II disease ("de novo") and those who present with CSII after relapsing post orchiectomy for CS I ("relapsed"). Emerging evidence suggests that these two groups have different outcomes with respect to RT and chemoradiation. Consequently, future trials may need to sub-stratify according to these groups., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The aim of this study was to evaluate the impact of tumour size and rete testis invasion in progression free survival of our patients with stage I testicular seminoma. A literature review is also made., Material and Methods: A retrospective observational study was performed. We included patients with stage I seminoma between January 2010 and July 2022. Patients without factors of poor prognostic -Group A- were compared with patients with factors of poor prognostic -Group B-. Kaplan-Meier curves and log-rank testing were used to compare progression free survival (PFS) between these groups. Statistical significance was considered at P≤.05., Results: 55 patients were included in this study. 20 patients (36.4%) were of good prognostic -Group A- and 35 (63.6%) had factors of poor prognostic -Group B-. The mean age was similar in both groups (mean±standard deviation), 38.62±9.04 years. The mean follow-up time was 63.5±33.6 months. All the patients in group A and 25.7% of the patients in group B underwent active surveillance (AS). 26 patients (74.3%) of the patients in Group B were treated with one cycle of adyuvant carboplatin. Three patients suffered a relapse with retroperitoneal lymph nodes (10.3%), all of them were treated with three cycles of BEP, with a complete response of the disease. No statistical significant differences were found in PFS between Group A and B (log Rank P=.317)., Conclusion: Individualization of adjuvant treatment in stage I seminoma is important, avoiding the adverse effects derived from them., (Copyright © 2023 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Patients with relapsed seminoma after first-line chemotherapy can be treated with salvage chemotherapy or postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). Based on prior experience, surgical management can have worse efficacy and increased morbidity compared to nonseminomatous germ cell tumor. Our aim was to characterize the surgical efficacy and difficulty in highly selected patients with residual disease after first-line chemotherapy., Materials and Methods: The Indiana University testis cancer database was queried to identify men who underwent PC-RPLND for seminoma between January 2011 and December 2021. Included patients underwent first-line chemotherapy and had evidence of retroperitoneal disease progression., Results: We identified 889 patients that underwent PC-RPLND, of which only 14 patients were operated on for seminoma. One patient was excluded for lack of follow-up. Out of 13 patients, only 3 patients were disease free with surgery only. Median follow up time was 29.9 months (interquartile ranges : 22.6-53.7). Two patients died of disease. The remaining 8 patients were treated successfully with salvage chemotherapy. During PC-RPLND, 4 patients required nephrectomy, 1 patient required an aortic graft, 2 patients required a partial ureterectomy, and 3 patients required partial or complete caval resection., Conclusion: The decision between salvage chemotherapy and PC-RPLND as second-line therapy can be challenging. Salvage chemotherapy is effective but is associated with short and long-term morbidity. Surgical efficacy in this setting seems to be limited, but careful selection of patients may lead to surgical success without affecting the ability to receive any systemic salvage therapies if necessary or causing life-threating morbidity., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: Late relapse (LR) of germ cell tumor (GCT) is defined as relapsed disease >2 years from initial treatment. LR remains a challenge both for optimal screening methods and management. We report the method of detection, treatments received, and outcomes in patients with chemotherapy-exposed vs chemotherapy-naïve LR GCT., Patients and Methods: The Indiana University testicular cancer database was queried identifying 131 patients with LR GCT evaluated at Indiana University from January 2000 to January 2019. Method of detection of LR was recorded along with site, treatment received, and survival outcomes. The cohort was divided into 4 groups according to seminoma versus non-seminoma GCT (NSGCT) and chemotherapy-exposed vs chemotherapy-naïve LR. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Medians with 95% confidence intervals were also calculated along with the 2-year probabilities., Results: Median age at LR was 38.3 (range, 19.3-56.8). Chemotherapy-exposed accounted for 75 (57%) and chemotherapy-naïve for 56 (43%) of cases. The 2-year OS comparing chemotherapy-exposed versus chemotherapy-naïve was 78.2% versus 100% (P = .0003). For the 72 chemo-exposed NSGCT LR pts, 2-year PFS based on treatment: surgery vs chemotherapy versus surgery + chemotherapy was 67.1% versus 0% versus 47.1% (P < 0.0001). Fifty-nine percent of chemotherapy-exposed LR had elevation of alpha fetoprotein (AFP) at LR diagnosis., Conclusion: GCT pts require lifetime follow-up with annual physical exam and tumor markers. Surgical resection, when feasible, remains the preferred treatment for chemotherapy-exposed LR. Chemotherapy-exposed LR has worse outcomes compared to chemotherapy-naïve LR patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: Stage II seminoma is responsive to chemo- or radiotherapy with a progression-free survival of 87-95% at 5 years but at the cost of short- and long-term toxicity. After evidence about these long-term morbidities emerged, four surgical cohorts investigating the role of retroperitoneal lymph node dissection (RPLND) as a treatment option for stage II disease were initiated., Recent Findings: Currently, two RPLND series have been published as a complete report, while data from other series have only been published as congress abstracts. In series without adjuvant chemotherapy, recurrence rates ranged from 13% to 30% after follow-ups of 21-32 months. In those receiving RPLND and adjuvant chemotherapy, the recurrence rate was 6% after a mean follow-up of 51 months. Across all trials, recurrent disease was treated with systemic chemotherapy (22/25), surgery (2/25), and radiotherapy (1/25). The rate of pN0 disease after RPLND varied between 4% and 19%. Postoperative complications were reported in 2-12%, while antegrade ejaculation was maintained in 88-95% of patients. Median length of stay ranged from 1 to 6 days., Summary: In men with clinical stage II seminoma, RPLND is a safe and promising treatment option. Further research is needed to determine the risk of relapse and to personalize treatment options based on patient-specific risk factors., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Germ-cell tumors (GCTs) are the most common malignancy in young men. There is a paucity of data on GCTs in developing countries. LACOG 0515 study aimed to evaluate clinical characteristics and treatment outcomes in patients with GCTs from Brazilian cancer centers., Materials and Methods: This is a retrospective cohort study evaluating male patients diagnosed with GCTs from 2000 to 2018 in 13 Brazilian hospitals. We described baseline characteristics, progression-free survival (PFS), and overall survival (OS)., Results: A total of 1232 patients were included, with a median age of 30 years. Histology was seminoma in 47.1% and non-seminoma GCT (NSGCT) in 52.9%. The primary tumor site was testis in 96.5%. At diagnosis, clinical stage I was present in 68.1% and 34.7% and clinical stages IS/II/III in 31.9% and 65.2% of patients with seminoma and NSCGT, respectively. Following orchiectomy, 55.2% of patients with clinical stage I were managed with surveillance. The 5-year disease-free survival rates among patients with stage I were 98.0% in seminoma and 92.3% in NSGCT, with 5-year OS of 99.6% and 97.6%, respectively. Among patients with advanced disease (IS, II, and III), the 5-year PFS were 88.7% in seminoma and 68.7% in NSGCT, with 5y-OS of 97.6% and 82.8%, respectively., Conclusion: This is the largest Brazilian cohort of GCTs. Our results show a high rate of adjuvant chemotherapy in patients with clinical stage I. Although our data demonstrate slightly inferior PFS compared with the International Germ Cell Cancer Collaborative Group and other contemporary series, the OS rates were similar., Competing Interests: Disclosure 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Mammalian target of rapamycin (mTOR) is an important serine/threonine kinase that plays a critical role in several processes including cell cycle, protein synthesis, and energy metabolism. Due to its multiple roles and general dysregulation in cancer, the mTOR pathway is an important target in cancer therapy. However, studies on mTOR activity in seminoma are limited. Therefore, our aim was to investigate the expression of mTOR signaling pathway proteins in the TCam-2 cell line after rapamycin treatment. TCam-2 cells were treated with different concentrations of rapamycin (control (no rapamycin treatment), 4 nM, 20 nM, 100 nM, 500 nM, and 1000 nM rapamycin) for 48 h and 72 h. mTOR, p-mTOR, P70S6K, p-P70S6K, proliferating cell nuclear antigen (PCNA), and caspase-3 expression levels were analyzed by western blot. Apotosis and cell cycle were analyzed by flow cytometry. After 48 h of rapamycin administration, mTOR activity was significantly decreased at 1000 nM (p < 0.05). In addition, P70S6K acitivity significantly decreased in groups at all rapamycin concentrations (***p < 0.001, ****p < 0.0001). After 72 h of rapamycin administration, mTOR pathway activity were significantly decreased at 100, 500, and 1000 nM rapamycin-treated groups (p < 0.05). Moreover, P70S6K expression decreased in all treatment groups (****p < 0.0001). Caspase-3 expression were similar in all groups. While PCNA expression tended to decrease at 48 h in a dose-dependent manner, this decrease was not significant. We detected decreased PCNA expression at 1000 nM rapamycin at 72 h (p < 0.05). The rate of apoptosis increased especially at 1000 nM rapamycin at 72 h (***p < 0.001). On the other hand, according to the results of the cell cycle experiment, G1 phase arrest was detected at all rapamycin doses at 48 and 72 h (***p < 0.001). Our study indicated that 1000 nM rapamycin may inhibit TCam-2 seminoma cells growth by halting cell proliferation through inhibition of G1-S transition. Therefore, we believe that the findings obtained will contribute to the development of new treatment approaches for seminoma patients in the future and in the process of restoring testicular functions and preserving fertility., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Seminoma is the most common type of testicular germ cell tumour and is highly sensitive to cisplatin therapy, which has not been fully elucidated. In this study, we comprehensively monitored dynamic changes of TCam-2 cells after cisplatin treatment. At an early stage, we found that both low and high concentrations of cisplatin induced the S-phase arrest in TCam-2 cells. By contrast, the G0G1 arrest was caused by cisplatin in teratoma NTERA-2 cells. Afterwards, high concentrations of cisplatin promoted the extrinsic apoptosis and high expressions of related genes (Fas/FasL-caspase-8/-3) in TCam-2 cells. However, when decreasing the cisplatin, the apoptotic cells were significantly reduced, and accompanied by cells showing senescence-like morphology, positive SA-β-gal staining and up-regulation of senescence-related genes (p53, p21 and p16). Furthermore, the cell cycle analysis revealed that most of the senescent TCam-2 cells were irreversibly arrested in the G2M phase. G2M arrest was also observed in NTERA-2 cells treated with a low concentration of cisplatin, while no senescence-related phenotype was discovered. In addition, we detected the γ-H2AX, a DNA damage marker protein, and reactive oxygen species (ROS) and found both of which were elevated with the increase of cisplatin in TCam-2 cells. In conclusion, the extrinsic apoptosis and senescence are involved in the growth kinetics of TCam-2 cells to cisplatin, which provide some implications for studies on cisplatin and seminoma., (© 2022 John Wiley & Sons Australia, Ltd.)

Purpose: To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT)., Methods: A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables., Results: The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the "poor prognosis" group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3-4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy., Conclusion: In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors., (© 2022. The Author(s).)

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

A previous study confirmed that miRNAs play an important role in the chemosensitivity of seminoma. Increasing evidence reveals that exosomes participate in the regulation of cisplatin resistance by carrying miRNAs. In this study, we further explored whether exosomes regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Initially, cisplatin-resistant TCam-2 cells were induced. Our results revealed that exosomes from cisplatin-resistant TCam-2 cells (rExos) could affect the viability of TCam-2 cells in the context of cisplatin treatment through regulation of both cell apoptosis and the cell cycle. Meanwhile, the levels of γ-H2AX were negatively modulated by rExos, which indicated that rExos could decrease the DNA damage from cisplatin. Furthermore, miR-193b-3p was enriched in rExos, and exosomal miR-193b-3p enhanced the proliferative ability of TCam-2 cells under cisplatin treatment. Mechanistically, exosomal miR-193b-3p targets ZBTB7A, which further decreases apoptosis and promotes cell cycle progression. Taken together, these findings indicate that exosomal miR-193b-3p regulates the chemosensitivity of TCam-2 cells to cisplatin through ZBTB7A signaling and could be a promising drug target for patients with chemoresistant seminoma.

Background: Standard treatment options for patients with stage IIA or stage IIB seminoma include either para-aortic and pelvic radiotherapy or three to four cycles of cisplatin-based combination chemotherapy. These options result in 3-year progression free survival rates of at least 90%, but bear risks for acute and late toxic effects, including secondary malignancies. We tested a novel approach combining de-escalated chemotherapy with de-escalated involved node radiotherapy, with the aim of reducing toxicity while preserving efficacy., Methods: In the single-arm, multicentre, phase 2 SAKK 01/10 trial, patients with stage IIA or IIB classic seminoma (either at primary diagnosis or at relapse during active surveillance for stage I) were enrolled at ten centres of the Swiss Group for Clinical Cancer Research and ten centres of the German Testicular Cancer Study Group. WHO performance status 0-2, age 18 years or older, and adequate bone marrow and kidney function were required for eligibility. Treatment comprised one cycle of carboplatin (area under the curve 7) followed by involved-node radiotherapy (30 Gy in 15 fractions for stage IIA disease and 36 Gy in 18 fractions for stage IIB disease). The primary endpoint was 3-year progression-free survival. Efficacy analyses were done on the full analysis set, which comprised all patients who signed the informed consent, were registered in the trial, initiated trial treatment, and met all medically relevant inclusion or exclusion criteria. Safety was assessed in all patients who were treated at least once with one of the trial treatments. The study is ongoing but no longer recruiting, and is registered with Clinicaltrials.gov, NCT01593241., Findings: Between Oct 18, 2012, and June 22, 2018, 120 patients were registered in the study. 116 patients were eligible and started treatment according to the study protocol (46 patients with stage IIA disease and 70 with stage IIB disease). After a median follow-up of 4·5 years (IQR 3·9-6·0), 3-year progression-free survival was 93·7% (90% CI 88·5-96·6). With a target progression-free survival of 95% at 3 years, the primary endpoint was not met. Acute treatment-related adverse events of any grade were noted in 58 (48%) of 116 patients, and grade 3 or 4 treatment-related adverse events occurred in the form of neutropenia in five (4%) patients, thrombocytopenia in three (3%) patients, and vomiting in one (1%) patient. No treatment-related deaths and no late treatment-related adverse events were reported. Serious adverse events were reported in five (4%) of 116 patients (one transient creatinine increase and four second primary tumours)., Interpretation: Despite the fact that the primary endpoint was not met, we observed favourable 3-year progression-free survival with single-dose carboplatin area under the curve 7 and involved-node radiotherapy, with minimal toxic effects. Our findings might warrant discussion with patients about the SAKK 01/10 regimen as an alternative to standard-of-care treatment, but more research on this strategy is needed., Funding: Swiss State Secretariat for Education, Research and Innovation and Rising Tide Foundation for Clinical Cancer Research., Competing Interests: Declaration of interests AP has received honoraria from Astellas, Debiopharm, Janssen, Merck Serono, and Sanofi; and travel support from Astellas, AstraZeneca, and Bayer. MP has received consulting fees from Abbvie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eisei, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, and Takeda; honoraria from Amgen, Bayer, Janssen, Nestle, and Sanofi; and travel support from AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Roche, Takeda, and Vifor. MH has received consulting fees from EusaPharma, Janssen, and Sanofi; honoraria from AstraZeneca, Amgen, Celgene, Janssen, Jazz Pharma, Sanofi, and Takeda; and travel support from Janssen. D-RB has received consulting fees from Astellas, Bayer, BMS, Ipsen, Janssen, MSD, and Novartis; and travel support from Ipsen and Janssen. DZ has received honoraria from BMS and travel support from Janssen; and has participated in advisory boards for BMS, Janssen, Merck-Serono, MSD, Pierre-Fabre, and Sanofi. RC has received consulting fees from Astellas, BMS, Bayer, Janssen, Sanofi, Roche, Novartis, MSD, Pfizer, Merck, Debiopharm, and AstraZeneca; and honoraria from Astellas, Roche, and Pfizer. AP, JB, MH, SK, AL, FZ, AD, A-CM, SG, and RC are members of the German Testicular Cancer Study Group. AP, SH, MP, AL, D-MA, PMP, D-RB, DZ, CS, CB, SG, and RC are members of the Swiss Group for Clinical Cancer Research. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: During the coronavirus disease 2019 (COVID-19) outbreak, the European Association of Urology (EAU) Guidelines Office Rapid Reaction Group (GORRG) recommended that patients with clinical stage I (CSI) seminoma be offered active surveillance (AS). This meta-analysis aimed to evaluate the efficacy of AS versus adjuvant treatment with chemotherapy or radiotherapy for improving the overall survival (OS) of CSI seminoma patients. Materials and Methods: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed/Medline, EMBASE, and Cochrane Library databases were searched. The primary outcome was 5-year OS, and the secondary outcome was the 5-year relapse-free survival (RFS). The outcomes were analyzed as odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 14 studies were included. Overall, the quality scores were relatively high, and little publication bias was noted. In terms of the 5-year OS, 7 studies were analyzed; there was no significant difference between AS and adjuvant treatment (OR, 0.99; 95% CI, 0.41−2.39; p = 0.97). In terms of 5-year RFS, 12 studies were analyzed. Adjuvant treatment reduced the risk of 5-year recurrence by 85% compared with AS (OR, 0.15; 95% CI, 0.08−0.26; p < 0.001). Conclusions: In terms of the OS in CSI seminoma patients, no intergroup difference was noted, so it is reasonable to offer AS, as recommended by the EAU GORRG until the end of the COVID-19 pandemic. However, since there is a large intergroup difference in the recurrence rate, further research on the long-term (>5 years) outcomes is warranted.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose: Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses., Methods: A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed., Results: Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (-3.5 to -0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths., Conclusion: Surveillance is a safe management approach-advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Background: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis., Methods: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients., Results: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value., Conclusions: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In metastatic seminoma, a strategy is needed for selecting patients for less intensive chemotherapy, to limit toxicities., Objective: To assess whether men with good-prognosis metastatic seminoma could be treated with two cycles of etoposide-cisplatin (EP) followed by only one cycle of carboplatin (CARBO) based on negative interim fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT)., Design, Setting, and Participants: A nonrandomised, multicentre, phase 2 trial was conducted (NCT01887340)., Intervention: All patients with baseline-positive FDG-PET/CT received EP for two cycles. After completing the first two cycles, the patients underwent a second FDG-PET/CT to assess the response. Patients with positive FDG-PET/CT proceeded directly to two additional EP cycles; those who achieved FDG-PET/CT negativity received one cycle of CARBO., Outcome Measurements and Statistical Analysis: The proportion of patients with negative interim FDG-PET/CT who received carboplatin was determined., Results and Limitations: Between 2013 and 2017, 102 patients were enrolled. After the first two EP cycles, FDG-PET/CT was available in 98 patients. Overall, 67 patients (68.4%; 95% confidence interval [CI]: 58.2-77.4) had negative FDG-PET/CT and proceeded to a single CARBO cycle. Twenty-seven patients (27.6%; 95% CI: 19.0-37.5) had positive FDG-PET/CT after two EP cycles. The 3-yr progression-free survival rate was 90.0% (95% CI: 74.4-96.5) in the EP group and 90.8% (95% CI: 81.4-95.7) in the CARBO group. The cumulative incidences of peripheral neuropathy and ototoxicity were significantly higher in the EP group., Conclusions: Omission of two cycles of EP based on negative FDG-PET/CT after two cycles of chemotherapy appears to be feasible. However, the absence of consensus criteria for FDG-PET/CT interpretation and the short follow-up need additional studies. This strategy does not warrant routine integration yet., Patient Summary: Men with good-prognosis metastatic seminoma were treated with fewer cycles of chemotherapy based on interim fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Omission of two cycles of chemotherapy based on negative FDG-PET/CT after two initial cycles appears to be feasible, thereby limiting the burden of treatment and toxicity., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy., Methods and Materials: Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse., Results: With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression., Conclusions: Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent and growing literature has reported that oleuropein (OLE), the main polyphenol in olive leaf extract, inhibits tumor cell proliferation and reduces the invasiveness properties of cancer cells; therefore, OLE may play a significant role in the development of new drugs for cancer treatment. These antineoplastic properties have been reported in many experimental cancer models, but the effect of OLE on seminoma cells is yet to be evaluated. In the present study, we demonstrate, for the first time, that OLE reduces cell viability in both intra- and extragonadal TCAM-2 and SEM-1 seminoma cells, respectively, in a dose-dependent manner. As shown by Western-blot analysis, OLE exposure reduced cyclin-D1 expression and upregulated p21 Cip/WAF1 , concomitantly affecting the upstream pathway of NF-κB, leading to the reduction of its nuclear content, thereby suggesting that OLE could modulate cell-cycle regulators by inhibiting NF-κB. Moreover, Annexin V staining revealed that OLE induced apoptosis in cancer cells and upregulated the pro-apoptotic factor BAX. Through wound-healing scratch and transmigration assays, we also demonstrated that OLE significantly reduced the migration and motility of TCAM-2 and SEM-1 cells, and downregulated the expression of TGFβ-1, which is known to be the main pro-fibrotic factor involved in the acquisition of the migratory and invasive properties of cancer cells. Collectively, our results indicate that OLE reduces seminoma cell proliferation, promotes apoptosis, and counteracts cell migration and motility. Further studies are needed to explore the molecular mechanisms underlying these observed effects.

Systematic follow-up examinations of patients cured of testicular cancer first gained attention by caregivers in the 1980s only after the management of the disease had significantly been improved by the introduction of cisplatin-based chemotherapy and almost synchronously, by the implementation of computerized tomography (CT) and serum tumor markers. Follow-up involves three aims: early diagnosis of recurrence, detection of treatment-related toxicity, and detection of secondary diseases. As the clinical presentation of testicular cancer is very heterogeneous, there is no uniform follow-up for the disease. Instead, risk-adapted follow-up schedules are required. Since the release of the German AWMF S3 guideline for the management of testicular cancer in 2019, high level evidence has accumulated for the noninferiority of magnetic resonance imaging (MRI) to CT with regard to abdominal imaging. Therefore, it is appropriate to modify the recommendations for follow-up given in the 2019 issue of the S3 guidelines. The modifications recommended herein relate to three issues: (1) Only three risk groups (instead of formerly four) are identified, i.e., seminoma (all stages); nonseminoma clinical stage 1b (i.e., pT2, with lymphovascular invasion) on surveillance; nonseminoma all other stages. All patients cured from poor risk disease or from relapses require individual follow-up schedules not included in the recommendations tabulated herein. (2) CT and abdominal sonography are replaced by MRI. (3) Chest X‑ray imaging during follow-up of seminoma patients is no longer recommended., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short- and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes., Objectives: To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10., Methods: We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified., Results and Limitations: 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy ± surgery, and three non-seminoma-related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ = grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%., Conclusion: For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies., Competing Interests: Conflict of interest statement All authors declare no conflict of interest in respect of this manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the perioperative and oncological outcomes after post-chemotherapy robot-assisted retroperitoneal lymph node dissection (PC-RARPLND)., Materials and Methods: We retrospectively reported the perioperative and oncological outcomes of all the patients with testicular cancer who underwent PC-RARPLND at three tertiary teaching centers. Descriptive statistical measures were used to report demographic, clinical, intraoperative, postoperative and oncological outcomes., Results: There were 43 consecutive patients who underwent PC-RARPLND at the participating institutions. Mean patient age was 29.2 years (± 8.2), BMI was 26.6 kg/m 2 (± 6.2). The mean size of retroperitoneal mass was 4.1 cm (± 3.5). Full bilateral template dissection was performed in 38 (88.3%) patients. Nerve sparing was attempted in 19 (44.1%) patients. Mean operative time was 374 min (± 132) and estimated blood loss was 292 ml (± 445.6). The mean postoperative LOS was 2.8 days (± 5.9). There was a total of 12 complications in 10 patients (Clavien grade I = 5, II = 3, III = 3 and IV = 1). Postoperative pathology demonstrated 24 patients (55%) with necrosis/fibrosis, 16 (37%) with teratoma and 3 (7%) with viable tumor. Mean lymph node (LN) yield was 26.5 LNs (SD ± 16.1). Patients were followed for a mean of 30.7 months (± 24.7). No deaths were documented during follow-up and 2 pulmonary recurrences were identified. Antegrade ejaculation was preserved in 70.6% of patient who underwent nerve sparing. Limitations included retrospective nature and limited follow up., Conclusion: PC-RAPLND is safe and technically reproducible. It provides improved morbidity and less convalescence., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: There is a lack of consensus regarding the management of post-chemotherapy residual mass in classical seminoma. The use of fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) may aid the detection of residual masses harbouring viable disease and help to tailor therapy. The aim of this study was to evaluate if PET-CT could identify patients who will benefit from locoregional radiotherapy., Materials and Methods: This ethics-approved study included patients with advanced classical seminoma primarily treated with standard platinum-based first-line chemotherapy. Patients were either observed or given adjuvant radiotherapy based on the clinician's preference and followed up. For this study, patients were stratified into two groups based on FDG PET-CT residual nodal maximum standardised uptake value (SUVmax): low risk (SUVmax <3) and high risk (SUVmax ≥3). Further subgroup analysis was carried out for patients with residual nodal size ≥3 cm and SUVmax ≥3, and this was considered as the very high risk group. The diagnostic accuracy of FDG PET-CT was assessed and survival was compared between the different groups., Results: Sixty-nine patients were included in the study: 48 patients were observed and 21 received radiotherapy. The low and high risk groups contained 50.7% and 49.3% of the patients, respectively. The very high risk subgroup had 24 patients. At a median follow-up of 44 months, locoregional failures in the radiotherapy and observation cohorts were 0% and 30% (P = 0.059) in the very high risk subgroup and 5.8% and 29.4% (P = 0.078) in the high risk group. The positive predictive value for the very high risk and high risk groups was 30% and 17.1%, respectively. The benefit of locoregional control failed to translate into overall survival benefit., Conclusion: A tailored, FDG PET-based risk-adapted treatment approach can refine the management of post-chemotherapy residual masses in seminoma. In this study, with the largest cohort of advanced seminoma patients treated with radiotherapy reported to date, radiotherapy seems to benefit patients with post-chemotherapy residual mass SUVmax ≥3., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with advanced seminoma have an exceedingly favorable prognosis. Studies aiming to reduce the total treatment burden and side effects in patients with well-defined disease and very good prognosis are warranted., Patients and Methods: In a prospective observational study, patients with advanced stage seminoma were treated with bleomycin, etoposide, and cisplatin (BEP) or EP according to guidelines. Fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) examinations were performed at baseline, after 2 cycles (PET/CT2) in all patients, and after chemotherapy at the physician's discretion. Disease response to treatment assessed by PET/CT was qualitatively evaluated by 2 independent nuclear medicine physicians. Contrast-enhanced CT scans were also performed according to guidelines (at baseline, after treatment, during follow-up). The study's primary endpoint was to evaluate the association between PET/CT2 findings and relapse-free survival., Results: From January 2009 to January 2017, a total of 75 consecutive patients were enrolled, of whom 70 were included for analysis. The clinical disease stage was IIA-B and IIC-III in 40% and 60%, respectively. By local assessment, 46 PET/CT2 scans (65.7%) were reported as negative, and 46% of these patients had stage IIC-III disease. Five-year relapse-free survival of PET/CT2-positive patients was 75% (95% confidence interval, 60-95) compared to 97.8% (95% confidence interval, 93.7-100) of PET/CT2-negative patients (P = .002). In univariate analyses, PET/CT2 was significantly associated with relapse-free survival (P = .02)., Conclusions: No residual FDG uptake after 2 cycles of conventional chemotherapy is prognostic in advanced seminoma, but it may be useful to optimize the standard prognostic risk groups and may be tested within larger prospective clinical trials of chemotherapy deescalation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Testicular cancer is relatively uncommon, but at the same time, it is the most common solid tumor in men between the ages of 20 and 34 years. Seminoma represents the most frequently encountered germ cell tumors. Because orchiectomy is usually performed before chemotherapy, little is known about the effect of systemic chemotherapy on primary testicular tumors. Furthermore, the testis has always been considered a sanctuary site, an immune-privileged site in which inadequate exposure of the tumor to chemotherapy may occur. We report the case of a young patient with advanced seminoma with a complete testicular response after four cycles of cisplatin-based chemotherapy. Then, we performed a systematic review of the literature reporting the studies published to date on the topic., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium., Materials and Methods: Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients., Results: Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH., Conclusion: PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor., Competing Interests: Jörg BeyerHonoraria: Roche, Janssen Oncology, AstraZeneca, Astellas Pharma, Bayer, Ipsen Gedske DaugaardConsulting or Advisory Role: Sanofi/Aventis, Astellas Pharma, Bayer, MSD Oncology, Bristol-Myers Squibb/PfizerTravel, Accommodations, Expenses: Astellas Pharma Darren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics, Astellas PharmaOther Relationship: UpToDate Alexey TryakinConsulting or Advisory Role: BioCad, Roche/Genentech, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeSpeakers' Bureau: Bayer Health, BioCad, Lilly, Merck Serono, Sanofi, Amgen, Bristol-Myers Squibb, Eisai, Merck Sharp & DohmeTravel, Accommodations, Expenses: Novartis, BioCad, Bayer, Veropharm, Sanofi Olof StahlHonoraria: Bayer Enrique Gonzalez-BillalabeitiaTravel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer, Janssen-Cilag, Astellas Pharma, Sanofi, Roche Ugo De GiorgiConsulting or Advisory Role: Pfizer, Janssen, Astellas Pharma, Sanofi, Bristol-Myers Squibb, Bayer, Ipsen, Merck, MSD, PharmaMar, NovartisResearch Funding: Sanofi, AstraZeneca, RocheTravel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Janssen, Pfizer, Roche Stephane CulineConsulting or Advisory Role: Bayer, Janssen, Astellas PharmaSpeakers' Bureau: Takeda, JanssenResearch Funding: Astellas PharmaTravel, Accommodations, Expenses: Ipsen, Janssen Ronald De WitHonoraria: Sanofi, Merck Sharp & DohmeConsulting or Advisory Role: Sanofi, Merck Sharp & Dohme, Janssen, Bayer, Astellas PharmaResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Bayer Aaron HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol-Myers Squibb, EisaiResearch Funding: Karyopharm Therapeutics, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Janssen, AstraZeneca/MedImmune, Astellas Pharma, Macrogenics Marko BebekHonoraria: Roche, Novartis, Janssen Oncology, Sanofi, Sandoz, Astellas PharmaResearch Funding: Roche, Astellas PharmaTravel, Accommodations, Expenses: Roche, Astellas Pharma, Sanofi, Janssen, Novartis Angelika TerbuchResearch Funding: Roche, AstraZeneca, MSD, Bristol-Myers Squibb Costantine AlbanyStock and Other Ownership Interests: AdvaxisHonoraria: Sanofi, AstraZeneca, Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, AstraZeneca/MedImmuneSpeakers' Bureau: SanofiResearch Funding: Astex Pharmaceuticals, Merck, Bristol-Myers Squibb, Lilly, BayerTravel, Accommodations, Expenses: Sanofi Marcus HentrichConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Hexal, Jazz Pharmaceuticals, TakedaSpeakers' Bureau: Amgen, Janssen-Cilag, Sanofi, Takeda, Bristol-Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Celgene, Janssen-Cilag, Takeda Jourik A. GietemaResearch Funding: Roche/Genentech, Abbvie, Siemens Robert A. HuddartEmployment: Aspen Parkside HospitalLeadership: Cancer Clinic London limited liability partnershipHonoraria: Janssen OncologyConsulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Janssen Oncology, Nektar, BayerSpeakers' Bureau: Roche, MSDResearch Funding: Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, JanssenPatents, Royalties, Other Intellectual Property: Royalties for drug discovery from JanssenTravel, Accommodations, Expenses: Janssen Oncology, Roche/Genentech, MSD Oncology, Nektar Anja LorchHonoraria: MSD Oncology, Merck, MSDConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, AstraZeneca, Roche, MSD Oncology, Janssen Oncology, Ipsen, Merck, PfizerTravel, Accommodations, Expenses: Ipsen, AstraZeneca Daniel Y. C. HengConsulting or Advisory Role: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, MerckResearch Funding: Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen Christopher J. SweeneyStock and Other Ownership Interests: LeuchemixConsulting or Advisory Role: Sanofi, Janssen Biotech, Astellas Pharma, Bayer, Genentech/Roche, AstraZeneca, Pfizer, Amgen, Celgene, LillyResearch Funding: Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Dendreon, PfizerPatents, Royalties, Other Intellectual Property: Leuchemix, Parthenolide, Dimethylaminoparthenolide. Exelixis: Abiraterone plus cabozantinib combination Eric WinquistHonoraria: Merck, Bayer, Eisai, Amgen, RocheResearch Funding: Roche/Genentech, Merck, Pfizer, Eisai, Ayala Pharmaceuticals Peter GrimisonResearch Funding: Tilray, Pfizer, MSD, Gilead Sciences, Boston Biomedical, Tigermed, Halozyme, Specialised Therapeutics, Medimmune, Pfizer, ASLAN Pharmaceuticals, Genentech, Eisai, Five Prime Therapeutics, QED Therapeutics, Janssen-Cilag Andrea NecchiEmployment: BayerStock and Other Ownership Interests: BayerHonoraria: Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bristol-Myers SquibbConsulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, GlaxoSmithKline, FerringResearch Funding: Merck Sharp & Dohme, AstraZeneca, IpsenTravel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen, Rainier TherapeuticsOther Relationship: Bayer Ben TranHonoraria: Astellas Pharma, Janssen-Cilag, Sanofi, Tolmar, Amgen, Bristol-Myers SquibbConsulting or Advisory Role: Amgen, Astellas Pharma, Bayer, Sanofi, Tolmar, Janssen-Cilag, Bristol-Myers Squibb, Ipsen, MSD Oncology, IQvia, Novartis, Pfizer/EMD Serono, AstraZeneca, Roche Molecular DiagnosticsResearch Funding: Astellas Pharma, Janssen-Cilag, Amgen, Pfizer, Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharp & Dohme, IpsenTravel, Accommodations, Expenses: Amgen, Astellas Pharma Axel HeidenreichHonoraria: Amgen, Astellas Pharma, Bayer, Ferring, Ipsen, Janssen-Cilag, Sanofi, TakedaConsulting or Advisory Role: Astellas Pharma, Bayer, Janssen-Cilag, Clovis Oncology, BMS Global, AstraZeneca, MSD OncologySpeakers' Bureau: Amgen, Astellas Pharma, Bayer, Ipsen, Johnson & Johnson, Sanofi, Takeda, PfizerResearch Funding: Astellas Pharma, Bayer, Sanofi, Bristol-Myers Squibb Jonathan ShamashSpeakers' Bureau: Pfizer/EMD Serono Cora N. SternbergConsulting or Advisory Role: Bayer, MSD, Pfizer, Roche, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Genzyme, Immunomedics, Foundation Medicine David J. VaughnResearch Funding: Merck Sharp & Dohme, Roche/Genentech, Astellas Pharma Ignacio DuranHonoraria: Bristol-Myers Squibb, Ipsen, Roche/Genentech, Janssen Oncology, MSD Oncology, Astellas Pharma, EUSA PharmaConsulting or Advisory Role: Roche/Genentech, MSD Oncology, Bayer, Bristol-Myers Squibb, Seattle Genetics, Pharmacyclics, Janssen Oncology, Novartis, ImmunomedicsResearch Funding: Roche/Genentech, AstraZeneca Spain, Janssen Oncology, Astellas PharmaTravel, Accommodations, Expenses: Roche/Genentech, AstraZeneca Spain, Ipsen Carsten BokemeyerHonoraria: Merck KGaA, Sanofi, Roche, Bayer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & DohmeConsulting or Advisory Role: Lilly/ImClone, Merck Serono, Sanofi, Bayer Schering Pharma, Merck Sharp & Dohme, GSO, AOK Health InsuranceResearch Funding: Abbvie, ADC Therapeutics, Agile Therapeutics, Alexion Pharmaceuticals, Amgen, Apellis Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BerGenBio, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Gilead Sciences, Glycotope GmbH, GlaxoSmithKline, Incyte, iOMEDICO, Isofol Medical, Janssen-Cilag, Karyopharm Therapeutics, Lilly, Millennium, MSD, Nektar, Novartis, Rafael Pharmaceuticals, Roche, Springworks Therapeutics, Taiho PharmaceuticalTravel, Accommodations, Expenses: Merck Serono, Sanofi, Pfizer, Bristol-Myers Squibb Anna PatrikidouConsulting or Advisory Role: Basilea Richard CathomasHonoraria: Janssen-Cilag, Astellas Pharma, Bristol-Myers Squibb, Debiopharm GroupConsulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Pfizer, Roche, MSD Oncology, Janssen-Cilag, Bayer, Sanofi, IpsenTravel, Accommodations, Expenses: AstraZeneca Silke GillessenConsulting or Advisory Role: Astellas Pharma, Janssen, Bayer, Orion Pharma GmbH, Tolero Pharmaceuticals, MSD Oncology, Roche, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda PharmaNo other potential conflicts of interest were reported.

Following orchiectomy, patients with clinical stage I (CSI) testicular seminoma may be managed by active surveillance (S) or adjuvant treatment (radiotherapy or chemotherapy). In view of the published data on long-term toxicity, especially second malignant neoplasms (SMNs), adjuvant radiotherapy (ART) is currently no longer recommended as an adjuvant therapy option for these patients. The purpose of our recent study was to compare the impact of two selected treatment approaches - S versus adjuvant chemotherapy (ACT) on the survival of patients with CSI testicular seminoma. This cross-sectional study analyzed a total of 139 patients collected at a single center between 10/2011-5/2020, with CSI testicular seminoma, stratified into two groups according to risk-adapted therapeutic approaches. In the S group (low-risk - without rete testis invasion - RTI, primary tumor size <4 cm), consisting of 77 patients, who underwent S, relapse occurred in 10 (13.0%) patients after a mean follow-up of 14.3 months. In the ACT group (high-risk - RTI and/or primary tumor size >4 cm), consisting of 62 patients, who were treated with ACT, relapse occurred in 5 (8.1%) patients after a mean follow-up of 11.6 months. Overall survival of patients in both groups was 100% with a mean follow-up of 43.9 months. A statistically significant difference in progression-free survival (PFS) between these two groups was not found. Based on our findings, ACT seems to be an adequate treatment for patients with a high risk of relapse, as well as S for those with a low risk of relapse. Despite its excellent prognosis, optimal management of CSI testicular seminoma remains controversial, with variations in expert opinion and international guidelines.

Introduction:  More than 90 % of all patients with testicular germ cell tumours can be cured effectively. The mainstay of treatment is chemotherapy with cisplatin, etoposide and bleomycin (PEB). This regimen is usually well tolerated and does not lead to serious adverse events. Cardiovascular complications are encountered very rarely, but have gained increasing attention in recent years., Case Description:  A 33-year-old man with a testicular seminoma, clinical stage 2b, was subjected to PEB chemotherapy. At the end of the first treatment course, he had an acute ST-elevation myocardial infarction. Coronary angiography revealed a circumscribed stenosis of the left circumflex branch of the left coronary artery with intima dissection and thrombotic deposits. No atherosclerotic changes were found. Management consisted of placement of a drug-eluting coronary stent. Chemotherapy was discontinued and the seminoma treatment completed by radiotherapy with 30 Gy applied to the retroperitoneal mass and a paraaortic template. Complete remission was achieved. 6 months thereafter, the patient was doing well and was disease-free., Comment:  About 0.3 % of all testis cancer patients undergoing cisplatin-based chemotherapy develop cardiovascular complications. Cisplatin-related endothelial damage with secondary thrombotic clotting is assumed to be etiologic in these cases. As there is little comorbidity, the prognostic outlook is favourable in most cases. Caregivers in charge of testis cancer management should be vigilant regarding cardiovascular complications to ensure immediate diagnostic and therapeutic measures in incident cases., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: In 2016, Kaiser Permanente Northern California began regionalizing testicular cancer care using population-based tumor board review. This mixed methods evaluation describes implementation outcomes and learnings., Methods: We conducted in-depth interviews with key stakeholders, administered surveys to local oncologists and urologists, and used clinical data to evaluate changes in care delivery during 2015-2018., Results: An average of 135 patients with testicular cancer were diagnosed each year. Interviews with 16 key stakeholders provided several insights. Implementation resulted in high levels of satisfaction, was dependent on leadership and staff at various levels, and required technology and consulting solutions aligned to user agreements and clinical workflows. Of 123 local oncologists and urologists who completed surveys, 97% understood why care was regionalized and 89% agreed that tumor board review improved treatment decisions. Among 177 patients with stage I seminoma, the percentage appropriately observed rather than treated with adjuvant chemotherapy or radiation therapy increased from 48% (95% CI, 35 to 62) in 2015 to 87% (75 to 99) in 2018. Review altered care based on pathology and radiology re-review in 14.5 % of cases., Conclusion: Regionalization was feasible and effective.

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.)

Purpose: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences., Methods: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups., Results: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free., Conclusion: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.

Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs)., Patients and Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes., Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76)., Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Disrupted fetal germline development underpins testicular germ cell neoplasia, which is increasing worldwide. The complex signaling milieu during normal testis development includes TGFβ superfamily ligands; this study tests the hypothesis that, activin A, a TGFβ superfamily member, can influence gonocyte development. The human seminoma-derived cell line, TCam-2, a model of fetal gonocytes, was cultured with activin A (1.25-25 ng/mL) for 48 h, or with 5 ng/mL activin A for short- (6, 24, and 48 h) and long-term (13 days) exposures, and downstream targets measured by qRT-PCR. Transcripts that exhibited significant dose-dependent responses to activin A included the early germ cell markers KIT, NODAL, and CRIPTO (NODALl co-receptor and activin inhibitor) which all increased and the differentiation marker DNMT3L which decreased. After 48 h, KIT, NODAL, and CRIPTO levels were significantly higher, while the differentiation marker NANOS2 was significantly lower. Interestingly, activin A exposure also significantly reduced both transcript and protein levels of the PIWI/piRNA pathway component DNMT3L. Because TCam-2 cells produce the activin inhibitor CRIPTO, CRIPTO was reduced using siRNA prior to activin A exposure. This selectively increased KIT in response to activin A. Other ligands present in the fetal testis (BMP4, FGF9, TGFβ1, and TGFβ2) induced distinct effects on germline marker expression. This study showed that activin A can directly modulate germline markers in this human gonocyte-like cell, promoting a less-differentiated phenotype. Additional findings indicate evidence of signaling crosstalk between activin A and NODAL, leading to target-specific effects on gonocyte differentiation.

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.

A 19-year-old man with abnormal findings on his chest X ray was referred to our hospital. A chest computed tomography scan revealed a 57 mm mass in the anterior mediastinum, and percutaneous needle biopsy was performed. Histopathological diagnosis was pure seminoma. Since the serum alphafetoprotein (AFP) level was normal and no abnormal findings were noted in the testis, the patient was diagnosed with mediastinal seminoma [International Germ Cell Consensus Classification (IGCCC) goodrisk group]. After three cycles of chemotherapy with bleomycin/etoposide/cisplatin [BEP], the tumor decreased in size to 32 mm, and a fluorodeoxyglucose-positron emission tomography scan indicated negative tumor findings. After four months, the residual tumor increased in size to 40 mm without any increase in the tumor marker levels. Surgical resection was performed, and the histopathological finding was only mature teratoma. Six months after the operation, there has been no recurrence.

Introduction : Testicular germ cell tumors (TGCTs) are the most common neoplasia in the young male population, and the incidence has been constantly increasing in many parts of the world. These tumors are classified into seminomas and non-seminomas, and those divided, in turn, into yolk sac tumors, embryonal cell carcinomas, choriocarcinomas, and teratomas. Although therapeutic approaches have improved, approximately 25% of the patients relapse or, in a small number of cases, show platinum-resistant disease. Areas covered : We review several molecular targets that have recently emerged as powerful tools for both diagnosis and therapy of TGCTs. Moreover, we reviewed the most frequent deregulated pathways involved in TGCT tumorigenesis, reporting drugs that may emerge as novel therapeutic agents. Expert opinion : TGCT treatment is mainly based on platinum-derivative therapy with high cure rates. However, in the refractory patients, there are few alternative treatments. Thus, different pharmacological approaches have to be thoroughly investigated to shed new light on TGCT pathogenesis and treatment.

Background: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m 2 ), and cisplatin (BE 360 P) chemotherapy, or surveillance., Objective: To test whether one cycle of BE 500 P achieves similar recurrence rates to two cycles of BE 360 P., Design, Setting, and Participants: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study., Intervention: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m 2 on days 1-3, and cisplatin 50 mg/m 2 on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis., Outcome Measurements and Statistical Analysis: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr., Results and Limitations: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants., Conclusions: BE 500 P is safe and the 2-yr MR rate is consistent with that seen following two BE 360 P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE 500 P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE 500 P as standard would reduce overall exposure to chemotherapy in this young population., Patient Summary: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

A residual mass (RM) is an abnormal image with a transverse axis of more than 1cm trans that remains visible on the CT scan performed after chemotherapy for metastatic germ cell tumors. Their management depends on the histology of the initial tumor. In the case of a non-seminomatous germ cell tumor, all residual lesions must be resected if the tumor markers are negative. The surgery usually begins with a retroperitoneal lymphadenectomy. This lymphadenectomy is a programed regional surgery and not the only resection of visible masses. All RM must be resected, regardless of their location, and may require successive actions. In order to limit its morbidity, modifications on the extent of the lymphadenectomy and the use of minimally invasive approaches are proposed by some center. When the initial tumor is a pure seminoma the attitude is different: the decay of the masses in post chemotherapy is often postponed. If lesions less than 3cm can be monitored, the others benefit from 18FDG PET at the end of chemotherapy: a positive attachment to PET is suspected of the presence of residual active tissue. The surgery of these RM is curative. If its extent is precise in the case of non-seminomatous tumor, it is more controversial in the case of seminoma. In the case of residual markers, surgery has a place in very specific situations., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Primary tumor size (PTS) is the main prognostic factor for relapse in clinical stage (CS) IA testicular seminoma (T1N0M0S0) and the 8th edition of the Tumor-Node-Metastasis staging system now subcategorizes pT1 tumors into pT1a and pT1b based on PTS (<3 cm and ≥3 cm, respectively). We attempted to assess PTS as a prognosticator for overall survival (OS) in CS IA seminoma and to evaluate the comparative effectiveness of active surveillance (AS) versus adjuvant therapy (AT) in patients with large primary tumors (LPT)., Methods and Materials: In the National Cancer Database (2004-2014), 2455 (47.7%) and 2685 (52.3%) patients with CS IA seminoma were treated with AS and AT, respectively. AT was defined as the receipt of chemotherapy or radiation within 3 months after orchiectomy. A cut-point analysis was performed to determine the optimal PTS threshold predicting OS at 5 years after orchiectomy. Inverse-probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox regression analyses were used to compare OS of patients with LPT (using the optimal PTS cut-point) treated with AS versus AT., Results: In adjusted analysis, pathologic T-stage (pT1a vs. pT1b) did not predict OS and no OS benefit was noted in pT1b patients treated with AT. The optimal PTS cut-point was 4.5 cm. In multivariable analysis, patients with LPT (≥4.5 cm) had an increased risk of overall mortality (HR = 1.87, P = 0.003). Kaplan-Meier curves revealed that OS was superior in patients with LPT treated with AT (IPTW-adjusted log-rank P = 0.029). In IPTW-adjusted Cox regression analysis, AT was associated with an OS benefit in patients with LPT (HR = 0.59, 95%CI: 0.39-0.91, P = 0.017)., Conclusions: In this National Cancer Database analysis, PTS was a predictor of OS in CS IA seminoma. An OS benefit was noted for individuals with LPT (defined as PTS ≥4.5 cm) managed with AT. These findings may warrant refinement of Tumor-Node-Metastasis staging system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cancer-specific survival rates in patients with learning difficulties (LD) are poorer than the general population. Issues such as delayed diagnosis, compliance, consent and needs for individualised care and support requirements can make it more demanding to manage these patients in a busy clinical environment. Our case highlights a patient with learning disabilities who presented with advanced testicular cancer due to delayed detection, and the challenges needing consideration to ensure such patients receive good care. This report also highlights an example of adapting curative intent treatment to an individual with complex needs, and the importance of patient and family involvement in decision-making to ensure these vulnerable patients receive safe and effective healthcare. The practicalities of multidisciplinary team working in the context of key legislation and existing frameworks to guide practice in the management of LD patients are also discussed., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)