Advances in radiation therapy for testicular seminoma.

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.

Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for seminoma: Limitations of surgical intervention after first-line chemotherapy.

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.

Evaluation of tumour size and rete testis invasion in progression free survival of our patients with stage i testicular seminoma. A retrospective observational study of a reference hospital center and literature review.

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.

The role of primary retroperitoneal lymph node dissection in the treatment of stage II seminoma.

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.

Late Relapse of Germ Cell Tumors After Prior Chemotherapy or Surgery-only.

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.

Effect of rapamycin treatment in human seminoma TCam-2 cells through inhibition of G1-S transition.

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.

Extrinsic apoptosis and senescence involved in growth kinetics of seminoma to cisplatin.

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-ß-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.

Multicenter Database of Patients with Germ-Cell Tumors: A Latin American Cooperative Oncology Group Registry (LACOG 0515).

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.

Surveillance versus Adjuvant Treatment with Chemotherapy or Radiotherapy for Stage I Seminoma: A Systematic Review and Meta-Analysis According to EAU COVID-19 Recommendations.

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.

Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial.

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.

Exosomal miR-193b-3p Contributes to Cisplatin Sensitivity in Seminoma by Targeting ZBTB7A.

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.

Paraneoplastic Demyelinating Inflammatory Neuropathy Revealing Metastatic Seminoma: A Case Report.

Paraneoplastic neurological syndrome (PNS) is uncommon and not well known. PNS can reveal cancer, but its role in seminomas has not been described explicitly. We report the case of a 36-year-old man with unremarkable medical history and no comorbidities who was diagnosed with a retroperitoneal metastatic seminoma. The patient's general condition deteriorated, and he developed progressive neurological palsy without other clinical anomalies. Electromyography revealed demyelinating, non-lengthy neuropathy. Guillain-Barré syndrome was initially suspected. However, a positron emission tomography scan revealed a retroperitoneal mass, and blood markers revealed increased human chorionic gonadotropin. The patient was diagnosed with PNS, and a computed tomography-guided biopsy revealed a metastatic seminoma without a primary tumor. No circulating neural antibodies were detected. Human polyvalent immunoglobulin was simultaneously administered with chemotherapy. After three cycles of a cisplatin-etoposide-bleomycin, a complete biological and metabolic response rate was observed, and his neurological symptoms rapidly improved. Four years later, the patient responded completely, without any neurological complaints. Paraneoplastic demyelinating inflammatory neuropathy can lead to advanced seminoma diagnosis. Prompt management of seminomas with cisplatin-based regimens provides the best chance of cure for both advanced seminoma and paraneoplastic syndrome.

Oleuropein Counteracts Both the Proliferation and Migration of Intra- and Extragonadal Seminoma Cells.

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 p21Cip/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 TGFß-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.

How to classify, diagnose, treat and follow-up extragonadal germ cell tumors? A systematic review of available evidence.

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.