RARE DISEASE
Non-seminomatous germ cell tumor of testis
Non-seminomatous germ cell tumor of testis
Non-seminomatous germ cell tumor of testis
Synonyms: Non-dysgerminomatous germ cell tumor of testis, Testicular non seminomatous germ cell tumor, Testicular non-dysgerminomatous germ cell tumor
Synonyms: Non-dysgerminomatous germ cell tumor of testis, Testicular non seminomatous germ cell tumor, Testicular non-dysgerminomatous germ cell tumor
Synonyms: Non-dysgerminomatous germ cell tumor of testis, Testicular non seminomatous germ cell tumor, Testicular non-dysgerminomatous germ cell tumor
Drug discovery
1
drug
With orphan designation
Overview
Non-seminomatous germ cell tumors (NSGCTs) are aggressive testicular cancers comprising embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma subtypes. They often present with elevated AFP or β-hCG levels and metastasize rapidly. Diagnosis involves orchiectomy, imaging, and tumor marker analysis. Treatment combines surgery, chemotherapy (BEP/EP regimens), and risk-adapted strategies, achieving >95% cure rates in early stages. Advanced or relapsed disease requires intensified therapy [1][3][6][12].
Burden
Global 5-year survival exceeds 95% for localized disease but drops to 71% in poor-risk metastatic cases [13][15].
In low-resource settings, 50–77% present with stage III disease, complicating management [2][7][14].
Long-term toxicities (cardiovascular, pulmonary, secondary malignancies) affect 15–20% of survivors [8][14].
Therapies
Localized disease: Radical inguinal orchiectomy ± adjuvant chemotherapy or retroperitoneal lymph node dissection (RPLND) [3][8].
Advanced/metastatic disease: 3–4 cycles of BEP (bleomycin, etoposide, cisplatin) or EP chemotherapy, tailored to IGCCCG risk stratification (good/intermediate/poor prognosis) [6][8][12].
Salvage therapies (e.g., TIP/VIP regimens) for relapse [8][13].
Categories: rare neoplastic diseases, rare transplant-related disorders, rare urogenital diseases
Research Papers
642 drug discovery papers about Non-seminomatous germ cell tumor of testis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
642 drug discovery papers about Non-seminomatous germ cell tumor of testis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-10 | Metastatic Testicular Germ Cell Tumor in a Patient With Neurofibromatosis Type 1: Treatment With Trametinib Based on NF1 Gene Mutation.
Neurofibromatosis type 1 (NF1) is a genetic disorder that increases the risk of various tumors. However, its association with testicular germ cell tumors (GCTs) is rare. We report a case of metastatic GCT in an NF1 patient treated with precision medicine. A 40-year-old male with NF1 presented with a left testicular non-seminomatous GCT and lung metastases. The tumor showed progressive disease after chemotherapy (VIP, TGP) and surgical removal of metastases. Comprehensive genomic profiling (CGP) test found a pathogenic NF1 frameshift mutation (p.Q514fs*43). Based on this finding, the patient received the MEK inhibitor trametinib under patient-proposed healthcare services (BELIEVE Trial). Treatment resulted in normalization of serum alpha-fetoprotein (AFP) for 6 months before the tumor eventually progressed. The patient died at 39 months after diagnosis. This is the first report of trametinib for a metastatic GCT with an NF1 mutation, suggesting a possible but limited treatment effect. The prospective trial of patient-proposed healthcare services with multiple targeted agents based on the results of gene profiling by multigene panel test (BELIEVE), NCCH1901/jRCTs031190104.
2026-05-28 | Depth of response to primary POMB/ACE chemotherapy predicts survival in poor prognosis germ-cell tumours.
Most chemotherapy regimens for poor-risk non-seminomatous germ cell tumours (PRGCT) deliver a fixed number of cycles; the role of variable treatment duration aiming for maximal response is unknown. Since the 1970s, we have utilised POMB/ACE chemotherapy for PRGCT, treating until marker normalisation. From mid-1990s, treatment was limited to 7 cycles. We describe outcomes with POMB/ACE for PRCGT, evaluating the association between treatment duration and survival. We conducted a retrospective cohort study across two UK tertiary cancer centres, identifying patients treated between 1978-2013. Complete response was defined based on normalisation of elevated tumour markers, absence of viable cancer in resection material and resolution of radiological abnormalities. Regression techniques were used to investigate the relationship between therapy duration and outcomes. 132 PRGCT patients completed POMB/ACE with 69.7% (n = 92) alive at 5 years. Number of cycles delivered significantly correlated with recurrence free survival (HR 0.52; 95% CI 0.38-0.71; p < 0.001) and complete biochemical response (OR 1.27; 95% CI 1.10-1.49; p = 0.0018). POMB/ACE discontinuation amongst patients with responding but not normalised tumour markers was associated with worse survival. Study limitations include the retrospective design. POMB/ACE is highly active for PRGCT. Treatment until maximal biochemical response is associated with superior survival outcomes and warrants further exploration.
2026-05-20 | Clinical Outcomes of the Alternative GAMMA Regimen in Relapsed Germ Cell Tumours.
Following promising results in a phase II trial evaluating GAMMA as salvage therapy for relapsed germ cell tumours (GCT) who had progressed on cisplatin-based chemotherapy, the GAMMA regimen was adopted into clinical practice at St Bartholomew's Hospital. This study provides the largest real-world evaluation of the GAMMA regimen to date, assessing its long-term effectiveness in an unselected patient population. This was a single-centre retrospective study of patients who progressed following cisplatin-based chemotherapy and were treated with GAMMA regimen between November 2012 and September 2023. Data collected included clinico-pathological features, treatment details and prognostic risk scores which are International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification and International Prognostic Factor Study Group (IPFSG) score. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were assessed. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 69 patients were included with a median age of 39 years. Most were male (94%) and had an ECOG performance status of 0-1 (76%). Non-seminomatous histology was observed in 80% and 74% had a gonadal primary tumour. BEP was the most common first-line treatment (89%). Poor-risk disease per IGCCCG criteria was seen in 41% while 39% were intermediate-risk by IPFSG. 64% completed all planned chemotherapy cycles; 10% discontinued due to toxicity. Stem cell mobilisation was successful in 91%. The most frequent treatment response was partial response marker negative (PRm-) (38%). The 2-year PFS and OS rates were 31% and 49%, respectively. By IPFSG risk group, 2-year PFS and OS ranged from 20%-50% and 20%-75%. Among patients with LDH ≥ 2.5xULN, 2-year PFS was 38% and OS was 47%. GAMMA demonstrates acceptable tolerability and maintains meaningful survival outcomes, supporting its use as a dose-intensified salvage treatment option for patients with relapsed GCT.
2026-03-01 | Impact of bleomycin shortage on real-world outcomes in germ cell tumors: A multicenter retrospective analysis in Brazil.
600 Background: Male germ cell tumors are rare malignancies, accounting for approximately 5% of all male cancers and predominantly affecting young adults. Most originate in the testis and are classified as seminomatous or non-seminomatous. Depending on clinical stage, different polychemotherapy regimens may be indicated, with or without bleomycin. Since 2017, Brazil—like several other countries—has faced recurrent shortages of bleomycin due to reduced global production, limited raw material availability, regulatory and logistical import barriers, and low commercial incentives for manufacturing this low-cost drug. In this context, this study aimed to evaluate the clinical impact of bleomycin unavailability on treatment outcomes in patients with germ cell tumors. Methods: A retrospective study was conducted including patients with germ cell tumors treated from 2017 to 2024 in two large public oncology centers in Brazil. Outcomes were compared between patients receiving bleomycin-containing regimens (BEP: bleomycin, etoposide, and cisplatin) and alternative regimens without bleomycin (EP: etoposide and cisplatin; VIP: etoposide, ifosfamide, and cisplatin). Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method, and factors associated with treatment type were evaluated through multivariate logistic regression. Additionally, hospitalization rates, treatment delays, and chemotherapy-related toxicities were assessed and compared between groups. Results: A total of 179 patients with germ cell tumors were evaluated. Among them, 57 received BEP, 36 received EP, and 13 received VIP. The comparative analysis of survival and treatment outcomes was performed between the BEP group and the combined non-bleomycin group (EP/VIP). There was no statistically significant difference in OS (p=0.593) or DFS (p=0.480) in the comparison of these 2 groups. Hospitalization rates (40.8% vs. 31.6%; p=0.323) and overall toxicity profiles were similar. However, patients treated without bleomycin presented a higher frequency of non-infectious hematologic toxicities (25.9% vs. 14.3%), which may have contributed to the significantly higher rate of treatment delays (59.2% vs. 33.3%; p=0.008). These adverse events generally did not require hospitalization but led to temporary chemotherapy postponements to allow hematologic recovery. Conclusions: Replacing bleomycin with alternative regimens (EP/VIP) did not compromise survival outcomes and showed comparable hospitalization and overall toxicity rates, although a higher rate of treatment delays was observed, likely due to increased mild or moderate hematologic toxicities. These real-world data support the feasibility of non-bleomycin regimens in contexts of drug shortage and contribute to evidence-based clinical decisions in germ cell tumor management.
2026-03-01 | Relapsed/refractory clinically advanced (CA) testicular non-seminomatous germ cell tumors (NSGCT): A genomic landscape study.
618 Background: The successful outcome for most men with NSGCT of testis after surgery and, in some cases, chemotherapy is a milestone in oncology. However, a minority of patients may become platinum-refractory with relapse or progression after chemotherapy. Comprehensive genomic profiling (CGP) has the potential to uncover new therapy targets for these patients. Methods: Hybrid capture based CGP was performed using the FoundationOne CDx assay on 182 CANSGCT to identify all classes of genomic alterations (GA). The site of the analyzed sample was available in 161/182 patients: 12.4% locoregional lymph nodes, 16.8% testis, 70.8% distant metastases. Microsatellite instability status (MSI), tumor mutational burden (TMB) and Homologous Recombination Deficiency (HRDsig) were determined from the sequencing data. Genomic ancestry and Cosmic trinucleotide signatures were also identified. PD-L1 expression was determined by IHC using Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). Most cases had relapsed after surgery and chemotherapy, either loco-regionally or with metastatic disease at the time of CGP. Results: 182 men with CANSGCT had median age of 33. Genomic ancestry revealed that 65.4% of patients were European, 29.1% were admixed American, 3.3% were African, 1.6% were East Asian and 0.5% were South Asian. There was a median of 3 GA per sequenced tumor. At 2.2% frequency, MSI-high status was rare and TMB was relatively low with 95% of cases having TMB < 10 mut/Mb. A positive HRD signature was identified in 4.7% of cases. Identification of specific genomic signatures was uncommon with 2.7% having MMR signature and 1.1% having a tobacco exposure signature. PD-L1 expression was low level in 18.1% and high level in 15.3% of cases. KRAS mutations were the most frequent individual GA with <1% KRAS G12C. Inactivation of PTEN (6.6%) and activation of KIT (4.9%) were GA with potentially associated targeted therapies. Conclusions: CGP of CANSGCT cases revealed potential therapy targets with opportunities for clinical trials, e.g. focused on PTEN/MTOR pathway and KIT. Although initial clinical experience with targeted agents and anti-PD1/L1 have yielded limited benefit in unselected patients with these tumors, further CGP-based study of refractory NSGCT is warranted to enable the development of biomarker-driven clinical trials designed to rescue men who exhibit platinum refractory disease. Study limitations include the retrospective nature, lack of comparison with the genomic landscape of platinum-sensitive tumors, lack of clinical outcomes data annotation, selection and confounding biases.
oligonucleotides
2023-07-30 | Epigenetic Factors and ncRNAs in Testicular Cancer
Testicular cancer is the most prevalent tumor among males aged 15 to 35, resulting in a significant number of newly diagnosed cases and fatalities annually. Non-coding RNAs (ncRNAs) have emerged as key regulators in various cellular processes and pathologies, including testicular cancer. Their involvement in gene regulation, coding, decoding, and overall gene expression control suggests their potential as targets for alternative treatment approaches for this type of cancer. Furthermore, epigenetic modifications, such as histone modifications, DNA methylation, and the regulation by microRNA (miRNA), have been implicated in testicular tumor progression and treatment response. Epigenetics may also offer critical insights for prognostic evaluation and targeted therapies in patients with testicular germ cell tumors (TGCT). This comprehensive review aims to present the latest discoveries regarding the involvement of some proteins and ncRNAs, mainly miRNAs and lncRNA, in the epigenetic aspect of testicular cancer, emphasizing their relevance in pathogenesis and their potential, given the fact that their specific expression holds promise for prognostic evaluation and targeted therapies.
2023-04-18 | Silencing of LINC00467 inhibits cell proliferation in testicular germ cell tumors cells
A significant decrease in LINC00467 expression in testicular germ cell tumors (TGCTs) was found in our previous study in comparison to adjacent tissue. Interestingly, the expression of LINC00467 correlated with the pathological grade of the tumor in TGCT patients. The higher the expression of LINC00467 was, the worse the prognosis of the patients with TGCT was. Despite these findings, the exact role of LINC00467 in the development of TGCTs requires further investigation. LINC00467 expression was downregulated in the NCCIT and TCam-2 cell lines via small interfering RNA (siRNA) silencing. The levels of gene expression were validated using quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Cell proliferation was evaluated by the MTT and Cell Counting Kit-8 (CCK8) assays, whereas flow cytometry was used to assess the effects on the cell cycle. Western blotting analysis was used to detect expression levels of protein. Additionally, RNA-sequencing and bioinformatics methods were used to investigate the mechanism of action of LINC00467 in TGCTs. The suppression of LINC00467 expression resulted in decreased cell proliferation and induced S-phase arrest. Furthermore, the suppression of LINC00467 downregulated proliferating cell nuclear antigen (PCNA), a protein related to cell cycle regulation, while it upregulated p21 expression. In other studies involving dihydrotestosterone (DHT) stimulation, it was observed that DHT could upregulate LINC00467 expression. In addition, silencing of the LINC00467 reversed the effect of testosterone on cell proliferation. The Gene Set Enrichment Analysis (GSEA) revealed that LINC00467 regulated the p53 pathway by modulating the expression of CCNG1. Our study found that LINC00467 regulates cell proliferation by inducing S-phase arrest through the cell cycle-related proteins PCNA and p21. These findings contribute to our understanding of non-coding RNAs mechanisms involved in the development of TGCTs.
2023-02-16 | Silencing of LINC00467 inhibits cell proliferation in testicular germ cell tumors cells Running Title: Silencing of LINC00467 regulates cell proliferation
Abstract Our previous study showed that LINC00467 expression decreased significantly in testicular germ cell tumors (TGCTs) compared with adjacent tissue. LINC00467 expression in TGCTs was upregulated at stages II/III compared with stage I, and was negatively correlated with the 5-year overall survival and 5-year disease-free survival. However, the role of LINC00467 in the development of TGCTs remains to be elucidated further. LINC00467 expression was silenced in the NCCIT and TCAM-2 cell lines using small interfering RNA (siRNA). The expression level of genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR) analyses. The MTT and CCK8 assays were used to detect cell proliferation. The effects on cell cycle were evaluated using flow cytometry. Western blotting analysis was used to detect the expression level of proteins, while RNA-sequencing and bioinformatics methods were used to explore the mechanism of action of LINC00467 in TGCTs. The silencing of LINC00467 expression decreased cell proliferation, induced S phase arrest, and downregulated the cell cycle-related protein PCNA expression while upregulating the expression of P21. Dihydrotestosterone (DHT) stimulation experiments showed that DHT could upregulate the expression of LINC00467 and that the silencing of LINC00467 could reverse the effect of testosterone on cell proliferation. The Gene Set Enrichment Analysis (GSEA) showed that the P53 signaling pathway was associated with LINC00467. Our study reported that LINC00467 regulated cell proliferation and induced S phase arrest in TGCTs cells through the cell cycle-related proteins, PCNA, and P21. These enriched the mechanism of non-coding RNAs in the development of TGCTs.
2021-12-03 | Impact of circulating microRNA test (miRNA-371a-3p) on appropriateness of treatment and cost outcomes in patients with Stage I non-seminomatous germ cell tumours.
To determine whether utilisation of a serum microRNA (miRNA) test could improve treatment appropriateness and cost-effectiveness for patients with Stage I non-seminomatous germ cell tumours (NSGCTs). A decision tree model was built to investigate treatment course, clinical and cost outcomes for patients with Stage IA (T1N0M0S0) and IB (T2-4N0M0S0) NSGCT. The model compared outcomes and cost of standard approach using histopathology, conventional serum tumour markers and radiographic staging (standard model) to a miRNA-based approach using the standard model + post-orchidectomy serum miR-371a-3p (marker model). Probabilities of expected treatment and outcomes were based on presence/absence of cancer upon entering into the model. Overtreatment was defined as adjuvant chemotherapy or primary retroperitoneal lymph node dissection in a patient without cancer. Undertreatment was defined as initial surveillance for a patient with cancer. Utilising the miRNA marker-based approach, 26% of patients avoid overtreatment and 8% avoid undertreatment in Stage IA NSGCT; 27% avoid overtreatment and 23% avoid undertreatment in Stage IB disease. Appropriate treatment decision-making increased from 65% to 94% and 50% to 92% for Stage IA and IB, respectively. The miRNA-based approach remained cost-effective over a wide range of performance characteristics with savings of ~$1400 (American dollars)/patient for both Stage IA and IB disease. A miRNA-based approach may potentially select patients with Stage I NSGCT for correct treatment in a cost-effective manner. Identification of residual teratoma-only remains an issue. Prospective studies are necessary to validate these findings.
2021-04-01 | The combination of microRNA-371a-3p and 375-5p can distinguish viable germ cell tumor and teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection specimens
To identify a combination of microRNAs (miRNA) to differentiate between viable tumor (V) or teratoma (T) and necrosis/fibrosis (N) in pcRPLND specimens of metastatic germ cell tumor (GCT) patients with residual masses ≥1 cm after chemotherapy. Biomarker guided therapy could reduce overtreatment with pcRPLND in patients with only N.We selected 48 metastatic GCT patients who had undergone pcRPLND. V, pure T and N was shown in the resected tissue of 16 patients, respectively. Of these areas total RNA was isolated and miRNA expression was analyzed for miR-371a-3p, 375-3p, and 375-5p using qPCR. ROC analysis was performed for each miRNA and for all combinations in order to determine the discriminatory capacity of V and T vs. N.On comparing V vs. N miR-371a-3p achieved the highest fold change (FC) of 31.1 (P=0.023) while for T vs. N miR-375-5p performed best (FC 64.2; P<0.001). Likewise, the most accurate AUC for V was 0.75 using miR-371a-3p, for T 0.80 using miR-375-5p. Combining the best performing miRNAs for V and T resulted in an AUC of 0.94 with a sensitivity of 93.75, specificity of 93.75, PPV of 96.8 and NPV of 83.3.By combining miR-371a-3p and miR-375-5p in pcRPLND tissue samples V and T could be distinguished from necrosis/fibrosis with great accuracy. This combination of miRNAs might serve as new biomarker in the future, in order to spare miRNA-negative patients from pcRPLND. However, further studies analyzing patient's serum are needed to confirm the clinical impact of these biomarkers.
cell therapies
2025-06-01 | P-001 Fertility among testicular cancer survivors at a male infertility clinic
Abstract Study question Sperm quality is often already abnormal at diagnosis in testicular cancer subjects. We evaluated the fertility of testicular cancer survivors in our male infertility clinic. Summary answer Testicular cancer survivors even with azoospermia can make fatherhood through ICSI following precise evaluation and optimal sperm retrieval surgery. What is known already General improvements in the prognosis of patients with cancer have been achieved through recent advances in surgery, radiotherapy, and chemotherapy treatments, thus increasing the number of patients surviving therapy. However, anti-cancer treatment has detrimental effect on spermatogenesis and testicular cancer inevitably results in there being a single testicle following treatment, subsequent fertility will be a concern. Cryopreservation of ejaculated sperm before cancer treatment is considered to be essential, however it is rarely performed. In contrast, the use of cryopreserved ejaculated sperm for infertility treatment actually occurs in limited number of patients. Study design, size, duration From 2004 through 2023, 3361 male infertility patients consulted our clinic, 117 (3.5%) of whom had a history of cancer treatment. Thirty-nine patients diagnosed with testicular cancer were evaluated for cancer treatment, semen findings, and infertility treatment. Participants/materials, setting, methods The median age was 36 years, the duration from termination of cancer treatment was 5.5 years, and the duration of infertility was 3.0 years. Seminoma was observed in 29 participants, and non-seminomatous germ cell tumor was in 10 participants. Main results and the role of chance Twenty patients were treated with high orchidectomy alone. Whereas three patients were treated with orchidectomy followed by chemotherapy and sixteen participants underwent subsequent retroperitoneal lymph node dissection (RPLND). Semen analyses revealed azoospermia in 26 participants, whereas oligoasthenozoospermia in 13. Although none of the these oligoasthenozoospermic patients achieved spontaneous pregnancy, three achieved pregnancy and delivery through ICSI. Sperm retrieval surgery was attempted in 18 participants with azoospermia. 13 participants underwent microscopic testicular sperm extraction (micro-TESE), two participants received onco-TESE, two patients received microscopic sperm aspiration (MESA), and one patient received retrograde vasal sperm aspiration (ReVSA). Successful motile sperm recovery was observed in 15 participants. 8 deliveries were obtained through ICSI using surgically retrieved sperm. Limitations, reasons for caution Although patients with azoospermia were informed of the need for sperm retrieval surgery, several participants did not choose to undergo the operation. Wider implications of the findings Testicular cancer survivors, even those with azoospermia, can achieve fatherhood through ICSI, after precise evaluation and appropriate sperm retrieval surgery. Trial registration number No
2023-09-30 | T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets
ABSTRACT BACKGROUND Immune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. METHODS Human testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. RESULTS Profound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. CONCLUSION Despite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients’ prognosis, and as putative targets for personalized immunotherapy.
2023-02-13 | Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors
Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.
2020-12-09 | FSH-R Human Early Male Genital Tract, Testicular Tumors and Sperm: Its Involvement in Testicular Disorders
The follicle-stimulating hormone receptor (FSH-R) expression was always considered human gonad-specific. The receptor has also been newly detected in extragonadal tissues. In this finding, we evaluated FSH-R expression in the human male early genital tract, in testicular tumors, and in sperm from healthy and varicocele patients. In sperm, we also studied the mechanism of FSH-R action. Immunohystochemistry and Western blot analysis showed FSH-R presence in the first pathways of the human genital tract, in embryonal carcinoma, and in sperm, but it was absent in seminoma and in lower varicocele. In sperm, FSH/FSH-R activity is mediated by G proteins activating the PKA pathway, as we observed by using the H89. It emerged that increasing FSH treatments induced motility, survival, capacitation, and acrosome reaction in both sperm samples. The different FSH-R expression in tumor testicular tissues may be discriminate by tumor histological type. In spermatozoa, FSH-R indicates a direct action of FSH in these cells, which could be beneficial during semen preparation for in vitro fertilization procedures. For instance, FSH positive effects could be relevant in idiopathic infertility and in the clinic surgery of varicocele. In conclusion, FSH-R expression may be considered a molecular marker of testicular disorders.
2018-10-05 | Lymphoma transformation of tumor infiltrating lymphocytes observed in testicular patient‑derived xenograft models
Testicular germ cell tumors (TGCTs) are highly sensitive to cisplatin‑based chemotherapy. Nevertheless, there are metastatic tumors that do not completely respond to front‑line chemotherapy. For these tumors, surgical resection of residual masses is necessary to achieve long‑term disease control. Resected tissues represent valuable clinical material, which may be used for the engraftment into immunocompromised mice to produce patient‑derived xenografts (PDXs). They typically maintain similarities to the parental tumors and therefore serve as more realistic preclinical models. Moreover, a correlation between PDX treatment outcomes and clinical response to chemotherapy has been previously described. The aim of the present study was to establish and characterize TGCT patient‑derived xenografts. These originated from retroperitoneal lymph node metastases infiltrated with TGCTs following previous cisplatin‑based chemotherapy, in order to analyze novel treatment options for cisplatin‑resistant testicular tumors. We generated two testicular patient‑derived xenograft models in SCID beige male mice. Immunohistochemical analyses demonstrated that histological characteristics of the primary tumor were not retained, and transformation into lymphoma, and eventually plasmocytoma, was observed. A potential explanation for the lymphoma transformation observed in PDXs may include tumor‑infiltrating lymphocytes (TILs) in xenografted samples of patients, which are transformed following engraftment into immunodeficient recipient mice. Based on these data, we indicated that lymphomagenesis prevention and terminal differentiation represent new challenges in the establishment of PDX models derived from patients with germ cell tumors.
antibodies
2024-01-19 | The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors
Testicular germ cell tumors (TGCTs) are cancers with very good prognosis, even in the metastatic setting, with high curative potential mainly attributed to the introduction of cisplatin-based chemotherapy. However, approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses. Therefore, there is an unmet need for novel therapeutic agents with improved efficacy and minimal long-term side effects. Recent advances in the development of immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have offered an opportunity to test their activity in various tumor types, including GCTs. This review aims to analyze the immune microenvironment of these tumors and present the most recently available data from studies that have tested immunotherapeutic agents against GCTs. The majority of the available knowledge derives from case reports or small cohort studies, particularly those involving ICIs of the PD-1/PD-L1 axis alone or in combination with anti-CTLA-4 monoclonal antibodies. Other immunotherapeutic targeted approaches, including antibody-drug conjugates, antibody prodrugs, vaccines, tyrosine kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapy, have biological rationales and have shown preliminary activity or are currently being tested. Growing evidence on these and other approaches will assist in broadening the currently limited treatment armamentarium against platinum-refractory TGCTs.
2023-10-06 | [A Case of Testicular Cancer with Solitary Iliac Bone Metastasis].
A 23-year-old male was aware of pain around his left hip joint and visited a nearby orthopedic clinic. Swelling of the right testis was pointed out, and a testicular tumor was suspected. He was referred to the urology department of a local hospital. Blood analysis showed an increase of α-fetoprotein (AFP) (3,620 ng/ml). Computed tomographic (CT) -scan revealed a left iliac bone metastasis and morbid fracture. Right radical inguinal orchiectomy was performed. The pathological examination revealed mixed germ cell tumor (embryonic carcinoma and immature teratoma: 70%, seminoma: 30%). The diagnosis was non-seminomatous germ cell tumor, stage IIIc, and poor risk on the International Germ Cell Consensus Classification. After one cycle of a bleomycin, etoposide and cisplatinum (BEP) regimen, he was referred to our hospital. After a total of 4 cycles of BEP, AFP was normalized. Denosumab was also administered monthly. The CT-scan showed a reduction of bone metastasis and recovery of ossification. Bone biopsy did not show viable tumor cells. Because extirpation of the remaining mass would require resection of the left part of the pelvic bone with significant functional loss of the left limb, we performed close follow-up after an additional 2 courses of the etoposide and cisplatin regimen. The patient is currently alive without recurrence at 45 months after the last systemic chemotherapy.
2023-08-14 | PRAME Is a Multifaceted Cancer Testis Antigen with Diverse Roles as a Biomarker and Therapeutic Target
Preferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen (CTA) that is selectively expressed in certain somatic tissues, predominantly in the testis and is overexpressed in various cancers. PRAME family proteins are leucine rich repeat proteins, that are localized in the nucleus and cytoplasm, with multifaceted roles in immunity, during gametogenesis and in the overall reproduction process. It is a widely studied CTA and has been associated with the prognosis and therapeutic outcome in patients with epithelial and non-epithelial tumors. PRAME has also been studied extensively as a therapeutic target. Moreover, it has been found to play a role in most of the well-known cancer hallmarks. Interestingly, the role of PRAME in tumorigenesis is paradoxical. Over the last decade, PRAME has garnered substantial interest as a target for immunotherapy. There are multiple clinical trials and pre-clinical studies targeting PRAME alone or in combination with other tumor antigens. This review article is an attempt to update our knowledge and understanding of the context-dependent oncogenic functions of PRAME in various carcinomas, and the current immunotherapeutic strategies, challenges, and perspectives on developing newer strategies to target PRAME for a better outcome.
2022-09-07 | Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo
Abstract Background Immunotherapy based on Bi-specific T Cell Engagers (TCE) represents one of the most attractive strategy to treat cancers resistant to conventional therapies. TCE are antibody-like proteins that simultaneously bind with one arm to a Tumor Associated Antigen (TAA) on cancer cells and with the other one to CD3 complex on a T-cell to form a TCR-independent immune synapse and circumvent Human Leucocyte Antigen restriction. Among them, the tribodies, such as Tb535H, a bi-specific molecule, made up of a Fab and a scFv domain both targeting 5T4 and another scFv targeting CD3, have demonstrated anti-tumor efficacy in preclinical studies. Methods Here, we generated five novel tri-specific and multi-functional tribodies, called 53X tribodies, composed of a 5T4 binding Fab arm and a CD3 binding scFv, but differently from the parental Tb535H, they contain an additional scFv derived from an antibody specific for an immune checkpoint, such as PD-1, PD-L1 or LAG-3. Results Compared with the parental Tb535H bi-specific T cell engager targeting 5T4, the novel 53X tribodies retained similar binding properties of Tb535H tribody, but showed enhanced anti-tumor potency due to the incorporation of the checkpoint inhibitory moiety. In particular, one of them, called 53L10, a tri-specific T cell engager targeting 5T4, CD3 and PD-L1, showed the most promising anti-tumor efficacy in vitro and led to complete tumor regression in vivo. Conclusions The novel tribodies have the potential to become strong and safe therapeutic drugs, allowing to reduce also the cost of production as one single molecule contains three different specificities including the anti-TAA, anti-CD3 and anti-IC binding arms.
2021-11-24 | Nivolumab for the salvage treatment of desperate germ cell tumor: A case report.
Testicular germ cell tumors (GCT) are the most common tumor in young men. Their distinctive feature is the exceptional response to platin based combination chemotherapy.Since the prognosis is poor in relapsed and refractory patients, the immune checkpoint inhibitors are candidate agents in these patients although clinical trials are mostly lacking. Herein, we describe a patient with a refractory nonseminomatous GCT using nivolumab as a last resort therapy and provided long term response without any significant toxicity. A 41-year-old male presented with the complaint of flank pain eleven years ago. The patient underwent a retroperitoneal lymph node excision and pathology reported as the mixed germ cell tumor. There were no mass in the testicles and the patient was diagnosed with a primary retroperitoneal GCT. Since the disease has progressed under multiple lines of chemotherapy and autologous stem cell transplantation, treatment was started with nivolumab. The patient started to treatment with nivolumab 3 mg/kg two weekly as a last resort treatment. The nivolumab was continued and the patient's response to this treatment is ongoing and has been stable for 13 months. There are limited treatment options in platinum-refractory germ cell tumors. Recently, immune checkpoint inhibitors tried in this setting with some success in especially non-seminomatous GCTs. We see a good response and prolonged benefit with the use of nivolumab in our patient. Further research including prospective studies on the use of immune checkpoint inhibitors in platinum-resistant testicular cancer can further delineate the role of immunotherapy.
small molecules
2026-07-10 | Metastatic Testicular Germ Cell Tumor in a Patient With Neurofibromatosis Type 1: Treatment With Trametinib Based on NF1 Gene Mutation.
Neurofibromatosis type 1 (NF1) is a genetic disorder that increases the risk of various tumors. However, its association with testicular germ cell tumors (GCTs) is rare. We report a case of metastatic GCT in an NF1 patient treated with precision medicine. A 40-year-old male with NF1 presented with a left testicular non-seminomatous GCT and lung metastases. The tumor showed progressive disease after chemotherapy (VIP, TGP) and surgical removal of metastases. Comprehensive genomic profiling (CGP) test found a pathogenic NF1 frameshift mutation (p.Q514fs*43). Based on this finding, the patient received the MEK inhibitor trametinib under patient-proposed healthcare services (BELIEVE Trial). Treatment resulted in normalization of serum alpha-fetoprotein (AFP) for 6 months before the tumor eventually progressed. The patient died at 39 months after diagnosis. This is the first report of trametinib for a metastatic GCT with an NF1 mutation, suggesting a possible but limited treatment effect. The prospective trial of patient-proposed healthcare services with multiple targeted agents based on the results of gene profiling by multigene panel test (BELIEVE), NCCH1901/jRCTs031190104.
2026-05-28 | Depth of response to primary POMB/ACE chemotherapy predicts survival in poor prognosis germ-cell tumours.
Most chemotherapy regimens for poor-risk non-seminomatous germ cell tumours (PRGCT) deliver a fixed number of cycles; the role of variable treatment duration aiming for maximal response is unknown. Since the 1970s, we have utilised POMB/ACE chemotherapy for PRGCT, treating until marker normalisation. From mid-1990s, treatment was limited to 7 cycles. We describe outcomes with POMB/ACE for PRCGT, evaluating the association between treatment duration and survival. We conducted a retrospective cohort study across two UK tertiary cancer centres, identifying patients treated between 1978-2013. Complete response was defined based on normalisation of elevated tumour markers, absence of viable cancer in resection material and resolution of radiological abnormalities. Regression techniques were used to investigate the relationship between therapy duration and outcomes. 132 PRGCT patients completed POMB/ACE with 69.7% (n = 92) alive at 5 years. Number of cycles delivered significantly correlated with recurrence free survival (HR 0.52; 95% CI 0.38-0.71; p < 0.001) and complete biochemical response (OR 1.27; 95% CI 1.10-1.49; p = 0.0018). POMB/ACE discontinuation amongst patients with responding but not normalised tumour markers was associated with worse survival. Study limitations include the retrospective design. POMB/ACE is highly active for PRGCT. Treatment until maximal biochemical response is associated with superior survival outcomes and warrants further exploration.
2026-05-20 | Clinical Outcomes of the Alternative GAMMA Regimen in Relapsed Germ Cell Tumours.
Following promising results in a phase II trial evaluating GAMMA as salvage therapy for relapsed germ cell tumours (GCT) who had progressed on cisplatin-based chemotherapy, the GAMMA regimen was adopted into clinical practice at St Bartholomew's Hospital. This study provides the largest real-world evaluation of the GAMMA regimen to date, assessing its long-term effectiveness in an unselected patient population. This was a single-centre retrospective study of patients who progressed following cisplatin-based chemotherapy and were treated with GAMMA regimen between November 2012 and September 2023. Data collected included clinico-pathological features, treatment details and prognostic risk scores which are International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification and International Prognostic Factor Study Group (IPFSG) score. Progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) were assessed. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 69 patients were included with a median age of 39 years. Most were male (94%) and had an ECOG performance status of 0-1 (76%). Non-seminomatous histology was observed in 80% and 74% had a gonadal primary tumour. BEP was the most common first-line treatment (89%). Poor-risk disease per IGCCCG criteria was seen in 41% while 39% were intermediate-risk by IPFSG. 64% completed all planned chemotherapy cycles; 10% discontinued due to toxicity. Stem cell mobilisation was successful in 91%. The most frequent treatment response was partial response marker negative (PRm-) (38%). The 2-year PFS and OS rates were 31% and 49%, respectively. By IPFSG risk group, 2-year PFS and OS ranged from 20%-50% and 20%-75%. Among patients with LDH ≥ 2.5xULN, 2-year PFS was 38% and OS was 47%. GAMMA demonstrates acceptable tolerability and maintains meaningful survival outcomes, supporting its use as a dose-intensified salvage treatment option for patients with relapsed GCT.
2026-03-01 | Impact of bleomycin shortage on real-world outcomes in germ cell tumors: A multicenter retrospective analysis in Brazil.
600 Background: Male germ cell tumors are rare malignancies, accounting for approximately 5% of all male cancers and predominantly affecting young adults. Most originate in the testis and are classified as seminomatous or non-seminomatous. Depending on clinical stage, different polychemotherapy regimens may be indicated, with or without bleomycin. Since 2017, Brazil—like several other countries—has faced recurrent shortages of bleomycin due to reduced global production, limited raw material availability, regulatory and logistical import barriers, and low commercial incentives for manufacturing this low-cost drug. In this context, this study aimed to evaluate the clinical impact of bleomycin unavailability on treatment outcomes in patients with germ cell tumors. Methods: A retrospective study was conducted including patients with germ cell tumors treated from 2017 to 2024 in two large public oncology centers in Brazil. Outcomes were compared between patients receiving bleomycin-containing regimens (BEP: bleomycin, etoposide, and cisplatin) and alternative regimens without bleomycin (EP: etoposide and cisplatin; VIP: etoposide, ifosfamide, and cisplatin). Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method, and factors associated with treatment type were evaluated through multivariate logistic regression. Additionally, hospitalization rates, treatment delays, and chemotherapy-related toxicities were assessed and compared between groups. Results: A total of 179 patients with germ cell tumors were evaluated. Among them, 57 received BEP, 36 received EP, and 13 received VIP. The comparative analysis of survival and treatment outcomes was performed between the BEP group and the combined non-bleomycin group (EP/VIP). There was no statistically significant difference in OS (p=0.593) or DFS (p=0.480) in the comparison of these 2 groups. Hospitalization rates (40.8% vs. 31.6%; p=0.323) and overall toxicity profiles were similar. However, patients treated without bleomycin presented a higher frequency of non-infectious hematologic toxicities (25.9% vs. 14.3%), which may have contributed to the significantly higher rate of treatment delays (59.2% vs. 33.3%; p=0.008). These adverse events generally did not require hospitalization but led to temporary chemotherapy postponements to allow hematologic recovery. Conclusions: Replacing bleomycin with alternative regimens (EP/VIP) did not compromise survival outcomes and showed comparable hospitalization and overall toxicity rates, although a higher rate of treatment delays was observed, likely due to increased mild or moderate hematologic toxicities. These real-world data support the feasibility of non-bleomycin regimens in contexts of drug shortage and contribute to evidence-based clinical decisions in germ cell tumor management.
2026-03-01 | Relapsed/refractory clinically advanced (CA) testicular non-seminomatous germ cell tumors (NSGCT): A genomic landscape study.
618 Background: The successful outcome for most men with NSGCT of testis after surgery and, in some cases, chemotherapy is a milestone in oncology. However, a minority of patients may become platinum-refractory with relapse or progression after chemotherapy. Comprehensive genomic profiling (CGP) has the potential to uncover new therapy targets for these patients. Methods: Hybrid capture based CGP was performed using the FoundationOne CDx assay on 182 CANSGCT to identify all classes of genomic alterations (GA). The site of the analyzed sample was available in 161/182 patients: 12.4% locoregional lymph nodes, 16.8% testis, 70.8% distant metastases. Microsatellite instability status (MSI), tumor mutational burden (TMB) and Homologous Recombination Deficiency (HRDsig) were determined from the sequencing data. Genomic ancestry and Cosmic trinucleotide signatures were also identified. PD-L1 expression was determined by IHC using Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). Most cases had relapsed after surgery and chemotherapy, either loco-regionally or with metastatic disease at the time of CGP. Results: 182 men with CANSGCT had median age of 33. Genomic ancestry revealed that 65.4% of patients were European, 29.1% were admixed American, 3.3% were African, 1.6% were East Asian and 0.5% were South Asian. There was a median of 3 GA per sequenced tumor. At 2.2% frequency, MSI-high status was rare and TMB was relatively low with 95% of cases having TMB < 10 mut/Mb. A positive HRD signature was identified in 4.7% of cases. Identification of specific genomic signatures was uncommon with 2.7% having MMR signature and 1.1% having a tobacco exposure signature. PD-L1 expression was low level in 18.1% and high level in 15.3% of cases. KRAS mutations were the most frequent individual GA with <1% KRAS G12C. Inactivation of PTEN (6.6%) and activation of KIT (4.9%) were GA with potentially associated targeted therapies. Conclusions: CGP of CANSGCT cases revealed potential therapy targets with opportunities for clinical trials, e.g. focused on PTEN/MTOR pathway and KIT. Although initial clinical experience with targeted agents and anti-PD1/L1 have yielded limited benefit in unselected patients with these tumors, further CGP-based study of refractory NSGCT is warranted to enable the development of biomarker-driven clinical trials designed to rescue men who exhibit platinum refractory disease. Study limitations include the retrospective nature, lack of comparison with the genomic landscape of platinum-sensitive tumors, lack of clinical outcomes data annotation, selection and confounding biases.
oligonucleotides
2023-07-30 | Epigenetic Factors and ncRNAs in Testicular Cancer
Testicular cancer is the most prevalent tumor among males aged 15 to 35, resulting in a significant number of newly diagnosed cases and fatalities annually. Non-coding RNAs (ncRNAs) have emerged as key regulators in various cellular processes and pathologies, including testicular cancer. Their involvement in gene regulation, coding, decoding, and overall gene expression control suggests their potential as targets for alternative treatment approaches for this type of cancer. Furthermore, epigenetic modifications, such as histone modifications, DNA methylation, and the regulation by microRNA (miRNA), have been implicated in testicular tumor progression and treatment response. Epigenetics may also offer critical insights for prognostic evaluation and targeted therapies in patients with testicular germ cell tumors (TGCT). This comprehensive review aims to present the latest discoveries regarding the involvement of some proteins and ncRNAs, mainly miRNAs and lncRNA, in the epigenetic aspect of testicular cancer, emphasizing their relevance in pathogenesis and their potential, given the fact that their specific expression holds promise for prognostic evaluation and targeted therapies.
2023-04-18 | Silencing of LINC00467 inhibits cell proliferation in testicular germ cell tumors cells
A significant decrease in LINC00467 expression in testicular germ cell tumors (TGCTs) was found in our previous study in comparison to adjacent tissue. Interestingly, the expression of LINC00467 correlated with the pathological grade of the tumor in TGCT patients. The higher the expression of LINC00467 was, the worse the prognosis of the patients with TGCT was. Despite these findings, the exact role of LINC00467 in the development of TGCTs requires further investigation. LINC00467 expression was downregulated in the NCCIT and TCam-2 cell lines via small interfering RNA (siRNA) silencing. The levels of gene expression were validated using quantitative real-time polymerase chain reaction (qRT-PCR) analyses. Cell proliferation was evaluated by the MTT and Cell Counting Kit-8 (CCK8) assays, whereas flow cytometry was used to assess the effects on the cell cycle. Western blotting analysis was used to detect expression levels of protein. Additionally, RNA-sequencing and bioinformatics methods were used to investigate the mechanism of action of LINC00467 in TGCTs. The suppression of LINC00467 expression resulted in decreased cell proliferation and induced S-phase arrest. Furthermore, the suppression of LINC00467 downregulated proliferating cell nuclear antigen (PCNA), a protein related to cell cycle regulation, while it upregulated p21 expression. In other studies involving dihydrotestosterone (DHT) stimulation, it was observed that DHT could upregulate LINC00467 expression. In addition, silencing of the LINC00467 reversed the effect of testosterone on cell proliferation. The Gene Set Enrichment Analysis (GSEA) revealed that LINC00467 regulated the p53 pathway by modulating the expression of CCNG1. Our study found that LINC00467 regulates cell proliferation by inducing S-phase arrest through the cell cycle-related proteins PCNA and p21. These findings contribute to our understanding of non-coding RNAs mechanisms involved in the development of TGCTs.
2023-02-16 | Silencing of LINC00467 inhibits cell proliferation in testicular germ cell tumors cells Running Title: Silencing of LINC00467 regulates cell proliferation
Abstract Our previous study showed that LINC00467 expression decreased significantly in testicular germ cell tumors (TGCTs) compared with adjacent tissue. LINC00467 expression in TGCTs was upregulated at stages II/III compared with stage I, and was negatively correlated with the 5-year overall survival and 5-year disease-free survival. However, the role of LINC00467 in the development of TGCTs remains to be elucidated further. LINC00467 expression was silenced in the NCCIT and TCAM-2 cell lines using small interfering RNA (siRNA). The expression level of genes was validated using quantitative real-time polymerase chain reaction (qRT-PCR) analyses. The MTT and CCK8 assays were used to detect cell proliferation. The effects on cell cycle were evaluated using flow cytometry. Western blotting analysis was used to detect the expression level of proteins, while RNA-sequencing and bioinformatics methods were used to explore the mechanism of action of LINC00467 in TGCTs. The silencing of LINC00467 expression decreased cell proliferation, induced S phase arrest, and downregulated the cell cycle-related protein PCNA expression while upregulating the expression of P21. Dihydrotestosterone (DHT) stimulation experiments showed that DHT could upregulate the expression of LINC00467 and that the silencing of LINC00467 could reverse the effect of testosterone on cell proliferation. The Gene Set Enrichment Analysis (GSEA) showed that the P53 signaling pathway was associated with LINC00467. Our study reported that LINC00467 regulated cell proliferation and induced S phase arrest in TGCTs cells through the cell cycle-related proteins, PCNA, and P21. These enriched the mechanism of non-coding RNAs in the development of TGCTs.
2021-12-03 | Impact of circulating microRNA test (miRNA-371a-3p) on appropriateness of treatment and cost outcomes in patients with Stage I non-seminomatous germ cell tumours.
To determine whether utilisation of a serum microRNA (miRNA) test could improve treatment appropriateness and cost-effectiveness for patients with Stage I non-seminomatous germ cell tumours (NSGCTs). A decision tree model was built to investigate treatment course, clinical and cost outcomes for patients with Stage IA (T1N0M0S0) and IB (T2-4N0M0S0) NSGCT. The model compared outcomes and cost of standard approach using histopathology, conventional serum tumour markers and radiographic staging (standard model) to a miRNA-based approach using the standard model + post-orchidectomy serum miR-371a-3p (marker model). Probabilities of expected treatment and outcomes were based on presence/absence of cancer upon entering into the model. Overtreatment was defined as adjuvant chemotherapy or primary retroperitoneal lymph node dissection in a patient without cancer. Undertreatment was defined as initial surveillance for a patient with cancer. Utilising the miRNA marker-based approach, 26% of patients avoid overtreatment and 8% avoid undertreatment in Stage IA NSGCT; 27% avoid overtreatment and 23% avoid undertreatment in Stage IB disease. Appropriate treatment decision-making increased from 65% to 94% and 50% to 92% for Stage IA and IB, respectively. The miRNA-based approach remained cost-effective over a wide range of performance characteristics with savings of ~$1400 (American dollars)/patient for both Stage IA and IB disease. A miRNA-based approach may potentially select patients with Stage I NSGCT for correct treatment in a cost-effective manner. Identification of residual teratoma-only remains an issue. Prospective studies are necessary to validate these findings.
2021-04-01 | The combination of microRNA-371a-3p and 375-5p can distinguish viable germ cell tumor and teratoma from necrosis in postchemotherapy retroperitoneal lymph node dissection specimens
To identify a combination of microRNAs (miRNA) to differentiate between viable tumor (V) or teratoma (T) and necrosis/fibrosis (N) in pcRPLND specimens of metastatic germ cell tumor (GCT) patients with residual masses ≥1 cm after chemotherapy. Biomarker guided therapy could reduce overtreatment with pcRPLND in patients with only N.We selected 48 metastatic GCT patients who had undergone pcRPLND. V, pure T and N was shown in the resected tissue of 16 patients, respectively. Of these areas total RNA was isolated and miRNA expression was analyzed for miR-371a-3p, 375-3p, and 375-5p using qPCR. ROC analysis was performed for each miRNA and for all combinations in order to determine the discriminatory capacity of V and T vs. N.On comparing V vs. N miR-371a-3p achieved the highest fold change (FC) of 31.1 (P=0.023) while for T vs. N miR-375-5p performed best (FC 64.2; P<0.001). Likewise, the most accurate AUC for V was 0.75 using miR-371a-3p, for T 0.80 using miR-375-5p. Combining the best performing miRNAs for V and T resulted in an AUC of 0.94 with a sensitivity of 93.75, specificity of 93.75, PPV of 96.8 and NPV of 83.3.By combining miR-371a-3p and miR-375-5p in pcRPLND tissue samples V and T could be distinguished from necrosis/fibrosis with great accuracy. This combination of miRNAs might serve as new biomarker in the future, in order to spare miRNA-negative patients from pcRPLND. However, further studies analyzing patient's serum are needed to confirm the clinical impact of these biomarkers.
cell therapies
2025-06-01 | P-001 Fertility among testicular cancer survivors at a male infertility clinic
Abstract Study question Sperm quality is often already abnormal at diagnosis in testicular cancer subjects. We evaluated the fertility of testicular cancer survivors in our male infertility clinic. Summary answer Testicular cancer survivors even with azoospermia can make fatherhood through ICSI following precise evaluation and optimal sperm retrieval surgery. What is known already General improvements in the prognosis of patients with cancer have been achieved through recent advances in surgery, radiotherapy, and chemotherapy treatments, thus increasing the number of patients surviving therapy. However, anti-cancer treatment has detrimental effect on spermatogenesis and testicular cancer inevitably results in there being a single testicle following treatment, subsequent fertility will be a concern. Cryopreservation of ejaculated sperm before cancer treatment is considered to be essential, however it is rarely performed. In contrast, the use of cryopreserved ejaculated sperm for infertility treatment actually occurs in limited number of patients. Study design, size, duration From 2004 through 2023, 3361 male infertility patients consulted our clinic, 117 (3.5%) of whom had a history of cancer treatment. Thirty-nine patients diagnosed with testicular cancer were evaluated for cancer treatment, semen findings, and infertility treatment. Participants/materials, setting, methods The median age was 36 years, the duration from termination of cancer treatment was 5.5 years, and the duration of infertility was 3.0 years. Seminoma was observed in 29 participants, and non-seminomatous germ cell tumor was in 10 participants. Main results and the role of chance Twenty patients were treated with high orchidectomy alone. Whereas three patients were treated with orchidectomy followed by chemotherapy and sixteen participants underwent subsequent retroperitoneal lymph node dissection (RPLND). Semen analyses revealed azoospermia in 26 participants, whereas oligoasthenozoospermia in 13. Although none of the these oligoasthenozoospermic patients achieved spontaneous pregnancy, three achieved pregnancy and delivery through ICSI. Sperm retrieval surgery was attempted in 18 participants with azoospermia. 13 participants underwent microscopic testicular sperm extraction (micro-TESE), two participants received onco-TESE, two patients received microscopic sperm aspiration (MESA), and one patient received retrograde vasal sperm aspiration (ReVSA). Successful motile sperm recovery was observed in 15 participants. 8 deliveries were obtained through ICSI using surgically retrieved sperm. Limitations, reasons for caution Although patients with azoospermia were informed of the need for sperm retrieval surgery, several participants did not choose to undergo the operation. Wider implications of the findings Testicular cancer survivors, even those with azoospermia, can achieve fatherhood through ICSI, after precise evaluation and appropriate sperm retrieval surgery. Trial registration number No
2023-09-30 | T cells in testicular germ cell tumors: new evidence of fundamental contributions by rare subsets
ABSTRACT BACKGROUND Immune cell infiltration is heterogeneous but common in testicular germ cell tumors (TGCT) and pre-invasive germ cell neoplasia in situ (GCNIS). Tumor-infiltrating T cells including regulatory T (Treg) and follicular helper T (Tfh) cells are found in other cancer entities, but their contributions to TGCT are unknown. METHODS Human testis specimens from independent patient cohorts were analyzed using immunohistochemistry, flow cytometry and single-cell RNA sequencing (scRNA-seq) with special emphasis on delineating T cell subtypes. RESULTS Profound changes in immune cell composition within TGCT, shifting from macrophages in normal testes to T cells plus B and dendritic cells in TGCT, were documented. In most samples (96%), the CD4+ T cell frequency exceeded that of CD8+ cells, with decreasing numbers from central to peripheral tumor areas, and to tumor-free, contralateral testes. T cells including Treg and Tfh were most abundant in seminoma compared to mixed tumors and embryonal carcinoma. CONCLUSION Despite considerable heterogeneity between patients, T cell subtypes form a key part of the TGCT microenvironment. The novel finding of rare Treg and Tfh cells in human testis suggests their involvement in TGCT pathobiology, with implications for understanding tumor progression, to assess patients’ prognosis, and as putative targets for personalized immunotherapy.
2023-02-13 | Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors
Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.
2020-12-09 | FSH-R Human Early Male Genital Tract, Testicular Tumors and Sperm: Its Involvement in Testicular Disorders
The follicle-stimulating hormone receptor (FSH-R) expression was always considered human gonad-specific. The receptor has also been newly detected in extragonadal tissues. In this finding, we evaluated FSH-R expression in the human male early genital tract, in testicular tumors, and in sperm from healthy and varicocele patients. In sperm, we also studied the mechanism of FSH-R action. Immunohystochemistry and Western blot analysis showed FSH-R presence in the first pathways of the human genital tract, in embryonal carcinoma, and in sperm, but it was absent in seminoma and in lower varicocele. In sperm, FSH/FSH-R activity is mediated by G proteins activating the PKA pathway, as we observed by using the H89. It emerged that increasing FSH treatments induced motility, survival, capacitation, and acrosome reaction in both sperm samples. The different FSH-R expression in tumor testicular tissues may be discriminate by tumor histological type. In spermatozoa, FSH-R indicates a direct action of FSH in these cells, which could be beneficial during semen preparation for in vitro fertilization procedures. For instance, FSH positive effects could be relevant in idiopathic infertility and in the clinic surgery of varicocele. In conclusion, FSH-R expression may be considered a molecular marker of testicular disorders.
2018-10-05 | Lymphoma transformation of tumor infiltrating lymphocytes observed in testicular patient‑derived xenograft models
Testicular germ cell tumors (TGCTs) are highly sensitive to cisplatin‑based chemotherapy. Nevertheless, there are metastatic tumors that do not completely respond to front‑line chemotherapy. For these tumors, surgical resection of residual masses is necessary to achieve long‑term disease control. Resected tissues represent valuable clinical material, which may be used for the engraftment into immunocompromised mice to produce patient‑derived xenografts (PDXs). They typically maintain similarities to the parental tumors and therefore serve as more realistic preclinical models. Moreover, a correlation between PDX treatment outcomes and clinical response to chemotherapy has been previously described. The aim of the present study was to establish and characterize TGCT patient‑derived xenografts. These originated from retroperitoneal lymph node metastases infiltrated with TGCTs following previous cisplatin‑based chemotherapy, in order to analyze novel treatment options for cisplatin‑resistant testicular tumors. We generated two testicular patient‑derived xenograft models in SCID beige male mice. Immunohistochemical analyses demonstrated that histological characteristics of the primary tumor were not retained, and transformation into lymphoma, and eventually plasmocytoma, was observed. A potential explanation for the lymphoma transformation observed in PDXs may include tumor‑infiltrating lymphocytes (TILs) in xenografted samples of patients, which are transformed following engraftment into immunodeficient recipient mice. Based on these data, we indicated that lymphomagenesis prevention and terminal differentiation represent new challenges in the establishment of PDX models derived from patients with germ cell tumors.
antibodies
2024-01-19 | The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors
Testicular germ cell tumors (TGCTs) are cancers with very good prognosis, even in the metastatic setting, with high curative potential mainly attributed to the introduction of cisplatin-based chemotherapy. However, approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses. Therefore, there is an unmet need for novel therapeutic agents with improved efficacy and minimal long-term side effects. Recent advances in the development of immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have offered an opportunity to test their activity in various tumor types, including GCTs. This review aims to analyze the immune microenvironment of these tumors and present the most recently available data from studies that have tested immunotherapeutic agents against GCTs. The majority of the available knowledge derives from case reports or small cohort studies, particularly those involving ICIs of the PD-1/PD-L1 axis alone or in combination with anti-CTLA-4 monoclonal antibodies. Other immunotherapeutic targeted approaches, including antibody-drug conjugates, antibody prodrugs, vaccines, tyrosine kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapy, have biological rationales and have shown preliminary activity or are currently being tested. Growing evidence on these and other approaches will assist in broadening the currently limited treatment armamentarium against platinum-refractory TGCTs.
2023-10-06 | [A Case of Testicular Cancer with Solitary Iliac Bone Metastasis].
A 23-year-old male was aware of pain around his left hip joint and visited a nearby orthopedic clinic. Swelling of the right testis was pointed out, and a testicular tumor was suspected. He was referred to the urology department of a local hospital. Blood analysis showed an increase of α-fetoprotein (AFP) (3,620 ng/ml). Computed tomographic (CT) -scan revealed a left iliac bone metastasis and morbid fracture. Right radical inguinal orchiectomy was performed. The pathological examination revealed mixed germ cell tumor (embryonic carcinoma and immature teratoma: 70%, seminoma: 30%). The diagnosis was non-seminomatous germ cell tumor, stage IIIc, and poor risk on the International Germ Cell Consensus Classification. After one cycle of a bleomycin, etoposide and cisplatinum (BEP) regimen, he was referred to our hospital. After a total of 4 cycles of BEP, AFP was normalized. Denosumab was also administered monthly. The CT-scan showed a reduction of bone metastasis and recovery of ossification. Bone biopsy did not show viable tumor cells. Because extirpation of the remaining mass would require resection of the left part of the pelvic bone with significant functional loss of the left limb, we performed close follow-up after an additional 2 courses of the etoposide and cisplatin regimen. The patient is currently alive without recurrence at 45 months after the last systemic chemotherapy.
2023-08-14 | PRAME Is a Multifaceted Cancer Testis Antigen with Diverse Roles as a Biomarker and Therapeutic Target
Preferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen (CTA) that is selectively expressed in certain somatic tissues, predominantly in the testis and is overexpressed in various cancers. PRAME family proteins are leucine rich repeat proteins, that are localized in the nucleus and cytoplasm, with multifaceted roles in immunity, during gametogenesis and in the overall reproduction process. It is a widely studied CTA and has been associated with the prognosis and therapeutic outcome in patients with epithelial and non-epithelial tumors. PRAME has also been studied extensively as a therapeutic target. Moreover, it has been found to play a role in most of the well-known cancer hallmarks. Interestingly, the role of PRAME in tumorigenesis is paradoxical. Over the last decade, PRAME has garnered substantial interest as a target for immunotherapy. There are multiple clinical trials and pre-clinical studies targeting PRAME alone or in combination with other tumor antigens. This review article is an attempt to update our knowledge and understanding of the context-dependent oncogenic functions of PRAME in various carcinomas, and the current immunotherapeutic strategies, challenges, and perspectives on developing newer strategies to target PRAME for a better outcome.
2022-09-07 | Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo
Abstract Background Immunotherapy based on Bi-specific T Cell Engagers (TCE) represents one of the most attractive strategy to treat cancers resistant to conventional therapies. TCE are antibody-like proteins that simultaneously bind with one arm to a Tumor Associated Antigen (TAA) on cancer cells and with the other one to CD3 complex on a T-cell to form a TCR-independent immune synapse and circumvent Human Leucocyte Antigen restriction. Among them, the tribodies, such as Tb535H, a bi-specific molecule, made up of a Fab and a scFv domain both targeting 5T4 and another scFv targeting CD3, have demonstrated anti-tumor efficacy in preclinical studies. Methods Here, we generated five novel tri-specific and multi-functional tribodies, called 53X tribodies, composed of a 5T4 binding Fab arm and a CD3 binding scFv, but differently from the parental Tb535H, they contain an additional scFv derived from an antibody specific for an immune checkpoint, such as PD-1, PD-L1 or LAG-3. Results Compared with the parental Tb535H bi-specific T cell engager targeting 5T4, the novel 53X tribodies retained similar binding properties of Tb535H tribody, but showed enhanced anti-tumor potency due to the incorporation of the checkpoint inhibitory moiety. In particular, one of them, called 53L10, a tri-specific T cell engager targeting 5T4, CD3 and PD-L1, showed the most promising anti-tumor efficacy in vitro and led to complete tumor regression in vivo. Conclusions The novel tribodies have the potential to become strong and safe therapeutic drugs, allowing to reduce also the cost of production as one single molecule contains three different specificities including the anti-TAA, anti-CD3 and anti-IC binding arms.
2021-11-24 | Nivolumab for the salvage treatment of desperate germ cell tumor: A case report.
Testicular germ cell tumors (GCT) are the most common tumor in young men. Their distinctive feature is the exceptional response to platin based combination chemotherapy.Since the prognosis is poor in relapsed and refractory patients, the immune checkpoint inhibitors are candidate agents in these patients although clinical trials are mostly lacking. Herein, we describe a patient with a refractory nonseminomatous GCT using nivolumab as a last resort therapy and provided long term response without any significant toxicity. A 41-year-old male presented with the complaint of flank pain eleven years ago. The patient underwent a retroperitoneal lymph node excision and pathology reported as the mixed germ cell tumor. There were no mass in the testicles and the patient was diagnosed with a primary retroperitoneal GCT. Since the disease has progressed under multiple lines of chemotherapy and autologous stem cell transplantation, treatment was started with nivolumab. The patient started to treatment with nivolumab 3 mg/kg two weekly as a last resort treatment. The nivolumab was continued and the patient's response to this treatment is ongoing and has been stable for 13 months. There are limited treatment options in platinum-refractory germ cell tumors. Recently, immune checkpoint inhibitors tried in this setting with some success in especially non-seminomatous GCTs. We see a good response and prolonged benefit with the use of nivolumab in our patient. Further research including prospective studies on the use of immune checkpoint inhibitors in platinum-resistant testicular cancer can further delineate the role of immunotherapy.
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Drug Discovery Landscape
1 orphan drug designation for Non-seminomatous germ cell tumor of testis.
1 orphan drug designation for Non-seminomatous germ cell tumor of testis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Technetium Tc99m murine monoclonal antibody to hCG | antibodies | FDA | 1989-08-07 | — | Immunomedics, Inc. |
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