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Acta Biochimica Et Biophysica Sinica May 2022Testicular seminoma is a relatively rare tumor which is mostly detected in male population aged from 15 to 35 years old. Although several molecular biomarkers have...
Testicular seminoma is a relatively rare tumor which is mostly detected in male population aged from 15 to 35 years old. Although several molecular biomarkers have been identified to be associated with testicular seminoma pathogenesis, the exact mechanism for testicular seminoma progression remains largely unknown. CDKN2A interacting protein (CDKN2AIP) has previously been identified as a tumor suppressor in multiple malignant diseases. In this study, we aimed to further explore its role in testicular seminoma as well as the underlying molecular mechanisms. Retrospective testicular seminoma clinical samples, normal tissues, NTERA-2 cell line, and mouse xenograft models were used in this study. RT-qPCR, western blot analysis, immunofluorescence microscopy, Co-IP and IP-MS experiments were performed to detect the expression of CDKN2AIP and its interaction with CARM1 and eIF4β. SA-β-gal staining assay and H3K9me3 activity experiments were used to subsequently evaluate the cell senescence and apoptosis. Mouse xenograft animal model was used for study. The results showed that CDKN2AIP is highly expressed in normal testis samples, and is significantly suppressed in testicular seminoma clinical samples and cell line model. Up-regulation of CDKN2AIP is significantly associated with the inhibition of testicular seminoma tumor growth and the increase of cell senescence and apoptosis. CDKN2AIP exhibits anti-tumor activity by interacting with CARM1 and eIF4β. CDKN2AIP induces testicular seminoma cell senescence by suppressing CARM1 expression and eIF4β phosphorylation. The CDKN2AIP-CARM1 and CDKN2AIP-eIF4β interactions, which induce tumor cell senescence and apoptosis, may be the potential druggable molecular pathways in testicular seminoma tumor pathogenesis and progression.
Topics: Animals; Humans; Male; Mice; Apoptosis; Apoptosis Regulatory Proteins; Cellular Senescence; Retrospective Studies; RNA-Binding Proteins; Seminoma; Testicular Neoplasms
PubMed: 35593475
DOI: 10.3724/abbs.2022040 -
Scientific Reports Sep 2023Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and...
Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and their implications for histopathological parameters and prognosis in TGCT using a data-driven explorative approach. Pre-surgery serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) and prolactin were measured in a retrospective multicenter TGCT cohort (n = 518). Clusters of patients were defined by latent class analysis. Clinical, pathologic and survival parameters were compared between the clusters by statistical hypothesis testing, Random Forest modeling and Peto-Peto test. Cancer tissue expression of sex hormone-related genes was explored in the publicly available TCGA cohort (n = 149). We included 354 patients with pure seminoma and 164 patients with non-seminomatous germ cell tumors (NSGCT), with a median age of 36 years. Three hormonal clusters were defined: 'neutral' (n = 228) with normal sex hormone homeostasis, 'testicle' (n = 91) with elevated T and E2, low pituitary hormones, and finally 'pituitary' subset (n = 103) with increased FSH and LH paralleled by low-to-normal levels of the gonadal hormones. Relapse-free survival in the hormonal subsets was comparable (p = 0.64). Cancer tissue expression of luteinizing hormone- and follicle-stimulating hormone-coding genes was significantly higher in seminomas, while genes of T and E2 biosynthesis enzymes were strongly upregulated in NSGCT. Substantial percentages of TGCT patients are at increased risk of sex hormone dysfunction at primary diagnosis before orchiectomy. TGCT may directly influence systemic hormonal homeostasis by in-situ synthesis of sex hormones.
Topics: Humans; Male; Adult; Neoplasm Recurrence, Local; Testicular Neoplasms; Gonadal Steroid Hormones; Neoplasms, Germ Cell and Embryonal; Luteinizing Hormone; Seminoma; Follicle Stimulating Hormone, Human
PubMed: 37669975
DOI: 10.1038/s41598-023-41915-7 -
3 Biotech Mar 2023Seminoma is the most common type of testicular germ cell tumors (TGCTs) among 15-44 years old men. Seminoma treatments include orchiectomy, platinum-based chemotherapy...
UNLABELLED
Seminoma is the most common type of testicular germ cell tumors (TGCTs) among 15-44 years old men. Seminoma treatments include orchiectomy, platinum-based chemotherapy and radiotherapy. These radical treatment methods cause up to 40 severe adverse long-term side effects including secondary cancers. Immunotherapy based on immune checkpoint inhibitors, which showed its efficiency for many types of cancer, can be important alternative to the platinum-based therapy for seminoma patients. However, five independent clinical trials evaluating the efficiency of immune checkpoint inhibitors for TGCTs treatment were shut down at the phase II due to lacking clinical efficacy and detailed mechanisms of this phenomena are yet to be discovered. Recently we identified two distinct seminoma subtypes based on transcriptomic data and here we focused on the analysis of seminoma microenvironment and its subtype-specific characteristics. Our analysis revealed that less differentiated subtype 1 of seminoma has immune microenvironment with significantly lower immune score and larger fraction of neutrophils. Both are features of the immune microenvironment at an early developmental stage. On the contrary, subtype 2 seminoma is characterized by the higher immune score and overexpression of 21 genes related to senescence-associated secretory phenotype. Seminoma single cell transcriptomic data showed that 9 out of 21 genes are predominantly expressed in immune cells. Therefore, we hypothesized that senescence of immune microenvironment can be one of the reasons for seminoma immunotherapy failure.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-023-03530-1.
PubMed: 36875959
DOI: 10.1007/s13205-023-03530-1 -
BMC Cancer Sep 2023Two thirds of patients with germ-cell cancer (GCC) present as clinical stage I (CSI). Following orchiectomy, active surveillance (AS) has become their standard...
BACKGROUND
Two thirds of patients with germ-cell cancer (GCC) present as clinical stage I (CSI). Following orchiectomy, active surveillance (AS) has become their standard management. However, 15-50% of patients eventually relapse with metastatic disease after AS. Relapses need to be detected early in order to achieve cure and avoid overtreatment.
METHODS
We retrospectively analyzed consecutive GCC patients treated at two Swiss academic centers between 2010 and 2020. Patients with stage IS and extragonadal primaries were excluded. We compared disease characteristics and survival outcomes of patients relapsed from initial CSI to patients with de novo metastatic disease. Primary endpoint was the IGCCCG category at the time of relapse. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS).
RESULTS
We identified 360 GCC patients with initial CSI and 245 de novo metastatic patients. After a median follow-up of 47 months, 81 of 360 (22.5%) CSI patients relapsed: 41 seminoma (Sem) and 40 non-seminoma (NSem) patients. All Sems relapsed in the IGCCCG good prognosis group. NSem relapsed with good 29/40 (72.5%) and intermediate 11/40 (27.5%) prognostic features; 95.1% of relapses occurred within five years post-orchiectomy. Only 3 relapsed NSem patients died from metastatic disease. Five-year OS for relapsed CSI patients was 100% for Sem and 87% (95% CI: 61-96%) for NSem patients; five-year PFS was 92% (95% CI: 77-97) and 78% (95% CI: 56-90) for Sem and NSem, respectively. When stratified by IGCCCG prognostic groups, good risk relapsed patients had a trend towards better OS and PFS as compared to de novo metastatic patients.
CONCLUSIONS
GCC patients who relapse after initial CSI can be detected early by active surveillance and have an excellent survival.
Topics: Humans; Male; Testicular Neoplasms; Retrospective Studies; Seminoma; Ethnicity; Neoplasms, Germ Cell and Embryonal; Neoplasms, Second Primary
PubMed: 37715132
DOI: 10.1186/s12885-023-11388-y -
World Journal of Urology Dec 2022The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options.
PURPOSE
The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options.
METHODS
A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed.
RESULTS
Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities.
CONCLUSIONS
RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.
Topics: Male; Humans; Seminoma; Retrospective Studies; Prospective Studies; Neoplasm Staging; Neoplasm Recurrence, Local; Testicular Neoplasms; Neoplasms, Second Primary
PubMed: 34779882
DOI: 10.1007/s00345-021-03873-5 -
Neurology Mar 2022There is an increasing body of evidence describing an association between anti-Kelch-like protein 11 (KLHL11) encephalitis and various tumors such as seminoma. However,...
There is an increasing body of evidence describing an association between anti-Kelch-like protein 11 (KLHL11) encephalitis and various tumors such as seminoma. However, when the diagnosis of neoplasia is uncertain and the clinical syndrome resembles those caused by other etiologies, the possibility of anti-KLHL11 encephalitis may not be obvious during early clinical evaluations. We present the case of a 68-year-old man with clinical features of anti-KLHL11 encephalitis, in whom no clear signs of an active neoplasia could be found. However, a burnt-out germ cell tumor was suspected. This case highlights the importance of having a high clinical suspicion for anti-KLHL11 encephalitis in patients who exhibit symptoms and signs, even in the absence of an active tumor.
Topics: Aged; Autoantibodies; Clinical Reasoning; Humans; Male; Neoplasms, Germ Cell and Embryonal; Seminoma; Testicular Neoplasms
PubMed: 35121670
DOI: 10.1212/WNL.0000000000200019 -
Translational Andrology and Urology Oct 2021Management of testicular germ cell tumor (GCT) patients is based on clinical determinants, mainly CT scan and serum tumor markers (alpha-fetoprotein, beta subunit of HCG... (Review)
Review
Management of testicular germ cell tumor (GCT) patients is based on clinical determinants, mainly CT scan and serum tumor markers (alpha-fetoprotein, beta subunit of HCG and LDH). Treatment decisions are usually straightforward for patients with clear evidence of metastatic disease, confirmed either by imaging tests or by unequivocal elevated tumor markers. However, there are several clinical scenarios where the assessment of metastatic disease is complicated by the limited specificity of the current imaging tests and serum tumor markers. These include patients with clinical stage IIA GCT with negative tumor markers and patients with post-chemotherapy residual disease where, in absence of clear indicators of GCT, decision making and patient treatment allocation become challenging. Therefore, more accurate biomarkers are critical to reduce the risk of under-or over-treatment and to always deliver the most optimal therapy. The objectives of this narrative review are to review the available publications about micro-RNAs in GCT s and their potential clinical applications. Two clusters of micro-RNAs, miR-371a-3p and miR-302/367, specifically expressed by both seminoma and non-seminoma GCT and easily detectable in the peripheral blood, have demonstrated to be promising in this endeavor. Large prospective trials are ongoing to define the operating characteristics of these biomarkers and their clinical utility to improve GCT patient management and reduce the error rate deriving from clinical uncertainty, therefore reducing the risk of sub-optimal treatments.
PubMed: 34804849
DOI: 10.21037/tau-20-1246 -
Annals of Oncology : Official Journal... Apr 2022
Topics: Follow-Up Studies; Humans; Male; Neoplasm Staging; Orchiectomy; Seminoma; Testicular Neoplasms
PubMed: 35065204
DOI: 10.1016/j.annonc.2022.01.002 -
JCO Global Oncology Jan 2021Since the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification in a 1997 study, high-income countries have reported a...
PURPOSE
Since the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification in a 1997 study, high-income countries have reported a significant increase in survival for poor prognosis patients. There are scant data on IGCCCG risk-stratified survival from low- and middle-income countries. We assessed the progression-free survival (PFS) and overall survival (OS) rates in a contemporary cohort of Belarusian patients with advanced germ cell cancer (GCC) stratified by the IGCCCG prognostic classification and analyzed prognostic factors for survival.
MATERIALS AND METHODS
The consecutive cohort of patients with clinical stage IIb-III testicular GCC or extragonadal germ cell tumors who received treatment or consultation in our two centers between 2010 and 2015 was included. All patients underwent primary chemotherapy. The patients were divided into seminoma and nonseminomatous germ cell carcinoma (NSGCC) subgroups. The Kaplan-Meier method was used to estimate 5-year PFS and OS.
RESULTS
This study included 111 patients with a median age of 32 years, 95% of whom were diagnosed with testicular cancer. Seminoma and NSGCC were identified in 32 (29%) and 79 (71%) patients, respectively. The median follow-up was 6.1 years. The 5-year PFS and OS rates for the entire cohort were 70% and 77%, respectively. In patients with good prognosis seminoma and good, intermediate, and poor prognosis NSGCC, the estimated PFS rates were 76%, 88%, 74%, and 39% and those for OS were 83%, 97%, 83%, and 38%, respectively.
CONCLUSION
In our cohort of Belarusian patients with advanced germ cell tumors, we failed to demonstrate an improvement in PFS and OS compared with the 1997 IGCCCG study. Moreover, survival in poor prognosis group is inferior to that in IGCCCG and all contemporary series from high-income countries.
Topics: Adult; Humans; Male; Neoplasms, Germ Cell and Embryonal; Prognosis; Republic of Belarus; Seminoma; Testicular Neoplasms
PubMed: 33434070
DOI: 10.1200/GO.20.00473 -
World Journal of Urology Feb 2022Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor...
PURPOSE
Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS.
METHODS
Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher's exact and Chi-square test.
RESULTS
Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death.
CONCLUSION
Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Etoposide; Humans; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Germ Cell and Embryonal; Orchiectomy; Seminoma; Testicular Neoplasms
PubMed: 34854948
DOI: 10.1007/s00345-021-03889-x