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Frontiers in Oncology 2023Testicular cancer is a common malignancy of young males and is believed to be originated from defective embryonic or adult germ cells. Liver kinase B1 (LKB1) is a...
Testicular cancer is a common malignancy of young males and is believed to be originated from defective embryonic or adult germ cells. Liver kinase B1 (LKB1) is a serine/threonine kinase and a tumor suppressor gene. LKB1 is a negative regulator of the mammalian target of rapamycin (mTOR) pathway, often inactivated in many human cancer types. In this study, we investigated the involvement of LKB1 in the pathogenesis of testicular germ cell cancer. We performed immunodetection of LKB1 protein in human seminoma samples. A 3D culture model of human seminoma was developed from TCam-2 cells, and two mTOR inhibitors were tested for their efficacy against these cancer cells. Western blot and mTOR protein arrays were used to show that these inhibitors specifically target the mTOR pathway. Examination of LKB1 showed reduced expression in germ cell neoplasia lesions and seminoma compared to adjacent normal-appearing seminiferous tubules where the expression of this protein was present in the majority of germ cell types. We developed a 3D culture model of seminoma using TCam-2 cells, which also showed reduced levels of LKB1 protein. Treatment of TCam-2 cells in 3D with two well-known mTOR inhibitors resulted in reduced proliferation and survival of TCam-2 cells. Overall, our results support that downregulation or loss of LKB1 marks the early stages of the pathogenesis of seminoma, and the suppression of downstream signaling to LKB1 might be an effective therapeutic strategy against this cancer type.
PubMed: 36969070
DOI: 10.3389/fonc.2023.1081110 -
Medicina (Kaunas, Lithuania) Mar 2024The incidence of testicular cancer (TC) has been rapidly increasing over the past years. Diagnosis and early treatment have shown good oncological control, guaranteeing... (Review)
Review
The incidence of testicular cancer (TC) has been rapidly increasing over the past years. Diagnosis and early treatment have shown good oncological control, guaranteeing the patient different treatment approaches according to histology and tumor stage. Currently, physicians usually prioritize oncological outcomes over sexual outcomes and quality of life, considering as a first aim the overall survival of the patients; however, differently from other neoplasms, quality of life is still strongly affected among TC patients, and sexual outcomes are frequently compromised after each TC treatment. Several studies have suggested that each treatment approach may be associated with sexual dysfunctions, including erectile dysfunction, ejaculatory disorders, fertility issues, and hormonal changes. Since testicular cancer patients are more frequently young men, the subject of this work is substantial and should be analyzed in detail to help specialists in the management of this disease. The aim of the current narrative review is to generally describe every treatment for TC, including surgery, chemotherapy, radiotherapy, and retroperitoneal lymph node dissection, and to establish which sexual dysfunction may be specifically associated with each therapy.
Topics: Humans; Testicular Neoplasms; Male; Sexual Dysfunction, Physiological; Quality of Life; Sexuality; Erectile Dysfunction
PubMed: 38674232
DOI: 10.3390/medicina60040586 -
Cancers Dec 2021Seminoma (SE) is the most frequent type of testicular tumour, affecting predominantly young men. Early detection and diagnosis of SE could significantly improve life...
Seminoma (SE) is the most frequent type of testicular tumour, affecting predominantly young men. Early detection and diagnosis of SE could significantly improve life quality and reproductive health after diagnosis and treatment. Copy number variation (CNV) has already been associated with various cancers as well as SE. In this study, we selected four genes (, , , and ) for CNV analysis in genomic DNA (gDNA), which are located on chromosomes susceptible to gains, and whose aberrant expression was already detected in SE. Furthermore, CNV was analysed in cell-free DNA (cfDNA) from seminal plasma. Analysis was performed by droplet digital polymerase chain reaction (ddPCR) on gDNA from SE and nonmalignant testicular tissue. Seminal plasma cfDNA from SE patients before and after surgery was analysed, as well as from healthy volunteers. The CNV hotspot in gDNA from SE tissue was detected for the first time in all analysed genes, and for two genes, and it was reflected in cfDNA from seminal plasma. Although clinical value is yet to be determined, presented data emphasize a potential use of CNV as a potential SE biomarker from a liquid biopsy.
PubMed: 35008352
DOI: 10.3390/cancers14010189 -
Urologia Internationalis 2021We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult... (Review)
Review
Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of...
OBJECTIVES
We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects.
MATERIALS AND METHODS
An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements.
RESULTS
Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy.
CONCLUSION
Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
Topics: Adult; Aftercare; Humans; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Germ Cell and Embryonal; Palliative Care; Practice Guidelines as Topic; Quality of Life; Sex Cord-Gonadal Stromal Tumors; Testicular Neoplasms
PubMed: 33486494
DOI: 10.1159/000511245 -
Cancers Aug 2020Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients... (Review)
Review
Available systemic treatment options for cancers of the genitourinary system have experienced great progress in the last decade. However, a large proportion of patients eventually develop resistance to treatment, resulting in disease progression and shorter overall survival. Biomarkers indicating the increasing resistance to cancer therapies are yet to enter clinical routine. Long non-coding RNAs (lncRNA) are non-protein coding RNA transcripts longer than 200 nucleotides that exert multiple types of regulatory functions of all known cellular processes. Increasing evidence supports the role of lncRNAs in cancer development and progression. Additionally, their involvement in the development of drug resistance across various cancer entities, including genitourinary malignancies, are starting to be discovered. Consequently, lncRNAs have been suggested as factors in novel therapeutic strategies to overcome drug resistance in cancer. In this review, the existing evidences on lncRNAs and their involvement in mechanisms of drug resistance in cancers of the genitourinary system, including renal cell carcinoma, bladder cancer, prostate cancer, and testicular cancer, will be highlighted and discussed to facilitate and encourage further research in this field. We summarize a significant number of lncRNAs with proposed pathways in drug resistance and available reported studies.
PubMed: 32756406
DOI: 10.3390/cancers12082148 -
European Urology Open Science Jun 2022We have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the...
BACKGROUND
We have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the recommended intensity of surveillance has decreased; however, the impact on relapse detection has not been investigated.
OBJECTIVE
To examine relapse rate, time to relapse, extent of disease, and burden of treatment at relapse across decreasing surveillance intensity over time.
DESIGN SETTING AND PARTICIPANTS
CSI GCT patients under active surveillance from 1981 to 2021 were included in this study.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Through four major iterations in both nonseminomatous (NSGCT) and seminoma surveillance schedules, visit frequency, blood testing, and imaging have been decreased successively. Low-dose, noncontrast computed tomography (CT) scans were adopted in 2011. Categorical variables and time to relapse were compared using chi-square and Fisher's exact or Kruskal-Wallis test, respectively.
RESULTS AND LIMITATIONS
A total of 1583 consecutive patients (942 with seminoma and 641 with NSGCT) were included. In seminoma, chest x-rays were reduced from 13 to one and CT scans were reduced from 20 to ten. Relapse rate, time to relapse, N or M category, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification did not change. In NSGCT, chest x-rays were reduced from 27 to zero and CT scans were reduced from 11 to five. Relapse rate (from 46.2% to 21.2%, = 0.002) and the median time to relapse (from 6.54 to 4.47 mo, = 0.025) decreased. No difference in relapsed disease burden was identified by N, M, and S category or IGCCCG classification. Treatment burden at relapse and GCT cancer deaths remained similar for seminoma and NSGCT. Limitations include the retrospective design and large time period covered.
CONCLUSIONS
Despite considerable reductions in surveillance intensity, we did not observe an increase in disease extent, treatment burden, or GCT cancer deaths upon relapse. These results support that our current lower-intensity active surveillance schedules are safe for managing CSI GCT.
PATIENT SUMMARY
Our current reduced-intensity surveillance schedules for clinical stage I germ cell tumors appear to be safe.
PubMed: 35638085
DOI: 10.1016/j.euros.2022.03.010 -
Archivio Italiano Di Urologia,... Sep 2023Introdubction: Stage I seminoma has a very good prognosis, yet approximately 15% have subclinical metastatic disease and will relapse after orchidectomy alone. Several...
UNLABELLED
Introdubction: Stage I seminoma has a very good prognosis, yet approximately 15% have subclinical metastatic disease and will relapse after orchidectomy alone. Several management approaches have been investigated. We aimed to evaluate the clinical outcomes of real-world patients with stage I seminoma, analysing prognostic factors influencing treatment choice and oncological outcomes.
METHODS
Retrospective, single institution study, with 55 patients diagnosed with clinical stage I seminoma between 2007 and 2020. Selected patients were analysed regarding three management approaches - surveillance, adjuvant radiotherapy and adjuvant carboplatin AUC7. Overall survival and progression-free survival outcomes were analysed. Predictors of treatment choice were determined, and predictors of recurrence were analysed in patients on active surveillance.
RESULTS
The median follow-up time was 91 months (13-165). Overall survival at 10 years was 98.2%. Stage I seminoma patients had a 1-, 3- and 10-year progression free survival of 98%, 94% and 89%, respectively. Three-year progression free survival was 92.0% for those on active surveillance (IC95%, 91.5-92.5%), 95.2% for carboplatin (IC95%, 94.8-95.6%) and 100% for those on adjuvant radiotherapy (p > 0.05). All relapses on active surveillance protocols occurred during the first 24 months. Overall, 43% of patients who underwent adjuvant treatment reported adverse effects of therapy, with higher incidence on radiotherapy group (63%).
CONCLUSIONS
Stage I seminoma have excellent prognosis, high cure rates, and low treatment-associated morbidity. Active surveillance is a safe modality when applied to selected patients. Adjuvant radiotherapy and adjuvant chemotherapy with carboplatin show similar results, with fewer adverse effects on chemotherapy arm.
PubMed: 37668558
DOI: 10.4081/aiua.2023.11513 -
Frontiers in Radiology 2023The aim of this systematic review was to evaluate the state of the art of radiomics in testicular imaging by assessing the quality of radiomic workflow using the... (Review)
Review
The aim of this systematic review was to evaluate the state of the art of radiomics in testicular imaging by assessing the quality of radiomic workflow using the Radiomics Quality Score (RQS) and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). A systematic literature search was performed to find potentially relevant articles on the applications of radiomics in testicular imaging, and 6 final articles were extracted. The mean RQS was 11,33 ± 3,88 resulting in a percentage of 31,48% ± 10,78%. Regarding QUADAS-2 criteria, no relevant biases were found in the included papers in the patient selection, index test, reference standard criteria and flow-and-timing domain. In conclusion, despite the publication of promising studies, radiomic research on testicular imaging is in its very beginning and still hindered by methodological limitations, and the potential applications of radiomics for this field are still largely unexplored.
PubMed: 37492385
DOI: 10.3389/fradi.2023.1141499 -
Cancer Treatment Reviews Aug 2020Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40 years. TCs are highly aneuploid and the 12p isochromosome is the most frequent... (Review)
Review
Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40 years. TCs are highly aneuploid and the 12p isochromosome is the most frequent chromosomal abnormality. The mutation rate is of TC is low, with recurrent mutations in KIT and KRAS observed only at low frequency in seminomas. Overall cure rates are high, even in a metastatic setting, resulting from excellent cisplatin sensitivity of TCs. Factors contributing to the observed cisplatin sensitivity include defective DNA damage repair and a hypersensitive apoptotic response to DNA damage. Nonetheless, around 10-20% of TC patients with metastatic disease cannot be cured by cisplatin-based chemotherapy. Resistance mechanisms include downregulation of OCT4 and failure to induce PUMA and NOXA, elevated levels of MDM2, and hyperactivity of the PI3K/AKT/mTOR pathway. Several pre-clinical approaches have proven successful in overcoming cisplatin resistance, including specific targeting of PARP, MDM2 or AKT/mTOR combined with cisplatin. Finally, patient-derived xenograft models hold potential for mechanistic studies and pre-clinical validation of novel therapeutic strategies in TC. While clinical trials investigating targeted drugs have been disappointing, pre-clinical successes with chemotherapy and targeted drug combinations fuel the need for further investigation in clinical setting.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Resistance, Neoplasm; Humans; Male; Molecular Targeted Therapy; Neoplasms, Germ Cell and Embryonal; Randomized Controlled Trials as Topic; Testicular Neoplasms
PubMed: 32593915
DOI: 10.1016/j.ctrv.2020.102054 -
Pathology, Research and Practice Feb 2023Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT), and it is included in the pT stage. However, its detection on...
BACKGROUND
Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT), and it is included in the pT stage. However, its detection on hematoxylin and eosin (H&E) slides is very challenging, and previous studies reported fair to moderate inter-observer agreement among dedicated uropathologists. In the present study, we tested H&E and a recently developed in-house double staining for OCT4/CD34 to detect LVI in GCTT.
METHODS
Nine authors [5 non-uropathologists and 4 uropathologists] independently evaluated 34 consecutive and retrospectively enrolled cases of GCTT. We assessed the inter-observer agreement (Fleiss's Kappa) with both H&E and OCT4/CD34. Besides, we compared the consensus diagnosis on both H&E and OCT4/CD34-stained sections with the original diagnosis to evaluate the pT re-staging (McNemar test) and identify the sources of disagreement.
RESULTS
The inter-observer agreement among uropathologists plus non-uropathologists was fair with both H&E (KF=0.398; p < 0.001) and OCT4/CD34 (KF=0.312; p < 0.001). OCT4/CD34 (KF=0.290; p < 0.001) slightly reduces the inter-observer agreement compared to H&E (KF=0.321; p < 0.001) for non-uropathologists; in contrast, OCT4/CD34 (KF=0.293; p < 0.001) significantly reduces the inter-observer agreement compared to H&E (KF=0.529; p < 0.001) for uropathologists, changing it from moderate to fair. Consensus diagnosis with H&E modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.070), with pT re-staging in 2/34 (5.9 %) cases (p: 0.500). Consensus diagnosis with OCT4/CD34 modified the LVI status of the original diagnosis in 8/34 (23.5 %) cases (p: 0.289), with pT re-staging in 3/34 (8.8 %) cases (p: 0.250). The consensus diagnosis with OCT4/CD34 modified the consensus diagnosis with H&E in 8/34 (23.5 %) cases (p: 0.727), and these findings resulted in pT-restaging in 3/34 (8.8 %) cases (p: 0.500). The sources of disagreement among uropathologists were: H&E [artefactual clefts misinterpreted as LVI in 4/6 (66.7 %) cases and true foci of LVI misinterpreted as clusters of histiocytes within the vessels in 2/6 (33.3 %) cases], OCT4/CD34 [artefactual clefts misinterpreted as LVI in 2/8 (25 %) cases, true LVI misinterpreted as artefactual clefts in 2/8 (25 %) cases or floaters in 4/8 (50 %) cases].
CONCLUSIONS
OCT4/CD34 does not improve the inter-observer agreement for the assessment of LVI in OCT4(+) GCTT. Consensus diagnosis with H&E modifies the LVI status in a significant number of cases, resulting in changes of the pT stage in a relatively small subgroup. Consensus diagnosis with OCT4/CD34 provides little additional benefit since it cannot exclude mimickers of LVI such as floaters and artefactual clefts. These results argue against the adoption of this diagnostic tool for the routine assessment of OCT4(+) GCTT.
Topics: Male; Humans; Eosine Yellowish-(YS); Hematoxylin; Carcinoma, Embryonal; Seminoma; Retrospective Studies; Testicular Neoplasms; Neoplastic Processes; Neoplasm Invasiveness; Prognosis
PubMed: 36706585
DOI: 10.1016/j.prp.2023.154337