Germ Cell Tumors Research Articles

Driver mutations associated with signatures of platinum sensitivity in germ cell tumors

We sought to evaluate the genomic and transcriptomic landscapes in primary and metastatic germ cell tumors (GCTs; N = 138) to uncover factors that drive cisplatin resistance. Prevalence was calculated for platinum-resistant alterations (PRAs; KRAS, TP53, and KIT mutations, and MDM2 amplification) and high copy number amplifications (CNA ≥ 6 copies). Tumors were designated as chemo-naïve (PreC, N = 66) or post-chemotherapy (PostC, N = 17). A transcriptomic signature associated with platinum sensitivity (PSS, high suggests increased sensitivity) was applied. KIT mutations were observed in 14.5% of primary versus 1.8% of met and 0% of lymph. TP53 mutations were identified in 10% of primary GCTs versus 17% of met and 16.7% of lymph. MDM2 CNAs were similar between sites. PRA-positive PreC GCTs had significantly lower average PSS scores compared to PRA-negative tumors. Lower PSS scores in chemo-naïve tumors were associated with PRAs, suggesting a potential mechanism for platinum resistance.

Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B

Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with “epidrugs” is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.

Metastatic Mesothelioma of the Tunica Vaginalis Presenting as Scrotal and Abdominal Nodules: A Case Report and Review of the Literature.

Mesothelioma of the tunica vaginalis testis (MMTVT) is a rare neoplasm comprising <3% of all cases of malignant mesothelioma (MM). MMTVT derives from the tunica vaginalis testis, an outpouching of the mesothelial-lined abdominal peritoneum that detaches from the abdominal cavity after the descent of the testis. Similar to pleural mesothelioma, asbestos exposure is a known risk factor. However, MMTVT has a better prognosis than pleural mesothelioma. Cutaneous metastases from MMTVT are exceedingly rare. Herein, we describe a case of a 67-year-old man with a history of asbestos exposure presenting with scrotal pain and indurated plaques on his lower abdomen and scrotum. Histologic sections showed a sheet-like dermal proliferation comprising epithelioid cells with necrosis and increased mitotic activity. The clinical and histologic differential diagnosis was broad, including metastatic carcinoma, melanoma, sarcoma, germ cell tumor, hematologic malignancy, neuroendocrine carcinoma, and malignant mesothelioma. By immunohistochemistry, the neoplastic cells were positive for WT1, D2-40, and AE1/AE3, with rare positivity for calretinin, consistent with a diagnosis of mesothelioma. Additional immunohistochemical studies provided no support for the other diagnostic considerations listed above. BAP1 showed retained nuclear expression (normal) by immunohistochemistry. A DNA sequencing panel identified copy number losses in CDKN2A, MTAP, CDKN2B, and NF2, which are frequently identified genetic alterations in malignant mesothelioma. Subsequent testicular imaging demonstrated a diffusely thickened scrotal wall with an enlarged left testicle. Overall, this represents a case of malignant mesothelioma presenting with cutaneous metastases to the scrotum and lower abdomen, with clinical and imaging features suggestive of primary MMTVT. The International Mesothelioma Interest Group recommends using at least 2 mesothelial markers, such as calretinin, WT1, CK5/6 or D2-40, and 2 epithelial markers, such as claudin-4, CEA, MOC-31, as well as a broad-spectrum cytokeratin stain (AE1/AE3) as part of an initial immunohistochemical panel. Metastatic mesothelioma should be included in the differential diagnosis of malignant epithelioid dermal tumors with unusual staining patterns.

Bilateral Somatically Derived Germ Cell Tumors With 12p Gains Arising in High-grade Serous Carcinomas of the Ovary: A Case Report and Review of the Literature.

Epithelial ovarian neoplasms are commonly observed in older patients, while germ cell tumors (GCTs) typically present in young individuals. When GCTs are detected in patients over 35yrs old, they often have an associated epithelial component, a phenomenon known as somatically derived GCTs. We report a unique case of mixed GCT involving bilateral ovaries with a background of high-grade serous carcinoma, including a yolk sac tumor and choriocarcinoma in the mixed GCT component. Somatically derived GCTs are rare with only 45 cases of ovarian carcinoma with somatic yolk sac tumor reported to date. Pathologists face diagnostic challenges in identifying somatically derived GCTs, as they can mimic high-grade epithelial neoplasms. Somatically derived GCTs have poor outcomes, therefore, precise diagnosis is crucial for prognostic and therapeutic considerations.

A case report of intrapulmonary mature teratoma with aspergilloma

Introduction: Teratomas are benign germ cell tumors composed of components from the ectoderm, mesoderm, and endoderm. While germ cell tumors account for 10-20% of anterior mediastinal masses, intrapulmonary teratomas (IPTs) are extremely rare. They typically occur in the third decade of life and may present as metastasis from gonadal tumors. This study reports a rare case of a mature IPT in the right middle lobe of the lung, initially misdiagnosed as pulmonary tuberculosis and aspergilloma. Case Presentation: A 17-year-old female presented with a 4-year history of cough with sputum and two episodes of hemoptysis. Despite negative tuberculosis tests, she was treated with anti-tubercular drugs and multiple antibiotics. Imaging revealed a 5.5-cm cavitary mass in the right middle lobe containing an aspergilloma. Surgical resection was performed, and the pathology confirmed a mature teratoma with aspergilloma colonization. The patient recovered well postoperatively and showed no signs of recurrence. Discussion: Teratomas are germ cell tumors rarely found in the lungs, with fewer than 100 cases reported globally. Diagnosis is challenging due to overlapping symptoms with other conditions such as tuberculosis. In this case, the presence of an aspergilloma further complicated the diagnosis. Complete surgical resection led to the patient's recovery. Conclusion: Mature IPTs with aspergilloma are extremely rare, and should be considered in the differential diagnosis of cavitary lung lesions. Early diagnosis and surgical resection are crucial for successful treatment.

Pulmonary metastases revealing a mixed germ cell tumor with a predominant yolk sac tumor component: A case report

Yolk sac tumor of the testis is rare in adults. Its diagnosis is histological, reproducing an extra-embryonic structure (endodermal sinus tissue). It can be present alone or associated with another component, thus forming a mixed germ cell tumor. Treatment involves orchiectomy and chemotherapy in extratesticular stages. Lymph node dissection is indicated if residual masses persist. These tumors are characterized by a poor prognosis at an advanced metastatic stage. However, we report the clinical case of a 69-year-old man who presented with pulmonary metastases from a mixed germ cell tumor of the testis with a predominant Yolk Sac Tumor component, treated by orchiectomy, chemotherapy, and lymph node dissection.

Socioeconomic background and childhood cancer survival in Germany – A nationwide register study

Abstract Introduction Evidence is accumulating that not all children with cancer have benefitted equally from diagnostic and therapeutic improvements and that socioeconomic conditions are also associated with prognosis - even in high-income countries where equal access to healthcare is presumed. We investigated the association between area-based socioeconomic background and childhood cancer survival in Germany with the ultimate aim to identify groups of children that may benefit from supportive interventions. Methods We identified all children with a first cancer diagnosis before the age of 15 years in 1997-2016 from the German Childhood Cancer Registry (N = 35,443). Based on individual residential address information (at diagnosis) we applied the German Index of Socioeconomic Deprivation as measure of area-based socioeconomic background. Using Cox proportional hazards models, we assessed the association between absolute area-based socioeconomic deprivation (AASD) and ten-year overall survival (OS) to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Results The Cox analysis (adjusted for diagnostic year, birth year and place of residence) revealed a null association for AASD and OS from all cancers combined (HR = 1.00, 95% CI 0.97; 1.03). Among children diagnosed with acute myeloid leukemia and germ cell tumors, a higher AASD (implying more severe levels of deprivation) was associated with worse survival, particularly pronounced in boys (HR = 1.18, 95% CI 1.01; 1.37; HR = 1.67, 95% CI 1.13; 2.45, respectively). The opposite was observed for childhood CNS tumours, yielding worse survival by decreasing AASD (HR = 0.93, 95% CI 0.88; 0.98) for both malignant and non-malignant CNS tumours. Conclusions Contrary to reports from other European countries, we found little evidence for pronounced social inequalities in childhood cancer survival in Germany based on a composite score, with inconsistent patterns across cancer types and age at diagnosis. Key messages • We found little evidence for pronounced social inequalities in childhood cancer survival in Germany on the area-based level. • Our findings indicated inconsistent patterns of social inequalities across cancer types and age at diagnosis.and age at diagnosis.

A patient with heterochronous double primary tumor of basal ganglia germ cell tumors followed by diffuse hemispheric glioma: a case report.

Basal ganglia germ cell tumor (BGGCT) is a rare central nervous system (CNS) tumor. Diffuse hemispheric gliomas, H3 G34-mutant (DHGs) is an invasive glioma involving the cerebral hemispheres. The diagnosis of DHGs depends on the integration of histopathology and molecular pathology. We reported a patient with an initial diagnosis of BGGCT that was sensitive to subsequent chemoradiotherapy. Unfortunately, a second high-grade glioma was found on magnetic resonance imaging (MRI) six years later. Subsequently, the tumor was completely removed after surgery and the following histopathology plus next generation sequencing (NGS) testing confirmed the diagnosis of DHGs. Interestingly, we found a germline likely pathogenic variant in FANCA. After surgery, the patient received Stupp regimen. The patient had a relapse 13months after the Stupp regimen and was doing well after surgery. This is the first report of a patient with heterochronous double primary tumor of BGGCT followed by DHGs.

Genomic landscape of adult testicular germ cell tumours in the 100,000 Genomes Project

Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.

Comparative analysis of testicular and non-testicular choriocarcinoma: a population-based study

Background: Germ cell tumors (GCTs) are common solid tumors in young men, originating in the testicles or outside the gonads. Choriocarcinoma, a rare and aggressive subtype, primarily affects females but can also occur in males. Treatment options depend on the stage and location of the tumor, with early recognition being crucial for better outcomes. Comparative studies between testicular and non-testicular choriocarcinoma are crucial for understanding distinct features and prognoses. Methods: The study utilized SEER*Stat software to extract data and applied statistical methods such as chi-square analysis and Kaplan-Meier method. Inclusion criteria focused on patients diagnosed with choriocarcinoma between 2000 and 2018, while exclusion criteria eliminated cases without histological confirmation or with other tumors. Results: Among 363 patients, 270 (74.4%) had testicular CC, and 93 (25.6%) had non-testicular CC. Notably, testicular CC was more common in white patients, which could indicate demographic or environmental factors at play. Patients with testicular CC were more likely to undergo surgery, suggesting a significant treatment trend. It’s worth exploring whether patient preferences or observed post-surgery improvements contribute to this pattern. Testicular CC had a higher 5-year OS rate of 54% versus 29%, and a higher 5-year CSS rate of 56.3% versus 31.9%, respectively. Conclusion: This study reveals distinct characteristics and treatment responses in testicular and non-testicular choriocarcinoma, emphasizing the need for personalized management based on subtype. Our findings highlight racial disparities in incidence and the efficacy of surgical intervention for both types, while chemotherapy benefits extragonadal cases and radiotherapy’s role requires further evaluation.

Surgical Challenges and Outcomes in Management of Benign Retroperitoneal Germ Cell Tumors—A Tertiary Care Centre Experience

Surgical Challenges and Outcomes in Management of Benign Retroperitoneal Germ Cell Tumors—A Tertiary Care Centre Experience

Epithelioid trophoblastic tumor in male patients with germ cell tumor: A clinicopathologic analysis of five cases

Epithelioid trophoblastic tumor (ETT) is an extremely rare chorionic-type neoplasm in the testis, with only seven cases reported in the literature. Here, we report five cases of testicular ETT from a single institution, constituting the largest series of this rare tumor to date. The patients had a mean age of 44 years (range, 20–68 years). Four patients had a previous history of testicular germ cell tumor (GCT) treated with chemotherapy, and they developed ETT in metastatic sites in a mean of 11 years (range, 3–15 years) after the initial diagnosis of testicular GCT. Only one patient had ETT in the testis. Three patients had a normal serum beta–human chorionic gonadotropin (β-hCG) level, and two patients had a level that was slightly elevated, but far below that typically seen in patients with choriocarcinoma. ETT was characterized by a proliferation of intermediate trophoblastic cells with abundant eosinophilic cytoplasm, and the tumors frequently had coagulative necrosis with eosinophilic debris, mimicking keratinizing squamous cell carcinoma. The trophoblastic phenotype of ETT was supported by its immunoreactivity for trophoblastic markers, including GATA-3 (3 of 3 cases tested), α-inhibin (3/4), p63 (3/5), and β-hCG (3/4). ETT was also positive for cytokeratin (4/4) and GCT marker SALL4 (3/3). Despite surgery and chemotherapy, two patients died of disease 17 months after ETT diagnosis, and three patients were alive with metastatic disease at a mean of 20 months (range, 15–28 months). Our results demonstrate that ETT may be an aggressive disease associated with distinct pathologic features and poor clinical outcome.

Stage-dependent treatment of seminomas

Germ cell neoplasms of the testis are rare solid tumors predominantly in young men. Seminomas are slightly more frequent than nonseminomatous germ cell tumors. A special feature of seminomas is that they are sensitive to radiation, so that this represents an option in tumor stages with few metastases; however, the guideline recommendation is cautious due to the increased risk of secondary malignancies. In nonmetastasized tumor stages active surveillance is the primary approach to avoid overtreatment of patients. This is also the reason for primary nerve-sparing retroperitoneal lymph node dissection in cases of a low metastasis load. This concept has already been implemented in the American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN) guidelines, whereas in the European Association of Urology (EAU) guidelines it is still considered to be an individual approach.

Analysis of environmental factors affecting the incidence of testicular cancer, with particular emphasis on testicular germ cell tumors (TGCTs). Literature review

Introduction: Testicular cancer is the most common malignancy among men in the 20-44 age group. Most of the incidence is testicular germ cell tumor. In recent years there has been a steady increase in the incidence of this cancer. For this reason, we analyzed available articles on environmental risk factors that may influence the incidence of increased testicular malignancies Material and methods: Review of the specialized literature in the field of urology and articles available on PubMed, searching by the keywords “testicular cancer,” “testicular cancer risk factors,” “germ cell tumor,” “tgct‘’Aim of the study: The purpose of the study is to review the available literature and research papers regarding risk factors for malignant tumors of the testis. Summary: In recent years, there has been an increase in the incidence of testicular cancer, especially among men aged 20-44 years. The vast majority of it is germ cell tumors (TGCT). This article discusses the influence of environmental factors on the development of testicular cancer, with particular emphasis on the induction of TGCT. Studies indicate an association between exposure to trichloroethylene and other solvents and the risk of TGCT induction. The role of exposure to pesticides (especially fungicides), organic chlorine compounds, and viruses was also indicated to increase the risk of developing TGCTs,. The association of neoplasia with marijuana and tobacco use has also been studied, but needs further research. There is a need for continued research regarding heavy metals, infertility and factors related to pregnancy and the perinatal period. It is necessary to know the mechanisms that induce the process of carcinogenesis in the testis, which will enable the use of prevention and prophylaxis.

New tumor markers for testicular cancer - in the here and now and in the future

Germ cell tumors of the testis are the most common tumor entities in young men. Since the introduction of platinum-based chemotherapy in the 1970s, most patients can be cured despite the aggressiveness of germ cell tumors. Optimal serum tumor markers are required for diagnostics, therapy monitoring and aftercare, and these are subject to high requirements. The conventional testicular tumor markers human chorionic gonadotropin (hCG), alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) only meet these requirements with insufficient sensitivity (30-70%). The markers investigated in recent decades, such as PLAP, CEA and NSE, have not become established. Currently, miRNA-371 is being researched in particular. Reliable findings are available for initial staging with significantly better specificities of miRNA-371 compared to conventional tumor markers. Further prospective studies are being conducted for other possible clinical applications, such as follow-up care, therapy monitoring or residual tumors, in order to investigate the revolutionary potential of miRNA-371 in these areas as well. Research is also currently being conducted on circulating tumor cells (CTCs) and cell-free DNA (cfNA) in various areas of application. With regard to germ cell tumors of the testis, however, these analyses are still in their infancy, but it is hoped that this will provide a further sufficient opportunity to use serum tumor markers.

Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

Diagnostic incidence and pitfalls of rete testis hyperplasia and hyaline globules in a multi-institutional study of 348 testicular germ cell tumors.

The concept of rete hyperplasia with hyaline globules simulating testicular yolk sac tumor was first reported in a mostly retrospective review over 30 years ago. Nonetheless, we continue to encounter examples where this scenario resulted in misdiagnosis. Herein, we sought to investigate the incidence of rete hyperplasia/hyaline globules in germ cell tumors and their associated subtypes and hypothesize an etiology. A consecutive series of 348 germ cell tumor orchiectomies was evaluated for the presence of rete hyperplasia and hyaline globules, with clinicopathologic features recorded. The incidence of rete hyperplasia and/or hyaline globules in our cohort was 30%, with 56% of specimens with rete hyperplasia containing concomitant hyaline globules. Hyaline globules were more often identified in specimens with nonfocal rete hyperplasia (78%) vs focal rete hyperplasia (22%). Absence of a yolk sac tumor component was seen in over half (61%) of orchiectomies with concurrent rete hyperplasia/hyaline globules (n = 105), inclusive of tumors with "pure" subtypes (ie, pure seminoma, pure teratoma, or pure embryonal carcinoma). Of these 105 specimens, rete invasion was seen in only 48%; notably, Paneth cell-like metaplasia was identified in efferent ductules/epididymis in 13%. Rete hyperplasia and hyaline globules are not uncommon findings in the setting of germ cell tumors (including occurrences in various pure/mixed germ cell tumors) and can show striking overlap with yolk sac tumor. We hypothesize that these histologic pitfalls evolve secondary to testicular obstruction by the tumor mass. Recognition of and distinguishing this morphologic mimicry is fundamental to guide appropriate clinical management.

Feasibility of transcranial Doppler to evaluate vasculopathy among survivors of childhood brain tumors exposed to cranial radiation therapy.

The ability of transcranial Doppler (TCD) to detect asymptomatic cerebrovascular disease among childhood brain tumor survivors following exposure to cranial radiation therapy has not been established. Survivors of childhood brain tumors, more than 3years since diagnosis and exposed to greater than 30Gy cranial radiation, underwent a history and physical exam, laboratory biomarkers of cerebrovascular disease (cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), high-sensitivity CRP, hemoglobin A1C, apoprotein A, and apoprotein B), and a TCD evaluation of their cerebral arteries. In all 165 cerebral arteries from 13 patients (medulloblastoma=10; germ cell tumor=3; females=5; mean age at diagnosis=8.0years; mean age at time of study=20.9years) were examined. Twenty-eight of 165 (17%) were considered abnormal by pre-specified criteria. Total 114 cerebral arteries from 13 patients were assessed for greater than 50% stenosis velocities. Arteries most likely to be considered abnormal included the distal bilateral vertebral arteries (right 38%, left 30%), basilar artery 30%, bilateral siphon internal carotid arteries (right 30%, left 23%), bilateral middle cerebral arteries (23% bilaterally), and bilateral anterior cerebral arteries (7% bilaterally). Two vessels had mean flow velocities consistent with 50% stenosis (1.8%). No vessels were found to have greater than 80% stenosis. TCD may be a useful and practical tool to examine asymptomatic cerebrovascular disease among childhood brain tumor survivors after exposure to cranial radiation therapy. Posterior circulation vessels appear to have the highest burden of disease in this group of brain tumor survivors, a majority of whom had medulloblastoma.

Surgical Approach and Recurrence Risk in Struma Ovarii: A Retrospective and Systematic Analysis.

Struma ovarii (SO) represents a rare subset of ovarian germ cell tumors, with approximately 5% transforming into malignant SO (MSO). This study retrospectively analyzed clinical data from 23 SO patients treated at the Cancer Hospital of the Chinese Academy of Medical Sciences between January 2013 and December 2023, including 17 benign SO (BSO) and 6 MSO cases. Additionally, a systematic review of 164 cases of MSO confined to the ovary, reported in the literature from 1946 to 2024, was conducted. Data on pathological type, treatment, and prognosis were extracted, and univariate and multivariate Cox regression analyses were performed to identify risk factors for recurrence in stage I MSO. The median age at diagnosis was higher for BSO compared to MSO (58 vs. 42.5 years), with 70.6% of patients being postmenopausal. BSO commonly presented with abdominal distension or mass, with more than half having ascites, while MSO patients were asymptomatic and lacked ascites. Cox regression analyses revealed that ovarian cystectomy was adversely associated with recurrence risk in stage I MSO, likely due to surgically induced capsular rent and potential tumor spillage. Significantly lower recurrence risks were observed in patients who underwent unilateral or bilateral salpingo-oophorectomy (HR = 0.36, P = 0.019; HR = 0.19, P = 0.004, respectively). This study highlights the importance of the surgical approach in the management of stage I MSO. A thorough preoperative discussion of the benefits and risks of different surgical approaches is recommended for patients desiring fertility preservation. Postoperative adjuvant therapy has not been shown to have a significant impact on prognosis. For the treatment of recurrent MSO, selecting appropriate surgical and adjuvant therapeutic strategies is essential to improve the long-term prognosis of MSO patients.

Refractory testicular germ cell tumors are highly sensitive to the targeting of polycomb pathway demethylases KDM6A and KDM6B.

Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with "epidrugs" is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4 , lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.