Germ Cell Tumors Research Articles

Efficacy and Safety of Three Cycles of TIP and Sequential High Dose Chemotherapy in Patients with Testicular Non-Seminomatous Germ Cell Tumors

Background: Salvage treatment options have not been validated in relapsed or refractory germ cell tumors. Moreover, the study populations including these patients have different heterogeneities. This study aimed to evaluate the efficacy and safety of three cycles of TIP sequential high-dose chemotherapy in patients with testicular non-seminomatous germ cell tumors who relapsed or had a refractory course after first-line platinum-based chemotherapy. Methods: Data of 141 patients who underwent three cycles of TIP followed by HDCT due to relapsed/refractory gonadal NSGCTs after first-line cisplatin-based chemotherapy (BEP/EP) at Gulhane School of Medicine Hospital Medical Oncology Department between January 2017 and May 2024 were evaluated retrospectively. Patients underwent a treatment regimen consisting of two phases. Initially, they received three cycles of induction therapy using a combination known as TIP, which includes paclitaxel, ifosfomide, and cisplatin. Following this, they were given a single cycle of high-dose chemotherapy. Demographic and clinicopathological features of patients and treatment-related complications and survival outcomes were recorded. Results: Median follow-up for all patients was 35.2 (95% CI, 29.45 to 41.07) months. Complete Response (CR) or marker negative Partial Response (PR) after HDCT was achieved in 84 (59.6%) patients. Median time for PFS not reached (NR) (95% CI, NR) in the entire group. The 2-year PFS rate was 51.8%. Median time for OS not reached (95% CI, NR) and the 2-year OS rate was 72.3%. The most common myelotoxicity observed after HDCT until engraftment was grade 4 neutropenia (100%) and grade 4 thrombocytopenia (96.5%). Transplantation-related mortality occurred in 7.1% of patients. Variables that remained statistically significant in multivariable analysis and were associated with poor prognosis for overall survival were platinum refractory disease and AFP and/or beta HCG elevation. Conclusions: Significant survival can be achieved after three cycles of TIP consecutive HDCT, while treatment-related mortality was found to be low.

Bilateral ovarian mature cystic teratoma with unilateral malignant transformation to adenocarcinoma: A case report.

Mature cystic teratoma (MCT) is the most common germ cell tumor of the ovary, comprising 20% of all ovarian neoplasms. Malignant transformation (MT) is an uncommon complication and occurs in approximately 1-3% of all MCTs. The most common histological type of MT is squamous cell carcinoma. Other rare transformations include - carcinoid tumors, melanoma, adenocarcinoma, and sarcoma. We present one such rare case of bilateral MCT with unilateral MT into mucinous adenocarcinoma of intestinal type.

Differential expression of metabolic enzymes in testicular germ cell tumors: The impact of glycolytic metabolism in embryonal carcinoma histotype.

Testicular germ cell tumors are the most common solid malignancies in young men, with increasing incidence worldwide. Broadly classified into seminomas and non-seminomas, they exhibit distinct biological behaviors and responses to treatment. Although metabolic reprogramming is an acknowledged cancer hallmark, metabolic pathways in testicular germ cell tumors remain poorly understood. This study investigates the differential expression of metabolic markers (GLUT-1, MCT1, MCT4, LDHA, HIF-1α) and the epigenetic enzyme KDM3A across various testicular germ cell tumor subtypes, aiming to understand how glycolytic metabolism is related to each histotype and how it may impact tumor aggressiveness, correlating with patient outcomes. The study involved 111 testicular germ cell tumor individual tumor components from 90 patients diagnosed and treated at a comprehensive cancer center. Immunohistochemistry was used to ascertain biomarker expression, with a combined score of percentage of stained tumor cells and intensity of staining. In silico analysis of the Cancer Genome Atlas database was performed for additional validation, using cBioPortal. Statistical analyses included Mann-Whitney U, Kruskal-Wallis, and anova tests, with significance set at p<0.05. Significant differences in the expression of metabolic markers across testicular germ cell tumor subtypes were disclosed. Embryonal carcinomas showed significantly higher expression of glycolytic markers (GLUT-1, MCT1, MCT4, LDHA) compared to other histotypes, suggesting heightened glycolytic activity. KDM3A depicted an inverse pattern, being significantly more expressed in seminomas. HIF-1α expression was generally low across all histological subtypes. Testicular germ cell tumors with necrosis showed higher expression of the metabolic players investigated. We highlighted distinct metabolic profiles among testicular germ cell tumor subtypes, particularly the prominent glycolytic activity in embryonal carcinomas, with higher hypoxia and reliance on lactate transport. Metabolic reprogramming in embryonal carcinoma may underlie the high proliferation of this tumor subtype, which frequently discloses necrosis. These findings suggest that targeted agents such as MCT1 inhibitors may be particularly useful for treating testicular germ cell tumors containing high proportion of embryonal carcinoma.

Non-Invasive miRNA Profiling for Differential Diagnosis and Prognostic Stratification of Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCT) are common in young adult men and have high cure rates. Conventional serum tumor markers and imaging are not able to differentiate between histologic subtypes of the disease, which portend different prognoses and require distinct therapeutic strategies. Micro-RNAs (miRNAs) are small non-coding transcripts involved in the post-transcriptional regulation of gene expression, which have emerged as promising biomarkers in a variety of tumors. This study aimed to assess the potential of differentially expressed miRNAs in differential diagnosis and prognostication among TGCT patients with various histologic subtypes. Transcriptomic analysis of 134 patients from The Cancer Genome Atlas (TCGA)-TGCT database was conducted. miRNA differential expression analysis among seminomatous, embryonal carcinoma, mixed GCT, and teratoma was performed, followed by ROC curve analysis of the most significantly up- and downregulated miRNAs, respectively. Statistical associations of miRNA expression with AJCC stage were also investigated along with miRNA target network analysis and evaluation of miRNA detection in patients' fluids. Upregulation of seven miRNAs (hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-200a, hsa-mir-200b, hsa-mir-203b, hsa-mir-375, hsa-mir-582) and downregulation of seven additional miRNAs (hsa-mir-105-1, hsa-mir-105-2, hsa-mir-4433a, hsa-mir-548x, hsa-mir-5708, hsa-mir-6715a, hsa-mir-767) were identified. miRNAs displayed a high sensitivity/specificity of 0.94/1.0 (AUC = 0.98) for the upregulated and 0.97/0.94 (AUC = 0.96) for the downregulated signature. Deregulated expression of these miRNAs was significantly associated with AJCC stage and distant organ metastasis (p < 0.001), overall supporting their prognostic strength. Both signatures were detectable in body fluids, particularly urine. miRNA target network analysis supported the functional role of these miRNAs in the regulation of cancer-related processes such as cell proliferation via deregulation of pivotal oncogenes. These findings support the clinical value of two novel miRNA signatures in differential diagnosis and prognostic stratification of various histologic subtypes of TGCT, with potential treatment implications.

Dysgerminoma of the Ovary: A Case Report and Review of the Literature

Introduction: Germ cell tumors account for 15-20% of ovarian tumors, with most being benign. Dysgerminomas, a rare malignant subtype, primarily affect young women and represent less than 5% of malignant ovarian tumors. These tumors are often diagnosed at stage I (70-80%) and exhibit high chemosensitivity, resulting in excellent outcomes with timely treatment. Material and Methods: A 28-year-old woman presented with chronic pelvic pain. Imaging and tumor marker analysis revealed a right ovarian mass. Laparotomy identified a 22 cm solidocystic tumor. Histopathology confirmed dysgerminoma, and management included right adnexectomy and peritoneal biopsies. Discussion: Dysgerminomas differ from adenocarcinomas with early onset, high chemosensitivity, and favorable prognosis. Imaging and tumor markers are vital for diagnosis and monitoring. Conservative surgery, combined with BEP chemotherapy, ensures excellent outcomes while preserving fertility and hormonal function. Conclusion: Dysgerminomas, though rare, are highly curable with early diagnosis and treatment. Conservative surgery and chemotherapy are critical for achieving favorable results and preserving fertility in young patients.

Yolk Sac Tumor of the Lung with Elements of Mixed Germ Cell Tumor in Pediatrics: Case presentation and literature review

Introduction: Germ cell tumors in childhood occur at a rate of 2 to 3 cases per million inhabitants, representing

Surgical management of testicular cancer with limited retroperitoneal disease.

Chemotherapy offers excellent long-term survival rates for men with clinical stage II germ cell tumours. However, in this predominantly younger population, chemotherapy is associated with long-term adverse effects. Primary retroperitoneal lymph node dissection (RPLND) may serve as an alternative treatment option, preserving oncological safety while potentially reducing adverse effects in men with limited retroperitoneal disease. The rate of negative surgical specimens (pN0) in primary RPLND series varies between 4% and 16% in seminoma and 12-29% in nonseminoma, respectively. This suggests that early restaging, novel biomarkers, and/or percutaneous biopsies should be considered to minimize overtreatment. In stage II seminoma, three prospective RPLND series with follow-up periods ranging from 22 to 51 months report recurrence rates between 6% and 30%. In contrast, only retrospective data are available for stage II nonseminoma, with follow-up periods and recurrence rates yet to be fully defined. Following primary RPLND with confirmed viable cancer, adjuvant chemotherapy reduces recurrence risk. In cases of recurrence after primary RPLND, first-line chemotherapy remains a highly effective salvage option. Ongoing research is needed to identify risk factors for contralateral retroperitoneal disease to refine surgical templates and to determine predictors of recurrence, allowing for more personalized decisions regarding the use of adjuvant chemotherapy and follow-up strategies. Men with clinical stage II germ cell tumours may benefit from RPLND due to its lower risk of long-term side effects. Chemotherapy is an effective salvage treatment if needed. Although RPLND is a safe and promising option, further studies are required to better understand relapse risks and to tailor treatment plans based on individual patient factors.

Mitochondrial genome variability and metabolic alterations reveal new biomarkers of resistance in testicular germ cell tumors.

Aim: Mutations in the mitochondrial (mt) genome contribute to metabolic dysfunction and their accumulation relates to disease progression and resistance development in cancer cells. This study explores the mutational status of the mt genome of cisplatin-resistant vs. -sensitive testicular germ cell tumor (TGCT) cells and explores its association with their respiration parameters, expression of respiratory genes, and preferences for metabolic pathways to reveal new markers of therapy resistance in TGCTs. Methods: Using Illumina sequencing with Twist Enrichment Panel, the mutations of mt genomes of sensitive 2102EP, H12.1, NTERA-2, T-cam and resistant 2102EP Cis, H12.1 ODM, 1411HP, 1777NRpmet, NTERA-2 Cis and T-cam Cis cell lines were identified. The mt respiration of the cells was assessed using high-resolution respirometry method (O2k-respirometer Oroboros) and the differential expression profiles of mt respiratory genes were determined using RT-qPCR. Associated preferences for metabolic pathways were compared using Glycolysis/OXPHOS assay. Results: In resistant TGCT cells, new mutations in mt genes MT-ND1-6, MT-RNR, MT-CO1-3, MT-ATP6, and MT-CYB were recognized. The respiratory rates of the 1777NRpmet cell line were the highest, while those of the 1411HP line the lowest; rates of the control and all other TGCT cell lines fell between these two lines. The statistically significant differences in gene expression of the respiratory genes were recorded only in NTERA-2 Cis and T-cam Cis cell lines. Sensitive cell lines NTERA-2 and 2102EP preferred oxidative phosphorylation (OXPHOS), while glycolysis was typical for resistant NTERA-2 Cis, 2102EP Cis and 1411HP cell lines. Metastatic 1777NRpmet cells seem to utilize both. An isogenic pair of cell lines H12.1 and H12.1ODM showed the opposite dependence, sensitive H12.1 preferring glycolysis, while resistant H12.1ODM OXPHOS. Conclusion: In summary, our study identified new mutations in mt genes of resistant TGCT cell lines that are associated with different mt respiration parameters, gene expression patterns and preferences for metabolic pathways, providing potential novel molecular biomarkers that distinguish the resistant TGCT phenotype or specify its histological classification.

Cancer Stage Geospatial Analysis to Optimize Educational Activities in Pediatric Oncology and Hematology: A Retrospective Cohort Study.

Enhancing therapy outcomes in pediatric oncology and hematology relies on robust epidemiological surveillance. This study aimed to estimate cancer stage-related survival in pediatric patients with lymphoma and solid tumors by assessing changes over time and identifying spatial clustering of patients diagnosed at advanced stages. This retrospective observational cohort study included pediatric cancer patients treated in a single Greater Poland center, constituting 9% of Polish children from 2004 to 2017. The incidence, cancer stage, and patient coordinates were analyzed. The follow-up period ranged from 5 to 18years. Survival differences across tumor stages were evaluated using Kaplan‒Meier curves, log-rank tests, and trend analysis. Geographical analysis was performed with Kulldorff's scan statistics and the Bernoulli model. Among 1094 diagnosed patients, 511 with lymphoma and solid tumors were eligible. There was a decreasing trend in advanced-stage diagnoses (p = 0.0001), with a nearly twofold increase in low-stage diagnoses (OR = 1.98 [1.22; 3.24], p = 0.0061) from 2009-2011 to 2015-2017. Hazard ratios for neuroblastoma and sarcoma patients were more than fourfold greater, while survival differences were not significant for patients with nephroblastoma, germ cell tumors, or lymphoma. This study shows cancer stage-related survival dynamics. A substantial decrease in advanced-stage diagnoses over time emphasizes improved early detection. Geographical analysis pinpointed clusters with prevalent late-stage diagnoses, offering a practical tool for targeted educational interventions. The study underscores the pivotal impact of cancer stage on survival outcomes, emphasizing the need for ongoing surveillance and tailored interventions to further optimize pediatric oncology and hematology care.

MicroRNAs in seminal plasma are able to discern infertile men at increased risk of developing testicular cancer.

Male infertility is a risk factor for the development of testicular germ cell tumors. In this study, we investigated microRNA profiles in seminal plasma to identify potential noninvasive biomarkers able to discriminate the men at highest risk of developing cancer among the infertile population. We compared the microRNA profiles of individuals affected by testicular germ cell tumors and healthy individuals with normal or impaired spermiograms using high-throughput technology and confirmed the results by single-assay digital PCR. We found that miR-221-3p and miR-222-3p were downregulated and miR-126-3p was upregulated in cancer patients compared to both infertile and fertile men. ROC curve analysis confirmed that miR-126 upregulation is able to identify cancer patients among the infertile male population. In addition, in-depth bioinformatics analysis based on weighted gene co-expression networks showed that the identified miRNAs regulate cellular pathways involved in cancer.

Successful Treatment Outcome of a Pediatric Malignant Germ Cell Tumor With an Extensive Cavo-atrial Tumor Thrombus Presenting as an Oncological Emergency

Background: Pediatric germ cell tumor (GCT) with extensive cavo-atrial tumor thrombus presenting as an oncologic emergency is extremely rare. Observation: A 13-month-old female child with sacrococcygeal GCT having inferior vena cava (IVC) and right atrial thrombus presenting with anasarca and respiratory distress is reported. Because of worsening symptoms post initiation of chemotherapy, tumor thrombus debulking from the right atrium and distal end of IVC was performed on day 9 on an emergency basis. Her symptoms improved, and after planned chemotherapy, tumor excision with coccygectomy could be done. The IVC thrombus remained inoperable due to sclerosis. She remains recurrent-free now 12 months post therapy.

PLAP expression is linked to invasive tumor growth in urothelial carcinoma of the bladder.

Placental alkaline phosphatase (PLAP) is a protein with a poorly understood function that is normally only expressed in the placenta. In cancer, PLAP expression is a hallmark of germ cell neoplasms, but it can also occur in urothelial carcinoma. To evaluate the potential clinical significance of PLAP expression in bladder cancer, METHODS: PLAP protein was analyzed by immunohistochemistry in more than 2500 urothelial bladder carcinomas in a tissue microarray format. PLAP staining was absent in normal urothelial cells but was observed in 15.9% of urothelial carcinomas, including 282 (11.5%) with weak, 57 (2.3%) with moderate, and 51 (2.1%) with strong staining. PLAP positivity occurred in 4.1% of 413 pTa G2 low-grade, 10.2% of 176 pTa G2 high-grade, and 7.2% of 97 pTa G3 tumors (p = 0.0636). As compared to pTa tumors, the PLAP positivity rate was markedly higher in 1341 pT2-4 carcinomas (19.8%, p < 0.0001). Within pT2-4 carcinomas, PLAP staining was unrelated to pT, pN, grade, L-status, V-status, overall survival, recurrence-free survival, and cancer-specific survival (p > 0.25). However, PLAP positivity was linked to p16 positivity (p = 0.0185), GATA3 positivity (p < 0.0001), and p63 expression loss (p = 0.0456). In summary, these data show that PLAP is expressed in a significant fraction of pT2-4 urothelial carcinomas, unrelated to cancer aggressiveness but associated with specific molecular features. Once anti-PLAP cancer drugs become effective, urothelial carcinoma is a candidate tumor entity for clinical evaluation.

The Role of Pulmonary Metastasectomy for Non‐Primary Lung Cancer: Umbrella Review of Meta‐Analyses

ABSTRACTBackground and ObjectivesDue to heterogeneous characteristics of primary cancers, the efficacy of pulmonary metastasectomy (PM) in nonprimary lung cancers has not been investigated. This study aims to investigate the clinical outcomes of PM for non‐primary lung cancer.MethodsA systematic search for meta‐analyses on PM for nonprimary lung cancers was conducted, encompassing publications up to January 3, 2024. This included seven primary cancers: renal cell, breast, adrenocortical, head and neck cancers, melanoma, germ cell tumors, and sarcoma. Overall survival and recurrence rates post‐PM were assessed using random‐effect models.ResultsThis study included 16 systematic‐review articles and 101 individual studies, involving 10 277 patients who underwent PM for nonprimary lung cancer. About half of the patients (47.1%) presented with multiple metastasis, and complete resection achieved in 87.2% [95% CI: 83.0–90.8]. The pooled 5‐year overall survival rate post‐PM was 41.2% [95%CI: 37.1%–45.4%]. Patients with germ cell tumors demonstrated higher survival rate (p &lt; 0.05), while melanoma exhibited the worst outcome (p &lt; 0.05). During follow‐up, 57.6% [95% CI: 46.4–68.1] had recurrence; 48% of them had intrathoracic‐only recurrence.ConclusionThis study underscores the survival benefits associated with PM. Overall survival rates following PM did not differ based on primary cancer types. These findings highlight the importance of recognizing and incorporating PM into clinical practice when appropriate.

Mature midline teratoma arising within a posterior thoracic myelomeningocele in an infant: A case report

Myelomeningocele can occur throughout the spinal axis but the area with the least common localization is the thoracic region which is uncommon. Rarely, these abnormalities coexist with a teratoma and only few reports of a teratoma arising from a myelomeningocele have been reported. Teratoma can also undergo malignant transformation to a non-germ cell malignancy. Here, we report an interesting case of a teratoma arising within thoracic myelomeningocele in an infant. A three month old girl born via vaginal delivery to two related Fulani parents presenting with upper back swelling noticed since birth. Pregnancy was claimed to be uneventful, mother never attended any antenatal clinic and delivery was at home. On examination patient was mildly dehydrated and malnourished. Status localis revealed an intact cystic midline upper back swelling measuring about 6x4cm, non-tender with no differential warmth. Radiographic evaluation was not done due to financial constraint. Grossly, three irregularly shaped firm to cystic to flabby tissues aggregating to 5x4x1.5cm, weighing 6g were received and microscopy revealed histologic features of a myelomeningocele with a teratoma having endodermal (respiratory epithelium, seromucinous glands) , ectodermal( skin) and mesodermal (cartilage) components.Teratoma is a germ cell neoplasm that contains differentiated elements derived from all three germ layers. The occurrence of a mature midline teratoma within a myelomeningocele is rare and what makes it even rarer is occurrence in the thoracic region. This can be confirmed by meticulous histopathologic evaluation.Myelomeningocele has variable prognosis based on localization and other accompanying abnormalities. Due to the risk of malignant transformation to non-germ cell tumours in teratoma, prompt histologic diagnosis and complete resection is important regardless of size of lesion and age of patient.

Primary retroperitoneal lymph node dissection in clinical stage 2a/b non-seminomatous germ cell tumour.

To reassess the role of primary retroperitoneal lymph node dissection (RPLND) in patients with marker-negative non-seminomatous germ cell tumour (NSGCT) clinical stage (CS) 2a, to explore results in patients with CS 2b and to evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for CS 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and disease-free survival (DFS). A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.01-1.07; P = 0.03), but no association was observed with DFS. The 5-year DFS rates in marker negative CS 2a and 2b were 79% and 76%. In men with non-teratomatous viable cancer in the RPLND specimen, the 5-year DFS rates for CS 2a and 2b were 95% and 87% with adjuvant chemotherapy, and 67% and 74% without adjuvant chemotherapy. We did not identify an association between the number of adjuvant chemotherapy cycles and DFS. Our study suggests considering primary RPLND not only in marker-negative CS 2a but also in CS 2b. Further research should determine the efficacy of primary RPLND in men with CS 2c and marker-positive CS 2, as well as which patients may benefit from adjuvant chemotherapy and the optimal cycle number.

Role of Neoadjuvant Immunotherapy in Genitourinary Malignancies.

Genitourinary (GU) malignancies are common and associated with significant morbidity and mortality. In patients with localized GU cancers, surgical resection or definitive radiation remain the mainstays of treatment. Despite definitive treatment, many patients with high-risk localized disease experience recurrence. There is growing interest in using neoadjuvant immunotherapy to improve outcomes. This narrative review summarizes the current evidence for neoadjuvant immunotherapy in patients with localized high-risk GU cancers including renal cell carcinoma, urothelial carcinoma, prostate cancer, penile squamous cell carcinoma, and testicular germ cell tumors. We also discuss ongoing clinical trials and candidate biomarkers to optimize patient selection and improve treatment outcomes.

A Signal-On Microelectrode Electrochemical Aptamer Sensor Based on AuNPs-MXene for Alpha-Fetoprotein Determination.

As a crucial biomarker for the early warning and prognosis of liver cancer diseases, elevated levels of alpha-fetoprotein (AFP) are associated with hepatocellular carcinoma and germ cell tumors. Herein, we present a novel signal-on electrochemical aptamer sensor, utilizing AuNPs-MXene composite materials, for sensitive AFP quantitation. The AuNPs-MXene composite was synthesized through a simple one-step method and modified on portable microelectrodes. As signal molecules, AFP aptamers were conjugated with methylene blue (MB) and immobilized on the electrode surface. When interacting with AFP, conformational changes in the aptamer-target complex caused MB to approach the electrode, and the electrochemical signal was enhanced through signal-on mechanisms. The developed sensor demonstrated high sensitivity and selectivity for AFP, with a log-linear relationship defined as 1-300 ng/mL, and the LOD was 0.05 ng/mL (S/N = 3). The method was applied to laboratorial and real clinical samples and presented satisfactory selectivity, reproducibility, and long-term stability. The proposed high-performance sensor highlights the potential of electrochemical aptamer sensors in improving the warning capabilities in disease management.

Testicular Mass in Children: A Case Report

Testicular sarcomas constitute only 1–2% of all testicular tumors and are mostly associated with germ cell tumors. Primary intratesticular localization is very rare and must be differentiated from paratesticular locations. Accurate diagnosis and early treatment are essential as it is an aggressive tumor with high metastatic potential and poor prognosis. The optimal treatment is based on radical inguinal orchidectomy and chemotherapy.

Otoprotective Effects of Sodium Thiosulfate by Demographic and Clinical Characteristics: A Report From Children's Oncology Group Study ACCL0431.

ACCL0431 was a randomized clinical trial that demonstrated efficacy of sodium thiosulfate (STS) for preventing cisplatin-induced hearing loss (CIHL) among patients 1-18years old. The purpose of this study was to evaluate possible differential STS otoprotection among patient subgroups. This secondary analysis included ACCL0431 participants treated with cisplatin and randomized to receive STS or not (observation). Hearing status was obtained at 4weeks and 12months post cisplatin therapy (SIOP Ototoxicity Scale). Cumulative incidence of CIHL (Grade 1+) was assessed across age, sex, race/ethnicity, cancer diagnosis, and cisplatin infusion duration. Associations between these variables and CIHL were assessed using multivariable logistic regression. Interaction terms were used to evaluate potential heterogeneity in STS effect sizes across subgroups. Among evaluable participants (n = 121), CIHL incidence was 22.4% with STS and 54.0% with observation. Odds of developing CIHL were greatest among children less than 5years versus older (randomization-adjusted odds ratio [OR] 2.94, 95% CI: 1.30-7.14) and those with neuroblastoma, hepatoblastoma, or medulloblastoma versus germ cell tumor or osteosarcoma (age- and randomization-adjusted OR 11.26, 95% CI: 3.08-47.35). STS otoprotective effect sizes were also greatest in the same highest risk groups by age (<5years: OR 0.08, 95% CI: 0.02-0.32; ≥5years: OR 0.39, 95% CI: 0.15-1.06) and cancer diagnosis (neuroblastoma/hepatoblastoma/medulloblastoma: OR 0.1, 95% CI: 0.02-0.45; germ cell tumor/osteosarcoma: OR 0.32, 95% CI: 0.06-1.25). Significant otoprotection from STS was noted across other subgroups with varied magnitudes of effect. STS otoprotection appears to differ across clinically meaningful subgroups, particularly age at diagnosis. These results inform clinical decision-making and future research.

Clinicopathological significance of SOX2 and FOXG1 expression patterns in ovarian immature teratomas

Objective: To investigate the relationship between the expression patterns of SOX2 and FOXG1 and the differentiation/development level of neural components in immature teratoma and to determine the clinical significance and potential application of this correlation in a clinical setting. Methods: We conducted a comprehensive whole transcriptome sequencing analysis to identify differentially expressed genes (DEGs) across various subtypes of ovarian germ cell tumors. Additionally, immunohistochemical staining of paraffin-embedded tissue sections was employed to assess the nuclear staining pattern of SOX2 and FOXG1 proteins within the tumor tissues. Results: The transcriptome sequencing data showed that transcription factors SOX2 and FOXG1 exhibited high levels of expression typically in immature teratoma and occupied a pivotal position within the protein-protein interaction network. Immunohistochemical staining revealed the absence of both SOX2 and FOXG1 protein expression in dysgerminoma and yolk sac tumor samples. In immature teratoma, immunohistochemical staining demonstrated diffuse expression of SOX2 and FOXG1 proteins within the inner layer of densely-arranged primitive neuroepithelial tubules. This pattern of expression suggested the presence of stem cell-like properties within these tumor cells. In the sparsely peripheral neurogliocytes, FOXG1 maintained a diffuse nuclear staining pattern resembling that of neuroepithelial cells, while SOX2 exhibited a scattered pattern of positive staining, hinting at a neural lineage differentiation potential. This spatial differential expression pattern of SOX2 and FOXG1 proteins in immature teratoma suggested that primitive neural components within these tumors often recapitulated the trajectory of neural formation and cortical development that was typically observed during embryogenesis. The primitive neural tube acted as the center that constantly moved from inside to outside, with a dynamic shift from the interior to the exterior, paralleled by the sequential differentiation of cell lineages from primitive neuroepithelial stem cells to radial glia, intermediate progenitor cells, and ultimately to precursor glia. Conclusions: This spatial expression pattern of SOX2 and FOXG1 proteins observed in immature teratoma mirrors the lineage differentiation and migration trajectories of primitive neuroepithelial components typically seen in embryonic neurogenesis and cortical development. In daily practice, the combined application of SOX2 and FOXG1 SOX2 and FOXG1 helps identify the primitive neuroepithelial components in immature teratoma, avoid misjudgment of similar morphologies, and thereby assist in the histological grading and clinical decision-making.