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Poor prognosis germ-cell tumours are only cured in about half of patients. We aimed to assess whether treatment intensification based on an early tumour marker decline will improve progression-free survival for patients with germ-cell tumours. In this phase 3, multicentre, randomised trial, patients were enrolled from France (20 centres), USA (one centre), and Slovakia (one centre). Patients were eligible if they were older than 16 years, had evidence of testicular, retroperitoneal, or mediastinal non-seminomatous germ cell tumours based on histological findings or clinical evidence and highly elevated serum human chorionic gonadotropin or alfa-fetoprotein concentrations that matched International Germ Cell Cancer Consensus Group poor prognosis criteria. After one cycle of BEP (intravenous cisplatin [20 mg/m2 per day for 5 days], etoposide [100 mg/m2 per day for 5 days], and intramuscular or intravenous bleomycin [30 mg per day on days 1, 8, and 15]), patients' human chorionic gonadotropin and alfa-fetoprotein concentrations were measured at day 18–21. Patients with a favourable decline in human chorionic gonadotropin and alfa-fetoprotein continued BEP (Fav-BEP group) for 3 additonal cycles, whereas patients with an unfavourable decline were randomly assigned (1:1) to receive either BEP (Unfav-BEP group) or a dose-dense regimen (Unfav-dose-dense group), consisting of intravenous paclitaxel (175 mg/m2 over 3 h on day 1) before BEP plus intravenous oxaliplatin (130 mg/m2 over 3 h on day 10; two cycles), followed by intravenous cisplatin (100 mg/m2 over 2 h on day 1), intravenous ifosfamide (2 g/m2 over 3 h on days 10, 12, and 14), plus mesna (500 mg/m2 at 0, 3, 7 and 11 h), and bleomycin (25 units per day, by continuous infusion for 5 days on days 10–14; two cycles), with granulocyte-colony stimulating factor (lenograstim) support. Centrally blocked computer-generated randomisation stratified by centre was used. The primary endpoint was progression-free survival and the efficacy analysis was done in the intention-to-treat population. The planned trial accrual was completed in May, 2012, and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00104676. Between Nov 28, 2003, and May 16, 2012, 263 patients were enrolled and 254 were available for tumour marker assessment. Of these 51 (20%) had a favourable marker assessment, and 203 (80%) had an unfavourable tumour marker decline; 105 were randomly assigned to the Unfav-dose-dense group and 98 to the Unfav-BEP group. 3-year progression-free survival was 59% (95% CI 49–68) in the Unfav-dose-dense group versus 48% (38–59) in the Unfav-BEP group (HR 0·66, 95% CI 0·44–1·00, p=0·05). 3-year progression-free survival was 70% (95% CI 57–81) in the Fav-BEP group (HR 0·66, 95% CI 0·49–0·88, p=0·01 for progression-free survival compared with the Unfav-BEP group). More grade 3–4 neurotoxic events (seven [7%] vs one [1%]) and haematotoxic events occurred in the Unfav-dose-dense group compared with in the Unfav-BEP group; there was no difference in grade 1–2 febrile neutropenia (18 [17%] vs 18 [18%]) or toxic deaths (one [1%] in both groups). Salvage high-dose chemotherapy plus a stem-cell transplant was required in six (6%) patients in the Unfav-dose-dense group and 16 (16%) in the Unfav-BEP group. Personalised treatment with chemotherapy intensification reduces the risk of progression or death in patients with poor prognosis germ-cell tumours and an unfavourable tumour marker decline. Institut National du Cancer (Programme Hospitalier de Recherche Clinique).

Germ cell tumor (GCT) patients with unfavourable response to first-line therapy still lack reliable diagnostic and effective treatment Detailed correlation of total extracellular DNA (ecDNA), other DNA species and endogenous DNase levels in GCT patients' plasma and translational utility remains under- investigated. We determined DNase plasma levels, ecDNA of different subcellular origin and neutrophil extracellular trap (NETs)-associated markers. Next, we determined the associations of these parameters with a level of the DNA damage, immune inflammatory index, specific immune cell subpopulations in a cohort of the 117 GCT patients and 19 matched healthy donors (HDs). Moreover, we investigated how exogenous DNase affects antitumor effect of cisplatin in GCT model of cisplatin-resistant embryonal carcinoma NTERA-2 CisR. Our data demonstrate that high level of ecDNA and low level of DNase in GCT patients' plasma is associated with significantly worse progression-free survival and overall survival. The level of the plasma ecDNA was five times higher in the GCT patients compared to the HDs. The patients with higher total ecDNA and ncDNA, but not mtDNA, had inferior PFS and OS compared to the patients with lower ecDNA (all p < 0.05). There was an inverse correlation between plasma DNase and ecDNA levels, and between plasma DNase level and clinical outcome. Importantly, combined treatment with cisplatin and human recombinant DNase I delayed growth of the NTERA-2 CisR xenografts and prolonged animal survival. Importantly, Pulmozyme significantly reduced intratumoral microvascular density in our preclinical model. Our data confirm the association between low plasma DNase activity and worse overall survival for the first time in GCT patients. This study further validated the prognostic value of total ecDNA in GCT patients. More importantly, our preclinical data substantiated beneficial effect of Pulmozyme combination with cisplatin treatment to improve the therapeutic outcome in refractory disease.

Germ cell tumors (GCTs) pose significant diagnostic challenges because of the limited performance of existing tumor markers. Here, we used phage immunoprecipitation sequencing (PhIP-Seq) to develop a unique immunosignature panel to improve diagnosing and differentiating GCT. Using 427 serum samples (150 GCT, 277 controls), we developed and validated an immunosignature panel (GCT-iSIGN) comprising 24 peptides from 16 unique proteins. This panel achieved 93% sensitivity, 99% specificity, and an area under the curve (AUC) of 0.98, identifying 23/24 biomarker-negative GCT cases. A secondary model (Sem-iSIGN), consisting of 17 peptides from five proteins, differentiated seminoma from nonseminoma with 96% specificity, 65% sensitivity, and AUC of 0.77. RNA sequencing data from The Cancer Genome Atlas confirmed differential overexpression of target antigens in testicular cancer. ELISA validation of ERVK7 and LUZP4 and immunohistochemical detection of ERVK7, MUC4, ZNF91, and LUZP4 in tumor tissues supported target expression. This study highlights PhIP-Seq immunoprofiling to identify serum-based immunosignature panels that can serve as biomarkers for GCTs. This approach addresses the shortcomings of conventional markers and offers a scalable, cost-effective tool for improving cancer diagnosis and management. Germ cell tumours are a complex and heterogenous type of tumour which are difficult to classify using biomarkers. Here, the authors use PhIP-seq to develop an immunosignature panel for classification.

Testicular germ cell tumors (TGCTs) are malignant neoplasms with a poor prognosis, and the absence of reliable biomarkers for patient stratification and diagnosis presents a significant challenge. We employed an integrated analysis of Single-Cell RNA-Sequencing and TCGA data to evaluate TNFSF10 as a potential biomarker for prognosis and immunotherapy in TGCTs. Our findings revealed that aberrant TNFSF10 expression was significantly associated with patient survival outcomes. Silencing TNFSF10 inhibited the proliferation, migration, and invasion of TGCT cells, highlighting its role in tumor progression. Moreover, TNFSF10 expression was closely correlated with various components of the tumor microenvironment, suggesting its involvement in both the biological behavior of TGCTs and their response to treatment. TNFSF10 emerges as a promising diagnostic and prognostic biomarker for stratification and targeted therapy in TGCTs, offering new prospects for personalized treatment strategies.

Testicular tumors are the most common tumors in adolescent and young men and germ cell tumors (TGCTs) account for most of all testicular cancers. Increasing incidence of TGCTs among males provides strong motivation to understand its biological and genetic basis. Gains of chromosome arm 12p and aneuploidy are nearly universal in TGCTs, but TGCTs have low point mutation rate. It is thought that TGCTs develop from premalignant intratubular germ cell neoplasia that is believed to arise from the failure of normal maturation of gonocytes during fetal or postnatal development. Progression toward invasive TGCTs (seminoma and nonseminoma) then occurs after puberty. Both inherited genetic factors and environmental risk factors emerge as important contributors to TGCT susceptibility. Genome-wide association studies have so far identified more than 30 risk loci for TGCTs, suggesting that a polygenic model fits better with the genetic landscape of the disease. Despite high cure rates because of its particular sensitivity to platinum-based chemotherapy, exploration of mechanisms underlying the occurrence, progression, metastasis, recurrence, chemotherapeutic resistance, early diagnosis and optional clinical therapeutics without long-term side effects are urgently needed to reduce the cancer burden in this underserved age group. Herein, we present an up-to-date review on clinical challenges, origin and progression, risk factors, TGCT mouse models, serum diagnostic markers, resistance mechanisms, miRNA regulation, and database resources of TGCTs. We appeal that more attention should be paid to the basic research and clinical diagnosis and treatment of TGCTs.

Genomic analyses show that primary germ-cell tumours are highly enriched for chromosomal reciprocal loss of heterozygosity, mutations in KRAS and have high mitochondrial priming, providing insight into chemosensitivity and the evolution of chemoresistance in this disease. Germ-cell tumour genomics Tumours formed from germ cells—those cells that develop in the embryo to become the cells of the reproductive system—tend to be more sensitive to chemotherapy than are many other adult cancers. To establish the basis for this chemosensitivity and the drivers of clinical resistance, Eliezer Van Allen, Christopher Sweeney and colleagues performed clinical whole-exome and transcriptome sequencing of germ-cell tumours from patients with various clinical outcomes, including the very rare case of death from germ-cell tumours. They find that primary germ-cell tumours are highly enriched for chromosomal reciprocal loss of heterozygosity, and for mutations in KRAS , and have high mitochondrial priming. This work provides insights into chemosensitivity and the evolution of chemoresistance in germ-cell tumours. Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes 1 , 2 . GCTs are histologically heterogeneous and distinctly curable with chemotherapy 3 . Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs 4 , 5 , 6 , but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53 . In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue 7 , we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers ( NANOG and POU5F1 ) 8 , 9 in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.

Testicular cancer is the most common solid malignancy in people with testicles aged 15–44 years, accounting for 1–2% of all tumours in males of all ages. Approximately 95% of testicular cancers are testicular germ cell tumours. This Seminar focuses on testicular cancer, with an emphasis on testicular germ cell tumours. We delve into the epidemiology, clinical presentation, disease management, controversies, clinical dilemmas, follow-up, and future directions. Furthermore, we explore distinct treatment approaches for seminoma and non-seminoma testicular germ cell tumours across all clinical stages and discuss post-treatment salvage options after relapse. Our Seminar aims to provide a comprehensive review of testicular cancer, to enhance understanding, and inform clinicians and researchers about the latest developments in management.

Background: Bleomycin–etoposid–cisplatin (BEP) chemotherapy is curative in most patients with disseminated germ cell cancer (GCC) but also associated with toxic actions and dysfunction in non-targeted tissues. We investigated changes in muscle function during BEP and the safety and efficacy of resistance training to modulate these changes. Methods: Thirty GCC patients were randomly assigned to resistance training (resistance training group (INT), n=15) or usual care (CON, n =15) during 9 weeks of BEP therapy. Resistance training consisted of thrice weekly sessions of four exercises, 3–4 sets/exercise of 10–15 repetitions at 12–15 repetition maximum load. The primary endpoint was muscle fibre size, assessed in muscle biopsies from musculus vastus lateralis. Secondary endpoints were fibre phenotype composition, body composition, strength, blood biochemistry and patient-reported endpoints. Healthy age-matched subjects (REF, n =19) performed the same RT-programme for comparison purposes. Results: Muscle fibre size decreased by −322  μ m 2 (95% confidence interval (CI): −899 to 255; P =0.473) in the CON-group and increased by +206  μ m 2 (95% CI: −384 to 796; P =0.257) in the INT-group (adjusted mean difference (AMD), +625  μ m 2 , 95% CI: −253 to 1503, P =0.149). Mean differences in type II fibre size (AMD, +823  μ m 2 , P =0.09) and lean mass (AMD, +1.49 kg, P =0.07) in favour of the INT-group approached significance. The REF-group improved all muscular endpoints and had significantly superior changes compared with the INT-group ( P <0.05). Conclusions: BEP was associated with significant reduction in lean mass and strength and trends toward unfavourable changes in muscle fibre size and phenotype composition. Resistance training was safe and attenuated dysfunction in selected endpoints, but BEP blunted several positive adaptations observed in healthy controls. Thus, our study does not support the general application of resistance training in this setting but larger-scaled trials are required to confirm this finding.

Introduction and objectives Postchemotherapy residual tumor resection (PC-RTR) is an important part of the multimodal treatment for patients with metastatic germ cell tumors. Simultaneous retroperitoneal and thoracic metastases often require consecutive surgical procedures. This study analyzes the histologic findings after abdominal and thoracic surgery in order to tailor the sequence and intensity of surgery. Patients and methods From a total of 671 PC-RTRs from 2008 to 2021 we analyzed 50 patients with stage III non-seminomatous germ cell tumor (NSGCT) who had undergone both retroperitoneal and thoracic postchemotherapy residual tumor resection after first-line and salvage chemotherapy. Results All patients included had stage III NSGCT. 39 and 11 patients received first-line and salvage chemotherapy, respectively. 45 (90%) patients received retroperitoneal resection first, followed by thoracic surgery. Three patients (6%) underwent thoracic surgery before retroperitoneal surgery and two patients (4%) underwent simultaneous surgery. Overall, the histology of retroperitoneal and thoracic specimens was discordant in 23% of cases. After first-line chemotherapy, of fourteen patients with necrosis in retroperitoneal histology, four patients had vital carcinoma in lung histology. In patients with teratoma in the retroperitoneum, the thoracic findings were concordant in most cases (78%). When teratomatous elements were also present in the orchiectomy specimen, concordance was 100%. After salvage chemotherapy, the discordance rate was 55%. Conclusion The data presented in this study underline that retroperitoneal residual masses with necrosis cannot reliably predict histologic findings of thoracic specimens. Patients with teratoma in the retroperitoneum have a high likelihood of teratoma in the thoracic specimen. Patient summary In this report we the compared the findings of metastasic testicular cancer patients who received thoracic and retroperitoneal surgery. We concluded that the findings of one location cannot entirely predict the results of another location.

Background Embryonal tumors with multilayered rosettes (ETMRs) are rare, highly aggressive pediatric brain neoplasms characterized by early onset and dismal prognosis. This study presents a comprehensive clinicopathological and molecular analysis of ETMR cases diagnosed over a 14-year period at National Cancer Institute, Cairo University, with a focus on diagnostic features, clinical presentation, and survival outcomes. Methods A retrospective review of 35 patients with histopathologically confirmed ETMRs was conducted. Demographic data, clinical symptoms, neuroimaging findings, histopathologic features-including rosette formation, mitotic activity, necrosis, and Ki67 proliferation index-as well as molecular analyses for C19MC amplification and LIN28A expression were evaluated. Kaplan-Meier survival curves and univariable Cox regression were used to assess prognostic associations. Results The cohort comprised 17 females and 18 males, with a median age of 36 months. Common presenting symptoms included signs of raised intracranial pressure, seizures, and motor deficits. Gross total resection was achieved in 43% of patients, and 48% received adjuvant chemoradiotherapy.Histopathologic examination consistently revealed ependymoblastic rosettes (true multilayered rosettes) and high mitotic activity. LIN28A was diffusely expressed in all assessable cases. Molecular confirmation by PCR testing was done in 20 cases. The median overall survival was 19 months. Factors associated with inferior survival included incomplete surgical resection, absence of adjuvant therapy, and presence of necrosis and high mitotic index. Conclusion ETMRs demonstrate consistent histological and immunohistochemical features that can guide diagnosis in resource-limited settings. Despite therapeutic advances, prognosis remains poor, underscoring the urgent need for novel therapeutic strategies. Molecular testing for C19MC amplification and LIN28A expression supports diagnostic confirmation and may hold future prognostic or therapeutic relevance.