Review

Authors: Abdullah Ozkok, Charles L Edelstein

Cisplatin and other platinum derivatives are the most widely used chemotherapeutic agents to treat solid tumors including ovarian, head and neck, and testicular germ cell tumors. A known complication of cisplatin administration is acute kidney injury (AKI). The nephrotoxic effect of cisplatin is cumulative and dose-dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI may result in chronic kidney disease. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, oxidative stress, inflammation, and vascular injury in the kidney. There is predominantly acute tubular necrosis and also apoptosis in the proximal tubules. There is activation of multiple proinflammatory cytokines and infiltration of inflammatory cells in the kidney. Inhibition of the proinflammatory cytokines TNF-α or IL-33 or depletion of CD4+ T cells or mast cells protects against cisplatin-induced AKI. Cisplatin also causes endothelial cell injury. An understanding of the pathogenesis of cisplatin-induced AKI is important for the development of adjunctive therapies to prevent AKI, to lessen the need for dose decrease or drug withdrawal, and to lessen patient morbidity and mortality.

Topics: Acute Kidney Injury; Antineoplastic Agents; Cisplatin; Female; Humans; Interleukin-33; Interleukins; Kidney Tubules, Proximal; Male; Neoplasms, Germ Cell and Embryonal; Oxidative Stress; Tumor Necrosis Factor-alpha

PubMed: 25165721
DOI: 10.1155/2014/967826

Review

Authors: B W Kristensen, L P Priesterbach-Ackley, J K Petersen...

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain; Brain Neoplasms; DNA Methylation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Humans; Immunohistochemistry; Molecular Targeted Therapy; Mutation; Neoplasms, Germ Cell and Embryonal; Prognosis; Survival Rate; Treatment Outcome

PubMed: 31124566
DOI: 10.1093/annonc/mdz164

Review

Authors: Lois B Travis, Darren R Feldman, Chunkit Fung...

Innovations in the care of adolescent and young adult (AYA) germ cell tumors (GCTs) are needed for one of the most common AYA cancers for which treatment has not significantly changed for several decades. Testicular GCTs (TGCTs) are the most common cancers in 15- to 39-year-old men, and ovarian GCTs (OvGCTs) are the leading gynecologic malignancies in women younger than 25 years. Excellent outcomes, even in widely metastatic disease using cisplatin-based chemotherapy, can be achieved since Einhorn and Donohue's landmark 1977 study in TGCT. However, as the severity of accompanying late effects (ototoxicity, neurotoxicity, cardiovascular disease, second malignant neoplasms, nephrotoxicity, and others) has emerged, efforts to deintensity treatment and find alternatives to cisplatin have taken on new urgency. Current innovations include the collaborative design of clinical trials that accrue GCTs across all ages and both sexes, including adolescents (previously on pediatric trials), and OvGCT (previously on gynecologic-only trials). Joint trials accrue larger sample sizes at a faster rate and therefore evaluate new approaches more rapidly. These joint trials also allow for biospecimen collection to further probe GCT etiology and underlying mechanisms of tumor growth, thus providing new therapeutic options. This AYA approach has been fostered by The Malignant Germ Cell International Consortium, which includes over 115 GCT disease experts from pediatric, gynecologic, and genitourinary oncologies in 16 countries. Trials in development incorporate, to our knowledge, for the first time, molecular risk stratification and precision oncology approaches on the basis of specific GCT biology. This collaborative AYA approach pioneering successfully in GCT could serve as a model for impactful research for other AYA cancer types.

Topics: Male; Humans; Female; Adolescent; Young Adult; Child; Adult; Cisplatin; Survivorship; Precision Medicine; Neoplasms, Germ Cell and Embryonal; Testicular Neoplasms; Genomics

PubMed: 37820296
DOI: 10.1200/JCO.23.01099

Authors: Bo Li, Shuang Zhao, Shouwei Li...

BACKGROUND

Intracranial germ cell tumors (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumors (NGGCTs). Previous studies have found that somatic mutations involving the mitogen-activated protein kinase/mTOR signaling pathway are common early events. However, a comprehensive genomic understanding of IGCTs is still lacking.

METHODS

We established a cohort including over 100 IGCTs and conducted genomic and transcriptomic sequencing.

RESULTS

We identified novel recurrent driver genomic aberrations, including USP28 truncation mutations and high-level copy number amplification of KRAS and CRKL caused by replication of extrachromosomal DNA. Three distinct subtypes associated with unique genomic and clinical profiles were identified with transcriptome analysis: Immune-hot, MYC/E2F, and SHH. Both immune-hot and MYC/E2F were predominantly identified in germinomas and shared similar mutations involving the RAS/MAPK signaling pathway. However, the immune-hot group showed an older disease onset age and a significant immune response. MYC/E2F was characterized by a younger disease onset age and increased genomic instability, with a higher proportion of tumors showing whole-genome doubling. Additionally, the SHH subtype was mostly identified in NGGCTs.

CONCLUSIONS

Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new treatment strategies in this setting.

Topics: Humans; Neoplasms, Germ Cell and Embryonal; Male; Brain Neoplasms; Adult; Female; Adolescent; Young Adult; Child; Mutation; Biomarkers, Tumor; Middle Aged; Prognosis; Gene Expression Profiling; Child, Preschool

PubMed: 38430549
DOI: 10.1093/neuonc/noae038

Authors: I Ray-Coquard, P Morice, D Lorusso...

Topics: Aftercare; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Europe; Female; Humans; Incidence; Long-Term Care; Medical Oncology; Neoplasm Staging; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Ovariectomy; Ovary; Societies, Medical; Survivorship; Treatment Outcome

PubMed: 29697741
DOI: 10.1093/annonc/mdy001

Review

Authors: Simona Secondino, Alessandra Viglio, Giuseppe Neri...

Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently classified within the non-germ neoplasia in-situ-derived tumors and has different clinical-pathologic features when compared with other forms of germ cell tumors (GCTs). A web-based search of MEDLINE/PubMed library data was performed in order to identify pertinent articles. In the vast majority of cases, STs are diagnosed at stage I and carry a very good prognosis. The treatment of choice is orchiectomy alone. Nevertheless, there are two rare variants of STs having very aggressive behavior, namely anaplastic ST and ST with sarcomatous transformation, that are resistant to systemic treatments and their prognosis is very poor. We have summarized all the epidemiological, pathological and clinical features available in the literature regarding STs that have to be considered as a specific entity compared to other germ GCTs, including seminoma. With the aim of improving the knowledge of this rare disease, an international registry is required.

Topics: Male; Humans; Seminoma; Rare Diseases; Testicular Neoplasms; Orchiectomy; Sarcoma; Neoplasms, Germ Cell and Embryonal

PubMed: 37298487
DOI: 10.3390/ijms24119529

Review

Authors: Furqan Shaikh, Matthew J Murray, James F Amatruda...

Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

Topics: Adolescent; Adult; Biomarkers, Tumor; Child; Female; Humans; Male; Neoplasms, Germ Cell and Embryonal; Ovarian Neoplasms; Pediatrics; Survivors; Testicular Neoplasms

PubMed: 27300675
DOI: 10.1016/S1470-2045(15)00545-8

Authors: Fadi Braiteh, Imrana Malik

Topics: Adult; Humans; Male; Mediastinal Neoplasms; Neoplasms, Germ Cell and Embryonal; Pneumopericardium; Pneumothorax; Positive-Pressure Respiration; Radiography; Radiotherapy, Adjuvant; Respiratory Distress Syndrome

PubMed: 18981451
DOI: 10.1503/cmaj.080707

Review

Authors: Milena Urbini, Sara Bleve, Giuseppe Schepisi...

The outcome of metastatic testicular germ cell tumor patients has been dramatically improved by cisplatin-based chemotherapy combinations. However, up to 30% of patients with advanced disease relapse after first-line therapy and require salvage regimens, which include treatments with conventional-dose chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. For these patients, prognosis estimation represents an essential step in the choice of medical treatment but still remains a complex challenge. The available histological, clinical, and biochemical parameters attempt to define the prognosis, but they do not reflect the tumor's molecular and pathological features and do not predict who will exhibit resistance to the several treatments. Molecular selection of patients and validated biomarkers are highly needed in order to improve current risk stratification and identify novel therapeutic approaches for patients with recurrent disease. Biomolecular biomarkers, including microRNAs, gene expression profiles, and immune-related biomarkers are currently under investigation in testicular germ cell tumors and could potentially hold a prominent place in the future treatment selection and prognostication of these tumors. The aim of this review is to summarize current scientific data regarding prognostic and predictive biomarkers for salvage therapy in testicular germ cell tumors.

Topics: Male; Humans; Hematopoietic Stem Cell Transplantation; Salvage Therapy; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Transplantation, Autologous; Testicular Neoplasms; Neoplasms, Germ Cell and Embryonal; Cisplatin; Biomarkers

PubMed: 38069192
DOI: 10.3390/ijms242316872

Authors: Mauri José Piazza, Almir Antonio Urbanetz

This review describes the germ cell neoplasms that are malignant and most commonly associated with several types of gonadal dysgenesis. The most common neoplasm is gonadoblastoma, while others including dysgerminomas, yolk-sac tumors and teratomas are rare but can occur. The purpose of this review is to evaluate the incidences of these abnormalities and the circumstances surrounding these specific tumors.According to well-established methods, a PubMed systematic review was performed, to obtain relevant studies published in English and select those with the highest-quality data.Initially, the first search was performed using gonadal dysgenesis as the search term, resulting in 12,887 PubMed papers, published, from 1945 to 2017. A second search using ovarian germ cell tumors as the search term resulted in 10,473 papers, published from 1960 to 2017. Another search was performed in Medline, using germ cell neoplasia as the search term, and this search resulted in 7,560 papers that were published between 2003 to 2016, with 245 new papers assessing gonadoblastomas.The higher incidence of germ cell tumors in gonadal dysgenesis is associated with a chromosomal anomaly that leads to the absence of germ cells in these gonads and, consequently, a higher incidence of neoplasms when these tumors are located inside the abdomen. Several hypotheses suggest that increased incidence of germ cell tumors involves all or part of the Y chromosome or different genes.

Topics: Female; Gonadal Dysgenesis; Humans; Incidence; Male; Neoplasms, Germ Cell and Embryonal; Risk Factors

PubMed: 31721911
DOI: 10.6061/clinics/2019/e408