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Annals of Oncology : Official Journal... Aug 2019Since 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... (Review)
Review
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 -
Neuro-oncology Apr 2022The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have...
The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.
Topics: Adolescent; Brain Neoplasms; Consensus; Germinoma; Humans; Male; Neoplasms, Germ Cell and Embryonal; Retrospective Studies; Testicular Neoplasms; Young Adult
PubMed: 34724065
DOI: 10.1093/neuonc/noab252 -
Acta Neuropathologica Oct 2022Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While... (Clinical Trial)
Clinical Trial
Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.
Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Child; Forkhead Transcription Factors; Glioblastoma; Hospitals; Humans; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive
PubMed: 35982322
DOI: 10.1007/s00401-022-02484-7 -
Annals of Oncology : Official Journal... Oct 2018
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 -
Advances in Experimental Medicine and... 2016Germ cell tumors (GCTs) are malignant cancers that arise from embryonic precursors known as Primordial Germ Cells. GCTs occur in neonates, children, adolescents and... (Review)
Review
Germ cell tumors (GCTs) are malignant cancers that arise from embryonic precursors known as Primordial Germ Cells. GCTs occur in neonates, children, adolescents and young adults and can occur in the testis, the ovary or extragonadal sites. Because GCTs arise from pluripotent cells, the tumors can exhibit a wide range of different histologies. Current cisplatin-based combination therapies cures most patients, however at the cost of significant toxicity to normal tissues. While GWAS studies and genomic analysis of human GCTs have uncovered somatic mutations and loci that might confer tumor susceptibility, little is still known about the exact mechanisms that drive tumor development, and animal models that faithfully recapitulate all the different GCT subtypes are lacking. Here, we summarize current understanding of germline development in humans and zebrafish, describe the biology of human germ cell tumors, and discuss progress and prospects for zebrafish GCT models that may contribute to better understanding of human GCTs.
Topics: Animals; Cell Differentiation; Disease Models, Animal; Humans; Neoplasms, Germ Cell and Embryonal; Zebrafish
PubMed: 27165367
DOI: 10.1007/978-3-319-30654-4_21 -
The Lancet. Oncology Apr 2016Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across... (Review)
Review
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 -
International Journal of Molecular... May 2023Spermatocytic tumor (ST) is a very rare disease, accounting for approximately 1% of testicular cancers. Previously classified as spermatocytic seminoma, it is currently... (Review)
Review
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 -
Frontiers in Endocrinology 2020The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel... (Review)
Review
The G protein-coupled estrogen receptor (GPER), also known as GPR30, is a widely conserved 7-transmembrane-domain protein which has been identified as a novel 17β-estradiol-binding protein that is structurally distinct from the classic oestrogen receptors (ERα and ERβ). There are still conflicting data regarding the exact role and the natural ligand of GPER/GPR30 in reproductive tracts as both male and female knock-out mice are fertile and have no abnormalities of reproductive organs. Testicular germ cell cancers (TGCCs) are the most common malignancy in young males and the most frequent cause of death from solid tumors in this age group. Clinical and experimental studies suggested that estrogens participate in the physiological and pathological control of male germ cell proliferation. In human seminoma cell line, while 17β-estradiol (E2) inhibits cell proliferation through an ERβ-dependent mechanism, an impermeable E2 conjugate (E2 coupled to BSA), cell proliferation is stimulated by activating ERK1/2 and protein kinase A through a membrane GPCR that we further identified as GPER/GPR30. The same effect was observed with low but environmentally relevant doses of BPA, an estrogenic endocrine disrupting compound. Furthermore, GPER/GPR30 is specifically overexpressed in seminomas but not in non-seminomas and this overexpression is correlated with an ERβ-downregulation. This GPER/GPR30 overexpression could be linked to some genetic variations, as single nucleotide polymorphisms, which was also reported in other hormone-dependent cancers. We will review here the implication of GPER/GPR30 in TGCCs pathophysiology and the arguments to consider GPER/GPR30 as a potential therapeutic target in humans.
Topics: Humans; Neoplasms, Germ Cell and Embryonal; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction; Testicular Neoplasms
PubMed: 33574796
DOI: 10.3389/fendo.2020.600404 -
The Journal of Thoracic and... Jun 2019
Topics: Humans; Neoplasms; Neoplasms, Germ Cell and Embryonal
PubMed: 31307144
DOI: 10.1016/j.jtcvs.2019.02.121 -
BMJ Clinical Evidence Jan 2016More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 30 to 34 years. Most testicular cancers are germ... (Review)
Review
INTRODUCTION
More than half of painless solid swellings of the body of the testis are malignant, with a peak incidence in men aged 30 to 34 years. Most testicular cancers are germ cell tumours and half of these are seminomas, which tend to affect older men and have a good prognosis.
METHODS AND OUTCOMES
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments following orchidectomy in men diagnosed with stage 1 germ cell tumours (confined to testis)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
RESULTS
At this update, 76 records were screened for inclusion. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 29 full publications. Of the 29 full articles evaluated, two systematic reviews and one RCT, were added at this update. Data from long-term follow-up of an already reported study were also added. We performed a GRADE evaluation for seven PICO combinations.
CONCLUSIONS
In this systematic overview, we categorised the efficacy for seven interventions based on information about the effectiveness and safety of adjuvant chemotherapy (including different drugs and the number of cycles), adjuvant radiotherapy (including different regimens), adjuvant surgery, and surveillance/observation.
Topics: Chemotherapy, Adjuvant; Humans; Male; Neoplasms, Germ Cell and Embryonal; Radiotherapy, Adjuvant; Testicular Neoplasms
PubMed: 26741128
DOI: No ID Found