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  • 1
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    Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo Clinic and Japanese consortium cohorts
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2021
    In:  Journal of Neurosurgery Vol. 134, No. 2 ( 2021-02), p. 446-456
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 134, No. 2 ( 2021-02), p. 446-456
    Abstract: Central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited. METHODS In Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan. RESULTS There was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04). CONCLUSIONS There appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.
    Type of Medium: Online Resource
    ISSN: 0022-3085 , 1933-0693
    URL: Article
    DOI: 10.3171/2019.11.JNS191576
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2021
    detail.hit.zdb_id: 2026156-1
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  • 2
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    GERM-01. GENETIC AND EPIGENETIC LANDSCAPE OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
    Oxford University Press (OUP) ; 2017
    In:  Neuro-Oncology Vol. 19, No. suppl_4 ( 2017-06), p. iv21-iv22
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 19, No. suppl_4 ( 2017-06), p. iv21-iv22
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/nox083.087
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 2094060-9
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  • 3
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    Integrated clinical, histopathological, and molecular data analysis of 190 central nervous system germ cell tumors from the iGCT Consortium
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. 12 ( 2019-12-17), p. 1565-1577
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. 12 ( 2019-12-17), p. 1565-1577
    Abstract: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. Methods Data from the Intracranial Germ Cell Tumor Genome Analysis (iGCT) Consortium were reviewed. A total of 190 cases were classified as primary germ cell tumors (GCTs) based on central pathological reviews. Results All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker positive and 6.1% of non-germinomatous GCTs were marker negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better progression-free survival than those at atypical sites (P = 0.03). A molecular clinical association study revealed frequent mitogen-activated protein kinase (MAPK) pathway mutations in males (51.4% vs 14.3%, P = 0.007), and phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway mutations in basal ganglia cases (P = 0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. Conclusions The in-depth findings of this study regarding clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz139
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 4
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    GC-09GENOME-WIDE DNA METHYLATION AND TRANSCRIPTOMIC PROFILING IN PRIMARY CENTRAL NERVOUS SYSTEM GERM CELL TUMORS SUGGESTS A PRIMORDIAL GERM CELL ORIGIN FOR GERMINOMA
    Oxford University Press (OUP) ; 2016
    In:  Neuro-Oncology Vol. 18, No. suppl 3 ( 2016-06), p. iii44.1-iii44
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 18, No. suppl 3 ( 2016-06), p. iii44.1-iii44
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/now072.09
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
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  • 5
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    Roles of Tumor Markers in Central Nervous System Germ Cell Tumors Revisited with Histopathology-Proven Cases in a Large International Cohort
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 4 ( 2022-02-15), p. 979-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 4 ( 2022-02-15), p. 979-
    Abstract: The central nervous system germ cell tumor (CNS GCT) is a rare and incompletely understood disease. A major outstanding question in the 2015 consensus document for CNS GCT management was the utility and interpretation of the tumor markers human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP) in the diagnosis of malignant non-germinomatous GCTs (hereafter NGGCTs) prior to treatment. In the current study, we assembled two geographically and ethnically different clinical cohorts from the Mayo Clinic (1988–2017) and the intracranial GCT Genome Analysis Consortium (iGCT Consortium) in Japan to address this question. Patients with both histopathological diagnosis and tumor markers available were eligible for inclusion (n = 162). Biopsy and surgical resection were performed in 85 and 77 cases, respectively. Among 77 resections, 35 demonstrated positivity for HCG, AFP, or both (45%). Seventeen of the marker-positive cases had no malignant non-germinomatous component identified on histopathology, but they were composed strictly of germinoma, teratoma, or both (49%). One embryonal carcinoma was the only marker-negative NGGCT in the study sample. Among 85 biopsies, 18 were marker positive (21%). Seven of these patients had no malignant non-germinomatous component on histopathology, suggesting the potential limitations of limited tissue sample volumes. Neither histopathological diagnosis nor tumor markers alone reliably diagnose NGGCTs due to the secretion of HCG and AFP by germinomas and teratomas. Treatment planning should incorporate integrated histopathological and laboratory-based diagnosis to optimize diagnostic and treatment strategies for this unusual and histologically heterogeneous tumor.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14040979
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 6
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    12p gain is predominantly observed in non-germinomatous germ cell tumors and identifies an unfavorable subgroup of central nervous system germ cell tumors
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. 5 ( 2022-05-04), p. 834-846
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. 5 ( 2022-05-04), p. 834-846
    Abstract: Central nervous system (CNS) germ cell tumors (GCTs) are neoplasms predominantly arising in pediatric and young adult populations. While germinomas generally respond to chemotherapy and radiation, non-germinomatous GCTs (NGGCTs) require more intensive treatment. This study aimed to determine whether 12p gain could predict the prognosis of CNS GCTs. Methods Eighty-two CNS GCTs were included in this study. The 12p gain was defined by an additional 12p in the background of potential polyploidy or polysomy. Cases were analyzed using an Illumina methylation 450K array for copy number investigations and validated by fluorescence in situ hybridization (FISH). Results A 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs (12% of germinoma cases and 50% of NGGCT cases), particularly in cases with malignant components, such as immature teratoma, yolk sac tumor, choriocarcinoma, and embryonal carcinoma. 12p gain and KIT mutation were mutually exclusive events. The presence of 12p gain correlated with shorter progression-free (PFS) and overall survival (OS) (10-year OS: 59% vs. 94%, with and without 12p gain, respectively, P = 0.0002), even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS (10-year OS: 47% vs. 90%, respectively, P = 0.02). The 12p copy number status was shared among histological components in mixed GCTs. Conclusions 12p gain may predict the presence of malignant components of NGGCTs, and poor prognosis of the patients. It may be associated with early tumorigenesis of CNS GCT.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab246
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    PATH-42. PROGNOSTIC FACTORS OF CNS GERM CELL TUMORS; MOLECULAR AND HISTOPATHOLOGICAL ANALYSES ON 154 CASES FROM THE IGCT CONSORTIUM
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi124-vi125
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi124-vi125
    Abstract: Germ cell tumors (GCTs) preferentially occurs in pediatric and young adult age groups. Chemo- and radiation therapies cause long-term sequelae in their later lives. We searched for clinical and histopathological features to predict the prognosis and affect treatment response, with a future goal of treatment stratification. METHODS A total of 154 GCT cases were included in the analysis. Total of 114 germinoma cases underwent measurement of tumor cell content on H-E specimen, and 82 GCT cases underwent 450K methylation analysis. 12p gain was determined on methylation-based copy number computation and FISH. Association with progression-free and overall survival (PFS/OS) was investigated. RESULTS The tumor cell content was widely distributed from & lt; 5% to 90% in the specimens, with a median value of 50%. Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content ( & lt; 50 %) (p=0.03). In multivariate analysis with tumor location, tumor cell content was the sole statistically significant prognostic factor (p=0.04). 12p gain was found in 25-out-of-82 cases (30%) and was more frequent in NGGCTs, particularly in cases with malignant components. The presence of 12p gain correlated with shorter PFS and OS, even with histology and tumor markers incorporated in the multivariate analysis. Among NGGCTs, 12p gain still had prognostic significance for PFS and OS. The 12p copy number status was shared among histological components in mixed GCTs. Whole-genome amplification was suggested by FISH. CONCLUSIONS We found that tumor cell content significantly affected the prognosis of germinomas. 12p gain predicts the presence of malignant components of NGGCTs, and poor prognosis of the patients. Furthermore, 12p is likely to be an early event in the tumorigenesis of GCT. These potentially open the possibility of leveraging these pathological and molecular factors in future clinical trials when stratifying the treatment intensity.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.494
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 8
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    GCT-09. Transcriptome and methylome profiles of CNS germ cell tumors and their comparison with testicular counterpart
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i56-i56
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i56-i56
    Abstract: BACKGROUND: The pathophysiology of CNS germ cell tumors (GCTs) has yet to be fully unraveled, resulting in the paucity of treatment options. The biological comparison with its testicular counterpart has not been interrogated. METHODS: In total, 84 cases of CNS GCT were investigated for methylation and transcriptome analyses, and an integrative analysis of the normal cells undergoing embryogenesis and testicular GCTs was conducted. RESULTS: Transcriptome analysis revealed germinoma and non-germinomatous GCTs (NGGCTs) were clearly separated. On transcriptome, germinoma was characterized by primitive cell state, closely related to primordial germ cell (PGC) with meiosis/mitosis potentials. NGGCT had a feature of more differentiated cell state directed toward organogenesis. Germinoma was subdivided into two clusters on integrated transcriptome and methylation analysis, and they are different in the age distribution and tumor cell content. CNS and testicular GCTs were divided based on histology, either germinoma/seminoma or NGGCT/non-seminomatous GCTs on methylation. Expression analysis mainly clustered them depending on the site of origin and histology. CONCLUSIONS: Expression profiles of CNS GCTs distinctly reflect the histological variabilities. Germinoma may be clustered into two groups, with possible differentiation in treatment intensity in the future. GCTs at CNS and gonads seem to have a mutual cell-of-origin and similar genomic backgrounds, which potentiates site-agnostic treatment development.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.203
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    PEDT-10 PHASE II TRIAL OF PATHOLOGY-BASED THREE-GROUP TREATMENT STRATIFICATION FOR PATIENTS WITH CNS GERM CELL TUMORS: A LONG-TERM FOLLOW-UP STUDY
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Advances Vol. 4, No. Supplement_3 ( 2022-12-03), p. iii11-iii11
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 4, No. Supplement_3 ( 2022-12-03), p. iii11-iii11
    Abstract: Phase II clinical trial funded by Ministry of Health, Labour and Welfare from 1995 to 2003 evaluated efficacy of pathology-based three-group treatment stratification for CNS germ cell tumors (GCTs). We here present long-term follow-up results. Methods Total 228 cases were registered. Germinoma was treated with carboplatin+etoposide (CARE) and extended-local irradiation, local irradiation was added for intermediate-prognosis-group, and poor-prognosis-group was treated with ifosfamide+cisplatin+etoposide (ICE) and whole-brain or craniospinal irradiation. Results Mean/median ages at diagnosis were 16.8/16 years and female-to-male ratio was 40-188. Registry included 123 germinomas, 76 intermediate-prognosis-group cases (including 38 germinoma with STGC), 28 poor-prognosis-group cases and 1 mature teratoma. Median 222-months follow-up was conducted, and 56 recurrences and 39 deaths were recorded. 10 and 20-year recurrence-free survival (RFS) for germinoma, intermediate and poor-prognosis-groups were 84/79%, 83/76% and 59/59%, respectively, and overall survival (OS) for each were 97/91%, 92/85% and 57/53%, respectively. Prognosis for germinoma with or without STGC was the same. Basal ganglia germinoma showed significantly shorter RFS but OS was not different from other locations. Median age at death was 24 years, and ages were significantly different depending on causes, such as disease-related (14 years on average) and complications (29 years). OS after recurrence at 5/10/20 years were 64/62/48%.Hormonal supplementation was seen in 82% for neurohypophyseal cases and antidiuretic hormone supplementation was most frequent (82%). Among available cases, 20-out-of-155 cases showed neoplastic/vascular complications, among which cavernous malformation was the most (n=9). Median period until complication presentation was 235 months, and the rate at 20 years was 11%. Conclusions Germinoma and intermediate-prognosis-group cases showed long-term survival for approximately 90%, while more intensive treatment would be necessitated for poor-prognosis-group. Long-term survivors often required hormonal supplementation, and increasing frequency of treatment-related complications was observed. There is no end of outpatient follow-up for CNS GCT patients.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdac167.038
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3009682-0
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  • 10
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    CS-04 INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Advances Vol. 1, No. Supplement_2 ( 2019-12-16), p. ii38-ii39
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 1, No. Supplement_2 ( 2019-12-16), p. ii38-ii39
    Abstract: We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. METHODS Data from the Intracranial Germ Cell Tumor Genome Analysis Consortium were reviewed. A total of 190 cases were classified as primary GCTs based on central pathological reviews. RESULTS All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker-positive and 6.1% of non-germinomatous GCTs were marker-negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better PFS than those at atypical sites (p=0.03). A molecular-clinical association study revealed frequent MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and PI3K/mTOR pathway mutations in basal ganglia cases (p=0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS These in-depth findings of this study regarding the clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdz039.175
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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