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  • 1
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    ATRX regulates glial identity and the tumor microenvironment in IDH-mutant glioma
    Springer Science and Business Media LLC ; 2021
    In:  Genome Biology Vol. 22, No. 1 ( 2021-12)
    Details
    In: Genome Biology, Springer Science and Business Media LLC, Vol. 22, No. 1 ( 2021-12)
    Abstract: Recent single-cell transcriptomic studies report that IDH-mutant gliomas share a common hierarchy of cellular phenotypes, independent of genetic subtype. However, the genetic differences between IDH-mutant glioma subtypes are prognostic, predictive of response to chemotherapy, and correlate with distinct tumor microenvironments. Results To reconcile these findings, we profile 22 human IDH-mutant gliomas using scATAC-seq and scRNA-seq. We determine the cell-type-specific differences in transcription factor expression and associated regulatory grammars between IDH-mutant glioma subtypes. We find that while IDH-mutant gliomas do share a common distribution of cell types, there are significant differences in the expression and targeting of transcription factors that regulate glial identity and cytokine elaboration. We knock out the chromatin remodeler ATRX, which suffers loss-of-function alterations in most IDH-mutant astrocytomas, in an IDH-mutant immunocompetent intracranial murine model. We find that both human ATRX-mutant gliomas and murine ATRX-knockout gliomas are more heavily infiltrated by immunosuppressive monocytic-lineage cells derived from circulation than ATRX-intact gliomas, in an IDH-mutant background. ATRX knockout in murine glioma recapitulates gene expression and open chromatin signatures that are specific to human ATRX-mutant astrocytomas, including drivers of astrocytic lineage and immune-cell chemotaxis. Through single-cell cleavage under targets and tagmentation assays and meta-analysis of public data, we show that ATRX loss leads to a global depletion in CCCTC-binding factor association with DNA, gene dysregulation along associated chromatin loops, and protection from therapy-induced senescence. Conclusions These studies explain how IDH-mutant gliomas from different subtypes maintain distinct phenotypes and tumor microenvironments despite a common lineage hierarchy.
    Type of Medium: Online Resource
    ISSN: 1474-760X
    URL: Article
    DOI: 10.1186/s13059-021-02535-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2040529-7
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  • 2
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    Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects
    American Society for Clinical Investigation ; 2023
    In:  Journal of Clinical Investigation Vol. 133, No. 5 ( 2023-3-1)
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 133, No. 5 ( 2023-3-1)
    Type of Medium: Online Resource
    ISSN: 1558-8238
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1172/JCI147087
    DOI: 10.1172/JCI147087DS1
    DOI: 10.1172/JCI147087DS2
    DOI: 10.1172/JCI147087DS3
    DOI: 10.1172/JCI147087DS4
    DOI: 10.1172/JCI147087DS5
    DOI: 10.1172/JCI147087DS6
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2023
    detail.hit.zdb_id: 2018375-6
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  • 3
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    Complementation of Human Papillomavirus Type 16 E6 and E7 by Jagged1-Specific Notch1-Phosphatidylinositol 3-Kinase Signaling Involves Pleiotropic Oncogenic Functions Independent of CBF1;Su(H);Lag-1 Activation
    American Society for Microbiology ; 2005
    In:  Journal of Virology Vol. 79, No. 12 ( 2005-06-15), p. 7889-7898
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 79, No. 12 ( 2005-06-15), p. 7889-7898
    Abstract: We have analyzed the induction and role of phosphatidylinositol 3-kinase (PI3K) by Notch signaling in human papillomavirus (HPV)-derived cancers. Jagged1, in contrast to Delta1, is preferentially upregulated in human cervical tumors. Jagged1 and not Delta1 expression sustained in vivo tumors by HPV16 oncogenes in HaCaT cells. Further, Jagged1 expression correlates with the rapid induction of PI3K-mediated epithelial-mesenchymal transition in both HaCaT cells and a human cervical tumor-derived cell line, suggestive of Delta1;Serrate/Jagged;Lag2 ligand-specific roles. Microarray analysis and dominant-negatives reveal that Notch-PI3K oncogenic functions can be independent of CBF1;Su(H);Lag-1 activation and instead relies on Deltex1, an alternative Notch effector.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.79.12.7889-7898.2005
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2005
    detail.hit.zdb_id: 1495529-5
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  • 4
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    Comprehensive immune cell profiling depicts an early immune response associated with severe coronavirus disease 2019 in cancer patients
    Wiley ; 2022
    In:  Immunology & Cell Biology Vol. 100, No. 1 ( 2022-01), p. 61-73
    Details
    In: Immunology & Cell Biology, Wiley, Vol. 100, No. 1 ( 2022-01), p. 61-73
    Abstract: Recent studies have highlighted multiple immune perturbations related to severe acute respiratory syndrome coronavirus 2 infection–associated respiratory disease [coronavirus disease 2019 (COVID‐19)]. Some of them were associated with immunopathogenesis of severe COVID‐19. However, reports on immunological indicators of severe COVID‐19 in the early phase of infection in patients with comorbidities such as cancer are scarce. We prospectively studied about 200 immune response parameters, including a comprehensive immune‐cell profile, inflammatory cytokines and other parameters, in 95 patients with COVID‐19 (37 cancer patients without active disease and intensive chemo/immunotherapy, 58 patients without cancer) and 21 healthy donors. Of 95 patients, 41 had severe disease, and the remaining 54 were categorized as having a nonsevere disease. We evaluated the association of immune response parameters with severe COVID‐19. By principal component analysis, three immune signatures defining characteristic immune responses in COVID‐19 patients were found. Immune cell perturbations, in particular, decreased levels of circulating dendritic cells (DCs) along with reduced levels of CD4 T‐cell subsets such as regulatory T cells (T regs ), type 1 T helper (Th1) and Th9; additionally, relative expansion of effector natural killer (NK) cells were significantly associated with severe COVID‐19. Compared with patients without cancer, the levels of terminal effector CD4 T cells, T regs , Th9, effector NK cells, B cells, intermediate‐type monocytes and myeloid DCs were significantly lower in cancer patients with mild and severe COVID‐19. We concluded that severely depleted circulating myeloid DCs and helper T subsets in the initial phase of infection were strongly associated with severe COVID‐19 independent of age, type of comorbidity and other parameters. Thus, our study describes the early immune response associated with severe COVID‐19 in cancer patients without intensive chemo/immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0818-9641 , 1440-1711
    URL: Issue
    URL: Article
    DOI: 10.1111/imcb.v100.1
    DOI: 10.1111/imcb.12504
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2011707-3
    SSG: 12
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  • 5
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    Clinical characteristics and outcomes of null-cell versus silent gonadotroph adenomas in a series of 1166 pituitary adenomas from a single institution
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2020
    In:  Neurosurgical Focus Vol. 48, No. 6 ( 2020-06), p. E13-
    Details
    In: Neurosurgical Focus, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 48, No. 6 ( 2020-06), p. E13-
    Abstract: Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs. METHODS The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected. RESULTS Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p 〈 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07–12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04–15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09–4.59; p = 0.030). CONCLUSIONS This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.
    Type of Medium: Online Resource
    ISSN: 1092-0684
    URL: Article
    DOI: 10.3171/2020.3.FOCUS20114
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2020
    detail.hit.zdb_id: 2026589-X
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  • 6
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    CSIG-10. ROLE OF c-Met/β1 INTEGRIN COMPLEX IN THE ESTABLISHMENT OF BRAIN METASTASES
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi46-vi46
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi46-vi46
    Abstract: Metastases cause 90% of human cancer deaths. The metastatic cascade involves five steps: invasion, intravasation, extravasation, colonization, and proliferation. While individual mediators of these processes have been investigated, their interactions remain undefined. We previously demonstrated increased formation of a structural complex between receptor tyrosine kinase c-Met and β1 integrin in metastases compared to primary tumors. We used novel cell culture models and in vivo assays to define the role of this complex in individual steps of the metastatic cascade. METHODS The iDimerize heterodimer system was inserted into MDA-MB-231 breast adenocarcinoma cells, allowing c-Met/β1 heterodimerization induction via A/C heterodimerizer treatment. Scratch assays and novel transwell assay modifications were used to measure migration, invasion, intravasation, and extravasation. Proximity ligation assay was performed to measure c-Met/β1 complex. Nanostring panel was used to transcriptionally profile cells. RESULTS c-Met/β1 complex induction promotes breast cancer invasion (p 〈 0.001), migration (p 〈 0.05), intravasation (p 〈 0.01), and adhesion to the vessel wall (p 〈 0.01). However, it does not increase extravasation in culture or in vivo. These effects may be driven by the ability of c-Met/β1 to increase mesenchymal character (p 〈 0.05) and stem cell population (p 〈 0.001). Nanostring analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction, particularly WNT7B (p 〈 0.05). OS2966, an antibody preventing c-Met/β1 binding, decreased invasion (p 〈 0.05), intravasation (p 〈 0.05), and mesenchymal morphology (p 〈 0.001) and gene expression (p 〈 0.001). Brain- and bone-seeking breast cancer cells have higher c-Met/β1 complex than controls (p 〈 0.05) and preferentially adhere to tissue-specific matrix (p 〈 0.01). CONCLUSIONS The c-Met/β1 complex drives breast cancer cell intravasation. While extravasation is not affected by the complex, preferential affinity for tissue-specific matrix enables the c-Met/β1 complex to drive breast cancer metastases to brain and bone. Pharmacological targeting of the complex may prevent metastases, particularly to the brain and bone.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.181
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 7
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    ITVT-02. Elucidating the pleiotropic effects of verteporfin photodynamic therapy in preclinical glioblastoma models
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi228-vi228
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi228-vi228
    Abstract: Glioblastoma (GBM) ranks the highest in mortality rate, incidence, and aggressiveness of primary brain tumor types. The highly malignant nature of GBM makes it difficult for mainstay treatments to have an effect beyond stabilizing the disease. Deregulation of receptor tyrosine kinase (RTKs), such as EGFR and PI3K, have been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), an FDA-approved macular degeneration therapy, has antitumor effects in in vitro and in vivo GBM preclinical models and phase I/II clinical trials for patients with EGFR mutated/amplified GBM by abrogating YAP/TAZ-TEAD interactions. As a porphyrin derivative, VP can exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate that VP-PDT reduces cell viability to a greater extent than solitary VP treatment (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.914
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 8
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    NCOG-54. SAFETY OF TRANSSPHENOIDAL SURGERY FOR NONFUNCTIONING PITUITARY ADENOMA IN ELDERLY PATIENTS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii141-ii141
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii141-ii141
    Abstract: Life expectancy has increased over the past century, shifting the demographic distribution towards older age groups. Elderly patients comprise up to 14% of patients with pituitary tumors, with most lesions being nonfunctioning adenomas (NFPAs). Here, we compare clinical and surgical outcomes and post-operative complications between non-elderly adult (age ≥ 18 years and ≤ 65 years) and elderly (age & gt; 65 years) NFPA patients. METHODS Retrospective review of 908 patients undergoing transsphenoidal surgery for NFPA at a single institution from 2007-2019. RESULTS Elderly patients represented 32.4% of patients. Both groups were similar in gender (57.3% vs 60.5% male;P=0.4), tumor size (2.56 vs 2.46 cm;P=0.2), and cavernous sinus invasion (35.8% vs 33.7%;P=0.6). Regarding post-operative outcomes, length of stay (1 vs 2 days; P=0.5), extent of resection (59.8% vs 64.8% GTR;P=0.2), CSF leak requiring surgical revision (4.3% vs 1.4%;P=0.06), 30-day readmission (8.1% vs 7.3%;P=0.7), infection (3.1% vs 2.0%;P=0.5), and new hypopituitarism (13.9% vs 12.0%;P=0.3) were similar between both groups. Elderly patients were less likely to have adjuvant radiation (8.7% vs 16.3%;P=0.009), future re-operation (3.8% vs 9.5%;P=0.003), and post-operative diabetes insipidus (DI) (3.7% vs 9.4%;P=0.002), and more likely to have post-operative hyponatremia (26.7% vs 16.4%;P & lt; 0.001) and new cranial nerve deficit (1.9% vs 0.0%;P=0.01). Elderly patients’ post-operative sodium peaked and troughed on POD3 (mean=138.7 mEq/L) and POD9 (mean=130.8 mEq/L), respectively, compared to non-elderly patients (peak POD2 mean=139.9 mEq/L, trough POD8 mean=131.3 mEq/L). CONCLUSION Our analysis revealed that elderly patients experienced more post-operative hyponatremia, while non-elderly patients experienced more post-operative DI. Elderly patients also experience later peak and trough in serum sodium, suggesting age-related differences in stalk-related morbidities of NFPA resection. Overall, our results show that transsphenoidal surgery for NFPA in elderly patients is safe with low complication rates. We hope our results will guide discussions with elderly patients regarding possible risks and outcomes.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa215.592
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 9
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    EXTH-04. ELUCIDATING THE PLEIOTROPIC EFFECTS OF VERTEPORFIN PHOTODYNAMIC THERAPY IN PRECLINICAL GLIOBLASTOMA MODELS
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi164-vi164
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi164-vi164
    Abstract: Glioblastoma (GBM) has the highest mortality rate, incidence, and therapy resistance of all primary brain tumors. Deregulation of the epidermal growth factor receptor (EGFR) has been implicated in GBM tumorigenesis. The expression of EGFR has been linked to hippo pathway transcriptional co-activators YAP and TAZ that bind to TEAD co-factors to drive the transcription of target genes. The convergence of EGFR signaling and the hippo pathway regulates stem cell programs, including proliferation, survival, and self-renewal. Verteporfin (VP), is an FDA-approved drug for photodynamic therapy (PDT) of macular degeneration. VP has been shown to have antitumor effects both in vitro and in vivo in GBM preclinical models. As a porphyrin derivative, VP can also exert therapeutic and photodynamic effects in the presence of 689 nm light; however, the efficacy of VP-PDT has not been explored in GBM. Our results indicate for the first time that VP-PDT reduces GBM cell viability to a greater extent than VP treatment alone (viability — 0.7 uM VP: 97%, 0.7 uM VP-PDT: 46%). The antitumor effects of VP-PDT are two pronged involving 1) inhibition of live cell dynamics, including migration and intravasation, by downregulating hippo pathway constituents YAP, TAZ and TEAD and transcriptional target EGFR and 2) induction of programmed cell death by reactive oxygen species. Our results suggest that VP-PDT can be a potential avenue for treating these incurable tumors.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.643
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 10
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    Identifying risk factors for postoperative diabetes insipidus in more than 2500 patients undergoing transsphenoidal surgery: a single-institution experience
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2022
    In:  Journal of Neurosurgery Vol. 137, No. 3 ( 2022-09-01), p. 647-657
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 137, No. 3 ( 2022-09-01), p. 647-657
    Abstract: Diabetes insipidus (DI) following transsphenoidal surgery can adversely impact quality of life and be difficult to manage. This study sought to characterize pre- and perioperative risk factors that may predispose patients to DI after pituitary surgery. METHODS A retrospective review of patients treated at a single institution from 2007 to 2019 was conducted. DI was defined as postoperative sodium 〉 145 mEq/L and urine output 〉 300 ml/hr and/or postoperative desmopressin (ddAVP) use. DI was further characterized as transient or permanent. Uni- and multivariate analyses were performed to determine variables associated with postoperative DI. RESULTS The authors identified 2529 patients who underwent transsphenoidal surgery at their institution. Overall, DI was observed in 270 (10.7%) of the 2529 patients, with 114 (4.5%) having permanent DI and 156 (6.2%) with transient symptoms. By pathology type, DI occurred in 31 (46.3%) of 67 craniopharyngiomas, 10 (14.3%) of 70 apoplexies, 46 (14.3%) of 322 Rathke’s cleft cysts, 77 (7.7%) of 1004 nonfunctioning pituitary adenomas (NFPAs), and 62 (7.6%) of 811 functioning pituitary adenomas (FPAs). Final lesion pathology significantly affected DI rates (p 〈 0.001). Multivariate analysis across pathologies showed that younger age (odds ratio [OR] 0.97, p 〈 0.001), intraoperative CSF encounter (OR 2.74, p 〈 0.001), craniopharyngioma diagnosis (OR 8.22, p = 0.007), and postoperative hyponatremia (OR 1.50, p = 0.049) increased the risk of DI. Because surgery for each pathology created specific risk factors for DI, the analysis was then limited to the 1815 pituitary adenomas (PAs) in the series, comprising 1004 NFPAs and 811 FPAs. For PAs, younger age (PA: OR 0.97, p 〈 0.001; NFPA: OR 0.97, p 〈 0.001; FPA: OR 0.97, p = 0.028) and intraoperative CSF encounter (PA: OR 2.99, p 〈 0.001; NFPA: OR 2.93, p 〈 0.001; FPA: OR 3.06, p 〈 0.001) increased DI rates in multivariate analysis. Among all PAs, patients with DI experienced peak sodium levels later than those without DI (postoperative day 11 vs 2). Increasing tumor diameter increased the risk of DI in FPAs (OR 1.52, p = 0.008), but not in NFPAs (p = 0.564). CONCLUSIONS In more than 2500 patients treated at a single institution, intraoperative CSF encounter, craniopharyngioma diagnosis, and young age all increased the risk of postoperative DI. Patients with postoperative hyponatremia exhibited higher rates of DI, suggesting possible bi- or triphasic patterns to DI. Greater vigilance should be maintained in patients meeting these criteria following transsphenoidal surgery to ensure early recognition and treatment of DI.
    Type of Medium: Online Resource
    ISSN: 0022-3085 , 1933-0693
    URL: Article
    DOI: 10.3171/2021.11.JNS211260
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2022
    detail.hit.zdb_id: 2026156-1
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