MRI for Growth hormone deficiency

MRI for Growth hormone deficiency

In patients with severe growth hormone deficiency and patients with multiple pituitary hormone deficiencies, MRI is more likely to be abnormal, and bone age is much delayed in patients with a history of prenatal disorder1)

MRI is indicated to rule out calcifications, tumors, and structural anomalies. But preliminary data indicate that most brain MRIs performed for routine evaluation of children with isolated growth hormone deficiency (IGHD) are not essential for determining the cause. Further studies with larger cohorts are needed in order to validate this proposed revision of current protocols 2).

Patients with abnormal MRI findings show a more favorable response to GH replacement therapy 3).


Pathogenic MRIs were uncommon in patients diagnosed with GHD except in the group with peak GH<3 ng/mL. There was a high frequency of incidental findings which often resulted in referrals to neurosurgery and repeat MRIs. Given the high cost of brain MRIs, their routine use in patients diagnosed with isolated GHD, especially patients with a peak GH of 7-10 ng/mL, should be reconsidered 4).


Xu et al. verified the advantages of using magnetic resonance imaging (MRI) for improving the diagnostic quality of growth hormone deficiency (GHD) in children with short stature caused by pituitary lesions. Clinical data obtained from 577 GHD patients with short stature caused by pituitary lesions were retrospectively analyzed. There were 354 cases (61.3%) with anterior pituitary dysplasia; 45 cases (7.8%) of pituitary stalk interruption syndrome (PSIS); 15 cases (2.6%) of pituitary hyperplasia due to primary hypothyroidism; 38 cases (6.6%) of Rathke cleft cyst; 68 cases (11.8%) of empty sella syndrome; 16 cases (2.8%) of pituitary invasion from Langerhans cell histiocytosis; 2 cases (0.3%) of sellar regional arachnoid cyst and 39 cases (6.8%) of craniopharyngioma. MRI results showed that the height of anterior pituitary in patients was less than normal. Location, size and signals of posterior pituitary and pituitary stalk were normal in anterior pituitary dysplasia. In all cases pituitary hyperplasia was caused by hypothyroidism. MRI results showed that anterior pituitary was enlarged, and we detected upward apophysis and obvious homogeneous enhancement. There were no pituitary stalk interruption and abnormal signal. We also observed that after hormone replacement therapy the size of pituitary gland was reduced. Anterior pituitary atrophy was observed in Rathke cleft cyst, empty sella syndrome, sellar regional arachnoid cyst and craniopharyngioma. The microstructure of hypophysis and sellar region was studied with MRI. We detected pituitary lesions, and the characteristics of various pituitary diseases of GHD in children with short stature. It was concluded that in children with GHD caused by pituitary lesions, MRI was an excellent method for early diagnosis. This method offers clinical practicability and we believe it can be used for differential diagnosis and to monitor the therapeutic effects 5).


1)

Naderi F, Eslami SR, Mirak SA, Khak M, Amiri J, Beyrami B, Shekarchi B, Poureisa M. Effect of growth hormone deficiency on brain MRI findings among children with growth restrictions. J Pediatr Endocrinol Metab. 2015 Jan;28(1-2):117-23. doi: 10.1515/jpem-2013-0294. PMID: 25153566.
2)

Oren A, Singer D, Rachmiel M, Hamiel U, Shiran SI, Gruber N, Levy-Shraga Y, Modan-Moses D, Eyal O. Questioning the Value of Brain Magnetic Resonance Imaging in the Evaluation of Children with Isolated Growth Hormone Deficiency. Horm Res Paediatr. 2020;93(4):245-250. doi: 10.1159/000509366. Epub 2020 Aug 24. PMID: 32836222.
3)

Ariza Jiménez AB, Martínez Aedo Ollero MJ, López Siguero JP. Differences between patients with isolated GH deficiency based on findings in brain magnetic resonance imaging. Endocrinol Diabetes Nutr. 2020 Feb;67(2):78-88. English, Spanish. doi: 10.1016/j.endinu.2019.09.001. Epub 2019 Nov 14. PMID: 31734177.
4)

Schmitt J, Thornton P, Shah AN, Rahman AKMF, Kubota E, Rizzuto P, Gupta A, Orsdemir S, Kaplowitz PB. Brain MRIs may be of low value in most children diagnosed with isolated growth hormone deficiency. J Pediatr Endocrinol Metab. 2021 Feb 22. doi: 10.1515/jpem-2020-0579. Epub ahead of print. PMID: 33618442.
5)

Xu C, Zhang X, Dong L, Zhu B, Xin T. MRI features of growth hormone deficiency in children with short stature caused by pituitary lesions. Exp Ther Med. 2017 Jun;13(6):3474-3478. doi: 10.3892/etm.2017.4377. Epub 2017 Apr 24. PMID: 28587427; PMCID: PMC5450600.

Update: Epidermal growth factor receptor

The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.
Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors.


The receptor for epidermal growth factor (EGFR) is a prime target for cancer therapy across a broad variety of tumor types. As it is a tyrosine kinase, small molecule tyrosine kinase inhibitors (TKIs) targeting signal transduction, as well as monoclonal antibody against the EGFR, have been investigated as anti-tumor agents. However, despite the long-known enigmatic EGFR gene amplification and protein overexpression in glioblastoma, the most aggressive intrinsic human brain tumor, the potential of EGFR as a target for this tumor type has been unfulfilled 1).
This is in sharp contrast with the observations in EGFR-mutant lung cancer.


The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.
Overexpression of epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) secondary to EGFR gene amplification is associated with a more aggressive tumor phenotype and a worse clinical outcome.


Epidermal growth factor receptor (EGFR), pMAPK, 4E-BP1, p4E-BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi-square, Student’s t, Pearson correlation, Spearman’s rho, and Mann-Whitney; ROC and Kaplan-Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E-BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E-BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples 2).


Ren et al., analyzed the microarray and proteomics profiles of tumor tissues from glioblastoma patients (N = 180), and identified potential RNA regulators of the Kininogen 1 (KNG1). Validation experiments in U87 glioblastoma cells showed that the regulation of KNG1 by CTU1, KIAA1274, and RAX was mediated by miR 138. The siRNA-mediated knockdown of CTU1, KIAA1274, or RAX in U87 cells and immortalized human endothelial cells (iHECs) significantly reduced KNG1 expression (P < 0.05 for all), which resulted in the upregulation of oncogenic EGFR signaling in both cell lines, and stimulated angiogenic processes in cultured iHECs and zebrafish and mouse xenograft models of glioblastoma-induced angiogenesis. Angiogenic transduction of iHECs occurred via the uptake of U87-derived exosomes enriched in miR-138, with the siRNA-mediated knockdown of KNG1, CTU1, KIAA1274, or RAX increasing the level of miR-138 enrichment to varying extents and enhancing the angiogenic effects of the U87-derived exosomes on iHECs. The competing endogenous RNA network of KNG1 represents potential targets for the development of novel therapeutic strategies for glioblastoma 3).

EGFRvIII

Fluorophore/nanoparticle labeled with anti-EGFR antibodies

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.
They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.
They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.
The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.
5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 4).

References

1)

Westphal M, Maire CL, Lamszus K. EGFR as a Target for Glioblastoma Treatment: An Unfulfilled Promise. CNS Drugs. 2017 Aug 8. doi: 10.1007/s40263-017-0456-6. [Epub ahead of print] PubMed PMID: 28791656.
2)

Martínez-Sáez E, Peg V, Ortega-Aznar A, Martínez-Ricarte F, Camacho J, Hernández-Losa J, Ferreres Piñas JC, Ramón Y Cajal S. peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas. Cancer Med. 2016 Jul 20. doi: 10.1002/cam4.817. [Epub ahead of print] PubMed PMID: 27440383.
3)

Ren Y, Ji N, Kang X, Wang R, Ma W, Hu Z, Liu X, Wang Y. Aberrant ceRNA-mediated regulation of KNG1 contributes to glioblastoma-induced angiogenesis. Oncotarget. 2016 Oct 14. doi: 10.18632/oncotarget.12659. PubMed PMID: 27764797.
4)

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.

Update: Hepatoma derived growth factor in neurosurgery

Hepatoma derived growth factor

Hepatoma-derived growth factor (HDGF) also known as high mobility group protein 1-like 2 (HMG-1L2) is a protein that in humans is encoded by the HDGF gene.
Hepatoma-derived growth factor (HDGF), a potential predictive and prognostic marker in several human cancers, is the firstly reported member of the HDGF family of proteins containing a well-conserved N-terminal amino acid sequence. HDGF is implicated in tumorigenesis by direct angiogenic activity, and its expression is correlated with aggressive biological ability of cancer cells including proliferation and angiogenesis.

Gliomas

HDGF is overexpressed in gliomas as compared to normal brain.
HDGF knockdown significantly inhibited the malignant phenotype of U87 cells, including the colony formation, migration and invasion in vitro, as well as tumorigenesis in vivo. The data also suggest that hepatocyte growth factor/scatter factor (HGF/SF) may contribute to the HDGF-associated aggressive behavior of glioma cells 1).
Findings of novel glioblastoma stem cell (GSC) -secreted molecules with pro-angiogenic properties (Semaphorin 3A, hepatoma derived growth factor) open the path to the design of a concerted attack of glioblastoma vasculature that could overcome the development of resistance to single-targeted therapies while keeping away the toxicity of the treatments 2).
GSC-conditioned medium induced neoangiogenesis, whereas HDGF-targeting siRNAs abrogated this effect. Altogether, the results identify a novel candidate, by which GSCs can support neoangiogenesis, a high-grade glioma hallmark. comparative proteomic analysis is useful to decipher molecular pathways, which underlie GSC properties 3)
HDGF is a mitogenic growth factor in glioma progression and can be a useful prognostic marker for GBM and therapeutic target for clinical management of glioma in the future 4).
Song et al. analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced temozolomide (TMZ)-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherinexpression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl 2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, the data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas 5).
Studies suggest that while blood vessels support glioma stem cells, these tumor cells in turn may regulate and contribute to the tumor vasculature by transdifferentiating into endothelial cells directly or through the secretion of regulatory growth factors such as vascular endothelial growth factor(VEGF) and hepatoma derived growth factor (HDGF) 6).

Spinal cord

Hepatoma‑derived growth factor‑2 (HDGF‑2) is expressed in neurons, astrocytes and oligodendrocytes of the adult mouse brain. However, it has remained elusive whether HDGF‑2 is expressed in the spinal cord and is involved in the its development and repair. In a study, the expression of HDGF‑2 was investigated in rat spinal cords at different developmental stages and following spinal cord injury (SCI). Protein levels of HDGF‑2 were examined using western blot analysis, while the distribution pattern and cell populations of HDGF‑2 protein expression were characterized using immunohistochemistry. Western blot analysis demonstrated that the levels of HDGF‑2 protein expression were the greatest in the spinal cord on embryonic day 19, and were also highly expressed in rat spinal cords on post‑natal day 7 (P7); however, they were low at P14 and not detectable at two months. HDGF‑2 expression was significantly upregulated in the embryonic spinal cord and injured spinal cord. By contrast, the expression of HDGF‑2 was low in uninjured adult spinal cords. HDGF‑2 expression in the fetal rat spinal cord and injured spinal cord was significantly higher than that in uninjured adult spinal cord tissues (P<0.05). The number of cells positive for HDGF‑2 was 141±62, 107±33 and 92±18 at days 1, 21 and 45 following SCI, respectively, as opposed to 50±9 in uninjured rats, and a significant difference was identified between the different time‑points following SCI (P<0.01). In conclusion, the overexpression of HDGF‑2 in the embryonic spinal cord and injured spinal cord may be involved in fetal spinal cord development and repair of SCI, respectively 7).

Lymphoma

HDGF may be a valuable factor in progression and prognosis for primary central nervous system lymphoma (PCNSL) through its angiogenic and proliferative activity. So, HDGF, CD31 and Ki67 expression in the specimens of 60 patients suffering from PCNSL was investigated by immunohistochemistry in this study. Their correlations with clinicopathologic features and prognosis were evaluated to determine whether HDGF, CD31 and Ki67 expression levels correlate with the prognosis of the 60 patients suffering from PCNSL. We found that all PCNSL specimens showed HDGF, CD31 and Ki67 expression with different expression levels. Statistical analysis showed that HDGF had a positive correlation with CD31, but not with Ki67. Patients with higher HDGF and CD31 expression level had poorer overall survival rates than those with lower expression levels of HDGF and CD31, while Ki67 expression level did not correlate with overall survival. Multivariate analysis revealed that postoperative adjuvant chemotherapy and high expression of HDGF was independent prognostic indicator of patient survival 8).
1) Zhang A, Long W, Guo Z, Guo Z, Cao BB. Downregulation of hepatoma-derived growth factor suppresses the malignant phenotype of U87 human glioma cells. Oncol Rep. 2012 Jul;28(1):62-8. doi: 10.3892/or.2012.1768. Epub 2012 Apr 20. PubMed PMID: 22576797.
2) Thirant C, Gavard J, Junier MP, Chneiweiss H. Critical multiple angiogenic factors secreted by glioblastoma stem-like cells underline the need for combinatorial anti-angiogenic therapeutic strategies. Proteomics Clin Appl. 2013 Jan;7(1-2):79-90. doi: 10.1002/prca.201200102. Review. PubMed PMID: 23229792.
3) Thirant C, Galan-Moya EM, Dubois LG, Pinte S, Chafey P, Broussard C, Varlet P, Devaux B, Soncin F, Gavard J, Junier MP, Chneiweiss H. Differential proteomic analysis of human glioblastoma and neural stem cells reveals HDGF as a novel angiogenic secreted factor. Stem Cells. 2012 May;30(5):845-53. doi: 10.1002/stem.1062. PubMed PMID: 22331796.
4) Hsu SS, Chen CH, Liu GS, Tai MH, Wang JS, Wu JC, Kung ML, Chan EC, Liu LF. Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas. J Neurooncol. 2012 Mar;107(1):101-9. doi: 10.1007/s11060-011-0733-z. Epub 2011 Oct 26. PubMed PMID: 22037800.
5) Song Y, Hu Z, Long H, Peng Y, Zhang X, Que T, Zheng S, Li Z, Wang G, Yi L, Liu Z, Fang W, Qi S. A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma. J Neurooncol. 2014 Sep;119(2):285-95. doi: 10.1007/s11060-014-1512-4. Epub 2014 Jul 2. PubMed PMID: 24986090.
6) Jhaveri N, Chen TC, Hofman FM. Tumor vasculature and glioma stem cells: Contributions to glioma progression. Cancer Lett. 2014 Dec 16. pii: S0304-3835(14)00783-6. doi: 10.1016/j.canlet.2014.12.028. [Epub ahead of print] PubMed PMID: 25527451.
7) Zhuang Z, Mei G, Liu W, Chen Y, Zeng J, Zhang W, Yao G, Wang X. Hepatoma‑derived growth factor‑2 is highly expressed during development and in spinal cord injury. Mol Med Rep. 2015 Aug 6. doi: 10.3892/mmr.2015.4195. [Epub ahead of print] PubMed PMID: 26252862.
8) Li SZ, Zhao YB, Cao WD, Qu Y, Luo P, Zhen HN, Chen XY, Yan ZF, Fei Z. The expression of hepatoma-derived growth factor in primary central nervous system lymphoma and its correlation with angiogenesis, proliferation and clinical outcome. Med Oncol. 2013;30(3):622. doi: 10.1007/s12032-013-0622-8. Epub 2013 Jun 15. PubMed PMID: 23771798.
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