The Expression of Estrogen Receptor Subtypes in Prolactinomas and Their Relationship to Tumor Biological Behavior

Dopamine agonists （DA） are a first-line therapy for prolactinomas （PA）. However, nearly 10% of prolactinomas do not respond to DA therapy. A considerable number of studies have shown that estrogen plays an important role in the development of prolactinomas. However, the expression of estrogen receptors （ER） in prolactinomas has not been fully explored. Accordingly, we examined the levels of ESR1 and its subtypes A5-DeI-ESR1 and ESR2 mRNA in prolactinomas. In the present study,

Application of endoscopic endonasal approach in skull base surgeries: summary of 1886 cases in a single center for 10 consecutive years

Background:Endonasal endoscopic skull base surgery has undergone rapid technological developments and is now widely performed,but its strengths and weaknesses deserve further investigation and deliberation.This study was performed to investigate the surgical indications,complications,and technical advantages and disadvantages of endonasal endoscopic skull base surgery.Methods:The clinical data of 1886 endoscopic endonasal skull base surgeries performed in our ward at Beijing Tiantan Hospital from June 2006 to June 2016 were retrospectively analyzed.Results:One thousand ninety-three(73.4%,1490)pituitary adenomas,54(24.9%,217)chordomas,28(80.0%,35)craniopharyngiomas,and 15(83.3%,18)meningiomas underwent total resection.Two patients died postoperatively,both having pituitary adenomas.Other postoperative complications included olfactory disorders(n=226,11.9%),postoperative cerebrospinal fluid leakage(n=78,4.1%),hypopituitarism(n=74,3.9%),diabetes insipidus(n=64,3.4%),intracranial infection(n=36,1.9%),epistaxis(n=24,1.3%),vascular injury(n=8,0.4%),optic nerve injury(n=8,0.4%),and oculomotor movement impairment(n=4,0.2%).In total,1517(80.4%)patients were followed up for 6 to 126 months(average,42.5 months)postoperatively.A total of 196(13.2%)pituitary adenomas and 13(37.1%)craniopharyngiomas recurred but no meningiomas recurred.Chordomas recurred in 97(44.7%)patients,in whom 5-year survival rate was 65%.Conclusion:Endoscopic surgery is an innovative surgical technique and the first choice for most midline extradural lesions such as chordomas,and an excellent choice for pituitary adenomas.It probably will be a good technique for many kinds of craniopharyngiomas and a common technique for most of skull base meningiomas,so the surgical indications of these cases should be chosen carefully to make good use of its respective advantages.

Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma

Background： Thyrotropin-secreting pituitary adenomas （TSHomas） are a rare cause of hyperthyroidism. Somatostatin （SST） analogs work by interacting with somatostatin receptors （SSTRs）. This study aimed to evaluate short-term preoperative octreotide （OCT） use in TSHoma patients and to investigate SSTR2 and SSTR5 expression and observe structural changes in tumor tissue. Methods： We reviewed records and samples from eight TSHoma patients treated between July 2012 and July 2015. We tested immunohistochemically for SSTR2/5 expression and examined TSHoma cells for morphological changes. Signed rank sum test was used to compare the efficacy of short-term preoperative OCT treatment. Results： OCT treatment （median time： 7.9 days, range： 3-16 days; median total dose： 1.8 mg, range： 0.94.2 mg） led to significant decrease in all patients＇ thyroid hormone levels （FT3 [nmol/L]： 8.33 [7.02, 12.29] to 4.67 [3.52, 5.37] [P = 0.008]; FT4 [pmol/L]： 25.36 [21.34, 28.99] to 16.66 [14.88, 21.49] [P = 0.016]; and TSH [gU/ml]： 5.80 [4.37, 6.78] to 0.57 [0.19, 1.24] [P = 0.008]）. All the eight tumor specimens expressed high SSTR2 protein levels; 5/8 expressed high SSTRS, but 3/8 that expressed low SSTR5 presented a significantly higher TS H suppression rate （P = 0.036）. Electron microscopy showed subcellular level impairments, including clumped nuclear chromatin and reduced cytoplasmic volume. Golgi complexes were observed in the OCT-treated TSHoma specimens. Conclusions： OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.

ROR1, an embryonic protein with an emerging role in cancer biology

Receptor tyrosine kinase-Uke orphan receptor 1 （ROR1） is a member of the ROR family consisting of ROR1 and ROR2. RORs contain two distinct extracellular cysteinerich domains and one transmembrane domain. Within the intracellular portion, ROR1 possesses a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain. RORs have been studied in the context of embryonic patterning and neurogenesis through a variety of homologs. These physiologic functions are dichotomous based on the requirement of the kinase domain. A growing literature has established ROR1 as a marker for cancer, such as in CLL and other blood malignancies. In addition, ROR1 is critically involved in progression of a number of blood and solid malignancies. RORt has been shown to inhibit apoptosis, potentiate EGFR signaling, and induce epithelialmesenchymal transition （EMT）. Importantly, ROR1 is only detectable in embryonic tissue and generally absent in adult tissue, making the protein an ideal drug target for cancer therapy.

Role of EGFL7/EGFR-signaling pathway in migration and invasion of growth hormone-producing pituitary adenomas

Currently, the primary therapeutic strategy for most growth hormone-producing pituitary adenomas(GHPA) is surgery. Due to the invasiveness of GHPA, high recurrence has limited the benefit of complete adenoma removal surgery. Epidermal growth factor-like domain 7(EGFL7) is a secreted factor implicated in tumor angiogenesis, growth, invasiveness and metastasis in GHPA. Herein, we observed that the expression level of EGFL7 and p-EGFR in invasive GHPAwas much higher than that of non-invasive GHPA. The overexpression of EGFL7 was positively correlated with activation of EGFR(p-EGFR). Noticeably, EGFL7 knockdown significantly inhibited activation of EGFR signaling cascades, including p-ERGR, p-AKT and p-ERK. Further studies showed that EGFL7 knockdown or pharmacological inhibition of EGFR-pathway, using EGFR inhibitor Tyrphostin AG-1478, significantly suppressed migration and invasion of GH3 and GT1-1 cells. In summary, our findings suggest that EGFL7 is a key factor for regulation of EGFR signaling pathway and plays an important role in migration and invasion of invasive GHPA.