An Expermental Study On Treament Of Invasive Pituitary Adenoma Using Temozolomide Combined With Radiosurgery

The incidence of pituitary adenoma is next to that of glioma and meningioma.The incidence rate of pituitary adenoma is third in intracranial tumors.Most pituitary adenomas are benign,non invasive tumors.They are confined to the sella turcica,or part of the development to the outside of the sella,and squeeze the surrounding structures,such as optic nerve crossing,cavernous sinus and so on.About 1/3 of pituitary adenomas are difficult to treat by surgery alone,including residual tumor,recurrent tumor and invasive pituitary adenoma after operation.Invasive pituitary adenoma is a tumor between benign pituitary adenoma and pituitary adenocarcinoma.Its histological morphology is benign,but its biological characteristics are malignant.In 2004,WHO defined an atypical pituitary adenoma characterized by aggressive growth and high mitotic activity(Ki67 index,>3%).Tumors often invade the structures of the saddle,diaphragm,dura and adjacent vessels,and the dural involvement of the sellar floor is an important sign of the invasiveness of pituitary adenomas.Invasive pituitary adenomas have a poor prognosis,mainly because of their large size,infiltration of surrounding tissue,rapid growth,and easy recurrence.There is no standard treatment for invasive pituitary adenomas,and the commonly used treatment options,including surgery,radiation therapy,and drug therapy,are difficult to control.The basic research on the invasiveness of pituitary adenoma is in progress.There is a difference in the gene expression profiles between invasive pituitary adenomas and non invasive pituitary adenomas.At the gene level,researchers have found that pituitary adenoma transforming genes are one of the initiating factors of pituitary adenomas and are closely related to invasiveness.Matrix metalloproteinases(MMP)are a group of proteolytic enzymes that are dependent on zinc ions and are thought to play an important role in the invasion and metastasis of many malignant tumors.Matrix metalloproteinase 9 is highly expressed in invasive pituitary adenomas,which may be related to the invasive growth of pituitary adenomas.Vascular endothelial growth factor(VEGF)is the most direct vasoactive protein,he can promote angiogenesis and improve microvascular permeability to plasma macromolecules penetrate the outer extracellular matrix,provide nutrition for the establishment of tumor cell and the formation of new blood vessels.Vascular endothelial growth factor and its receptor expression in tumor cells and vascular endothelial cells were invasive pituitary adenoma;while in non invasive pituitary adenomas,mainly expressed in tumor cells,rarely expressed in vascular endothelial cells.With the increase of invasiveness,it is suggested that it may promote the angiogenesis of pituitary adenoma through its receptor and stimulate the growth and invasion of pituitary adenoma.Surgery is considered to be the best treatment modality for invasive pituitary adenomas,which can rapidly relieve tumor compression symptoms and intracranial hypertension.Alternative procedures include transsphenoidal microsurgery,endoscopic surgery,extended approach surgery,and craniotomy.However,invasive pituitary adenoma is easy to recur after operation.For non invasive pituitary adenomas,radiation therapy is generally recommended as a third line treatment for patients who have failed surgery and medications,or patients who have been left behind after surgery.But radiation therapy is one of the most important treatments for invasive pituitary adenomas.Stereotactic radiosurgery has developed rapidly in the past half century.Because the narrow beam focused on the therapeutic target,the surrounding normal tissues received extremely low doses.Radiosurgery for pituitary adenomas is also progressing.High resolution MRI for localization and postoperative follow-up can clearly show the tumor boundary and its surrounding structures,and dynamic enhancement of thin slice scan is helpful to identify tumor boundaries.The application of the planning system and its escalating software capabilities in the treatment plan improves both accuracy and function with the formulation of a conformal treatment plan.Gamma knife is the most widely used means of treatment in radiosurgery.He used cobalt 60 as a source of radiation and was treated at once.There were fewer complications after treatment.Sheehan et al reported a tumor control rate of 90.3% in 418 patients with pituitary adenomas treated with gamma knife radiosurgery.In recent years,the application of temozolomide in the treatment of pituitary carcinoma and invasive pituitary adenomas is popular,because the evaluation and treatment effect of the drug application and 06-methylguanine-DNA methyltransferase(MGMT)controversial relationship between,therefore has not yet been formally in the clinic application.The association between MGMT and temozolomide in the treatment of pituitary tumors is also seen in intracranial high-grade gliomas and other malignancies.Temozolomide is a second generation alkylating agent that induces DNA damage and inhibits transcription in 06-methyl guanine(06-MeG)base,which was previously used primarily in the treatment of malignant gliomas,malignant melanoma,or intracranial metastases.The drug for the treatment of pituitary adenoma,is a large number of clinical practice confirmed lomustine,fluorouracil and cisplatin,etoposide based on traditional chemotherapy drugs only can prolong the survival time of the patients can not inhibit the growth of tumor,and temozolomide through the antitumor effect and curative effect.In view of the effect of temozolomide on other intracranial tumors,such as Lim "tried to temozolomide treatment of pituitary adenocarcinoma patients,the intracranial metastases can be controlled,hormone metabolism disorder and clinical symptoms were significantly improved.A long-term follow-up study of patients with Fadul pituitary adenocarcinoma also obtained the same conclusion,therefore,temozolomide for invasive pituitary adenoma poor surgery and radiotherapy effect has good prospects for treatment.In 2006,Svro first reported therapeutic effect of temozolomide in treatment of prolactinomas,clinical symptoms and signs of patients were improved significantly,serum MGMT showed low expression,confirmed that temozolomide for such tumors,follow-up study of Kovacs are further confirmed this view.However,1 patients with ACTH adenoma did not receive the same efficacy after Kovacs and temozolomide therapy.The immunohistochemical staining showed that the tumor cell nucleus MGMT was highly expressed.In view of the above clinical findings,Kovacs et al suggest that the changes in MGMT expression may serve as an important indicator of the efficacy of temozolomide pretreatment.In 2008,Kovacs reported 2 cases of invasive pituitary adenoma(1 cases of prolactin adenocarcinoma and 1 cases of invasive growth hormone adenoma)in patients with temozolomide efficacy results,first proposed the MGMT expression change and the effect of chemotherapy drugs was negatively related to the view.n 2009,McCormack immunohistochemical staining on the 2 cases of temozolomide in the treatment of patients with effective tumor tissue sections showed that MGMT expression was low,and the clinical manifestation and imaging findings are significantly improved.Other clinical studies conducted over the same period have also led to the same finding that the expression of MGMT is of guiding significance in predicting the efficacy of temozolomide in the treatment of invasive pituitary adenomas or pituitary adenocarcinoma.This topic will study from the following two aspects:At first:Cell groups and treatments,with 99% isodose line wrapped around the target,respectively by 10 and 20 Gy margin dose on rat pituitary adenoma cell line GH3,MMQ underwent gamma knife irradiation for radiotherapy group;on rat pituitary adenoma cell lines GH3 and MMQ with IC50 dose of temozolomide treatment drugs for 24 hours the treatment group;on rat pituitary adenoma cell lines GH3,MMQ and IC50 dose of temozolomide treatment 24 hours after radiotherapy group irradiation combined treatment group 1;rat pituitary adenoma cell line GH3,MMQ line radiation treatment group after irradiation with the same conditions with the IC50 dose of temozolomide 24 hour amine treatment combined treatment group 2;in untreated control cells.The second aspect:The cells were treated with cell cycle,apoptosis,RT-PCR,Western-Blot detection,and Elisa detection of culture medium Result:1)the effect of combined therapy is better than simple gamma knife treatment and only temozolomide treatment;2)the combined group of gamma knife radiosurgery is better than the combination of temozolomide treatment;3)gamma knife radiosurgery has a certain sensitization effect on temozolomide treatment of invasive pituitary adenomas.