The Basical Study And Clinical Application Of Intraoperative Ultrasound In Brain Glioma Resections

[Background and Objection]:Glial neoplasms are the most common malignant brain tumor.The reported incidence of primary glioma is 16.7 per 100,000 persons.In our country,gliomas constituted about 35.26%-60.96%(average 44.69%) of intracranial tumors.In the past decades,advances in neuroimaging techniques,as in computed tomography(CT),magnetic resonance imaging(MRI),functional MRI (fMRI),magnetic resonance angiography(MRA),position emission tomography (PET),magnetic resonance spectroscopy(MRS) and magnetoencephalography(MEG) etc,provided the means of high resolution imaging of the head and its contents. Preoperative accurate localization and differential diagnosis of brain glioma are not puzzlement for neurosurgeons.By the main time,accompaniment of those new concept and technique of therapy,there have been considerable progresses in the treatment of gliomas.But the prognoses of this malignant tumor are still unacceptable. The mean survival times for glioma are no more than several years,for glioblastomas are about 8 months.It is a great challenge for neurosurgeon to improve the therapy outcome that to prolong the free survival time.The concept has been confirmed by some uncontrolled and retrospective studies of surgical series and accepted by majority of the neurosurgeons that the most effective management course of gliomas, whether low-or high-grade,is maximum surgical resection followed by adjuvant irradiation and chemotherapy.Among these processes,the most dominating one is the surgical resection.Appropriate neurosurgical dissection often offers the patients with gliomas an improved quality of life,a prolonged survival,and an improved control of neurological defects.In order to obtain the best possible outcome for the patients,a real gross total glioma resection is desirable.An ideal surgical resection of glioma acquires accurate localization and precise delineation of the margin.With preoperative identify of the morphological features of gliomas by CT and MRI, especially guided by neuro-navigation system,it is a facility task for neurosurgeons to find a safe and quick route reaching the lesions.It had been verified that a neurosurgeon's view of residual glioma alone could be incorrect.In about 70%of the high-grade gliomas,residual tumor could be demonstrated by early postoperative MRI.Therefore,many different intraoperative techniques are chosen to optimize the surgical result.It is well known that intraoperative MRI is the most reliable and valuable intraoperative imaging to evaluate the extent of resection,identify the residual glioma and improve the operative outcome,but it is too expensive for most clinics around the world.The intraoperative MRI technologies demand special equipment and solutions in the operating room.It cannot be adopted as routine application except few neurosurgical centers.One of the disadvantages of the navigation system is the inability to provide real time information during the operation if the neurosurgeons want;the other is brain shift caused by removal of tumor tissue and the lose of CFS,which will make navigation based on preoperative images inaccurate.Because of its simple,quick and cheap handling,intraoperative ultrasound (IOUS) has been performed as an alterative real time imaging modality.Ultrasound has been shown to be especially efficacious for several functions,namely localizing, defining borders of lesions and differentiating the tumor from cyst or necrosis.A series reported results showed IOUS to be 100%effective in localizing almost all types of brain tumor.But the value of ultrasound for resection control was still controversial.The possible sources of this argument include:no unified technological manual for performing ultrasound exam during the operation;multiplicity of ultrasonic imaging standard for residual tissue and tumor borders;comparison of ultrasonic image with difference references;no study assessed the value of IOUS pathologically,for detecting residual glioma and improving removal rate. An unobvious blind-spot in the reported papers about neurosurgical IOUS can be sough that almost all of the studies were focused on the patients intended total resection,but the value of it for protecting anatomy structure and neurological function in the patients with gliomas in eloquent areas who intended subtotal resection was ignored.Another notable weakness of routine IOUS for resection control is unascertainable in delineating the margin between the high-grade glioma and the peritumoral edema tissue.Some new ultrasonic concepts,namely Doppler ultrasound,harmonic imaging,contrasted-ultrasound,etc,were suggested useful to improve value of resection control on the basement of malignant pathology of glioma, especially the significant difference between the levels of angiogenesis within the tumor and outsides edema tissue.Reflecting these specifics,these studies included following objectives.1.To evaluate the value of IOUS for detecting residual glioma by comparing with pathology.To retrofit the previously reported intraoperative artifices with new measures to overcome the uncertain variances among ultrasonographic images for the residual tumor caused by a diversity of the intraoperative ultrasonographic technique.2.To evaluate the benefit of IOUS with technological improvements for detecting residual glioma and improving completely removal rate.3.To evaluate the reliability and contribution of IOUS,in patients with gliomas in functional important regions and intended subtotal resections,for archiving the purpose to obtain maximum surgical dissection of glioma without violating the cortex of eloquent area.4.To confirm the pathological mechanism of the PDU in improving the preciseness of routine ultrasound in delineating the gliomal margin.The capability and reliability of intraoperative PDU for distinguish glioma from edema tissue.The angiogenesis of high-grade gliomas and peritumoral edema are investigated by intraoperative PDU during the predictive gross total resection.Whether there is a significant difference between the levels of macroscopic angiogenesis within gliomas and surrounding edemas,measured by PDU shown asⅥ,is determined.The correlation between theⅥmeasured by PDU and microscopic angiogenesis (microvessel density) will be assessed by immunohistochemical examination.Part One The value of intraoperative high-resolution ultrasound for detecting residual glioma:a histopathologial study[Objective]:Some technological improvements were adapted:to elevate the imaging quality of intraoperative high-resolution ultrasound;to establish the intraoperative performing manual of ultrasound;increase the reliability and security of ultrasound in the resection of brain gliomas.The value of the retrofitted ultrasound for detecting residual glioma was assessed by comparing with histopathology.[Methods]:Thirty-seven gliomas,gross total resection was intended in all cases, were examined by technologically improved high-resolution ultrasound at the end of conventional microneurosurgery.There were 21 men and 16 women,who ranged in age from 14 to 62 years(median 40 years).There were 38 brain lesions shown on preoperative MRI images.Single lesion was revealed in 36 cases and double in the other one.All of the operations were navigated by ultrasonography.Instrument used for IOUS scan was a GE-LOGIQ Book XP scanner.A special intraoperative high-frequency probe with small-footprint design,sterilized by epoxyethane,was used.The functional area of the transducer was moved on the surface of brain or inner wall of dissection cavity directly.The sterile plastic sheath that used in previous reported study was then unnecessary,There was no separate layer between the probe and the aim region except saline coupling the two superficies.Operative route was designed according to the preoperative MRI.Sometime,a slightly widen cranial hole was unavoidable for unrestricted local and perform of the probe.The ultrasound scanning was performed at the time that there was no residual tumor detected by neurosurgeon under the microscopy.Before ultrasound exam,the operation cavity was filled with saline,after the spatula and cottonoids in the operation cavity were removed completely to ensure good image quality.The scanning surface of the transducer was kept on a parallel with the target surface during the whole process. The positive ultrasonic diagnosis of residual tumor was made by revealed hyperechoic mass adhered to or under the cavity wall.The thin hyperechoic rim on the surface was considered no predictive value.The biopsy specimens were matched with every positive sonographic site as well as with every negative resection cavity in five sites.The ultrasonic diagnoses were compared to histopathology.[Result]:With the benefits of special-design intrao-perative probe and new technique,the appearance of the ambiguous sonographic signs,matched with inhomogeneous histopathologic results,had been reduced.Sensitivity,specificity and accuracy of improved ultrasound in detecting residual tumor were 65.71%,98.34% and 95.25%,respectively.91.67%(11/12) of the ultrasonic pseudo-negative cases occurred in high-grade glioma.[Conclusion]:With proper technological adjustments and then high image quality, IOUS could be used as a reliable real-time imaging measure with great security for detecting residual glioma.Part Two The value of intraoperative ultrasound for improving the completely removal rate of brain gliomas[Objective]:To evaluate the benefit of IOUS in detecting residual glioma and improving the completely removal rate.[Methods]:Between Jun 2005 and Dec 2007,totally 64 gliomas intended gross total resection preoperatively were included in our study.IOUS was performed at the end of conventional micro-neurosurgery to detect residual tumor.Biopsy specimen was taken in each sonographic positive site and the other five negative sites scattered in the wall of resection cavity.Pathologic diagnosis of the biopsy specimens was matched with every positive sonographic site as well as with every negative site.If a sonographic positive diagnosis was upheld by neurosurgeon,with the navigation of ultrasound,an additional dissection for residual tumor was undertaken.A x~2 test was used to analyses whether there was a significant difference of the rate of radical resection caused by IOUS.[Results]:Confirmed by postoperative histopathology,8 cases,32 cases,15 cases and 9 cases were sorted into WHO gradeⅠ-gradeⅣ,respectively.Among the 53 positive sites marked by ultrasound,48 true and 5 false positive diagnoses were revealed by histopathology.In the 320 sonographic negative sites,diagnoses of 284 sites were true and of other sites were false.Sensitivity,specificity and accuracy of ultrasound in detecting residual tumor were 57.14%,98.27%and 89.01%, respectively.Pathologic total glioma resection was recorded in 13 cases(20.31%,4 gradeⅠ,8 gradeⅡ,1 gradeⅢ) at the end of conventional micro-neurosurgery.After additional resections navigated by ultrasound,total resection was obtained in 26 cases(40.63%,7 gradeⅠ,17 gradeⅡ,2 gradeⅢ).The results show the rate of total resection in low-grade glioma group was increased significantly(P＜0.05) and almost no change of the rate could be recorded in high-grade group.[Conclusion]:IOUS was a reliable real-time imaging technique with great security for detecting residual glioma.With the aid of IOUS,neurosurgical surgeons could gain a significantly improved rate of radical resection in low-grade gliomas.Part Three Subtotal resection of subcortical gliomas in eloquent areas controlled by intraoperative ultrasound[Objective]:To evaluate reliability and contribution of IOUS for avoiding damages of anatomic structures and neurological injuries as well as increasing resection rate by the mean time,in the subtotal resection of gliomas located in functionally important regions.[Methods]:Fifteen patients with gliomas located subcortically in the eloquent areas were operated on using IOUS.There were 9 men and 6 women in gender,ranged in age from 16 to 53 years(median 37 years).There were ten lesions in central eloquent regions,three near the optic center and two near the lateral fissure.Post-operative pathological confirmed that there were eight low-grade gliomas and the others were high-grade gliomas.The localization of the focus and the correlation of them with the cortex were ascertained by preoperative MRI,as well as the preoperative volume of each lesion.Operations were navigated by ultrasonography.Instrument used for IOUS scan was a GE LOGIQ BookXP scanner.A special intraoperative probe with small-footprint design,sterilized by epoxyethane,was adopted.The initial ultrasound exam was performed through the unopened dura.The real time images both of lesion and eloquent cortex were recorded to design the operation route.In vicinity of the cortex,the nearest sulcus without any large vessels was chosen as the pathway to reach the aim.From the outsides to the inner lesion,an underlying way of the cortex to the aim was guided by ultrasound.When the resection cavity enlarged and the wall extended proximity to the upper cortex,a real time monitor of the residual tumor in this region was shown by ultrasound.The resection withdrew until extent marched the boundary zone between glioma and the cortex,whether there were residual tumors revealed or not.The volume and localization of the residual gliomas were measured and recorded.The other part of glioma,which was beyond the superficial cortex,was intended total resection.All patients underwent an early postoperative MRI.The efficacy of ultrasound for resection control was determined by comparing the volumes measured by IOUS with that measured by postoperative MRI.The variance of the volumes measured by both modalities was no more than 20 percent, 20～30 percent,or＞30 percent,a good,a moderate or a poor define level of the ultrasound was determined,respectively.An independent-samples T test was used to evaluate the difference between the IOUS and MRI volumes.The influence of WHO grades and volume of tumors on the correlation between the IOUS and MRI was analysis by an independent-samples rank sum test.[Results]:At the end of the operations,residual gliomas under the cortex were shown by ultrasound in 13 cases,with volume range 0.62ml～17.78ml(5.49±5.69ml).The volumes of these residual gliomas measured postoperative MRI were 0.37～24.56ml(7.14±8.43ml).There was no significant difference between these two groups(t=0.616,P=0.543).Compared with preoperative MRI,no more anatomic damages of functional areas could be revealed.A good correlation in comparing IOUS-and MRI-tumor volumetric result of subtotal resection was recorded in 9 cases (60.00%).Two(13.33%) and four(26.67%) cases showed a moderate and poor correlation respectively.The deviation between the different imaging grew obviously with tumor volume much than 30ml(Z=-2.239,P=0.025).WHO grade of gliomas shown no significant influence on the variances(Z=-0.198,P=0.843).[Conclusion]:IOUS was not only helpful in determining the secure route to reaching the subcortical lesions in eloquent areas,but also useful in reaching the target that dissected tumor volume as much as possible without detriment of normal cortex.The reliability of IOUS relate with tumor size in an inverse feedback.Part Four Intraoperative evaluation of angiogenesis within high-grade gliomas and peritumoral edema by power Doppler ultrasound[Objective]:The angiogenesis in high-grade gliomas and peritumoral edema were investigated by intraoperative PDU during the predictive gross total resection.The correlation between angiogenesis level measured by PDU and pathological level was assessed by immunohistochemical examination.[Methods]:In twenty-five high-grade gliomas predicted gross total tumor resections, PDU was performed in every case,and the imaging was recorded on cine clips. Regions of interest within tumor and peritumor edema zone were analyzed off-line by Photoshop soft.Tumoral and peritumoral blood flow were quantified by intraoperative PDU shown as power Doppler vascularity index(Ⅵ).Tumoral and peritumoral MVD were evaluated at immunohistochemical staining of CD34.The Student t-test was used to evaluate potential difference in both of ultrasonic and immunohistochemical parameters between the tumor mass and the surrounding edema tissue zone.The correlation between the ultrasonic measure of vascularity(Ⅵ) in gliomas and edema with the MVD in corresponding areas respectively were investigated by Spearman correlation test.[Results]:Both of ultrasonic measurement(Ⅵ) and immunohistochemical analysis (MVD) revealed significant difference in vascularity levels of gliomas and edema (both t=0.000,P＜0.01).For the entire cohort,theⅥcorrelated with the MVD(within tumor,r=0.747;in peritumoral edema zone,r=0.672,respectively).[Conclusions]:Between the vascularity in tumor and peritumor edema tissue,eitherⅥmeasured by PDU or MVD assessed by immunohistochemical staining,significant differences was revealed.A significant correlation,in glioma or edema,was shown between PDU measurement of glioma vascularity and the MVD assessed by immunohistochemical analysis.PDU was accurate and reliable in measuring different vascularity in glioma and edema tissue.Because it is rapid and non-invasive, intraoperative ultrasonic quantification is beneficial in real time distinguishing glioma from surrounding edema zone.Further improvement in intraoperative PDU techniques to recognize tumor or edema should be establishment of the practical manual for real time handling...