杨祚璋 黄云超 许建波 孙洪瀑 刘鹏杰 吴中雄 袁 涛 [摘要]目的 探讨经皮椎体成形术(PVP)联合125I粒子植入治疗脊柱转移瘤患者的临床疗效。方法 将80例脊椎转移瘤患者,随机分为单纯PVP组40例,PVP联合125I粒子植入组(联合治疗组)40例。单纯PVP组是在DSA机引导下经皮穿刺,将骨水泥注射到患椎内。联合治疗组是PVP术中联合125I粒子植入。结果 联合治疗组和单纯PVP组术后KPS 评分分别为(92.5±7.1)分及(87.7±7.3)分,较术前(68.9±7.9) 分及(69.4±8.3) 分明显增高,两组比较差异有统计学意义(P14例,乳腺癌19例,肝癌4例,大肠癌2例,胃癌1例。累及胸椎23例,腰椎17例。脊椎节段:1个节段21例,2个节段16例,3个节段3例。KPS 评分68.9±7.9分。单纯PVP组男20例,女20例,年龄23~84岁,平均60.7岁。原发灶:肺癌14例,乳腺癌18例,肝癌5例,大肠癌3例,胃癌1例。累及胸椎23例,腰椎17例。脊椎节段:1个节段20例,2个节段16例,3个节段4例。KPS 评分69.4±8.3分。入组条件:(1)经病理学和(或)细胞学证实的恶性肿瘤患者;(2)脊髓功能评价Frankel分级E级;(3)预计生存期 3个月;(4)椎体病灶以溶骨性病变为主;(5)持续疼痛,药物、物理治疗等无明显改善。2.治疗计划系统(TPS)和靶区处方剂量确定:本治疗计划系统由核工业总公司北京科霖众医学技术研究所提供。每例患者治疗前将其CT/MRI图像扫入该系统的软件内进行三维立体数字化影像重建,根据病灶大小、位置以及与周围正常组织间的关系,精确制定、绘制出立体的图标和等剂量曲线及吸收剂量指示。同时给出临床需要的放射源初始剂量,施源器进针坐标和深度指示,并打印出治疗计划表格。3.手术方法:确定手术的适应证后,本组手术均在介入手术室内在DSA机引导下进行。患者取俯卧位,采用椎弓根入路,并测量椎弓根的倾斜角度、穿刺点的棘突旁开距离及穿刺点皮肤至椎弓根的深度,穿刺点位于棘突旁开2~3cm处。用1%利多卡因局麻,在正位透视下,当穿刺针抵达骨皮质和进针深度未超过椎弓根前缘时,针尖应位于椎弓根透影“牛眼征”之内。当穿刺针穿透骨皮质进入椎体后,取出针芯,利用针管作为通道,将125I粒子植入针插入针管内,进针过程中按0.3cm间距在靶区植入125I粒子,注意尽量采用双侧椎弓根入路进针,如一侧针尖方向在椎体中上部,另一侧针尖方向应向椎体中下部,使125I粒子在椎体内呈三维分布。建议用针尖为斜面穿的穿刺针,进针时可根据需要不断调整针尖方向,可使125I粒子植入位置更加理想。待穿刺及125I粒子植入完成后,向针管推注造影剂5ml,DSA记录造影剂在椎体内弥散情况及静脉回流情况。负压抽吸尽椎体内遗留造影剂及血液,使椎体内压力降低。骨水泥(国产 PMMA加入非离子造影剂混合)现场调配后抽入注射器,至“牙膏期”时注射,注射时应在侧位透视下全程监视(图1),密切观察是否有骨水泥向椎体外渗漏,推注时不断旋转针尖方向使骨水泥填充趋于良好。注射完毕后将穿刺针退至骨皮质,插入针芯,旋转穿刺针,避免骨水泥将针粘住,在骨水泥硬化前拔针。骨水泥注射量一般为2~9ml,胸椎平均为4.5ml,腰椎平均为6.0ml。4.统计学方法:计量资料采用t检验,计数资料采用x2检验。结果1.术中和术后情况:本组 80例 126个病变椎体中,40例62病变椎体根据术前TPS治疗计划进行了PVP联合125I粒子植入,其中单侧穿刺 16个椎体,双侧穿刺 46个椎体,125I粒子植入5~10粒/椎体,平均6.5粒/椎体,初始剂量2.92cGy/h/粒子,90%等剂量曲线包括90%肿瘤靶体积,肿瘤周边匹配剂量(MPD)80cGy~100cGy;40例64病变椎体进行了单纯PVP 术,其中单侧穿刺20个椎体,双侧穿刺 44个椎体。手术穿刺成功率均为100%,未出现神经根和脊髓受压症状。术后 CT 检查骨水泥在椎体内呈点、片状分布(图2)。2.近期疗效: 联合治疗组和单纯PVP组KPS 评分分别为(92.5±7.1)分及(87.7±7.3)分,较术前明显增高,两组比较差异有统计学意义(P0.05)。1例T6转移性肺癌并椎体后缘软组织肿块形成患者,行T6 PVP联合125I粒子植入术,术后2月复查MRI片发现椎体后缘软组织肿块完全消失,术后1年复查MRI片未见局部肿瘤复发(图3abc)。4.并发症:本组病例中手术均顺利,联合治疗组有6例、单纯PVP组有7例发生少许骨水泥椎旁渗漏,无脊髓受压、肺栓塞、神经根受压等并发症发生。联合治疗组无放射性脊髓炎发生,亦无白细胞减少,免疫功能降低,粒子脱落等并发症发生。 讨论1. PVP术中联合125I粒子植入的增效作用: PVP作为局部治疗措施,可增加脊柱稳定性,达到缓解或消除疼痛和防止椎体塌陷的目的,而抗肿瘤作用有限。125I粒子源半衰期长,低能量,持续性,定位精确,正好针对肿瘤组织细胞无节制的增殖,具有肿瘤杀伤作用[2-5]。将放射源准确地植入到靶组织内,并根据靶组织的体积、密度(半价层)以及与邻近重要器官的关系进行合理布源,可以达到“定向爆破”,最大限度杀灭癌细胞,最小限度损伤正常组织及功能。本研究两组治疗前后KPS 评分均有明显提高,但联合治疗组优于单纯PVP组。1例T6转移性肺癌并椎体后缘软组织肿块形成患者,行T6 PVP联合125I粒子植入术,术后2月复查MRI片发现椎体后缘软组织肿块完全消失,术后1年复查MRI片未见局部肿瘤复发,说明局部肿瘤病灶控制良好。2.预防并发症: 恶性肿瘤由于浸润和破坏范围广,PVP 术后主要并发症是骨水泥渗漏,据国外统计达 65%左右[6]。此外,骨水泥单体亦可随静脉回流引起肺动脉栓塞。本组病例无严重并发症发生,可能与下列因素有关:推注骨水泥前行椎体内DSA机造影可见数字减影显示有无造影剂向椎管内渗漏及了解椎体静脉回流情况。术中反复抽吸吸出椎体内物质可以有效降低椎体内压力,使骨水泥填充趋于良好。骨水泥在“牙膏期”用螺旋式加压装置推入。不盲目追求填充量或完全填满椎体,因为疼痛缓解程度与注射量不成正比[1]。应用针尖为斜面的穿刺针,进针时能很好控制针尖方向,推注骨水泥时不断调整针尖方向可使骨水泥填充效果更加完好,减少了渗漏发生率。根据术前TPS治疗计划进行了PVP联合125I粒子植入,可以使90%等剂量曲线包括90%肿瘤靶体积,肿瘤周边匹配剂量80cGy~100cGy,这有利于瘤细胞的杀灭而保护外周正常组织。参考文献[1] 杨祚璋,许建波,袁涛,等 . 经皮穿刺椎体成形术治疗28例脊柱转移瘤. 癌症,2005,24:194-198.[2] Anglesio S, Calamia E, Fiandra C,et al. Prostate brachytherapy with iodine-125 seeds: radiation protection issues. Tumori, 2005,91:335-338.[3] Xue J, Waterman F, Handler J, Gressen E.Localization of linked 125I seeds in postimplant TRUS images for prostate brachytherapy dosimetry. Int J Radiat Oncol Biol Phys, 2005 ,62:912-919.[4]徐静,梅铭惠,陈谦,等.术中组织间植入125I粒子治疗肝恶性肿瘤, 中华实验外科杂志,2005,22:368-369.[5] 罗开元,赵泉,杨镛,等.125I粒子组织间植入对大肠癌的抑制作用及其机制, 中华实验外科杂志,2006,23:70-71.[6] Mathis JM, Barr JD, Belkoff SM,et al. Percutaneous vertebroplasty. A developing standrd of care for vertebral compression fractures. Am J Neuroradiol,2001,22:373-381.
YANG Zuozhang 杨祚璋,XU Jianbo 许建波,JIN Congguo 金从国,LIU Pengjie 刘鹏杰,YUAN Tao 袁涛,QIAN Baosheng 钱保生,ZHANG Jinyu 张晋煜,LI Wengzhong 李文忠,LI Jianlin 李建林,XIAO Yanbin 肖砚斌,PENG Ming 彭敏,LI Yu 李浴,LUAN Li 栾丽Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical College, Tumor Hospital of Yunnan Province, Kunming, Yunnan, 650118, ChinaOBJECTIVE To explore the clinical effect in patients with metastatic spinal tumors treated by percutaneous vertebroplasty (PVP ) under the guidance of digital subtraction angiography (DSA ).METHODS A total of 110 cases with a metastatic spinal tumor were divided into 55 cases in the treatment group (group A ) and 55 cases in the control group (group B ). The general clinical data were statistically analyzed before treatment with the parameters showing no differences. Group A was treated by PVP and chemotherapy as well. The group B was treated by the regular chemotherapy and regular radiation therapy. The same chemotherapy program was used for the same type of disease. All cases were provided with a follow-up survey for 12 months. During the follow-up survey, changes in the quality of life, in evaluation of and in vertebral column stability as well as adverse reaction were observed.RESULTS The statistics showed a significant difference between the 2 groups, specifically changes in the quality of life and evaluation of bone pain (P<0.05,t1=2.74,t2=9.02﹚. During the follow-up survey, 5 cases in group A died of other organ complilcations, the death rate being 9.1% (5 out of 55), but all survived more than 3 months following PVP. The vertebral columns of the survivors were kept stable, with no pathological fractures occurring in the vertebral bodies filled with bone cement, there were no obvious adverse reactions and paraplegia occurred. Thirteen cases died in group B with a death rate of 23.6% (13 out of 55). Pathological compression fractures in the vertebral bodies occurred in 30 cases, and 12 cases of complicated paraplegia were noted. The incident rate of paraplegia was 21.8% (12 out of 55). CONCLUSION: PVP is a simple operation causing only small wounds and few complications. It can effectively alleviate pain of metastatic spinal tumors in patients, improve quality of life and reduce the incidence rate of paraplegia.KEYWORDS: percutaneous vertebroplasty, spine, metastatic tumor, intervention, bone cement Metastases are the primary complication of malignant tumors. Metastatic spinal tumors are the most commom metastatic bone tumors with 20% of malignant tumors involving bone metastases. In most cases metastatic lesions occur in the thoracic spine, some in the lumbar spinal and some in the cervical spine [1].There are many therapeutic methods to treat metastatic spinal tumors, but no ideal therapy is known at present. In our hospital since 2003 we treated 55 patients with metastatic spinal tumors, using percutaneous vertebroplasty (PVP) under the guidance of digital subtraction angiography (DSA). The procedure produced good clinical results which are summarized in this report.1 Materials and methods 1.1 General A total of 110 patients with metastatic spinal tumor were divided into 55 cases in the treatment groupand 55 cases in the control group (Table 1). All cases which were chosen met the following criteria: (1) the pathological diagnosis was based on the original focuses or pathological centra; (2) there were no symptoms related to the compression of the spiral cord or nerve roots; (3) all of the patients presented with a combination of neck ,bake ,or waist pain; (4) the number of pathological centra was no more than 3. The clinical data listed in Table 1 showed no statistically significant differences, P>0.05. After treatment with PVP, the patients in the treatment group were treated by the regular chemotherapy. Patients in the control group were treated by the regular radiation therapy at spinal tumor focuses and whole chemotherapy.1.2 Instruments and pharmaceuticals A China-produced instruments for percutaneous vertebroplasty was used, including the puncture needles and the device to increase pressure in the spiral injector ( produced by Shan dong Longguan Company). The puncture needles were comprised of those for the cervical spine, thoracic or lumbar spine. The needle diameters were 2.5 mm and 3.5 mm respectively ranging in length from 100 to 150 mm and were used to puncture the vertebral bodies to produce a tunnel for the polymethylmethacrylate (PMMA) injection. There was a disposable 10 ml medical injector inside the device to increase pressure in the spiral injector that is used to inject the PMMA (produced by Tianjin synthetic industrial institution).75% of meglumine diatrizoate was added to enhance the development of the PMMA under X-ray. The preparation ratio of the power (g), the liquid (ml) to the contrast agent (ml) was 3:2:1.Table 1. The analysis of clinical parameters in 110 patients with metastatic spinal tumor before treatment Parameters Group A(treatment group) Group B(control group) P –value Age 62.34±5.60 59.95±9.03 0.728Gender Male 25 26 0.686Female 30 29Original disease Colon cancer 9 8Hepato carcinoma 8 8Breast carcinoma 20 19 0.762Pulmonary carcinoma 12 24Gastric cancer 6 4Unidentified 0 2Vertebral bodies 1 32 25 2 20 22 0.246 3 3 8Metaststic area Cervical vertebrae 12 23Thoracic vertebrae 27 35 0.192Lumbar vertebrae 35 30Sacrum 7 5Evaluation of pain 14.3±1.51 14.5±1.84 0.700Physical agility 85.9±6.71 82.8±7.66 0.122Mental status 104.8±12.3 104.4±12.1 0.901Quality of life 166.6±15.01 17.00±16.58 0.4351.3 The operating method Prior to the operation, eath patient was examined by X-ray ,a CT scan (computed tomographic ), or by MRI (magnetic resonance imaging ), to determine the location and number of vertebral bodies which involved a tumor, the collapse of the vertebral bodies, the degree of osteolytic lesion, the integrity of the spinal cord compression. Examinations on the patient’s heart , lung, liver and kidney functions, blood sugar, PT, and test for iodine allergy were conducted prior to the procedure. The patients were given analgesics 15 min before the operation. After determining the indication to operate, the operations in the intervention operating room were conducted under the guidance of DSA. For the cervical spine : the patient was instructed to lie flat in a supine position with a pillow under his shoulder. The plane of the pathologically changed vertebral body on the screen of the DSA was selected on lateral fluoroscopy position. The puncture point between the trachea and the vertebral artery was determined according to the mark of the chosen plane. After performing local anesthesia, the middle finger and the forefinger was used to press the front edge of the vertebral body between the space of the trachea and the carotid artery, which pushing the trachea towards the other side at the same time. The puncture needle was placed 0.5 to 1.0 cm to the medial side of the carotid artery. Insert the needle as the needle and the sagittal plane of the vertebral body while maintaining a 15 to 20 degree angle. The needle tip was in 1/3 of the front edge of the vertebral body on lateral fluoroscopy position (Fig .1).The needle tip was at the center of the vertebral body or deviating to left or right 0.3 cm on the front fluoroscopy position (Fig .2). For the thoracic and lumbar spine : the patient was instructed to lie flat in the prostrate position. Punctured via the pedicle of vertebral arch approach, measured the inclination degree of the pedicle of vertebral arch, the distance of the spinal process of the puncture point, the depth from puncture point to the pedicle of vertebral arch. The puncture point was placed 2 to 3 cm beside the spinal process and local anesthesia of 1% lidocaine was administed. When the puncture needle arrived at the bore cortex, and the depth of the intrusion needle didn’t exceed the front of the pedicle of the vertebral arch, on the front of fluoroscopy position, the needle tip should be within the “buphthalmos” of fluoroscopy of the pedicle of the vertebral arch (Fig .3). When the puncture needle went through the bone cortex and entered the vertebral body, on a lateral fluoroscopy position, the puncture needle was slowly hammered into the 1/3 of the front of the pedicle of the vertebral arch.It showed that puncture needle tip had exceeded the center of the pedicle of the vertebral arch on the front fluoroscopy position. It is preferable to use puncture needle with a beveled needlepoint as it is easier to control the direction of needle while injecting the fluid. The bone around the puncture point at the sacroiliac joint was damaged most. After finishing the puncture, the syringe piston was removed and 5 ml of contrast medium infused into the injection-tube. The circumfluence of the contrast medium was noted by the DSA. The pressure in the centra was depressed by sucking out the tumor and blood which remained in the centra. The bone cement was prepared using China-produced PMMA and non-ionic contrast medium. The bone cement was infused into the injection-tube and injected when the bone cement became like paste. The whole process of injection was supervised on a lateral fluoroscopy position to prevent the bone cement from leaking outside of the vertebral body (Fig .4). The point of the needle direction was continuously revolved in order to transfer the bone cement well while pushing the plunge. After injection, the puncture needle was withdrawn to the bone cortex, inserted the syringe piston, turned the puncture needle to prevent the bone cement from sticking it. The needle was pulled out before the bone cement hardened. The total volume of injected cement ranged from 2 to 9 ml. The average amounts were 2.5 ml for the cervical spine, 5.5 ml for the thoracic spine and 7.0 ml for the cervical vertebra.[2] The patients were reexamined by CT 15 to 20 min after the injection when the polyreaction of the bone cement had completed (Fig .5 ).1.4 Evaluation of the therapeutic effect 1.4.1 Changes in quality of life after treatment We used a short-form health survey (SF-36) to survey of life [3]. The form included 11 items with each item including many questions. The score was calculated based on the answers chosen and the final score adjusted by a formula with a higher score representing healthier to patients. Among the items, a score of no .1, 3, 4, 7, 8 and 11 referred to physical agility, a score of no .5, 6, 9 and 10 referred mental status. The score of physical agility +the score of mental status =the total score of quality of life.1.4.2 Relief of bone pain after treatmentThe degree of the relief of bone pain was based on the evaluation of pain which was calculated as pain degree ×pain frequency. The degree of pain and frequency was based on the UICC standard. The degree of pain sorted into 5 classes, i.e. 0, 1, 2, 3, 4[4]. The patients’ degree of pain and frequency were written down when getting up and going to bed, and the score of pain calculated. The evaluation of the analgesic effect and the standard classes of pain relief were :0 for no relief, Ⅰfor light relief, Ⅱfor moderate relief, Ⅲ for high relief, Ⅳ for complete relief. Statistical treatment SPSS 10.0 statistical software was used for statistical analysis. The t-test was used for measurement data and the X 2-test used for enumeration of the data.2 Results The patients in the treated group were operated smoothly. There were 57 vertebral bodies injected via one side and 24 vertebral bodies injected via both sides. Regular chemotherapy was given to the patients after the operation and regular radiation therapy and chemotherapy were employed for the patients in the control group. Evaluation of the therapeutic effect was done subsequently.2.1 The changes in the quality of life and evaluation of bone painAccording to the evaluation of quality of life by the SF-36, there was no significant difference in the quality of life between the 2 groups before treatment. After treatment, the quality of life in the treatment group obviously improved, whereas quality of life in the control group declined. A significant difference in the quality of life between the 2 groups is shown in Table 2 (P <0.05﹚.Bone pain was relieved in both groups after treatment, but in the treated group, bone pain stopped in 6 to 72 h post operation, with an effective rate of 100%. And the degree of pain relief was significantly higher than that of the control group (P <0.05 ,Table 2﹚.table 2 The comparison of quality of life and evaluation of pain between the 2 groups after treatment (x ±s )Group n Physical agility Mental status Total quality of life Evaluation of pain Treated 160±76 185±87 345±152 6.4±2.2 55Control 112±71 130±73 242±134 12.3±1.7 55 t 1 2.49 2.58 2.74 9.02 P <0.05 <0.05 <0.05 <0.05 2.2 Patient outcome All patients were given the follow-up survey for 12 months. During the follow-up period, 5 patients died because of other organs complications in group A. The death rate was 9.1% (5 out of 55). Shift of the vertebral bodies was not found. There were changes in the physiological arch, angulation and olisthe of vertebral bodies what had existed before treatment didn’t develop. There were no further vertebral body compressions, spinal cord or never compressions on paraplegia. Treatment of the vertebral bodies permanently eliminated the pain. Thirteen patients died in group B showing a death rate of 23.6% (13 out of 55). Pathological compression fractures in the vertebral bodies occurred in 30 cases were complicated with group B paraplegia. The incidence rate of paraplegia was 21.8% (12 out of 55).2.3 Complications Six patients with a metastatic spinal tumor developed a pathological compression fracture after treatment with PVP and the PMMA leaked to the front of the vertebral bodies. Since there were no clinical symptoms, no further treatment was needed. There were no complications of spinal cord compression, pulmonary embolism and never root compression occurred. 3 Discussion The vertebral column is where metastatic bone tumor occur most frequently. At the metastatic site, the tumor cells produce osteoclastic-activating factors which activate osteoclasts, causing enhancement of the bone absorption and induction of bone lesions[5]. The injury of the metastatic focus to the vertebral body and its accessories induce to a vertebral column pathological fracture causing the stability of the vertebral column to decline. This results in severe back pain, even never function disorder and a predisposition to pathological fracture. Some mental symptoms such as depression and irritability may occur, severely affecting the quality of life. With the development of tumor therapy, more attention has been paid to the improvement of the quality of life which is a measurer of the therapeutic effect[6]. There are many therapeutic methods treat to metastatic spinal tumors, such as radiation therapy, chemotherapy, radioisotope therapy, biphosphonates therapy, analgesia therapy and palliative operations. Choice of a therapeutic method depends on the histological type of the primary tumor, the nerve function situation before treatment, the number of vertebral bodies involved, the degree of spinal canal compromise, the patient’s physical status, the degree of pain, and so on. The degree of pain relief can be more than 75% by radiation therapy, but it takes 1 to 2 weeks to produce an effect. The biggest weakness of radiation therapy is that it does not resolve the problem of instability of the vertebral column caused by tumor damage, but increases the danger of vertebral body collapse and never compression[7]. A surgical operation is suitable for patients with spinal cord compression, but it results in big wounds and many complication and is not suitable for nonadjacent multiple vertebral body metastatic tumors.In recent years, along with the rapid development of interventional techniques, PVP has become one of the focuses in spinal surgery result in only small wounds and thus is gaining the attention of more surgeons[9-12]. PVP is used in treating metastatic spinal tumor in our hospital as it is effective in relieving the patient’s pain and improving the quality of life. Both Cotton et al. and Cortet et al.[14]reported that by treatment of metastatic vertebral body tumors with PVP, the rate of eliminating pain and relieving pain significantly was 67.5% and 68.5% respectively, whereas the rate of relieving pain partially was 30%. The efficient rate of relieving pain in our research was 100%. The location of the centra which were cured through PVP were not found any shift, namely the change of the original physiological bend and the other abnormal change including angularity, slide and so on did not go worse any more and it were not appeared that the symptoms included the centra were futher compressed, the spinal cord or the never roots were subjected to press and lead to paralysis, as well the cured centrums appeared the ache symptom again. So this indicates that the spinal column stability is good after PVP. Most of the vertebral bodies involved with a tumor were fulfilled uniformly by bone cement, which could delay tumor development and provide constructional substitution and thus possibly prevent further lesion of vertebral bodies, collapse and vertebral cord compression[15]. In 6 patients with a metastatic spinal tumor, pathological compression fractures developed after performing PVP. The PMMA leaked to the front of the vertebral bodies, but there were no clinical symptoms and no other complications occurred. The results demonstrated that PVP is a safe operation resulting in only small wounds. This study revealed the following : the most outstanding feature of the technique is to cure intractable pain caused by metastatic spinal tumor. The procedure improves the stability of the vertebral column and significantly improves quality of life. Performing the operation under the guidance of DSA can enhance its safety. Repeatedly sucking out the centra contents can effectively lower the pressure inside it and allow the bone cement to fill well. Use of a puncture needle with a beveled point allows better control of the direction of the needle during the procedure. Adjusting the needlepoint direction continuously while pushing in the bone cement permits good filling and reduces the leakage rate of the bone cement, in summary, we consider that PVP can relieve pain effectively caused by osteolytic metastatic spinal tumors. It can enhance the strength of the vertebral bodies and improve the stability of the vertebral column. It is a safe and easy operation causing only small wounds and is without a systemic toxic effect. It is suitable for multiple metastatic spinal tumors (Fig .6,7). Therefore, PVP is an effective treatment for mestastatic spinal tumors. It will achieve a better therapeutic effect if combined with radiation therapy, chemotherapy and other complex treatments. At present, PVP is the most appropriate therapy for patients whose pathologic change from a metastatic spinal tumor result in a difficult excision and if there is no compression symptoms of the spinal cord and nerve roots. 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