Evaluation and Management of Spinal Axis Tumors

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CHAPTER 311 Evaluation and Management of Spinal Axis Tumors

Metastatic

Metastatic spinal disease is becoming increasingly common. As patients survive longer as a consequence of improvements in cancer treatments, metastases to the spine are affecting quality of live as well as survival. Historically, the treatment of spinal metastatic disease was palliative radiation, but newer surgical techniques have demonstrated superiority in many cases to radiation alone. In this chapter, we review the various epidemiologic, diagnostic, and treatment issues involved in caring for the patient with metastatic spinal disease.

Epidemiology

It is estimated that 1,437,180 men and women (745,180 men and 692,000 women) will be diagnosed with and 565,650 men and women will die of cancer of all sites in 2008 (http://seer.cancer.gov/csr/1975_2005/results_single/sect_01_table.01.pdf). Fifty to 70% of all cancer patients have metastases at the time of their death, and the spine is the most common osseous site.13 As shown in Figure 311-1, about 5% to 10% of cancer patients and up to 40% of patients with preexisting nonspinal bone metastases will develop metastatic epidural spinal cord compression from metastases.2,48 Of those with spinal disease, 10% to 20% will develop symptomatic spinal cord compression, resulting in 20,000 to 30,000 cases per year.9 This number is expected to increase as the baby-boomer population ages and advances in cancer treatment improve longevity, resulting in more metastatic disease.7,10,11

About 50% of spinal metastases arise from one of three primary sites—breast, lung, or prostate6,12—with additional cases from renal, gastrointestinal, thyroid, sarcoma, and the lymphoreticular malignancies, lymphoma and multiple myeloma. Metastases from prostate, breast, melanoma, and lung commonly cause spinal metastases in 90.5%, 74.3%, 54.5%, and 44.9% of patients, respectively.2 However, the risk for neurological deficits as a result of epidural spinal cord compression varies with the site of primary disease, as follows: 22% with breast cancer, 15% with lung cancer, and 10% with prostate cancer.7 Overall, 10% of patients will present with no known history of cancer, although in some of the older surgical literature, this figure was as high as 70% of the study population.11,1316 In more than 50% of these cases, the lung is the primary source of malignancy.7,15

The thoracic spine is the most common site of disease (70%), followed by the lumbar spine (20%) and cervical spine (10%).6,7,17 Metastatic spinal disease can arise in any of three locations: the vertebral column (85%), the paravertebral region (10% to 15%), and rarely the epidural or subarachnoid and intramedullary space (<5%).6,7,17 The posterior half of the vertebral body is usually involved first, with the anterior body, lamina, and pedicles invaded later.18 Intradural metastases, including intramedullary, from non-neural primary tumors are extremely rare but have been reported.19,20 Multiple lesions at noncontiguous levels occur in 10% to 40% of cases.6,7,17,21

Presentation and Diagnosis

The usual presenting symptom of bony metastases is pain. Pain usually precedes neurological signs of spinal cord compression by a prolonged period. There are two types of pain: mechanical and tumor related. Tumor-related pain usually begins insidiously and is progressive. It is often described as a dull, constant ache that is notably worse at night (nocturnal pain) or early in the morning. This is thought to be related to venous engorgement of the tumor causing increasing mass effect on surrounding pain-sensitive structures, such as the periosteum, dura, nerve roots, cauda equina, or spinal cord. The pain is usually located at the diseased site, but sometimes it can be referred to other regions such as the interscapular area and shoulders for cervical with thoracic involvement and the sacroiliac and iliac crest regions with lumbar disease. Mechanical pain is the result of destruction of the vertebrae to the point that there is enough structural abnormality causing instability. This pain is increased by standing, increased activity, and coughing and decreased by assuming a supine position, similar to the pain experienced with traumatic instability. It often results from vertebral body collapse.

Spinal cord compression results from any one or a combination of four processes: direct compression from an enlarging soft tissue mass, pressure caused by fracture and retropulsion of bony fragments into the canal, severe kyphosis following vertebral collapse, and, rarely, extension of a paraspinal tumor through the intervertebral foramen. Neurological symptoms are usually gradually progressive, but alternatively may occur rapidly and present as a neurological emergency. Neurological symptoms can broadly be divided into radicular and myelopathic, the features of which depend on the level and extent of disease. Myelopathy often presents as a gait disturbance, followed by spasticity, generalized weakness, sensory loss, and autonomic dysfunction. Bowel and bladder dysfunction, which may be present on initial evaluation, is rarely unaccompanied by other symptoms. When it does appear as the only symptom, the lesion is most likely at the level of the conus medullaris. Painless urinary retention with incontinence or recurrent urinary tract infections, especially in males, strongly suggests a neurological cause. Patients who have lesions at multiple levels are more likely to be nonambulatory.22 All patients with metastatic disease should undergo a thorough baseline neurological examination. The results can be classified into well-known neurological scales such as the extended Frankel23 grading system (Table 311-1), the Eastern Cooperative Oncology Group (ECOG) performance score (Table 311-2), and the American Spinal Injury Association (ASIA) score (Table 311-3). Other authors have used a scale that focuses on gait (Table 311-4).

TABLE 311-1 Frankel Grade

GRADE DESCRIPTION
A No motor or sensory function
B Preserved sensation only, no motor function
C

D E Normal neurological functions

From Frankel HL, Hancock DO, Hyslop G, et al. The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia. I. Paraplegia. 1969;7:179.

TABLE 311-2 Eastern Cooperative Oncology Group Performance Status Grades

GRADE DESCRIPTION
0 Fully active, able to carry on all predisease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (light housework, office work)
2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours
3 Capable of only limited self-care, confined to bed or chair >50% of waking hours
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5 Dead

TABLE 311-3 American Spinal Injury Association Impairment Scale

GRADE DESCRIPTION
A (complete) No motor or sensory function is preserved through S4-5.
B (incomplete) Sensory but no motor function is preserved below the neurological level and extends through S4-5.
C (incomplete) Motor function is preserved below the neurological level, and most key muscles below the neurological level have a muscle grade <3.
D (incomplete) Motor function is preserved below the neurological level, and most key muscles below the neurological level have a muscle grade ≥3.
E (normal) Motor and sensory function are normal.

TABLE 311-4 Gait Scale

GRADE DESCRIPTION
1 Normal
2 Gait with assistance
3 Paresis without gait function but still able to move legs
4 Paraplegia

In patients with suspected epidural spinal cord compression from metastatic disease, the entire spine needs to be imaged. Magnetic resonance imaging (MRI) is the most sensitive and specific imaging modality for detecting metastatic disease. It provides excellent soft tissue, bone marrow, and neural structure visualization in the axial, coronal, and sagittal planes. Sagittal screening images can quickly evaluate the entire spine. Other modalities include plain radiographs, bone scans, and computed tomography (CT) enhanced with myelography. Radiographs are abnormal in 85% of patients with metastatic epidural compression.6 Most metastatic lesions are osteolytic, and 30% to 60% of the bone must be removed before it is visible on plain radiographs.7 Only 5% of metastases cause an osteoblastic response. Radionuclide bone scans are usually more sensitive but less specific in detecting metastatic disease than plain radiographs.57 Radionuclide studies identify areas of increased bone deposition. Therefore, they can easily detect osteoblastic metastases but can only detect osteolytic lesions if there is a significant amount of bone repair occurring. CT with coronal and sagittal reconstructions is more sensitive and specific than radionuclide scans.6 When combined with myelography, it provides a detailed image of both the bony and neural structures. The bony detail is especially important when planning surgical decompression. CT myelogram is useful for patients who have had spinal reconstruction with placement of metallic instrumentation, including titanium, because it is often difficult to obtain good-quality images on MRI because of artifact. However, performing a myelogram can cause neurological worsening if it is done in the presence of a high-grade block rostral to the puncture.6,7

Management

Deciding on the optimal treatment for these patients is often a difficult and complex process because of the numerous issues involved and requires input from the spine surgeon, oncologist, radiation oncologist, patient, and family members.24 With the rare exception of when the spine is the sole site of newly metastatic disease in a patient whose cancer has been successfully treated in the past, treatment is considered palliative. It is imperative that treatment be rendered as soon as possible because neurological outcome after treatment is primarily dependent on the neurological status before treatment.25,26 The primary histology and posttreatment ambulatory status are the factors that have been most consistently cited as determining survival.2729 In one study, the median survival for breast cancer was 650 days, whereas for lung cancer it was 120 days.30 The issues that are most important to these often sick and debilitated patients are their ambulatory function, pain control, autonomic function (sexual and bowel and bladder control), overall survival, and quality of life.24

Treatment can involve chemotherapy, radiation therapy, surgery, or combination.31 Indications for surgery include radioresistant tumors (sarcoma, lung, colon, renal cell, breast), obvious spinal instability, clinically significant neural compression secondary to retropulsed bone or from spinal deformity, intractable pain unresponsive to nonoperative measures, and radiation failure (progression of deficit during treatment or spinal cord tolerance reached). Even if the patient satisfies one or more of these indications, the type and goals of surgery must be determined by the patient’s ability to tolerate the procedure (i.e., the patient’s general medical condition coupled with the complexity of the proposed operation) and, more importantly, by their estimated life expectancy. The latter is primarily based on the extent and aggressiveness of the cancer and its response to previous therapies. In general, the goals of surgery are to correct and prevent any further deformity by stabilizing the spine, decompress neural structures (spinal cord and nerves), obtain a diagnosis if the primary is unknown, and prevent local recurrence.

Harrington32 devised a five-category classification scheme for metastatic spine tumors based on bone destruction and neurological compromise: (1) no significant neurological involvement; (2) involvement of bone without collapse or instability; (3) major neurological impairment (sensory or motor) without significant involvement of bone; (4) vertebral collapse with pain resulting from mechanical causes or instability, but with no significant neurological compromise; and (5) vertebral collapse or instability combined with major neurological impairment. He mainly recommended that patients in categories 1, 2, and 3 be treated nonsurgically with chemotherapy, hormonal manipulation, or local irradiation. Patients in categories 4 or 5 require surgical intervention, but the definitive treatment option for those in category 3 were less clear.

The concept of spinal instability has been cited as a major factor in determining whether a patient is a surgical candidate. Kostuik and associates33 defined stability using a two-column concept of spinal architecture. Their anterior column consists of the entire vertebral body including the cortex, whereas the posterior column consists of pedicles, laminae, and spinous processes. The anterior column was further divided into anterior and posterior halves, as well as left and right sides, which results in four quadrants within the vertebral body. The posterior column is divided into left and right sides, for a total of six vertebral segments. The authors thought that the spine was stable if no more than two of the six segments were destroyed and unstable if three or more segments were destroyed. Tomita and colleagues34 stated that instability was present if any of the following features were present: transitional deformity, vertebral body collapse greater than 50%, three column involvement (as defined by Denis35), or involvement of the same column in two or more adjacent levels. Cybulski’s definition was simpler: pathologic fracture or evidence of bone in the spinal canal.36 It has been difficult to implement the concept of spinal instability as a factor in determining treatment because there is no agreed-on definition and the implication of such a designation is uncertain. There are certainly many patients who have been treated successfully with radiation who would have fit one definition or another of spinal instability. In fact, although the authors of the randomized controlled trial evaluating surgery compared with radiotherapy alone (see later) categorized the study patients on the presence or absence of spinal instability using the definition by Cybulski, it was neither an exclusion criteria nor a factor controlled for in the randomization process (18 of 51 patients in the radiation arm and 20 of 50 in surgery arm had an “unstable” spine).37

Most surgeons would agree that surgery should only be offered to patients with an estimated life expectancy of greater than 3 to 6 months.38 However, determining this estimate is difficult and is usually left to the expertise of the individual oncologist. In an effort to more accurately predict survival, Tokuhashi and associates proposed a preoperative prognostic scoring system in 1990 with a revised version in 1998.39,40 Their model takes into account six variables: general medical condition (Karnofsky performance score), number of extraspinal metastases, number of vertebral metastases, status of metastases to the major internal organs, primary tumor type, and presence of a neurological deficit (Table 311-5). In this revised system, total scores of 0 to 8, 9 to 11, and 12 to 15 predicted with high accuracy a life expectancy of less than 6 months, 6 months or more, and 1 year or more, respectively.39 Using this scoring system, excisional surgery (i.e., circumferential decompressive surgery with reconstruction and stabilization) was performed in those with a score greater than 12. Conservative treatment, which primarily consisted of radiation alone, was performed in patients with a score of 0 to 8. In patients with a score of 9 to 11, palliative surgery (posterior decompression alone or instrumented) was undertaken, and only in the rare patient with a single spinal lesion and no visceral metastases was excisional surgery considered. Several others, including the authors, have used this scoring system and have found it useful in making decisions regarding treatment.4145 Another similar scoring system, using the Karnofsky score, primary tumor, and presence of visceral metastases, has shown similar abilities to stratify patient survival.46

TABLE 311-5 Tokuhashi Scoring System

PROGNOSTIC FACTOR POINTS
General Condition (Karnofsky Performance Status)%
Poor (10-40) 0
Moderate (50-70) 1
Good (80-100) 2
No. of Extraspinal Bone Metastases Foci
3 or more 0
1-2 1
0 2
No. of Metastases in the Vertebral Body  
3 or more 0
2 1
1 2
Metastases to the Major Internal Organs
Unremovable 0
Removable 1
No metastases 2
Primary Site of the Cancer
Lung, stomach  
Kidney, liver, uterus, other, unidentified  
Thyroid, prostate, breast, rectum  
Spinal Cord Palsy
Complete 0
Incomplete 1
None 2

From Tokuhashi Y, Matsuzaki H, Oda H, et al. A revised scoring system for preoperative evaluation of metastatic spine tumor prognosis. Spine. 2005;30:2186.

The scoring system by Tomita and associates used three factors: grade of malignancy, visceral metastases, and bone metastases (Table 311-6).34 For patients with a score of 2 or 3, the treatment goal is long-term local control and a wide marginal excision. For a score of 4 or 5 points, marginal or intralesional excision is recommended for middle-term local control. For a score of 6 or 7 points, the treatment goal is short-term palliation with palliative surgery; and finally, a score of 8 to 10 indicates nonoperative supportive care. The median survival times were 38.2, 21.5, 10.1, and 5.3 months, respectively. Of note, paralysis was specifically excluded as a prognostic factor because the authors believed that this did not significantly alter survival. Some authors think that this system is inadequate because it does not take into account pain and neurological function.47

TABLE 311-6 Tomita Scoring System

PROGNOSTIC FACTOR POINTS
Primary Tumor  
Slow growth (breast, prostate, thyroid) 1
Moderate growth (kidney, uterus) 2
Rapid growth (lung, liver, stomach, colon, unknown primary) 4
Visceral Metastases  
Treatable 2
Untreatable 4
Bone Metastases  
Solitary or isolated 1
Multiple 2

From Tomita K, Kawahara N, Kobayashi T, et al. Surgical strategy for spinal metastases. Spine. 2001;26:298.

North and coworkers devised a prognostic scoring system for survival and ambulatory status based on their surgical treatment of 61 patients.29 They identified risk factors for poor outcome for both outcomes after surgery and then, based on the presence or absence of these factors, calculated median survival and ambulatory rates (Tables 311-7 and 311-8). Their study highlighted the importance of tumor pathology, overall median survival of 10 months with breast cancer being 1.7 years and lung cancer 3 months, and the detrimental effect of additive risk factors. A number of other algorithms have been put forth, each with their own set of factors, but all take into consideration the degree of systemic disease, the type of cancer, and the overall prognosis of the patient.38,48,49

TABLE 311-7 Risk Factors for Poor Outcome after Decompressive Spinal Surgery

OUTCOME DESCRIPTION OF RISK FACTOR
Ambulation

Survival

From North RB, LaRocca VR, Schwartz J, et al. Surgical management of spinal metastases: analysis of prognostic factors during a 10-year experience. J Neurosurg Spine. 2005;2:564.

TABLE 311-8 Prognostic Scoring System for Ambulatory Status and Survival after Decompressive Spinal Surgery

OUTCOME PROGNOSIS
Ambulation  
Breast cancer Very low probability of losing ability to walk
Other tumor and 0 or 1 other risk factor 72% likely to walk at 1.6 yr
Other tumor and 2 or 3 other risk factors 50% likely to walk at 1.8-3.5 mo
Survival  
Breast cancer 50% alive at 1.7 yr
Other tumor, no other risk factor 50% alive at 8.8 mo
Other tumor and 1 or more risk factor 50% alive at 4.3 mo

From North RB, LaRocca VR, Schwartz J, et al. Surgical management of spinal metastases: analysis of prognostic factors during a 10-year experience. J Neurosurg Spine. 2005;2:564.

Medications

There is strong evidence to support the use of steroids in patients with newly diagnosed metastatic spinal disease that causes spinal cord dysfunction. Steroids have numerous theoretical benefits, including reducing vasogenic edema, protecting against lipid peroxidation and hydrolysis, enhancing blood flow, preventing ischemia and intracellular calcium accumulation, stabilizing lysosomal membranes, attenuating the inflammatory response, and supporting cellular energy metabolism.50 Dexamethasone is the most widely used steroid in patients with cancer, but methylprednisolone is more commonly used in trauma.

Loading doses range from 10 to 100 mg, followed by 4 to 24 mg 4 times a day and tapered down over several weeks.5,6,17,5154 Larger doses are often used for those patients who present with a severe baseline or worsening neurological examination. Some physicians advocate using the trauma dose protocol in patients with rapid neurological deterioration.55 In a well-designed randomized controlled trial (RCT) that compared high-dose dexamethasone followed by radiotherapy with radiotherapy alone, 81% of patients in the treatment group were ambulatory after treatment compared with 63% in the control group.54 In another RCT, patients with a complete myelographic block who received a bolus of 100 mg followed by a standard maintenance dose had no better pain relief, ambulation, or bladder function than those who received a 10-mg bolus and the same maintenance therapy.56 It is clear, however, that higher doses are associated with more complications.57 Therefore, an appropriate regimen of dexamethasone would be an initial bolus of 10 mg followed by 16 mg/day and tapered over several weeks depending on the patient’s response to other treatments.57a Dexamethasone can often be a bridging therapy during the interval between when the patient presents and the time that a final decision is made regarding the optimal therapy (i.e., surgery versus radiation). Rarely does the patient’s neurological status decline within the first few days of presentation while taking steroids.

Steroids are not necessary for patients who present without clinical evidence of spinal cord compression. In a cohort study of 20 patients published by Maranzano and associates, all presented without neurological deficits or with only a radiculopathy.58 After radiation without steroids, all patients remained ambulatory. Finally, steroids do have an oncolytic effect on some tumors, namely lymphoma and thymoma. For patients in whom these tumors are suspected, steroids should be withheld until enough tissue is obtained to make a diagnosis.5

Bisphosphonates are a family of drugs that have shown to be effective in treating or preventing some of the complications related to osseous metastases in various cancers.59,60 There are two types of bisphosphonates: pyrophosphates (e.g., clodronate, etidronate) and aminobisphosphonates (e.g., pamidronate, zoledronic acid). These drugs work by inhibiting osteoclast activity and thus decreasing bone resorption. They also have direct tumoricidal effect. There have been a number of RCTs evaluating the use of bisphosphonates in the prevention of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, radiation or surgery for bone metastases, or hypercalcemia. When these SREs are taken collectively, bisphosphonates have been shown to decrease the number of and time to an SRE in prostate cancer,61,62 breast cancer,6365 multiple myeloma,64,66 lung cancer,67 and renal cell carcinoma.68 Not all bisphosphonates are equally effective. For example, Small and colleagues69 found that pamidronate did not prevent SREs, decrease analgesic use, or increase mobility in patients with metastatic prostate cancer compared with placebo. Conversely, zoledronic acid has been shown to be of benefit in prostate cancer.70

Ross and colleagues71 performed a meta-analysis of the evidence for the use of bisphosphonates in skeletal metastases from various cancers. Only randomized trials were analyzed, and the primary outcome measures were time to first SRE and reduction in skeletal morbidity assessed by pathologic fractures (vertebral, nonvertebral, combined), treatment (orthopedic surgery or radiotherapy), hypercalcemia, and spinal cord compression. Data from 18 studies were eligible for the meta-analyses, allowing the authors to analyze the effect of bisphosphonates on individual SREs rather than as a whole. They found that bisphosphonates significantly reduced the odds of suffering vertebral, nonvertebral, or combined fractures and hypercalcemia, but not spinal cord compression. Fewer patients underwent radiotherapy, but orthopedic surgery rates were not decreased. Benefits were apparent only after 6 months. Therefore, based on available data, bisphosphonates can reduce the incidence of morbidity related to skeletal metastases but should not be used with the intention of preventing spinal cord compression or as a treatment once it develops. They can be used in patients with multiple, painful spinal metastases that are not causing neurological symptoms or spinal cord compression.

Few metastatic tumors causing spinal cord compression are treated solely with chemotherapy. There are numerous reports in the literature documenting successful decompression in lymphoma,7278 breast cancer,79 prostate cancer,80 germ cell tumors,8184 hepatoblastoma,85 neuroblastoma,86,87 and Ewing’s sarcoma.87,88 Most of the literature is small case series and case reports and is disproportionately represented by pediatric patients.87,89,90 However, special mention needs to be given to prostate cancer. Patients with newly diagnosed, untreated prostate cancer and spinal metastases with spinal cord compression may be effectively treated with hormonal therapy followed by radiation.91,92 The lesions may be osteolytic, osteoblastic, or mixed. Typically, ketoconazole is started and gradually titrated up for the first several weeks. This effectively shuts off the production of testosterone (chemical castration). This can also be achieved by surgical castration. During this time period, the prostate-specific antigen (PSA) and testosterone levels are followed to assess for a response. If these levels decrease, ketoconazole is eventually switched over to chronic antiandrogen therapy with bicalutamide (Casodex) and goserelin acetate (Zoladex), avoiding the complications that are associated with long-term ketoconazole use. If the patient remains neurologically stable, conventional external-beam radiotherapy is initiated. However, if during the antiandrogen therapy there is no response based on the PSA or testosterone or the patient develops new or worsening neurological status, surgery should be performed, followed by radiation. Huddart and coworkers found that age younger than 65 years, no previous hormonal therapy, and a single level of compression were factors predictive of better outcome.93 Patients with no prior hormone therapy had a median survival of 627 days, but there was a 45% risk for developing a further episode of cord compression at the same or new site by 2 years.

Surgery

There has been an explosion of literature on the surgical management of spinal metastatic disease. This is due in part to the growing recognition of the beneficial effects of surgery in terms of preserving or restoring neurological function and relieving pain, coupled with the availability of surgical approaches and instrumentation that allow aggressive decompression and reconstruction of the spine. For many years, laminectomy was the only surgical option offered to patients with metastatic spine disease. In fact, “surgery” is to some extent still equated with laminectomy, contributing to the radiotherapy bias. One of the reasons that laminectomy was the dominant surgical procedure is its relative ease. It can be performed quickly with minimal intraoperative risk and does not require spinal column reconstruction or placement of internal stabilization devices. Despite its widespread use, there was no consensus among surgeons at the time regarding its effectiveness. Some thought that it was the only reasonable hope for recovering neurological deficits, whereas others found it to be of little value except for obtaining tissue to make a diagnosis and relieving pain.94,95 These surgeries were associated with significant complications, specifically wound infection or dehiscence and spinal instability. Findlay’s review of the literature found the incidence of these complications to be about 11%.96

After a number of years, it became clear that laminectomy alone or in combination with radiation was no more effective in terms of preserving or restoring neurological function than radiation alone (Table 311-9). For instance, in 1978, Gilbert and colleagues17 published a single-institution, retrospective analysis of 235 patients treated with either decompressive laminectomy followed by radiation (n = 65) or radiation alone (n = 170). After treatment, 46% of those who underwent the combination treatment were ambulatory, compared with 49% of those who had radiation alone. The pretreatment neurological function was the most reliable indicator of posttreatment function. There was no significant difference in the rate of neurological recovery between the two groups. Of the 22 patients who developed rapidly progressive weakness (<48 hours), 9 underwent surgery, and 13 received radiation. None of the surgical patients improved, but 7 of the radiation patients did. The authors concluded that radiation should be the treatment of choice and that a decompressive laminectomy is indicated in only three situations: (1) to establish a diagnosis; (2) to treat a relapse if the patient is unable to undergo further radiation; and (3) if symptoms progress during radiation.

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