Unknown Primary Site, Carcinoma of, Childhood


Approximately 1.2 million patients present with cancer each year in the United States. Of these, approximately 600,000 persons have metastases to bone. In contrast, 2,700 patients per year develop primary bone sarcoma. In addition, the age range of patients with sarcoma is different from that of individuals with carcinoma of bone; most metastatic bone lesions occur in adults older than 50 years, while most sarcomas occur in adolescents or young adults (< 30 y). Therefore, a bone-occupying mass in an adult is much more likely to be a focus of metastatic carcinoma than to be a primary sarcoma of bone; however, in a patient with a bone lesion with no documentation of metastatic disease, caution is warranted to ensure the correct diagnosis.

In females, the breasts and lungs are the most common primary disease sites; approximately 80% of cancers that spread to bone arise in these locations.In males, cancers of the prostate and lungs make up 80% of the carcinomas that metastasize to bone. The remaining 20% of primary disease sites in patients of both sexes are the kidney, gut, and thyroid, as well as sites of unknown origin.

Most patients with metastatic bone disease survive for 6-48 months. In general, patients with breast and prostate carcinoma live longer than do persons with lung carcinoma.3 Patients with renal cell or thyroid carcinoma have a variable life expectancy.

The orthopedic surgeon has 2 major tasks to perform when treating patients who develop bone metastases.The first task is to biopsy a bony lesion of unknown origin, which may be found during evaluation/staging studies or as a result of a patient's symptoms.

The orthopedic surgeon's second task is to manage the stabilization of impending or already completed pathologic fractures of bones in a critical area, such as an upper or lower extremity, the pelvis, or the spine. In one study of patients with breast carcinoma, 19% of the patients developed a pathologic fracture or hypercalcemia as the first sign that the carcinoma had spread to bone. Moreover, 10% of the patients suffered spinal cord compression, and 9% of them experienced bone marrow failure. It is important to develop strategies that emphasize maintenance of function, including ambulation, in these patients for the remainder of their lives and to intervene when possible before a fracture occurs. The associated morbidity and mortality rate is greater when intervention is delayed.

See also the following related topic in Medscape:
Resource Center Breast Cancer

See also the following related topics in eMedicine:

  • Bone Metastases
  • Vertebral Fracture


Previously, the 2 main theories of how tumor cells metastasize and grow in bones were Paget's fertile soil hypothesis and Ewing's circulation theory. However, a substantial amount of work has more clearly defined the metastatic process to bone. Bone metastases occur in a predictable distribution. In order of frequency, the most common locations include the following:

  • Spine
  • Pelvis
  • Ribs
  • Proximal limb girdles

The red marrow theory, combined with knowledge about the cytokine stimulation of metastases, provides an excellent explanation of how this distribution occurs. Metastases distal to the knee and elbow are extremely uncommon, but approximately 50% of these acral metastases are secondary to primary lung tumors. Carcinomas, such as those of the breast and prostate, rarely exhibit such a distinct pattern.

Bone destruction, secondary to metastases, is clearly caused by the activation of osteoclasts rather than by the direct destruction of bone by tumor cells. In 1995, Mundy and Yoneda described the cellular events necessary for the success of the metastatic process, including the attachment of tumor cells to the basement membrane, the production of proteolytic enzymes by tumor cells (such as metalloproteinases, which are enzymes that disrupt basement membranes), and the migration of tumor cells through the basement membranes into surrounding tissue, especially the arteriolar network.

Once in the bloodstream, these tumor cells must be capable of surviving the intravascular killer T cells; they must also successfully attach to the basement membrane of the vessel at the distant site, break it down, and migrate into the surrounding tissues. Because these cells cannot survive further than 100 mm away from a capillary, they must also produce angiogenesis factors to stimulate capillary ingrowth.

Needless to say, something must attract these tumor cells to a specific site in the body, but that process is not as clear. Type I collagen, a byproduct of bone resorption, has been shown to be a chemotactic factor that attracts tumor cells to bone. Cell adhesion molecules, such as laminin, E-cadherin, and integrins, also have been identified as substances that facilitate the attachment of metastatic cells to basement membranes.

Once at the distant site, destruction of the host bone must be accomplished. Tumor cells are also able to up-regulate osteoclasts through the production of RANK ligand, a potent stimulator of osteoclastic activity. This substance recruits and activates osteoclasts in order to destroy trabecular and cortical bone. RANK ligand and other chemotactic factors, as noted above, up-regulate osteoclasts for the degradation of bone, producing pockets or holes in the bone in which the tumor cells to grow.

Another important substance that stimulates bone resorption is parathyroid hormone – related peptide (PTHrP). This substance is expressed by breast carcinoma cells, as well as by oat cell tumors of the lung, and is a potent stimulant of osteoclasts. In 1996, Guise and colleagues reported elevated PTHrP levels in the bone marrow plasma (as compared with serum plasma levels) in rats with tumors.

An interesting concept, reported in 1995 by Mundy and Yoneda, is that myeloma cells are especially adapted to producing bone destruction through direct stimulation of osteoclasts.5 During the resorption process, the osteoclasts release interleukin-6, which is a major regulatory factor in the growth of myeloma cells. Additional myeloma cells further stimulate increased osteoclastic production in a continuous feedback mechanism. This enhances survival of the tumor cells and further destruction of the bone.

The process by which bone metastases develop appears to be the following:

  • Cells from the primary site must, through the process of neovascularization or through migration to the nearest blood vessel, attach to the basement membrane of the vessel wall and produce proteolytic enzymes that disrupt the basement membrane.
  • The cells then migrate through the basement membrane and float away in the bloodstream to a distant site. If they survive the journey to the distant site, the tumor cells attach to the basement membrane of the vessel wall using proteolytic enzymes (integrins/cadherins). After disrupting the receptor site basement membrane, they migrate into the substance of the distal host tissue. Producing the chemotactic factors noted above, as well as RANK ligand, these cells stimulate osteoclast activity to produce bone resorption.
  • A feedback relationship, such as that present in myeloma cells, then produces continued osteoclast stimulation for bone resorption and tumor cell growth, providing for continued growth and survival of the metastatic cells. This, in turn, progressively destroys cancellous and cortical bone at the distant osseous site.

This osteoclastic bone resorption can be modified by bisphosphonates; these substances are presently being used in the management of metastatic breast carcinoma and multiple myeloma.Future research and modification of RANK ligand will produce additional substances that can further arrest or retard bone destruction by metastatic disease.

Other intriguing research is being conducted in the area of angiogenesis inhibition. Presently, such efforts are being directed at patients with GI tumors. Additional research in the areas of combined large vessel embolization and microscopic angiogenesis inhibition needs to be done.

Frequency United States

See Background.


In general, once skeletal metastases are present, patient survival is dramatically shortened. For example, the 5-year overall survival rate for people with prostate cancer is 93%, but once skeletal metastases are present, the average survival time is only 29 months. However, patients are surviving and remaining active for longer periods as treatment protocols improve. These factors make the orthopedic surgeon's task in prophylactic or reconstructive surgery more challenging. In addition, perioperative complications are greater in this population.

  • The perioperative mortality rate is approximately 8%.
  • The perioperative infection rate is approximately 4% and increases in previously irradiated sites.


Most patients with skeletal metastases are older than 50 years.

Clinical History

Although pain is an important symptom of musculoskeletal metastases, it is nonspecific. The pain pattern can be helpful if, in addition to being activity-related, it is present at rest and at night, especially in patients older than 50 years. However, this pain pattern can be present in patients with osteomyelitis and Paget disease, and in these instances, it is also is nonspecific.

Diagnostic factors

An orthopedic surgeon will be consulted in the following instances to help evaluate a patient with a suspicious bony defect.

  • In the first instance, the surgeon is asked to help evaluate a patient a patient who has experienced a pathologic fracture or who has a known primary carcinoma as well as a bony defect.
  • In the second, more worrisome instance, the surgeon is consulted in the evaluation of a patient whose bony defect was serendipitously found during the radiologic evaluation of another condition.

In the above instances, the orthopedist must perform 3 functions:

  • Determine the cause of the bony defect.
    • In a limited number of patients, bony defects are often found serendipitously during radiographic evaluation of the affected part for other reasons. In these instances, the orthopedist is asked to determine if the discovered bony defect is a benign event requiring no further management or one that needs further investigation. The following are examples of such defects.
      • The stippled, calcific, benign-appearing enchondroma found in the proximal humerus during an evaluation of a patient for a rotator cuff tear
      • Bony physiologic changes in the intertrochanteric area of the proximal femur, which may be found on plain anteroposterior (AP) pelvic radiographs during evaluation of the pelvis for other reasons
      • An area of fibrous dysplasia, which may be observed on radiographs that have been taken of a patient involved in some traumatic event
    • It is often difficult to determine whether a bony defect found during a bone survey for metastatic disease is the result of that disease or of some other condition. For instance, a benign bone island, an area of osteopoikilosis or fibrous dysplasia, can produce a similar radiographic appearance. A bone biopsy is often required to determine the actual diagnosis of such a defect. If the patient has already been diagnosed as having a primary tumor, the management of the recently discovered bony defect is relatively uncomplicated.
    • When the diagnosis of the bony defect needs to be proven for therapeutic reasons, biopsy is appropriate. For example, the radiotherapist or oncologist may need confirmation that the recently discovered bony defect is the same as the primary tumor or that the bony site results from another condition. Bone biopsies can be accomplished in a number of ways, but for the diagnosis of bony metastases, the most appropriate and least invasive method for making a diagnosis is needle biopsy.
  • Predict the probability of fracture.7
    • If the biopsy confirms that the bony defect has been caused by metastatic disease, the orthopedist must then decide if the defect fits the criteria for an impending fracture. The definition of an impending fracture is the presence of a bony defect that is likely to result in a pathologic fracture with physiologic loading (ie, activities of daily living). In this case, the orthopedist should determine the probability of fracture by examining plain radiographic findings and by conducting an interview with the patient. Quantitating the risk of fracture based on plain radiography alone is very subjective because the broad guidelines in the literature are based on small numbers of patients and, therefore, are limited in value. Using them can result in errors of judgment more than 50% of the time.
    • According to a 1995 report by Hipp and colleagues, useful criteria are as follows: defect geometry affecting load-bearing capacity, the histologic cell causing the defect (ie, blastic, lytic, or mixed), and the anatomic site (femoral neck vs greater trochanter).8 For instance, according to the study, the factor of risk for fracture of a normal proximal femur is approximately 0.4. The thinnest part of a cortical wall is the critical factor for predicting loss of strength. Central lesions with a 50% symmetrical loss of bone produce a 60% loss of bending strength. In patients who have eccentric bone loss, a 50% bone mass reduction results in a 90% reduction of bending strength. Therefore, a lesion located in areas that increase the risk factors to the bone must be considered.
    • Length of a bony lesion has been reported as critical only in torsional loads. The load-bearing capacity of bone apparently depends on: 1) the location of the defect with respect to the applied load, 2) the type of applied load, 3) the amount of bone loss, and 4) the condition of the remaining bone. The anatomic location of a bony lesion also is important. As the literature has shown, a drill hole that has been placed inappropriately in the lateral femoral shaft (at or below the level of the lesser trochanter) for fixation of a nonneoplastic femoral neck fracture results in a high risk of bone fracture with weight bearing through the lateral femoral cortical drill hold defect. Therefore, a similarly sized metastatic lesion in this area can be expected to create a similarly high fracture risk.
  • Prophylactically fix a pathologic or impending fracture.
    • When a bony site displays radiographic and clinical evidence of an impending or already completed pathologic fracture, surgical stabilization is indicated. Most current literature supports the prophylactic fixation of impending fractures to minimize morbidity and protect function. In contrast, waiting for an impending fracture to occur increases morbidity and mortality and affects the patient's ability to regain function in as short a time as possible.
    • Because the life span of these patients is limited, the goal of management needs to be centered on returning as much function as possible as rapidly as possible.

Treatment Medical Care

  • Hematologic
    • Patients with myeloma, leukemia, or metastatic carcinoma may have anemia, thrombocytopenia, and leukopenia secondary to chronic disease and marrow replacement.
    • If liver disease, metastatic or otherwise, is present, then a coagulopathy may be present as well.
    • Perioperative resuscitation with appropriate factors and cellular elements is essential.
    • With predisposition for thrombosis, provide prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism.
  • Metabolic
    • Hypercalcemia is common.
    • Treat with hydration, bisphosphonates, and mithramycin.
  • Nutritional - A nutritional deficiency may retard wound healing and the potential for rehabilitation.
  • Response - Monitoring the response of skeletal metastases to radiation therapy or medical therapy (eg, chemotherapy, bisphosphonates) is difficult. This is because increased bone deposition from an osteoblastic metastasis (such as that which may result from prostate or breast carcinoma) can have a similar appearance on a bone scan or, often, a radiograph to deposition from posttreatment consolidation. Metastatic prostate carcinoma is the most common cause of osteoblastic metastases in men.
  • Pain - Pain relief is probably the best guide to the regression of a lesion.

Surgical Care Indication for spine treatment

The spine is the most common location of metastatic disease. The timing of treatment is critical in persons with spinal metastases because patients with spinal disease have a life expectancy of 6 months to more than 2 years, depending on the primary tumor type.9 The overall condition of the patient, the individual's chance for improvement with presently available treatment options, and the personal wishes of the patient have to be considered when deciding between surgical and nonsurgical management of spinal disease. In general, patients with at least 6-12 weeks of life expectancy may be surgical candidates, depending on the location of the lesion in the spine and the impending neurologic consequences of disease progression at that level.

The surgical procedures performed on patients with spinal disease fall into the following 2 categories:

  • Diagnostic - Diagnostic management is usually performed with core needle biopsies up to the level of D8 and with open biopsies or minimally invasive costotransversectomies above the level of D8.
  • Therapeutic - Such treatment is performed to manage pain, decompress neural elements, and restore mechanical stability to the spine. In rare incidents of radioresistant tumors, such as those occurring in thyroid and renal cell carcinoma, a surgical resection and intercalary stabilization may serve as the only effective treatment modality. However, success with tumor embolization for such metastases has been reported to offer improved longevity in patients with these specific tumors.

Obtaining a biopsy is not necessary in all patients with metastatic disease of the spine. In patients with myeloma, a core needle biopsy of the iliac crest is part of the staging process and is appropriate for diagnosis, which means that a biopsy of a defect in a vertebral body is not required. Percutaneous core needle biopsies have successful positive results in 65% of destructive (lytic) lesions of vertebrae metastases but in only 20-25% of blastic ones. Open biopsy has a yield success rate of 85%, regardless of the lesion type. Always remember to obtain a culture and Gram stain on all specimens, because infection is a great imitator of disease in bone, especially in the spine.

Percutaneous needle biopsy of C2 can be performed through a transoral approach. In this author's experience, biopsy of the C1 and C3 vertebrae can also be accomplished through this approach, but the procedure is much more difficult than it is for C2. This procedure must be performed under fluoroscopic control at all times. When using the transoral approach, a broad-spectrum antibiotic covering multiple floras should be administered during the perioperative period to prevent secondary infections.

An open biopsy of the thoracic spine above T8 is best performed through a costotransversectomy. When the biopsy is performed with a needle, fluoroscopic/CT scanning control is best used. Biopsies can be safely obtained from lesions below D8 with a core needle, such as the Craig, using the Ottolenghi technique.

Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis, because nearly 95% of patients who are ambulatory at the start of radiation therapy remain so. Patients who start with limited ambulatory neurologic function have a 60% chance of improvement after radiation therapy. In those persons who have lost sphincter function, the chance of regaining it is no greater than 40%. The point is that the possibility of regaining cord function once it is lost as a result of spinal metastasis is dismal and needs to be avoided by early diagnosis, treatment, and, if indicated, surgical intervention.

The efficacy of radiation therapy is dependent on the radiosensitivity of the tumor. The presence of bone in the spinal canal or of a circumferential epidural tumor limits the success of management with radiation therapy alone. Patients with these conditions and cord compromise have been shown to experience improved outcomes with radical tumor resection and internal fixation/stabilization.

The objectives of therapeutic surgical treatment for spinal metastases include decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine.The most important of these criteria is decompression of neural elements, because the loss of neural function is almost always an unrecoverable catastrophe, especially in anterior cord injury.

Anterior or posterolateral decompression, combined with AP reconstruction, allows for the treatment of a wide variety of patient problems. Using such techniques, 75-100% of patients experience improved pain outcomes; some neurologic improvement occurs in 50-75% of patients. More importantly, 95% of patients without preoperative neural deficits maintain their function after these procedures. Once neurologic function is lost, less than 40% of patients regain it.

Surgical intervention has risks, because patients with metastatic disease have poor nutritional status, low platelet counts, and low total white cell counts. These constitutional deficits, combined with radiation therapy, place patients at high risk for wound infections and other complications, including excessive blood loss (with certain tumors, such as myelomas, as well as renal cell and papillary thyroid carcinomas), myocardial infarction, DVT, and pneumonia. The incidence of such complications varies from 10-15%, depending on the patient's underlying condition.

As with long bone fractures, prognostic indicators can be used in evaluating patients with spinal metastases, helping to predict which patients may progress to vertebral collapse, spinal cord compression, and neurologic dysfunction. Although not ideal, these indicators, are very helpful.

The 4-column concept, which is based on radiographic criteria and includes the concept of laterality, provides one set of prognostic indicators. Tumor destruction of fewer than 3 columns (ie, 2 or 1) suggests stability of the spine; a spine in which 3-4 columns have been destroyed is considered unstable and in need of stabilization. Tumor biology and location also are helpful indicators.

Indications for therapeutic surgical therapeutic are as follows:

  • Primary surgical intervention is appropriate when adjuvant therapy alone will fail to produce long-lasting success. Radioresistant tumors, mechanical instability from bone destruction, and the presence of bone in the spinal canal, as well as circumferential epidural tumors, fit the indication for primary surgical treatment.
  • Therapeutic surgical procedures are necessary when the progression of neurologic symptoms occurs despite the administration of the primary method of nonoperative treatment (ie, radiotherapy, chemotherapy).
  • Therapeutic surgery is also necessary when fracture, instability, or tumor progression, with impending or actual spinal cord compression, is present.

In the cervical spine, pain and instability are the most common indications of disease. Neurologic deficits are relatively uncommon in the upper cervical spine because of the larger canal diameter, occurring in only 15% of cases of upper spinal disease metastases. In the lower cervical spine, 25-35% of lesions produce spinal cord compression. Appropriate treatment depends on the degree of involvement. In the C1 and C2 bodies, lateral mass involvement is the critical factor because of the primary role these structures play in the overall stability of this area. Patients with destruction of the lateral mass of C1 do not obtain pain relief from radiation therapy alone because of rotatory instability. They require posterior stabilization from the occiput to C2, with postoperative radiation therapy.

Patients with C2 body involvement and minimally displaced fractures or with diffuse involvement of the entire body can be treated with radiation therapy and immobilization in a cervical orthosis until fracture stability and bony restitution has occurred. With gross destruction of the body of C2 and instability, surgery may be indicated as dictated by the patient's condition and neurologic status. This may require posterior fusion or a combined anterior and posterior approach. Patients who are not surgical candidates need to be treated with realignment and immobilization with a halo vest and radiation therapy. Patients with posterior C2 involvement require radiation therapy and an orthosis for pain control. If the spinous processes of C2 are lost, cervical kyphosis can ensue.

Anterior decompression and reconstruction with autologous or allograft bone are effective means of achieving decompression and stabilization with 1- or 2-level anterior metastatic disease from C3-C7. Additional posterior stabilization is usually necessary for disease that has more than 2 levels of involvement.

In the thoracic and lumbar spine, metastatic disease occurs most frequently in the vertebral body. Therefore, anterior decompression and stabilization is the most effective means of decompressing the spinal canal. This allows for correction of the deformity caused by the tumor and for direct stabilization of the involved portion of the vertebral body. Depending on the level and extent of the lesion, the surgical approach varies from an anterior thoracotomy to a thoracoabdominal or retroperitoneal approach. Up to 2 contiguous levels can be approached, decompressed, and stabilized. More than 2 levels of involvement require the addition of posterior segmental stabilization to provide adequate mechanical stability.

The posterior approach (with no anterior stabilization) should be reserved for diffuse disease over many levels or for isolated posterior disease alone. The fixation of 2 levels above and 2 levels below the involved areas, using segmental instrumentation, is necessary for proper stabilization. AP decompression and stabilization also is required for circumferential disease or after the decompression of multiple levels.

Surgical fixation of long bones

Open internal fixation of long bones is usually the preferred method of treatment for the management of long bone metastatic disease accompanied by an impending or completed fracture. Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred.

Some locations deserve special consideration. Replacement arthroplasty, unipolar or bipolar, is most appropriate for pathologic fractures of the femoral and humeral head or neck. This is also the preferred management technique for distal femoral or proximal tibial condylar defects. Although the proximal femur and humerus are frequent sites of metastases, it has been found that metastases are less frequent at the distal femoral and proximal tibial locations. The latter 2 sites are usually associated with melanoma, myeloma, or lymphoma.

Standard or cemented stems, including calcar replacements, are appropriate in the proximal femur. Standard cemented stems are also appropriate in the proximal humerus. Presently, off-the-shelf femoral and humeral devices are available in long straight or bowed stems. The longest stem possible should be used in these situations to stabilize any actual or potential additional lesions distal to the proximal site.

Good clinical results, rapid return to function, and almost no wear complications are observed because of the shortened life span (ie, 4-48 mo) of these patients. The use of long, cemented stems does carry an increased risk that during the procedure, cardiac arrest will occur secondary to pressurization of the cement, and appropriate measures need to be taken to minimize such an event during the placement of the stem.Such measures include distal venting of the canal with drill holes, meticulous canal preparation, avoidance of hyperpressurization, and the staging of bilateral procedures, as well as the provision of adequate hydration and blood pressure support to the patient during this part of the process.

In the author's opinion, the use of the dynamic hip screw or plate for the fixation of pathologic proximal femoral fractures is inappropriate because of the increased risk from already existing defects or the potential for additional metastatic defects in the femur distal to the initial lesion. Although the successful use of such a construct for the surgical management of intertrochanteric femoral fractures has been reported, the frequently deficient medial femoral cortex wall defects, combined with the inability to address any bony disease distal to this type of construct, make it a relatively poor choice.

The use of intramedullary fixation devices, such as third-generation cephalomedullary implants in the femur and other designs, is the preferred method of fixation for long bone fractures (that is, fractures of the tibia or humerus). The use of cement is still helpful in the filling of large defects in the bone, but the present day locking devices are well suited for the stabilization of these bones. The use of radiation therapy after healing of the surgical wound also is critical and can result in the healing of pathologic fractures, especially in the case of lesions related to breast cancer.

When discovered, defects of almost any size in the ulna and radius, although rare, need to be fixed, because the ulna and radius are subject to constant torsional loads secondary to the pronation/supination actions of the forearm. Dysfunction of the forearm for the patient with a pathologic fracture of one of these bones is poorly tolerated. If possible, a firmly fixed device is needed to protect these small bones from further stress.

The issue of concurrent, lateral acetabular metastases with proximal femoral disease is appropriate to mention. Microscopic disease of the bone has been found around the acetabulum in 83% of patients during replacement arthroplasty for pathologic femoral neck fractures. Based on this data, some authors have recommended routine total hip arthroplasty (THR) for management of this event.

However, this microscopic disease has not been clearly shown to cause clinical failures after femoral side – only replacements, and the goal of this type of surgery, which is to return patients to as much function as possible, is not realized with THR. Additionally, because radiation therapy is used postoperatively to manage such microscopic foci, whether THR affords any benefit over the use of unipolar devices is questionable. Continuing to use hemiarthroplasty is probably appropriate for proximal femoral disease management, unless clear evidence of structural compromise is present on preoperative evaluation of these patients.

In the event of a THR, the use of a cemented socket is highly recommended, because postoperative irradiation and the primary disease process, as described in Pathophysiology, limit any advantage that might be gained from employing a porous ingrowth device. Larger lesions may require the use of acetabular cages and/or the use of Harrington-type reconstruction with Kirschner wires (K-wires) and cement.With more extensive disease, a saddle prosthesis or resection arthroplasty may be needed.

The percutaneous introduction of polymethylmethacrylate (vertebroplasty) may be a minimally invasive treatment alternative for patients with 1- or 2-level vertebral body compression fractures.Originally described for the management of osteoporotic compression fractures, the procedure has risks, which include (particularly) the development of neurologic complications. It is presently being introduced into the orthopedic community as an additional tool to help in the management of patients with the above-mentioned compression fractures.

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