Three-dimensional (3-D) printing is a rapidly evolving technology with both medical and nonmedical applications.^1,2 Rapid prototyping involves creating a physical model of human tissue from a 3-D computer-generated rendering.³ The method relies on export of Digital Imaging and Communications in Medicine (DICOM)–based computed tomography (CT) or magnetic resonance imaging (MRI) data into standard triangular language (STL) format. Reducing CT or MRI slice thickness increases resolution of the final model.² Five types of rapid prototyping exist: STL, selective laser sintering, fused deposition modeling, multijet modeling, and 3-D printing.

Most implant manufacturers can produce a 3-D model based on surgeon-provided DICOM images. The ability to produce anatomical models in an office-based setting is a more recent development. Three-dimensional modeling may allow for more accurate and extensive preoperative planning than radiographic examination alone does, and may even allow surgeons to perform procedures as part of preoperative preparation. This can allow for early recognition of unanticipated intraoperative problems or of the need for special techniques and implants that would not have been otherwise available, all of which may ultimately reduce operative time.

The breadth of applications for office-based 3-D prototyping is not well described in the orthopedic surgery literature. In this article, we describe 7 cases of complex orthopedic disorders that were surgically treated after preoperative planning in which use of a 3-D printer allowed for “mock” surgery before the actual procedures. In 3 of the cases, the models were made by the implant manufacturers. Working with these models prompted us to buy a 3-D printer (Fortus 250; Stratasys, Eden Prairie, Minnesota) for in-office use. In the other 4 cases, we used this printer to create our own models. As indicated in the manufacturer’s literature, the printer uses fused deposition modeling, which builds a model layer by layer by heating thermoplastic material to a semi-liquid state and extruding it according to computer-controlled pathways.

We present preoperative images, preoperative 3-D modeling, and intraoperative and postoperative images along with brief case descriptions (Table). The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

A 28-year-old woman with a history of spondyloepiphyseal dysplasia presented to our clinic with bilateral hip pain. About 8 years earlier, she had undergone bilateral proximal and distal femoral osteotomies. Her function had initially improved, but over the 2 to 3 years before presentation she began having more pain and stiffness with activity. At time of initial evaluation, she was able to walk only 1 to 2 blocks and had difficulty getting in and out of a car and up out of a seated position.

On physical examination, the patient was 3 feet 10 inches tall and weighed 77 pounds. She ambulated with decreased stance phase on both lower extremities and had developed a significant amount of increased forward pelvic inclination and increased lumbar lordosis. Both hips and thighs had multiple healed scars from prior surgeries and pin tracts. Range of motion (ROM) on both sides was restricted to 85° of flexion, 10° of internal rotation, 15° of external rotation, and 15° of abduction.

Plain radiographs showed advanced degenerative joint disease (DJD) of both hips with dysplastic acetabuli and evidence of healed osteotomies (Figure 1). Femoral deformities, noted bilaterally, consisted of marked valgus proximally and varus distally. Preoperative CT was used to create a 3-D model of the pelvis and femur. The model was created by the same implant manufacturer that produced the final components (Depuy, Warsaw, Indiana). Corrective femoral osteotomy was performed on the model to allow for design and use of a custom implant, while the modeled pelvis confirmed the ability to reproduce the normal hip center with a 44-mm conventional hemispherical socket.

After surgery, the patient was able to ambulate without a limp and return to work. Her hip ROM was pain-free passively and actively with flexion to 100°, internal rotation to 35°, external rotation to 20°, and abduction to 30°.

Case 2

A 48-year-old woman with a history of Crowe IV hip dysplasia presented to our clinic with a chronically dislocated right total hip arthroplasty (THA) (Figure 2). Her initial THA was revised 1 year later because of acetabular component failure. Two years later, she was diagnosed with a deep periprosthetic infection, which was ultimately treated with 2-stage reimplantation. She subsequently dislocated and underwent re-revision of the S-ROM body and stem (DePuy Synthes, Warsaw, Indiana). At a visit after that revision, she was noted to be chronically dislocated, and was sent to our clinic for further management.

Preoperative radiographs showed a right uncemented THA with the femoral head dislocated toward the false acetabulum, retained hardware, and an old ununited trochanteric fragment. Both the femoral and acetabular components appeared well-fixed, though the acetabular component was positioned inferior, toward the obturator foramen.

Preoperative CT with metal artifact subtraction was used to create a 3-D model of the residual bony pelvis. The model was made by an implant manufacturer (Zimmer, Warsaw, Indiana). The shape of the superior defect was amenable to reconstruction using a modified revision trabecular metal socket. The pelvic model was reamed to accept a conventional hemispherical socket. The defect was reamed to accept a modified revision trabecular metal socket. The real implant was fashioned before surgery and was sterilized to avoid the need for intraoperative modification. Use of the preoperative model significantly reduced the time that would have been needed to modify the implant during actual surgery.

The patient’s right THA was revised. At time of surgery, the modified revision trabecular metal acetabular component was noted to seat appropriately in the superior defect. The true acetabulum was reestablished, and a hemispherical socket was placed with multiple screws. The 2 components were then unitized using cement in the same manner as would be done with an off-the-shelf augment.

Case 3

A 57-year-old man presented with a 10-year history of right knee pain. About 30 years before presentation at our clinic, he was treated for an open right tibia fracture sustained in a motorcycle accident. He had been treated nonsurgically, with injections, but they failed to provide sustained relief.

Preoperative radiographs showed severe advanced DJD in conjunction with an extra-articular posttraumatic varus tibial shaft deformity (Figure 3). An implant manufacturer (Zimmer) used a CT scan to create a model of the deformity. The resultant center of rotation angle was calculated using preoperative images and conventional techniques for deformity correction, and a lateral closing-wedge osteotomy was performed on the CT-based model. The initial attempt at deformity correction was slightly excessive, and the amount of resected bone slightly thicker than the calculated wedge, resulting in a valgus deformity. This error was noted, and the decision was made to recut a new model with a slight amount of residual varus that could be corrected during the final knee arthroplasty procedure.

Corrective osteotomy was performed with a lateral plate. Six months later, the patient had no residual pain, and CT confirmed union at the osteotomy site and a slight amount of residual varus. The patient then underwent routine total knee arthroplasty (TKA) using an abbreviated keel to avoid the need for removal of the previously placed hardware. The varus deformity was completely corrected.

Case 4

A 73-year-old man had a history of shoulder pain dating back to his childhood. Despite treatment with nonsteroidal anti-inflammatory drugs, physical therapy, and injections, his debilitating pain persisted. Physical examination revealed limited ROM and an intact rotator cuff.

Plain radiographs showed severe DJD of the glenohumeral joint (Figure 4). Severe erosions of the glenoid were noted, prompting further workup with CT, which showed significant bone loss, particularly along the posterior margin of the glenoid. We used our 3-D printer to create a model of the scapula from CT images. The model was then reamed in the usual fashion to accept a 3-pegged glenoid component. On placement of a trial implant, a large deficiency was seen posteriorly. We thought the size and location of the defect made it amenable to grafting using the patient’s humeral head.

The patient elected to undergo right total shoulder arthroplasty. During the procedure, the glenoid defect was found to be identical to what was encountered with the model before surgery. A portion of the patient’s humeral head was then fashioned to fit the defect, and was secured with three 2.7-mm screws, after provisional fixation using 2.0-mm Kirschner wires. The screws were countersunk, and the graft was contoured by hand to match the previous reaming. A 3-pegged 52-mm glenoid component was then cemented into position with excellent stability.

Case 5

A 64-year-old man presented to our clinic with left hip pain 40 years after THA. The original procedure was performed for resolved proximal femoral osteomyelitis. Plain radiographs showed a loose cemented McKee-Farrar hip arthroplasty (Figure 5). Because of the elevated position of the acetabular component relative to the native hip center, CT was used to determine the amount of femoral bone loss.

We used our 3-D printer to create a model and tried to recreate the native hip center with conventional off-the-shelf implants. A 50-mm hemispherical socket trial was placed in the appropriate location, along with a trabecular metal augment trial to provide extended coverage over the superolateral portion of the socket. Noted between the socket and the augment was a large gap; a substantial amount of cement would have been needed to unitize the construct. We thought a custom acetabular component would avoid the need for cement. In addition, given the patient’s small stature, the conventional acetabular component would allow a head only 32 mm in diameter. With a custom implant, the head could be enlarged to 36 mm, providing improved ROM and stability.

The patient underwent revision left hip arthroplasty using a custom acetabular component. A 3-D model available at time of surgery was used to aid implant placement.

Case 6

A 23-year-old man with multiple hereditary exostoses presented to our clinic with a painful mass in the left calf. Plain radiographs showed extensive osteochondromatosis involving the left proximal tibiofibular joint (Figure 6). The exostosis extended posteromedially, displacing the arterial trifurcation. MRI showed a small cartilage cap without evidence of malignant transformation.

CT angiogram allowed the vasculature to be modeled along with the deformity. A 3-D model was fabricated. The model included the entire proximal tibiofibular joint, as well as the anterior tibial, peroneal, and posterior tibial arteries. Cautious intralesional resection was recommended because of the proximity to all 3 vessels.

The patient underwent tumor resection through a longitudinal posterior approach. The interval between the medial and lateral heads of the gastrocnemius muscles was developed to expose the underlying soleus muscle. The soleus was split longitudinally from its hiatus to the inferior portion of the exostosis. This allowed for identification of the trifurcation and the tibial nerve, which were protected. Osteotomes were used to resect the mass at its base, the edges were carefully trimmed, and bone wax was placed over the defect. Anterior and lateral to this mass was another large mass (under the soleus muscle), which was also transected using an osteotome. The gastrocnemius and soleus muscles were then reflected off the fibula in order to remove 2 other exostoses, beneath the neck and head of the fibula.

Case 7

A 71-year-old man with a history of idiopathic lymphedema and peripheral neuropathy presented to our clinic with a left cavovarus foot deformity and a history of recurrent neuropathic foot ulcers (Figure 7). Physical examination revealed a callus over the lateral aspect of the base of the fifth metatarsal. Preoperative radiograph showed evidence of prior triple arthrodesis with a cavovarus foot deformity. CT scan was used to create a 3-D model of the foot. The model was then used to identify an appropriate location for lateral midtarsal and calcaneal closing-wedge osteotomies.

The patient underwent midfoot and hindfoot surgical correction. At surgery, the lateral closing-wedge osteotomies were performed according to the preoperative model. Radiographs 1 year after surgery showed correction of the forefoot varus.

Discussion

Three-dimensional printing for medical applications of anatomical modeling is not a new concept.^1,3,4 Its use has been reported for a variety of applications in orthopedic surgery, including the printing of porous and metallic surfaces⁵ and bone-tissue engineering.^6-9 Rapid prototyping for medical application was first reported in 1990 when a CT-based model was used to create a cranial bone.¹⁰ Reports of using the technique are becoming more widespread, particularly in the dental and maxillofacial literature, which includes reports on a variety of applications, including patient-specific drill guides, splints, and implants.^11-14 The ability to perform mock surgery in advance of an actual procedure provides an invaluable opportunity to anticipate potential intraoperative problems, reduce operative time, and improve the accuracy of reconstruction.

Office-based rapid prototyping that uses an in-house 3-D printer is a novel application of this technology. It allows for creation of a patient-specific model for preoperative planning purposes. We are unaware of any other reports demonstrating the breadth and utility of office-based rapid prototyping in orthopedic surgery. For general reference, a printer similar to ours requires an initial investment of $52,000 to $56,000. This cost generally covers the printer, printer base cabinet, installation, training, and printer software (different from the 3-D modeling software), plus a 1-year warranty. A service agreement costs about $4000 annually. Printer and model supply expenses depend on the material used for the model (eg, ABS [acrylonitrile butadiene styrene]) and on the size and complexity of the 3-D models created. Average time to generate an appropriately formatted 3-D printing file is about 1 hour, though times can vary largely, according to amount of metal artifact subtraction necessary and the experience of the software user. For the rare, extremely complex deformities that require a significant amount of metal artifact subtraction, file preparation times can exceed 3 or 4 hours. We think these preparation times will decrease as communication between radiology file export format and modeling software ultimately allows for metal artifact subtraction images to function within the modeling software environment. Once an appropriately formatted file has been created, typical printing times vary according to the size of the to-be-modeled bone. For a hemipelvis, printing time is 30 to 40 hours; printing that is started on a Friday afternoon will be complete by Monday morning.

There are few reports of rapid prototyping in orthopedic surgery. In 2003, Minns and colleagues¹⁵ used a 3-D model in the planning of a tibial resection for TKA. They found the model to be accurate at time of surgery, resulting in appropriate tibial coverage by a conventional meniscal-bearing implant. Munjal and colleagues¹⁶ reported on 10 complex failed hip arthroplasty cases in which patients had revision surgery after preoperative planning using 3-D modeling techniques. The authors found that, in 8 of the 10 cases, conventional classification systems of bone loss were inaccurate in comparison with the prototype. Four cases required reconstruction with a custom triflange when conventional implants were not deemed reasonable based on the pelvic model. Tam and colleagues¹⁷ reported using a 3-D prototype as an aid in surgical planning for resection of a scapular osteochondroma in a 6-year-old patient. They found the rapid prototype to be useful at time of resection—similar to what we found with 1 patient (case 6). Adding contrast media to our patient’s scan allowed for 3-D visualization of the lesion and the encased vasculature. Fu and colleagues¹⁸ reported using a patient-specific drill template to insert anterior transpedicular screws. They constructed 24 prototypes of a formalin-preserved cervical vertebra to create a patient-specific biocompatible drill template for use in correcting multilevel cervical instability. They found the technique to be highly reproducible and accurate. Zein and colleagues¹⁹ used a rapid prototype of 3 consecutive human livers to preoperatively identify the vascular and biliary tract anatomy. They reported a high degree of accuracy—mean dimensional errors of less than 4 mm for the entire model and 1.3 mm for the vascular diameter.

The models created by implant manufacturers in this series were used to perform “mock” surgery before the actual procedures. Working with these models prompted us to buy our own 3-D printer. The learning curve can be steep, but commercially available 3-D printers allow for prompt in-office production of high-quality realistic prototypes at relatively low per-case cost (Figure 8). Three-dimensional modeling allows surgeons to assess the accuracy of their original surgical plans and, if necessary, correct them before surgery. Although computer-aided design models are useful, the ability to “perform surgery preoperatively” adds another element to surgeons’ understanding of the potential issues that may arise. Also, an in-office printer can help improve surgeons’ understanding and control over the process by which images are translated from radiographic file to 3-D model. Disadvantages of an in-office system include start-up and maintenance costs, office space requirements, and a significant learning curve for software and hardware applications. In addition, creation of 3-D models requires close interaction with radiologists who can provide appropriately formatted DICOM images, as metal artifact subtraction can be challenging. We think that, as image formatting and software capabilities are continually refined, this technology will become an invaluable part of multiple subspecialties across orthopedic surgery, with potentially infinite clinical, educational, and research applications.

Three-dimensional (3-D) printing is a rapidly evolving technology with both medical and nonmedical applications.^1,2 Rapid prototyping involves creating a physical model of human tissue from a 3-D computer-generated rendering.³ The method relies on export of Digital Imaging and Communications in Medicine (DICOM)–based computed tomography (CT) or magnetic resonance imaging (MRI) data into standard triangular language (STL) format. Reducing CT or MRI slice thickness increases resolution of the final model.² Five types of rapid prototyping exist: STL, selective laser sintering, fused deposition modeling, multijet modeling, and 3-D printing.

Most implant manufacturers can produce a 3-D model based on surgeon-provided DICOM images. The ability to produce anatomical models in an office-based setting is a more recent development. Three-dimensional modeling may allow for more accurate and extensive preoperative planning than radiographic examination alone does, and may even allow surgeons to perform procedures as part of preoperative preparation. This can allow for early recognition of unanticipated intraoperative problems or of the need for special techniques and implants that would not have been otherwise available, all of which may ultimately reduce operative time.

The breadth of applications for office-based 3-D prototyping is not well described in the orthopedic surgery literature. In this article, we describe 7 cases of complex orthopedic disorders that were surgically treated after preoperative planning in which use of a 3-D printer allowed for “mock” surgery before the actual procedures. In 3 of the cases, the models were made by the implant manufacturers. Working with these models prompted us to buy a 3-D printer (Fortus 250; Stratasys, Eden Prairie, Minnesota) for in-office use. In the other 4 cases, we used this printer to create our own models. As indicated in the manufacturer’s literature, the printer uses fused deposition modeling, which builds a model layer by layer by heating thermoplastic material to a semi-liquid state and extruding it according to computer-controlled pathways.

We present preoperative images, preoperative 3-D modeling, and intraoperative and postoperative images along with brief case descriptions (Table). The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

A 28-year-old woman with a history of spondyloepiphyseal dysplasia presented to our clinic with bilateral hip pain. About 8 years earlier, she had undergone bilateral proximal and distal femoral osteotomies. Her function had initially improved, but over the 2 to 3 years before presentation she began having more pain and stiffness with activity. At time of initial evaluation, she was able to walk only 1 to 2 blocks and had difficulty getting in and out of a car and up out of a seated position.

On physical examination, the patient was 3 feet 10 inches tall and weighed 77 pounds. She ambulated with decreased stance phase on both lower extremities and had developed a significant amount of increased forward pelvic inclination and increased lumbar lordosis. Both hips and thighs had multiple healed scars from prior surgeries and pin tracts. Range of motion (ROM) on both sides was restricted to 85° of flexion, 10° of internal rotation, 15° of external rotation, and 15° of abduction.

Plain radiographs showed advanced degenerative joint disease (DJD) of both hips with dysplastic acetabuli and evidence of healed osteotomies (Figure 1). Femoral deformities, noted bilaterally, consisted of marked valgus proximally and varus distally. Preoperative CT was used to create a 3-D model of the pelvis and femur. The model was created by the same implant manufacturer that produced the final components (Depuy, Warsaw, Indiana). Corrective femoral osteotomy was performed on the model to allow for design and use of a custom implant, while the modeled pelvis confirmed the ability to reproduce the normal hip center with a 44-mm conventional hemispherical socket.

After surgery, the patient was able to ambulate without a limp and return to work. Her hip ROM was pain-free passively and actively with flexion to 100°, internal rotation to 35°, external rotation to 20°, and abduction to 30°.

Case 2

A 48-year-old woman with a history of Crowe IV hip dysplasia presented to our clinic with a chronically dislocated right total hip arthroplasty (THA) (Figure 2). Her initial THA was revised 1 year later because of acetabular component failure. Two years later, she was diagnosed with a deep periprosthetic infection, which was ultimately treated with 2-stage reimplantation. She subsequently dislocated and underwent re-revision of the S-ROM body and stem (DePuy Synthes, Warsaw, Indiana). At a visit after that revision, she was noted to be chronically dislocated, and was sent to our clinic for further management.

Preoperative radiographs showed a right uncemented THA with the femoral head dislocated toward the false acetabulum, retained hardware, and an old ununited trochanteric fragment. Both the femoral and acetabular components appeared well-fixed, though the acetabular component was positioned inferior, toward the obturator foramen.

Preoperative CT with metal artifact subtraction was used to create a 3-D model of the residual bony pelvis. The model was made by an implant manufacturer (Zimmer, Warsaw, Indiana). The shape of the superior defect was amenable to reconstruction using a modified revision trabecular metal socket. The pelvic model was reamed to accept a conventional hemispherical socket. The defect was reamed to accept a modified revision trabecular metal socket. The real implant was fashioned before surgery and was sterilized to avoid the need for intraoperative modification. Use of the preoperative model significantly reduced the time that would have been needed to modify the implant during actual surgery.

The patient’s right THA was revised. At time of surgery, the modified revision trabecular metal acetabular component was noted to seat appropriately in the superior defect. The true acetabulum was reestablished, and a hemispherical socket was placed with multiple screws. The 2 components were then unitized using cement in the same manner as would be done with an off-the-shelf augment.

Case 3

A 57-year-old man presented with a 10-year history of right knee pain. About 30 years before presentation at our clinic, he was treated for an open right tibia fracture sustained in a motorcycle accident. He had been treated nonsurgically, with injections, but they failed to provide sustained relief.

Preoperative radiographs showed severe advanced DJD in conjunction with an extra-articular posttraumatic varus tibial shaft deformity (Figure 3). An implant manufacturer (Zimmer) used a CT scan to create a model of the deformity. The resultant center of rotation angle was calculated using preoperative images and conventional techniques for deformity correction, and a lateral closing-wedge osteotomy was performed on the CT-based model. The initial attempt at deformity correction was slightly excessive, and the amount of resected bone slightly thicker than the calculated wedge, resulting in a valgus deformity. This error was noted, and the decision was made to recut a new model with a slight amount of residual varus that could be corrected during the final knee arthroplasty procedure.

Corrective osteotomy was performed with a lateral plate. Six months later, the patient had no residual pain, and CT confirmed union at the osteotomy site and a slight amount of residual varus. The patient then underwent routine total knee arthroplasty (TKA) using an abbreviated keel to avoid the need for removal of the previously placed hardware. The varus deformity was completely corrected.

Case 4

A 73-year-old man had a history of shoulder pain dating back to his childhood. Despite treatment with nonsteroidal anti-inflammatory drugs, physical therapy, and injections, his debilitating pain persisted. Physical examination revealed limited ROM and an intact rotator cuff.

Plain radiographs showed severe DJD of the glenohumeral joint (Figure 4). Severe erosions of the glenoid were noted, prompting further workup with CT, which showed significant bone loss, particularly along the posterior margin of the glenoid. We used our 3-D printer to create a model of the scapula from CT images. The model was then reamed in the usual fashion to accept a 3-pegged glenoid component. On placement of a trial implant, a large deficiency was seen posteriorly. We thought the size and location of the defect made it amenable to grafting using the patient’s humeral head.

The patient elected to undergo right total shoulder arthroplasty. During the procedure, the glenoid defect was found to be identical to what was encountered with the model before surgery. A portion of the patient’s humeral head was then fashioned to fit the defect, and was secured with three 2.7-mm screws, after provisional fixation using 2.0-mm Kirschner wires. The screws were countersunk, and the graft was contoured by hand to match the previous reaming. A 3-pegged 52-mm glenoid component was then cemented into position with excellent stability.

Case 5

A 64-year-old man presented to our clinic with left hip pain 40 years after THA. The original procedure was performed for resolved proximal femoral osteomyelitis. Plain radiographs showed a loose cemented McKee-Farrar hip arthroplasty (Figure 5). Because of the elevated position of the acetabular component relative to the native hip center, CT was used to determine the amount of femoral bone loss.

We used our 3-D printer to create a model and tried to recreate the native hip center with conventional off-the-shelf implants. A 50-mm hemispherical socket trial was placed in the appropriate location, along with a trabecular metal augment trial to provide extended coverage over the superolateral portion of the socket. Noted between the socket and the augment was a large gap; a substantial amount of cement would have been needed to unitize the construct. We thought a custom acetabular component would avoid the need for cement. In addition, given the patient’s small stature, the conventional acetabular component would allow a head only 32 mm in diameter. With a custom implant, the head could be enlarged to 36 mm, providing improved ROM and stability.

The patient underwent revision left hip arthroplasty using a custom acetabular component. A 3-D model available at time of surgery was used to aid implant placement.

Case 6

A 23-year-old man with multiple hereditary exostoses presented to our clinic with a painful mass in the left calf. Plain radiographs showed extensive osteochondromatosis involving the left proximal tibiofibular joint (Figure 6). The exostosis extended posteromedially, displacing the arterial trifurcation. MRI showed a small cartilage cap without evidence of malignant transformation.

CT angiogram allowed the vasculature to be modeled along with the deformity. A 3-D model was fabricated. The model included the entire proximal tibiofibular joint, as well as the anterior tibial, peroneal, and posterior tibial arteries. Cautious intralesional resection was recommended because of the proximity to all 3 vessels.

The patient underwent tumor resection through a longitudinal posterior approach. The interval between the medial and lateral heads of the gastrocnemius muscles was developed to expose the underlying soleus muscle. The soleus was split longitudinally from its hiatus to the inferior portion of the exostosis. This allowed for identification of the trifurcation and the tibial nerve, which were protected. Osteotomes were used to resect the mass at its base, the edges were carefully trimmed, and bone wax was placed over the defect. Anterior and lateral to this mass was another large mass (under the soleus muscle), which was also transected using an osteotome. The gastrocnemius and soleus muscles were then reflected off the fibula in order to remove 2 other exostoses, beneath the neck and head of the fibula.

Case 7

A 71-year-old man with a history of idiopathic lymphedema and peripheral neuropathy presented to our clinic with a left cavovarus foot deformity and a history of recurrent neuropathic foot ulcers (Figure 7). Physical examination revealed a callus over the lateral aspect of the base of the fifth metatarsal. Preoperative radiograph showed evidence of prior triple arthrodesis with a cavovarus foot deformity. CT scan was used to create a 3-D model of the foot. The model was then used to identify an appropriate location for lateral midtarsal and calcaneal closing-wedge osteotomies.

The patient underwent midfoot and hindfoot surgical correction. At surgery, the lateral closing-wedge osteotomies were performed according to the preoperative model. Radiographs 1 year after surgery showed correction of the forefoot varus.

Discussion

Three-dimensional printing for medical applications of anatomical modeling is not a new concept.^1,3,4 Its use has been reported for a variety of applications in orthopedic surgery, including the printing of porous and metallic surfaces⁵ and bone-tissue engineering.^6-9 Rapid prototyping for medical application was first reported in 1990 when a CT-based model was used to create a cranial bone.¹⁰ Reports of using the technique are becoming more widespread, particularly in the dental and maxillofacial literature, which includes reports on a variety of applications, including patient-specific drill guides, splints, and implants.^11-14 The ability to perform mock surgery in advance of an actual procedure provides an invaluable opportunity to anticipate potential intraoperative problems, reduce operative time, and improve the accuracy of reconstruction.

Office-based rapid prototyping that uses an in-house 3-D printer is a novel application of this technology. It allows for creation of a patient-specific model for preoperative planning purposes. We are unaware of any other reports demonstrating the breadth and utility of office-based rapid prototyping in orthopedic surgery. For general reference, a printer similar to ours requires an initial investment of $52,000 to $56,000. This cost generally covers the printer, printer base cabinet, installation, training, and printer software (different from the 3-D modeling software), plus a 1-year warranty. A service agreement costs about $4000 annually. Printer and model supply expenses depend on the material used for the model (eg, ABS [acrylonitrile butadiene styrene]) and on the size and complexity of the 3-D models created. Average time to generate an appropriately formatted 3-D printing file is about 1 hour, though times can vary largely, according to amount of metal artifact subtraction necessary and the experience of the software user. For the rare, extremely complex deformities that require a significant amount of metal artifact subtraction, file preparation times can exceed 3 or 4 hours. We think these preparation times will decrease as communication between radiology file export format and modeling software ultimately allows for metal artifact subtraction images to function within the modeling software environment. Once an appropriately formatted file has been created, typical printing times vary according to the size of the to-be-modeled bone. For a hemipelvis, printing time is 30 to 40 hours; printing that is started on a Friday afternoon will be complete by Monday morning.

There are few reports of rapid prototyping in orthopedic surgery. In 2003, Minns and colleagues¹⁵ used a 3-D model in the planning of a tibial resection for TKA. They found the model to be accurate at time of surgery, resulting in appropriate tibial coverage by a conventional meniscal-bearing implant. Munjal and colleagues¹⁶ reported on 10 complex failed hip arthroplasty cases in which patients had revision surgery after preoperative planning using 3-D modeling techniques. The authors found that, in 8 of the 10 cases, conventional classification systems of bone loss were inaccurate in comparison with the prototype. Four cases required reconstruction with a custom triflange when conventional implants were not deemed reasonable based on the pelvic model. Tam and colleagues¹⁷ reported using a 3-D prototype as an aid in surgical planning for resection of a scapular osteochondroma in a 6-year-old patient. They found the rapid prototype to be useful at time of resection—similar to what we found with 1 patient (case 6). Adding contrast media to our patient’s scan allowed for 3-D visualization of the lesion and the encased vasculature. Fu and colleagues¹⁸ reported using a patient-specific drill template to insert anterior transpedicular screws. They constructed 24 prototypes of a formalin-preserved cervical vertebra to create a patient-specific biocompatible drill template for use in correcting multilevel cervical instability. They found the technique to be highly reproducible and accurate. Zein and colleagues¹⁹ used a rapid prototype of 3 consecutive human livers to preoperatively identify the vascular and biliary tract anatomy. They reported a high degree of accuracy—mean dimensional errors of less than 4 mm for the entire model and 1.3 mm for the vascular diameter.

The models created by implant manufacturers in this series were used to perform “mock” surgery before the actual procedures. Working with these models prompted us to buy our own 3-D printer. The learning curve can be steep, but commercially available 3-D printers allow for prompt in-office production of high-quality realistic prototypes at relatively low per-case cost (Figure 8). Three-dimensional modeling allows surgeons to assess the accuracy of their original surgical plans and, if necessary, correct them before surgery. Although computer-aided design models are useful, the ability to “perform surgery preoperatively” adds another element to surgeons’ understanding of the potential issues that may arise. Also, an in-office printer can help improve surgeons’ understanding and control over the process by which images are translated from radiographic file to 3-D model. Disadvantages of an in-office system include start-up and maintenance costs, office space requirements, and a significant learning curve for software and hardware applications. In addition, creation of 3-D models requires close interaction with radiologists who can provide appropriately formatted DICOM images, as metal artifact subtraction can be challenging. We think that, as image formatting and software capabilities are continually refined, this technology will become an invaluable part of multiple subspecialties across orthopedic surgery, with potentially infinite clinical, educational, and research applications.

Three-dimensional (3-D) printing is a rapidly evolving technology with both medical and nonmedical applications.^1,2 Rapid prototyping involves creating a physical model of human tissue from a 3-D computer-generated rendering.³ The method relies on export of Digital Imaging and Communications in Medicine (DICOM)–based computed tomography (CT) or magnetic resonance imaging (MRI) data into standard triangular language (STL) format. Reducing CT or MRI slice thickness increases resolution of the final model.² Five types of rapid prototyping exist: STL, selective laser sintering, fused deposition modeling, multijet modeling, and 3-D printing.

Most implant manufacturers can produce a 3-D model based on surgeon-provided DICOM images. The ability to produce anatomical models in an office-based setting is a more recent development. Three-dimensional modeling may allow for more accurate and extensive preoperative planning than radiographic examination alone does, and may even allow surgeons to perform procedures as part of preoperative preparation. This can allow for early recognition of unanticipated intraoperative problems or of the need for special techniques and implants that would not have been otherwise available, all of which may ultimately reduce operative time.

The breadth of applications for office-based 3-D prototyping is not well described in the orthopedic surgery literature. In this article, we describe 7 cases of complex orthopedic disorders that were surgically treated after preoperative planning in which use of a 3-D printer allowed for “mock” surgery before the actual procedures. In 3 of the cases, the models were made by the implant manufacturers. Working with these models prompted us to buy a 3-D printer (Fortus 250; Stratasys, Eden Prairie, Minnesota) for in-office use. In the other 4 cases, we used this printer to create our own models. As indicated in the manufacturer’s literature, the printer uses fused deposition modeling, which builds a model layer by layer by heating thermoplastic material to a semi-liquid state and extruding it according to computer-controlled pathways.

We present preoperative images, preoperative 3-D modeling, and intraoperative and postoperative images along with brief case descriptions (Table). The patients provided written informed consent for print and electronic publication of these case reports.

Case Reports

Case 1

A 28-year-old woman with a history of spondyloepiphyseal dysplasia presented to our clinic with bilateral hip pain. About 8 years earlier, she had undergone bilateral proximal and distal femoral osteotomies. Her function had initially improved, but over the 2 to 3 years before presentation she began having more pain and stiffness with activity. At time of initial evaluation, she was able to walk only 1 to 2 blocks and had difficulty getting in and out of a car and up out of a seated position.

On physical examination, the patient was 3 feet 10 inches tall and weighed 77 pounds. She ambulated with decreased stance phase on both lower extremities and had developed a significant amount of increased forward pelvic inclination and increased lumbar lordosis. Both hips and thighs had multiple healed scars from prior surgeries and pin tracts. Range of motion (ROM) on both sides was restricted to 85° of flexion, 10° of internal rotation, 15° of external rotation, and 15° of abduction.

Plain radiographs showed advanced degenerative joint disease (DJD) of both hips with dysplastic acetabuli and evidence of healed osteotomies (Figure 1). Femoral deformities, noted bilaterally, consisted of marked valgus proximally and varus distally. Preoperative CT was used to create a 3-D model of the pelvis and femur. The model was created by the same implant manufacturer that produced the final components (Depuy, Warsaw, Indiana). Corrective femoral osteotomy was performed on the model to allow for design and use of a custom implant, while the modeled pelvis confirmed the ability to reproduce the normal hip center with a 44-mm conventional hemispherical socket.

After surgery, the patient was able to ambulate without a limp and return to work. Her hip ROM was pain-free passively and actively with flexion to 100°, internal rotation to 35°, external rotation to 20°, and abduction to 30°.

Case 2

A 48-year-old woman with a history of Crowe IV hip dysplasia presented to our clinic with a chronically dislocated right total hip arthroplasty (THA) (Figure 2). Her initial THA was revised 1 year later because of acetabular component failure. Two years later, she was diagnosed with a deep periprosthetic infection, which was ultimately treated with 2-stage reimplantation. She subsequently dislocated and underwent re-revision of the S-ROM body and stem (DePuy Synthes, Warsaw, Indiana). At a visit after that revision, she was noted to be chronically dislocated, and was sent to our clinic for further management.

Preoperative radiographs showed a right uncemented THA with the femoral head dislocated toward the false acetabulum, retained hardware, and an old ununited trochanteric fragment. Both the femoral and acetabular components appeared well-fixed, though the acetabular component was positioned inferior, toward the obturator foramen.

Preoperative CT with metal artifact subtraction was used to create a 3-D model of the residual bony pelvis. The model was made by an implant manufacturer (Zimmer, Warsaw, Indiana). The shape of the superior defect was amenable to reconstruction using a modified revision trabecular metal socket. The pelvic model was reamed to accept a conventional hemispherical socket. The defect was reamed to accept a modified revision trabecular metal socket. The real implant was fashioned before surgery and was sterilized to avoid the need for intraoperative modification. Use of the preoperative model significantly reduced the time that would have been needed to modify the implant during actual surgery.

The patient’s right THA was revised. At time of surgery, the modified revision trabecular metal acetabular component was noted to seat appropriately in the superior defect. The true acetabulum was reestablished, and a hemispherical socket was placed with multiple screws. The 2 components were then unitized using cement in the same manner as would be done with an off-the-shelf augment.

Case 3

A 57-year-old man presented with a 10-year history of right knee pain. About 30 years before presentation at our clinic, he was treated for an open right tibia fracture sustained in a motorcycle accident. He had been treated nonsurgically, with injections, but they failed to provide sustained relief.

Preoperative radiographs showed severe advanced DJD in conjunction with an extra-articular posttraumatic varus tibial shaft deformity (Figure 3). An implant manufacturer (Zimmer) used a CT scan to create a model of the deformity. The resultant center of rotation angle was calculated using preoperative images and conventional techniques for deformity correction, and a lateral closing-wedge osteotomy was performed on the CT-based model. The initial attempt at deformity correction was slightly excessive, and the amount of resected bone slightly thicker than the calculated wedge, resulting in a valgus deformity. This error was noted, and the decision was made to recut a new model with a slight amount of residual varus that could be corrected during the final knee arthroplasty procedure.

Corrective osteotomy was performed with a lateral plate. Six months later, the patient had no residual pain, and CT confirmed union at the osteotomy site and a slight amount of residual varus. The patient then underwent routine total knee arthroplasty (TKA) using an abbreviated keel to avoid the need for removal of the previously placed hardware. The varus deformity was completely corrected.

Case 4

A 73-year-old man had a history of shoulder pain dating back to his childhood. Despite treatment with nonsteroidal anti-inflammatory drugs, physical therapy, and injections, his debilitating pain persisted. Physical examination revealed limited ROM and an intact rotator cuff.

Plain radiographs showed severe DJD of the glenohumeral joint (Figure 4). Severe erosions of the glenoid were noted, prompting further workup with CT, which showed significant bone loss, particularly along the posterior margin of the glenoid. We used our 3-D printer to create a model of the scapula from CT images. The model was then reamed in the usual fashion to accept a 3-pegged glenoid component. On placement of a trial implant, a large deficiency was seen posteriorly. We thought the size and location of the defect made it amenable to grafting using the patient’s humeral head.

The patient elected to undergo right total shoulder arthroplasty. During the procedure, the glenoid defect was found to be identical to what was encountered with the model before surgery. A portion of the patient’s humeral head was then fashioned to fit the defect, and was secured with three 2.7-mm screws, after provisional fixation using 2.0-mm Kirschner wires. The screws were countersunk, and the graft was contoured by hand to match the previous reaming. A 3-pegged 52-mm glenoid component was then cemented into position with excellent stability.

Case 5

A 64-year-old man presented to our clinic with left hip pain 40 years after THA. The original procedure was performed for resolved proximal femoral osteomyelitis. Plain radiographs showed a loose cemented McKee-Farrar hip arthroplasty (Figure 5). Because of the elevated position of the acetabular component relative to the native hip center, CT was used to determine the amount of femoral bone loss.

We used our 3-D printer to create a model and tried to recreate the native hip center with conventional off-the-shelf implants. A 50-mm hemispherical socket trial was placed in the appropriate location, along with a trabecular metal augment trial to provide extended coverage over the superolateral portion of the socket. Noted between the socket and the augment was a large gap; a substantial amount of cement would have been needed to unitize the construct. We thought a custom acetabular component would avoid the need for cement. In addition, given the patient’s small stature, the conventional acetabular component would allow a head only 32 mm in diameter. With a custom implant, the head could be enlarged to 36 mm, providing improved ROM and stability.

The patient underwent revision left hip arthroplasty using a custom acetabular component. A 3-D model available at time of surgery was used to aid implant placement.

Case 6

A 23-year-old man with multiple hereditary exostoses presented to our clinic with a painful mass in the left calf. Plain radiographs showed extensive osteochondromatosis involving the left proximal tibiofibular joint (Figure 6). The exostosis extended posteromedially, displacing the arterial trifurcation. MRI showed a small cartilage cap without evidence of malignant transformation.

CT angiogram allowed the vasculature to be modeled along with the deformity. A 3-D model was fabricated. The model included the entire proximal tibiofibular joint, as well as the anterior tibial, peroneal, and posterior tibial arteries. Cautious intralesional resection was recommended because of the proximity to all 3 vessels.

The patient underwent tumor resection through a longitudinal posterior approach. The interval between the medial and lateral heads of the gastrocnemius muscles was developed to expose the underlying soleus muscle. The soleus was split longitudinally from its hiatus to the inferior portion of the exostosis. This allowed for identification of the trifurcation and the tibial nerve, which were protected. Osteotomes were used to resect the mass at its base, the edges were carefully trimmed, and bone wax was placed over the defect. Anterior and lateral to this mass was another large mass (under the soleus muscle), which was also transected using an osteotome. The gastrocnemius and soleus muscles were then reflected off the fibula in order to remove 2 other exostoses, beneath the neck and head of the fibula.

Case 7

A 71-year-old man with a history of idiopathic lymphedema and peripheral neuropathy presented to our clinic with a left cavovarus foot deformity and a history of recurrent neuropathic foot ulcers (Figure 7). Physical examination revealed a callus over the lateral aspect of the base of the fifth metatarsal. Preoperative radiograph showed evidence of prior triple arthrodesis with a cavovarus foot deformity. CT scan was used to create a 3-D model of the foot. The model was then used to identify an appropriate location for lateral midtarsal and calcaneal closing-wedge osteotomies.

The patient underwent midfoot and hindfoot surgical correction. At surgery, the lateral closing-wedge osteotomies were performed according to the preoperative model. Radiographs 1 year after surgery showed correction of the forefoot varus.

Discussion

Three-dimensional printing for medical applications of anatomical modeling is not a new concept.^1,3,4 Its use has been reported for a variety of applications in orthopedic surgery, including the printing of porous and metallic surfaces⁵ and bone-tissue engineering.^6-9 Rapid prototyping for medical application was first reported in 1990 when a CT-based model was used to create a cranial bone.¹⁰ Reports of using the technique are becoming more widespread, particularly in the dental and maxillofacial literature, which includes reports on a variety of applications, including patient-specific drill guides, splints, and implants.^11-14 The ability to perform mock surgery in advance of an actual procedure provides an invaluable opportunity to anticipate potential intraoperative problems, reduce operative time, and improve the accuracy of reconstruction.

Office-based rapid prototyping that uses an in-house 3-D printer is a novel application of this technology. It allows for creation of a patient-specific model for preoperative planning purposes. We are unaware of any other reports demonstrating the breadth and utility of office-based rapid prototyping in orthopedic surgery. For general reference, a printer similar to ours requires an initial investment of $52,000 to $56,000. This cost generally covers the printer, printer base cabinet, installation, training, and printer software (different from the 3-D modeling software), plus a 1-year warranty. A service agreement costs about $4000 annually. Printer and model supply expenses depend on the material used for the model (eg, ABS [acrylonitrile butadiene styrene]) and on the size and complexity of the 3-D models created. Average time to generate an appropriately formatted 3-D printing file is about 1 hour, though times can vary largely, according to amount of metal artifact subtraction necessary and the experience of the software user. For the rare, extremely complex deformities that require a significant amount of metal artifact subtraction, file preparation times can exceed 3 or 4 hours. We think these preparation times will decrease as communication between radiology file export format and modeling software ultimately allows for metal artifact subtraction images to function within the modeling software environment. Once an appropriately formatted file has been created, typical printing times vary according to the size of the to-be-modeled bone. For a hemipelvis, printing time is 30 to 40 hours; printing that is started on a Friday afternoon will be complete by Monday morning.

There are few reports of rapid prototyping in orthopedic surgery. In 2003, Minns and colleagues¹⁵ used a 3-D model in the planning of a tibial resection for TKA. They found the model to be accurate at time of surgery, resulting in appropriate tibial coverage by a conventional meniscal-bearing implant. Munjal and colleagues¹⁶ reported on 10 complex failed hip arthroplasty cases in which patients had revision surgery after preoperative planning using 3-D modeling techniques. The authors found that, in 8 of the 10 cases, conventional classification systems of bone loss were inaccurate in comparison with the prototype. Four cases required reconstruction with a custom triflange when conventional implants were not deemed reasonable based on the pelvic model. Tam and colleagues¹⁷ reported using a 3-D prototype as an aid in surgical planning for resection of a scapular osteochondroma in a 6-year-old patient. They found the rapid prototype to be useful at time of resection—similar to what we found with 1 patient (case 6). Adding contrast media to our patient’s scan allowed for 3-D visualization of the lesion and the encased vasculature. Fu and colleagues¹⁸ reported using a patient-specific drill template to insert anterior transpedicular screws. They constructed 24 prototypes of a formalin-preserved cervical vertebra to create a patient-specific biocompatible drill template for use in correcting multilevel cervical instability. They found the technique to be highly reproducible and accurate. Zein and colleagues¹⁹ used a rapid prototype of 3 consecutive human livers to preoperatively identify the vascular and biliary tract anatomy. They reported a high degree of accuracy—mean dimensional errors of less than 4 mm for the entire model and 1.3 mm for the vascular diameter.

The models created by implant manufacturers in this series were used to perform “mock” surgery before the actual procedures. Working with these models prompted us to buy our own 3-D printer. The learning curve can be steep, but commercially available 3-D printers allow for prompt in-office production of high-quality realistic prototypes at relatively low per-case cost (Figure 8). Three-dimensional modeling allows surgeons to assess the accuracy of their original surgical plans and, if necessary, correct them before surgery. Although computer-aided design models are useful, the ability to “perform surgery preoperatively” adds another element to surgeons’ understanding of the potential issues that may arise. Also, an in-office printer can help improve surgeons’ understanding and control over the process by which images are translated from radiographic file to 3-D model. Disadvantages of an in-office system include start-up and maintenance costs, office space requirements, and a significant learning curve for software and hardware applications. In addition, creation of 3-D models requires close interaction with radiologists who can provide appropriately formatted DICOM images, as metal artifact subtraction can be challenging. We think that, as image formatting and software capabilities are continually refined, this technology will become an invaluable part of multiple subspecialties across orthopedic surgery, with potentially infinite clinical, educational, and research applications.

Children often present to orthopedic surgeons with angular deformities about the knee. Temporary hemiepiphysiodesis, which is a frequently performed procedure to address such deformities, is safe and reversible. Specifically, tension band plating has become one of the most commonly performed techniques, especially given its low complication rates and minimally invasive nature.^1-4 Complications reported with this method include mechanical hardware failure,⁵ implant migration,⁴ and recurvatum.³

We present an unreported complication of a synovial fistula formation after the removal of a tension band plate in a child who had achieved appropriate correction of her genu valgum. The patient and her family provided written informed consent for print and electronic publication of this case report.

Case Report

An 11-year-old girl presented to the pediatric orthopedics clinic with concern for genu valgum of the right lower extremity. She underwent a right proximal tibia medial hemiepiphysiodesis via tension band plating technique. Her clinic visit 4 weeks after surgery showed well-healed incisions and no signs of infection. She achieved appropriate correction and underwent hardware removal approximately 6 months after her initial surgery. 

One month after hardware removal, the patient began to notice increased swelling and erythema around her incision site with associated pain. No fluid or drainage was seen at that time. She underwent irrigation and débridement shortly thereafter, and the wound was left open for wet-to-dry dressing changes (Figure 1). Intraoperative cultures were negative, but the patient received empiric antibiotic therapy. She continued to have difficulty with wound healing for the next month and was referred to plastic surgery. She underwent repeat irrigation and débridement, followed by coverage with a split-thickness skin graft by the plastic surgery service. Intraoperative cultures were again negative. During both irrigation and débridement procedures, care was taken to remain superficial and not violate the knee capsule.

At her 2-week postoperative check, the bolster covering the split thickness skin graft was removed, which revealed a 2×2-mm area of clear erosion near the central portion of her wound with synovial fluid drainage (Figure 2). Because of concern for a synovial fistula, magnetic resonance imaging (MRI) of the right knee was obtained, which confirmed the synovial fistula (Figures 3A, 3B). The coronal cut on MRI clearly showed the fistula with synovial fluid tracking into the epiphyseal screw tract through the breached capsule and to the level of the skin. She was immobilized in a long leg cast with the knee in extension for 6 weeks. Upon return, her fistula had closed, and she has not had any more wound issues. 

Discussion

To our knowledge, this is the first report of a synovial fistula after temporary hemiepiphysiodesis performed via tension band plating. Capsular knee anatomy may explain the etiology of the synovial fistula after hardware removal. The medial knee capsule composition and attachment sites have been extensively studied.⁶ In contrast to other joints, such as the shoulder, elbow, ankle, and hip, the metaphysis of the knee lies outside the capsule because the capsule inserts proximal at the level of the physis.⁷ During tension band plating, the epiphyseal screw breaches the capsule but serves as a plug while in place, which prevents the formation of a synovial fistula. When the screw is removed, the capsular rent spontaneously closes in almost all cases. However, the opportunity exists for a synovial fistula to form while the capsule heals, as evidenced by the current case. Such an issue does not apply to the metaphyseal screw because it is inserted outside the capsule.  

Although it is possible that the synovial fistula was inadvertently created during one of the irrigation and débridement procedures, this is very unlikely. The surgeons who performed these washout procedures are knowledgeable and familiar with knee anatomy. Both irrigation and débridement procedures were superficial, and care was taken not to violate the knee capsule.

A synovial fistula after knee surgery is rare. Larsen⁸ described the fistula as a phenomenon that develops when excessive synovial fluid forces its way through a synovial incision with knee flexion and muscle contraction. Such a complication is most routinely described after knee arthroscopy. Proffer and colleagues⁹ reported an incidence of 6.1 per 1000 after knee arthroscopies. The average number of days until fistula diagnosis was 6 days (range, 3-10 days). All fistulae were treated with immobilization and closed after an average of 9 days (range, 7-14 days). There were no associated infections, although prophylactic antibiotics were given. A national survey found that knee fistulae accounted for only 3.2% of all complications of knee arthroscopy.¹⁰ 

The treatment for a synovial fistula is largely nonoperative. Most will resolve with a brief period of immobilization, which allows the fistula to close.^9-10 Literature addressing fistulae that fail to heal with nonoperative treatment is limited. Excision and direct closure of the fistula, especially when chronic, often proves futile and leads to a high recurrence rate.¹¹ An alternative but more extensive treatment involves excision and coverage with a myofascial flap.¹²

Complications reported after tension band plating are uncommon. Two studies reported no complications regarding the use of the tension band plate.^1-2 Burghardt and colleagues,⁵ in reporting the results of a multicenter survey, found that 15% of surgeons who had used tension band plating had seen a total of 65 cases of mechanical failure. In all cases, the screws, not the plate, failed. Another study reported implant migration in 1 patient but attributed the complication to a technical error from placing the distal screw too close to the physis.⁴ A third study documented that 2 patients developed clinically significant recurvatum, most likely because of anterior placement of the plate.³ It is important to identify a synovial fistula postoperatively because it provides a direct route for pathogens from the external environment to enter the intra-articular space and the opportunity for a septic joint to develop. Infection should always be ruled out and, if present, appropriately treated. 

Conclusion

Physicians performing tension band plating in the knee should be aware of the possible complication of a synovial fistula, which has traditionally been reported only in relation to knee arthroscopy. Given the proposed etiology of the synovial fistula, we recommend a brief period of immobilization of 3 to 5 days after tension band plate removal, allowing the capsular rent to heal and minimizing the risk of a synovial fistula.

Children often present to orthopedic surgeons with angular deformities about the knee. Temporary hemiepiphysiodesis, which is a frequently performed procedure to address such deformities, is safe and reversible. Specifically, tension band plating has become one of the most commonly performed techniques, especially given its low complication rates and minimally invasive nature.^1-4 Complications reported with this method include mechanical hardware failure,⁵ implant migration,⁴ and recurvatum.³

We present an unreported complication of a synovial fistula formation after the removal of a tension band plate in a child who had achieved appropriate correction of her genu valgum. The patient and her family provided written informed consent for print and electronic publication of this case report.

Case Report

An 11-year-old girl presented to the pediatric orthopedics clinic with concern for genu valgum of the right lower extremity. She underwent a right proximal tibia medial hemiepiphysiodesis via tension band plating technique. Her clinic visit 4 weeks after surgery showed well-healed incisions and no signs of infection. She achieved appropriate correction and underwent hardware removal approximately 6 months after her initial surgery. 

One month after hardware removal, the patient began to notice increased swelling and erythema around her incision site with associated pain. No fluid or drainage was seen at that time. She underwent irrigation and débridement shortly thereafter, and the wound was left open for wet-to-dry dressing changes (Figure 1). Intraoperative cultures were negative, but the patient received empiric antibiotic therapy. She continued to have difficulty with wound healing for the next month and was referred to plastic surgery. She underwent repeat irrigation and débridement, followed by coverage with a split-thickness skin graft by the plastic surgery service. Intraoperative cultures were again negative. During both irrigation and débridement procedures, care was taken to remain superficial and not violate the knee capsule.

At her 2-week postoperative check, the bolster covering the split thickness skin graft was removed, which revealed a 2×2-mm area of clear erosion near the central portion of her wound with synovial fluid drainage (Figure 2). Because of concern for a synovial fistula, magnetic resonance imaging (MRI) of the right knee was obtained, which confirmed the synovial fistula (Figures 3A, 3B). The coronal cut on MRI clearly showed the fistula with synovial fluid tracking into the epiphyseal screw tract through the breached capsule and to the level of the skin. She was immobilized in a long leg cast with the knee in extension for 6 weeks. Upon return, her fistula had closed, and she has not had any more wound issues. 

Discussion

To our knowledge, this is the first report of a synovial fistula after temporary hemiepiphysiodesis performed via tension band plating. Capsular knee anatomy may explain the etiology of the synovial fistula after hardware removal. The medial knee capsule composition and attachment sites have been extensively studied.⁶ In contrast to other joints, such as the shoulder, elbow, ankle, and hip, the metaphysis of the knee lies outside the capsule because the capsule inserts proximal at the level of the physis.⁷ During tension band plating, the epiphyseal screw breaches the capsule but serves as a plug while in place, which prevents the formation of a synovial fistula. When the screw is removed, the capsular rent spontaneously closes in almost all cases. However, the opportunity exists for a synovial fistula to form while the capsule heals, as evidenced by the current case. Such an issue does not apply to the metaphyseal screw because it is inserted outside the capsule.  

Although it is possible that the synovial fistula was inadvertently created during one of the irrigation and débridement procedures, this is very unlikely. The surgeons who performed these washout procedures are knowledgeable and familiar with knee anatomy. Both irrigation and débridement procedures were superficial, and care was taken not to violate the knee capsule.

A synovial fistula after knee surgery is rare. Larsen⁸ described the fistula as a phenomenon that develops when excessive synovial fluid forces its way through a synovial incision with knee flexion and muscle contraction. Such a complication is most routinely described after knee arthroscopy. Proffer and colleagues⁹ reported an incidence of 6.1 per 1000 after knee arthroscopies. The average number of days until fistula diagnosis was 6 days (range, 3-10 days). All fistulae were treated with immobilization and closed after an average of 9 days (range, 7-14 days). There were no associated infections, although prophylactic antibiotics were given. A national survey found that knee fistulae accounted for only 3.2% of all complications of knee arthroscopy.¹⁰ 

The treatment for a synovial fistula is largely nonoperative. Most will resolve with a brief period of immobilization, which allows the fistula to close.^9-10 Literature addressing fistulae that fail to heal with nonoperative treatment is limited. Excision and direct closure of the fistula, especially when chronic, often proves futile and leads to a high recurrence rate.¹¹ An alternative but more extensive treatment involves excision and coverage with a myofascial flap.¹²

Complications reported after tension band plating are uncommon. Two studies reported no complications regarding the use of the tension band plate.^1-2 Burghardt and colleagues,⁵ in reporting the results of a multicenter survey, found that 15% of surgeons who had used tension band plating had seen a total of 65 cases of mechanical failure. In all cases, the screws, not the plate, failed. Another study reported implant migration in 1 patient but attributed the complication to a technical error from placing the distal screw too close to the physis.⁴ A third study documented that 2 patients developed clinically significant recurvatum, most likely because of anterior placement of the plate.³ It is important to identify a synovial fistula postoperatively because it provides a direct route for pathogens from the external environment to enter the intra-articular space and the opportunity for a septic joint to develop. Infection should always be ruled out and, if present, appropriately treated. 

Conclusion

Physicians performing tension band plating in the knee should be aware of the possible complication of a synovial fistula, which has traditionally been reported only in relation to knee arthroscopy. Given the proposed etiology of the synovial fistula, we recommend a brief period of immobilization of 3 to 5 days after tension band plate removal, allowing the capsular rent to heal and minimizing the risk of a synovial fistula.

Children often present to orthopedic surgeons with angular deformities about the knee. Temporary hemiepiphysiodesis, which is a frequently performed procedure to address such deformities, is safe and reversible. Specifically, tension band plating has become one of the most commonly performed techniques, especially given its low complication rates and minimally invasive nature.^1-4 Complications reported with this method include mechanical hardware failure,⁵ implant migration,⁴ and recurvatum.³

We present an unreported complication of a synovial fistula formation after the removal of a tension band plate in a child who had achieved appropriate correction of her genu valgum. The patient and her family provided written informed consent for print and electronic publication of this case report.

Case Report

An 11-year-old girl presented to the pediatric orthopedics clinic with concern for genu valgum of the right lower extremity. She underwent a right proximal tibia medial hemiepiphysiodesis via tension band plating technique. Her clinic visit 4 weeks after surgery showed well-healed incisions and no signs of infection. She achieved appropriate correction and underwent hardware removal approximately 6 months after her initial surgery. 

One month after hardware removal, the patient began to notice increased swelling and erythema around her incision site with associated pain. No fluid or drainage was seen at that time. She underwent irrigation and débridement shortly thereafter, and the wound was left open for wet-to-dry dressing changes (Figure 1). Intraoperative cultures were negative, but the patient received empiric antibiotic therapy. She continued to have difficulty with wound healing for the next month and was referred to plastic surgery. She underwent repeat irrigation and débridement, followed by coverage with a split-thickness skin graft by the plastic surgery service. Intraoperative cultures were again negative. During both irrigation and débridement procedures, care was taken to remain superficial and not violate the knee capsule.

At her 2-week postoperative check, the bolster covering the split thickness skin graft was removed, which revealed a 2×2-mm area of clear erosion near the central portion of her wound with synovial fluid drainage (Figure 2). Because of concern for a synovial fistula, magnetic resonance imaging (MRI) of the right knee was obtained, which confirmed the synovial fistula (Figures 3A, 3B). The coronal cut on MRI clearly showed the fistula with synovial fluid tracking into the epiphyseal screw tract through the breached capsule and to the level of the skin. She was immobilized in a long leg cast with the knee in extension for 6 weeks. Upon return, her fistula had closed, and she has not had any more wound issues. 

Discussion

To our knowledge, this is the first report of a synovial fistula after temporary hemiepiphysiodesis performed via tension band plating. Capsular knee anatomy may explain the etiology of the synovial fistula after hardware removal. The medial knee capsule composition and attachment sites have been extensively studied.⁶ In contrast to other joints, such as the shoulder, elbow, ankle, and hip, the metaphysis of the knee lies outside the capsule because the capsule inserts proximal at the level of the physis.⁷ During tension band plating, the epiphyseal screw breaches the capsule but serves as a plug while in place, which prevents the formation of a synovial fistula. When the screw is removed, the capsular rent spontaneously closes in almost all cases. However, the opportunity exists for a synovial fistula to form while the capsule heals, as evidenced by the current case. Such an issue does not apply to the metaphyseal screw because it is inserted outside the capsule.  

Although it is possible that the synovial fistula was inadvertently created during one of the irrigation and débridement procedures, this is very unlikely. The surgeons who performed these washout procedures are knowledgeable and familiar with knee anatomy. Both irrigation and débridement procedures were superficial, and care was taken not to violate the knee capsule.

A synovial fistula after knee surgery is rare. Larsen⁸ described the fistula as a phenomenon that develops when excessive synovial fluid forces its way through a synovial incision with knee flexion and muscle contraction. Such a complication is most routinely described after knee arthroscopy. Proffer and colleagues⁹ reported an incidence of 6.1 per 1000 after knee arthroscopies. The average number of days until fistula diagnosis was 6 days (range, 3-10 days). All fistulae were treated with immobilization and closed after an average of 9 days (range, 7-14 days). There were no associated infections, although prophylactic antibiotics were given. A national survey found that knee fistulae accounted for only 3.2% of all complications of knee arthroscopy.¹⁰ 

The treatment for a synovial fistula is largely nonoperative. Most will resolve with a brief period of immobilization, which allows the fistula to close.^9-10 Literature addressing fistulae that fail to heal with nonoperative treatment is limited. Excision and direct closure of the fistula, especially when chronic, often proves futile and leads to a high recurrence rate.¹¹ An alternative but more extensive treatment involves excision and coverage with a myofascial flap.¹²

Complications reported after tension band plating are uncommon. Two studies reported no complications regarding the use of the tension band plate.^1-2 Burghardt and colleagues,⁵ in reporting the results of a multicenter survey, found that 15% of surgeons who had used tension band plating had seen a total of 65 cases of mechanical failure. In all cases, the screws, not the plate, failed. Another study reported implant migration in 1 patient but attributed the complication to a technical error from placing the distal screw too close to the physis.⁴ A third study documented that 2 patients developed clinically significant recurvatum, most likely because of anterior placement of the plate.³ It is important to identify a synovial fistula postoperatively because it provides a direct route for pathogens from the external environment to enter the intra-articular space and the opportunity for a septic joint to develop. Infection should always be ruled out and, if present, appropriately treated. 

Conclusion

Physicians performing tension band plating in the knee should be aware of the possible complication of a synovial fistula, which has traditionally been reported only in relation to knee arthroscopy. Given the proposed etiology of the synovial fistula, we recommend a brief period of immobilization of 3 to 5 days after tension band plate removal, allowing the capsular rent to heal and minimizing the risk of a synovial fistula.

The goal of surgical treatment of adolescent idiopathic scoliosis (AIS) is to prevent disability associated with curve progression.¹ Early studies tended to focus on radiographic measures, such as curve correction and sagittal balance, rather than on improvements in quality of life (QOL).^2-5 Although studies have reported on QOL in patients treated surgically for scoliosis,^6-11 these studies were largely limited by small sample size and inclusion of patients with congenital and neuromuscular scoliosis,⁹ lack of a generic measure of QOL,^6,7 or lack of surgical treatment of patients in the cohort.¹⁰

We conducted a study to determine disease-specific and general health-related QOL (HR-QOL) in young adults who underwent surgical correction of their spinal deformity during adolescence and to evaluate associated complications and reoperations.

Materials and Methods

After obtaining institutional review board approval, we queried the surgical database of a large metropolitan tertiary referral center for consecutive patients who had undergone spine deformity correction between the ages of 10 and 17 years (January 1993–December 2003). Hospital and medical records were retrospectively reviewed to confirm the diagnosis of AIS. Patients with congenital, neuromuscular, juvenile, or infantile scoliosis were excluded. Patients with intraspinal pathology (eg, tethered cord, syringomyelia), developmental delay, chromosomal abnormality, or congenital heart disease were also excluded. Patients were contacted by mail or telephone, and the Scoliosis Research Society–22R (SRS-22R)^12-15 and the Short Form–12 (SF-12)¹⁶ were administered. Standard demographic and surgical data were also collected.

The SRS-22R is a scoliosis-specific HR-QOL questionnaire with 22 items, 5 domains (pain, activity, appearance, mental, satisfaction), and a total score.^12-15 Each domain score ranges from 1 to 5 (higher scores indicating better outcomes). The SRS-22R is the outcome instrument most widely used to measure HR-QOL changes in patients with scoliosis, and it is available in several languages.^17-26

The SF-12, a 12-item self-administered short-form health status survey developed in the Medical Outcomes Study, measures patient-based health status. Two composite scores can be calculated: physical composite summary (PCS) and mental composite summary (MCS).¹⁶ Using norm-based scoring, all domain scales have a mean (SD) of 50 (10) based on the general 1998 US population. Thus, scores under 50 fall below the general population mean.

In addition, patients were surveyed to determine the incidence of spine-related symptoms and complaints, including activity limitations, rib prominence, waistline asymmetry, back pain, limited range of motion (ROM), shortness of breath, wound/scar problems, lung disease/asthma, heart disease, high blood pressure, and arthritis. Data regarding postoperative treatment regimens of physical therapy, narcotic pain medication, spinal/epidural injections, and nonsteroidal anti-inflammatory drug (NSAID) use were collected. Patients were also queried regarding their current working status and smoking status.

Standard demographic and surgical data were collected from hospital and office charts and radiographs. Data collected included history of bracing, age at index surgery, number of levels fused, surgical approach (anterior, posterior, combined), postoperative complications (eg, ileus, wound infection, anemia, pneumonia), and immediate preoperative and final postoperative radiographic measures. Data on need for subsequent revision surgery and indications for revision surgery were also collected.

Preoperative and latest follow-up radiographs were measured to determine curve magnitude, sagittal and coronal balance, and percentage curve correction. Coronal balance was defined as the distance between a plumb line drawn vertically from the spinous process of C7 and the central sacral line on full-length posteroanterior radiographs. Sagittal balance was defined as the distance of a plumb line drawn vertically from the center of the body of C7 and the posterosuperior endplate of S1.²⁷

Regression analysis was performed to identify factors predictive of SRS-22R total scores. Factors included in the analysis were sex, age at surgery, Lenke type, surgery type (anterior, posterior, anteroposterior), number of levels fused, lowest instrumented vertebra, perioperative complications, percentage curve correction, postoperative coronal and sagittal balance, smoking status, and need for revision surgery. Although age and sex were considered variables outside the surgeon’s control, they were included in the model, as previous studies have shown that SRS scores varied by age and sex both in adolescents²⁸ and adults.²⁹ Significance was set at P < .01. All data analysis was performed with IBM SPSS Version 19.0 (Somers, New York).

Results

Of the 384 postoperative patients identified for study inclusion, 134 (35%) completed surveys. Sixteen patients with nonidiopathic scoliosis were excluded, leaving 118 available for analysis. Of the remaining patients, 248 (64%) could not be contacted because of a change in address or phone number. Two patients (1%) were unwilling to complete survey requests. There was no statistically significant difference in demographics between patients with and without follow-up data available. Demographics are summarized in Table 1. There were 109 females (92%). Mean (SD) age at surgery was 14.1 (1.9) years. Only 37 (31%) were braced before surgery. Table 2 summarizes the radiographic data. Mean (SD) major Cobb angle was 49.7° (7.8°). Eighty-five patients (72%) underwent posterior fusion with instrumentation using hooks only; another 16 (14%) had anterior-only surgery, and another 17 (14%) had combined anterior-posterior surgery. A mean of 7.8 levels were fused. Index surgery data and lowest instrumented vertebra distribution are summarized in Table 3. Mean (SD) percentage curve correction was 48.9% (8.4%).

Seven patients had a total of 8 perioperative complications: anemia requiring transfusion (2), ileus necessitating nasogastric tube insertion (2), superficial wound infection treated with oral antibiotics and local wound care (2), wound drainage and erythema (1), and pneumonia (1). Mean (SD) length of clinical and radiographic follow-up was 57.9 (36.3) months.

Table 4 summarizes the long-term complications. Of the 38 patients with long-term complications, 14 required reoperation. The indications were disc herniation (2 patients), painful instrumentation (7), crankshaft phenomenon (1), nonunion (1), and adjacent-level degeneration (3). Both disc herniations were at L5–S1, several segments below the distal extent of the fusion. Of the 7 patients who had painful instrumentation removed, 6 had the entire construct removed, and 1 had the proximal half of a rod taken out. The 3 patients with adjacent-level degeneration had stenosis at the distal end of the construct—at L5–S1 (2 patients) or L2–L3 (1 patient).

Mean (SD) time between surgery and completion of the surveys/questionnaires was 12.7 (3.2) years (range, 10-18 years). Mean age of respondents was 26.8 years. Twenty-five respondents (21%) were smokers. Mean (SD) outcome scores were 50.9 (9.4) for SF-12 PCS and 49.4 (10.2) for SF-12 MCS. Eighteen patients (15%) had SF-12 PCS scores 1 SD below normal, and 15 (13%) had SF-12 MCS scores 1 SD below normal. Mean (SD) SRS-22R Total score was 4.0 (0.7). Means, standard deviations, and distribution of SRS domain scores are summarized in Table 5. Of the variables, only current smoking (P < .001) was predictive of SRS-22R Total scores, accounting for 20% of their variability (Table 6).

One hundred patients (85%) had jobs, mostly desk jobs. The postoperative limitations most commonly reported are summarized in Table 7. These included at least intermittent back pain in 90 patients (76%), limited ROM in 52 (44%), and activity limitations in 54 (46%). Less common limitations were waistline imbalance in 41 (35%), rib prominence in 28 (24%), wound/scar problems in 18 (15%), and shortness of breath in 18 (15%). Other related medical problems were lung disease/asthma in 11 (9%), osteoarthritis/degenerative arthritis in 11 (9%), heart disease in 3 (3%), and high blood pressure in 2 (2%).

A minority of patients also participated in postoperative treatment regimens. The most common treatment was regular use of NSAIDs (25 patients, 21%). Other treatments were physical therapy (14, 12%), narcotic pain medication use (5, 4%), and epidural steroid injections (5, 4%). Table 8 summarizes the postoperative treatments used by patients with scoliosis.

Discussion

A major concern about prophylactic interventions for diseases is that the treatment will harm the patient. This is especially true for major spine surgery performed on adolescents with minimal symptoms. Although the incidence of perioperative complications in children undergoing corrective spinal surgery for AIS has been reported,^30-32 the effect of the surgery on the disease-specific HR-QOL outcomes of these individuals as young adults has not been previously studied. Over the past few decades, a paradigm shift in understanding health and disability has occurred, with increased emphasis being placed on HR-QOL outcomes measures and understanding disability as relating to a measureable impact of the functioning of an individual after a change in health or environment. This change was substantiated when the World Health Organization endorsed the International Classification of Functioning, Disability and Health.³³ In light of this shift, we present the disease-specific and general HR-QOL outcomes of young adults who had undergone surgical correction for spinal deformity during adolescence, as well as their associated complications and reoperations, in an attempt to identify targets for improvement.

Our patient-reported outcomes demonstrated a high incidence of occasional back pain, activity-related complaints, and limited ROM. Comparison of our cohort’s SRS-22R outcomes with previously published normative values for the unaffected adolescent population^28,34 suggests worse scores for the disease-specific SRS-22R domains of pain and appearance. In 2012, Daubs and colleagues³⁴ reported that normative scores on various SRS-22 domains were statistically lower with age (scores decreased from age 10 to age 19 years). Both Verma and colleagues²⁸ and Daubs and colleagues³⁴ reported lower scores for females than for males. Therefore, it is unclear whether the differences observed in our cohort may be accounted for by the larger proportion of females compared with the normative data.

General health scores on the SF-12 were similar to the population norm (mean [SD]) of 50 (10) referenced by Ware and colleagues.¹⁶ These findings suggest that, though pain and appearance may be statistically lower in our cohort—as measured with the SRS-22R—the cohort’s spine-related symptoms do not seem to lower its general health. Eighty-five percent of the patients were working at the time of the survey, further supporting a relatively normal level of overall function. In a retrospective review by Takayama and colleagues,⁹ similar results were found with regard to working after AIS fusion surgery. Of 32 patients treated surgically for scoliosis, at a mean of 21.1 years after the index fusion 27 (84.4%) were or had been engaged in various occupations without marked difficulty.

Our results in a cohort of patients with segmental instrumentation using hooks are similar to results in other studies of long-term HR-QOL measures in patients with AIS and Harrington rod instrumentation. Danielsson and Nachemson³⁵ evaluated patients with surgically treated AIS with at least 20-year follow-up and reported that, in their surgical cohort with a mean age of 39.7 years, mean SF-36 PCS score was 50.9, and mean SF-36 MCS score was 50.2. In a recent study of patients with AIS and Harrington rod instrumentation, those of a mean age of 32.3 years had a mean score of 50.9 for both SF-36 PCS and SF-36 MCS.³⁶

Regression analysis identified only smoking as a predictor of SRS-22R Total scores. This finding, that smokers have a lower health state, is expected even in the general population.³⁷ Interestingly, bracing before surgery, Lenke type, surgery type, number of levels fused, lowest instrumented vertebra, incidence of perioperative complications, percentage curve correction, postoperative sagittal and coronal balance, and need for revision surgery did not influence HR-QOL measures in this cohort.

Our cohort’s incidence of occasional back pain was 76% (90/118 patients). Other reports have had similar findings. In 2012, Bas and colleagues³⁸ studied self-reported pain in 126 consecutive patients with scoliosis and instrumented fusion. In their cohort, “most participants reported ‘no pain’ (38.5%) or ‘mild pain’ (30.8%) and 72.1% of participants reported a current work/school activity level of 100% normal.” Also in 2012, Rushton and Grevitt³⁹ reported on a review and statistical analysis of the literature on HR-QOL in adolescents with untreated AIS and in unaffected adolescents. Their goal was to identify whether there were any differences in HR-QOL and, if so, whether they were clinically relevant. The authors concluded that pain and self-image tended to be statistically lower among cohorts with AIS but that only self-image was consistently different clinically between untreated patients with AIS and their unaffected peers.

Cosmetic complaints, though less common than functional concerns, affected a substantial percentage of our cohort. Waistline imbalance complaints were more common than rib prominence or scar-related complaints. The validity of patient-reported waistline imbalance is not known but may contribute to the SRS-22R outcomes in this cohort, particularly with regard to appearance scores. Respiratory symptoms, particularly those related to shortness of breath, were reported by 15% of patients. Respiratory symptoms may be in part secondary to underlying lung disease; smoking was reported by 21% of patients and asthma by 9%.

Few additional postoperative treatments were reported by patients. The most common treatment was regular use of NSAIDs (21%), followed by postoperative physical therapy (12%). Opiate medication use and spinal injections were rare—consistent with results reported by Danielsson and Nachemson³⁵ in 2003.

Implant-related complaints, including painful instrumentation (13%) and implant prominence (9%), were some of the most common complaints in our study group. Although not all symptomatic instrumentation required surgical revision, 7 (50%) of the 14 additional spine surgeries were related to painful and/or prominent posterior instrumentation. Additional spine surgery was reported in 11.9% of our patients. Other indications for reoperation were disc herniation, crankshaft phenomenon, nonunion, and adjacent-level degeneration. Our rate of revision surgery is supported by the literature. In 2009, Luhmann and colleagues⁴⁰ reported that 41 (3.9%) of 1057 primary spine fusions for idiopathic scoliosis required reoperation; the indications included infection (16/1057, 1.5%), pseudarthrosis (12, 1.1%), and painful/prominent implant (7, 0.7%). Richards and colleagues⁴¹ similarly reported on 1046 patients who underwent fusion for AIS. Of these patients, 135 underwent 172 repeat surgical interventions (12.9% reoperation rate), with 29 (21.5%) of the 135 undergoing 2 or more separate procedures. The most common reasons for reoperation were infection, symptomatic implant, and pseudarthrosis. The authors concluded that repeat surgeries were relatively common after the initial surgical procedures. Having a clearer understanding of instrumentation-related complaints and reoperations may lead to improvement in this surgeon-controlled variable.

There are limitations to this study. The data regarding clinical courses were collected by retrospective chart review, which has known limitations. To offset this, we collected prospective outcome data with use of the SF-12, the SRS-22R, and a spine-related complaints questionnaire. No control group was available for comparison of outcomes in our cohort. We used the SF-12 and previously published normative values for the SRS-22R for comparison with population norms. Such comparisons have inherent limitations, as the groups vary by sex and mean age; our cohort was primarily female and more than a decade older than the controls.

Only 35% of the patients who met the inclusion criteria had complete data that could be included in our analysis. Although there was no statistically significant difference in demographics between patients with and without follow-up data available, this low response rate could have introduced selection bias. Ideally, patients should have been seen in clinic, standing radiographs should have been taken, and pulmonary function tests should have been performed. However, these patients were asymptomatic, and ethical and insurance issues prevented those actions. Thus, any radiographic changes occurring over the intervening years, from the last clinic visit to completion of the surveys, were not documented. This situation may or may not have limited our findings, as other authors have found low correlation between radiographic outcomes and clinical outcome measures.^13,14,19,36 During the period when these surgeries were performed, segmental spine instrumentation with hooks was the standard of care for deformity correction in AIS; therefore, all posterior instrumentations were done with hook-only segmental fixation. Current pedicle screw–based techniques that allow for additional correction of the deformity may provide different outcomes in the future.

We think that, despite the inherent limitations of this study, our data will be useful in the treatment of AIS. Our results suggest that postoperative spinal complaints are common and that, compared with an unaffected adolescent population, patients with AIS score significantly lower on pain and appearance domains of outcomes testing at a mean of 12.7 years after index fusion. Nevertheless, the outcomes do not seem to be of sufficient severity to affect general health and QOL as measured by outcomes testing.

Spinal deformity correction is performed to prevent impaired pulmonary function and spine-related disability later in life.^42,43 Thus, longer-term studies, involving patients in their fifth and sixth decades of life, are needed to determine whether patients with AIS will have QOL outcomes, pulmonary function, and spine-related problems similar to those in the general population. In this cohort of young adults, smoking status was the only predictor of HR-QOL measures, and spinal deformity correction did not lead to decreased HR-QOL.

The goal of surgical treatment of adolescent idiopathic scoliosis (AIS) is to prevent disability associated with curve progression.¹ Early studies tended to focus on radiographic measures, such as curve correction and sagittal balance, rather than on improvements in quality of life (QOL).^2-5 Although studies have reported on QOL in patients treated surgically for scoliosis,^6-11 these studies were largely limited by small sample size and inclusion of patients with congenital and neuromuscular scoliosis,⁹ lack of a generic measure of QOL,^6,7 or lack of surgical treatment of patients in the cohort.¹⁰

We conducted a study to determine disease-specific and general health-related QOL (HR-QOL) in young adults who underwent surgical correction of their spinal deformity during adolescence and to evaluate associated complications and reoperations.

Materials and Methods

After obtaining institutional review board approval, we queried the surgical database of a large metropolitan tertiary referral center for consecutive patients who had undergone spine deformity correction between the ages of 10 and 17 years (January 1993–December 2003). Hospital and medical records were retrospectively reviewed to confirm the diagnosis of AIS. Patients with congenital, neuromuscular, juvenile, or infantile scoliosis were excluded. Patients with intraspinal pathology (eg, tethered cord, syringomyelia), developmental delay, chromosomal abnormality, or congenital heart disease were also excluded. Patients were contacted by mail or telephone, and the Scoliosis Research Society–22R (SRS-22R)^12-15 and the Short Form–12 (SF-12)¹⁶ were administered. Standard demographic and surgical data were also collected.

The SRS-22R is a scoliosis-specific HR-QOL questionnaire with 22 items, 5 domains (pain, activity, appearance, mental, satisfaction), and a total score.^12-15 Each domain score ranges from 1 to 5 (higher scores indicating better outcomes). The SRS-22R is the outcome instrument most widely used to measure HR-QOL changes in patients with scoliosis, and it is available in several languages.^17-26

The SF-12, a 12-item self-administered short-form health status survey developed in the Medical Outcomes Study, measures patient-based health status. Two composite scores can be calculated: physical composite summary (PCS) and mental composite summary (MCS).¹⁶ Using norm-based scoring, all domain scales have a mean (SD) of 50 (10) based on the general 1998 US population. Thus, scores under 50 fall below the general population mean.

In addition, patients were surveyed to determine the incidence of spine-related symptoms and complaints, including activity limitations, rib prominence, waistline asymmetry, back pain, limited range of motion (ROM), shortness of breath, wound/scar problems, lung disease/asthma, heart disease, high blood pressure, and arthritis. Data regarding postoperative treatment regimens of physical therapy, narcotic pain medication, spinal/epidural injections, and nonsteroidal anti-inflammatory drug (NSAID) use were collected. Patients were also queried regarding their current working status and smoking status.

Standard demographic and surgical data were collected from hospital and office charts and radiographs. Data collected included history of bracing, age at index surgery, number of levels fused, surgical approach (anterior, posterior, combined), postoperative complications (eg, ileus, wound infection, anemia, pneumonia), and immediate preoperative and final postoperative radiographic measures. Data on need for subsequent revision surgery and indications for revision surgery were also collected.

Preoperative and latest follow-up radiographs were measured to determine curve magnitude, sagittal and coronal balance, and percentage curve correction. Coronal balance was defined as the distance between a plumb line drawn vertically from the spinous process of C7 and the central sacral line on full-length posteroanterior radiographs. Sagittal balance was defined as the distance of a plumb line drawn vertically from the center of the body of C7 and the posterosuperior endplate of S1.²⁷

Regression analysis was performed to identify factors predictive of SRS-22R total scores. Factors included in the analysis were sex, age at surgery, Lenke type, surgery type (anterior, posterior, anteroposterior), number of levels fused, lowest instrumented vertebra, perioperative complications, percentage curve correction, postoperative coronal and sagittal balance, smoking status, and need for revision surgery. Although age and sex were considered variables outside the surgeon’s control, they were included in the model, as previous studies have shown that SRS scores varied by age and sex both in adolescents²⁸ and adults.²⁹ Significance was set at P < .01. All data analysis was performed with IBM SPSS Version 19.0 (Somers, New York).

Results

Of the 384 postoperative patients identified for study inclusion, 134 (35%) completed surveys. Sixteen patients with nonidiopathic scoliosis were excluded, leaving 118 available for analysis. Of the remaining patients, 248 (64%) could not be contacted because of a change in address or phone number. Two patients (1%) were unwilling to complete survey requests. There was no statistically significant difference in demographics between patients with and without follow-up data available. Demographics are summarized in Table 1. There were 109 females (92%). Mean (SD) age at surgery was 14.1 (1.9) years. Only 37 (31%) were braced before surgery. Table 2 summarizes the radiographic data. Mean (SD) major Cobb angle was 49.7° (7.8°). Eighty-five patients (72%) underwent posterior fusion with instrumentation using hooks only; another 16 (14%) had anterior-only surgery, and another 17 (14%) had combined anterior-posterior surgery. A mean of 7.8 levels were fused. Index surgery data and lowest instrumented vertebra distribution are summarized in Table 3. Mean (SD) percentage curve correction was 48.9% (8.4%).

Seven patients had a total of 8 perioperative complications: anemia requiring transfusion (2), ileus necessitating nasogastric tube insertion (2), superficial wound infection treated with oral antibiotics and local wound care (2), wound drainage and erythema (1), and pneumonia (1). Mean (SD) length of clinical and radiographic follow-up was 57.9 (36.3) months.

Table 4 summarizes the long-term complications. Of the 38 patients with long-term complications, 14 required reoperation. The indications were disc herniation (2 patients), painful instrumentation (7), crankshaft phenomenon (1), nonunion (1), and adjacent-level degeneration (3). Both disc herniations were at L5–S1, several segments below the distal extent of the fusion. Of the 7 patients who had painful instrumentation removed, 6 had the entire construct removed, and 1 had the proximal half of a rod taken out. The 3 patients with adjacent-level degeneration had stenosis at the distal end of the construct—at L5–S1 (2 patients) or L2–L3 (1 patient).

Mean (SD) time between surgery and completion of the surveys/questionnaires was 12.7 (3.2) years (range, 10-18 years). Mean age of respondents was 26.8 years. Twenty-five respondents (21%) were smokers. Mean (SD) outcome scores were 50.9 (9.4) for SF-12 PCS and 49.4 (10.2) for SF-12 MCS. Eighteen patients (15%) had SF-12 PCS scores 1 SD below normal, and 15 (13%) had SF-12 MCS scores 1 SD below normal. Mean (SD) SRS-22R Total score was 4.0 (0.7). Means, standard deviations, and distribution of SRS domain scores are summarized in Table 5. Of the variables, only current smoking (P < .001) was predictive of SRS-22R Total scores, accounting for 20% of their variability (Table 6).

One hundred patients (85%) had jobs, mostly desk jobs. The postoperative limitations most commonly reported are summarized in Table 7. These included at least intermittent back pain in 90 patients (76%), limited ROM in 52 (44%), and activity limitations in 54 (46%). Less common limitations were waistline imbalance in 41 (35%), rib prominence in 28 (24%), wound/scar problems in 18 (15%), and shortness of breath in 18 (15%). Other related medical problems were lung disease/asthma in 11 (9%), osteoarthritis/degenerative arthritis in 11 (9%), heart disease in 3 (3%), and high blood pressure in 2 (2%).

A minority of patients also participated in postoperative treatment regimens. The most common treatment was regular use of NSAIDs (25 patients, 21%). Other treatments were physical therapy (14, 12%), narcotic pain medication use (5, 4%), and epidural steroid injections (5, 4%). Table 8 summarizes the postoperative treatments used by patients with scoliosis.

Discussion

A major concern about prophylactic interventions for diseases is that the treatment will harm the patient. This is especially true for major spine surgery performed on adolescents with minimal symptoms. Although the incidence of perioperative complications in children undergoing corrective spinal surgery for AIS has been reported,^30-32 the effect of the surgery on the disease-specific HR-QOL outcomes of these individuals as young adults has not been previously studied. Over the past few decades, a paradigm shift in understanding health and disability has occurred, with increased emphasis being placed on HR-QOL outcomes measures and understanding disability as relating to a measureable impact of the functioning of an individual after a change in health or environment. This change was substantiated when the World Health Organization endorsed the International Classification of Functioning, Disability and Health.³³ In light of this shift, we present the disease-specific and general HR-QOL outcomes of young adults who had undergone surgical correction for spinal deformity during adolescence, as well as their associated complications and reoperations, in an attempt to identify targets for improvement.

Our patient-reported outcomes demonstrated a high incidence of occasional back pain, activity-related complaints, and limited ROM. Comparison of our cohort’s SRS-22R outcomes with previously published normative values for the unaffected adolescent population^28,34 suggests worse scores for the disease-specific SRS-22R domains of pain and appearance. In 2012, Daubs and colleagues³⁴ reported that normative scores on various SRS-22 domains were statistically lower with age (scores decreased from age 10 to age 19 years). Both Verma and colleagues²⁸ and Daubs and colleagues³⁴ reported lower scores for females than for males. Therefore, it is unclear whether the differences observed in our cohort may be accounted for by the larger proportion of females compared with the normative data.

General health scores on the SF-12 were similar to the population norm (mean [SD]) of 50 (10) referenced by Ware and colleagues.¹⁶ These findings suggest that, though pain and appearance may be statistically lower in our cohort—as measured with the SRS-22R—the cohort’s spine-related symptoms do not seem to lower its general health. Eighty-five percent of the patients were working at the time of the survey, further supporting a relatively normal level of overall function. In a retrospective review by Takayama and colleagues,⁹ similar results were found with regard to working after AIS fusion surgery. Of 32 patients treated surgically for scoliosis, at a mean of 21.1 years after the index fusion 27 (84.4%) were or had been engaged in various occupations without marked difficulty.

Our results in a cohort of patients with segmental instrumentation using hooks are similar to results in other studies of long-term HR-QOL measures in patients with AIS and Harrington rod instrumentation. Danielsson and Nachemson³⁵ evaluated patients with surgically treated AIS with at least 20-year follow-up and reported that, in their surgical cohort with a mean age of 39.7 years, mean SF-36 PCS score was 50.9, and mean SF-36 MCS score was 50.2. In a recent study of patients with AIS and Harrington rod instrumentation, those of a mean age of 32.3 years had a mean score of 50.9 for both SF-36 PCS and SF-36 MCS.³⁶

Regression analysis identified only smoking as a predictor of SRS-22R Total scores. This finding, that smokers have a lower health state, is expected even in the general population.³⁷ Interestingly, bracing before surgery, Lenke type, surgery type, number of levels fused, lowest instrumented vertebra, incidence of perioperative complications, percentage curve correction, postoperative sagittal and coronal balance, and need for revision surgery did not influence HR-QOL measures in this cohort.

Our cohort’s incidence of occasional back pain was 76% (90/118 patients). Other reports have had similar findings. In 2012, Bas and colleagues³⁸ studied self-reported pain in 126 consecutive patients with scoliosis and instrumented fusion. In their cohort, “most participants reported ‘no pain’ (38.5%) or ‘mild pain’ (30.8%) and 72.1% of participants reported a current work/school activity level of 100% normal.” Also in 2012, Rushton and Grevitt³⁹ reported on a review and statistical analysis of the literature on HR-QOL in adolescents with untreated AIS and in unaffected adolescents. Their goal was to identify whether there were any differences in HR-QOL and, if so, whether they were clinically relevant. The authors concluded that pain and self-image tended to be statistically lower among cohorts with AIS but that only self-image was consistently different clinically between untreated patients with AIS and their unaffected peers.

Cosmetic complaints, though less common than functional concerns, affected a substantial percentage of our cohort. Waistline imbalance complaints were more common than rib prominence or scar-related complaints. The validity of patient-reported waistline imbalance is not known but may contribute to the SRS-22R outcomes in this cohort, particularly with regard to appearance scores. Respiratory symptoms, particularly those related to shortness of breath, were reported by 15% of patients. Respiratory symptoms may be in part secondary to underlying lung disease; smoking was reported by 21% of patients and asthma by 9%.

Few additional postoperative treatments were reported by patients. The most common treatment was regular use of NSAIDs (21%), followed by postoperative physical therapy (12%). Opiate medication use and spinal injections were rare—consistent with results reported by Danielsson and Nachemson³⁵ in 2003.

Implant-related complaints, including painful instrumentation (13%) and implant prominence (9%), were some of the most common complaints in our study group. Although not all symptomatic instrumentation required surgical revision, 7 (50%) of the 14 additional spine surgeries were related to painful and/or prominent posterior instrumentation. Additional spine surgery was reported in 11.9% of our patients. Other indications for reoperation were disc herniation, crankshaft phenomenon, nonunion, and adjacent-level degeneration. Our rate of revision surgery is supported by the literature. In 2009, Luhmann and colleagues⁴⁰ reported that 41 (3.9%) of 1057 primary spine fusions for idiopathic scoliosis required reoperation; the indications included infection (16/1057, 1.5%), pseudarthrosis (12, 1.1%), and painful/prominent implant (7, 0.7%). Richards and colleagues⁴¹ similarly reported on 1046 patients who underwent fusion for AIS. Of these patients, 135 underwent 172 repeat surgical interventions (12.9% reoperation rate), with 29 (21.5%) of the 135 undergoing 2 or more separate procedures. The most common reasons for reoperation were infection, symptomatic implant, and pseudarthrosis. The authors concluded that repeat surgeries were relatively common after the initial surgical procedures. Having a clearer understanding of instrumentation-related complaints and reoperations may lead to improvement in this surgeon-controlled variable.

There are limitations to this study. The data regarding clinical courses were collected by retrospective chart review, which has known limitations. To offset this, we collected prospective outcome data with use of the SF-12, the SRS-22R, and a spine-related complaints questionnaire. No control group was available for comparison of outcomes in our cohort. We used the SF-12 and previously published normative values for the SRS-22R for comparison with population norms. Such comparisons have inherent limitations, as the groups vary by sex and mean age; our cohort was primarily female and more than a decade older than the controls.

Only 35% of the patients who met the inclusion criteria had complete data that could be included in our analysis. Although there was no statistically significant difference in demographics between patients with and without follow-up data available, this low response rate could have introduced selection bias. Ideally, patients should have been seen in clinic, standing radiographs should have been taken, and pulmonary function tests should have been performed. However, these patients were asymptomatic, and ethical and insurance issues prevented those actions. Thus, any radiographic changes occurring over the intervening years, from the last clinic visit to completion of the surveys, were not documented. This situation may or may not have limited our findings, as other authors have found low correlation between radiographic outcomes and clinical outcome measures.^13,14,19,36 During the period when these surgeries were performed, segmental spine instrumentation with hooks was the standard of care for deformity correction in AIS; therefore, all posterior instrumentations were done with hook-only segmental fixation. Current pedicle screw–based techniques that allow for additional correction of the deformity may provide different outcomes in the future.

We think that, despite the inherent limitations of this study, our data will be useful in the treatment of AIS. Our results suggest that postoperative spinal complaints are common and that, compared with an unaffected adolescent population, patients with AIS score significantly lower on pain and appearance domains of outcomes testing at a mean of 12.7 years after index fusion. Nevertheless, the outcomes do not seem to be of sufficient severity to affect general health and QOL as measured by outcomes testing.

Spinal deformity correction is performed to prevent impaired pulmonary function and spine-related disability later in life.^42,43 Thus, longer-term studies, involving patients in their fifth and sixth decades of life, are needed to determine whether patients with AIS will have QOL outcomes, pulmonary function, and spine-related problems similar to those in the general population. In this cohort of young adults, smoking status was the only predictor of HR-QOL measures, and spinal deformity correction did not lead to decreased HR-QOL.

The goal of surgical treatment of adolescent idiopathic scoliosis (AIS) is to prevent disability associated with curve progression.¹ Early studies tended to focus on radiographic measures, such as curve correction and sagittal balance, rather than on improvements in quality of life (QOL).^2-5 Although studies have reported on QOL in patients treated surgically for scoliosis,^6-11 these studies were largely limited by small sample size and inclusion of patients with congenital and neuromuscular scoliosis,⁹ lack of a generic measure of QOL,^6,7 or lack of surgical treatment of patients in the cohort.¹⁰

We conducted a study to determine disease-specific and general health-related QOL (HR-QOL) in young adults who underwent surgical correction of their spinal deformity during adolescence and to evaluate associated complications and reoperations.

Materials and Methods

After obtaining institutional review board approval, we queried the surgical database of a large metropolitan tertiary referral center for consecutive patients who had undergone spine deformity correction between the ages of 10 and 17 years (January 1993–December 2003). Hospital and medical records were retrospectively reviewed to confirm the diagnosis of AIS. Patients with congenital, neuromuscular, juvenile, or infantile scoliosis were excluded. Patients with intraspinal pathology (eg, tethered cord, syringomyelia), developmental delay, chromosomal abnormality, or congenital heart disease were also excluded. Patients were contacted by mail or telephone, and the Scoliosis Research Society–22R (SRS-22R)^12-15 and the Short Form–12 (SF-12)¹⁶ were administered. Standard demographic and surgical data were also collected.

The SRS-22R is a scoliosis-specific HR-QOL questionnaire with 22 items, 5 domains (pain, activity, appearance, mental, satisfaction), and a total score.^12-15 Each domain score ranges from 1 to 5 (higher scores indicating better outcomes). The SRS-22R is the outcome instrument most widely used to measure HR-QOL changes in patients with scoliosis, and it is available in several languages.^17-26

The SF-12, a 12-item self-administered short-form health status survey developed in the Medical Outcomes Study, measures patient-based health status. Two composite scores can be calculated: physical composite summary (PCS) and mental composite summary (MCS).¹⁶ Using norm-based scoring, all domain scales have a mean (SD) of 50 (10) based on the general 1998 US population. Thus, scores under 50 fall below the general population mean.

In addition, patients were surveyed to determine the incidence of spine-related symptoms and complaints, including activity limitations, rib prominence, waistline asymmetry, back pain, limited range of motion (ROM), shortness of breath, wound/scar problems, lung disease/asthma, heart disease, high blood pressure, and arthritis. Data regarding postoperative treatment regimens of physical therapy, narcotic pain medication, spinal/epidural injections, and nonsteroidal anti-inflammatory drug (NSAID) use were collected. Patients were also queried regarding their current working status and smoking status.

Standard demographic and surgical data were collected from hospital and office charts and radiographs. Data collected included history of bracing, age at index surgery, number of levels fused, surgical approach (anterior, posterior, combined), postoperative complications (eg, ileus, wound infection, anemia, pneumonia), and immediate preoperative and final postoperative radiographic measures. Data on need for subsequent revision surgery and indications for revision surgery were also collected.

Preoperative and latest follow-up radiographs were measured to determine curve magnitude, sagittal and coronal balance, and percentage curve correction. Coronal balance was defined as the distance between a plumb line drawn vertically from the spinous process of C7 and the central sacral line on full-length posteroanterior radiographs. Sagittal balance was defined as the distance of a plumb line drawn vertically from the center of the body of C7 and the posterosuperior endplate of S1.²⁷

Regression analysis was performed to identify factors predictive of SRS-22R total scores. Factors included in the analysis were sex, age at surgery, Lenke type, surgery type (anterior, posterior, anteroposterior), number of levels fused, lowest instrumented vertebra, perioperative complications, percentage curve correction, postoperative coronal and sagittal balance, smoking status, and need for revision surgery. Although age and sex were considered variables outside the surgeon’s control, they were included in the model, as previous studies have shown that SRS scores varied by age and sex both in adolescents²⁸ and adults.²⁹ Significance was set at P < .01. All data analysis was performed with IBM SPSS Version 19.0 (Somers, New York).

Results

Of the 384 postoperative patients identified for study inclusion, 134 (35%) completed surveys. Sixteen patients with nonidiopathic scoliosis were excluded, leaving 118 available for analysis. Of the remaining patients, 248 (64%) could not be contacted because of a change in address or phone number. Two patients (1%) were unwilling to complete survey requests. There was no statistically significant difference in demographics between patients with and without follow-up data available. Demographics are summarized in Table 1. There were 109 females (92%). Mean (SD) age at surgery was 14.1 (1.9) years. Only 37 (31%) were braced before surgery. Table 2 summarizes the radiographic data. Mean (SD) major Cobb angle was 49.7° (7.8°). Eighty-five patients (72%) underwent posterior fusion with instrumentation using hooks only; another 16 (14%) had anterior-only surgery, and another 17 (14%) had combined anterior-posterior surgery. A mean of 7.8 levels were fused. Index surgery data and lowest instrumented vertebra distribution are summarized in Table 3. Mean (SD) percentage curve correction was 48.9% (8.4%).

Seven patients had a total of 8 perioperative complications: anemia requiring transfusion (2), ileus necessitating nasogastric tube insertion (2), superficial wound infection treated with oral antibiotics and local wound care (2), wound drainage and erythema (1), and pneumonia (1). Mean (SD) length of clinical and radiographic follow-up was 57.9 (36.3) months.

Table 4 summarizes the long-term complications. Of the 38 patients with long-term complications, 14 required reoperation. The indications were disc herniation (2 patients), painful instrumentation (7), crankshaft phenomenon (1), nonunion (1), and adjacent-level degeneration (3). Both disc herniations were at L5–S1, several segments below the distal extent of the fusion. Of the 7 patients who had painful instrumentation removed, 6 had the entire construct removed, and 1 had the proximal half of a rod taken out. The 3 patients with adjacent-level degeneration had stenosis at the distal end of the construct—at L5–S1 (2 patients) or L2–L3 (1 patient).

Mean (SD) time between surgery and completion of the surveys/questionnaires was 12.7 (3.2) years (range, 10-18 years). Mean age of respondents was 26.8 years. Twenty-five respondents (21%) were smokers. Mean (SD) outcome scores were 50.9 (9.4) for SF-12 PCS and 49.4 (10.2) for SF-12 MCS. Eighteen patients (15%) had SF-12 PCS scores 1 SD below normal, and 15 (13%) had SF-12 MCS scores 1 SD below normal. Mean (SD) SRS-22R Total score was 4.0 (0.7). Means, standard deviations, and distribution of SRS domain scores are summarized in Table 5. Of the variables, only current smoking (P < .001) was predictive of SRS-22R Total scores, accounting for 20% of their variability (Table 6).

One hundred patients (85%) had jobs, mostly desk jobs. The postoperative limitations most commonly reported are summarized in Table 7. These included at least intermittent back pain in 90 patients (76%), limited ROM in 52 (44%), and activity limitations in 54 (46%). Less common limitations were waistline imbalance in 41 (35%), rib prominence in 28 (24%), wound/scar problems in 18 (15%), and shortness of breath in 18 (15%). Other related medical problems were lung disease/asthma in 11 (9%), osteoarthritis/degenerative arthritis in 11 (9%), heart disease in 3 (3%), and high blood pressure in 2 (2%).

A minority of patients also participated in postoperative treatment regimens. The most common treatment was regular use of NSAIDs (25 patients, 21%). Other treatments were physical therapy (14, 12%), narcotic pain medication use (5, 4%), and epidural steroid injections (5, 4%). Table 8 summarizes the postoperative treatments used by patients with scoliosis.

Discussion

A major concern about prophylactic interventions for diseases is that the treatment will harm the patient. This is especially true for major spine surgery performed on adolescents with minimal symptoms. Although the incidence of perioperative complications in children undergoing corrective spinal surgery for AIS has been reported,^30-32 the effect of the surgery on the disease-specific HR-QOL outcomes of these individuals as young adults has not been previously studied. Over the past few decades, a paradigm shift in understanding health and disability has occurred, with increased emphasis being placed on HR-QOL outcomes measures and understanding disability as relating to a measureable impact of the functioning of an individual after a change in health or environment. This change was substantiated when the World Health Organization endorsed the International Classification of Functioning, Disability and Health.³³ In light of this shift, we present the disease-specific and general HR-QOL outcomes of young adults who had undergone surgical correction for spinal deformity during adolescence, as well as their associated complications and reoperations, in an attempt to identify targets for improvement.

Our patient-reported outcomes demonstrated a high incidence of occasional back pain, activity-related complaints, and limited ROM. Comparison of our cohort’s SRS-22R outcomes with previously published normative values for the unaffected adolescent population^28,34 suggests worse scores for the disease-specific SRS-22R domains of pain and appearance. In 2012, Daubs and colleagues³⁴ reported that normative scores on various SRS-22 domains were statistically lower with age (scores decreased from age 10 to age 19 years). Both Verma and colleagues²⁸ and Daubs and colleagues³⁴ reported lower scores for females than for males. Therefore, it is unclear whether the differences observed in our cohort may be accounted for by the larger proportion of females compared with the normative data.

General health scores on the SF-12 were similar to the population norm (mean [SD]) of 50 (10) referenced by Ware and colleagues.¹⁶ These findings suggest that, though pain and appearance may be statistically lower in our cohort—as measured with the SRS-22R—the cohort’s spine-related symptoms do not seem to lower its general health. Eighty-five percent of the patients were working at the time of the survey, further supporting a relatively normal level of overall function. In a retrospective review by Takayama and colleagues,⁹ similar results were found with regard to working after AIS fusion surgery. Of 32 patients treated surgically for scoliosis, at a mean of 21.1 years after the index fusion 27 (84.4%) were or had been engaged in various occupations without marked difficulty.

Our results in a cohort of patients with segmental instrumentation using hooks are similar to results in other studies of long-term HR-QOL measures in patients with AIS and Harrington rod instrumentation. Danielsson and Nachemson³⁵ evaluated patients with surgically treated AIS with at least 20-year follow-up and reported that, in their surgical cohort with a mean age of 39.7 years, mean SF-36 PCS score was 50.9, and mean SF-36 MCS score was 50.2. In a recent study of patients with AIS and Harrington rod instrumentation, those of a mean age of 32.3 years had a mean score of 50.9 for both SF-36 PCS and SF-36 MCS.³⁶

Regression analysis identified only smoking as a predictor of SRS-22R Total scores. This finding, that smokers have a lower health state, is expected even in the general population.³⁷ Interestingly, bracing before surgery, Lenke type, surgery type, number of levels fused, lowest instrumented vertebra, incidence of perioperative complications, percentage curve correction, postoperative sagittal and coronal balance, and need for revision surgery did not influence HR-QOL measures in this cohort.

Our cohort’s incidence of occasional back pain was 76% (90/118 patients). Other reports have had similar findings. In 2012, Bas and colleagues³⁸ studied self-reported pain in 126 consecutive patients with scoliosis and instrumented fusion. In their cohort, “most participants reported ‘no pain’ (38.5%) or ‘mild pain’ (30.8%) and 72.1% of participants reported a current work/school activity level of 100% normal.” Also in 2012, Rushton and Grevitt³⁹ reported on a review and statistical analysis of the literature on HR-QOL in adolescents with untreated AIS and in unaffected adolescents. Their goal was to identify whether there were any differences in HR-QOL and, if so, whether they were clinically relevant. The authors concluded that pain and self-image tended to be statistically lower among cohorts with AIS but that only self-image was consistently different clinically between untreated patients with AIS and their unaffected peers.

Cosmetic complaints, though less common than functional concerns, affected a substantial percentage of our cohort. Waistline imbalance complaints were more common than rib prominence or scar-related complaints. The validity of patient-reported waistline imbalance is not known but may contribute to the SRS-22R outcomes in this cohort, particularly with regard to appearance scores. Respiratory symptoms, particularly those related to shortness of breath, were reported by 15% of patients. Respiratory symptoms may be in part secondary to underlying lung disease; smoking was reported by 21% of patients and asthma by 9%.

Few additional postoperative treatments were reported by patients. The most common treatment was regular use of NSAIDs (21%), followed by postoperative physical therapy (12%). Opiate medication use and spinal injections were rare—consistent with results reported by Danielsson and Nachemson³⁵ in 2003.

Implant-related complaints, including painful instrumentation (13%) and implant prominence (9%), were some of the most common complaints in our study group. Although not all symptomatic instrumentation required surgical revision, 7 (50%) of the 14 additional spine surgeries were related to painful and/or prominent posterior instrumentation. Additional spine surgery was reported in 11.9% of our patients. Other indications for reoperation were disc herniation, crankshaft phenomenon, nonunion, and adjacent-level degeneration. Our rate of revision surgery is supported by the literature. In 2009, Luhmann and colleagues⁴⁰ reported that 41 (3.9%) of 1057 primary spine fusions for idiopathic scoliosis required reoperation; the indications included infection (16/1057, 1.5%), pseudarthrosis (12, 1.1%), and painful/prominent implant (7, 0.7%). Richards and colleagues⁴¹ similarly reported on 1046 patients who underwent fusion for AIS. Of these patients, 135 underwent 172 repeat surgical interventions (12.9% reoperation rate), with 29 (21.5%) of the 135 undergoing 2 or more separate procedures. The most common reasons for reoperation were infection, symptomatic implant, and pseudarthrosis. The authors concluded that repeat surgeries were relatively common after the initial surgical procedures. Having a clearer understanding of instrumentation-related complaints and reoperations may lead to improvement in this surgeon-controlled variable.

There are limitations to this study. The data regarding clinical courses were collected by retrospective chart review, which has known limitations. To offset this, we collected prospective outcome data with use of the SF-12, the SRS-22R, and a spine-related complaints questionnaire. No control group was available for comparison of outcomes in our cohort. We used the SF-12 and previously published normative values for the SRS-22R for comparison with population norms. Such comparisons have inherent limitations, as the groups vary by sex and mean age; our cohort was primarily female and more than a decade older than the controls.

Only 35% of the patients who met the inclusion criteria had complete data that could be included in our analysis. Although there was no statistically significant difference in demographics between patients with and without follow-up data available, this low response rate could have introduced selection bias. Ideally, patients should have been seen in clinic, standing radiographs should have been taken, and pulmonary function tests should have been performed. However, these patients were asymptomatic, and ethical and insurance issues prevented those actions. Thus, any radiographic changes occurring over the intervening years, from the last clinic visit to completion of the surveys, were not documented. This situation may or may not have limited our findings, as other authors have found low correlation between radiographic outcomes and clinical outcome measures.^13,14,19,36 During the period when these surgeries were performed, segmental spine instrumentation with hooks was the standard of care for deformity correction in AIS; therefore, all posterior instrumentations were done with hook-only segmental fixation. Current pedicle screw–based techniques that allow for additional correction of the deformity may provide different outcomes in the future.

We think that, despite the inherent limitations of this study, our data will be useful in the treatment of AIS. Our results suggest that postoperative spinal complaints are common and that, compared with an unaffected adolescent population, patients with AIS score significantly lower on pain and appearance domains of outcomes testing at a mean of 12.7 years after index fusion. Nevertheless, the outcomes do not seem to be of sufficient severity to affect general health and QOL as measured by outcomes testing.

Spinal deformity correction is performed to prevent impaired pulmonary function and spine-related disability later in life.^42,43 Thus, longer-term studies, involving patients in their fifth and sixth decades of life, are needed to determine whether patients with AIS will have QOL outcomes, pulmonary function, and spine-related problems similar to those in the general population. In this cohort of young adults, smoking status was the only predictor of HR-QOL measures, and spinal deformity correction did not lead to decreased HR-QOL.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

SAN FRANCISCO—Low-molecular-weight heparin (LMWH) should replace warfarin as thromboprophylaxis in cancer patients, according to a speaker at the 2014 ASH Annual Meeting.

Results of the phase 3 CATCH trial showed that long-term treatment with the LMWH tinzaparin was associated with a 35% lower risk of recurrent venous thromboembolism (VTE) when compared to warfarin, although the difference between the treatment arms was not statistically significant.

Patients who received tinzaparin did have a significantly lower risk of symptomatic deep vein thrombosis (DVT) and clinically relevant, non-major bleeding.

However, there was no difference between the treatment arms with regard to major bleeding or overall mortality.

Agnes Y.Y. Lee, MD, of the University of British Columbia and Vancouver Coastal Health in British Columbia, Canada, presented these results at ASH as LBA-2.*

“CATCH is the largest randomized trial studying treatment of cancer-associated thrombosis,” she said. “It provides confirmatory data for improved efficacy of low-molecular-weight heparin over warfarin.”

The trial included 900 cancer patients from 164 centers around the world. The mean patient age was 59 (range, 18-89), and 59% were female. The most common cancers were gynecologic, colorectal, upper gastrointestinal, and lung.

Patients were stratified by geographic region, tumor characteristics, and history of VTE. They were randomized to receive tinzaparin at 175 IU/kg once daily for 6 months (n=449) or initial tinzaparin at 175 IU/kg once daily for 5 to 10 days overlapped and followed by dose-adjusted warfarin for 6 months (n=451).

In all, 416 patients completed treatment with tinzaparin, and 401 completed warfarin treatment. The patients were followed up to 6 months or death, whichever came first.

Efficacy data 

The primary efficacy outcome was recurrent VTE, which included symptomatic DVT and/or pulmonary embolism (PE), incidental proximal DVT and/or PE, and fatal PE.

The rate of recurrent VTE was 7.2% in the tinzaparin arm and 10.5% in the warfarin arm (hazard ratio [HR]=0.65, P=0.07). This represents a 35% reduction in recurrent VTE with the LMWH.

In the per-protocol analysis, the rates of recurrent VTE were 8.3% and 12.7%, respectively (HR=0.62), which translates to a 38% reduction in recurrent VTE with tinzaparin.

“Pre-specified efficacy analyses further showed that tinzaparin significantly reduced symptomatic, recurrent DVT by 52%,” Dr Lee noted. “There were very few symptomatic PEs, equal numbers of fatal PEs occurred in each arm, and there were only 2 incidental thrombotic events, both in the warfarin arm.”

Symptomatic, non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR=0.48, P=0.04). Symptomatic, non-fatal PE occurred in 3 patients (0.7%) and 2 patients (0.4%), respectively. And fatal PE occurred in 17 patients (3.8%) in each arm (HR=0.96).

“We were clearly disappointed that our primary efficacy outcome did not achieve statistical significance,” Dr Lee said. “But our sample size was based on an estimated recurrent [VTE] rate of 12.6% in the warfarin group, and we only saw a 10% [sic] recurrence. So, basically, our study was slightly underpowered to achieve statistical significance.”

“I think that, given the symptomatic DVT results, as well as the per-protocol analysis, in additon to all the previous data on low-molecular-weight heparin, this is still very strong confirmatory data that low-molecular-weight heparin is more effective than warfarin therapy in treating cancer patients with thrombosis.”

Safety and mortality

The primary safety endpoint was major bleeding, which occurred in 2.9% of patients in the tinzaparin arm and 2.6% in the warfarin arm (HR=0.89).

The rate of clinically relevant, non-major bleeding was 11.1% and 16.2%, respectively (HR=0.69, P=0.03).

“Tinzaparin reduced the rate of clinically relevant, non-major bleeding by 31%,” Dr Lee noted.

On the other hand, there was no significant difference between the arms with regard to 180-day overall mortality, which was 34.2% in the tinzaparin arm and 32.3% in the warfarin arm (HR=1.08).

This research was sponsored by LEO Pharma, the company developing tinzaparin (Innohep).

*Information in the abstract differs from that presented at the meeting.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

ASH attendees gather

in the Moscone Center

SAN FRANCISCO—The first-in-human study of AG-221 has confirmed IDH2 as a therapeutic target in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to investigators.

From the first dose of therapy, the high plasma level observed in patients “translates into a drastic decrease in 2-HG,” said Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York.

Mutations in IDH1 and IDH2 result in the accumulation of the oncometabolite 2-HG. And high levels of 2-HG prompt epigenetic changes to the cell, resulting in impaired cellular differentiation.

“By cycle 1, day 15, at all dose levels, there was fantastic inhibition of 2-HG,” Dr Stein said. “Indeed, this drastic inhibition of 2-HG led to profound clinical benefit.”

He presented interim results of the phase 1 study of AG-221 at the 2014 ASH Annual Meeting (abstract 115).*

The investigators have treated 73 patients with advanced IDH2-mutation-positive hematologic malignancies since the study began in September 2013.

Patients were a median age of 67 years (range, 33-90), and 74% had IDH2 R140 mutations. Most had relapsed/refractory AML (n=55), and the rest had MDS (n=6), untreated AML (n=5), chronic myelomonocytic leukemia (n=5), and myeloid sarcoma (n=1).

Patients received AG-221 as a single agent orally, once or twice a day, continuously, in 28-day cycles. Four dose-expansion cohorts at 100 mg each day were added last October.

To date, the maximum tolerated dose has not been reached, with the highest cumulative daily dose being 300 mg. Investigators observed a single dose-limiting toxicity in 1 patient: grade 5 hypoxia with fungal pneumonia and septic shock.

As of the data cutoff on October 1, 2014, 38 patients were still on therapy, and 35 had discontinued. Five patients withdrew after achieving complete remission (CR) in order to pursue allogeneic transplant.

Dr Stein pointed out that although the median number of prior chemotherapy regimens for the entire cohort was 2, “all of the patients who went on study were predicted to have dismal outcomes with conventional therapy.”

Safety

The therapy was well tolerated, with the most common adverse events (AEs) overall being typical for patients with advanced AML: nausea (23%), pyrexia (19%), and diarrhea (17%).

The majority of serious AEs were disease-related and unrelated to the study drug, Dr Stein said. Thirteen patients experienced 21 serious AEs that were possibly or probably related to treatment.

Investigators observed treatment-related leukocytosis in 3 patients, “but we think that is a differentiating effect of the study drug,” Dr Stein said.

He also pointed out that there was no increase in AEs with increased dose of the drug.

Of the 11 deaths reported, 9 were unrelated to the drug, and 2—sepsis/hypoxia and atrial flutter—were possibly related. The 30-day and 60-day all-cause mortality rates were 4.1% and 13.7%, respectively.

Efficacy

Of the 45 patients who were treated for at least 1 cycle and were evaluable for efficacy, 15 achieved a CR (n=6) or a CR with incomplete blood count recovery. The overall response rate is 56% (25/45).

“Responses appear durable,” Dr Stein commented, “and 90% of responders have had a response duration of at least 3 months, with the earliest patients on study having had durable responses for over 6 months.”

Many of the durable responses are partial remissions, he noted.

Seventeen patients have stable disease, and many of these patients remain on study. Two patients had progressive disease.

“Patients with stable disease have remained on study for a similar amount of time as the responders,” Dr Stein said, “suggesting that, despite the lack of a formal partial remission, many patients are deriving clinical benefit from study treatment.”

This study was sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Previous results from this study were presented at the 2014 EHA Annual Congress. Based on those results, AG-221 received fast track designation from the US Food and Drug Administration.

*Data in the presentation were updated from the abstract.

Telephone-based programs to encourage and support quitting smoking—known as “quitlines”—have been established as effective both clinically and in the “real world.” However, quitlines rely on smokers calling in for them to work. Researchers from the Tobacco Cessation and Prevention Program and the Massachusetts Department of Public Health, both in Boston, say being referred to quitlines by their health care providers might help even more smokers quit.

The researchers collected data for 2,737 provider-referred and 530 self-referred smokers from the Massachusetts Smokers’ Helpline, which offers evidence-based proactive telephone counseling sessions, nicotine replacement therapy (NRT), and self-help materials. They then examined differences in demographics, service utilization, and quit outcomes. The primary outcome was quit status at the 6- to 8-month follow-up.

Twenty percent of provider-referred clients quit smoking; 26% of self-referred clients quit. Provider-referred smokers who used the quitline services had higher odds of quitting, compared with those who used methods not including a quitline. However, the provider-referral model was limited by lower enrollment, lower use, and poorer outcomes compared with self-referred services. Patients aged 18 to 34 years and those aged > 65 years had the best chances of quitting and staying smoke-free. Patients referred from private practices were more likely to quit than were those referred from a hospital.

Provider-referred smokers who read the self-help materials had 1.2 times the odds of quitting compared with those who didn’t. Using any amount of the 2-week supply of NRT doubled the odds of quitting. Clients who used a combination of counseling and NRT had the greatest success, with more than triple the chances of quitting, compared with clients who did neither.

Self-referred smokers also had good results, although not usually as quickly as provider-referred smokers, who saw significantly improved outcomes after 3 counseling sessions. It took 4 sessions for the self-referred smokers to see the same results.

Readiness to quit was an important predictor of success. Tobacco dependence also predicted quitting success. Clients in both groups who could wait > 30 minutes before smoking their first cigarette had better luck than did those who had to smoke immediately after waking.

The researchers suggest some ways to improve the provider-referred model. One is to offer more support for smokers from lower socioeconomic levels. According to other research, those smokers may need more treatment content and access to more intensive pharmacotherapy, the researchers say.

It might also help all quitline clients, they add, to minimize the wait time between referral and actual provision of service. Longer wait times can “increase the room for ambivalence for any smoker,” they note, “but may be especially detrimental for provider-referred smokers who are less ready to make a quit attempt.”

And what is the provider’s role in assessing patient readiness to quit and preparing patients for the quitline services? In reality, the researchers say, not all patients have received an evidence-based intervention or are ready to quit when they are enrolled. Moreover, many are lost in the callback process. Using 3 callback attempts, the Massachusetts quitline only reaches 40% of their potential quitters. Upping the callback rate to 5 attempts raises the reach slightly, to 50%. That shows the need, the researchers say, for better and more frequent provider training, outreach, feedback reporting, clinical champions on site, and systems support.

Source
Song G, Landau AS, Gorin TJ, Keithly L. Am J Prev Med. 2014;47(4):392-402.
doi: 10.1016/j.amepre.2014.05.043.

Telephone-based programs to encourage and support quitting smoking—known as “quitlines”—have been established as effective both clinically and in the “real world.” However, quitlines rely on smokers calling in for them to work. Researchers from the Tobacco Cessation and Prevention Program and the Massachusetts Department of Public Health, both in Boston, say being referred to quitlines by their health care providers might help even more smokers quit.

The researchers collected data for 2,737 provider-referred and 530 self-referred smokers from the Massachusetts Smokers’ Helpline, which offers evidence-based proactive telephone counseling sessions, nicotine replacement therapy (NRT), and self-help materials. They then examined differences in demographics, service utilization, and quit outcomes. The primary outcome was quit status at the 6- to 8-month follow-up.

Twenty percent of provider-referred clients quit smoking; 26% of self-referred clients quit. Provider-referred smokers who used the quitline services had higher odds of quitting, compared with those who used methods not including a quitline. However, the provider-referral model was limited by lower enrollment, lower use, and poorer outcomes compared with self-referred services. Patients aged 18 to 34 years and those aged > 65 years had the best chances of quitting and staying smoke-free. Patients referred from private practices were more likely to quit than were those referred from a hospital.

Provider-referred smokers who read the self-help materials had 1.2 times the odds of quitting compared with those who didn’t. Using any amount of the 2-week supply of NRT doubled the odds of quitting. Clients who used a combination of counseling and NRT had the greatest success, with more than triple the chances of quitting, compared with clients who did neither.

Self-referred smokers also had good results, although not usually as quickly as provider-referred smokers, who saw significantly improved outcomes after 3 counseling sessions. It took 4 sessions for the self-referred smokers to see the same results.

Readiness to quit was an important predictor of success. Tobacco dependence also predicted quitting success. Clients in both groups who could wait > 30 minutes before smoking their first cigarette had better luck than did those who had to smoke immediately after waking.

The researchers suggest some ways to improve the provider-referred model. One is to offer more support for smokers from lower socioeconomic levels. According to other research, those smokers may need more treatment content and access to more intensive pharmacotherapy, the researchers say.

It might also help all quitline clients, they add, to minimize the wait time between referral and actual provision of service. Longer wait times can “increase the room for ambivalence for any smoker,” they note, “but may be especially detrimental for provider-referred smokers who are less ready to make a quit attempt.”

And what is the provider’s role in assessing patient readiness to quit and preparing patients for the quitline services? In reality, the researchers say, not all patients have received an evidence-based intervention or are ready to quit when they are enrolled. Moreover, many are lost in the callback process. Using 3 callback attempts, the Massachusetts quitline only reaches 40% of their potential quitters. Upping the callback rate to 5 attempts raises the reach slightly, to 50%. That shows the need, the researchers say, for better and more frequent provider training, outreach, feedback reporting, clinical champions on site, and systems support.

Source
Song G, Landau AS, Gorin TJ, Keithly L. Am J Prev Med. 2014;47(4):392-402.
doi: 10.1016/j.amepre.2014.05.043.

Telephone-based programs to encourage and support quitting smoking—known as “quitlines”—have been established as effective both clinically and in the “real world.” However, quitlines rely on smokers calling in for them to work. Researchers from the Tobacco Cessation and Prevention Program and the Massachusetts Department of Public Health, both in Boston, say being referred to quitlines by their health care providers might help even more smokers quit.

The researchers collected data for 2,737 provider-referred and 530 self-referred smokers from the Massachusetts Smokers’ Helpline, which offers evidence-based proactive telephone counseling sessions, nicotine replacement therapy (NRT), and self-help materials. They then examined differences in demographics, service utilization, and quit outcomes. The primary outcome was quit status at the 6- to 8-month follow-up.

Twenty percent of provider-referred clients quit smoking; 26% of self-referred clients quit. Provider-referred smokers who used the quitline services had higher odds of quitting, compared with those who used methods not including a quitline. However, the provider-referral model was limited by lower enrollment, lower use, and poorer outcomes compared with self-referred services. Patients aged 18 to 34 years and those aged > 65 years had the best chances of quitting and staying smoke-free. Patients referred from private practices were more likely to quit than were those referred from a hospital.

Provider-referred smokers who read the self-help materials had 1.2 times the odds of quitting compared with those who didn’t. Using any amount of the 2-week supply of NRT doubled the odds of quitting. Clients who used a combination of counseling and NRT had the greatest success, with more than triple the chances of quitting, compared with clients who did neither.

Self-referred smokers also had good results, although not usually as quickly as provider-referred smokers, who saw significantly improved outcomes after 3 counseling sessions. It took 4 sessions for the self-referred smokers to see the same results.

Readiness to quit was an important predictor of success. Tobacco dependence also predicted quitting success. Clients in both groups who could wait > 30 minutes before smoking their first cigarette had better luck than did those who had to smoke immediately after waking.

The researchers suggest some ways to improve the provider-referred model. One is to offer more support for smokers from lower socioeconomic levels. According to other research, those smokers may need more treatment content and access to more intensive pharmacotherapy, the researchers say.

It might also help all quitline clients, they add, to minimize the wait time between referral and actual provision of service. Longer wait times can “increase the room for ambivalence for any smoker,” they note, “but may be especially detrimental for provider-referred smokers who are less ready to make a quit attempt.”

And what is the provider’s role in assessing patient readiness to quit and preparing patients for the quitline services? In reality, the researchers say, not all patients have received an evidence-based intervention or are ready to quit when they are enrolled. Moreover, many are lost in the callback process. Using 3 callback attempts, the Massachusetts quitline only reaches 40% of their potential quitters. Upping the callback rate to 5 attempts raises the reach slightly, to 50%. That shows the need, the researchers say, for better and more frequent provider training, outreach, feedback reporting, clinical champions on site, and systems support.

Source
Song G, Landau AS, Gorin TJ, Keithly L. Am J Prev Med. 2014;47(4):392-402.
doi: 10.1016/j.amepre.2014.05.043.

Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.

Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.

Blood for transfusion

Credit: UAB Hospital

Long-term mortality is not affected by the amount of blood a patient receives following surgery, according to research published in The Lancet.

Investigators compared a liberal transfusion strategy, in which patients received blood to maintain a hemoglobin level at 100 g/L or higher, and a restrictive strategy, in which patients received blood when hemoglobin levels were lower than 80 g/L or if they had symptoms of anemia.

And, at about 3 years of follow-up, there was no difference in mortality between the two groups.

Jeffrey L. Carson, MD, of Robert Wood Johnson Medical School in New Jersey, and his colleagues conducted this research, analyzing data from the FOCUS trial, which included patients from 47 hospitals in the US and Canada.

The trial enrolled 2016 adults age 50 and older, with a history of or risk factors for cardiovascular disease, who had postoperative hemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture.

Patients were randomized by a central telephone system to the liberal (n=1007) or restrictive (n=1009) transfusion groups. The investigators analyzed the long-term mortality of these patients, which was established by linking participants to national death registries in the US and Canada.

The results revealed no difference in mortality from cardiovascular disease, cancer, or severe infection due to the amount of the blood given after surgery.

This supports the initial results of the FOCUS trial, which Dr Carson and his colleagues published in NEJM in 2011 and which demonstrated the safety of fewer transfusions in the short-term.

For the current analysis, the median duration of follow-up was 3.1 years. Eight hundred and forty-one patients (42%) died during that time—432 in the liberal transfusion group and 409 in the restrictive transfusion group. This difference was not statistically significant, with a hazard ratio of 1.09 and a P value of 0.21.

“There has been a steady decline in the amount of blood in transfusions given to patients in the past 3 to 5 years,” Dr Carson noted. “I think it is very reassuring that we have found that using less blood is okay, not just from a short-term perspective, but also a long-term perspective.”

Medical experts had worried that larger amounts of transfused blood might suppress immune function—which could lead to death from infection or cancer—or that smaller transfusions might worsen a patient’s chronic heart disease by depriving the heart of oxygen and other nutrients that it might have absorbed by pumping more blood.

But in both instances, Dr Carson and his colleagues found no difference in long-term death rates, regardless of the number of transfusions.

Dr Carson noted that there are health conditions, such as heart attacks, where the effects of the two transfusion strategies are less certain. Preliminary evidence suggests heart attack patients need more blood, not less. But additional studies are needed to confirm that.