The sesamoid bones are a major contributor to normal gait, with more than 50% of body weight transmitted through the hallux metatarsophalangeal joint (MTPJ) complex. There are varying amounts of stress on the sesamoids, dependent on the gait cycle.^1,2 The sesamoids act as a fulcrum to increase the mechanical force of the flexor hallucis brevis tendon.³ Sesamoid pathology can be a source of significant morbidity in patients, especially young athletes or laborers who spend long hours on their feet. More common causes of isolated sesamoid discomfort include sesamoiditis, fracture, and avascular necrosis, with neoplastic, infectious, and inflammatory conditions rarely isolated to the sesamoid.

Gout is a systemic disorder of uric acid metabolism characterized by deposition of monosodium urate crystals in soft tissues and joints.¹ This deposition leads to tophus formation with an accompanying inflammatory response. Gout progresses through 3 stages, beginning with acute gout, which may end with chronic, recurrent, and tophaceous gouty arthritis. The hallux MTPJ is the most common joint affected by gout, with few case reports of primary sesamoid gout.^1-2,4 We present a case of gout, with radiographic findings isolated to the medial sesamoid, that mimicked a neoplastic process in a patient with no known history of gout. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 37-year-old laborer presented for evaluation of a right sesamoid injury he sustained 4 months earlier when he fell off a ladder and had acute onset plantar hallux MTPJ pain and swelling. He was treated by an outside physician for a presumptive diagnosis of a medial sesamoid fracture with rest and controlled ankle movement (CAM) boot immobilization that resulted in slowly improving symptoms. In discussion of the patient’s history, he reported that 1 year earlier he had a traumatic event with similar symptoms of MTPJ pain and swelling. At that time, treatment with a CAM boot resulted in complete resolution of pain. His outside physician performed a hematologic workup for gout, which showed a normal uric acid level.

On examination, the patient presented with edema to the right hallux MTPJ and mild tenderness to palpation of the medial sesamoid. He had no pain with motion of the hallux MTPJ or with palpation of the lateral sesamoid. His radiographs showed a bipartite versus fractured sesamoid (Figures 1A, 1B) and serial magnetic resonance imaging (MRI) showed an MTPJ effusion and hyperintense signal in the medial sesamoid, but no erosive findings or soft-tissue masses (Figures 2A, 2B).

The patient was treated with wedge-sandal forefoot offloading, leading to resolution of symptoms over 6 weeks, at which point he was transitioned to normal shoe wear and allowed to progress in his activity as dictated by his symptoms. He presented for reevaluation approximately 2 weeks later with acute, atraumatic onset of plantar left hallux pain and swelling. His examination showed diffuse hallux MTPJ swelling and tenderness isolated to the medial sesamoid. An attempt at aspiration of the MTPJ yielded no fluid, and the patient again was placed in a forefoot-offloading sandal.

Radiographs of the left foot showed an expansile destructive lesion of the medial sesamoid with interval change from his previous imaging approximately 3 months earlier, obtained as part of his contralateral foot evaluation (Figure 3). MRI with and without contrast showed an expansile process isolated to the medial sesamoid with cortical thinning and marrow replacement (Figures 4A-4D). 

Because of continued discomfort and lack of a definitive diagnosis, an excisional biopsy of the sesamoid was performed. Intraoperatively, the sesamoid was extensively fragmented with near complete replacement by a chalky tophus, as well as chalky deposition throughout the hallux MTPJ. No significant degenerative changes were observed. Surgical pathology showed bone and fibroconnective tissue with deposits of negative birefringement needle-shaped crystals consistent with monosodium urate deposition and foreign body histocytic reaction, as well as repair reaction of bone (Figures 5A, 5B).

Postoperatively, the patient was again placed in a forefoot-offloading wedge sandal for 6 weeks, followed by progression of activity as dictated by his symptoms. He was also evaluated by a rheumatologist and started on medical treatment for gout, with complete resolution of his bilateral hallux pain. He has been able to return to his previous employment.

Discussion

The sesamoid bones are an important component of the hallux MTPJ complex, giving a mechanical advantage to the flexor hallucis brevis tendons in plantar flexion of the hallux.⁵ Many pathologic conditions have been well described in the literature, including fracture, sesamoiditis, nonunion, avascular necrosis, and plantar keratosis. There is also a 10% incidence of bipartite sesamoids, most commonly isolated to the medial sesamoid, with up to 25% of patients presenting with bilateral bipartite sesamoids.⁵ Neoplastic processes of the sesamoid are rare, with a paucity of reports in the literature.^6,7  Gout is a condition in which hyperuricemia, due to an imbalance in uric acid production and excretion, leads to deposition of monosodium urate crystals in joints, bones, and soft tissues, causing an inflammatory reaction. Risk factors for gout are male sex, advanced age, and ethnicity, as well as obesity, high protein diet, alcohol use, hypertension, and certain medications. Precipitation of acute attacks has been associated with acute trauma, and the first MTPJ is the most common location for an acute attack.⁸

Isolated sesamoid lesions are rare, with few isolated case reports in the literature. Benign and malignant lesions appear most often in the metatarsals, with the calcaneus being the second most commonly afflicted site.⁹ The typical differential diagnosis for isolated lytic bone lesions includes fibrous dysplasia, osteoblastoma, giant cell tumor, metastatic lesion, multiple myeloma, aneurysmal bone cyst, chondroblastoma, brown tumor, infection, eosinophilic granuloma, enchondroma, and bone cyst, with no reports in the literature to our knowledge of these entities presenting in the hallux MTPJ sesamoid. In contrast, gout typically begins with normal radiographic findings, and later leads to erosive, “punched out” lesions on either side of the MTPJ.²

Hyperuricemia is an essential part of the pathophysiology of gout, but not all patients with an acute gouty attack have elevated uric acid levels and, in contrast, may actually have normal or low levels in 12% to 43% of cases.⁸ The most accurate time frame for assessment of serum uric acid levels is 2 weeks or more after subsidence of an acute event.⁸ The normal uric acid levels seen in our patient were most likely due to the fact that the workup was undertaken during an acute attack. The difficulty with establishing the diagnosis was compounded by bilateral involvement, history of trauma, negative joint aspiration, and atypical radiographic findings. A number of reports have described patients with tophus deposits prior to or in the absence of gouty arthritis or a gouty attack.¹⁰ Risk factors for this presentation include female sex, the predominant or exclusive involvement of fingers, chronic kidney disease, and treatment with a diuretic or anti-inflammatory drug.¹⁰

Conclusion

Our case report illustrates the difficulty in diagnosing an acute gouty attack in a patient with a history of trauma and atypical radiographic findings. The hallux MTPJ is the most common location of acute gouty attacks, but the medial sesamoid as an isolated location is a rare site of presentation. The combination of pain isolated to palpation of the sesamoid and radiographs that showed an aggressive and rapidly expansile lesion of the medial sesamoid raised concerns about a neoplastic lesion. Practitioners should consider acute gout in patients with sesamoid pain and with radiographs showing an expansile sesamoid lesion.

The sesamoid bones are a major contributor to normal gait, with more than 50% of body weight transmitted through the hallux metatarsophalangeal joint (MTPJ) complex. There are varying amounts of stress on the sesamoids, dependent on the gait cycle.^1,2 The sesamoids act as a fulcrum to increase the mechanical force of the flexor hallucis brevis tendon.³ Sesamoid pathology can be a source of significant morbidity in patients, especially young athletes or laborers who spend long hours on their feet. More common causes of isolated sesamoid discomfort include sesamoiditis, fracture, and avascular necrosis, with neoplastic, infectious, and inflammatory conditions rarely isolated to the sesamoid.

Gout is a systemic disorder of uric acid metabolism characterized by deposition of monosodium urate crystals in soft tissues and joints.¹ This deposition leads to tophus formation with an accompanying inflammatory response. Gout progresses through 3 stages, beginning with acute gout, which may end with chronic, recurrent, and tophaceous gouty arthritis. The hallux MTPJ is the most common joint affected by gout, with few case reports of primary sesamoid gout.^1-2,4 We present a case of gout, with radiographic findings isolated to the medial sesamoid, that mimicked a neoplastic process in a patient with no known history of gout. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 37-year-old laborer presented for evaluation of a right sesamoid injury he sustained 4 months earlier when he fell off a ladder and had acute onset plantar hallux MTPJ pain and swelling. He was treated by an outside physician for a presumptive diagnosis of a medial sesamoid fracture with rest and controlled ankle movement (CAM) boot immobilization that resulted in slowly improving symptoms. In discussion of the patient’s history, he reported that 1 year earlier he had a traumatic event with similar symptoms of MTPJ pain and swelling. At that time, treatment with a CAM boot resulted in complete resolution of pain. His outside physician performed a hematologic workup for gout, which showed a normal uric acid level.

On examination, the patient presented with edema to the right hallux MTPJ and mild tenderness to palpation of the medial sesamoid. He had no pain with motion of the hallux MTPJ or with palpation of the lateral sesamoid. His radiographs showed a bipartite versus fractured sesamoid (Figures 1A, 1B) and serial magnetic resonance imaging (MRI) showed an MTPJ effusion and hyperintense signal in the medial sesamoid, but no erosive findings or soft-tissue masses (Figures 2A, 2B).

The patient was treated with wedge-sandal forefoot offloading, leading to resolution of symptoms over 6 weeks, at which point he was transitioned to normal shoe wear and allowed to progress in his activity as dictated by his symptoms. He presented for reevaluation approximately 2 weeks later with acute, atraumatic onset of plantar left hallux pain and swelling. His examination showed diffuse hallux MTPJ swelling and tenderness isolated to the medial sesamoid. An attempt at aspiration of the MTPJ yielded no fluid, and the patient again was placed in a forefoot-offloading sandal.

Radiographs of the left foot showed an expansile destructive lesion of the medial sesamoid with interval change from his previous imaging approximately 3 months earlier, obtained as part of his contralateral foot evaluation (Figure 3). MRI with and without contrast showed an expansile process isolated to the medial sesamoid with cortical thinning and marrow replacement (Figures 4A-4D). 

Because of continued discomfort and lack of a definitive diagnosis, an excisional biopsy of the sesamoid was performed. Intraoperatively, the sesamoid was extensively fragmented with near complete replacement by a chalky tophus, as well as chalky deposition throughout the hallux MTPJ. No significant degenerative changes were observed. Surgical pathology showed bone and fibroconnective tissue with deposits of negative birefringement needle-shaped crystals consistent with monosodium urate deposition and foreign body histocytic reaction, as well as repair reaction of bone (Figures 5A, 5B).

Postoperatively, the patient was again placed in a forefoot-offloading wedge sandal for 6 weeks, followed by progression of activity as dictated by his symptoms. He was also evaluated by a rheumatologist and started on medical treatment for gout, with complete resolution of his bilateral hallux pain. He has been able to return to his previous employment.

Discussion

The sesamoid bones are an important component of the hallux MTPJ complex, giving a mechanical advantage to the flexor hallucis brevis tendons in plantar flexion of the hallux.⁵ Many pathologic conditions have been well described in the literature, including fracture, sesamoiditis, nonunion, avascular necrosis, and plantar keratosis. There is also a 10% incidence of bipartite sesamoids, most commonly isolated to the medial sesamoid, with up to 25% of patients presenting with bilateral bipartite sesamoids.⁵ Neoplastic processes of the sesamoid are rare, with a paucity of reports in the literature.^6,7  Gout is a condition in which hyperuricemia, due to an imbalance in uric acid production and excretion, leads to deposition of monosodium urate crystals in joints, bones, and soft tissues, causing an inflammatory reaction. Risk factors for gout are male sex, advanced age, and ethnicity, as well as obesity, high protein diet, alcohol use, hypertension, and certain medications. Precipitation of acute attacks has been associated with acute trauma, and the first MTPJ is the most common location for an acute attack.⁸

Isolated sesamoid lesions are rare, with few isolated case reports in the literature. Benign and malignant lesions appear most often in the metatarsals, with the calcaneus being the second most commonly afflicted site.⁹ The typical differential diagnosis for isolated lytic bone lesions includes fibrous dysplasia, osteoblastoma, giant cell tumor, metastatic lesion, multiple myeloma, aneurysmal bone cyst, chondroblastoma, brown tumor, infection, eosinophilic granuloma, enchondroma, and bone cyst, with no reports in the literature to our knowledge of these entities presenting in the hallux MTPJ sesamoid. In contrast, gout typically begins with normal radiographic findings, and later leads to erosive, “punched out” lesions on either side of the MTPJ.²

Hyperuricemia is an essential part of the pathophysiology of gout, but not all patients with an acute gouty attack have elevated uric acid levels and, in contrast, may actually have normal or low levels in 12% to 43% of cases.⁸ The most accurate time frame for assessment of serum uric acid levels is 2 weeks or more after subsidence of an acute event.⁸ The normal uric acid levels seen in our patient were most likely due to the fact that the workup was undertaken during an acute attack. The difficulty with establishing the diagnosis was compounded by bilateral involvement, history of trauma, negative joint aspiration, and atypical radiographic findings. A number of reports have described patients with tophus deposits prior to or in the absence of gouty arthritis or a gouty attack.¹⁰ Risk factors for this presentation include female sex, the predominant or exclusive involvement of fingers, chronic kidney disease, and treatment with a diuretic or anti-inflammatory drug.¹⁰

Conclusion

Our case report illustrates the difficulty in diagnosing an acute gouty attack in a patient with a history of trauma and atypical radiographic findings. The hallux MTPJ is the most common location of acute gouty attacks, but the medial sesamoid as an isolated location is a rare site of presentation. The combination of pain isolated to palpation of the sesamoid and radiographs that showed an aggressive and rapidly expansile lesion of the medial sesamoid raised concerns about a neoplastic lesion. Practitioners should consider acute gout in patients with sesamoid pain and with radiographs showing an expansile sesamoid lesion.

The sesamoid bones are a major contributor to normal gait, with more than 50% of body weight transmitted through the hallux metatarsophalangeal joint (MTPJ) complex. There are varying amounts of stress on the sesamoids, dependent on the gait cycle.^1,2 The sesamoids act as a fulcrum to increase the mechanical force of the flexor hallucis brevis tendon.³ Sesamoid pathology can be a source of significant morbidity in patients, especially young athletes or laborers who spend long hours on their feet. More common causes of isolated sesamoid discomfort include sesamoiditis, fracture, and avascular necrosis, with neoplastic, infectious, and inflammatory conditions rarely isolated to the sesamoid.

Gout is a systemic disorder of uric acid metabolism characterized by deposition of monosodium urate crystals in soft tissues and joints.¹ This deposition leads to tophus formation with an accompanying inflammatory response. Gout progresses through 3 stages, beginning with acute gout, which may end with chronic, recurrent, and tophaceous gouty arthritis. The hallux MTPJ is the most common joint affected by gout, with few case reports of primary sesamoid gout.^1-2,4 We present a case of gout, with radiographic findings isolated to the medial sesamoid, that mimicked a neoplastic process in a patient with no known history of gout. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 37-year-old laborer presented for evaluation of a right sesamoid injury he sustained 4 months earlier when he fell off a ladder and had acute onset plantar hallux MTPJ pain and swelling. He was treated by an outside physician for a presumptive diagnosis of a medial sesamoid fracture with rest and controlled ankle movement (CAM) boot immobilization that resulted in slowly improving symptoms. In discussion of the patient’s history, he reported that 1 year earlier he had a traumatic event with similar symptoms of MTPJ pain and swelling. At that time, treatment with a CAM boot resulted in complete resolution of pain. His outside physician performed a hematologic workup for gout, which showed a normal uric acid level.

On examination, the patient presented with edema to the right hallux MTPJ and mild tenderness to palpation of the medial sesamoid. He had no pain with motion of the hallux MTPJ or with palpation of the lateral sesamoid. His radiographs showed a bipartite versus fractured sesamoid (Figures 1A, 1B) and serial magnetic resonance imaging (MRI) showed an MTPJ effusion and hyperintense signal in the medial sesamoid, but no erosive findings or soft-tissue masses (Figures 2A, 2B).

The patient was treated with wedge-sandal forefoot offloading, leading to resolution of symptoms over 6 weeks, at which point he was transitioned to normal shoe wear and allowed to progress in his activity as dictated by his symptoms. He presented for reevaluation approximately 2 weeks later with acute, atraumatic onset of plantar left hallux pain and swelling. His examination showed diffuse hallux MTPJ swelling and tenderness isolated to the medial sesamoid. An attempt at aspiration of the MTPJ yielded no fluid, and the patient again was placed in a forefoot-offloading sandal.

Radiographs of the left foot showed an expansile destructive lesion of the medial sesamoid with interval change from his previous imaging approximately 3 months earlier, obtained as part of his contralateral foot evaluation (Figure 3). MRI with and without contrast showed an expansile process isolated to the medial sesamoid with cortical thinning and marrow replacement (Figures 4A-4D). 

Because of continued discomfort and lack of a definitive diagnosis, an excisional biopsy of the sesamoid was performed. Intraoperatively, the sesamoid was extensively fragmented with near complete replacement by a chalky tophus, as well as chalky deposition throughout the hallux MTPJ. No significant degenerative changes were observed. Surgical pathology showed bone and fibroconnective tissue with deposits of negative birefringement needle-shaped crystals consistent with monosodium urate deposition and foreign body histocytic reaction, as well as repair reaction of bone (Figures 5A, 5B).

Postoperatively, the patient was again placed in a forefoot-offloading wedge sandal for 6 weeks, followed by progression of activity as dictated by his symptoms. He was also evaluated by a rheumatologist and started on medical treatment for gout, with complete resolution of his bilateral hallux pain. He has been able to return to his previous employment.

Discussion

The sesamoid bones are an important component of the hallux MTPJ complex, giving a mechanical advantage to the flexor hallucis brevis tendons in plantar flexion of the hallux.⁵ Many pathologic conditions have been well described in the literature, including fracture, sesamoiditis, nonunion, avascular necrosis, and plantar keratosis. There is also a 10% incidence of bipartite sesamoids, most commonly isolated to the medial sesamoid, with up to 25% of patients presenting with bilateral bipartite sesamoids.⁵ Neoplastic processes of the sesamoid are rare, with a paucity of reports in the literature.^6,7  Gout is a condition in which hyperuricemia, due to an imbalance in uric acid production and excretion, leads to deposition of monosodium urate crystals in joints, bones, and soft tissues, causing an inflammatory reaction. Risk factors for gout are male sex, advanced age, and ethnicity, as well as obesity, high protein diet, alcohol use, hypertension, and certain medications. Precipitation of acute attacks has been associated with acute trauma, and the first MTPJ is the most common location for an acute attack.⁸

Isolated sesamoid lesions are rare, with few isolated case reports in the literature. Benign and malignant lesions appear most often in the metatarsals, with the calcaneus being the second most commonly afflicted site.⁹ The typical differential diagnosis for isolated lytic bone lesions includes fibrous dysplasia, osteoblastoma, giant cell tumor, metastatic lesion, multiple myeloma, aneurysmal bone cyst, chondroblastoma, brown tumor, infection, eosinophilic granuloma, enchondroma, and bone cyst, with no reports in the literature to our knowledge of these entities presenting in the hallux MTPJ sesamoid. In contrast, gout typically begins with normal radiographic findings, and later leads to erosive, “punched out” lesions on either side of the MTPJ.²

Hyperuricemia is an essential part of the pathophysiology of gout, but not all patients with an acute gouty attack have elevated uric acid levels and, in contrast, may actually have normal or low levels in 12% to 43% of cases.⁸ The most accurate time frame for assessment of serum uric acid levels is 2 weeks or more after subsidence of an acute event.⁸ The normal uric acid levels seen in our patient were most likely due to the fact that the workup was undertaken during an acute attack. The difficulty with establishing the diagnosis was compounded by bilateral involvement, history of trauma, negative joint aspiration, and atypical radiographic findings. A number of reports have described patients with tophus deposits prior to or in the absence of gouty arthritis or a gouty attack.¹⁰ Risk factors for this presentation include female sex, the predominant or exclusive involvement of fingers, chronic kidney disease, and treatment with a diuretic or anti-inflammatory drug.¹⁰

Conclusion

Our case report illustrates the difficulty in diagnosing an acute gouty attack in a patient with a history of trauma and atypical radiographic findings. The hallux MTPJ is the most common location of acute gouty attacks, but the medial sesamoid as an isolated location is a rare site of presentation. The combination of pain isolated to palpation of the sesamoid and radiographs that showed an aggressive and rapidly expansile lesion of the medial sesamoid raised concerns about a neoplastic lesion. Practitioners should consider acute gout in patients with sesamoid pain and with radiographs showing an expansile sesamoid lesion.

SAN FRANCISCO – Despite the shorter course of care, dose-dense adjuvant chemotherapy for breast cancer may be considerably more costly than standard-dose chemotherapy, authors of a small study caution.

Neil Osterweil/Frontline Medical News

Among patients treated with four cycles of doxorubicin and cyclophosphamide (the AC regimen), the total cost for those treated with one cycle every 2 weeks (dose-dense schedule) was 77% higher than for patients treated once every 3 weeks, reported Helen O’Donovan, a medical student from Bon Secours Hospital and University College Cork, Ireland, and her associates.

The difference in cost was largely accounted for by the necessity for neutropenia prophylaxis with granulocytic colony stimulating factor (GCSF) among patients who received the dose-dense schedule, Ms. O’Donovan said in an interview at the 2015 ASCO Breast Cancer Symposium.

The mean cost of four doses of GCSF at her center was € 4,176 ($4,703). In the United States, a single syringe (one dose) of the long-acting GCSF pegfilgrastim (Neulasta) costs approximately $5,000 at retail pharmacies.

“We wanted to see whether GCSF in the long run might be cheaper if it could reduce admissions. It turns out that it wasn’t,” said Ms. O’Donovan.

To determine this, the investigators conducted a retrospective study comparing costs for patients treated with dose-dense chemotherapy with those treated once every 3 weeks for the same number of cycles. Because the hospital’s standard of care for several years has been the dose-dense regimen, the researchers were able to identify only 13 patients who had received the 3-week regimen. They matched these patients by age and year of diagnosis to 13 controls treated with dose-dense therapy.

All patients had early-stage breast cancer with no evidence of metastases and all were treated with AC-based chemotherapy with or without a taxane.

In all, six patients in the dose-dense group and five in the 3-week group required hospitalization for complications during chemotherapy. The mean duration of hospitalization was similar, at 4.7 and 4.6 days, respectively.

All patients in the dose-dense group received GCSF, compared with seven patients in the 3-week group. As noted, the mean costs for GCSF among patients with dose-dense chemotherapy were € 4,176 ($4,703), compared with € 1,900 ($2,139) for patients treated in the longer protocol (P = .0005).

Although the mean costs of hospitalization were not significantly different between the groups, adding in the cost of GCSF boosted the total costs to €6,163 ($6,937) vs. €3,486 ($3,923), and this difference was significant (P = .048).

Despite the GCSF prophylaxis and 100% compliance, febrile neutropenia was the most common reason for hospitalization in each group, with two patients in the dose-dense requiring hospitalization for 3 and 9 days, and three patients in the 3-week group needing admission, one for 4 days, and two for 8 days.

The authors acknowledged that the sample size was small, and that there may have been selection bias in the assignment of patients to the 3-week group.

SAN FRANCISCO – Despite the shorter course of care, dose-dense adjuvant chemotherapy for breast cancer may be considerably more costly than standard-dose chemotherapy, authors of a small study caution.

Neil Osterweil/Frontline Medical News

Among patients treated with four cycles of doxorubicin and cyclophosphamide (the AC regimen), the total cost for those treated with one cycle every 2 weeks (dose-dense schedule) was 77% higher than for patients treated once every 3 weeks, reported Helen O’Donovan, a medical student from Bon Secours Hospital and University College Cork, Ireland, and her associates.

The difference in cost was largely accounted for by the necessity for neutropenia prophylaxis with granulocytic colony stimulating factor (GCSF) among patients who received the dose-dense schedule, Ms. O’Donovan said in an interview at the 2015 ASCO Breast Cancer Symposium.

The mean cost of four doses of GCSF at her center was € 4,176 ($4,703). In the United States, a single syringe (one dose) of the long-acting GCSF pegfilgrastim (Neulasta) costs approximately $5,000 at retail pharmacies.

“We wanted to see whether GCSF in the long run might be cheaper if it could reduce admissions. It turns out that it wasn’t,” said Ms. O’Donovan.

To determine this, the investigators conducted a retrospective study comparing costs for patients treated with dose-dense chemotherapy with those treated once every 3 weeks for the same number of cycles. Because the hospital’s standard of care for several years has been the dose-dense regimen, the researchers were able to identify only 13 patients who had received the 3-week regimen. They matched these patients by age and year of diagnosis to 13 controls treated with dose-dense therapy.

All patients had early-stage breast cancer with no evidence of metastases and all were treated with AC-based chemotherapy with or without a taxane.

In all, six patients in the dose-dense group and five in the 3-week group required hospitalization for complications during chemotherapy. The mean duration of hospitalization was similar, at 4.7 and 4.6 days, respectively.

All patients in the dose-dense group received GCSF, compared with seven patients in the 3-week group. As noted, the mean costs for GCSF among patients with dose-dense chemotherapy were € 4,176 ($4,703), compared with € 1,900 ($2,139) for patients treated in the longer protocol (P = .0005).

Although the mean costs of hospitalization were not significantly different between the groups, adding in the cost of GCSF boosted the total costs to €6,163 ($6,937) vs. €3,486 ($3,923), and this difference was significant (P = .048).

Despite the GCSF prophylaxis and 100% compliance, febrile neutropenia was the most common reason for hospitalization in each group, with two patients in the dose-dense requiring hospitalization for 3 and 9 days, and three patients in the 3-week group needing admission, one for 4 days, and two for 8 days.

The authors acknowledged that the sample size was small, and that there may have been selection bias in the assignment of patients to the 3-week group.

SAN FRANCISCO – Despite the shorter course of care, dose-dense adjuvant chemotherapy for breast cancer may be considerably more costly than standard-dose chemotherapy, authors of a small study caution.

Neil Osterweil/Frontline Medical News

Among patients treated with four cycles of doxorubicin and cyclophosphamide (the AC regimen), the total cost for those treated with one cycle every 2 weeks (dose-dense schedule) was 77% higher than for patients treated once every 3 weeks, reported Helen O’Donovan, a medical student from Bon Secours Hospital and University College Cork, Ireland, and her associates.

The difference in cost was largely accounted for by the necessity for neutropenia prophylaxis with granulocytic colony stimulating factor (GCSF) among patients who received the dose-dense schedule, Ms. O’Donovan said in an interview at the 2015 ASCO Breast Cancer Symposium.

The mean cost of four doses of GCSF at her center was € 4,176 ($4,703). In the United States, a single syringe (one dose) of the long-acting GCSF pegfilgrastim (Neulasta) costs approximately $5,000 at retail pharmacies.

“We wanted to see whether GCSF in the long run might be cheaper if it could reduce admissions. It turns out that it wasn’t,” said Ms. O’Donovan.

To determine this, the investigators conducted a retrospective study comparing costs for patients treated with dose-dense chemotherapy with those treated once every 3 weeks for the same number of cycles. Because the hospital’s standard of care for several years has been the dose-dense regimen, the researchers were able to identify only 13 patients who had received the 3-week regimen. They matched these patients by age and year of diagnosis to 13 controls treated with dose-dense therapy.

All patients had early-stage breast cancer with no evidence of metastases and all were treated with AC-based chemotherapy with or without a taxane.

In all, six patients in the dose-dense group and five in the 3-week group required hospitalization for complications during chemotherapy. The mean duration of hospitalization was similar, at 4.7 and 4.6 days, respectively.

All patients in the dose-dense group received GCSF, compared with seven patients in the 3-week group. As noted, the mean costs for GCSF among patients with dose-dense chemotherapy were € 4,176 ($4,703), compared with € 1,900 ($2,139) for patients treated in the longer protocol (P = .0005).

Although the mean costs of hospitalization were not significantly different between the groups, adding in the cost of GCSF boosted the total costs to €6,163 ($6,937) vs. €3,486 ($3,923), and this difference was significant (P = .048).

Despite the GCSF prophylaxis and 100% compliance, febrile neutropenia was the most common reason for hospitalization in each group, with two patients in the dose-dense requiring hospitalization for 3 and 9 days, and three patients in the 3-week group needing admission, one for 4 days, and two for 8 days.

The authors acknowledged that the sample size was small, and that there may have been selection bias in the assignment of patients to the 3-week group.

The literature includes only 2 case reports of bony avulsion fracture of the origin of the brachioradialis^1,2 and, up until now, no case reports of isolated avulsion of the extensor carpi radialis longus and brachioradialis origins from the lateral epicondyle and lateral supracondylar ridge. In this article, we report the case of a 31-year-old man who sustained this injury during a fall onto his outstretched right hand, and we present our surgical repair technique. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 31-year-old right hand–dominant garbage truck worker sustained a right elbow injury and presented 2 months later. He described slipping and falling onto his outstretched right hand while doing his work. He could not describe the exact mechanism or action or position of the arm at time of impact but thought he tried to catch himself on the truck during the fall. At time of injury, he had immediate pain and swelling to the lateral aspect of the right elbow and difficulty when he attempted lifting. He denied antecedent elbow symptoms before the injury. After evaluation by an outside occupational medicine physician, he engaged in treatment consisting of activity modification and physical therapy, including range-of-motion (ROM) exercises and iontophoresis. This course of management failed to completely relieve his symptoms, and he was unable to return to work.

The patient presented to our institution 9 weeks after injury with complaints of pain along the lateral aspect of the elbow, painful flexion-extension, and continued swelling. The pain had been unrelieved with anti-inflammatory medications and opioids. Physical examination revealed tenderness and swelling along the lateral epicondyle and extensor mass of the right elbow. The patient had tenderness, marked weakness, and a palpable soft-tissue defect at the origin of the extensor mass with resisted extension of the wrist (Figure 1). Elbow ROM was from 20° to 120° of flexion, 60° of pronation, and 60° of supination. No varus or valgus instability was present about the elbow. Radiographs did not show any fracture or dislocation. Magnetic resonance imaging (MRI) did not definitively show extensor tendon avulsion but did identify signal change of the common extensor tendon (Figures 2A, 2B). Advanced imaging was inconclusive, but, given the patient’s history and physical examination findings, he was diagnosed with an avulsion injury of the origin of the extensor mass of the right elbow.

The patient was brought to the operating room, administered general anesthesia, and placed supine on the operating table with a tourniquet on the upper arm. A lateral 4.5-cm incision was made centered over the lateral epicondyle. The origin of the extensor mass was exposed, and isolated avulsions of the extensor carpi radialis longus and the brachioradialis were identified (Figures 3, 4). Underlying the avulsed sleeve of tissue, the origin of the extensor carpi radialis brevis was found intact. The lateral supracondylar ridge and the lateral epicondyle of the humerus were débrided, and 3 transosseous holes were drilled (using a 2.3-mm bit) through the lateral epicondyle. Four Mason-Allen sutures were placed into the tendon of the common extensor origin using No. 2 braided polyester suture (Ethibond Excel, Ethicon) (Figure 5). The tendon was reduced down to the native footprint, and the sutures were passed through the drill holes and tied down securely (Figure 6). The skin was then closed using layered 4-0 absorbable monofilament suture (Monocryl, Ethicon). The patient was placed in a posterior mold plaster splint with 90° of elbow flexion and with the wrist in 30° of extension.

On postoperative day 3, the patient was seen for a wound check and was placed in a long-arm fiberglass cast (90° of elbow flexion, forearm in neutral, 25° of wrist extension) for immobilization. One week after surgery, he was transitioned to a removable thermoplastic splint, and physical therapy for ROM was initiated. He was allowed therapist-guided active extension of the elbow and flexion of the wrist but was restricted to passive flexion of the elbow and extension of the wrist. Seven weeks after surgery, passive ROM about the elbow was measured, and he was found to have 120° of flexion, 0° extension, 80° pronation, and 80° supination. At 12 weeks, the physical therapy regimen was advanced to include muscle strengthening and active wrist extension and elbow flexion. At 16 weeks, the wrist extensors demonstrated 5/5 strength (Medical Research Council grading system), and the patient was cleared for full activity and weight-bearing without restriction. He returned to work pain-free and without restrictions 18 weeks after surgery. At 2-year follow-up, he had a Mayo performance elbow score of 100 and an Oxford elbow score of 48.^3,4 He had full active ROM, full strength, and no subjective pain and was back doing heavy lifting at his job.

Discussion

The brachioradialis, extensor carpi radialis longus, and extensor carpi radialis brevis originate from the anterolateral aspect of the lateral column of the distal humeral metaphysis and form the dorsal mobile wad. The origin of the brachioradialis is about 7 cm in length and begins about 10 to 11 cm above the elbow.⁵ The origin and insertions of the mobile wad, specifically the brachioradialis, provide a tremendous mechanical advantage with respect to elbow flexion against resistance, particularly with the forearm in the pronated and semipronated positions.⁶ With the elbow in 30° of flexion, a force 3 times the body weight can be encountered during strenuous lifting.^6,7 We hypothesized these large forces likely led to this injury pattern in the patient we have described.

The literature includes 2 case reports of avulsion fracture of the brachioradialis muscle from its origin on the lateral supracondylar humeral ridge.^1,2 To our knowledge, however, there have been no reports of pure avulsion. In our patient’s case, there was no bony fracture, but rather avulsion of the extensor carpi radialis longus and brachioradialis at their origin, with the underlying fibers of the extensor carpi radialis brevis remaining in continuity. Because of the rarity of this injury pattern, there was a significant delay in diagnosis. On initial presentation, the differential diagnosis for lateral elbow pain and tenderness included occult fracture, intracapsular plica, osteochondritis dissecans lesion, radial tunnel syndrome, lateral or posterolateral instability, and lateral epicondylitis. Given the absence of antecedent elbow symptoms before the injury, the dynamic soft-tissue asymmetry of the mobile wad with wrist extension, and the palpable soft-tissue defect, we thought the presentation was inconsistent with a simple inflammatory or overuse syndrome, such as lateral epicondylitis. In addition, the physical examination findings were inconsistent with radial tunnel syndrome or disruption of the lateral collateral ligament complex. Elbow MRI did not show an occult fracture, plica, or osteochondritis dissecans lesion but did reveal joint effusion and signal change in the common extensor tendon origin. Interestingly, MRI did not definitively show a tear of the mobile wad. This may be explained by the fact that the fibers of the underlying extensor carpi radialis brevis remained intact. Also potentially involved are the static nature of MRI and potentially suboptimal sequencing and axis of acquisition resulting from the relative infrequency of imaging this joint at certain health care institutions. Our case demonstrates the limitations of MRI in this setting and highlights the need for a detailed history and thorough physical examination for diagnosis.

Funk and colleagues⁸ used electromyography (EMG) to study the activity of the elbow musculature in uninjured subjects. EMG data were obtained with the elbow joint subjected to resisted flexion, extension, abduction, and adduction. During resisted elbow flexion, there was an increasing amount of activity in the extensor carpi radialis with larger angles of elbow flexion. In addition, the brachioradialis demonstrated the most muscle activity of any of the elbow flexors with 90° or more of elbow flexion and forearm pronation, as opposed to other positions in which the brachialis was the primary flexor. For this reason, we hypothesized that our patient’s forearm was pronated and his elbow flexed to 90° or more when he braced for impact. The ensuing injury resulted from a violent eccentric contraction that caused extensive rupture of the lateral elbow musculature from its broad origin. With the forearm in supination or neutral position, we would have expected a possible injury to the distal biceps as opposed to the brachioradialis and extensor carpi radialis.

In our patient, this injury caused much functional disability, especially with elbow flexion and wrist extension. We hypothesized that, for the muscles to function properly, anatomical restoration would have to be achieved at their known footprint to maintain their mechanical advantage. Therefore, surgical intervention was indicated in our patient, an active laborer. Given the absence of an osseous fracture fragment in this injury pattern, healing must occur at the bone–tendon interface. As tendinous healing is more tenuous and protracted than osseous healing, we preferred transosseous repair. We believed that better tendon-to-bone healing would be possible with drilled osseous tunnels rather than with suture anchors. New studies describing alternative successful methods of treatment would add to our limited body of knowledge regarding this rare injury.

Conclusion

This is the first report of avulsion of the extensor carpi radialis longus and brachioradialis from their origins. Given the biomechanics and anatomy of the dorsal mobile wad, we posit that our patient’s injury occurred when he fell onto his outstretched hand secondary to overwhelming eccentric muscle contracture at time of impact. This injury caused significant upper extremity dysfunction, and surgical intervention was required.

The literature includes only 2 case reports of bony avulsion fracture of the origin of the brachioradialis^1,2 and, up until now, no case reports of isolated avulsion of the extensor carpi radialis longus and brachioradialis origins from the lateral epicondyle and lateral supracondylar ridge. In this article, we report the case of a 31-year-old man who sustained this injury during a fall onto his outstretched right hand, and we present our surgical repair technique. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 31-year-old right hand–dominant garbage truck worker sustained a right elbow injury and presented 2 months later. He described slipping and falling onto his outstretched right hand while doing his work. He could not describe the exact mechanism or action or position of the arm at time of impact but thought he tried to catch himself on the truck during the fall. At time of injury, he had immediate pain and swelling to the lateral aspect of the right elbow and difficulty when he attempted lifting. He denied antecedent elbow symptoms before the injury. After evaluation by an outside occupational medicine physician, he engaged in treatment consisting of activity modification and physical therapy, including range-of-motion (ROM) exercises and iontophoresis. This course of management failed to completely relieve his symptoms, and he was unable to return to work.

The patient presented to our institution 9 weeks after injury with complaints of pain along the lateral aspect of the elbow, painful flexion-extension, and continued swelling. The pain had been unrelieved with anti-inflammatory medications and opioids. Physical examination revealed tenderness and swelling along the lateral epicondyle and extensor mass of the right elbow. The patient had tenderness, marked weakness, and a palpable soft-tissue defect at the origin of the extensor mass with resisted extension of the wrist (Figure 1). Elbow ROM was from 20° to 120° of flexion, 60° of pronation, and 60° of supination. No varus or valgus instability was present about the elbow. Radiographs did not show any fracture or dislocation. Magnetic resonance imaging (MRI) did not definitively show extensor tendon avulsion but did identify signal change of the common extensor tendon (Figures 2A, 2B). Advanced imaging was inconclusive, but, given the patient’s history and physical examination findings, he was diagnosed with an avulsion injury of the origin of the extensor mass of the right elbow.

The patient was brought to the operating room, administered general anesthesia, and placed supine on the operating table with a tourniquet on the upper arm. A lateral 4.5-cm incision was made centered over the lateral epicondyle. The origin of the extensor mass was exposed, and isolated avulsions of the extensor carpi radialis longus and the brachioradialis were identified (Figures 3, 4). Underlying the avulsed sleeve of tissue, the origin of the extensor carpi radialis brevis was found intact. The lateral supracondylar ridge and the lateral epicondyle of the humerus were débrided, and 3 transosseous holes were drilled (using a 2.3-mm bit) through the lateral epicondyle. Four Mason-Allen sutures were placed into the tendon of the common extensor origin using No. 2 braided polyester suture (Ethibond Excel, Ethicon) (Figure 5). The tendon was reduced down to the native footprint, and the sutures were passed through the drill holes and tied down securely (Figure 6). The skin was then closed using layered 4-0 absorbable monofilament suture (Monocryl, Ethicon). The patient was placed in a posterior mold plaster splint with 90° of elbow flexion and with the wrist in 30° of extension.

On postoperative day 3, the patient was seen for a wound check and was placed in a long-arm fiberglass cast (90° of elbow flexion, forearm in neutral, 25° of wrist extension) for immobilization. One week after surgery, he was transitioned to a removable thermoplastic splint, and physical therapy for ROM was initiated. He was allowed therapist-guided active extension of the elbow and flexion of the wrist but was restricted to passive flexion of the elbow and extension of the wrist. Seven weeks after surgery, passive ROM about the elbow was measured, and he was found to have 120° of flexion, 0° extension, 80° pronation, and 80° supination. At 12 weeks, the physical therapy regimen was advanced to include muscle strengthening and active wrist extension and elbow flexion. At 16 weeks, the wrist extensors demonstrated 5/5 strength (Medical Research Council grading system), and the patient was cleared for full activity and weight-bearing without restriction. He returned to work pain-free and without restrictions 18 weeks after surgery. At 2-year follow-up, he had a Mayo performance elbow score of 100 and an Oxford elbow score of 48.^3,4 He had full active ROM, full strength, and no subjective pain and was back doing heavy lifting at his job.

Discussion

The brachioradialis, extensor carpi radialis longus, and extensor carpi radialis brevis originate from the anterolateral aspect of the lateral column of the distal humeral metaphysis and form the dorsal mobile wad. The origin of the brachioradialis is about 7 cm in length and begins about 10 to 11 cm above the elbow.⁵ The origin and insertions of the mobile wad, specifically the brachioradialis, provide a tremendous mechanical advantage with respect to elbow flexion against resistance, particularly with the forearm in the pronated and semipronated positions.⁶ With the elbow in 30° of flexion, a force 3 times the body weight can be encountered during strenuous lifting.^6,7 We hypothesized these large forces likely led to this injury pattern in the patient we have described.

The literature includes 2 case reports of avulsion fracture of the brachioradialis muscle from its origin on the lateral supracondylar humeral ridge.^1,2 To our knowledge, however, there have been no reports of pure avulsion. In our patient’s case, there was no bony fracture, but rather avulsion of the extensor carpi radialis longus and brachioradialis at their origin, with the underlying fibers of the extensor carpi radialis brevis remaining in continuity. Because of the rarity of this injury pattern, there was a significant delay in diagnosis. On initial presentation, the differential diagnosis for lateral elbow pain and tenderness included occult fracture, intracapsular plica, osteochondritis dissecans lesion, radial tunnel syndrome, lateral or posterolateral instability, and lateral epicondylitis. Given the absence of antecedent elbow symptoms before the injury, the dynamic soft-tissue asymmetry of the mobile wad with wrist extension, and the palpable soft-tissue defect, we thought the presentation was inconsistent with a simple inflammatory or overuse syndrome, such as lateral epicondylitis. In addition, the physical examination findings were inconsistent with radial tunnel syndrome or disruption of the lateral collateral ligament complex. Elbow MRI did not show an occult fracture, plica, or osteochondritis dissecans lesion but did reveal joint effusion and signal change in the common extensor tendon origin. Interestingly, MRI did not definitively show a tear of the mobile wad. This may be explained by the fact that the fibers of the underlying extensor carpi radialis brevis remained intact. Also potentially involved are the static nature of MRI and potentially suboptimal sequencing and axis of acquisition resulting from the relative infrequency of imaging this joint at certain health care institutions. Our case demonstrates the limitations of MRI in this setting and highlights the need for a detailed history and thorough physical examination for diagnosis.

Funk and colleagues⁸ used electromyography (EMG) to study the activity of the elbow musculature in uninjured subjects. EMG data were obtained with the elbow joint subjected to resisted flexion, extension, abduction, and adduction. During resisted elbow flexion, there was an increasing amount of activity in the extensor carpi radialis with larger angles of elbow flexion. In addition, the brachioradialis demonstrated the most muscle activity of any of the elbow flexors with 90° or more of elbow flexion and forearm pronation, as opposed to other positions in which the brachialis was the primary flexor. For this reason, we hypothesized that our patient’s forearm was pronated and his elbow flexed to 90° or more when he braced for impact. The ensuing injury resulted from a violent eccentric contraction that caused extensive rupture of the lateral elbow musculature from its broad origin. With the forearm in supination or neutral position, we would have expected a possible injury to the distal biceps as opposed to the brachioradialis and extensor carpi radialis.

In our patient, this injury caused much functional disability, especially with elbow flexion and wrist extension. We hypothesized that, for the muscles to function properly, anatomical restoration would have to be achieved at their known footprint to maintain their mechanical advantage. Therefore, surgical intervention was indicated in our patient, an active laborer. Given the absence of an osseous fracture fragment in this injury pattern, healing must occur at the bone–tendon interface. As tendinous healing is more tenuous and protracted than osseous healing, we preferred transosseous repair. We believed that better tendon-to-bone healing would be possible with drilled osseous tunnels rather than with suture anchors. New studies describing alternative successful methods of treatment would add to our limited body of knowledge regarding this rare injury.

Conclusion

This is the first report of avulsion of the extensor carpi radialis longus and brachioradialis from their origins. Given the biomechanics and anatomy of the dorsal mobile wad, we posit that our patient’s injury occurred when he fell onto his outstretched hand secondary to overwhelming eccentric muscle contracture at time of impact. This injury caused significant upper extremity dysfunction, and surgical intervention was required.

The literature includes only 2 case reports of bony avulsion fracture of the origin of the brachioradialis^1,2 and, up until now, no case reports of isolated avulsion of the extensor carpi radialis longus and brachioradialis origins from the lateral epicondyle and lateral supracondylar ridge. In this article, we report the case of a 31-year-old man who sustained this injury during a fall onto his outstretched right hand, and we present our surgical repair technique. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 31-year-old right hand–dominant garbage truck worker sustained a right elbow injury and presented 2 months later. He described slipping and falling onto his outstretched right hand while doing his work. He could not describe the exact mechanism or action or position of the arm at time of impact but thought he tried to catch himself on the truck during the fall. At time of injury, he had immediate pain and swelling to the lateral aspect of the right elbow and difficulty when he attempted lifting. He denied antecedent elbow symptoms before the injury. After evaluation by an outside occupational medicine physician, he engaged in treatment consisting of activity modification and physical therapy, including range-of-motion (ROM) exercises and iontophoresis. This course of management failed to completely relieve his symptoms, and he was unable to return to work.

The patient presented to our institution 9 weeks after injury with complaints of pain along the lateral aspect of the elbow, painful flexion-extension, and continued swelling. The pain had been unrelieved with anti-inflammatory medications and opioids. Physical examination revealed tenderness and swelling along the lateral epicondyle and extensor mass of the right elbow. The patient had tenderness, marked weakness, and a palpable soft-tissue defect at the origin of the extensor mass with resisted extension of the wrist (Figure 1). Elbow ROM was from 20° to 120° of flexion, 60° of pronation, and 60° of supination. No varus or valgus instability was present about the elbow. Radiographs did not show any fracture or dislocation. Magnetic resonance imaging (MRI) did not definitively show extensor tendon avulsion but did identify signal change of the common extensor tendon (Figures 2A, 2B). Advanced imaging was inconclusive, but, given the patient’s history and physical examination findings, he was diagnosed with an avulsion injury of the origin of the extensor mass of the right elbow.

The patient was brought to the operating room, administered general anesthesia, and placed supine on the operating table with a tourniquet on the upper arm. A lateral 4.5-cm incision was made centered over the lateral epicondyle. The origin of the extensor mass was exposed, and isolated avulsions of the extensor carpi radialis longus and the brachioradialis were identified (Figures 3, 4). Underlying the avulsed sleeve of tissue, the origin of the extensor carpi radialis brevis was found intact. The lateral supracondylar ridge and the lateral epicondyle of the humerus were débrided, and 3 transosseous holes were drilled (using a 2.3-mm bit) through the lateral epicondyle. Four Mason-Allen sutures were placed into the tendon of the common extensor origin using No. 2 braided polyester suture (Ethibond Excel, Ethicon) (Figure 5). The tendon was reduced down to the native footprint, and the sutures were passed through the drill holes and tied down securely (Figure 6). The skin was then closed using layered 4-0 absorbable monofilament suture (Monocryl, Ethicon). The patient was placed in a posterior mold plaster splint with 90° of elbow flexion and with the wrist in 30° of extension.

On postoperative day 3, the patient was seen for a wound check and was placed in a long-arm fiberglass cast (90° of elbow flexion, forearm in neutral, 25° of wrist extension) for immobilization. One week after surgery, he was transitioned to a removable thermoplastic splint, and physical therapy for ROM was initiated. He was allowed therapist-guided active extension of the elbow and flexion of the wrist but was restricted to passive flexion of the elbow and extension of the wrist. Seven weeks after surgery, passive ROM about the elbow was measured, and he was found to have 120° of flexion, 0° extension, 80° pronation, and 80° supination. At 12 weeks, the physical therapy regimen was advanced to include muscle strengthening and active wrist extension and elbow flexion. At 16 weeks, the wrist extensors demonstrated 5/5 strength (Medical Research Council grading system), and the patient was cleared for full activity and weight-bearing without restriction. He returned to work pain-free and without restrictions 18 weeks after surgery. At 2-year follow-up, he had a Mayo performance elbow score of 100 and an Oxford elbow score of 48.^3,4 He had full active ROM, full strength, and no subjective pain and was back doing heavy lifting at his job.

Discussion

The brachioradialis, extensor carpi radialis longus, and extensor carpi radialis brevis originate from the anterolateral aspect of the lateral column of the distal humeral metaphysis and form the dorsal mobile wad. The origin of the brachioradialis is about 7 cm in length and begins about 10 to 11 cm above the elbow.⁵ The origin and insertions of the mobile wad, specifically the brachioradialis, provide a tremendous mechanical advantage with respect to elbow flexion against resistance, particularly with the forearm in the pronated and semipronated positions.⁶ With the elbow in 30° of flexion, a force 3 times the body weight can be encountered during strenuous lifting.^6,7 We hypothesized these large forces likely led to this injury pattern in the patient we have described.

The literature includes 2 case reports of avulsion fracture of the brachioradialis muscle from its origin on the lateral supracondylar humeral ridge.^1,2 To our knowledge, however, there have been no reports of pure avulsion. In our patient’s case, there was no bony fracture, but rather avulsion of the extensor carpi radialis longus and brachioradialis at their origin, with the underlying fibers of the extensor carpi radialis brevis remaining in continuity. Because of the rarity of this injury pattern, there was a significant delay in diagnosis. On initial presentation, the differential diagnosis for lateral elbow pain and tenderness included occult fracture, intracapsular plica, osteochondritis dissecans lesion, radial tunnel syndrome, lateral or posterolateral instability, and lateral epicondylitis. Given the absence of antecedent elbow symptoms before the injury, the dynamic soft-tissue asymmetry of the mobile wad with wrist extension, and the palpable soft-tissue defect, we thought the presentation was inconsistent with a simple inflammatory or overuse syndrome, such as lateral epicondylitis. In addition, the physical examination findings were inconsistent with radial tunnel syndrome or disruption of the lateral collateral ligament complex. Elbow MRI did not show an occult fracture, plica, or osteochondritis dissecans lesion but did reveal joint effusion and signal change in the common extensor tendon origin. Interestingly, MRI did not definitively show a tear of the mobile wad. This may be explained by the fact that the fibers of the underlying extensor carpi radialis brevis remained intact. Also potentially involved are the static nature of MRI and potentially suboptimal sequencing and axis of acquisition resulting from the relative infrequency of imaging this joint at certain health care institutions. Our case demonstrates the limitations of MRI in this setting and highlights the need for a detailed history and thorough physical examination for diagnosis.

Funk and colleagues⁸ used electromyography (EMG) to study the activity of the elbow musculature in uninjured subjects. EMG data were obtained with the elbow joint subjected to resisted flexion, extension, abduction, and adduction. During resisted elbow flexion, there was an increasing amount of activity in the extensor carpi radialis with larger angles of elbow flexion. In addition, the brachioradialis demonstrated the most muscle activity of any of the elbow flexors with 90° or more of elbow flexion and forearm pronation, as opposed to other positions in which the brachialis was the primary flexor. For this reason, we hypothesized that our patient’s forearm was pronated and his elbow flexed to 90° or more when he braced for impact. The ensuing injury resulted from a violent eccentric contraction that caused extensive rupture of the lateral elbow musculature from its broad origin. With the forearm in supination or neutral position, we would have expected a possible injury to the distal biceps as opposed to the brachioradialis and extensor carpi radialis.

In our patient, this injury caused much functional disability, especially with elbow flexion and wrist extension. We hypothesized that, for the muscles to function properly, anatomical restoration would have to be achieved at their known footprint to maintain their mechanical advantage. Therefore, surgical intervention was indicated in our patient, an active laborer. Given the absence of an osseous fracture fragment in this injury pattern, healing must occur at the bone–tendon interface. As tendinous healing is more tenuous and protracted than osseous healing, we preferred transosseous repair. We believed that better tendon-to-bone healing would be possible with drilled osseous tunnels rather than with suture anchors. New studies describing alternative successful methods of treatment would add to our limited body of knowledge regarding this rare injury.

Conclusion

This is the first report of avulsion of the extensor carpi radialis longus and brachioradialis from their origins. Given the biomechanics and anatomy of the dorsal mobile wad, we posit that our patient’s injury occurred when he fell onto his outstretched hand secondary to overwhelming eccentric muscle contracture at time of impact. This injury caused significant upper extremity dysfunction, and surgical intervention was required.

When the recent photo of a drowned Syrian toddler woke up the world to the Syrian refugee crisis more viscerally than ever before, multiple nations announced plans to take in more refugees. According to the U.S. State Department, approximately 10,000 Syrian refugees are already in processing, eventually headed to cities that may include Atlanta, San Diego, Houston, Dallas, Chicago, Boston, Boise, Nashville, Tucson, Buffalo, and Erie.

To pediatricians, that boy on the beach represents a child who might have ended up in their practice with diverse, complex needs greatly exceeding the typical needs of a U.S. child coming in for a well-child visit.

Rachel Unkovic/International Rescue Committee/CC BY 2.0

“Families are coming from a country that has been ravaged by civil war for over 4 years,” Dr. Susan S. Reines, a pediatrician with the Southeast Kaiser Permanente Medical Group and lead pediatrician for the Refugee Pediatric Clinic at DeKalb County Board of Health in Decatur, Georgia, said in an interview. “Cities have been destroyed, and millions have been forced to leave their homes and are displaced either within Syria or in neighboring countries.”

About a third of the more than 58,000 refugees admitted to the United States in 2012 were under 18 years old. Although the majority that year hailed from Bhutan, Burma, and Iraq, an increasing number of children have been coming from war-torn Syria since June 2014. The proposed ceiling for all refugees in the United States 2015 fiscal year is 70,000, a “significant number” of whom will be children with their families, according to a State Department spokesperson.

These children come with “unique medical, developmental and psychosocial needs,” noted Dr. Thomas J. Seery and fellow authors of “Caring for Refugee Children,” a Pediatrics in Review article recommended by Dr. Reines for pediatricians who may be caring for refugee children.

“The health care infrastructure of Syria is broken and many hospitals have closed, medications are difficult to obtain, and numerous doctors have fled the violence,” Dr. Reines said. She compared the anticipated health care problems of these children with those seen among Iraqi refugee children:

• Undernutrition and micronutrient deficiencies.

• Infectious diseases such as vaccine-preventable diseases like measles, but also typhoid, tuberculosis, and parasitic infections.

• Dental disease.

• Surgically amenable congenital anomalies such as congenital heart disease, myelomeningocele, and others that have not been repaired.

• Neurologic problems, such as cerebral palsy, intellectual disability, and autism.

• Hearing loss.

• Posttraumatic stress disorder (PTSD),depression, and anxiety.

• Trauma such as gunshot wounds, shrapnel injuries, and genital trauma secondary to sexual violence.

• Sequelae from illnesses that previously were easily treated, such as hearing loss and ear complications from otitis media, and rheumatic fever from inadequately treated strep throat.

• Underimmunization.

Various resources listed below, including Dr. Seery’s paper, can help guide providers in assessing and meeting these needs, and navigating paperwork and the U.S. refugee system. These resources also can help practitioners address the mental health concerns these patients and their families may face.

Mental health needs

Even children in the best physical shape will have experienced significant upheaval that could lead to depression, anxiety, and PTSD – conditions more common among refugee children than in the general population, research has shown.

“Mental health conditions will be especially present in these children uprooted from their homes and families, and exposed to the violence of war,” Dr. Francis E. Rushton Jr. of the department of pediatrics at the University of South Carolina, Columbia, and a member of the American Academy of Pediatrics Committee on Community Health Services, said in an interview. Of the four major areas of health care need he described for these children, two relate to mental health: toxic mental stress and fractured families and the lack of nurture.

One challenge pediatricians face, however, is recognizing these conditions despite cultural differences that could obscure them.

“It is not uncommon for teens and adults to deny symptoms of depression, stress, and anxiety in early encounters,” Dr. Reines said. “Many cultures stigmatize psychiatric or mental health problems, and refugees may be reluctant to admit they are having difficulties.”

One way around this obstacle is to ask patients and their parents about sleep, energy level, appetite, weight changes, and thoughts of harming one’s self, she said. Mental stress also manifests as somatic symptoms, such as headaches, stomach aches, and back pain, particularly in teens.

“Infants and toddlers are generally most adaptable as long as parents are coping well, and can provide a buffer for stress with a safe and nurturing environment,” Dr. Reines said. Children of parents with depression or PTSD, or who have lost a parent, may feel abandoned and experience depression or developmental delays.

Although school-age children may have nightmares, show anxiety, and cling to their parents, they usually transition well to their new homes. Adolescents face the biggest difficulties, especially if they have lost a parent, must care for their siblings, or have experienced sexual trauma. “They may have more vivid memories of disturbing events and a greater understanding of what their family has endured,” Dr. Reines said. Further, language and educational deficits can lead to alienation and embarrassment, yet families may rebuff behavioral health referrals.

“In these cases, it’s best to keep communication open, encourage dialogue with family, and try to find an activity or sport the refugee can participate in to improve self-esteem,” Dr. Reines said.

Avoiding cultural confusion

While cultural challenges are obvious – language barriers may necessitate translators or bicultural caseworkers – others may be more subtle. Developmental screening questions that rely on blocks, certain pictures, or other culturally specific bases, for example, may not adequately capture a child’s development.

Dr. Reines stresses a strategy for managing cultural differences that is recommended in Dr. Seery’s article: striving for cultural humility rather than cultural competence.

“It is impossible for U.S. physicians who have never practiced outside of our culture and are not bicultural or bilingual to become truly culturally competent in health care delivery for so many refugee populations,” Dr. Reines said. Instead then, cultural humility emphasizes showing respect, interest, and a willingness to learn from patients, she explained.

Cultural humility is a “lifelong process” that also demands flexibility and “allows the practitioner to release the false sense of security associated with stereotyping,” Dr. Seery and his colleagues wrote.

At the same time, pediatricians are guarding against inadvertent stereotyping; however, they can be aware of some cultural generalities that may apply to their Syrian refugee patients.

“Arab communities stress the importance of family rather than the individual and are often more modest than Westerners,” Dr. Rushton said. Further, “Arab families frequently experience discrimination on the basis of their religion in the United States, and pediatricians should be aware of ongoing traumatization even after arrival in America,” he said.

Teens may become embarrassed with discussions about sex or alcohol because few teens from the Middle East drink or become sexually active before marriage, Dr. Reines added. She noted that a Muslim male may not shake hands with females outside his family – a practice providers should respect – and that important religious holidays such as Ramadan may influence a family’s compliance with a treatment plan.

Perhaps the most important commonality, however, is one universal to most refugee families, regardless of their home country.

“The vast majority of families that we meet show incredible courage and resilience, and caring for their children is their highest priority,” Dr. Reines said. “We can learn a great deal from these families, and caring for their children is a tremendously rewarding experience.”

Other cultural resources:

CDC Refugee Health Guidelines

Bridging Refugee Youth and Children’s Services

“The Middle of Everywhere: Helping Refugees Enter the American Community,” by Mary Pipher (Orlando: Mariner Books, 2003)

“Immigrant Medicine,” a textbook by Patricia Walker, M.D., and Elizabeth Barnett, M.D. (New York, N.Y.: Elsevier, 2007)

“Opening cultural doors: Providing culturally sensitive healthcare to Arab American and American Muslim patients” (Am J Obstet Gynecol. 2005 Oct;193]:1307-11).

ethnoMedCenter for Applied Linguistics

When the recent photo of a drowned Syrian toddler woke up the world to the Syrian refugee crisis more viscerally than ever before, multiple nations announced plans to take in more refugees. According to the U.S. State Department, approximately 10,000 Syrian refugees are already in processing, eventually headed to cities that may include Atlanta, San Diego, Houston, Dallas, Chicago, Boston, Boise, Nashville, Tucson, Buffalo, and Erie.

To pediatricians, that boy on the beach represents a child who might have ended up in their practice with diverse, complex needs greatly exceeding the typical needs of a U.S. child coming in for a well-child visit.

Rachel Unkovic/International Rescue Committee/CC BY 2.0

“Families are coming from a country that has been ravaged by civil war for over 4 years,” Dr. Susan S. Reines, a pediatrician with the Southeast Kaiser Permanente Medical Group and lead pediatrician for the Refugee Pediatric Clinic at DeKalb County Board of Health in Decatur, Georgia, said in an interview. “Cities have been destroyed, and millions have been forced to leave their homes and are displaced either within Syria or in neighboring countries.”

About a third of the more than 58,000 refugees admitted to the United States in 2012 were under 18 years old. Although the majority that year hailed from Bhutan, Burma, and Iraq, an increasing number of children have been coming from war-torn Syria since June 2014. The proposed ceiling for all refugees in the United States 2015 fiscal year is 70,000, a “significant number” of whom will be children with their families, according to a State Department spokesperson.

These children come with “unique medical, developmental and psychosocial needs,” noted Dr. Thomas J. Seery and fellow authors of “Caring for Refugee Children,” a Pediatrics in Review article recommended by Dr. Reines for pediatricians who may be caring for refugee children.

“The health care infrastructure of Syria is broken and many hospitals have closed, medications are difficult to obtain, and numerous doctors have fled the violence,” Dr. Reines said. She compared the anticipated health care problems of these children with those seen among Iraqi refugee children:

• Undernutrition and micronutrient deficiencies.

• Infectious diseases such as vaccine-preventable diseases like measles, but also typhoid, tuberculosis, and parasitic infections.

• Dental disease.

• Surgically amenable congenital anomalies such as congenital heart disease, myelomeningocele, and others that have not been repaired.

• Neurologic problems, such as cerebral palsy, intellectual disability, and autism.

• Hearing loss.

• Posttraumatic stress disorder (PTSD),depression, and anxiety.

• Trauma such as gunshot wounds, shrapnel injuries, and genital trauma secondary to sexual violence.

• Sequelae from illnesses that previously were easily treated, such as hearing loss and ear complications from otitis media, and rheumatic fever from inadequately treated strep throat.

• Underimmunization.

Various resources listed below, including Dr. Seery’s paper, can help guide providers in assessing and meeting these needs, and navigating paperwork and the U.S. refugee system. These resources also can help practitioners address the mental health concerns these patients and their families may face.

Mental health needs

Even children in the best physical shape will have experienced significant upheaval that could lead to depression, anxiety, and PTSD – conditions more common among refugee children than in the general population, research has shown.

“Mental health conditions will be especially present in these children uprooted from their homes and families, and exposed to the violence of war,” Dr. Francis E. Rushton Jr. of the department of pediatrics at the University of South Carolina, Columbia, and a member of the American Academy of Pediatrics Committee on Community Health Services, said in an interview. Of the four major areas of health care need he described for these children, two relate to mental health: toxic mental stress and fractured families and the lack of nurture.

One challenge pediatricians face, however, is recognizing these conditions despite cultural differences that could obscure them.

“It is not uncommon for teens and adults to deny symptoms of depression, stress, and anxiety in early encounters,” Dr. Reines said. “Many cultures stigmatize psychiatric or mental health problems, and refugees may be reluctant to admit they are having difficulties.”

One way around this obstacle is to ask patients and their parents about sleep, energy level, appetite, weight changes, and thoughts of harming one’s self, she said. Mental stress also manifests as somatic symptoms, such as headaches, stomach aches, and back pain, particularly in teens.

“Infants and toddlers are generally most adaptable as long as parents are coping well, and can provide a buffer for stress with a safe and nurturing environment,” Dr. Reines said. Children of parents with depression or PTSD, or who have lost a parent, may feel abandoned and experience depression or developmental delays.

Although school-age children may have nightmares, show anxiety, and cling to their parents, they usually transition well to their new homes. Adolescents face the biggest difficulties, especially if they have lost a parent, must care for their siblings, or have experienced sexual trauma. “They may have more vivid memories of disturbing events and a greater understanding of what their family has endured,” Dr. Reines said. Further, language and educational deficits can lead to alienation and embarrassment, yet families may rebuff behavioral health referrals.

“In these cases, it’s best to keep communication open, encourage dialogue with family, and try to find an activity or sport the refugee can participate in to improve self-esteem,” Dr. Reines said.

Avoiding cultural confusion

While cultural challenges are obvious – language barriers may necessitate translators or bicultural caseworkers – others may be more subtle. Developmental screening questions that rely on blocks, certain pictures, or other culturally specific bases, for example, may not adequately capture a child’s development.

Dr. Reines stresses a strategy for managing cultural differences that is recommended in Dr. Seery’s article: striving for cultural humility rather than cultural competence.

“It is impossible for U.S. physicians who have never practiced outside of our culture and are not bicultural or bilingual to become truly culturally competent in health care delivery for so many refugee populations,” Dr. Reines said. Instead then, cultural humility emphasizes showing respect, interest, and a willingness to learn from patients, she explained.

Cultural humility is a “lifelong process” that also demands flexibility and “allows the practitioner to release the false sense of security associated with stereotyping,” Dr. Seery and his colleagues wrote.

At the same time, pediatricians are guarding against inadvertent stereotyping; however, they can be aware of some cultural generalities that may apply to their Syrian refugee patients.

“Arab communities stress the importance of family rather than the individual and are often more modest than Westerners,” Dr. Rushton said. Further, “Arab families frequently experience discrimination on the basis of their religion in the United States, and pediatricians should be aware of ongoing traumatization even after arrival in America,” he said.

Teens may become embarrassed with discussions about sex or alcohol because few teens from the Middle East drink or become sexually active before marriage, Dr. Reines added. She noted that a Muslim male may not shake hands with females outside his family – a practice providers should respect – and that important religious holidays such as Ramadan may influence a family’s compliance with a treatment plan.

Perhaps the most important commonality, however, is one universal to most refugee families, regardless of their home country.

“The vast majority of families that we meet show incredible courage and resilience, and caring for their children is their highest priority,” Dr. Reines said. “We can learn a great deal from these families, and caring for their children is a tremendously rewarding experience.”

Other cultural resources:

CDC Refugee Health Guidelines

Bridging Refugee Youth and Children’s Services

“The Middle of Everywhere: Helping Refugees Enter the American Community,” by Mary Pipher (Orlando: Mariner Books, 2003)

“Immigrant Medicine,” a textbook by Patricia Walker, M.D., and Elizabeth Barnett, M.D. (New York, N.Y.: Elsevier, 2007)

“Opening cultural doors: Providing culturally sensitive healthcare to Arab American and American Muslim patients” (Am J Obstet Gynecol. 2005 Oct;193]:1307-11).

ethnoMedCenter for Applied Linguistics

When the recent photo of a drowned Syrian toddler woke up the world to the Syrian refugee crisis more viscerally than ever before, multiple nations announced plans to take in more refugees. According to the U.S. State Department, approximately 10,000 Syrian refugees are already in processing, eventually headed to cities that may include Atlanta, San Diego, Houston, Dallas, Chicago, Boston, Boise, Nashville, Tucson, Buffalo, and Erie.

To pediatricians, that boy on the beach represents a child who might have ended up in their practice with diverse, complex needs greatly exceeding the typical needs of a U.S. child coming in for a well-child visit.

Rachel Unkovic/International Rescue Committee/CC BY 2.0

“Families are coming from a country that has been ravaged by civil war for over 4 years,” Dr. Susan S. Reines, a pediatrician with the Southeast Kaiser Permanente Medical Group and lead pediatrician for the Refugee Pediatric Clinic at DeKalb County Board of Health in Decatur, Georgia, said in an interview. “Cities have been destroyed, and millions have been forced to leave their homes and are displaced either within Syria or in neighboring countries.”

About a third of the more than 58,000 refugees admitted to the United States in 2012 were under 18 years old. Although the majority that year hailed from Bhutan, Burma, and Iraq, an increasing number of children have been coming from war-torn Syria since June 2014. The proposed ceiling for all refugees in the United States 2015 fiscal year is 70,000, a “significant number” of whom will be children with their families, according to a State Department spokesperson.

These children come with “unique medical, developmental and psychosocial needs,” noted Dr. Thomas J. Seery and fellow authors of “Caring for Refugee Children,” a Pediatrics in Review article recommended by Dr. Reines for pediatricians who may be caring for refugee children.

“The health care infrastructure of Syria is broken and many hospitals have closed, medications are difficult to obtain, and numerous doctors have fled the violence,” Dr. Reines said. She compared the anticipated health care problems of these children with those seen among Iraqi refugee children:

• Undernutrition and micronutrient deficiencies.

• Infectious diseases such as vaccine-preventable diseases like measles, but also typhoid, tuberculosis, and parasitic infections.

• Dental disease.

• Surgically amenable congenital anomalies such as congenital heart disease, myelomeningocele, and others that have not been repaired.

• Neurologic problems, such as cerebral palsy, intellectual disability, and autism.

• Hearing loss.

• Posttraumatic stress disorder (PTSD),depression, and anxiety.

• Trauma such as gunshot wounds, shrapnel injuries, and genital trauma secondary to sexual violence.

• Sequelae from illnesses that previously were easily treated, such as hearing loss and ear complications from otitis media, and rheumatic fever from inadequately treated strep throat.

• Underimmunization.

Various resources listed below, including Dr. Seery’s paper, can help guide providers in assessing and meeting these needs, and navigating paperwork and the U.S. refugee system. These resources also can help practitioners address the mental health concerns these patients and their families may face.

Mental health needs

Even children in the best physical shape will have experienced significant upheaval that could lead to depression, anxiety, and PTSD – conditions more common among refugee children than in the general population, research has shown.

“Mental health conditions will be especially present in these children uprooted from their homes and families, and exposed to the violence of war,” Dr. Francis E. Rushton Jr. of the department of pediatrics at the University of South Carolina, Columbia, and a member of the American Academy of Pediatrics Committee on Community Health Services, said in an interview. Of the four major areas of health care need he described for these children, two relate to mental health: toxic mental stress and fractured families and the lack of nurture.

One challenge pediatricians face, however, is recognizing these conditions despite cultural differences that could obscure them.

“It is not uncommon for teens and adults to deny symptoms of depression, stress, and anxiety in early encounters,” Dr. Reines said. “Many cultures stigmatize psychiatric or mental health problems, and refugees may be reluctant to admit they are having difficulties.”

One way around this obstacle is to ask patients and their parents about sleep, energy level, appetite, weight changes, and thoughts of harming one’s self, she said. Mental stress also manifests as somatic symptoms, such as headaches, stomach aches, and back pain, particularly in teens.

“Infants and toddlers are generally most adaptable as long as parents are coping well, and can provide a buffer for stress with a safe and nurturing environment,” Dr. Reines said. Children of parents with depression or PTSD, or who have lost a parent, may feel abandoned and experience depression or developmental delays.

Although school-age children may have nightmares, show anxiety, and cling to their parents, they usually transition well to their new homes. Adolescents face the biggest difficulties, especially if they have lost a parent, must care for their siblings, or have experienced sexual trauma. “They may have more vivid memories of disturbing events and a greater understanding of what their family has endured,” Dr. Reines said. Further, language and educational deficits can lead to alienation and embarrassment, yet families may rebuff behavioral health referrals.

“In these cases, it’s best to keep communication open, encourage dialogue with family, and try to find an activity or sport the refugee can participate in to improve self-esteem,” Dr. Reines said.

Avoiding cultural confusion

While cultural challenges are obvious – language barriers may necessitate translators or bicultural caseworkers – others may be more subtle. Developmental screening questions that rely on blocks, certain pictures, or other culturally specific bases, for example, may not adequately capture a child’s development.

Dr. Reines stresses a strategy for managing cultural differences that is recommended in Dr. Seery’s article: striving for cultural humility rather than cultural competence.

“It is impossible for U.S. physicians who have never practiced outside of our culture and are not bicultural or bilingual to become truly culturally competent in health care delivery for so many refugee populations,” Dr. Reines said. Instead then, cultural humility emphasizes showing respect, interest, and a willingness to learn from patients, she explained.

Cultural humility is a “lifelong process” that also demands flexibility and “allows the practitioner to release the false sense of security associated with stereotyping,” Dr. Seery and his colleagues wrote.

At the same time, pediatricians are guarding against inadvertent stereotyping; however, they can be aware of some cultural generalities that may apply to their Syrian refugee patients.

“Arab communities stress the importance of family rather than the individual and are often more modest than Westerners,” Dr. Rushton said. Further, “Arab families frequently experience discrimination on the basis of their religion in the United States, and pediatricians should be aware of ongoing traumatization even after arrival in America,” he said.

Teens may become embarrassed with discussions about sex or alcohol because few teens from the Middle East drink or become sexually active before marriage, Dr. Reines added. She noted that a Muslim male may not shake hands with females outside his family – a practice providers should respect – and that important religious holidays such as Ramadan may influence a family’s compliance with a treatment plan.

Perhaps the most important commonality, however, is one universal to most refugee families, regardless of their home country.

“The vast majority of families that we meet show incredible courage and resilience, and caring for their children is their highest priority,” Dr. Reines said. “We can learn a great deal from these families, and caring for their children is a tremendously rewarding experience.”

Other cultural resources:

CDC Refugee Health Guidelines

Bridging Refugee Youth and Children’s Services

“The Middle of Everywhere: Helping Refugees Enter the American Community,” by Mary Pipher (Orlando: Mariner Books, 2003)

“Immigrant Medicine,” a textbook by Patricia Walker, M.D., and Elizabeth Barnett, M.D. (New York, N.Y.: Elsevier, 2007)

“Opening cultural doors: Providing culturally sensitive healthcare to Arab American and American Muslim patients” (Am J Obstet Gynecol. 2005 Oct;193]:1307-11).

ethnoMedCenter for Applied Linguistics

Spondylolysis, a defect in the pars interarticularis, is the single most common identifiable source of persistent low back pain in adolescent athletes.^1,2 The diagnosis of spondylolysis is confirmed by radiographic imaging.³ However, there is controversy regarding which imaging modality is preferred—specifically, which to use for first-line advanced imaging after plain radiographs are obtained.³ Single-photon emission computed tomography (SPECT) consistently has been shown to be the most sensitive modality, and it is considered the gold standard.^4-7 Patients with a positive SPECT scan are then routinely imaged with computed tomography (CT) for bone detail and staging of the pars defect.⁸ This imaging or diagnostic sequence yields organ-specific radiation doses (15-30 mSv) as much as 50-fold higher than those of plain radiography.⁹ Recent epidemiologic studies have shown that this organ dose results in an increased risk of cancer, especially in children.¹⁰

Diagnosis is crucial in early-stage lumbar spondylolysis, as osseous healing can occur with conservative treatment.^11,12 High signal change (HSC) in the pedicle or pars interarticularis (Figure 1) on fluid-specific (T2) magnetic resonance imaging (MRI) sequences has been shown to be important in the diagnosis of early spondylolysis and, subsequently, a good predictor of bony healing.^13,14 We conducted a study to determine the clinical and radiographic characteristics associated with the diagnosis of early or active spondylolysis.

Materials and Methods

The study was reviewed and approved by the local institutional review board. Using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for spondylolysis (756.11), we retrospectively identified patients (age, 12-21 years) from 2002–2011 billing data from a single specialty spine practice. Baseline data—including height, weight, sex, age, symptom duration, sporting activities, defect location, pain score, and previous treatments—were collected from a standardized patient intake questionnaire and office medical records. We also determined radiographic data, including level, laterality (right vs left, unilateral vs bilateral), presence of listhesis, and slip grade and percentage. CT scans were reviewed to confirm the spondylolysis diagnosis and to measure parameters described by Fujii and colleagues.¹⁵ These parameters include spondylolysis chronicity (early, progressive, terminal) (Figure 2), distance from defect to posterior margin of vertebral body, and defect angle relative to posterior margin of vertebral body. We also measured sagittal radiographic parameters, including pelvic incidence and lumbar lordosis.

Pars lesions were divided into active and inactive defects¹⁶ based on signal characteristics on either MRI or SPECT (Figure 3). Defects with a positive SPECT or HSC on T2 MRI were classified as active; all other defects were classified as inactive. All MRIs were reviewed by a radiologist, and any mention of HSC in the pedicle or pars of the corresponding level was considered positive. For the sake of accuracy, all MRIs were also reviewed by a spine surgeon. All CT measurements were done by 1 of 2 authors. Demographic, clinical, and radiographic characteristics were compared between patients with active defects and patients with inactive defects. Independent t tests and Fisher exact tests were used to compare continuous and categorical variables, respectively. Threshold P was set at .01 to account for the small sample size and multiple concurrent comparisons.

Results

Fifty-seven patients (29 males, 28 females) with a total of 108 pars defects (6 unilateral, 102 bilateral) were identified. Mean age was 14.64 years. Of the 108 defects, 49 were classified as active and 59 as inactive. SPECT results were available for 52 defects, MRI results for 85, and CT results for 76 (Table 1). There was no difference between the active and inactive groups in age (14.7 vs 14.6 years; P = .083), body mass index (24.2 vs 21.7 kg/m²; P = .034), symptom duration (236.3 vs 397.4 days; P = .016), lumbar lordosis (27.4° vs 32.1°; P = .097), pelvic incidence (59.0° vs 61.2°; P = .488), slip percentage (9.5% vs 14.2%; P = .034), and laterality (right vs left, P = .847; unilateral vs bilateral, P = .281) (Table 2). There was a significant difference between the active and inactive groups in sex (35 vs 19 males; P < .0001) and presence of listhesis (16 vs 35; P = .006) (Table 2).

Of the 49 active defects, 3 were graded as early, 10 as progressive, and 11 as terminal (Table 3). There was a statistically significant (P < .0001) difference between active and inactive lesions for each stage. Mean distance from posterior margin of the vertebral body was 0.57 mm and 0.68 mm for inactive and active lesions, respectively (P = .007). There was no significant difference (P = .294) in the posterior angle of the vertebral body and the defect between inactive (20.54°) and active (24.73°) lesions (Table 3).

Subanalysis by sex showed no difference in age (males, 16.4 years vs females, 18.7 years; P = .073), slip percentage (10.4% vs 13.4%; P = .168), or presence or absence of slip (25 vs 26; P > .99) (Table 4).

Discussion

Increasing MRI resolution combined with increasing concern about unnecessary radiation exposure has added to the attractiveness of MRI in the diagnosis of spondylolysis. Spondylolysis progresses on a continuum, starting with a stress reaction (early or active defect) and ending with either healing or nonunion of the pars defect (terminal defect) (Figure 4). Although risk factors for progression are not clearly defined, Fujii and colleagues¹⁵ showed that the reaction around the defect is the most important factor for osseous union. It would then make sense that the earlier the spondylolytic defect is identified, the higher the likelihood for union, especially with nonoperative treatment such as rest, activity restriction, and bracing.^12,17

There is a lack of consensus regarding MRI use in the diagnosis of spondylolysis. Masci and colleagues¹⁸ prospectively evaluated 50 defects in 39 patients using a 1.5-Tesla MRI scanner, concluded MRI is inferior to SPECT/CT, and recommended that SPECT remain the first-line advanced imaging modality. Conversely, Campbell and colleagues⁴ prospectively evaluated 40 defects in 22 patients using a 1.0-Tesla magnet and concluded that MRI can be used as an effective and reliable first-line advanced imaging modality. These are the only 2 prospective studies conducted within the past decade. Both were underpowered and used outdated technology (newer MRI scanners use 3.0-Tesla magnets). In addition, specific imaging characteristics (eg, edema in pars or pedicle on fluid-specific sequences) that suggest a positive finding—versus overt fracture on T1 MRI—have been recently emphasized. Neither Masci and colleagues¹⁸ nor Campbell and colleagues⁴ detailed what constituted a positive MRI finding. Although an adequately powered prospective study will provide a better analysis of the utility of MRI versus SPECT, such a study is costly and time-consuming. It is important to identify patient and lesion characteristics to help optimize the usefulness of MRI. It is also important to identify the subset of patients most likely to experience osseous healing of active defects,¹⁶ as this is the same subset of patients most likely to respond to nonoperative treatment.

We conducted the present study to identify any clinical or radiographic characteristics associated with the diagnosis of early or active spondylolysis. Almost equal numbers of active and inactive defects (49, 59) were identified. There were no differences in patient characteristics, including age, body mass index, and symptom duration. However, there was a significant sex difference—a relatively high proportion of males with active spondylolysis. This finding, which had been reported before,^16,19,20 is probably the result of several factors, including males’ lower lumbar spine bone mineral density²¹; their relatively less spinal flexibility, which affects the distribution of torsional loads on the spine²²; and their relatively greater participation in sports, especially sports involving high-velocity, torsional loading of the lumbar spine.²³ Studies are needed to delineate the extent to which sex influences the development and persistence of active spondylolytic lesions. Alternatively, a subanalysis revealed an age difference, between our female and male cohorts (18.7 vs 16.4 years), that may have contributed to the high proportion of males with active spondylolysis.

Although the groups’ difference in symptom duration was not significant, it was trending toward significance. As discussed, it could be explained that, along the continuum of disease, earlier defects are more active and either achieve fibrous or osseous union or become chronic and “burn out” to inactive lesions, potentially leading to a listhesis.²⁴ The listhesis association was higher in the inactive group than in the active group (P = .006). The difference in numbers of active and inactive defects at each stage (early, progressive, late) confirms this finding, with no inactive lesions in the early and progressive stages and many fewer active lesions in the terminal stage. Overall, presence of a spondylolisthesis on plain radiographs may obviate the need for SPECT or MRI, as it indicates an inactive chronic lesion—unless new symptoms are suspicious for reactivation or development of previously described adjacent-level pars defects.

No other radiographic parameters were found to be significant—consistent with findings of other studies.^2,5,16 Pelvic incidence has been shown to predict progression of spondylisthesis, but under our study parameters it appears not to be associated with development of a slip.

This study had several weaknesses. First, it was retrospective, and imaging parameters were inconsistent, as we included patients who underwent imaging at other facilities. Second, the timing of imaging was inconsistent. Ideally, the same sequence protocol would be used, and all imaging studies (MRI, SPECT, CT) would be performed within a specific period after the initial concern for a spondylolysis was raised. Last, not all patients underwent all 3 advanced imaging modalities; having all 3 would have allowed for a retrospective comparison of MRI and SPECT sensitivity in detecting spondylolysis. Such a comparison would have been interesting, though it was not the goal of this study.

With its technological improvements and lack of radiation exposure, MRI is becoming more attractive as a first-line advanced imaging modality. Although the superiority of MRI over SPECT is yet to be confirmed, clinical use of MRI in the evaluation of spondylolysis seems to be increasing. It is therefore important to characterize the spondylolytic defects that are readily detected with MRI.

Active or early juvenile spondylolysis appears to be associated with males and absence of an associated listhesis. These clinical and radiographic characteristics may be important in the identification of patients with higher potential for osseous healing after nonoperative treatment.

Spondylolysis, a defect in the pars interarticularis, is the single most common identifiable source of persistent low back pain in adolescent athletes.^1,2 The diagnosis of spondylolysis is confirmed by radiographic imaging.³ However, there is controversy regarding which imaging modality is preferred—specifically, which to use for first-line advanced imaging after plain radiographs are obtained.³ Single-photon emission computed tomography (SPECT) consistently has been shown to be the most sensitive modality, and it is considered the gold standard.^4-7 Patients with a positive SPECT scan are then routinely imaged with computed tomography (CT) for bone detail and staging of the pars defect.⁸ This imaging or diagnostic sequence yields organ-specific radiation doses (15-30 mSv) as much as 50-fold higher than those of plain radiography.⁹ Recent epidemiologic studies have shown that this organ dose results in an increased risk of cancer, especially in children.¹⁰

Diagnosis is crucial in early-stage lumbar spondylolysis, as osseous healing can occur with conservative treatment.^11,12 High signal change (HSC) in the pedicle or pars interarticularis (Figure 1) on fluid-specific (T2) magnetic resonance imaging (MRI) sequences has been shown to be important in the diagnosis of early spondylolysis and, subsequently, a good predictor of bony healing.^13,14 We conducted a study to determine the clinical and radiographic characteristics associated with the diagnosis of early or active spondylolysis.

Materials and Methods

The study was reviewed and approved by the local institutional review board. Using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for spondylolysis (756.11), we retrospectively identified patients (age, 12-21 years) from 2002–2011 billing data from a single specialty spine practice. Baseline data—including height, weight, sex, age, symptom duration, sporting activities, defect location, pain score, and previous treatments—were collected from a standardized patient intake questionnaire and office medical records. We also determined radiographic data, including level, laterality (right vs left, unilateral vs bilateral), presence of listhesis, and slip grade and percentage. CT scans were reviewed to confirm the spondylolysis diagnosis and to measure parameters described by Fujii and colleagues.¹⁵ These parameters include spondylolysis chronicity (early, progressive, terminal) (Figure 2), distance from defect to posterior margin of vertebral body, and defect angle relative to posterior margin of vertebral body. We also measured sagittal radiographic parameters, including pelvic incidence and lumbar lordosis.

Pars lesions were divided into active and inactive defects¹⁶ based on signal characteristics on either MRI or SPECT (Figure 3). Defects with a positive SPECT or HSC on T2 MRI were classified as active; all other defects were classified as inactive. All MRIs were reviewed by a radiologist, and any mention of HSC in the pedicle or pars of the corresponding level was considered positive. For the sake of accuracy, all MRIs were also reviewed by a spine surgeon. All CT measurements were done by 1 of 2 authors. Demographic, clinical, and radiographic characteristics were compared between patients with active defects and patients with inactive defects. Independent t tests and Fisher exact tests were used to compare continuous and categorical variables, respectively. Threshold P was set at .01 to account for the small sample size and multiple concurrent comparisons.

Results

Fifty-seven patients (29 males, 28 females) with a total of 108 pars defects (6 unilateral, 102 bilateral) were identified. Mean age was 14.64 years. Of the 108 defects, 49 were classified as active and 59 as inactive. SPECT results were available for 52 defects, MRI results for 85, and CT results for 76 (Table 1). There was no difference between the active and inactive groups in age (14.7 vs 14.6 years; P = .083), body mass index (24.2 vs 21.7 kg/m²; P = .034), symptom duration (236.3 vs 397.4 days; P = .016), lumbar lordosis (27.4° vs 32.1°; P = .097), pelvic incidence (59.0° vs 61.2°; P = .488), slip percentage (9.5% vs 14.2%; P = .034), and laterality (right vs left, P = .847; unilateral vs bilateral, P = .281) (Table 2). There was a significant difference between the active and inactive groups in sex (35 vs 19 males; P < .0001) and presence of listhesis (16 vs 35; P = .006) (Table 2).

Of the 49 active defects, 3 were graded as early, 10 as progressive, and 11 as terminal (Table 3). There was a statistically significant (P < .0001) difference between active and inactive lesions for each stage. Mean distance from posterior margin of the vertebral body was 0.57 mm and 0.68 mm for inactive and active lesions, respectively (P = .007). There was no significant difference (P = .294) in the posterior angle of the vertebral body and the defect between inactive (20.54°) and active (24.73°) lesions (Table 3).

Subanalysis by sex showed no difference in age (males, 16.4 years vs females, 18.7 years; P = .073), slip percentage (10.4% vs 13.4%; P = .168), or presence or absence of slip (25 vs 26; P > .99) (Table 4).

Discussion

Increasing MRI resolution combined with increasing concern about unnecessary radiation exposure has added to the attractiveness of MRI in the diagnosis of spondylolysis. Spondylolysis progresses on a continuum, starting with a stress reaction (early or active defect) and ending with either healing or nonunion of the pars defect (terminal defect) (Figure 4). Although risk factors for progression are not clearly defined, Fujii and colleagues¹⁵ showed that the reaction around the defect is the most important factor for osseous union. It would then make sense that the earlier the spondylolytic defect is identified, the higher the likelihood for union, especially with nonoperative treatment such as rest, activity restriction, and bracing.^12,17

There is a lack of consensus regarding MRI use in the diagnosis of spondylolysis. Masci and colleagues¹⁸ prospectively evaluated 50 defects in 39 patients using a 1.5-Tesla MRI scanner, concluded MRI is inferior to SPECT/CT, and recommended that SPECT remain the first-line advanced imaging modality. Conversely, Campbell and colleagues⁴ prospectively evaluated 40 defects in 22 patients using a 1.0-Tesla magnet and concluded that MRI can be used as an effective and reliable first-line advanced imaging modality. These are the only 2 prospective studies conducted within the past decade. Both were underpowered and used outdated technology (newer MRI scanners use 3.0-Tesla magnets). In addition, specific imaging characteristics (eg, edema in pars or pedicle on fluid-specific sequences) that suggest a positive finding—versus overt fracture on T1 MRI—have been recently emphasized. Neither Masci and colleagues¹⁸ nor Campbell and colleagues⁴ detailed what constituted a positive MRI finding. Although an adequately powered prospective study will provide a better analysis of the utility of MRI versus SPECT, such a study is costly and time-consuming. It is important to identify patient and lesion characteristics to help optimize the usefulness of MRI. It is also important to identify the subset of patients most likely to experience osseous healing of active defects,¹⁶ as this is the same subset of patients most likely to respond to nonoperative treatment.

We conducted the present study to identify any clinical or radiographic characteristics associated with the diagnosis of early or active spondylolysis. Almost equal numbers of active and inactive defects (49, 59) were identified. There were no differences in patient characteristics, including age, body mass index, and symptom duration. However, there was a significant sex difference—a relatively high proportion of males with active spondylolysis. This finding, which had been reported before,^16,19,20 is probably the result of several factors, including males’ lower lumbar spine bone mineral density²¹; their relatively less spinal flexibility, which affects the distribution of torsional loads on the spine²²; and their relatively greater participation in sports, especially sports involving high-velocity, torsional loading of the lumbar spine.²³ Studies are needed to delineate the extent to which sex influences the development and persistence of active spondylolytic lesions. Alternatively, a subanalysis revealed an age difference, between our female and male cohorts (18.7 vs 16.4 years), that may have contributed to the high proportion of males with active spondylolysis.

Although the groups’ difference in symptom duration was not significant, it was trending toward significance. As discussed, it could be explained that, along the continuum of disease, earlier defects are more active and either achieve fibrous or osseous union or become chronic and “burn out” to inactive lesions, potentially leading to a listhesis.²⁴ The listhesis association was higher in the inactive group than in the active group (P = .006). The difference in numbers of active and inactive defects at each stage (early, progressive, late) confirms this finding, with no inactive lesions in the early and progressive stages and many fewer active lesions in the terminal stage. Overall, presence of a spondylolisthesis on plain radiographs may obviate the need for SPECT or MRI, as it indicates an inactive chronic lesion—unless new symptoms are suspicious for reactivation or development of previously described adjacent-level pars defects.

No other radiographic parameters were found to be significant—consistent with findings of other studies.^2,5,16 Pelvic incidence has been shown to predict progression of spondylisthesis, but under our study parameters it appears not to be associated with development of a slip.

This study had several weaknesses. First, it was retrospective, and imaging parameters were inconsistent, as we included patients who underwent imaging at other facilities. Second, the timing of imaging was inconsistent. Ideally, the same sequence protocol would be used, and all imaging studies (MRI, SPECT, CT) would be performed within a specific period after the initial concern for a spondylolysis was raised. Last, not all patients underwent all 3 advanced imaging modalities; having all 3 would have allowed for a retrospective comparison of MRI and SPECT sensitivity in detecting spondylolysis. Such a comparison would have been interesting, though it was not the goal of this study.

With its technological improvements and lack of radiation exposure, MRI is becoming more attractive as a first-line advanced imaging modality. Although the superiority of MRI over SPECT is yet to be confirmed, clinical use of MRI in the evaluation of spondylolysis seems to be increasing. It is therefore important to characterize the spondylolytic defects that are readily detected with MRI.

Active or early juvenile spondylolysis appears to be associated with males and absence of an associated listhesis. These clinical and radiographic characteristics may be important in the identification of patients with higher potential for osseous healing after nonoperative treatment.

Spondylolysis, a defect in the pars interarticularis, is the single most common identifiable source of persistent low back pain in adolescent athletes.^1,2 The diagnosis of spondylolysis is confirmed by radiographic imaging.³ However, there is controversy regarding which imaging modality is preferred—specifically, which to use for first-line advanced imaging after plain radiographs are obtained.³ Single-photon emission computed tomography (SPECT) consistently has been shown to be the most sensitive modality, and it is considered the gold standard.^4-7 Patients with a positive SPECT scan are then routinely imaged with computed tomography (CT) for bone detail and staging of the pars defect.⁸ This imaging or diagnostic sequence yields organ-specific radiation doses (15-30 mSv) as much as 50-fold higher than those of plain radiography.⁹ Recent epidemiologic studies have shown that this organ dose results in an increased risk of cancer, especially in children.¹⁰

Diagnosis is crucial in early-stage lumbar spondylolysis, as osseous healing can occur with conservative treatment.^11,12 High signal change (HSC) in the pedicle or pars interarticularis (Figure 1) on fluid-specific (T2) magnetic resonance imaging (MRI) sequences has been shown to be important in the diagnosis of early spondylolysis and, subsequently, a good predictor of bony healing.^13,14 We conducted a study to determine the clinical and radiographic characteristics associated with the diagnosis of early or active spondylolysis.

Materials and Methods

The study was reviewed and approved by the local institutional review board. Using the International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code for spondylolysis (756.11), we retrospectively identified patients (age, 12-21 years) from 2002–2011 billing data from a single specialty spine practice. Baseline data—including height, weight, sex, age, symptom duration, sporting activities, defect location, pain score, and previous treatments—were collected from a standardized patient intake questionnaire and office medical records. We also determined radiographic data, including level, laterality (right vs left, unilateral vs bilateral), presence of listhesis, and slip grade and percentage. CT scans were reviewed to confirm the spondylolysis diagnosis and to measure parameters described by Fujii and colleagues.¹⁵ These parameters include spondylolysis chronicity (early, progressive, terminal) (Figure 2), distance from defect to posterior margin of vertebral body, and defect angle relative to posterior margin of vertebral body. We also measured sagittal radiographic parameters, including pelvic incidence and lumbar lordosis.

Pars lesions were divided into active and inactive defects¹⁶ based on signal characteristics on either MRI or SPECT (Figure 3). Defects with a positive SPECT or HSC on T2 MRI were classified as active; all other defects were classified as inactive. All MRIs were reviewed by a radiologist, and any mention of HSC in the pedicle or pars of the corresponding level was considered positive. For the sake of accuracy, all MRIs were also reviewed by a spine surgeon. All CT measurements were done by 1 of 2 authors. Demographic, clinical, and radiographic characteristics were compared between patients with active defects and patients with inactive defects. Independent t tests and Fisher exact tests were used to compare continuous and categorical variables, respectively. Threshold P was set at .01 to account for the small sample size and multiple concurrent comparisons.

Results

Fifty-seven patients (29 males, 28 females) with a total of 108 pars defects (6 unilateral, 102 bilateral) were identified. Mean age was 14.64 years. Of the 108 defects, 49 were classified as active and 59 as inactive. SPECT results were available for 52 defects, MRI results for 85, and CT results for 76 (Table 1). There was no difference between the active and inactive groups in age (14.7 vs 14.6 years; P = .083), body mass index (24.2 vs 21.7 kg/m²; P = .034), symptom duration (236.3 vs 397.4 days; P = .016), lumbar lordosis (27.4° vs 32.1°; P = .097), pelvic incidence (59.0° vs 61.2°; P = .488), slip percentage (9.5% vs 14.2%; P = .034), and laterality (right vs left, P = .847; unilateral vs bilateral, P = .281) (Table 2). There was a significant difference between the active and inactive groups in sex (35 vs 19 males; P < .0001) and presence of listhesis (16 vs 35; P = .006) (Table 2).

Of the 49 active defects, 3 were graded as early, 10 as progressive, and 11 as terminal (Table 3). There was a statistically significant (P < .0001) difference between active and inactive lesions for each stage. Mean distance from posterior margin of the vertebral body was 0.57 mm and 0.68 mm for inactive and active lesions, respectively (P = .007). There was no significant difference (P = .294) in the posterior angle of the vertebral body and the defect between inactive (20.54°) and active (24.73°) lesions (Table 3).

Subanalysis by sex showed no difference in age (males, 16.4 years vs females, 18.7 years; P = .073), slip percentage (10.4% vs 13.4%; P = .168), or presence or absence of slip (25 vs 26; P > .99) (Table 4).

Discussion

Increasing MRI resolution combined with increasing concern about unnecessary radiation exposure has added to the attractiveness of MRI in the diagnosis of spondylolysis. Spondylolysis progresses on a continuum, starting with a stress reaction (early or active defect) and ending with either healing or nonunion of the pars defect (terminal defect) (Figure 4). Although risk factors for progression are not clearly defined, Fujii and colleagues¹⁵ showed that the reaction around the defect is the most important factor for osseous union. It would then make sense that the earlier the spondylolytic defect is identified, the higher the likelihood for union, especially with nonoperative treatment such as rest, activity restriction, and bracing.^12,17

There is a lack of consensus regarding MRI use in the diagnosis of spondylolysis. Masci and colleagues¹⁸ prospectively evaluated 50 defects in 39 patients using a 1.5-Tesla MRI scanner, concluded MRI is inferior to SPECT/CT, and recommended that SPECT remain the first-line advanced imaging modality. Conversely, Campbell and colleagues⁴ prospectively evaluated 40 defects in 22 patients using a 1.0-Tesla magnet and concluded that MRI can be used as an effective and reliable first-line advanced imaging modality. These are the only 2 prospective studies conducted within the past decade. Both were underpowered and used outdated technology (newer MRI scanners use 3.0-Tesla magnets). In addition, specific imaging characteristics (eg, edema in pars or pedicle on fluid-specific sequences) that suggest a positive finding—versus overt fracture on T1 MRI—have been recently emphasized. Neither Masci and colleagues¹⁸ nor Campbell and colleagues⁴ detailed what constituted a positive MRI finding. Although an adequately powered prospective study will provide a better analysis of the utility of MRI versus SPECT, such a study is costly and time-consuming. It is important to identify patient and lesion characteristics to help optimize the usefulness of MRI. It is also important to identify the subset of patients most likely to experience osseous healing of active defects,¹⁶ as this is the same subset of patients most likely to respond to nonoperative treatment.

We conducted the present study to identify any clinical or radiographic characteristics associated with the diagnosis of early or active spondylolysis. Almost equal numbers of active and inactive defects (49, 59) were identified. There were no differences in patient characteristics, including age, body mass index, and symptom duration. However, there was a significant sex difference—a relatively high proportion of males with active spondylolysis. This finding, which had been reported before,^16,19,20 is probably the result of several factors, including males’ lower lumbar spine bone mineral density²¹; their relatively less spinal flexibility, which affects the distribution of torsional loads on the spine²²; and their relatively greater participation in sports, especially sports involving high-velocity, torsional loading of the lumbar spine.²³ Studies are needed to delineate the extent to which sex influences the development and persistence of active spondylolytic lesions. Alternatively, a subanalysis revealed an age difference, between our female and male cohorts (18.7 vs 16.4 years), that may have contributed to the high proportion of males with active spondylolysis.

Although the groups’ difference in symptom duration was not significant, it was trending toward significance. As discussed, it could be explained that, along the continuum of disease, earlier defects are more active and either achieve fibrous or osseous union or become chronic and “burn out” to inactive lesions, potentially leading to a listhesis.²⁴ The listhesis association was higher in the inactive group than in the active group (P = .006). The difference in numbers of active and inactive defects at each stage (early, progressive, late) confirms this finding, with no inactive lesions in the early and progressive stages and many fewer active lesions in the terminal stage. Overall, presence of a spondylolisthesis on plain radiographs may obviate the need for SPECT or MRI, as it indicates an inactive chronic lesion—unless new symptoms are suspicious for reactivation or development of previously described adjacent-level pars defects.

No other radiographic parameters were found to be significant—consistent with findings of other studies.^2,5,16 Pelvic incidence has been shown to predict progression of spondylisthesis, but under our study parameters it appears not to be associated with development of a slip.

This study had several weaknesses. First, it was retrospective, and imaging parameters were inconsistent, as we included patients who underwent imaging at other facilities. Second, the timing of imaging was inconsistent. Ideally, the same sequence protocol would be used, and all imaging studies (MRI, SPECT, CT) would be performed within a specific period after the initial concern for a spondylolysis was raised. Last, not all patients underwent all 3 advanced imaging modalities; having all 3 would have allowed for a retrospective comparison of MRI and SPECT sensitivity in detecting spondylolysis. Such a comparison would have been interesting, though it was not the goal of this study.

With its technological improvements and lack of radiation exposure, MRI is becoming more attractive as a first-line advanced imaging modality. Although the superiority of MRI over SPECT is yet to be confirmed, clinical use of MRI in the evaluation of spondylolysis seems to be increasing. It is therefore important to characterize the spondylolytic defects that are readily detected with MRI.

Active or early juvenile spondylolysis appears to be associated with males and absence of an associated listhesis. These clinical and radiographic characteristics may be important in the identification of patients with higher potential for osseous healing after nonoperative treatment.

Medicare beneficiaries’ demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has increased significantly over the past several years, with recent studies reporting 209,945 primary THAs and 243,802 primary TKAs performed annually.^1,2 With this demand has come an increase in the percentage of patients discharged to an extended-care facility (ECF) for skilled nursing care or acute rehabilitation—an estimated 49.3% for THA and 41.5% for TKA.^1,2 To qualify for discharge to an ECF, Medicare beneficiaries are required to have an inpatient stay of at least 3 consecutive days.³ Although the basis of this rule is unclear, it is thought to prevent hasty discharge of unstable patients.

We conducted a study to explore the effect of this policy on length of stay (LOS) in a population of patients who underwent primary total joint arthroplasty (TJA). Based on a pilot study by our group, we hypothesized that such a statuary requirement would be associated with increased LOS and would not prevent discharge of potentially unstable patients. Specifically, we explored whether patients who could have been discharged earlier experienced any later inpatient complications or 30-day readmission to justify staying past their discharge readiness.

Materials and Methods

Institutional review board approval was obtained for this study. Between 2011 and 2012, the senior authors (Dr. Wellman, Dr. Attarian, Dr. Bolognesi) treated 985 patients with Current Procedural Terminology (CPT) codes 27130 (THA) and 27447 (TKA). Of the 985 patients, 287 (29.13%) were discharged to an ECF and were included in the study. Three of the 287 were excluded: 2 for requiring preadmission for medical optimization and 1 for having another procedure with plastic surgery. All patients were admitted from home on day of surgery and had a standardized clinical pathway with respect to pain control, mobilization, and anticoagulation. Physical therapy and occupational therapy (PT/OT) were initiated on day of surgery and were continued daily until discharge.

The primary outcome was discharge readiness, defined as meeting the criteria of stable blood pressure, pulse, and breathing; no fever over 101.5°F for 24 hours before discharge; wound healing with no concerns; pain controlled with oral medications; and ambulation or the potential for rehabilitation at the receiving facility. Secondary outcomes were changes in PT/OT progress, medical interventions, and 30-day readmission rate. PT/OT progress was categorized as either slow or steady by the therapist assigned to each patient at time of hospitalization. Steady progress indicated overall improvement on several measures, including transfers, ambulation distance, and ability to adhere to postoperative precautions; slow progress indicated no improvement on these measures.

Results for continuous variables were summarized with means, standard deviations, and ranges, and results for categorical variables were summarized with counts and percentages. Student t test was used to evaluate increase in LOS, and the McNemar test for paired data was used to analyze rehabilitation gains from readiness-for-discharge day to the next postoperative day (POD). SAS Version 9.2 software (SAS Institute) was used for all analyses.

Results

Of the 284 patients included in the study, 203 were female (71.5%), 81 male (28.5%). Mean (SD) age was 68 (11) years (range, 21-92 years). One hundred seventy-nine patients (63.0%) underwent TKA, and 105 (37.0%) underwent THA. Two hundred twenty-seven patients (80.0%) were discharged to skilled nursing care, and 57 (20.1%) to inpatient rehabilitation. Mean (SD) LOS was 3.44 (0.92) days (range, 3-9 days). One hundred eighty-three patients (64.4%) were ready for discharge on POD 2, 76 (26.8%) on POD 3, and 25 (8.8%) after POD 3. Delaying discharge until POD 3 increased LOS by 1.08 days (P < .001). Two hundred nine patients (73.6%) were discharged on POD 3, and 75 (26.4%) after POD 3. Reasons for being discharged after POD 3 were lack of ECF bed availability (48 patients, 64.0%) and postoperative complications (27 patients, 36.0%). Patients ready for discharge on POD 2 had fewer complications than patients ready after POD 2 (P < .001).

Analysis of the 183 patients who were ready for discharge on POD 2 demonstrated a statistically significant (P = .038) change in rehabilitation progress by staying an additional hospital day. However, this difference was not clinically significant: Only 17.5% of patients improved, while 82.5% remained unchanged or declined in progress. Most important, among patients who demonstrated rehabilitation gains, the improvement was not sufficient to change the decision regarding discharge destination. Three patients (1.6%) ready for discharge on POD 2 were readmitted within 30 days of discharge (2 for wound infection, 1 for syncope). Risk for 30-day readmission or development of an inpatient complication in patients ready for discharge on POD 2 was not significant (P = .073). Table 1 summarizes the statistical results.

As age 65 years or older is one of the major criteria for Medicare eligibility, a secondary analysis was performed to explore whether there were age-related differences in the study outcomes. We found no significant differences between patients 65 years or older and patients younger than 65 years with respect to discharge readiness, LOS, postoperative complications, or 30-day readmission. Table 2 summarizes the statistical results based on age.

Discussion

Consistent with our pilot study,⁴ the majority of patients discharged to an ECF were ready for discharge on POD 2. Delaying discharge until POD 3 increased LOS by 1.08 days with no significant risk in 30-day readmission if patients were allowed to be discharged 1 day earlier. Different from our pilot study results, however, 17.5% of patients who stayed past their discharge readiness showed improvement in PT/OT progress, though this was not clinically sufficient to alter the decision regarding discharge destination. This difference can be attributed to the fact that the current study (vs the pilot study) was adequately powered for this outcome.

Our study was specifically designed to evaluate the effect of Medicare’s 3-day rule—the requirement of an inpatient hospital stay of at least 3 consecutive days to qualify for coverage for treatment at an ECF. This policy creates tremendous unnecessary hospitalization and resource utilization and denies patients earlier access to specialized postacute care. To put the economic implications of this policy in perspective, almost half of the 1 million TJAs performed annually are performed for Medicare beneficiaries, and almost half of those patients are discharged to an ECF.^1,2,5 This equates to about 161,000 days of unnecessary hospitalization per year (64.4% of 250,000 patients), which translates into $310,730,000 in expenditures based on an average cost of $1930 per inpatient day for state/local government, nonprofit, and for-profit hospitals.⁶ Furthermore, with a growing trend toward outpatient TJA, the Medicare statute may leave substantial bills for patients who happen to require unplanned discharge to an ECF.

This study had its weaknesses. First, it was a retrospective review of charts at a single tertiary-care hospital. However, observer bias may have been eliminated, as the data were collected before a study was planned. An outcome such as discharge readiness, if prospectively assessed, could easily have been influenced by study personnel. Second, our patient sample was too small to definitively resolve this issue and be able to effect public policy change. However, there was sufficient power for the primary outcome. We also analyzed a consecutive group of patients who underwent a standardized postoperative clinical pathway with clear discharge-readiness criteria.

The effect of this study in the era of the Patient Protection and Affordable Care Act and its Bundled Payments for Care Improvement (BPCI) initiative deserves special attention. The BPCI initiative is divided into 4 models that reconcile payments associated with an episode of care (eg, TKA) against a predetermined payment amount.⁷ Relevant to our study, BPCI model 2 covers inpatient hospitalization up to 30, 60, or 90 days after discharge and includes a waiver of the 3-day rule for inpatient hospitalization. There are only 60 BPCI model 2–participating health care organizations. On the basis of our study results, we think the waiver is a step in the right direction, as no demonstrable benefits were realized from having patients stay hospitalized longer. However, the waiver should not be limited to select entities, and we hope that, with further research, the statutory requirement of 3-day inpatient hospitalization will be repealed.

Conclusion

Our study results call into question the validity of Medicare’s 3-day rule, and we hope they stimulate further research to definitively resolve this question. The majority of our study patients destined for discharge to an ECF could have been safely discharged on POD 2. The implications of reducing LOS cannot be overstated. From a hospital perspective, reducing LOS eliminates unnecessary hospitalization and resource utilization. From a patient perspective, it allows earlier access to specialized care and eliminates billing confusion. From a payer perspective, it may reduce costs significantly.

Medicare beneficiaries’ demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has increased significantly over the past several years, with recent studies reporting 209,945 primary THAs and 243,802 primary TKAs performed annually.^1,2 With this demand has come an increase in the percentage of patients discharged to an extended-care facility (ECF) for skilled nursing care or acute rehabilitation—an estimated 49.3% for THA and 41.5% for TKA.^1,2 To qualify for discharge to an ECF, Medicare beneficiaries are required to have an inpatient stay of at least 3 consecutive days.³ Although the basis of this rule is unclear, it is thought to prevent hasty discharge of unstable patients.

We conducted a study to explore the effect of this policy on length of stay (LOS) in a population of patients who underwent primary total joint arthroplasty (TJA). Based on a pilot study by our group, we hypothesized that such a statuary requirement would be associated with increased LOS and would not prevent discharge of potentially unstable patients. Specifically, we explored whether patients who could have been discharged earlier experienced any later inpatient complications or 30-day readmission to justify staying past their discharge readiness.

Materials and Methods

Institutional review board approval was obtained for this study. Between 2011 and 2012, the senior authors (Dr. Wellman, Dr. Attarian, Dr. Bolognesi) treated 985 patients with Current Procedural Terminology (CPT) codes 27130 (THA) and 27447 (TKA). Of the 985 patients, 287 (29.13%) were discharged to an ECF and were included in the study. Three of the 287 were excluded: 2 for requiring preadmission for medical optimization and 1 for having another procedure with plastic surgery. All patients were admitted from home on day of surgery and had a standardized clinical pathway with respect to pain control, mobilization, and anticoagulation. Physical therapy and occupational therapy (PT/OT) were initiated on day of surgery and were continued daily until discharge.

The primary outcome was discharge readiness, defined as meeting the criteria of stable blood pressure, pulse, and breathing; no fever over 101.5°F for 24 hours before discharge; wound healing with no concerns; pain controlled with oral medications; and ambulation or the potential for rehabilitation at the receiving facility. Secondary outcomes were changes in PT/OT progress, medical interventions, and 30-day readmission rate. PT/OT progress was categorized as either slow or steady by the therapist assigned to each patient at time of hospitalization. Steady progress indicated overall improvement on several measures, including transfers, ambulation distance, and ability to adhere to postoperative precautions; slow progress indicated no improvement on these measures.

Results for continuous variables were summarized with means, standard deviations, and ranges, and results for categorical variables were summarized with counts and percentages. Student t test was used to evaluate increase in LOS, and the McNemar test for paired data was used to analyze rehabilitation gains from readiness-for-discharge day to the next postoperative day (POD). SAS Version 9.2 software (SAS Institute) was used for all analyses.

Results

Of the 284 patients included in the study, 203 were female (71.5%), 81 male (28.5%). Mean (SD) age was 68 (11) years (range, 21-92 years). One hundred seventy-nine patients (63.0%) underwent TKA, and 105 (37.0%) underwent THA. Two hundred twenty-seven patients (80.0%) were discharged to skilled nursing care, and 57 (20.1%) to inpatient rehabilitation. Mean (SD) LOS was 3.44 (0.92) days (range, 3-9 days). One hundred eighty-three patients (64.4%) were ready for discharge on POD 2, 76 (26.8%) on POD 3, and 25 (8.8%) after POD 3. Delaying discharge until POD 3 increased LOS by 1.08 days (P < .001). Two hundred nine patients (73.6%) were discharged on POD 3, and 75 (26.4%) after POD 3. Reasons for being discharged after POD 3 were lack of ECF bed availability (48 patients, 64.0%) and postoperative complications (27 patients, 36.0%). Patients ready for discharge on POD 2 had fewer complications than patients ready after POD 2 (P < .001).

Analysis of the 183 patients who were ready for discharge on POD 2 demonstrated a statistically significant (P = .038) change in rehabilitation progress by staying an additional hospital day. However, this difference was not clinically significant: Only 17.5% of patients improved, while 82.5% remained unchanged or declined in progress. Most important, among patients who demonstrated rehabilitation gains, the improvement was not sufficient to change the decision regarding discharge destination. Three patients (1.6%) ready for discharge on POD 2 were readmitted within 30 days of discharge (2 for wound infection, 1 for syncope). Risk for 30-day readmission or development of an inpatient complication in patients ready for discharge on POD 2 was not significant (P = .073). Table 1 summarizes the statistical results.

As age 65 years or older is one of the major criteria for Medicare eligibility, a secondary analysis was performed to explore whether there were age-related differences in the study outcomes. We found no significant differences between patients 65 years or older and patients younger than 65 years with respect to discharge readiness, LOS, postoperative complications, or 30-day readmission. Table 2 summarizes the statistical results based on age.

Discussion

Consistent with our pilot study,⁴ the majority of patients discharged to an ECF were ready for discharge on POD 2. Delaying discharge until POD 3 increased LOS by 1.08 days with no significant risk in 30-day readmission if patients were allowed to be discharged 1 day earlier. Different from our pilot study results, however, 17.5% of patients who stayed past their discharge readiness showed improvement in PT/OT progress, though this was not clinically sufficient to alter the decision regarding discharge destination. This difference can be attributed to the fact that the current study (vs the pilot study) was adequately powered for this outcome.

Our study was specifically designed to evaluate the effect of Medicare’s 3-day rule—the requirement of an inpatient hospital stay of at least 3 consecutive days to qualify for coverage for treatment at an ECF. This policy creates tremendous unnecessary hospitalization and resource utilization and denies patients earlier access to specialized postacute care. To put the economic implications of this policy in perspective, almost half of the 1 million TJAs performed annually are performed for Medicare beneficiaries, and almost half of those patients are discharged to an ECF.^1,2,5 This equates to about 161,000 days of unnecessary hospitalization per year (64.4% of 250,000 patients), which translates into $310,730,000 in expenditures based on an average cost of $1930 per inpatient day for state/local government, nonprofit, and for-profit hospitals.⁶ Furthermore, with a growing trend toward outpatient TJA, the Medicare statute may leave substantial bills for patients who happen to require unplanned discharge to an ECF.

This study had its weaknesses. First, it was a retrospective review of charts at a single tertiary-care hospital. However, observer bias may have been eliminated, as the data were collected before a study was planned. An outcome such as discharge readiness, if prospectively assessed, could easily have been influenced by study personnel. Second, our patient sample was too small to definitively resolve this issue and be able to effect public policy change. However, there was sufficient power for the primary outcome. We also analyzed a consecutive group of patients who underwent a standardized postoperative clinical pathway with clear discharge-readiness criteria.

The effect of this study in the era of the Patient Protection and Affordable Care Act and its Bundled Payments for Care Improvement (BPCI) initiative deserves special attention. The BPCI initiative is divided into 4 models that reconcile payments associated with an episode of care (eg, TKA) against a predetermined payment amount.⁷ Relevant to our study, BPCI model 2 covers inpatient hospitalization up to 30, 60, or 90 days after discharge and includes a waiver of the 3-day rule for inpatient hospitalization. There are only 60 BPCI model 2–participating health care organizations. On the basis of our study results, we think the waiver is a step in the right direction, as no demonstrable benefits were realized from having patients stay hospitalized longer. However, the waiver should not be limited to select entities, and we hope that, with further research, the statutory requirement of 3-day inpatient hospitalization will be repealed.

Conclusion

Our study results call into question the validity of Medicare’s 3-day rule, and we hope they stimulate further research to definitively resolve this question. The majority of our study patients destined for discharge to an ECF could have been safely discharged on POD 2. The implications of reducing LOS cannot be overstated. From a hospital perspective, reducing LOS eliminates unnecessary hospitalization and resource utilization. From a patient perspective, it allows earlier access to specialized care and eliminates billing confusion. From a payer perspective, it may reduce costs significantly.

Medicare beneficiaries’ demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA) has increased significantly over the past several years, with recent studies reporting 209,945 primary THAs and 243,802 primary TKAs performed annually.^1,2 With this demand has come an increase in the percentage of patients discharged to an extended-care facility (ECF) for skilled nursing care or acute rehabilitation—an estimated 49.3% for THA and 41.5% for TKA.^1,2 To qualify for discharge to an ECF, Medicare beneficiaries are required to have an inpatient stay of at least 3 consecutive days.³ Although the basis of this rule is unclear, it is thought to prevent hasty discharge of unstable patients.

We conducted a study to explore the effect of this policy on length of stay (LOS) in a population of patients who underwent primary total joint arthroplasty (TJA). Based on a pilot study by our group, we hypothesized that such a statuary requirement would be associated with increased LOS and would not prevent discharge of potentially unstable patients. Specifically, we explored whether patients who could have been discharged earlier experienced any later inpatient complications or 30-day readmission to justify staying past their discharge readiness.

Materials and Methods

Institutional review board approval was obtained for this study. Between 2011 and 2012, the senior authors (Dr. Wellman, Dr. Attarian, Dr. Bolognesi) treated 985 patients with Current Procedural Terminology (CPT) codes 27130 (THA) and 27447 (TKA). Of the 985 patients, 287 (29.13%) were discharged to an ECF and were included in the study. Three of the 287 were excluded: 2 for requiring preadmission for medical optimization and 1 for having another procedure with plastic surgery. All patients were admitted from home on day of surgery and had a standardized clinical pathway with respect to pain control, mobilization, and anticoagulation. Physical therapy and occupational therapy (PT/OT) were initiated on day of surgery and were continued daily until discharge.

The primary outcome was discharge readiness, defined as meeting the criteria of stable blood pressure, pulse, and breathing; no fever over 101.5°F for 24 hours before discharge; wound healing with no concerns; pain controlled with oral medications; and ambulation or the potential for rehabilitation at the receiving facility. Secondary outcomes were changes in PT/OT progress, medical interventions, and 30-day readmission rate. PT/OT progress was categorized as either slow or steady by the therapist assigned to each patient at time of hospitalization. Steady progress indicated overall improvement on several measures, including transfers, ambulation distance, and ability to adhere to postoperative precautions; slow progress indicated no improvement on these measures.

Results for continuous variables were summarized with means, standard deviations, and ranges, and results for categorical variables were summarized with counts and percentages. Student t test was used to evaluate increase in LOS, and the McNemar test for paired data was used to analyze rehabilitation gains from readiness-for-discharge day to the next postoperative day (POD). SAS Version 9.2 software (SAS Institute) was used for all analyses.

Results

Of the 284 patients included in the study, 203 were female (71.5%), 81 male (28.5%). Mean (SD) age was 68 (11) years (range, 21-92 years). One hundred seventy-nine patients (63.0%) underwent TKA, and 105 (37.0%) underwent THA. Two hundred twenty-seven patients (80.0%) were discharged to skilled nursing care, and 57 (20.1%) to inpatient rehabilitation. Mean (SD) LOS was 3.44 (0.92) days (range, 3-9 days). One hundred eighty-three patients (64.4%) were ready for discharge on POD 2, 76 (26.8%) on POD 3, and 25 (8.8%) after POD 3. Delaying discharge until POD 3 increased LOS by 1.08 days (P < .001). Two hundred nine patients (73.6%) were discharged on POD 3, and 75 (26.4%) after POD 3. Reasons for being discharged after POD 3 were lack of ECF bed availability (48 patients, 64.0%) and postoperative complications (27 patients, 36.0%). Patients ready for discharge on POD 2 had fewer complications than patients ready after POD 2 (P < .001).

Analysis of the 183 patients who were ready for discharge on POD 2 demonstrated a statistically significant (P = .038) change in rehabilitation progress by staying an additional hospital day. However, this difference was not clinically significant: Only 17.5% of patients improved, while 82.5% remained unchanged or declined in progress. Most important, among patients who demonstrated rehabilitation gains, the improvement was not sufficient to change the decision regarding discharge destination. Three patients (1.6%) ready for discharge on POD 2 were readmitted within 30 days of discharge (2 for wound infection, 1 for syncope). Risk for 30-day readmission or development of an inpatient complication in patients ready for discharge on POD 2 was not significant (P = .073). Table 1 summarizes the statistical results.

As age 65 years or older is one of the major criteria for Medicare eligibility, a secondary analysis was performed to explore whether there were age-related differences in the study outcomes. We found no significant differences between patients 65 years or older and patients younger than 65 years with respect to discharge readiness, LOS, postoperative complications, or 30-day readmission. Table 2 summarizes the statistical results based on age.

Discussion

Consistent with our pilot study,⁴ the majority of patients discharged to an ECF were ready for discharge on POD 2. Delaying discharge until POD 3 increased LOS by 1.08 days with no significant risk in 30-day readmission if patients were allowed to be discharged 1 day earlier. Different from our pilot study results, however, 17.5% of patients who stayed past their discharge readiness showed improvement in PT/OT progress, though this was not clinically sufficient to alter the decision regarding discharge destination. This difference can be attributed to the fact that the current study (vs the pilot study) was adequately powered for this outcome.

Our study was specifically designed to evaluate the effect of Medicare’s 3-day rule—the requirement of an inpatient hospital stay of at least 3 consecutive days to qualify for coverage for treatment at an ECF. This policy creates tremendous unnecessary hospitalization and resource utilization and denies patients earlier access to specialized postacute care. To put the economic implications of this policy in perspective, almost half of the 1 million TJAs performed annually are performed for Medicare beneficiaries, and almost half of those patients are discharged to an ECF.^1,2,5 This equates to about 161,000 days of unnecessary hospitalization per year (64.4% of 250,000 patients), which translates into $310,730,000 in expenditures based on an average cost of $1930 per inpatient day for state/local government, nonprofit, and for-profit hospitals.⁶ Furthermore, with a growing trend toward outpatient TJA, the Medicare statute may leave substantial bills for patients who happen to require unplanned discharge to an ECF.

This study had its weaknesses. First, it was a retrospective review of charts at a single tertiary-care hospital. However, observer bias may have been eliminated, as the data were collected before a study was planned. An outcome such as discharge readiness, if prospectively assessed, could easily have been influenced by study personnel. Second, our patient sample was too small to definitively resolve this issue and be able to effect public policy change. However, there was sufficient power for the primary outcome. We also analyzed a consecutive group of patients who underwent a standardized postoperative clinical pathway with clear discharge-readiness criteria.

The effect of this study in the era of the Patient Protection and Affordable Care Act and its Bundled Payments for Care Improvement (BPCI) initiative deserves special attention. The BPCI initiative is divided into 4 models that reconcile payments associated with an episode of care (eg, TKA) against a predetermined payment amount.⁷ Relevant to our study, BPCI model 2 covers inpatient hospitalization up to 30, 60, or 90 days after discharge and includes a waiver of the 3-day rule for inpatient hospitalization. There are only 60 BPCI model 2–participating health care organizations. On the basis of our study results, we think the waiver is a step in the right direction, as no demonstrable benefits were realized from having patients stay hospitalized longer. However, the waiver should not be limited to select entities, and we hope that, with further research, the statutory requirement of 3-day inpatient hospitalization will be repealed.

Conclusion

Our study results call into question the validity of Medicare’s 3-day rule, and we hope they stimulate further research to definitively resolve this question. The majority of our study patients destined for discharge to an ECF could have been safely discharged on POD 2. The implications of reducing LOS cannot be overstated. From a hospital perspective, reducing LOS eliminates unnecessary hospitalization and resource utilization. From a patient perspective, it allows earlier access to specialized care and eliminates billing confusion. From a payer perspective, it may reduce costs significantly.

NEW YORK  - Older adults living in long-term care are more than twice as likely as their peers living at home to suffer a fracture, and a new guideline endorsed by the Scientific Advisory Council of Osteoporosis Canada explains how to reduce their risk.

Residents of long-term care tend to be frailer and have more health problems than similar people who live on their own, which explains the higher risk of fractures in long-term care facilities, said lead author Dr. Alexandra Papaioannou of McMaster University and Hamilton Health Sciences in Hamilton, Ontario.

"Up to a third of seniors in long-term care suffer a fracture," often of the hip or spine, she said. For these residents, "long-term care is their home, the nurses know them, and acute care can be a frightening traumatic experience for residents."

The authors developed the new guideline based on input from older people and their families, who most wanted to avoid pain, loss of activity, and hospitalization, Papaioannou said. They also studied published literature on the risks and benefits of strategies to prevent fracture.

The guideline strongly recommends calcium supplementation of 1200 mg or three servings of dairy daily for people older than 70. These calcium levels reduce hip fracture risk and slightly reduce the risk of other fractures, but they may also cause gastrointestinal side effects. For residents who want to avoid these, supplementation may not be a good option, the authors write.

Residents at high risk of fracture, i.e., those with prior fracture of the hip or spine, more than one prior fracture, or one prior fracture and recent use of glucocorticoids, should also take daily vitamin D3 supplements, which are more affordable than vitamin D2, the authors wrote online September 14 in CMAJ.

They also recommend that high-risk residents take alendronate weekly, or risedronate weekly or monthly, as first-line therapy to prevent fractures, as long as they do not have difficulty swallowing and can remain upright for 30 minutes after administration, and they do not have severe renal insufficiency.

For residents who are at high risk of fractures and who have difficulty taking oral medications, they recommend zoledronic acid or denosumab as first-line therapy.

High-risk residents who are mobile should wear hip-protectors, which can protect against fracture in the event of a fall. Low-risk residents who are mobile may wear the devices, depending on their values and preferences.

Balance, strength, and functional exercise can help prevent falls for low-risk residents, and may be useful for high-risk residents, but the exercise itself increases the risk of fall slightly.

Lastly, the authors recommend that all residents have "multifactorial interventions" that are tailored to each individual and include medication reviews, environmental hazard assessment, assistive device use, exercise, and educational interventions for staff.

"Many residents have multiple medical conditions and we need to make sure that they include their lifespan and goals of care in the assessment," Papaioannou said. "The goals of those with short lifespans may be very different from those with longer lifespans."

These recommendations are similar to those for residential care facilities in Australia and the ones made by the Society for Post-Acute and Long-Term Care Medicine in the U.S., the authors point out.

"The document is an excellent guide on how to identify patients at risk, who should be treated and how," said Dr. Gustavo Duque, director of the Musculoskeletal Ageing Research Program at the University of Sydney in Australia.

Doctors often reduce medications for residents who are admitted to nursing homes without realizing that those with osteoporosis or previous fractures are more likely to suffer a fracture at their new residence than in the community, Duque, who was not involved in writing the new guideline, said by email.

"Ceasing osteoporosis treatment has demonstrated to increase the risk of fractures," Duque said. "Unfortunately we see that situation every day."

NEW YORK  - Older adults living in long-term care are more than twice as likely as their peers living at home to suffer a fracture, and a new guideline endorsed by the Scientific Advisory Council of Osteoporosis Canada explains how to reduce their risk.

Residents of long-term care tend to be frailer and have more health problems than similar people who live on their own, which explains the higher risk of fractures in long-term care facilities, said lead author Dr. Alexandra Papaioannou of McMaster University and Hamilton Health Sciences in Hamilton, Ontario.

"Up to a third of seniors in long-term care suffer a fracture," often of the hip or spine, she said. For these residents, "long-term care is their home, the nurses know them, and acute care can be a frightening traumatic experience for residents."

The authors developed the new guideline based on input from older people and their families, who most wanted to avoid pain, loss of activity, and hospitalization, Papaioannou said. They also studied published literature on the risks and benefits of strategies to prevent fracture.

The guideline strongly recommends calcium supplementation of 1200 mg or three servings of dairy daily for people older than 70. These calcium levels reduce hip fracture risk and slightly reduce the risk of other fractures, but they may also cause gastrointestinal side effects. For residents who want to avoid these, supplementation may not be a good option, the authors write.

Residents at high risk of fracture, i.e., those with prior fracture of the hip or spine, more than one prior fracture, or one prior fracture and recent use of glucocorticoids, should also take daily vitamin D3 supplements, which are more affordable than vitamin D2, the authors wrote online September 14 in CMAJ.

They also recommend that high-risk residents take alendronate weekly, or risedronate weekly or monthly, as first-line therapy to prevent fractures, as long as they do not have difficulty swallowing and can remain upright for 30 minutes after administration, and they do not have severe renal insufficiency.

For residents who are at high risk of fractures and who have difficulty taking oral medications, they recommend zoledronic acid or denosumab as first-line therapy.

High-risk residents who are mobile should wear hip-protectors, which can protect against fracture in the event of a fall. Low-risk residents who are mobile may wear the devices, depending on their values and preferences.

Balance, strength, and functional exercise can help prevent falls for low-risk residents, and may be useful for high-risk residents, but the exercise itself increases the risk of fall slightly.

Lastly, the authors recommend that all residents have "multifactorial interventions" that are tailored to each individual and include medication reviews, environmental hazard assessment, assistive device use, exercise, and educational interventions for staff.

"Many residents have multiple medical conditions and we need to make sure that they include their lifespan and goals of care in the assessment," Papaioannou said. "The goals of those with short lifespans may be very different from those with longer lifespans."

These recommendations are similar to those for residential care facilities in Australia and the ones made by the Society for Post-Acute and Long-Term Care Medicine in the U.S., the authors point out.

"The document is an excellent guide on how to identify patients at risk, who should be treated and how," said Dr. Gustavo Duque, director of the Musculoskeletal Ageing Research Program at the University of Sydney in Australia.

Doctors often reduce medications for residents who are admitted to nursing homes without realizing that those with osteoporosis or previous fractures are more likely to suffer a fracture at their new residence than in the community, Duque, who was not involved in writing the new guideline, said by email.

"Ceasing osteoporosis treatment has demonstrated to increase the risk of fractures," Duque said. "Unfortunately we see that situation every day."

NEW YORK  - Older adults living in long-term care are more than twice as likely as their peers living at home to suffer a fracture, and a new guideline endorsed by the Scientific Advisory Council of Osteoporosis Canada explains how to reduce their risk.

Residents of long-term care tend to be frailer and have more health problems than similar people who live on their own, which explains the higher risk of fractures in long-term care facilities, said lead author Dr. Alexandra Papaioannou of McMaster University and Hamilton Health Sciences in Hamilton, Ontario.

"Up to a third of seniors in long-term care suffer a fracture," often of the hip or spine, she said. For these residents, "long-term care is their home, the nurses know them, and acute care can be a frightening traumatic experience for residents."

The authors developed the new guideline based on input from older people and their families, who most wanted to avoid pain, loss of activity, and hospitalization, Papaioannou said. They also studied published literature on the risks and benefits of strategies to prevent fracture.

The guideline strongly recommends calcium supplementation of 1200 mg or three servings of dairy daily for people older than 70. These calcium levels reduce hip fracture risk and slightly reduce the risk of other fractures, but they may also cause gastrointestinal side effects. For residents who want to avoid these, supplementation may not be a good option, the authors write.

Residents at high risk of fracture, i.e., those with prior fracture of the hip or spine, more than one prior fracture, or one prior fracture and recent use of glucocorticoids, should also take daily vitamin D3 supplements, which are more affordable than vitamin D2, the authors wrote online September 14 in CMAJ.

They also recommend that high-risk residents take alendronate weekly, or risedronate weekly or monthly, as first-line therapy to prevent fractures, as long as they do not have difficulty swallowing and can remain upright for 30 minutes after administration, and they do not have severe renal insufficiency.

For residents who are at high risk of fractures and who have difficulty taking oral medications, they recommend zoledronic acid or denosumab as first-line therapy.

High-risk residents who are mobile should wear hip-protectors, which can protect against fracture in the event of a fall. Low-risk residents who are mobile may wear the devices, depending on their values and preferences.

Balance, strength, and functional exercise can help prevent falls for low-risk residents, and may be useful for high-risk residents, but the exercise itself increases the risk of fall slightly.

Lastly, the authors recommend that all residents have "multifactorial interventions" that are tailored to each individual and include medication reviews, environmental hazard assessment, assistive device use, exercise, and educational interventions for staff.

"Many residents have multiple medical conditions and we need to make sure that they include their lifespan and goals of care in the assessment," Papaioannou said. "The goals of those with short lifespans may be very different from those with longer lifespans."

These recommendations are similar to those for residential care facilities in Australia and the ones made by the Society for Post-Acute and Long-Term Care Medicine in the U.S., the authors point out.

"The document is an excellent guide on how to identify patients at risk, who should be treated and how," said Dr. Gustavo Duque, director of the Musculoskeletal Ageing Research Program at the University of Sydney in Australia.

Doctors often reduce medications for residents who are admitted to nursing homes without realizing that those with osteoporosis or previous fractures are more likely to suffer a fracture at their new residence than in the community, Duque, who was not involved in writing the new guideline, said by email.

"Ceasing osteoporosis treatment has demonstrated to increase the risk of fractures," Duque said. "Unfortunately we see that situation every day."

Patient undergoing CT scan

Photo by Angela Mary Butler

Clinicians should stratify patients with suspected acute pulmonary embolism (PE) to ensure use of the appropriate diagnostic strategy, according to guidelines from the American College of Physicians (ACP).

The ACP’s guidelines, published in Annals of Internal Medicine, are designed to help clinicians identify patients who should undergo diagnostic testing for PE—D-dimer and imaging—and those who should not.

“The use of computed tomography (CT) for the evaluation of patients with suspected pulmonary embolism is increasing, despite no evidence that this increased use has led to improved patient outcomes, while exposing patients to unnecessary risks and expense,” said ACP President Wayne J. Riley, MD.

“ACP’s advice is designed to help physicians identify patients for whom a PE is so unlikely that they need no further testing, for whom plasma D-dimer testing can provide additional risk stratification, and for whom imaging is indicated because of their high risk and clinical presentation.”

The guidelines say the first step for clinicians evaluating patients with suspected acute PE is to use a validated clinical prediction rule to estimate the patients’ pre-test probability of PE. The Wells and Geneva rules have been validated and are considered equally accurate in predicting the probability of PE.

In patients who have a low pre-test probability of PE, clinicians should apply the Pulmonary Embolism Rule-Out Criteria (PERC) rule. Clinicians should not obtain D-dimer tests or imaging studies in patients with a low pre-test probability of PE and who meet all 8 PERC.

Patients who have an intermediate pre-test probability of PE or patients with low pre-test probability of PE who do not meet all PERC should have a high sensitivity D-dimer test as the initial step in diagnosis.

Clinicians should not use imaging as the initial test in patients who have a low or intermediate pre-test probability of PE.

Since normal D-dimer levels increase with age, clinicians should use age-adjusted D-dimer thresholds (age times 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine whether imaging is warranted.

Clinicians should not use imaging in low- or intermediate-risk patients with a D-dimer below the age-adjusted cutoff.

“While highly sensitive, plasma D-dimer testing is nonspecific, and false-positives can lead to unnecessary imaging,” said guideline author Ali S. Raja, MD, of Massachusetts General Hospital in Boston.

“The use of an age-adjusted threshold resulted in maintenance of sensitivities with improved specificities in all age groups.”

Patients with high pre-test probability of PE should undergo imaging with CT pulmonary angiography. Clinicians should reserve V/Q scans for patients who have a contraindication for CT pulmonary angiography or if CT pulmonary angiography is not available.

Clinicians should avoid obtaining a D-dimer measurement in patients with a high pre-test probability of PE.

Patient undergoing CT scan

Photo by Angela Mary Butler

Clinicians should stratify patients with suspected acute pulmonary embolism (PE) to ensure use of the appropriate diagnostic strategy, according to guidelines from the American College of Physicians (ACP).

The ACP’s guidelines, published in Annals of Internal Medicine, are designed to help clinicians identify patients who should undergo diagnostic testing for PE—D-dimer and imaging—and those who should not.

“The use of computed tomography (CT) for the evaluation of patients with suspected pulmonary embolism is increasing, despite no evidence that this increased use has led to improved patient outcomes, while exposing patients to unnecessary risks and expense,” said ACP President Wayne J. Riley, MD.

“ACP’s advice is designed to help physicians identify patients for whom a PE is so unlikely that they need no further testing, for whom plasma D-dimer testing can provide additional risk stratification, and for whom imaging is indicated because of their high risk and clinical presentation.”

The guidelines say the first step for clinicians evaluating patients with suspected acute PE is to use a validated clinical prediction rule to estimate the patients’ pre-test probability of PE. The Wells and Geneva rules have been validated and are considered equally accurate in predicting the probability of PE.

In patients who have a low pre-test probability of PE, clinicians should apply the Pulmonary Embolism Rule-Out Criteria (PERC) rule. Clinicians should not obtain D-dimer tests or imaging studies in patients with a low pre-test probability of PE and who meet all 8 PERC.

Patients who have an intermediate pre-test probability of PE or patients with low pre-test probability of PE who do not meet all PERC should have a high sensitivity D-dimer test as the initial step in diagnosis.

Clinicians should not use imaging as the initial test in patients who have a low or intermediate pre-test probability of PE.

Since normal D-dimer levels increase with age, clinicians should use age-adjusted D-dimer thresholds (age times 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine whether imaging is warranted.

Clinicians should not use imaging in low- or intermediate-risk patients with a D-dimer below the age-adjusted cutoff.

“While highly sensitive, plasma D-dimer testing is nonspecific, and false-positives can lead to unnecessary imaging,” said guideline author Ali S. Raja, MD, of Massachusetts General Hospital in Boston.

“The use of an age-adjusted threshold resulted in maintenance of sensitivities with improved specificities in all age groups.”

Patients with high pre-test probability of PE should undergo imaging with CT pulmonary angiography. Clinicians should reserve V/Q scans for patients who have a contraindication for CT pulmonary angiography or if CT pulmonary angiography is not available.

Clinicians should avoid obtaining a D-dimer measurement in patients with a high pre-test probability of PE.

Patient undergoing CT scan

Photo by Angela Mary Butler

Clinicians should stratify patients with suspected acute pulmonary embolism (PE) to ensure use of the appropriate diagnostic strategy, according to guidelines from the American College of Physicians (ACP).

The ACP’s guidelines, published in Annals of Internal Medicine, are designed to help clinicians identify patients who should undergo diagnostic testing for PE—D-dimer and imaging—and those who should not.

“The use of computed tomography (CT) for the evaluation of patients with suspected pulmonary embolism is increasing, despite no evidence that this increased use has led to improved patient outcomes, while exposing patients to unnecessary risks and expense,” said ACP President Wayne J. Riley, MD.

“ACP’s advice is designed to help physicians identify patients for whom a PE is so unlikely that they need no further testing, for whom plasma D-dimer testing can provide additional risk stratification, and for whom imaging is indicated because of their high risk and clinical presentation.”

The guidelines say the first step for clinicians evaluating patients with suspected acute PE is to use a validated clinical prediction rule to estimate the patients’ pre-test probability of PE. The Wells and Geneva rules have been validated and are considered equally accurate in predicting the probability of PE.

In patients who have a low pre-test probability of PE, clinicians should apply the Pulmonary Embolism Rule-Out Criteria (PERC) rule. Clinicians should not obtain D-dimer tests or imaging studies in patients with a low pre-test probability of PE and who meet all 8 PERC.

Patients who have an intermediate pre-test probability of PE or patients with low pre-test probability of PE who do not meet all PERC should have a high sensitivity D-dimer test as the initial step in diagnosis.

Clinicians should not use imaging as the initial test in patients who have a low or intermediate pre-test probability of PE.

Since normal D-dimer levels increase with age, clinicians should use age-adjusted D-dimer thresholds (age times 10 ng/mL rather than a generic 500 ng/mL) in patients older than 50 years to determine whether imaging is warranted.

Clinicians should not use imaging in low- or intermediate-risk patients with a D-dimer below the age-adjusted cutoff.

“While highly sensitive, plasma D-dimer testing is nonspecific, and false-positives can lead to unnecessary imaging,” said guideline author Ali S. Raja, MD, of Massachusetts General Hospital in Boston.

“The use of an age-adjusted threshold resulted in maintenance of sensitivities with improved specificities in all age groups.”

Patients with high pre-test probability of PE should undergo imaging with CT pulmonary angiography. Clinicians should reserve V/Q scans for patients who have a contraindication for CT pulmonary angiography or if CT pulmonary angiography is not available.

Clinicians should avoid obtaining a D-dimer measurement in patients with a high pre-test probability of PE.

Laurence Cooper, MD, PhD

Photo courtesy of MDACC

NEW YORK—Researchers have used a nonviral approach to create chimeric antigen receptor (CAR) T cells and tested these cells in safety trials.

Patients with advanced lymphoma or leukemia were infused with the nonvirally modified CD19-directed CAR T cells after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

Eighty-six percent of autologous HSCT recipients were alive 24 months after infusion, and 53% of allogeneic HSCT recipients were alive with a median follow-up of 6.5 months.

“Gratifyingly, the patients have not demonstrated any acute or late toxicity to these CAR T-cell infusions,” said Laurence Cooper, MD, PhD, formerly of MD Anderson Cancer Center (MDACC) in Houston, Texas, and now with Ziopharm Oncology.

Dr Cooper presented these results at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Some of the technology he described was conducted at MDACC. Dr Cooper is currently a visiting scientist there and will continue to supervise the development of this technology.

Dr Cooper said the appeal of this nonviral approach, which is a modified Sleeping Beauty approach, “is it essentially avoids the complexity of making a virus, a lentivirus or a retrovirus, it can be done at quite low cost, and really allows for a nimbleness to this system.”

Using a simple blood draw of 200 cc of peripheral blood—the process does not require apheresis—the T cells can be expanded on a feeder cell layer and genetically reprogrammed.

Sleeping Beauty system

The researchers reprogrammed the T cells using a 2-plasmid Sleeping Beauty system, which is a transposon/transposase system.

The transposon DNA plasmid codes for the cargo load, which, in this case, is the CAR. At the same time, the transposase DNA plasmid is electroporated, “which is really the secret sauce of the transposition event,” Dr Cooper explained.

After electroporation, the transposon/transposase are co-cultured with K562-derived artificial antigen-presenting cells (aAPC) and expanded with the integrated transposon of K562-aAPC. In this case, CD19 is on the aAPC.

CD19 is co-expressed with other co-stimulatory molecules, CD86 and 4-1BB ligand.

In addition, the researchers added a molecule of interleukin 15 that’s sewn in frame to the Fc region of an immunoglobulin that then activates the T cell in the context of these co-stimulatory molecules.

The T cells that have stable integrants of the CAR grow out over time. And those that have transient expression of the CAR die by neglect.

“By day 14, most of the T cells have the CAR sewn into the genome and are stably expressed,” Dr Cooper said.

The CAR used for these safety trials at MDACC targets CD19 and uses mouse scFv held in frame with an immunoglobulin 4 Fc (IgG4Fc) stalk.

It’s tunneled through the T-cell membrane and has 2 costimulatory molecules, signal 1 delivered by phosphorylation of the immunoreceptor tyrosine-based activation motif in CD3ζ and signal 2 by the costimulatory domain CD28.

The researchers tested the CD19 CARs in 2 clinical settings—one with T cells that were patient-derived and infused after autologous HSCT, and the second with T cells that were derived from a third party and infused after allogeneic HSCT.

Infusion after autologous HSCT

The researchers first tried the CARs in 7 non-Hodgkin lymphoma patients who had an autologous HSCT. Their median age was 52 (range, 36-61).

Five patients received a starting CAR T-cell dose of 5x10⁸ cells/m², and 2 received 5x10⁹ cells/m².

Six patients (86%) remain alive and are in complete remission (CR) at a median follow-up of 24 months.

Infusion after allogeneic HSCT

The researchers expanded the investigation to a wider cohort of 19 patients who had undergone allogeneic HSCT.

Seventeen patients had advanced CD19-positive acute lymphoblastic leukemia, and 2 had non-Hodgkin lymphoma. Their median age was 35 (range, 21-56).

All patients were on graft-versus-host disease (GVHD) prophylaxis with tacrolimus at the time of CAR infusion. A subset of these allogeneic transplant patients had haploidentical donors rather than matched sibling donors.

Five patients received a CAR T-cell dose of 10⁶, 6 patients received 10⁷, 5 received 5x10⁷, and 3 received 5x10⁸ cells/m² based on recipient body surface area.

Fifty-eight percent of patients (11/19) achieved a CR, and 10 remain alive a median of 6.5 months after CAR T-cell infusion.

Three patients developed GVHD, 1 with steroid-refractory acute liver disease, 1 with grade 2 acute skin disease, and 1 with chronic limited skin disease. The incidence of GVHD was lower than historical controls at MDACC, Dr Cooper said.

“[G]ratifyingly, in this clinical setting of minimal disease, patients did not have any acute or late toxicity from these infusions,” he added.

And the rate of cytomegalovirus reactivation after CAR T-cell infusion was 24%, compared with 41% for patients after transplant at MDACC without CAR T-cell infusion.

Eight patients received haploidentical HSCT followed by CAR T-cell infusion, and 75% (6/8) remain in CR.

Persistence of infused T cells

The researchers used 2 forms of PCR—qPCR and droplet PCR—to map the fate of the CARs.

“Roughly speaking, for these patients, and this is in line with the literature, in terms of those T cells that are activated through CD28 in contrast to 4-1BB, these T cells are, on average, living about 28 or so days post-infusion,” Dr Cooper noted.

He said this is similar to results observed with CARs being tested at the National Cancer Institute and Memorial Sloan-Kettering Cancer Center.

Laurence Cooper, MD, PhD

Photo courtesy of MDACC

NEW YORK—Researchers have used a nonviral approach to create chimeric antigen receptor (CAR) T cells and tested these cells in safety trials.

Patients with advanced lymphoma or leukemia were infused with the nonvirally modified CD19-directed CAR T cells after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

Eighty-six percent of autologous HSCT recipients were alive 24 months after infusion, and 53% of allogeneic HSCT recipients were alive with a median follow-up of 6.5 months.

“Gratifyingly, the patients have not demonstrated any acute or late toxicity to these CAR T-cell infusions,” said Laurence Cooper, MD, PhD, formerly of MD Anderson Cancer Center (MDACC) in Houston, Texas, and now with Ziopharm Oncology.

Dr Cooper presented these results at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Some of the technology he described was conducted at MDACC. Dr Cooper is currently a visiting scientist there and will continue to supervise the development of this technology.

Dr Cooper said the appeal of this nonviral approach, which is a modified Sleeping Beauty approach, “is it essentially avoids the complexity of making a virus, a lentivirus or a retrovirus, it can be done at quite low cost, and really allows for a nimbleness to this system.”

Using a simple blood draw of 200 cc of peripheral blood—the process does not require apheresis—the T cells can be expanded on a feeder cell layer and genetically reprogrammed.

Sleeping Beauty system

The researchers reprogrammed the T cells using a 2-plasmid Sleeping Beauty system, which is a transposon/transposase system.

The transposon DNA plasmid codes for the cargo load, which, in this case, is the CAR. At the same time, the transposase DNA plasmid is electroporated, “which is really the secret sauce of the transposition event,” Dr Cooper explained.

After electroporation, the transposon/transposase are co-cultured with K562-derived artificial antigen-presenting cells (aAPC) and expanded with the integrated transposon of K562-aAPC. In this case, CD19 is on the aAPC.

CD19 is co-expressed with other co-stimulatory molecules, CD86 and 4-1BB ligand.

In addition, the researchers added a molecule of interleukin 15 that’s sewn in frame to the Fc region of an immunoglobulin that then activates the T cell in the context of these co-stimulatory molecules.

The T cells that have stable integrants of the CAR grow out over time. And those that have transient expression of the CAR die by neglect.

“By day 14, most of the T cells have the CAR sewn into the genome and are stably expressed,” Dr Cooper said.

The CAR used for these safety trials at MDACC targets CD19 and uses mouse scFv held in frame with an immunoglobulin 4 Fc (IgG4Fc) stalk.

It’s tunneled through the T-cell membrane and has 2 costimulatory molecules, signal 1 delivered by phosphorylation of the immunoreceptor tyrosine-based activation motif in CD3ζ and signal 2 by the costimulatory domain CD28.

The researchers tested the CD19 CARs in 2 clinical settings—one with T cells that were patient-derived and infused after autologous HSCT, and the second with T cells that were derived from a third party and infused after allogeneic HSCT.

Infusion after autologous HSCT

The researchers first tried the CARs in 7 non-Hodgkin lymphoma patients who had an autologous HSCT. Their median age was 52 (range, 36-61).

Five patients received a starting CAR T-cell dose of 5x10⁸ cells/m², and 2 received 5x10⁹ cells/m².

Six patients (86%) remain alive and are in complete remission (CR) at a median follow-up of 24 months.

Infusion after allogeneic HSCT

The researchers expanded the investigation to a wider cohort of 19 patients who had undergone allogeneic HSCT.

Seventeen patients had advanced CD19-positive acute lymphoblastic leukemia, and 2 had non-Hodgkin lymphoma. Their median age was 35 (range, 21-56).

All patients were on graft-versus-host disease (GVHD) prophylaxis with tacrolimus at the time of CAR infusion. A subset of these allogeneic transplant patients had haploidentical donors rather than matched sibling donors.

Five patients received a CAR T-cell dose of 10⁶, 6 patients received 10⁷, 5 received 5x10⁷, and 3 received 5x10⁸ cells/m² based on recipient body surface area.

Fifty-eight percent of patients (11/19) achieved a CR, and 10 remain alive a median of 6.5 months after CAR T-cell infusion.

Three patients developed GVHD, 1 with steroid-refractory acute liver disease, 1 with grade 2 acute skin disease, and 1 with chronic limited skin disease. The incidence of GVHD was lower than historical controls at MDACC, Dr Cooper said.

“[G]ratifyingly, in this clinical setting of minimal disease, patients did not have any acute or late toxicity from these infusions,” he added.

And the rate of cytomegalovirus reactivation after CAR T-cell infusion was 24%, compared with 41% for patients after transplant at MDACC without CAR T-cell infusion.

Eight patients received haploidentical HSCT followed by CAR T-cell infusion, and 75% (6/8) remain in CR.

Persistence of infused T cells

The researchers used 2 forms of PCR—qPCR and droplet PCR—to map the fate of the CARs.

“Roughly speaking, for these patients, and this is in line with the literature, in terms of those T cells that are activated through CD28 in contrast to 4-1BB, these T cells are, on average, living about 28 or so days post-infusion,” Dr Cooper noted.

He said this is similar to results observed with CARs being tested at the National Cancer Institute and Memorial Sloan-Kettering Cancer Center.

Laurence Cooper, MD, PhD

Photo courtesy of MDACC

NEW YORK—Researchers have used a nonviral approach to create chimeric antigen receptor (CAR) T cells and tested these cells in safety trials.

Patients with advanced lymphoma or leukemia were infused with the nonvirally modified CD19-directed CAR T cells after autologous or allogeneic hematopoietic stem cell transplant (HSCT).

Eighty-six percent of autologous HSCT recipients were alive 24 months after infusion, and 53% of allogeneic HSCT recipients were alive with a median follow-up of 6.5 months.

“Gratifyingly, the patients have not demonstrated any acute or late toxicity to these CAR T-cell infusions,” said Laurence Cooper, MD, PhD, formerly of MD Anderson Cancer Center (MDACC) in Houston, Texas, and now with Ziopharm Oncology.

Dr Cooper presented these results at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

Some of the technology he described was conducted at MDACC. Dr Cooper is currently a visiting scientist there and will continue to supervise the development of this technology.

Dr Cooper said the appeal of this nonviral approach, which is a modified Sleeping Beauty approach, “is it essentially avoids the complexity of making a virus, a lentivirus or a retrovirus, it can be done at quite low cost, and really allows for a nimbleness to this system.”

Using a simple blood draw of 200 cc of peripheral blood—the process does not require apheresis—the T cells can be expanded on a feeder cell layer and genetically reprogrammed.

Sleeping Beauty system

The researchers reprogrammed the T cells using a 2-plasmid Sleeping Beauty system, which is a transposon/transposase system.

The transposon DNA plasmid codes for the cargo load, which, in this case, is the CAR. At the same time, the transposase DNA plasmid is electroporated, “which is really the secret sauce of the transposition event,” Dr Cooper explained.

After electroporation, the transposon/transposase are co-cultured with K562-derived artificial antigen-presenting cells (aAPC) and expanded with the integrated transposon of K562-aAPC. In this case, CD19 is on the aAPC.

CD19 is co-expressed with other co-stimulatory molecules, CD86 and 4-1BB ligand.

In addition, the researchers added a molecule of interleukin 15 that’s sewn in frame to the Fc region of an immunoglobulin that then activates the T cell in the context of these co-stimulatory molecules.

The T cells that have stable integrants of the CAR grow out over time. And those that have transient expression of the CAR die by neglect.

“By day 14, most of the T cells have the CAR sewn into the genome and are stably expressed,” Dr Cooper said.

The CAR used for these safety trials at MDACC targets CD19 and uses mouse scFv held in frame with an immunoglobulin 4 Fc (IgG4Fc) stalk.

It’s tunneled through the T-cell membrane and has 2 costimulatory molecules, signal 1 delivered by phosphorylation of the immunoreceptor tyrosine-based activation motif in CD3ζ and signal 2 by the costimulatory domain CD28.

The researchers tested the CD19 CARs in 2 clinical settings—one with T cells that were patient-derived and infused after autologous HSCT, and the second with T cells that were derived from a third party and infused after allogeneic HSCT.

Infusion after autologous HSCT

The researchers first tried the CARs in 7 non-Hodgkin lymphoma patients who had an autologous HSCT. Their median age was 52 (range, 36-61).

Five patients received a starting CAR T-cell dose of 5x10⁸ cells/m², and 2 received 5x10⁹ cells/m².

Six patients (86%) remain alive and are in complete remission (CR) at a median follow-up of 24 months.

Infusion after allogeneic HSCT

The researchers expanded the investigation to a wider cohort of 19 patients who had undergone allogeneic HSCT.

Seventeen patients had advanced CD19-positive acute lymphoblastic leukemia, and 2 had non-Hodgkin lymphoma. Their median age was 35 (range, 21-56).

All patients were on graft-versus-host disease (GVHD) prophylaxis with tacrolimus at the time of CAR infusion. A subset of these allogeneic transplant patients had haploidentical donors rather than matched sibling donors.

Five patients received a CAR T-cell dose of 10⁶, 6 patients received 10⁷, 5 received 5x10⁷, and 3 received 5x10⁸ cells/m² based on recipient body surface area.

Fifty-eight percent of patients (11/19) achieved a CR, and 10 remain alive a median of 6.5 months after CAR T-cell infusion.

Three patients developed GVHD, 1 with steroid-refractory acute liver disease, 1 with grade 2 acute skin disease, and 1 with chronic limited skin disease. The incidence of GVHD was lower than historical controls at MDACC, Dr Cooper said.

“[G]ratifyingly, in this clinical setting of minimal disease, patients did not have any acute or late toxicity from these infusions,” he added.

And the rate of cytomegalovirus reactivation after CAR T-cell infusion was 24%, compared with 41% for patients after transplant at MDACC without CAR T-cell infusion.

Eight patients received haploidentical HSCT followed by CAR T-cell infusion, and 75% (6/8) remain in CR.

Persistence of infused T cells

The researchers used 2 forms of PCR—qPCR and droplet PCR—to map the fate of the CARs.

“Roughly speaking, for these patients, and this is in line with the literature, in terms of those T cells that are activated through CD28 in contrast to 4-1BB, these T cells are, on average, living about 28 or so days post-infusion,” Dr Cooper noted.

He said this is similar to results observed with CARs being tested at the National Cancer Institute and Memorial Sloan-Kettering Cancer Center.