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C OPYRIGHT Ó 2017 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

Magnetic Resonance-Guided Focused Ultrasound

Versus Conventional Radiation Therapy for Painful
Bone Metastasis
A Matched-Pair Study
Hsin-Lun Lee, MD, Chia-Chun Kuo, MD, Jo-Ting Tsai, MD, PhD, Chun-You Chen, MD, Meng-Huang Wu, MD,
and Jeng-Fong Chiou, MD, PhD

Investigation performed at the Taipei Medical University Hospital, Taipei, Taiwan

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) is an alternative local therapy for patients with
painful bone metastasis for whom standard conventional radiation therapy (RT) has failed. However, the therapeutic
effects of MRgFUS as a first-line treatment for bone metastasis remain uncertain.
Methods: A matched-pair study was conducted to compare the therapeutic effects of MRgFUS with those of conventional
RT as a first-line treatment for patients with painful bone metastasis. The MRgFUS and RT-treated groups were matched
1:2 by age, sex, primary cancer, pretreatment pain score, and treated site.
Results: According to the criteria for patient eligibility and matching, 21 and 42 patients (total, 63 patients) with bone
metastasis treated with MRgFUS and conventional RT, respectively, were enrolled for analyses. The median ages of the
MRgFUS and RT-treated patients were 59 and 61 years, respectively. Among the enrolled patients, 52% were male and
48% were female. The results showed that both MRgFUS and RT were effective. However, MRgFUS was more efficient than
RT in terms of the time course of pain palliation as it yielded a significantly higher response rate at 1 week after treatment
(71% versus 26%, p = 0.0009).
Conclusions: MRgFUS provides a similar overall treatment response rate but faster pain relief compared with conven-
tional RT and has the potential to serve as the first-line treatment for painful bone metastasis in selected patients.
Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

B
one metastasis is one of the most prevalent types of
metastases, resulting in pain and functional disability
affecting the functional status and quality of life of pa-
tients with cancer1-3. Current approaches for bone metastasis
are individualized according to a patient’s overall prognosis
and often combine local therapies with disease-appropriate
systemic drugs for maintaining quality of life4.
Traditionally, conventional radiation therapy (RT) has
been the mainstay of local therapy to relieve pain and restore
function of patients with symptomatic bone metastasis, whereas
surgery has been reserved for patients with pathological or
impending fracture5. In general, RT provides a response rate in
the range of 60% to 80% in terms of pain relief 6,7. However,
the periodic use of analgesics to achieve optimal pain control,
despite the associated adverse effects, is common4,5. With the
advancement of medical technology, the use of thermal ablation
techniques such as high-intensity focused ultrasound, radiofre-
quency ablation, and cryoablation as alternative local therapies
for painful bone metastasis has been increasing to reduce anal-
gesic use8-11. High-intensity focused ultrasound hyperthermia,
which induces coagulative necrosis of targeted lesions in the
thermal range of 65°C to 85°C12, shows an enhanced therapeutic
ratio in the treatment of bone metastasis, as compared with
locations other than bone, because the rate of absorption of its
ultrasound energy in cortical bone is 50 times higher than that in
other biological tissues13,14.
Magnetic resonance-guided focused ultrasound (MRgFUS),
which integrates magnetic resonance (MR) imaging guidance

Disclosure: This research was supported in part by a research grant from Taipei Medical University Hospital, Taipei Medical University, Taiwan
(105TMUH-NE-02). The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/
E316).

J Bone Joint Surg Am. 2017;99:1572-8 d http://dx.doi.org/10.2106/JBJS.16.01248

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with high-intensity focused ultrasound hyperthermia, allows
continuous monitoring of the treatment location and tem-
perature mapping through MR thermometry to ensure precise
heating of the targeted lesion15-17. MRgFUS has been demon-
strated to be effective in pain management for patients with
bone metastasis and has a response rate of 64.3% to 72.0% for
patients for whom conventional RT has failed and who meet
the accessibility criteria for use of the device18-20. These criteria
were summarized11,20 as (1) no unstable underlying disease (e.g.,
active infection, recent cerebrovascular accident, and acute car-
diovascular disease) or contraindications for MR imaging; (2) a
visible bone lesion at least 1 cm away from the tissues at risk (e.g.,
nerve bundles, skin, and hollow viscera) as seen on MR images;
(3) a bone lesion treatable by high-intensity focused ultrasound
and not shielded by dense tissues (e.g., extensive scarring and non-
targeted bones) or air (e.g., hollow viscera); and (4) a targeted
bone lesion located in the shoulder, the rib cage, the pelvis, an
extremity (excluding joints), or dorsal spinal vertebrae below L2.
The therapeutic effects of MRgFUS as a first-line treat-
ment for bone metastasis remain inconclusive. We therefore
conducted this matched-pair study to compare the therapeutic
effects of MRgFUS with those of conventional RT in patients
with painful bone metastasis.
Materials and Methods
Patient Eligibility
W e retrospectively reviewed the electronic medical records of patients with
bone metastasis treated with MRgFUS or conventional RT between
January 1, 2011, and June 30, 2015, at Taipei Medical University Hospital,
Taiwan. The inclusion criteria for enrollment in this study were (1) a solitary
distinguishable painful bone metastasis with a score of ‡4 on the 11-point
numerical rating scale (NRS, with 0 indicating no pain and 10 indicating the
21
worst pain imaginable) irrespective of pain medication; (2) no previous local
therapy to the targeted bone lesion; (3) the ability to access the targeted bone
lesion with both MRgFUS
11,20
and RT; (4) an unchanged schedule of systemic
therapy, including chemotherapy, targeted therapy, hormonal therapy, and
bone-targeted agents (e.g., bisphosphonates and receptor activator of nuclear
factor-kB ligand [RANKL] inhibitors), 2 weeks before and 3 months after the
intervention with MRgFUS or RT; (5) a Karnofsky performance status of ‡60
before the intervention; and (6) survival and regular follow-up of ‡3 months
22
after the MRgFUS or RT intervention. Patients with a Mirels score of >7,
indicating impending pathological fracture, or with substantial comorbidities
according to clinical judgment were excluded.
This study was approved by the Taipei Medical University - Joint In-
stitutional Review Board. In our institute, patients with newly diagnosed bone
metastasis are discussed by a multidisciplinary cancer team to determine the
treatment strategy and evidence-based management. Conventional RT was
recommended as the standard first-line treatment for those with confirmed
23
localized pain induced by a specific metastatic bone lesion seen on MR or
22
computed tomography (CT) imaging and with a Mirels score of £7, irre-
spective of whether pain medicine was administered. MRgFUS treatment was
11,20
reserved for those who refused irradiation and met the accessibility criteria
for use of MRgFUS as an alternative. We performed CT simulations to localize
the targeted bone lesion with optimal patient positioning before both treat-
ments and then repeated the positions on the treatment couch to avoid repo-
sitioning and to facilitate treatment delivery.
MRgFUS Treatment
The MRgFUS procedure began with acquiring a series of MR images over the
targeted area. Midazolam and meperidine were intravenously administered for
M A G N E T I C R E S O N A N C E - G U I D E D F O C U S E D U LT R A S O U N D V S .
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24
conscious sedation, as specified by the American Society of Anesthesiologists ,
after lesion localization. Physicians identified symptomatic bone lesions
by viewing MR images on the workstation of the Exablate 2000 system
(INSIGHTEC); the physicians delineated regions for treatment and marked
“risky” areas (e.g., nerve bundles and regions with extensive scarring) as “no-pass
zones,” thereby instructing the device to avoid these areas. After the verification
and any appropriate modification of the treatment plan calculated by the plan-
ning software, therapeutic high-intensity focused ultrasound was delivered to the
region for treatment with real-time temperature monitoring using MR imaging.
This energy delivery (sonication) process was repeated at multiple adjacent points
to cover the entire target volume. Additional intravenous morphine was ad-
ministered during treatment depending on the intraprocedure pain or as deemed
necessary. After treatment, a contrast-enhanced MR imaging study was performed
18
to assess the effects of the thermal ablation . Nonsteroidal anti-inflammatory
drugs and corticosteroids were administered for 3 days for prophylaxis of local
inflammation.
Conventional RT
Three-dimensional conformal RT delivered using a linear accelerator with a 6
or 10-MV x-ray beam was the standard technique for bone irradiation in this
study. Physicians contoured a clinical target volume enclosing the symptomatic
bone lesion with avoidance of surrounding organs at risk on image sets of CT
simulation. An additional 5 to 10-mm margin was maintained to form the
planning target volume. The dose scheme of palliative RT was 30.0 to 37.5 Gy
in 10 to 15 fractions.
Response Evaluation and Follow-up
The treatment response was assessed using the criteria of the International
Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in
25
Bone Metastases . In this set of criteria, a complete response indicates re-
duction of pain to 0 on the NRS at the treated site without a concomitant
increase in the morphine-equivalent daily dose. A partial response is defined
as pain reduction of ‡2 points on the NRS at the treated site without an in-
crease in the morphine-equivalent daily dose, or a reduction of ‡25% in the
morphine-equivalent daily dose from baseline without an increase in the pain
score on the NRS.
Two experienced radiation oncologists independently evaluated the treat-
ment response and adverse events related to MRgFUS and RTat 1 and 2 weeks and
1, 2, and 3 months after each treatment. Patients who exhibited a complete or
partial response were classified as responders, and the others were classified as
nonresponders. Treatment-related adverse events were documented according to
26
the Common Terminology Criteria for Adverse Events, version 4.03 .
Matched-Pair Design and Statistical Analysis
A matched-pair study was conducted as exploratory research for comparing the
therapeutic effects of MRgFUS with those of conventional RT as a first-line
treatment for patients with painful bone metastasis. The MRgFUS and RT-
treated groups were matched 1:2 by age (±5 years), sex, primary cancer, pre-
treatment pain score on the NRS (moderate and severe), and treated site. The
primary end point of this study was the clinical treatment response rate in terms
25
of successful pain palliation at each evaluation point after either MRgFUS or
RT, whereas the secondary end points were a change in the pain score on the
NRS and a change in the morphine-equivalent daily dose and treatment-related
adverse events during the 3 months after treatment.
The comparison of categorical variables between the 2 groups was
performed using the chi-square test, whereas the comparison of continuous
and ordinal variables was done with the Student t test or Mann-Whitney U test.
The comparison of the changes in the NRS score and morphine-equivalent
daily dose between the 2 groups at each evaluation point was performed using
the Student t test. The Fisher exact test was used to analyze the difference in
response rate between the 2 treatment modalities. The overall survival rate was
calculated from the day of commencement of the MRgFUS or RT to the date
of death or last follow-up. We used the Kaplan-Meier method to plot overall
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survival curves for each group, and we compared these curves using the log-
rank test. A 2-sided p value of <0.05 was considered significant. All statistical
analyses were performed using Python 2.7 with the SciPy module (version
0.14.0) or the Lifelines module (version 0.9.2).
Results
Clinical Characteristics
metastasis, 426 patients (56%) underwent RT, 45 (6%) un-
derwent surgery, 29 (4%) received MRgFUS, and 263 (34%)
underwent observation with systemic medication. On the basis
of the 1:2 matching procedure, 21 and 42 patients (total, 63
patients) treated using MRgFUS and conventional RT, respec-
tively, were enrolled for analysis according to the criteria for

A ccording to the electronic medical records, 763 patients

were documented to have newly diagnosed bone metastasis
during the study period. For the first-line management of bone
patient eligibility and matching.
The clinical characteristics of MRgFUS and RT-treated
patients are listed in Table I. No significant differences in age,

TABLE I Clinical Characteristics of Matched Pairs of Patients with Bone Metastasis Treated with MRgFUS and RT

Characteristics MRgFUS (N = 21) RT (N = 42) P Value

Age* (yr) 59 (40 to 83) 61 (39 to 88) 0.3768

Sex (no. [%]) 1.0000
Male 11 (52%) 22 (52%)
Female 10 (48%) 20 (48%)
Pretreatment Karnofsky performance status* 80 (60 to 90) 80 (60 to 90) 0.6911
Primary cancer (no. [%]) 1.0000
Breast 4 (19%) 8 (19%)
Nasopharyngeal 4 (19%) 8 (19%)
Colorectal 3 (14%) 6 (14%)
Non-small-cell lung 3 (14%) 6 (14%)
Hepatocellular carcinoma 2 (10%) 4 (10%)
Prostate 2 (10%) 4 (10%)
Renal cell carcinoma 1 (5%) 2 (5%)
Cervical 1 (5%) 2 (5%)
Thymic 1 (5%) 2 (5%)
Systemic therapy (no. [%])
Chemotherapy 15 27 0.7768
Targeted therapy 1 6 0.4785
Hormonal therapy 6 8 0.5922
Bone-targeted agents 3 5 0.8936
Pretreatment NRS pain score† (points) 6.57 ± 1.62 6.21 ± 1.61 0.4186
Moderate (4 to 6) (no. [%]) 8 (38%) 16 (38%) 1.0000
Severe (7 to 10) (no. [%]) 13 (62%) 26 (62%) 1.0000
Pretreatment morphine-equivalent daily dose† (mg/day) 49.89 ± 57.53 47.64 ± 57.41 0.8888
Treated site (no. [%]) 1.0000
Pelvis‡ 18 (85%) 36 (86%)
Zone 1 12 32 0.2070
Zone 2 1 5 0.6489
Zone 3 2 3 0.8691
Zone 4 9 23 0.5328
Limb 2 (10%) 4 (10%)
Upper 1 2
Lower 1 2
Rib cage 1 (5%) 2 (5%)
Targeted lesion size† (cm) 5.15 ± 1.92 5.77 ± 3.11 0.4122

*The values are given as the median with the range in parentheses. †The values are given as the mean and standard deviation. ‡The involved
33,34
anatomic regions of the pelvis were classified according to the system of Enneking et al. .
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Fig. 1
Mean NRS pain scores at each evaluation point after treatment of patients
with bone metastasis with MRgFUS and RT. The error bars indicate the
95% confidence interval (CI).
sex distribution, primary cancer, pretreatment NRS pain
score, treated site, or systemic therapy were observed between
the MRgFUS and RT-treated patients in the matched pairs. The
pretreatment Karnofsky performance status (p = 0.6911) and
targeted lesion size (p = 0.4122) were also similar between the 2
treatment groups. All MRgFUS-treated patients underwent a
single procedure for a targeted bone lesion in the size range
of 2.3 to 9.8 cm. In the series as a whole, 38% experienced
moderate pain and 62% experienced severe pain. The vast
majority (85%) of the treated sites were in the pelvic bone,
followed by the limbs (10%) and rib cage (5%).
Treatment Response
All of the recruited patients with bone metastasis were followed
for at least 3 months after treatment with either MRgFUS or
RT. The mean pretreatment NRS pain score (and standard
deviation) was 6.57 ± 1.62 and 6.21 ± 1.61 in the MRgFUS and
RT-treated groups, respectively (p = 0.4186). The changes in
the NRS pain score over time are shown in Figure 1. The mean
NRS pain score of the MRgFUS-treated patients was signifi-
cantly lower at 1 week (2.5 versus 4.8, p < 0.0001), 2 weeks (2.1
versus 3.6, p = 0.0188), and 3 months (1.0 versus 2.3, p =
0.0269) after treatment than those of the RT-treated patients;
however, the scores did not differ significantly at 1 month (2.0
versus 2.8, p = 0.1849) or 2 months (1.7 versus 2.2, p = 0.3509)
after treatment. The mean pretreatment morphine-equivalent
daily dose was 49.89 ± 57.53 mg/day in the MRgFUS-treated
group and 47.64 ± 57.41 mg/day in the RT-treated group (p =
0.8888). Figure 2 represents the mean morphine-equivalent
daily dose change from baseline (in mg) at each evaluation
point, which did not differ significantly between the 2 treat-
ment groups at 1 week (212.7 versus 21.2, p = 0.1934), 2 weeks
(222.4 versus 0.2, p = 0.0905), 1 month (220.9 versus 3.0,
p = 0.1191), 2 months (211.4 versus 24.2, p = 0.6310), or
3 months (28.4 versus 22.9, p = 0.7418) after treatment.
M A G N E T I C R E S O N A N C E - G U I D E D F O C U S E D U LT R A S O U N D V S .
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The treatment response rates of the MRgFUS and
RT-treated patients at each evaluation point are presented in
Figure 3. At 1 week after treatment, 71% of the MRgFUS-treated
patients and 26% of the RT-treated patients experienced a
treatment response (p = 0.0009). By the second week after
treatment, the MRgFUS-treated patients showed a trend toward
a significantly higher response rate than the RT-treated patients
(76% versus 50%, p = 0.0600). The differences in treat-
ment response rates between the MRgFUS and RT-treated pa-
tients were not significant at 1 month (81% versus 67%, p =
0.3753), 2 months (81% versus 74%, p = 0.7548), or 3 months
(76% versus 71%, p = 0.7706). The overall complete-response
rates at 3 months were 43% and 29% in the MRgFUS and
RT-treated patients (p = 0.2729), respectively. Of the 5 patients
in the MRgFUS group and the 12 in the RT group who were
classified as nonresponders, 1 and 4, respectively, had radio-
graphic evidence of tumor progression and received subsequent
RT and MRgFUS, respectively, at the treated site. The cancer
treatment was also altered to achieve pain relief and disease
control.
Outcome and Toxicity
The median overall survival time was 12.7 and 9.8 months after
treatment with MRgFUS and RT, respectively (p = 0.6184;
see Appendix). The treatment-related adverse events within
3 months are presented in the Appendix. No adverse events
above grade 226 were documented for either the MRgFUS or
the RT-treated patients. While under conscious sedation dur-
ing the sonication carried out for the MRgFUS procedure,
2 (10%) of the 21 patients reported grade-2 pain and required
temporary treatment interruption. One case of grade-2 myo-
sitis was observed 3 days after the MRgFUS and was relieved
by administering anti-inflammatory drugs until the 2-week
follow-up evaluation. No fever, fracture, or neuropathy was
observed during the follow-up period. Among the RT-treated
patients, 2 (5%) with pelvic RT experienced transient grade-2
Fig. 2
Mean changes (compared with baseline) in the morphine-equivalent daily
dose (MEDD) at each evaluation point after treatment of patients with bone
metastasis with MRgFUS and RT. The error bars indicate the 95% CI.
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Fig. 3
Treatment response rates at each evaluation point after treatment
of patients with bone metastasis with MRgFUS and RT.
diarrhea, which stabilized after administration of antidiarrheal
medicines during the treatment course.
Discussion
I n this matched-pair study, we compared the clinical out-
comes of MRgFUS with those of conventional RT as the first-
line treatment for patients with painful bone metastasis. The
results showed that both MRgFUS and RT, which provided
response rates of >70% at the 3-month follow-up evaluation,
were effective. MRgFUS was more efficient than RT in terms
of the time course of pain palliation as it was associated with
a significantly higher response rate at 1 week after treatment
(71% versus 26%, p = 0.0009). At 2 weeks post-treatment, the
MRgFUS-treated patients exhibited a trend toward a more
favorable response rate compared with the RT-treated patients
(76% versus 50%, p = 0.0600). Throughout the follow-up
period, the rate of responders was higher in the MRgFUS-treated
group than in the RT-treated group; however, the difference
was not statistically significant after 1 week. The total treatment
time and cost of MRgFUS and RT were similar in our study (see
Appendix).
Currently, conventional RT is the initial treatment of
choice for painful bone metastasis and offers a 60% to 80%
treatment response rate, including a 15% to 40% complete-
response rate, as determined using patient-scored pain assess-
ment7. The putative mechanism of pain relief involves the
inactivation of osteoclasts to change the microenvironment of
bone resorption followed by sterilization of cancer cells to
reduce tumor-induced compression5. With the development
of highly conformal RT, limited evidence has shown that
stereotactic body radiation therapy is useful to re-irradiate
recurrent bone metastasis because it effectively spares adja-
cent critical structures27. However, the efficacy and safety
of stereotactic body radiation therapy as a first-line treatment
for bone metastasis remain to be validated by clinical trials28.
Furthermore, advanced minimally invasive techniques allow
the precise percutaneous delivery of thermal ablative methods
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and provide alternative means for tumor management. For
instance, radiofrequency ablation has been reported to con-
siderably reduce pain in patients with osteolytic bone metastasis
for whom standard treatments have failed29. In contrast, few
studies on cryoablation have shown its effectiveness in treating
painful bone metastasis9,10.
Recently, MRgFUS has emerged as an alternative treat-
ment for painful bone metastasis by delivering high-intensity
focused ultrasound energy to induce thermal damage in the
targeted area under MR imaging guidance and thermome-
try18,19. A previous multicenter study showed rapid pain relief at
3 days and a 72% response rate (36% partial-response and 36%
complete-response rates) at 3 months after MRgFUS treat-
ment18. Furthermore, a phase-III randomized controlled study
demonstrated that the response rate of MRgFUS-treated pa-
tients was higher than that of a placebo group (64.3% versus
20%, p < 0.001) at 3 months after treatment, and the MRgFUS-
treated group showed acceptable complications20. According
to preliminary evidence, rapid and durable pain relief can
result from immediate periosteal nerve ablation and thermal
necrosis of the targeted bone tumor followed by remineralization
of the trabecular bone and bone healing a few months later11,18,19,30.
Consequently, MRgFUS provides an alternative means to over-
come radioresistance and is recommended for patients with bone
metastasis for whom RT is considered to have failed11,20.
Similar to previously reported studies, the current study
showed a comparative overall response rate of 76% and 71% at
3 months after MRgFUS and RT, respectively. Neither treat-
ment modality was associated with adverse events above grade
226. The most common complication of MRgFUS in the cur-
rent study was procedure-related pain, including a 14% rate of
positioning-related pain and a 33% rate of sonication-related
pain, which typically resolved 1 day after treatment. Because
MRgFUS treatment is usually completed in a single procedure—
except when it is used for recurrent or new lesions—local,
regional, or general anesthesia might be incorporated with
cautious monitoring to further reduce procedure-related pain11.
Improvements in cancer-specific treatments have in-
creased the duration of survival of patients presenting with
bone metastasis. The median overall survival of the patients
with bone metastasis in the current study was 12.7 and 9.8 months
after MRgFUS and RT, respectively, which is longer than the
previously reported median survival of 30 weeks following
treatment for bone metastasis31. However, patients with painful
bone metastasis frequently have inadequate pain management
despite an increased understanding of effective methods of
treatment for cancer-related pain32. Therefore, optimizing the
treatment strategy for patients with bone metastasis by inte-
grating multimodal treatments with minimal toxicities to reduce
pain, restore function, and maintain quality of life is imperative.
The primary limitations of the current study are the
small sample size and the retrospective design. By adopting
a matched-pair design to mitigate potential bias, we demon-
strated that, when used as the first-line treatment for pain-
ful bone metastasis in selected patients, MRgFUS provides a
similar overall treatment response rate with regard to pain
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relief, and provides pain relief more efficiently, as compared
with conventional RT. However, the application of MRgFUS
is constrained by its ablative nature and device-related re-
strictions, which exclude the skull, most of the spine, and lesions
that are not at least 1 cm away from tissues at risk. Another
limitation of our study was that we reported clinical responses
for a limited, 3-month follow-up period. With the increase in
survival of patients with bone metastasis, longer follow-up du-
rations with objective radiographic evaluation of responses
should be incorporated into future studies to elucidate the role
of and optimize patient selection for MRgFUS and RT.
Appendix
A figure demonstrating the overall survival of the patients
after the MRgFUS and RT as well as tables showing the
treatment-related acute adverse events after, and procedure time
and costs of, the MRgFUS and RT are available with the online
version of this article as a data supplement at jbjs.org (http://
links.lww.com/JBJS/E317). n
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