Radiofrequency Ablation, an Effective Modality of Treatment in

S P E C I A L
C l i n i c a l
C a s e
F E A T U R E
S e m i n a r
Radiofrequency Ablation, an Effective Modality of
Treatment in Tumor-Induced Osteomalacia: A Case
Series of Three Patients
Swati Jadhav, Rajeev Kasaliwal, Nitin S. Shetty, Suyash Kulkarni,
Krantikumar Rathod, Bhavesh Popat, Harshal Kakade, Amol Bukan, Shruti Khare,
Sweta Budyal, Varsha S. Jagtap, Anurag R. Lila, Tushar Bandgar,
and Nalini S. Shah
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Department of Endocrinology (S.J., R.K.), Seth G. S. Medical College and King Edward Memorial
Hospital, Parel, Mumbai, 400012, India; Department of Radiodiagnosis (N.S.She., S.Ku.), Tata Memorial
Centre, Parel, Mumbai 400012, India; and Departments of Radiology (K.R., B.P.) and Endocrinology
(H.K., A.B., S.Kh., S.B., V.S.J., A.R.L., T.B., N.S.Sha.), Seth G. S. Medical College and King Edward
Memorial Hospital, Parel, Mumbai, 400012, India
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Context: Tumor-induced osteomalacia is curable if the tumors can be totally excised. However,
when the tumors are present in locations that make surgery disproportionately risky, the need for
less invasive strategies like radiofrequency ablation (RFA) is realized.
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Patients and Methods: We describe three patients with suspected tumor-induced osteomalacia
who were treated in our department between 2006 and 2013 with tumors in surgically difficult
locations and were subjected to single or multiple sessions of RFA. The response was documented
in terms of symptomatic improvement, phosphorus normalization, and follow-up 99mTechnitiumlabelled hydrazinonicotinyl-Tyr3-octreotide (99mTc HYNIC TOC) scan.
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Results: Two of the three individuals, patient A (with a 1.5 ⫻ 1.2-cm lesion in the head of the right
femur) and patient B (with a 1.3 ⫻ 1.2-cm lesion on the endosteal surface of the shaft of the left
femur), achieved complete remission with single sessions of RFA. Three months after the procedure, 99mTc HYNIC TOC scans revealed the absence of uptake at the previous sites, corroborating
with the clinical improvement and phosphorus normalization. Patient C had a large 5.6 ⫻ 6.5-cm
complex lesion in the lower end of the left femur with irregular margins, loculations, and bone
grafts placed in previous surgery. He failed to achieve remission after multiple sessions of RFA due
to the complex nature of the lesion, although the tumor burden was reduced significantly as
documented on serial 99mTc HYNIC TOC scans.
Conclusions: Although surgery remains the treatment of choice, RFA could be an effective, less
invasive, and safe modality of treatment in judiciously selected patients. (J Clin Endocrinol Metab
99: 3049 –3054, 2014)
umor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with predominantly benign tumors of mesenchymal origin. Less than 400 cases
have been reported to date (1). It is a syndrome of acquired
hypophosphatemic osteomalacia caused by “phosphatonins” like fibroblast growth factor (FGF) 23 (the most
T
well characterized), FGF7, secreted frizzle-related protein 4, and matrix extracellular protein (2, 3). Histopathologically, the tumors associated with TIO are classified as phosphaturic mesenchymal tumors (PMTs),
the most common of which is the PMT mixed connective tissue variant, and others being PMT osteoblas-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received December 25, 2013. Accepted June 6, 2014.
First Published Online June 24, 2014
Abbreviations: CT, computed tomography; FGF, fibroblast growth factor; MRI, magnetic
resonance imaging; PMT, phosphaturic mesenchymal tumor; RFA, radiofrequency ablation; SPECT, single photon emission CT; 99mTc HYNIC TOC, 99mTechnitium-labelled hydrazinonicotinyl-Tyr3-octreotide; TIO, tumor-induced osteomalacia; TMP/GFR, tubular
maximum for phosphate corrected for glomerular filtration rate.
doi: 10.1210/jc.2013-4515
J Clin Endocrinol Metab, September 2014, 99(9):3049 –3054
jcem.endojournals.org
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3049
RFA in Tumor-Induced Osteomalacia
J Clin Endocrinol Metab, September 2014, 99(9):3049 –3054
99m
Tc HYNIC TOC scan
Whole body planar acquisition was done 4 hours after iv
injection of 15 mCi of 99mTc-HYNIC-TOC, followed by regional single photon emission CT (SPECT)/CT (Infinia Hawkeye; GE Healthcare). SPECT data were acquired in a 128 ⫻ 128
matrix through 360° rotation with 64 projections with an acquisition time of 20 seconds per projection in a step-and-shoot
mode, with low-dose CT used for attenuation correction and
anatomic characterization.
Anatomical imaging
Anatomical characterization of the lesions was done using CT
or MRI scans. CT scans were obtained on a 64-slice Philips Brilliance CT scanner (Philips Healthcare), whereas MRI scans were
performed on a 1.5 T Siemens Sonata MR scanner (Siemens
Medical Solutions, Inc).
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Radiofrequency ablation
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After the procedure was explained to the patients and their
informed consent was obtained, RFA was performed under
general anesthesia. A multislice CT scanner machine was used,
with the regional scan limited to the area of lesion using low
radiation protocol (75 mA, 120 kV) to reduce the radiation
exposure.
An 11-gauge bone biopsy needle (Cook Medical) was used to
enter the lesions using all aseptic precautions, and biopsy of the
lesions was performed before ablation. All of the lesions were
entered manually without the need of a drill. RFA was performed
using multi-tined monopolar electrodes (RITA Medical Systems
Inc, AngioDynamics), and ablation was performed for an adequate time (5–10 min), depending on the size of the lesion, with
a target temperature of 90°C. Overlapping ablations were done
to achieve complete ablation. Particular care was taken if the part
of the lesion was adjacent to the joint surface or articular cartilage. Postprocedure physiotherapy was recommended for all patients. Patients who had lesions in weight-bearing areas were
advised to rest and to refrain from carrying weights for 3 weeks.
RFA was repeated after 1 month for the larger lesions in which
residue was expected (patient C).
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toma-like variant, ossifying fibroma-like variant, and
non-ossifying fibroma-like variant (4). Rare associations with malignant neoplasms like prostatic carcinoma and renal cell carcinoma have also been reported
(5, 6). The localization of these tumors is often challenging because they can be present anywhere from the
head to the toes, in soft tissues as well as in the bones,
and are often small in size. Hence, the best strategy to
localize them is to do functional imaging (with somatostatin receptor-based scans) first, followed by targeted anatomical imaging (computed tomography [CT]
or magnetic resonance imaging [MRI]) (7).
The patients with TIO can be cured completely if the
tumor is properly localized and completely excised. Although surgery remains the treatment of choice, these tumors are often in difficult locations, deep in the bones or
close to joints. In such circumstances, surgery might endanger the adjacent joints, or disproportionate tissue injury might occur in an attempt to access the tumor. These
are the cases where less invasive modalities of treatment
like radiofrequency ablation (RFA) are required. We describe our experience with RFA in three TIO patients with
tumors in such difficult locations.
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Jadhav et al
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Patients and Methods
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We describe three patients with suspected TIO who were
treated in our department between 2006 and 2013 and were
offered single or multiple sessions of RFA as a modality of
treatment for various reasons (as described later). The details
of clinical history, physical examination, biochemistry, functional imaging, anatomical characterization, and follow-up
for clinical outcome were reviewed for each patient. The diagnosis of TIO was presumed based on clinical features, biochemical profile, imaging characteristics, and the response to
treatment. Bone biopsy was not performed in any of the
patients.
Biochemical assays
Routine biochemical evaluation included serum calcium,
phosphorus, alkaline phosphatase, creatinine, albumin, 25hydroxyvitamin D, 1,25-dihydroxyvitamin D, PTH, tubular
maximum for phosphate corrected for glomerular filtration
rate (TMP/GFR), and FGF23. Tubular resorption of phosphate was measured from spot fasting urine and serum phosphorus and creatinine at baseline, and TMP/GFR was calculated with the use of a nomogram reported by Bijvoet et al (8).
FGF23 was assessed by ELISA (FGF23 [C-terminal] kit; Immunotopics, Inc). The kit has a sensitivity of 3.0 RU/mL and
intra-assay and interassay coefficients of variation of 5 and
7.3%, respectively.
Functional imaging
Each of the three patients was subjected to functional imaging
with a 99mTechnitium-labelled hydrazinonicotinyl-Tyr3-octreotide (99mTc HYNIC TOC) scan.
Results
The baseline characteristics of the patients are given in
Table 1.
Patient A was a 38-year-old man who presented with
a 6-year history of low backache, diffuse bony pains,
and proximal muscle weakness gradually progressing to
the extent that he had difficulty in performing daily
activities. There was evidence on x-rays of osteomalacia
with multiple pseudofractures. On evaluation, patient
A was found to have hypophosphatemia with renal
phosphate wasting and a high normal FGF23, which
was inappropriate for low phosphorus. For a diagnosis
of oncogenic hypophosphatemic osteomalacia, a 99mTc
HYNIC TOC scan was performed, and the lesion was
found to be localized to the tumor in the head of right
femur. A corresponding contrast-enhancing lesion was
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doi: 10.1210/jc.2013-4515
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Baseline Characteristics: Symptoms, Biochemistry, Imaging, and Follow-Up
Size of the lesion, cm
Tc HYNIC TOC
Anatomical imaging (CT/MRI)
Histopathology
Duration of follow-up after RFA, mo
38
M
6
LBP, PMW, LP
9.6
1.2
3.5
243
110
24
10.2
30
1.25
47.9
28
F
8
LBP, PMW, LP
8.4
1.4
2.6
207
55
27.7
9.39
35
0.68
54.1
49
M
17
LBP, PMW, LP, FR
8.1
1
2.03
261
198
30.3
19.6
0.25
45.5
144.9
23
162.4
41
6000
5500
Head of right femur
Endosteal surface of proximal
shaft of left femur
1.3 ⫻ 1.2
Positive
CT and MRI
NA
15
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Patient C
1.5 ⫻ 1.2
Positive
MRI
NA
12
Lower end of left femur
5.6 ⫻ 6.5
Positive
CT
Non-ossifying fibroma
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99m
Patient B
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Age, y
Sex
Duration of symptoms, y
Symptoms
Calcium, mg/dL (9 –11)
Phosphorus, mg/dL (2.5– 4.5)
Post RFA (day 7)
Alkaline phosphatase, U/L (20 –140)
Post RFA (6 months)
25-hydroxyvitamin D, ng/mL (20 –70)
1,25-dihydroxyvitamin D, pg/mL (19.6 –54.6)
Post RFA (6 mo)
TMP/GFR
PTH, pg/mL (15– 65)
FGF23, RU/mL (0 –150)
Pre RFA
Post RFA (d 7)
Localization
Site of the lesion
Patient A
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Table 1.
jcem.endojournals.org
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Abbreviations: M, male; F, female; LBP, low back pain; PMW, proximal muscle weakness; LP, limbs pain; FR, fractures; NA, not available. Normal
range is given in parentheses.
to the endosteal surface of the proximal shaft of the left
femur, suggesting a diagnosis of TIO. In her case as well,
it was anticipated that accessing the lesion via open
surgery would lead to disproportionate tissue dissection, and hence she was offered a single session of RFA
after discussion with orthopedic surgeons and the interventional radiology teams. The biopsy of the lesion
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found on MRI scan. Owing to the location of the tumor,
it was felt that accessing the tumor surgically would
involve the probability of a breach of the hip joint.
Hence, after discussion with the orthopedic surgeons
and the interventional radiology team, the patient was
offered a single session of RFA. The biopsy of the lesion
was performed before ablation. However, it revealed
only scanty fibrocartilaginous tissue, insufficient for
opinion. The MRI scan performed 7 days after RFA
confirmed complete ablation of the lesion, but there
were postinflammatory changes. The phosphorus returned to normal (3.5 mg/dL) when evaluated 7 days
after the RFA, and FGF23 decreased further from the
baseline value (Table 1). His symptoms resolved completely within 3 months, and he resumed his job. Three
months after RFA, a repeat functional scan with 99mTc
HYNIC TOC showed an absence of uptake in the femoral lesion, further corroborating complete remission
(Figure 1).
Patient B was a 29-year-old woman, a homemaker
who had been incapacitated by low back ache, proximal
muscle weakness, and diffuse lower limb pain of 8-year
duration. Skeletal survey revealed multiple pseudofractures suggesting osteomalacia. She had hypophosphatemia with inappropriately elevated FGF23 (Table
1). Considering a diagnosis of TIO, a 99mTc HYNIC
TOC scan was performed, and the lesion was localized
Figure 1. Patient A. A, 99mTc HYNIC TOC SPECT CT scan showing
uptake in the head of right femur. B, Post contrast T1W fat-saturated
sequence of MRI showing enhancing lesion in the same area. C, RFA
needle in situ. D, Three months after RFA, 99mTc HYNIC TOC SPECT/CT
scan showing the absence of uptake in the same area.
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3052
Jadhav et al
RFA in Tumor-Induced Osteomalacia
J Clin Endocrinol Metab, September 2014, 99(9):3049 –3054
Figure 3. Patient C. A, CT scan showing tumor in the lower end of
left femur. Long arrow shows the bone graft in place, and smaller
arrows show the irregular margins and loculations. B and C, RFA
needle placement during first and second sessions, respectively. D,
Before RFA, 99mTc HYNIC TOC SPECT/CT scan showing diffuse uptake
throughout the lesion. E and F, Sequential reduction in the uptake on
99m
Tc HYNIC TOC SPECT/CT scan after first and fourth RFAs,
respectively.
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be achieved after multiple sessions of RFA, and phosphorus as well as FGF23 failed to normalize.
Discussion
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performed before ablation yielded fibrocartilaginous
tissue insufficient for any opinion. A MRI scan performed 3 days after RFA revealed no residual lesion, but
there were postinflammatory changes. Seven days after
RFA, her phosphorus and FGF23 had normalized (2.6
mg/dL and 41 RU/mL, respectively). She had complete
resolution of symptoms within 3 months, and she could
resume all of her previous activities. The 99mTc HYNIC
TOC scan performed 3 months later demonstrated an
absence of uptake in the previous site in the femur, thus
underscoring complete remission (Figure 2).
Patient C was a 48-year-old man who had a longstanding history of low backache and diffuse lower limb
pain of 17-years duration. He had hypophosphatemia,
multiple pseudofractures on x-rays, and an elevated
FGF23. He was presumed to have hypophosphatemic
osteomalacia and was on long-term phosphorus supplements. The lesion was localized to the lower end of
the right femur when he presented with a pathological
fracture. He underwent his first surgery in 2006, when
bone curettage and grafting were done. However, complete excision could not be achieved due to the extensive
nature of the lesion, and he continued to be on medical
management. In 2013, after a joint consultation, he was
offered RFA as an alternative mode of therapy because
repeat surgery would have involved a high risk of amputation of the lower limb. Owing to the large and complex nature of the lesion with irregular margins and
bone grafts in place, it was envisioned that he might
require multiple sessions of RFA. After four sessions of
RFA, the serial functional imaging with 99mTc HYNIC
TOC scans revealed sequential reduction of uptake in
the corresponding ablated areas, suggesting reduction
in tumor load (Figure 3). However, remission could not
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Figure 2. Patient B. A and B, 99mTc HYNIC TOC SPECT/CT scans
showing uptake in shaft of left femur. C, CT scan showing the lesion
in the same area. D, RFA needle in situ. E and F, Three months after
RFA, the absence of uptake on 99mTc HYNIC TOC SPECT/CT scan.
TIO is a debilitating phosphate-wasting disorder caused
by predominantly mesenchymal tumors producing
phosphatonins like FGF23 and others. The intriguing
feature of these tumors is that apart from the production
of phosphaturic factors, they are otherwise largely benign, although rare associations with malignant tumors
have also been reported (5, 6). These tumors require
complete excision for cure of the underlying condition.
However, as described above, these tumors are often
present in difficult locations where the need for less
invasive modality is realized. In our experience, RFA
can be a useful modality for such situations.
RFA was first described for the treatment of hepatic
tumors in 1990 (9). Since then, its use has found wider
application in the management of various tumors. It is
based on the principle of achieving thermal ablation of
the tissue by use of alternating electric current that operates in the range of 200 –1200 kHz. As the alternating
electric current passes through the tissue, ions in the
tissue attempt to follow the alternating direction of the
current, frictional heat is generated that ablates the tissue in the vicinity of the electrode, and the conduction
of heat causes farther tissue ablation (9). In the management of bone tumors like osteoid osteoma, RFA is
now the preferred modality of treatment because it is
associated with significantly less duration of hospital-
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doi: 10.1210/jc.2013-4515
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phosphorus normalization, and the disappearance of uptake on functional imaging (99mTc HYNIC TOC scans).
To the best of our knowledge, this is the first study to
corroborate remission with functional imaging. One of the
limitations of our study was that the biopsies performed
before ablation in patients A and B could not yield sufficient tissue to give any conclusive opinion. However, in
the absence of histopathology, the clinical and biochemical improvement after ablation provided convincing corroborative evidence to suggest that the targeted lesions
were the causative ones.
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Conclusions
Although surgery remains the treatment of choice, RFA
could be an effective, less invasive, and safe modality of
treatment in patients with TIO having tumors in surgically
difficult to access locations. The smaller size of the lesion,
well-delineated margins, and expertise of the RFA team
are the important determinants for a successful outcome
of RFA in these patients. Hence, judicious selection of
patients for RFA is important for the success of the
procedure.
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ization, no major complications, and a rapid convalescence (10, 11).
The literature regarding the use of RFA as a treatment
modality in TIO is scarce. To the best of our knowledge,
there has been a singular case report where Hesse et al
(12) subjected a 40-year-old woman with a lesion in the
head of the femur to two sessions of RFA, resulting in
remission that was demonstrated clinically, biochemically, and on MRI. The decision to use RFA in this
patient was made to avert the risk of total hip arthroplasty. The use of a less invasive modality for the treatment of TIO was also described by Tutton et al (13)
when they successfully treated a 51-year-old male patient with TIO, who had a tumor in the right iliac bone,
with CT-guided percutaneous ethanol ablation and
cryoablation.
In our series, two patients (patients A and B) achieved
complete remission after a single session of RFA,
whereas patient C continued to have persistent disease
after four sessions. The failure of RFA in patient C
might be attributed to several factors. The lesion in patient C was much larger in size than the other two patients (Table 1). Size of the lesion is one of the important
determinants for the success of RFA. It has been shown
in patients with liver metastasis from colorectal cancers
that the rate of recurrence after RFA increases with the
increasing size of lesions, reflecting the difficulty in
achieving complete ablation in larger tumors (14). In
addition, patients A and B had tumors with well-delineated margins, whereas patient C had a lesion with irregular margins and loculations due to bone grafts
placed during previous surgery. These factors precluded
accurate placement of a needle and achievement of uniform and complete ablation. The secretory nature of the
tumors associated with TIO makes the achievement of
complete ablation particularly important. Hence, although the tumor burden was significantly reduced in
patient C, as documented on serial 99mTc HYNIC TOC
scans, FGF23 failed to normalize due to the persistent
secretion from a small remnant that was inaccessible for
ablation.
Even with surgery, which is the preferred first line of
treatment for TIO, resection with wide margins is necessary for ensuring remission (7). Extending the same
principle to RFA, the importance of achieving complete
ablation, including a rim of perilesional normal tissue,
for achieving remission cannot be over emphasized.
There were no reported side effects of the procedure,
and the patients could be discharged within 24 hours of
hospitalization.
In our series, we attempted to demonstrate remission by
multiple congruent parameters, ie, clinical improvement,
3053
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Acknowledgments
Address all correspondence and requests for reprints to: Dr.
Swati Jadhav, MBBS, MD, Senior Resident, Department of Endocrinology, Seth G. S. Medical College and King Edward Memorial Hospital, Parel, Mumbai. Maharashtra, 400012, India.
E-mail: [email protected].
Disclosure Summary: The authors have no conflicts of interest to disclose.
References
1. Jiang Y, Xia WB, Xing XP, et al. Tumor-induced osteomalacia: an
important cause of adult-onset hypophosphatemic osteomalacia in
China: report of 39 cases and review of the literature. J Bone Miner
Res. 2012;27:1967–1975.
2. White KE, Larsson TE, Econs MJ. The roles of specific genes implicated as circulating factors involved in normal and disordered
phosphate homeostasis: frizzled related protein-4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 23. Endocr
Rev. 2006;27:221–241.
3. Habra MA, Jimenez C, Huang SC, et al. Expression analysis of
fibroblast growth factor-23, matrix extracellular phosphoglycoprotein, secreted frizzled-related protein-4, and fibroblast growth factor-7: identification of fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein as major factors involved in tumorinduced osteomalacia. Endocr Pract. 2008; 14:1108 –1114.
4. Weidner N, Santa Cruz D. Phosphaturic mesenchymal tumors. A
polymorphous group causing osteomalacia or rickets. Cancer. 1987;
59:1442–1454.
5. Mak MP, da Costa e Silva VT, Martin RM, et al. Advanced prostate
cancer as a cause of oncogenic osteomalacia: an underdiagnosed
condition. Support Care Cancer. 2012;20:2195–2197.
24/09/2014
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3054
Jadhav et al
RFA in Tumor-Induced Osteomalacia
J Clin Endocrinol Metab, September 2014, 99(9):3049 –3054
6. Xie Y, Li HZ. Oncogenic osteomalacia caused by renal cell carcinoma. J Clin Endocrinol Metab. 2013;98:4597– 4598.
7. Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced
osteomalacia. Endocr Relat Cancer. 2011;18:R53–R77.
8. Bijvoet OL, Morgan DB, Fourman P. The assessment of phosphate
reabsorption. Clin Chim Acta. 1969;26:15–24.
9. Rhim H, Goldberg SN, Dodd GD 3rd, et al. Essential techniques for
successful radio-frequency thermal ablation of malignant hepatic
tumors. Radiographics. 2001;21:S17–S35.
10. Rehnitz C, Sprengel SD, Lehner B, et al. CT-guided radiofrequency
ablation of osteoid osteoma and osteoblastoma: clinical success and
long-term follow up in 77 patients. Eur J Radiol. 2012;81:3426 –
3434.
Co
pi
aa
ut
or
iza
da
po
rC
DR
11. Rosenthal DI, Hornicek FJ, Wolfe MW, Jennings LC, Gebhardt
MC, Mankin HJ. Percutaneous radiofrequency coagulation of osteoid osteoma compared with operative treatment. J Bone Joint Surg
Am. 1998;80:815– 821.
12. Hesse E, Rosenthal H, Bastian L. Radiofrequency ablation of a tumor
causing oncogenic osteomalacia. N Engl J Med. 2007;357:422–424.
13. Tutton S, Olson E, King D, Shaker JL. Successful treatment of tumor-induced osteomalacia with CT-guided percutaneous ethanol
and cryoablation. J Clin Endocrinol Metab. 2012;97:3421–3425.
14. Künzli BM, Abitabile P, Maurer CA. Radiofrequency ablation of
liver tumors: actual limitations and potential solutions in the future.
World J Hepatol. 2011;3:8 –14.
24/09/2014
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