Ultrasound-guided fine-needle aspiration biopsy of parathyroid adenomas in patients undergoing parathyroidectomy does not lead to clinically significant fibrosis

Introduction

Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder (1,2). Bilateral neck exploration (BNE) is a common procedure done for treatment for PHPT, this method however necessitates the examination of all parathyroids (3).

In recent practice, minimally invasive parathyroidectomy (MIP) (4-6) has largely overtaken traditional BNE as the surgery of choice for PHPT, expectation being that most patients (>80%) will have single gland disease (SGD), thereby avoiding more extensive surgical exploration. Accurate identification of parathyroid adenoma (PA) is essential for minimally invasive treatment of PHPT (7) in cases of a single adenoma. However, some parathyroid lesions are atypical in location and appearance on ultrasound (US).

A meta-analysis demonstrated up to 16% of glands being in ectopic, locations: including 12% in the neck and ~4% in the mediastinum. with majority being found in retroesophageal/paraoesophageal space (31.4%), intra-thyroidal (20.3%, Figure 1), carotid sheath (17.7%), thyrothymic ligament (17%), tracheoesophageal groove (5.1%), and (8.4%) in other locations (thyroid cartilage, retropharyngeal space, and adjacent to hyoid bone) (8). This makes pre-operative localization important and helpful.

Figure 1 Ultrasound image showing an arrow pointing towards an intrathyroidal parathyroid adenoma.

While the success rate of both BNE and MIP are similar, MIP reduces the operative time and complications (hypocalcemia, recurrent laryngeal nerve injury), resulting in greater patient satisfaction (9,10). Several imaging modalities for pre-operative localization are available and can be utilized to make patients eligible for becoming potential MIP candidates, including US, single photon emission computed tomography-methoxyisobutylisonitrile (SPECT-MIBI), 4-dimensional computed tomography (4D-CT) scanning and recently choline positron emission tomography/CT (PET/CT), which has shown high efficacy in detecting PAs, with reported sensitivities ranging from 90% to 98%. It is particularly useful when first line imaging techniques such as US and SPECT-MIBI are inconclusive or yield negative results (11). However, this technique is not yet available in our health care system. Typically, pre-operative localization is routinely performed with parathyroid scintigraphy (SPECT-Sestamibi) and US. SPECT-Sestamibi is readily available with a wide imaging field allowing the detection of ectopic glands (12), thyroid nodules, thyroiditis, and lymphadenopathy however can result in false-positive scans (12,13). The sensitivity of US depends on the location of the PA; with sensitivity reported to be 55% to 87%, and lower in cases with ectopic parathyroid tissues or normocalcemic PHPT (14). Parathyroid hormone (PTH)-washout is an accurate indicator of parathyroid tissue. Fine-needle aspiration (FNA)-PTH can be used to establish the nature and etiology of the lesion, discriminating parathyroid gland from thyroid lesions or cervical lymph nodes (15,16). There have been, however, reports of PTH-washout biopsy leading to prolonged operative time and parathyroid fibrosis (17,18).

The primary aim of this study was to investigate the impact of PTH washout on fibrosis in real-world settings at a dedicated thyroid/parathyroid clinic, performing 1–2 passes and utilizing 25/27-gauge needles. We also wanted to ascertain the operative success, defined as normalization of calcium levels post operatively between patients who were biopsy localized versus patients who had negative localization/unsuccessful biopsy. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-26/rc).

Methods

During the years 2018 and 2022, a total of 124 patients were referred to our Thyroid/Parathyroid Clinic for a diagnosis of PHPT for pre-operative localization primarily by our community-based Ear, Nose, and Throat (ENT) surgeons, out of these 70 were available for the study (Table 1). The inclusion criterion was a bio-chemical diagnosis of PHPT (19). We excluded patients with family history of multiple endocrine neoplasia (MEN), familial hyperparathyroidism, previous parathyroidectomy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional review board of Intermountain Health (IRB # 1052390). Informed consent was taken from all the patients.

US was performed in the clinic by two skilled endocrinologists with extensive experience performing US and FNA. High-resolution, real-time ultrasonography was performed with 10- to 13-MHz scanners equipped with color Doppler imaging, if a lesion was deemed highly suspicious for a PA patient was referred to surgery and excluded from the study, 40 patients had lesions that were identified as being unequivocal for a PA.

These lesions were biopsied, using 25-gauge needles in 21 patients and 27-gauge needle in 3 patients, between 1–2 passes were done and negative pressure aspiration was applied under US guidance. After removal, the needle was rinsed with 1 mL 0.9% normal saline into two collection tubes and sent to lab, immunochemiluminometric assay (ICMA) was used and confirmed by dilution, assay detection limit was 10 pg/mL. Localization was confirmed if PTH washout was higher than the serum concentration.

SPECT-Sestamibi scintigraphy was performed utilizing technetium sestamibi, incorporating right and left oblique views and single-photon emission CT images. All images were interpreted by the assigned nuclear medicine specialists who performed the scans. The patients with biopsy localization had their surgical pathology reviewed in a blinded fashion by an experienced histopathologist (D.V.M., who is an experienced pathologist at Intermountain Medical Center). The PAs were given a grade 0 score if they had no fibrosis, grade 1 score implied a mild 25% fibrosis (Figure 2), grade 2 score implied a 50% fibrosis, grade 3 implied 75% fibrosis (Figure 3) and grade 4 suggested 100% fibrosis. We then compared the histopathology of 28 controls that were randomly selected, operated on at the same hospital without localization with PTH washout. The fibrosis scores on these controls were also recorded by the same histopathologist. One year post operative follow up was available for 19 patients who were biopsy localized and 12 patients who had a biopsy for a suspected lesion for PA but had negative PTH washout, we compared post operative calcium and PTH levels between these two groups (Figures 4,5).

Figure 2 Low power (×20) photomicrograph (hematoxylin-eosin) of a parathyroid gland showing a central area of collagen-rich replacement type fibrosis occupying <25% of the total tissue surface area. This gland was not aspirated prior to surgery.

Figure 3 Low power (×20) photomicrograph (hematoxylin-eosin) of a parathyroid gland showing extensive collagen-rich replacement fibrosis occupying >50% of the total tissue surface area. This gland was (curiously) also not aspirated prior to surgery.

Figure 4 Bar graph showing calcium cure rates for localized versus non localized surgical approaches.

Figure 5 Bar graph showing PTH cure rates for localized versus non localized surgical approaches. PTH, parathyroid hormone.

Statistical analysis

Data were analyzed by using R version 4.3.3 {R Core Team [2024], Vienna, Austria}. Qualitative values were reported as percent (n) and compared using Fisher’s exact test. Sensitivity and specificity were computed to compare US and CT results to biopsy results.

Results

In patients with localization with PTH washout, mean pre-operative calcium was 10.8 mg/dL with mean PTH of 120 pg/mL. Mean 24-hour urine for calcium was 299 mg/dL, The patients in the non-localized cohort had a mean pre-operative calcium level of 11.2 mg/dL. Mean pre-operative PTH of 123 pg/mL and a mean 24-hour urine calcium level of 252 md/dL showing the two cohorts to be well matched (Table 1). The performance of the pre-operative localization modalities used was studied, this showed the sensitivity of US to be around 95.8% and specificity around 37.5%. SPECT-Sestamibi study had a sensitivity of 50% and specificity of 33.3%.

A total of 7 out of the study population of 40 patients were found to have multi-gland disease, 2 in the biopsy localized cohort and 5 in the biopsy negative cohort. In the biopsy localized cohort both patients had two adenomas resected that were hyperplastic on the same side. In the non-localized cohort, 2 patients had multi-gland disease and the remaining 3 had unilateral double adenomas on final histopathology. The surgical findings correlated with the localization in the biopsy positive cohort with no false positive or false negative results.

Fibrosis evaluation in the 24-biopsy proven cohort revealed that 16 patients (67%) showed no fibrosis (grade 0). Seven patients (29%) showed grade 1 fibrosis, and 1 patient (3%) showed grade 2 fibrosis, no patient with a successful parathyroid biopsy showed moderate or severe fibrosis signifying grade 3 or 4 fibrosis. In the 28 patients serving as controls, 18 patients (60%) had grade 0 fibrosis, 2 patients (7%) had grade 1 fibrosis, 7 patients (23%) had grade 2 fibrosis, and 1 patient (3%) showed grade 3 fibrosis. Analysis shows no statistically significant difference in fibrosis across all grades (P value =0.99). There was not a significant difference in fibrosis score 1 by needle gauge (Fisher’s exact test, P>0.99). However, the paucity of 27-gauge biopsied patients in comparison to 25-gauge, precludes us from offering a more reliable comparison.

Cure rate described as normal post operative calcium sustained at 12 months was available for 19 out of the 24 biopsy localized patients, these were in turn compared to 12 patients with follow up available who had a biopsy, but were negative for localization based on PTH washout, this showed a 95% cure rate for the 19 localized patients vs. 67% for 12 non-localized patients (Figures 4,5). Eight patients who had negative localization with US and SPECT-Sestamibi also underwent 4D-CT scans; 4 out of the 8 had positive localization studies.

Discussion

MIP has a lower risk of complications, shorter operation time, more rapid recovery, and more favorable cosmetic results compared to conventional bilateral neck dissection. Since MIP is becoming more common, the need for pre-operative localization has become paramount. Since no evidence-based guidelines are yet available for an optimal pre-operative imaging strategy, clinicians should be familiar with the safety, sensitivity, cost effectiveness and specificity of the pre-operative localization techniques available in their health care systems.

Although FNA is generally considered a useful preoperative diagnostic tool for thyroid nodules, it is generally not recommended for parathyroid suspected lesions due to concern about complications, such as hematoma, parathyromatosis, and misdiagnosis as malignancy during histopathological study (20,21). However, in ectopic locations or atypical lesions where accurate characterization is difficult, FNA may be indicated. Positive localization can be appreciated especially in cases of intrathyroidal PAs. Recent studies report the incidence of intrathyroidal PAs to be between 1.3% and 2.4% in patients with PHPT (22,23), which presents diagnostic and therapeutic dilemmas and can lead to sacrifice thyroid lobectomy. Radiofrequency ablation has been used and shown to be a thyroid sparing intervention with excellent results (24) making an FNA-PTH washout necessary prior to this percutaneous intervention (Figure 1).

The guidelines of the American Association of Endocrine Surgeons do not recommend parathyroid FNA for localization except in unusual and difficult cases of PHPT (25,26) due to the perceived risk of it causing complications, there are diverging opinions on this supposed phenomenon of fibrosis after biopsy, this causes confusion and might prevent appropriate imaging and localization. We are not able to find any large studies which show complications such as fibrosis when using 25/27-gauge needles. A large paper from Poland describes a very low complication rate (27).

A few recent relevant studies report on the issue of fibrosis. Steen et al. (18) reported on histological artifacts after parathyroid FNA but did not mention needle gauge or number of passes, a paper by Norman et al. (17) evaluated 30 patients for fibrosis post biopsy. This study also did not report which needle gauge was utilized in 8 out of 30 subjects and did not report on how many passes were done for a significant number of patients studied, whereas our study clearly reports needle gauge and number of passes and their impact on operative success in this cohort. The results noted in this paper will help encourage treating physicians to be able to use US-FNA where clinically indicated, without significantly increasing the risk of causing surgical complications.

The results of the diagnostic accuracy of US may be difficult to generalize, as the modality is operator dependent, the lack of established US criteria for distinguishing a thyroid nodule from an enlarged parathyroid gland is problematic, factors such as shape, echogenicity, and vascularity can in some instances more accurately distinguish between thyroid and parathyroid nodules (28). A meta-analysis assessing the performance of US showed a pooled sensitivity or detection rate of 76.1% (29).

The reported sensitivity and specificity of SPECT-Sestamibi is at around 86% and 93%; ultrasonography, 61% and 87%, respectively (25). The choice of imaging modality must give consideration to efficacy, expertise, cost effectiveness and availability of such techniques. There is no current universally accepted algorithm for imaging localization, many institutions tend to use a combination of MIBI scintigraphy and US (30).

In our study, SPECT-Sestamibi showed a 50% sensitivity suggesting the need for another imaging modality like US, and in cases of unequivocal lesions the necessity for FNA-PTH washout for more accurate localization. Our data shows that when 25- or 27-gauge needles are used in performing 1–2 passes under US guidance no significant difference in fibrosis (grade 1) is noted, compared to when no biopsy is performed. The success of surgery was higher in the patients who had a biopsy positive PTH washout (95% vs. 67%) in patients who had negative PTH washout, though this did not meet statistical significance. There was no difference between the biopsy localized and non-localized groups in terms of incidence of multigland disease (MGD).

While not considered routine, this study shows that the judicious use of US-guided (USG) parathyroid biopsy can be employed in patients with atypical lesions noted on US with a diagnosis of PHPT and meeting indications for surgery. A recent study highlights the superiority of 4D-CT to US and SPECT-Sestamibi (31). And several experts use a combination of US and 4D-CT; however, in our healthcare system patients who were US negative for localization when sent for 4D-CT, had poor results in terms of localization (32).

A previous report on 20 patients with PHPT who were US negative for localization sent for 4D-CT showed a sensitivity of 36.36% with a positive predictive value of 50% (32). 4D-CT also costs between $1,800–2,200, while average neck US are around $130. current paper also had 8 US negative patients sent for 4D-CT scanning. The test was positive in 4 out of 8 patients, suggesting a sensitivity of 50% in US negative cases, indicating lower sensitivity after negative neck US, which is consistent with a previous report (32). Suggesting that in US negative patients, 4D-CT has clearly not replicated sensitivity and specificity that are nationally reported making the safe use of US-FNA of suspicious yet unequivocal lesions necessary.

There have been reports of PAs with previous FNA showing increased risk of a fibrotic reaction leading to adhesions to surrounding structures and histological alterations resembling malignancy (17,18,25). This study did not have any biopsied gland reported as suspicious for malignancy on the final histopathology reports. Parathyroid carcinoma is a rare cause of PHPT, when these patients are compared with patients with PAs, patients with parathyroid carcinomas are more likely to have symptoms, a neck mass, bone, and kidney disease, marked hypercalcemia, and very high serum PTH concentrations with the diagnosis being typically made clinically at the time of surgery. Considering these factors, we conclude that the judicious use of FNA-PTH is appropriate in specific clinical situations, and the risk of obfuscating the final histopathology extremely low (Table 2).

The study has several limitations. In the biopsy negative cohort, we were not able to have the pathology correlated to the area noted on US, so we are unclear as to the false negative rate. We used normalized calcium as a marker for cure, the average post operative PTH was high normal; however, we are aware of elevated PTH/high normal PTH as a fairly common occurrence after a successful parathyroidectomy (defined as sustained normocalcemia), and there are several papers confirming this. A recent review published in Endocrine practice states: “Within 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated PTH concentration. No evidence suggests that postoperative normocalcemic PTH elevation is an indication of surgical failure and recurrent hypercalcemia” (33).

The study could not see a pattern in number of passes and fibrosis risk, since the number of patients with fibrosis was quite small. We also do not have the exact data points about the timeline between biopsy and surgery. However, we can comfortably report that the surgery was a minimum of 3–4 weeks after FNA (this reflects the turnaround time for PTH washout results/arranging patients follow up in our system). A recent report (11) has shown choline PET/CT as having high sensitivity and specificity in detection of hyperfunctioning parathyroid tissue, we were unable to study this modality due to lack of availability.

Conclusions

The use of USG-FNA for atypical lesions suspected to be PAs, can be safely performed utilizing 25/27-gauge needles in settings of PHPT. This study shows no association of parathyroid FNA with fibrosis or histopathological diagnostic dilemmas when compared to controls. Positive PTH washout patients had a higher cure rate compared to negative PTH washout patients.

Acknowledgments

The authors would like to thank Dr. Betsy Batcher, MD for her invaluable help in organizing this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-26/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-26/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-26/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-26/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional review board of Intermountain Health (IRB # 1052390). Informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Fraser WD. Hyperparathyroidism. Lancet 2009;374:145-58. [Crossref] [PubMed]
2. Bilezikian JP. Primary Hyperparathyroidism. J Clin Endocrinol Metab 2018;103:3993-4004. [Crossref] [PubMed]
3. Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005;132:359-72. [Crossref] [PubMed]
4. Kunstman JW, Udelsman R. Superiority of minimally invasive parathyroidectomy. Adv Surg 2012;46:171-89. [Crossref] [PubMed]
5. Greene AB, Butler RS, McIntyre S, et al. National trends in parathyroid surgery from 1998 to 2008: a decade of change. J Am Coll Surg 2009;209:332-43. [Crossref] [PubMed]
6. Udelsman R, Åkerström G, Biagini C, et al. The surgical management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 2014;99:3595-606. [Crossref] [PubMed]
7. Kunstman JW, Kirsch JD, Mahajan A, et al. Clinical review: Parathyroid localization and implications for clinical management. J Clin Endocrinol Metab 2013;98:902-12. [Crossref] [PubMed]
8. Phitayakorn R, McHenry CR. Incidence and location of ectopic abnormal parathyroid glands. Am J Surg 2006;191:418-23. [Crossref] [PubMed]
9. Singh Ospina NM, Rodriguez-Gutierrez R, Maraka S, et al. Outcomes of Parathyroidectomy in Patients with Primary Hyperparathyroidism: A Systematic Review and Meta-analysis. World J Surg 2016;40:2359-77. [Crossref] [PubMed]
10. Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg 2011;253:585-91. [Crossref] [PubMed]
11. Broos WAM, van der Zant FM, Knol RJJ, et al. Choline PET/CT in parathyroid imaging: a systematic review. Nucl Med Commun 2019;40:96-105. [Crossref] [PubMed]
12. Barczynski M, Golkowski F, Konturek A, et al. Technetium-99m-sestamibi subtraction scintigraphy vs. ultrasonography combined with a rapid parathyroid hormone assay in parathyroid aspirates in preoperative localization of parathyroid adenomas and in directing surgical approach. Clin Endocrinol (Oxf) 2006;65:106-13. [Crossref] [PubMed]
13. Isik S, Akbaba G, Berker D, et al. Thyroid-related factors that influence preoperative localization of parathyroid adenomas. Endocr Pract 2012;18:26-33. [Crossref] [PubMed]
14. Cunha-Bezerra P, Vieira R, Amaral F, et al. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism. J Med Imaging Radiat Oncol 2018; Epub ahead of print. [Crossref]
15. Castellana M, Virili C, Palermo A, et al. Primary hyperparathyroidism with surgical indication and negative or equivocal scintigraphy: safety and reliability of PTH washout. A systematic review and meta-analysis. Eur J Endocrinol 2019;181:245-53. [Crossref] [PubMed]
16. Bancos I, Grant CS, Nadeem S, et al. Risks and benefits of parathyroid fine-needle aspiration with parathyroid hormone washout. Endocr Pract 2012;18:441-9. [Crossref] [PubMed]
17. Norman J, Politz D, Browarsky I. Diagnostic aspiration of parathyroid adenomas causes severe fibrosis complicating surgery and final histologic diagnosis. Thyroid 2007;17:1251-5. [Crossref] [PubMed]
18. Steen S, Hysek M, Zedenius J, et al. Cyto-morphological features of parathyroid lesions: Fine-needle aspiration cytology series from an endocrine tumor referral center. Diagn Cytopathol 2022;50:75-83. [Crossref] [PubMed]
19. Grant CS, Thompson G, Farley D, et al. Primary hyperparathyroidism surgical management since the introduction of minimally invasive parathyroidectomy: Mayo Clinic experience. Arch Surg 2005;140:472-8; discussion 478-9. [Crossref] [PubMed]
20. Wei CH, Harari A. Parathyroid carcinoma: update and guidelines for management. Curr Treat Options Oncol 2012;13:11-23. [Crossref] [PubMed]
21. Kim J, Horowitz G, Hong M, et al. The dangers of parathyroid biopsy. J Otolaryngol Head Neck Surg 2017;46:4. [Crossref] [PubMed]
22. Goodman A, Politz D, Lopez J, et al. Intrathyroid parathyroid adenoma: incidence and location--the case against thyroid lobectomy. Otolaryngol Head Neck Surg 2011;144:867-71. [Crossref] [PubMed]
23. Chandramohan J, Sigamani E, Abraham DT, et al. Intrathyroid parathyroid adenomas-uncommon tumors at unusual sites: A cross sectional study. J Clin Diagn Res 2020;14:EC12-EC17.
24. Aljammal J, Orozco I, Raashid S, et al. Radiofrequency Ablation Is a Thyroid Sparing Treatment Option for Primary Hyperparathyroidism Caused by an Intrathyroidal Parathyroid Adenoma. VideoEndocrinology 2022;9:84-5.
25. Patel KN, Yip L, Lubitz CC, et al. The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Ann Surg 2020;271:e21-e93. [Crossref] [PubMed]
26. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg 2016;151:959-68. [Crossref] [PubMed]
27. Obołończyk Ł, Karwacka I, Wiśniewski P, et al. The Current Role of Parathyroid Fine-Needle Biopsy (P-FNAB) with iPTH-Washout Concentration (iPTH-WC) in Primary Hyperparathyroidism: A Single Center Experience and Literature Review. Biomedicines 2022;10:123. [Crossref] [PubMed]
28. Juhlin CC, Zedenius J. Distinguishing between thyroid and parathyroid nodules by ultrasound: a potential game-changer in clinical practice? Lancet Reg Health Eur 2023;35:100769. [Crossref] [PubMed]
29. Cheung K, Wang TS, Farrokhyar F, et al. A meta-analysis of preoperative localization techniques for patients with primary hyperparathyroidism. Ann Surg Oncol 2012;19:577-83. [Crossref] [PubMed]
30. Zafereo M, Yu J, Angelos P, et al. American Head and Neck Society Endocrine Surgery Section update on parathyroid imaging for surgical candidates with primary hyperparathyroidism. Head Neck 2019;41:2398-409. [Crossref] [PubMed]
31. Strauss SB, Roytman M, Phillips CD. Parathyroid Imaging: Four-dimensional Computed Tomography, Sestamibi, and Ultrasonography. Neuroimaging Clin N Am 2021;31:379-95. [Crossref] [PubMed]
32. Ahmad S, Aljammal J. Abstract #1160: Performance of 4-D CT Scan in Localization of Parathyroid Adenomas in Ultrasound Negative Population. Endocrine Practice 2016;22:281.
33. Biskobing DM. Significance of elevated parathyroid hormone after parathyroidectomy. Endocr Pract 2010;16:112-7. [Crossref] [PubMed]