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International Journal of Endocrinology
Volume 2017, Article ID 4208178, 8 pages
https://doi.org/10.1155/2017/4208178
Research Article

Therapeutic Outcomes of Patients with Multifocal Papillary Thyroid Microcarcinomas and Larger Tumors

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
2Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Keelung, Taiwan
3Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Keelung, Taiwan

Correspondence should be addressed to Jen-Der Lin; wt.gro.hmgc.mda@djnie

Received 20 December 2016; Revised 2 March 2017; Accepted 9 April 2017; Published 31 May 2017

Academic Editor: Thomas J. Fahey

Copyright © 2017 Soh-Ching Ng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A retrospective review of 626 patients with multifocal papillary thyroid carcinoma (PTC) including 147 patients (23.5%) with multifocal papillary thyroid microcarcinoma (PTMC) from a total of 2,536 patients with PTC who visited the Chang Gung Medical Center in Linkou, Taiwan, was performed. A comparison of the clinical features between 626 multifocal and 1,910 solitary PTC cases showed that patients in the multifocal PTC group were older and had a smaller mean tumor size, a more advanced tumor-node-metastasis (TNM) stage, and a higher percentage of nonremission status compared to patients in the solitary PTC group. Of the 626 patients with multifocal PTC, the group with larger tumors showed a more advanced TNM stage, a higher percentage of lymph node metastasis and soft tissue invasion, and a higher nonremission rate compared to the multifocal PTMC group. Of the 626 patients with multifocal PTC, 25 patients (4%) died during a mean follow-up period of 7.1 ± 5.3 years. Kaplan-Meier survival curves showed a significantly lower survival rate associated with multifocal PTMC compared to that with solitary PTMC.

1. Introduction

Multifocal papillary thyroid carcinoma (PTC) may present as microcarcinoma (≤1.0 cm) or larger tumors in two or more individual locations within the thyroid gland. An increase in the incidence of papillary thyroid microcarcinoma (PTMC) and multifocal PTC has been reported in the recent decade [13]. Intrathyroid multifocal PTMC is categorized as a low-risk group in recent American Thyroid Association (ATA) guidelines [4]. In contrast, multifocal PTMC with extrathyroidal extensions is categorized as an intermediate-risk group. Bilateral multifocal PTMC has a worse prognosis than unilateral PTMC [5, 6]. Multifocal PTC may be diagnosed as “incidental” in the final histopathology examination or “nonincidental” if it is diagnosed before or during thyroid surgery [7, 8]. For both incidental and nonincidental PTCs, prognostic factors of these patients are important to determine whether a second surgery for complete total thyroidectomy is necessary. Postoperative radioiodine (131I) remnant ablation and other imaging techniques are important for identifying patients with a high risk of incidental or nonincidental PTC [9]. However, data are lacking concerning the long-term therapeutic outcomes of patients with multifocal PTMC and multifocal PTC with larger tumors in order to provide appropriate therapeutic modalities for these patient groups. Analyses of long-term follow-up results after multiple modality treatments are important and may provide better therapeutic strategies for the treatment of patients with multifocal PTC.

The aims of this study were to investigate the long-term follow-up outcomes of patients after different therapeutic strategies for the treatment of multifocal PTC including PTMC and larger tumors. We analyzed different therapeutic strategies including surgical methods, 131I remnant ablation, 131I treatment, imaging studies, and external radiotherapy. Various therapeutic strategies and risk factors for cancer mortality and recurrence in different patient groups were analyzed.

2. Materials and Methods

We selected 3265 patients with PTC from a total of 4062 patients with thyroid cancer who had undergone thyroid surgery between 1977 and 2013 at the Chang Gung Medical Center in Linkou, Taiwan. Patients who did not undergo a follow-up for over 1 year and who underwent the initial thyroid surgery at a different hospital and patients without data regarding tumor sizes were excluded from our analyses (Figure 1). All patients had undergone primary thyroid surgery and a long-term clinical follow-up at Chang Gung Medical Center. Frozen tissue specimens from 525 patients were obtained during surgery and evaluated by pathologists. Initially, each specimen was assessed macroscopically to identify the most significant nodules and the most invasive tumors and to plan the surgical dissection of the surgical sample. Intraoperative examinations of the frozen section were performed on the cut surface of the thyroid nodules including the interface between the nodule and adjacent thyroid tissue. A total thyroidectomy was performed on patients with PTC with extrathyroidal extensions and lymph node metastasis. Patients with PTMC and an absence of extrathyroidal invasion as diagnosed by postoperative histopathology underwent follow-up care if they had undergone a subtotal thyroidectomy. Subtotal thyroidectomy was defined as removing more than 50% of the entire gland on both lobes. One hundred and forty patients received secondary thyroid operations for a complete thyroidectomy after PTC was confirmed by histology.

Figure 1: Distribution of papillary thyroid carcinoma patients in the current study. PTC: papillary thyroid cancer; PTMC: papillary thyroid microcarcinoma.

A total of 2536 PTC patients were enrolled in this study, including 626 patients with multifocal PTC and 147 patients with multifocal PTMC. In contrast, there were 1910 patients with solitary PTC including 420 (22.0%) patients with papillary microcarcinomas. After thyroid surgery, patients were staged using the Union for International Cancer Control tumor-node-metastasis (TNM) criteria (6th edition) [10]. All thyroid carcinoma tissues were pathologically classified according to the World Health Organization criteria [11]. PTMC was defined as the largest tumor in the final histological slides. Cases were defined as multifocal if two or more isolated foci of PTC were found.

In our center, patients with PTC at high or intermediate risk were recommended to undergo thyroid 131I remnant ablation 4 to 6 weeks after thyroidectomy [4]. The dose of 131I ablation for most patients was 30–100 mCi (1.1–3.7 GBq). One week after 131I administration, a whole-body scan (WBS) was performed using a dual-head gamma camera (Siemens Medical Solutions USA Inc., USA). Thyroid scintigraphy was performed using a pinhole collimator with a 4 mm aperture placed 7 cm above the neck for a total of 50,000 counts for 30 minutes. Levothyroxine treatment was initiated to decrease the levels of thyroid-stimulating hormone without inducing clinical thyrotoxicosis. If 131I uptake extended beyond the thyroid bed, patients were classified as having residual disease or metastasis unless proven to be a false-positive result. Higher therapeutic doses of 3.7–7.4 GBq (100–200 mCi) were administered to these patients. Patients receiving doses exceeding 1.1 GBq were isolated at hospital admission. A WBS was performed 2 weeks after administering higher therapeutic doses of 131I. Neck ultrasonography was performed 6–12 months after thyroidectomy to exclude the possibility of local recurrence.

At the end of 2014, patients were categorized into four groups: thyroid cancer mortality, nonremission, remission, and disease-free. The remission group consisted of patients with negative 131I WBS results and no evidence of local or distant metastasis upon noninvasive examination. Disease-free patients were defined as patients in remission with undetectable levels of stimulated thyroglobulin (Tg) and undetectable Tg antibodies at the final follow-up appointment.

The Chang Gung Medical Foundation Institutional Review Board approved this study (104-3901B); the requirement for informed consent was waived because of the retrospective nature of the study.

In our hospital, serum Tg levels were measured using an immunoradiometric assay kit (CIS Bio International, Gif-sur-Yvette, France) before the end of 2014. The detection limit of the Tg kit was 0.5 ng/mL. The functional sensitivity of this assay, as assessed in our laboratory, was 1.2 ng/mL. Tg antibody levels were measured using a competitive radioimmunoassay (Biocode, Liège, Belgium) with an analytical sensitivity of 6 IU/mL.

Unpaired t-tests were used to compare continuous data between groups. Categorical data were compared using chi-square or Fisher’s exact tests for small data sets. Cancer-related mortality was calculated, and the follow-up period was determined from the date of diagnosis to the date of cancer-related mortality of the last survivor undergoing follow-up care. Survival rates were calculated using the Kaplan-Meier method and compared using a log-rank test [12]. A multivariate Cox proportional hazard regression model was used to estimate the mortality risk. All statistical analyses were performed using the SPSS software, version 17.0 (SPSS Inc., Chicago, IL, USA). were considered statistically significant in all tests.

3. Results

Table 1 illustrates the clinical features of the 2536 patients with PTC categorized into a multifocal group (626 patients, 24.7%) and a solitary tumor (1910 patients, 75.3%) group. Patients in the multifocal PTC group were older, had a smaller mean tumor size and a higher percentage, had undergone a total or complete thyroidectomy, and showed more advanced clinical and TNM stages; a higher percentage of patients were in nonremission. In addition, the multifocal PTC group had a higher mean postoperative accumulated 131I dose and a lower percentage in disease-free status compared to the solitary PTC group. In contrast, sex, postoperative serum Tg levels, histological variants of PTC, thyroid cancer-specific mortality, and total mortality did not differ significantly between these two groups.

Table 1: Clinical features of multifocal or solitary papillary thyroid cancer.

Of the 626 patients with multifocal PTC, 147 (23.5%) patients had tumors of less than or equal to 1.0 cm. The group with larger tumors had a significantly higher percentage of patients that had undergone a total thyroidectomy, had a more advanced TNM stage, had a higher percentage of lymph node metastasis and soft tissue invasion, and had a higher nonremission rate than the patient group with multifocal PTMC (Table 2). Age, sex, disease-specific mortality, overall mortality, and disease-free status did not differ significantly between these groups. The follicular variant of PTC was observed in 15.8% of all multifocal PTC diagnoses. The larger tumor group had a higher percentage of follicular variant PTC compared to the microcarcinoma group (17.7% versus 9.5%; ).

Table 2: Clinical features of multifocal papillary thyroid cancer in different tumor sizes.

Of the 626 patients, 31 (5.0%) underwent subtotal or lobectomy. Most of these patients presented with small tumor sizes and a less advanced TNM stage. There were single patients with lymph node metastasis, soft tissue invasion, and distant metastasis. Due to old age or advanced local invasion, three patients did not undergo a complete thyroidectomy. After the mean follow-up period of 7.1 years, the nonremission rate, disease-specific mortality, and overall mortality did not differ significantly between patients that had undergone a total thyroidectomy and patients who had undergone less aggressive surgical treatments. Of the 626 patients, 335 patients had clinical stage 1 disease, without lymph node metastasis, soft tissue invasion, or distant metastasis. At the end of the follow-up period, there was no disease-specific mortality in these 335 patients; however, there were nine cases of nonthyroid cancer mortality. In addition, 17 of the 335 patients presented with recurrent disease after a thyroidectomy including 10 patients with lymph node metastasis and 2 patients with thyroid bed soft tissue recurrence.

After the mean follow-up period of 7.1 ± 5.3 years, 131 (20.9%) patients were diagnosed as having a nonremission status. Table 3 shows the clinical characteristics of patients in remission and nonremission. The nonremission group was predominantly male and had larger tumor sizes, higher postoperative levels of serum Tg, a more advanced TNM stage, higher disease-specific and total mortality, and a lower percentage of patients in disease-free status. There were no statistically significant differences in age or surgical procedures between the remission and nonremission groups; however, patients in the nonremission group received higher accumulated doses of 131I and a higher percentage of patients underwent external radiotherapy.

Table 3: Clinical features of multifocal papillary thyroid cancer in nonremission or remission.

Of the 626 patients with multifocal PTC, 25 (4%) patients died during a mean follow-up period of 7.1 ± 5.3 years. A comparison of risk factors between the cancer mortality and survival groups revealed that male sex, older age, larger tumor size, higher postoperative serum levels of Tg, and advanced TNM stage differed significantly between these groups (Table 4). Multivariant analyses were performed using the Cox proportional hazards regression model and revealed that only age differed significantly between the survival and mortality groups (Table 5). The 5-, 10-, and 20-year survival rates of the 2536 patients with PTC were 97.3%, 95.7%, and 91.6%, respectively. Figure 2 shows the Kaplan-Meier survival curves of the patients in the multifocal PTMC, multifocal larger PTC, solitary PTMC, and solitary larger PTC groups. The 5-, 10-, and 20-year survival rates of the four groups were 98.9%, 96.4%, 99.7%, and 96.8%; 93.7%, 95.2%, 99.7%, and 95.0%; and 93.7%, 91.4%, 99.0%, and 90.3%, respectively. The survival rates of patients with solitary PTMC were significantly different from the survival rates of patients in the other three groups (Figure 2). There were no significant differences in survival rates between the other three groups.

Table 4: Clinical features of multifocal papillary thyroid cancer in cancer mortality.
Table 5: Multivariate analysis by the Cox proportional hazards regression model for survival and mortality.
Figure 2: Kaplan-Meier survival curves of the four subject groups: multifocal PTMC, multifocal larger PTC, solitary PTMC, and solitary larger PTC. PTMC: papillary thyroid microcarcinoma.

4. Discussion

Multifocal PTC is the most frequently diagnosed multifocal, well-differentiated thyroid cancer, although follicular and medullary thyroid cancer may also present with PTC in the same patient [13]. Patients may be categorized as having multifocal PTMC, multifocal larger PTC, and mixed multifocal PTMC with larger tumors. In our study, one-quarter of the PTC cases were multifocal. Although the mean tumor size of the largest multifocal tumor was smaller than that in the solitary PTC group, the clinical and TNM stages were more advanced. In contrast to that in a recent study, the multifocal group in our study had a higher nonremission rate and a lower percentage of patients were disease-free when compared to the solitary PTC group [14]. These discordant results may due to the larger number of patients enrolled and the longer follow-up period in our study.

In our study, 23.5% of multifocal PTCs were microcarcinomas. This ratio was close to the reported proportion of PTMC in an earlier study [15]. The prognosis of multifocal PTC was better than the prognosis for multifocal follicular or Hurthle cell histology [16]. However, more data are required regarding the long-term therapeutic outcomes of multifocal PTC in microcarcinoma or larger tumors, as well as how unilateral or bilateral tumors and the number of tumors in multifocal carcinoma may affect treatment outcomes [1, 17]. Our study response to the consensus report of the European Society of Endocrine Surgeons suggests that prognosis might be impaired in clinical multifocal PTC, but the effect might be less or none in [18]. Our results showed that multifocal papillary microcarcinoma had a lower relapse rate than larger tumors; however, there were no statistically significant differences in cancer and overall mortality after a mean follow-up of 7.1 ± 5.3 years.

Diagnosis of multifocal PTC may occur preoperatively by ultrasound and fine-needle aspiration cytology (FNAC), during surgery by a frozen section, and postoperatively by final histopathology examination. There are few reports concerning the preoperative diagnosis of multifocal PTC, especially PTMC. The main explanation is that FNAC is not recommended for thyroid nodules of less than 1 cm. However, preoperative diagnosis of multifocal PTC including the location and number of tumors may be important information for surgical strategy and decision-making [16]. A recent study showed that bilateral multifocal PTC had a worse prognosis than unilateral multifocal PTC [5]. Lymph node dissection may be indicated in cases of multifocal PTC [19]. In our study, analysis of patients that underwent a less than total thyroidectomy for multifocal PTC did not show a worse prognosis than that of patients who had undergone a total thyroidectomy.

In our study, the multifocal PTC group had a higher percentage of patients in nonremission status compared to the solitary PTC group. As reported previously, PTMC had a low percentage of patients in nonremission compared to that of patients with multifocal larger tumor PTC [2]. However, we also found that disease-specific mortality did not differ significantly between multifocal PTMC and larger tumor PTC groups. In contrast, patients with multifocal PTMC had a worse prognosis and disease-specific survival rates compared to patients with solitary PTMC. A higher percentage of soft tissue invasion and distant metastasis in multifocal PTMC are part of reasons with poor prognosis than that in solitary PTMC. The use of 131I ablation for the treatment of multifocal PTMC is questioned by the European consensus and American Thyroid Association (ATA) guidelines [18, 20]. In our study, 3.4% of multifocal PTMC had distant metastasis. A more aggressive postoperative remnant ablation and longer follow-up period than that of solitary PTMC are indicated.

Several studies have assessed the clonal origin of multifocal PTC [2124]. However, the results were inconsistent. BRAF gene mutation combined with X chromosome inactivation analyses has been used to evaluate the clonal origins of tumors and has showed that bilateral, recurrent, and metastatic PTCs often arise from a single clone and that intrathyroid metastasis may play an important role in the development of bilateral tumors [21]. In contrast, assessment of multifocal thyroid tumors using genetic alteration analyses and miRNA profiling found that multifocal PTC did not necessarily evolve from single PTC progenitor foci [20]. In the clinic, different histological patterns like follicular variant and classical PTC in different thyroid lobes are not unusual. Both intrathyroid lymphatic spreading and different clonal origins may be present in multifocal PTC [24]. This study has several strengths, including a nearly 10-year follow-up period of a large number of patients, which has strengthened the conclusions. The patients enrolled were diagnosed and treated at a single medical center, which may make the data more consistent. However, due to the enrollment period of over 30 years, examination and therapeutic modalities may likely have changed over time.

5. Conclusion

Multifocal PTMC had a lower recurrence rate than multifocal larger tumor PTC; however, there was no difference in cancer-specific mortality rates. These patients need a follow-up because there is a risk of recurrence.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

  1. N. Qu, L. Zhang, Q. H. Ji et al., “Number of tumor foci predicts prognosis in papillary thyroid cancer,” BMC Cancer, vol. 14, no. 12, p. 914, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. K. J. Kim, S. M. Kin, Y. S. Lee, W. Y. Chung, H. S. Chang, and C. S. Park, “Prognostic significance of tumor multifocality in papillary thyroid carcinoma and its relationship with primary tumor size: a retrospective study of 2,309 consecutive patients,” Annals of Surgical Oncology, vol. 22, no. 1, pp. 125–131, 2015. View at Publisher · View at Google Scholar · View at Scopus
  3. J. D. Lin, S. T. Chen, T. C. Chao, C. Hsueh, and H. F. Weng, “Diagnosis and therapeutic strategy of papillary thyroid microcarcinoma,” Archives of Surgery, vol. 140, no. 10, pp. 940–945, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. B. R. Haugen, E. K. Alexander, K. C. Bible et al., “2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer,” Thyroid, vol. 26, no. 1, pp. 1–133, 2016. View at Publisher · View at Google Scholar · View at Scopus
  5. W. Wang, X. Su, K. He et al., “Comparison of the clinicopathologic features and prognosis of bilateral versus unilateral multifocal papillary thyroid cancer: an updated study with more than 2000 consecutive patients,” Cancer, vol. 122, no. 2, pp. 198–206, 2016. View at Publisher · View at Google Scholar · View at Scopus
  6. S. F. Kuo, S. F. Lin, T. C. Chao, C. Hsueh, K. J. Lin, and J. D. Lin, “Prognosis of multifocal papillary thyroid carcinoma,” International Journal of Endocrinology, vol. 809382, no. 12, p. 2013, 2013. View at Publisher · View at Google Scholar · View at Scopus
  7. E. Dunki-Jacobs, K. Grannan, S. McDonough, and A. M. Engel, “Clinically unsuspected papillary microcarcinomas of the thyroid: a common finding with favorable biology?” The American Journal of Surgery, vol. 203, no. 2, pp. 140–144, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. A. Kiriakopoulos, A. Petralias, and D. Linos, “Multifocal versus solitary papillary thyroid carcinoma,” World Journal of Surgery, vol. 40, no. 9, pp. 2139–2143, 2016. View at Publisher · View at Google Scholar · View at Scopus
  9. J. D. Lin, S. F. Kuo, T. C. Chao, and C. Hsueh, “Incidental and non-incidental papillary thyroid microcarcinoma,” Annals of Surgical Oncology, vol. 15, no. 8, pp. 2287–2292, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. L. H. Sobin and UICC, TNM Classification of Malignant Tumors, Wiley-Liss, New York, 6th edition edition, 2002.
  11. R. A. Delellis, R. V. Lloyd, P. U. Heitx, and C. Eng, “Pathology and genetics of tumors of endocrine organs,” World Health Organization of Tumours, IARC, Lyon, 2004. View at Google Scholar
  12. D. D. Zhang, X. H. Zhou, D. H. Freeman, and J. L. Freema, “A non-parametric method for the comparison of partial areas under ROC curves and its application to large health care data sets,” Statistics in Medicine, vol. 21, no. 5, pp. 701–715, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. K. Kaliszewski, A. Zubkiewicz-Kucharska, B. Wojtczak, and M. Strutyńska-Karpińska, “Multi- and unifocal thyroid microcarcinoma: are there any differences?” Advances in Clinical and Experimental Medicine, vol. 25, no. 3, pp. 485–492, 2016. View at Publisher · View at Google Scholar · View at Scopus
  14. A. A. Tam, D. Özdemir, N. Çuhacı et al., “Association of multifocality, tumor number, and total tumor diameter with clinicopathological features in papillary thyroid cancer,” Endocrine, vol. 53, no. 3, pp. 774–783, 2016. View at Publisher · View at Google Scholar · View at Scopus
  15. J. D. Lin, “Increased incidence of papillary thyroid microcarcinoma with decreased tumor size of thyroid cancer,” Medical Oncology, vol. 27, no. 2, pp. 510–518, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. E. J. Kuo, S. A. Roman, and J. A. Sosa, “Patients with follicular and Hurthle cell microcarcinomas have compromised survival: a population level study of 22,738 patients,” Surgery, vol. 154, no. 6, pp. 1246–1253, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. H. J. Kim, S. Y. Sohn, H. W. Jang, S. W. Kim, and J. H. Chung, “Multifocality, but not bilaterality, is a predictor of disease recurrence/persistence of papillary thyroid carcinoma,” World Journal of Surgery, vol. 37, no. 2, pp. 376–384, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Iacobone, S. Jansson, M. Barczyński, and P. Goretzki, “Multifocal papillary thyroid carcinoma - a consensus report of the European Society of Endocrine Surgeons (ESES),” Langenbeck’s Archives of Surgery, vol. 399, no. 2, pp. 141–154, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Al Afif, B. A. Williams, M. H. Rigby et al., “Multifocal papillary thyroid cancer increases the risk of central lymph node metastasis,” Thyroid, vol. 25, no. 9, pp. 1008–1012, 2016. View at Google Scholar
  20. E. Krčálová, J. Horáček, L. Kudlej et al., “Is radioiodine administration in patients with papillary thyroid multifocal microcarcinoma unnecessary?” Endocrinology Diabetes & Metabolism Case Report, vol. 2016, no. 5, p. 150138, 2016. View at Publisher · View at Google Scholar
  21. W. Wang, H. Wang, X. Teng et al., “Clonal analysis of bilateral, recurrent, and metastatic papillary thyroid carcinomas,” Human Pathology, vol. 41, no. 9, pp. 1299–1309, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. S. T. Aherne, P. C. Smyth, R. J. Flavin Russell SM et al., “Geographical mapping of a multifocal thyroid tumour using genetic alteration analysis & miRNA profiling,” Molecular Cancer, vol. 7, no. 12, p. 89, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. E. Kuhn, L. Teller, S. Piana, J. Rosai, and M. J. Merino, “Different clonal origin of bilateral papillary thyroid carcinoma, with a review of the literature,” Endocrine Pathology, vol. 23, no. 2, pp. 101–107, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. Z. Lu, J. Sheng, Y. Zhang et al., “Clonality analysis of multifocal papillary thyroid carcinoma by using genetic profiles,” The Journal of Pathology, vol. 239, no. 1, pp. 72–83, 2016. View at Publisher · View at Google Scholar · View at Scopus