Reader TTS

ABSTRACT Limited data indicated radiotherapy might provide survival benefits to patients with distantly metastatic nasopharyngeal carcinoma (mNPC). We used the Surveillance Epidemiology and

End Results database to examine the role of radiotherapy in the treatment of mNPC. Patients with mNPC at presentation diagnosed between 1988 and 2012 were enrolled. The outcome of interest

included overall survival (OS) and cancer-specific survival (CSS). A total of 679 patients with a median follow-up of 13 months were identified. Four hundred forty-eight patients received

radiotherapy and 231 did not. Radiotherapy was associated with significantly improved OS and CSS in both univariate and multivariate analyses. Weighted Cox regression by inverse probability

of treatment weighting (IPTW) using propensity score (PS) showed a 50% reduced risk of mortality in patients who received radiotherapy with regards to both OS (HR: 0.50, 95% CI: 0.41–0.60, p

 < 0.001) and CSS (HR: 0.50, 95% CI: 0.40–0.61, p < 0.001), respectively. Further, patients with a younger age (<65 year-old), diagnosed after 2003, with non-keratinizing carcinoma

or undifferentiated carcinoma, and who received surgery had better outcomes for both OS and CSS. Local radiotherapy was associated with improved survival in patients with mNPC. Our findings

warrant prospective investigation in clinical trials. SIMILAR CONTENT BEING VIEWED BY OTHERS IMPROVED OVERALL SURVIVAL IS ASSOCIATED WITH ADJUVANT CHEMOTHERAPY AFTER DEFINITIVE CONCURRENT

CHEMORADIOTHERAPY FOR N3 NASOPHARYNGEAL CANCER Article Open access 04 August 2022 RISK-ADAPTED LOCOREGIONAL RADIOTHERAPY STRATEGIES BASED ON A PROGNOSTIC NOMOGRAM FOR DE NOVO METASTATIC

NASOPHARYNGEAL CARCINOMA PATIENTS TREATED WITH CHEMOIMMUNOTHERAPY Article Open access 17 February 2024 SURVIVAL AMONG SUBGROUPS OF PATIENTS WITH STAGE II NASOPHARYNGEAL CARCINOMA Article

Open access 29 April 2022 INTRODUCTION Nasopharyngeal cancer (NPC) is highly sensitive to both radiation therapy and chemotherapy. Radiation alone is the treatment of choice for early stage

NPC, and concurrent chemoradiation is the current standard for locoregionally advanced disease1. The prevailing use of intensity-modulated radiation therapy (IMRT) with or without

chemotherapy has significantly improved outcome after definitive treatment for NPC. However, approximately 10% of patients present with metastatic NPC (mNPC) at initial diagnosis, and an

additional 10% of patients develop metastatic failure after definitive treatment2. Metastatic NPC (mNPC) is an incurable condition. Based on the NCCN guideline for the management of head and

neck cancers3, cisplatin-based chemotherapy is considered its initial management choice for mNPC, and radiation therapy for the primary lesion is only recommended for patients who achieved

complete response after systemic chemotherapy. The addition of local therapy such as radiation to systemic chemotherapy for metastatic cancer has been practiced for a number of diseases with

success in improving treatment outcome including survival. Despite data demonstrating improved survival with tumor burden reduction using radiotherapy in metastatic foci4, 5 and primary

tumor6,7,8 in other malignancies, the recommended utilization of active radiotherapy or chemoradiation for mNPC patients by NCCN is not supported by any large-scale observational or

prospective studies. Potential benefit of radiotherapy was only suggested by case reports and retrospective series with limited sample size9,10,11. Therefore, we conducted a study using the

Surveillance, Epidemiology, and End Results (SEER) database to determine whether NPC patients diagnosed with distant metastasis who received radiation therapy had an improved survival

compared with patients who did not. MATERIALS AND METHODS PATIENTS The SEER registry, which captures 28% of the American population, contains information on patient demographics, tumor

characteristics, and choice of primary treatment modality12. We queried the SEER Registry using SEERSTAT version 8.2.1 to identify patients with metastatic NPC diagnosed from 1988 through

2012. Patients with nasopharyngeal carcinoma were identified by International Classification of Disease-O-3 (ICD-O-3) site codes C110-C119 and histologic codes 8010, 8020, 8070–8073, 8021

and 8082. Metastatic cases were defined as extent of disease (EOD-10) code 85 (for cases before 2004) and Collaborative staging metastasis at diagnosis (CS Mets at Dx) code 10, 40, 50 and 60

(for cases diagnosed at 2004 and after). Histology of NPC was classified into squamous cell carcinoma (ICD-O-3 codes 8070, 8071), non-keratinizing carcinoma (ICD-O-3 codes 8072, 8073),

undifferentiated carcinomas (ICD-O-3 codes 8020, 8021 and 8082) and not otherwise specified group (ICD-O-3 code 8010). Only patients treated with beam radiation (with or without other type

of radiotherapy) were included. Cases with missing data on the status of radiotherapy were excluded. STATISTICAL ANALYSIS The difference in baseline demographic characteristics between

patients treated with and without radiotherapy were compared by Pearson’s chi-squared test or Fisher’s exact test for categorical variables. Outcomes of interest included overall survival

(OS) and nasopharyngeal cancer-specific survival (CSS) based on complete-case analyses. For univariate analyses, Kaplan-Meier method with log-rank test and univariate Cox proportional

hazards (PH) model were used. Age, gender, race, histology, year of diagnosis, status of surgery and radiotherapy were included in the multivariate analysis by Cox PH model. Multiple

imputation by MICE was used for missing values regarding to race, grade, histology and surgery13. All available covariates, the log form of survival time, event indicator, as well as

cumulative hazard _H_ _0_ (_T_) were used as predictors for multiple imputation. Five imputed datasets were generated. Univariate and multivariate analyses by Cox regression were performed

on each imputed dataset. Results were then pooled by Rubin’s Rules. In order to balance the difference in the baseline characteristics between patients treated with and without radiotherapy,

inverse probability of treatment weighting (IPTW) using propensity score was applied14,15,16. Logistic regression was used to generate the propensity scores of the baseline characteristics.

The IPTW was defined as (Z/e) + [(1 − Z)/(1 − e)] (Z = 1 denotes radiotherapy received while Z = 0 denotes radiotherapy not received; e denotes propensity score)17. The IPTWs were then

stabilized to avoid extreme weights that may result in unreliable outcome18. Multivariate analyses were performed by Cox PH model with the IPTWs incorporated. Standardized mean difference

(SMD) was used to evaluate the balance of baseline characteristics before and after IPTW using PS. P values < 0.05 (2-sided) were considered statistically significant. All statistical

analyses were performed using R environment for statistical computing and graphics (version. 3.2.3). RESULTS DEMOGRAPHIC CHARACTERISTICS A total of 679 cases with metastatic NPC diagnosed

between 1988 and 2012 were identified. Among those, 448 patients (66.0%) received radiotherapy while 231 patients (34.0%) did not. The median follow-up was 13 months, and mortality occurred

in 513 (75.6%) patients. All baseline characteristics were summarized in Table 1. Patients less than 65 years old were more likely to receive radiotherapy (64.1% vs. 74.3%, p = 0.007). While

other characteristics were similar in groups with and without radiotherapy. SURVIVAL ANALYSES The results of univariate analyses by Cox regression were detailed in Table 2. Radiotherapy was

associated with significantly improved overall survival (HR: 0.50, 95% CI: 0.41–0.60, p < 0.001) and cancer-specific survival (HR: 0.50, 95% CI: 0.41–0.61, p < 0.001). In addition,

younger age (<65 years), disease diagnosed after 2004, races other than black and white, patients with non-keratinizing or undifferentiated carcinoma and patients who received surgery

were associated with significantly improved OS and CSS. Female patients had a better CSS than males. Races other than white and black showed an improved OS. Additionally, patients with tumor

grade IV had improved OS. KM survival curve for radiotherapy was shown in Fig. 1. Consistent to univariate analyses, multivariate analyses by Cox PH model showed radiotherapy was

independently associated with a 50% lower risk of mortality in regard to both OS (HR: 0.50, 95% CI: 0.42–0.61, p < 0.001) and CSS (HR: 0.50, 95% CI: 0.41–0.62, p < 0.001). Table 3

showed the results of un-weighted multivariate analyses of OS and CSS. Though chi-squared tests showed baseline characteristics were generally balanced except age, by examining the

standardized mean difference (SMD) of those variables between two groups, we observed two out of six variables had a SMD larger than 10%, while the others approached 10%, indicating possible

confounding (Table 4 and Fig. 2). Thus, we performed weighted Cox PH regression using IPTW derived from propensity score. After weighting, SMDs of all 6 variables were below 10%, indicating

baseline characteristics were more comparable in the weighted sample. Table 5 shows the results of weighted multivariate analyses using IPTW by PS. Similarly, a 50% reduced risk of

mortality was found for radiotherapy, for both OS (HR: 0.50, 95% CI: 0.41–0.60, p < 0.001) and CSS (HR: 0.50, 95% CI: 0.40–0.61, p < 0.001). An older age (≥65) was associated with an

91% increased risk of mortality for OS (HR: 1.91, 95% CI: 1.57–2.31, p < 0.001) and a 87% increased risk for CSS (HR: 1.87, 95% CI: 1.49–2.34, p < 0.001). Compared with earlier cases,

patients diagnosed between 2004–2012 had better OS (HR: 0.63, 95% CI: 0.53–0.76, p < 0.001) and CSS (HR: 0.66, 95% CI: 0.54–0.81, p < 0.001). Surgical resection was also related to

improved outcomes for both OS (HR: 0.58, 95% CI: 0.43–0.78, p < 0.001) and CSS (HR: 0.56, 95% CI: 0.39–0.80, p = 0.002). Compared to squamous cell carcinoma, patients with either

non-keratinizing carcinoma or undifferentiated carcinoma had a better OS (HR: 0.77, 95% CI: 0.63–0.96, p = 0.020) and CSS (HR: 0.75, 95% CI: 0.59–0.95, p = 0.016). Female patients had a

better CSS (HR: 0.78, 95% CI: 0.61–0.99, p = 0.045) but not OS (HR: 0.84, 95% CI: 0.69–1.03, p = 0.101). No significant difference was found between different races. DISCUSSION NPC is the

most commonly diagnosed head and neck malignancy in Southern China. Approximately 10% of patients are diagnosed with distant metastasis (i.e., Stage IVC). Although radiation therapy (or

combined chemoradiation therapy) are routinely used for the treatment of non-metastatic NPC, systemic chemotherapy remains the initial management of choice for patients diagnosed with

metastatic disease3. Despite the ability of chemotherapy to prolong survival and curtail disease-related symptoms, resistance to cytotoxic agents ultimately develops. The introduction of

multi-agent regimens with the addition of newer, more novel agents such as taxotere and gemcitabine to cisplatin has shown improvement in survival. Nevertheless, the 5-year overall survival

rate for patients with mNPC is only 20%11, 19, in stark contrast to >80% for patients diagnosed without meta stasis. Decreasing tumor burden using radiotherapy improves survival in a

number of malignancies. For example, local radiation therapy to the primary or metastatic disease improves survival in patients with metastatic breast cancer, renal cell carcinoma, prostate

cancer, lung cancer, and primary brain tumor4,5,6,7,8. Prospective data do not exist regarding a survival benefit for patients with mNPC undergoing treatment of the primary tumor. However,

results from a case series of 5 patients and retrospective studies with limited sample size suggested improved outcome in terms of long-term survival with radiation to the primary disease

focus in NPC patients presented with metastasis at diagnosis. In their retrospective study of 125 patients diagnosed with stage IVC mNPC between 1993 and 2001, Yeh _et al_. discovered that

the 1-year overall survival (OS) rates were 25%, 36%, and 48% for patients received no treatment, chemotherapy (CDDP/5-FU regimen) alone, or radiation therapy alone, respectively. The

authors did not study the effect of local therapy in mNPC patients treated with systemic chemotherapy, and interestingly, patients received radiotherapy alone to the head and neck area had

better OS than those received systemic chemotherapy10. Similar findings were reported in another retrospective study of 105 patients who were treated with chemotherapy followed by high-dose

chemo-radiation. The median survival of patients in this series was 25 months, and the 2-/5-year OS rates were 50% and 17%, respectively11. However, the authors did not compare the OS of

this group of patients with those who did not receive radiation therapy in the same institution. Further, the results of a SEER analysis of 177 patients with mNPC diagnosed at presentation

suggested that the use of radiation therapy improved OS as compared to those without19. The 5-year OS rates were 28% versus 3% (p < 0.0001) favoring the use of radiation therapy in mNPC

patients. Furthermore, the authors also concluded that younger age and non-white race were favorable prognostic factors for mNPC. However, that report was presented in an abstract format and

detailed knowledge of the analysis has never been published in a manuscript format. The number of patients included in the analysis was also limited and the treatment technology used might

be obsolete as only patients diagnosed from 1988 to 2002 were included. SEER is a comprehensive population-based database in the United States that includes disease stage at initial

diagnosis, initial treatments performed, and accurate data regarding patient survival. However, NPC is a much more commonly diagnosed disease in Southeastern Asia as compared to United

States. Nevertheless, SEER remains an ideal approach to studying the survival of patients diagnosed with mNPC especially in recent time periods due to the relative completeness of the data.

In the present analyses, we included a total of 679 patients diagnosed with mNPC at initial presentation from the 1988 to 2012 SEER database. These patients were treated in the “real-world”

setting as compared with potentially selected patients included in a clinical trial or single institutional experience. We chose to include only mNPC patients diagnosed between 1988 and

2012, it can be assumed that chemotherapy was widely used for patients with metastatic NPC during the time period. We discovered that the use of radiation therapy, to the primary disease

and/or the metastatic foci, significantly improved overall survival (OS) and cancer specific survival (CSS). These results were consistent with those of earlier unpublished SEER based

analyses, case reports, as well as those of the retrospective studies. Our SEER data analysis of 679 patients provides additional evidence (level of evidence: 2b). As such, we consider the

current recommendation from the NCCN guideline of radiation therapy in patients diagnosed with metastatic NPC after achieving CR to systemic chemotherapy is reasonable. Nevertheless, whether

it is appropriate to omit radiotherapy in patients who achieved partial response or stable disease after chemotherapy cannot be supported by our findings. Mechanisms underlying the survival

benefit of the local radiation therapy to mNPC remain unknown. Eliminating the primary tumor burden of nasopharyngeal cancer, which is close to the critical organs such as carotid arteries,

brain, and brainstem, and could reduce the probability of death by uncontrolled local disease progression. In addition, tumor burden reduction could reduce the primary or secondary source

of cancer cells for metastasis by “self-seeding”20. Studies have also demonstrated that increased serum EBV-DNA counts, an indicator of disease burden, is related to disease progression and

reduced survival21. Treatment of the primary or metastatic foci of NPC may therefore reduce the number of circulating tumor cells. Another potential mechanism in favor of radiation to local

disease foci could be removing tumor-promoting factors and immunosuppressive cytokines. Retrospective studies are inherited with pitfalls such as selection bias. For example, it is unclear

whether patients received radiotherapy in this cohort were healthier or have more symptoms that need symptomatic control. Certain variables unavailable from SEER database limited our

analysis and precluded controlling for any potential selection bias. These variables include site-specific codes for radiation therapy. Therefore, it is not possible to differentiate whether

the survival benefits were derived from irradiating the primary or metastatic foci. This question would be best answered in a large-scale retrospective study or prospective trial. Another

drawback is that the regimen/timing/dosage of chemotherapy and schedule of chemotherapy relative to radiation is unknown. The lack of chemotherapy details is especially important given the

influence of chemotherapy on mNPC progression and survival. However, as in our matched cohort, radiation and non-radiation groups were matched and comparable in terms of all demographic and

clinical characteristics. These characteristics were critical in determining the other variables including treatment modalities, thus the use of chemotherapy, which is considered the primary

treatment for NPC, would be expected to be similar between the 2 groups. SEER database also lacks information regarding the extent of the metastatic foci, an entity that undoubtedly

influences patient survival. In addition, we also have no data on patients’ performance status and comorbidity. Despite of these insufficiencies, it is clear to us that tumor burden

reduction from local therapy significantly improved overall survival in NPC patients diagnosed with metastasis, although further investigations are needed to understand the optimal

application of radiation therapy that can maximize such benefit. To our knowledge this is the first published population based study to evaluate the effectiveness of local RT in patients

with mNPC. However, we only addressed the patients presented with DM at initial diagnosis. For patients develop distant failure or both distant and local failure after definitive treatment

for their originally localized disease, whether radiation therapy to the metastatic foci (or both metastatic and local recurrent foci) at the time or recurrence provide a survival benefit

was not addressed in our study. Results from a number of studies have indicated that DM occurred after definitive treatment of NPC has better long-term survival as compared to those

presented at initial diagnosis22. Therefore, local treatment might be more important in salvaging NPC patients who failed distantly after definitive treatment. CONCLUSION Despite the

inherent limitations of this SEER-based study, our results suggest that radiation therapy provided to NPC patients with distant metastasis at diagnosis confers a survival benefit. Because of

the lack of site-specific EBRT codes, it was not possible to examine the difference of the survival advantage of radiation therapy to the primary or metastatic sites on patient survival.

Nevertheless, our results, in combination with results from other retrospective series, suggest that the recommendation of radiation therapy for local disease foci in the head and neck

region after sufficient disease control by chemotherapy from the NCCN guideline is reasonable. Nevertheless, large-scale retrospective studies or organized prospective clinical trials

designed not only to demonstrate a survival advantage with radiation of the primary tumor but also to identify patients most likely to benefit is necessary. REFERENCES * Al-Sarraf, M. How we

wrote a landmark nasopharyngeal intergroup phase III protocol in North America. _J Radiat Oncol_ 1, 95–98 (2012). Article  Google Scholar  * Lin, J. Adjuvant chemotherapy in advanced

nasopharyngeal carcinoma based on plasma EBV load. _J Radiat Oncol_ 1, 117–127 (2012). Article  CAS  Google Scholar  * NCCN Guidelines for Treatment of Head and Neck Cancers.

http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. * Majewski, W. _et al_. The efficacy of stereotactic radiotherapy for metastases from renal cell carcinoma. _Neoplasma_

63, 99–106 (2016). Article  CAS  PubMed  Google Scholar  * Zhu, H. _et al_. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer

with distant metastasis. _Cancer_ 117, 5423–5431 (2011). Article  PubMed  Google Scholar  * Cho, Y. _et al_. Does Radiotherapy for the Primary Tumor Benefit Prostate Cancer Patients with

Distant Metastasis at Initial Diagnosis? _PLoS One_ 11, e0147191 (2016). Article  PubMed  PubMed Central  Google Scholar  * Le Scodan, R. _et al_. Breast cancer with synchronous metastases:

survival impact of exclusive locoregional radiotherapy. _J Clin Oncol_ 27, 1375–1381 (2009). Article  PubMed  Google Scholar  * Nitta, T. & Sato, K. Prognostic implications of the extent

of surgical resection in patients with intracranial malignant gliomas. _Cancer_ 75, 2727–2731 (1995). Article  CAS  PubMed  Google Scholar  * Setton, J., Wolden, S., Caria, N. & Lee, N.

Definitive treatment of metastatic nasopharyngeal carcinoma: Report of 5 cases with review of literature. _Head Neck_ 34, 753–757 (2012). Article  PubMed  Google Scholar  * Yeh, S. A.,

Tang, Y., Lui, C. C. & Huang, E. Y. Treatment outcomes of patients with AJCC stage IVC nasopharyngeal carcinoma: benefits of primary radiotherapy. _Jpn J Clin Oncol_ 36, 132–136 (2006).

Article  PubMed  Google Scholar  * Lin, S. _et al_. Combined high-dose radiation therapy and systemic chemotherapy improves survival in patients with newly diagnosed metastatic

nasopharyngeal cancer. _Am J Clin Oncol_ 35, 474–479 (2012). Article  ADS  CAS  PubMed  Google Scholar  * Hankey, B. F., Ries, L. A. & Edwards, B. K. The surveillance, epidemiology, and

end results program: a national resource. _Cancer Epidemiol Biomarkers Prev_ 8, 1117–1121 (1999). CAS  PubMed  Google Scholar  * van Buuren, S. & Oudshoorn, K. Mice: Multivariate

imputation by chained equations in R. _Journal of Statistical Software_ 45 (2011). * Rosenbaum, P. & Rubin, D. The central role of the propensity score in observational studies for

causal effects _Biometrika_, 41–55 (1983). * Rosenbaum, P. Model-based direct adjustment. _J Amer Statist Assoc_, 387–394 (1987). * Austin, P. C. The performance of different propensity

score methods for estimating marginal hazard ratios. _Stat Med_ 32, 2837–2849 (2013). Article  MathSciNet  PubMed  Google Scholar  * Lunceford, J. K. & Davidian, M. Stratification and

weighting via the propensity score in estimation of causal treatment effects: a comparative study. _Stat Med_ 23, 2937–2960 (2004). Article  PubMed  Google Scholar  * Cole, S. R. &

Hernan, M. A. Constructing inverse probability weights for marginal structural models. _Am J Epidemiol_ 168, 656–664 (2008). Article  PubMed  PubMed Central  Google Scholar  * Dandona, M.

_et al_. Survival for nasopharyngeal cancer with distant metastatic disease at presentation [abstract]. _J Clin Oncol_ 27, (Suppl; abstr e17004) (2009). * Comen, E., Norton, L. &

Massague, J. Clinical implications of cancer self-seeding. _Nat Rev Clin Oncol_ 8, 369–377 (2011). PubMed  Google Scholar  * Lin, J. C. _et al_. Quantification of plasma Epstein-Barr virus

DNA in patients with advanced nasopharyngeal carcinoma. _N Engl J Med_ 350, 2461–2470 (2004). Article  CAS  PubMed  Google Scholar  * Teo, P. M., Kwan, W. H., Lee, W. Y., Leung, S. F. &

Johnson, P. J. Prognosticators determining survival subsequent to distant metastasis from nasopharyngeal carcinoma. _Cancer_ 77, 2423–2431 (1996). Article  CAS  PubMed  Google Scholar 

Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, 201321, China Jiyi Hu, Jing Gao, Weixu Hu,

 Xiyin Guan & Jiade J. Lu * Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201321, China Lin Kong Authors * Jiyi Hu

View author publications You can also search for this author inPubMed Google Scholar * Lin Kong View author publications You can also search for this author inPubMed Google Scholar * Jing

Gao View author publications You can also search for this author inPubMed Google Scholar * Weixu Hu View author publications You can also search for this author inPubMed Google Scholar *

Xiyin Guan View author publications You can also search for this author inPubMed Google Scholar * Jiade J. Lu View author publications You can also search for this author inPubMed Google

Scholar CONTRIBUTIONS J.J.L. and L.K. planned the study. J.H., J.G., W.H. and X.G. queried the database and analyzed the data. J.J.L., L.K. and J.H. wrote the manuscript. J.J.L. and L.K.

supervised the entire study. All authors reviewd the manuscript. CORRESPONDING AUTHORS Correspondence to Lin Kong or Jiade J. Lu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare

that they have no competing interests. ADDITIONAL INFORMATION PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional

affiliations. RIGHTS AND PERMISSIONS OPEN ACCESS This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution

and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if

changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the

material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to

obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Hu, J., Kong, L., Gao, J. _et al._ Use of Radiation Therapy in Metastatic Nasopharyngeal Cancer Improves Survival: A SEER Analysis. _Sci Rep_ 7, 721 (2017).

https://doi.org/10.1038/s41598-017-00655-1 Download citation * Received: 30 April 2016 * Accepted: 09 March 2017 * Published: 07 April 2017 * DOI: https://doi.org/10.1038/s41598-017-00655-1

SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to

clipboard Provided by the Springer Nature SharedIt content-sharing initiative