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Table of Contents
ORIGINAL ARTICLE
Year : 2023  |  Volume : 9  |  Issue : 3  |  Page : 314-321

Shenyi capsule prolongs postoperative survival of patients with nonsmall cell lung cancer: A multicenter, randomized, controlled trial


Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

Date of Submission14-Nov-2021
Date of Acceptance11-Dec-2021
Date of Web Publication20-Jul-2023

Correspondence Address:
Prof. Bing-Kui Piao
Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange Street, Xicheng, Beijing 100053
China
Prof. Hong-Sheng Lin
Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixiange Street, Xicheng, Beijing 100053
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2311-8571.382023

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  Abstract 


Objective: The objective of this study was to examine the effect of the postsurgical administration of Shenyi capsules on the outcome and overall survival of patients with nonsmall cell lung cancer (NSCLC). Materials and Methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients with stages I–IIIA NSCLC were randomized to Shenyi or placebo groups (treatment duration: 6 months) and followed up for 10 years. One-year, 2-year, 5-year, and 10-year survival rates and survival times were calculated. Symptoms, quality of life, traditional Chinese medicine (TCM) syndrome, and recurrence were evaluated. Results: A total of 361 patients (treatment group, n = 185; placebo group, n = 176) were randomized and followed up for 10 years. The two groups had similar baseline demographic and clinical characteristics. Among all 361 patients, the treatment group had significantly longer median survival (31 months, respectively) than the placebo group (22.3 months, P < 0.01). In stage II or III patients, recurrence and metastasis rates in the treatment group were lower than those in the placebo group (P < 0.05). The treatment group also had significantly longer 1-year and 2-year survival rates based on the full analysis set and per-protocol set; however, there was no statistically significant difference in the 5-year and 10-year survival rates (P < 0.01 for all comparisons). Multivariate analysis of variance showed that the interaction between stage and age had a significant impact on overall survival (P < 0.05). Compared with the placebo group, the treatment group showed a significant decrease in TCM syndrome (P < 0.01) and a significant increase in the Karnofsky Performance Score (P < 0.01) and body weight (P < 0.05). Conclusions: Adjunctive therapy with Shenyi capsules significantly prolonged the 1-year and 2-year survival rates after surgery and improved the quality of life. Moreover, none of the patients experienced severe adverse effects. These results suggest that Shenyi capsules may have clinical applications in treating patients with NSCLC.

Keywords: Lung cancer, placebo, postoperative, Shenyi capsule, traditional Chinese medicine


How to cite this article:
Li DR, Hou W, Hua BJ, Zhang PT, Xiong L, Liu H, Mao QY, Lin HS, Piao BK. Shenyi capsule prolongs postoperative survival of patients with nonsmall cell lung cancer: A multicenter, randomized, controlled trial. World J Tradit Chin Med 2023;9:314-21

How to cite this URL:
Li DR, Hou W, Hua BJ, Zhang PT, Xiong L, Liu H, Mao QY, Lin HS, Piao BK. Shenyi capsule prolongs postoperative survival of patients with nonsmall cell lung cancer: A multicenter, randomized, controlled trial. World J Tradit Chin Med [serial online] 2023 [cited 2023 Sep 25];9:314-21. Available from: https://www.wjtcm.net/text.asp?2023/9/3/314/382023




  Introduction Top


Lung cancer is a major global public health concern. The 2020 World Health Organization (WHO) Cancer Report showed that the global incidence of lung cancer among all malignant tumors ranks second at 2.2 million, and the death toll ranks first at 1.8 million. Lung cancer is also the most common malignancy in China, with an incidence rate of 37.3% of cancers[1] and accounts for 27% of cancer-related deaths.[2] The incidence and mortality of lung cancer continue to increase, and there are an estimated 500,000–600,000 new lung cancer cases in China annually. In 2020, there were more than 810,000 new lung cancer cases in China. The WHO predicts that by 2025, China will have more than one million new cases of lung cancer per year and the highest prevalence of lung cancer worldwide.[3] The 5-year survival rate for lung cancer patients in China has only increased by 3% in the past 20 years, from 12.7% in 1975–1977 to 15.7% in 1996–2004.[4] This finding may be due to delays in diagnosis and a lack of effective therapies.[5] Thus, it is imperative to develop new therapeutic strategies for the treatment of lung cancer.

Failure to control the recurrence and metastasis of nonsmall cell lung cancer (NSCLC) after surgery is a major reason for the poor therapeutic efficacy of current treatments.[6] Thus, it is crucial to prevent metastasis of lung cancer for successful therapy, and many lung cancer studies have focused on this topic. Our experience over the past decade indicates that traditional Chinese medicine (TCM) may help improve the long-term survival of patients with lung cancer after surgery.[7] Based on the results of preliminary and clinical studies that examined the prevention of recurrence and metastasis of lung cancer, we investigated the effects of strengthening antipathogenic qi on the recurrence and metastasis of NSCLC after surgery and sought to confirm the therapeutic efficacy of TCM in preventing the recurrence and metastasis of lung cancer.

This study was conducted between February 2002 and May 2012 and examined patients from 27 tertiary hospitals (21 centers), who had experience in cancer therapy. Based on evidence-based medicine (EBM) and good clinical practice (GCP), we performed a multicenter, randomized, double-blind, placebo-controlled study in patients with stages I–IIIA NSCLC. The primary endpoint of this study was the survival rate. Strict follow-up procedures, rigorous study plans, and data quality controls were used. Biometric experts participated in this study. Criteria that are widely accepted by oncologists were used to evaluate the therapeutic efficacy and assess the advantages of TCM in the attenuation of TCM syndromes, prevention of recurrence and metastasis, improvement of quality of life, and prolongation of survival. This study examined the efficacy of TCM in the treatment of lung cancer after surgery.


  Materials and Methods Top


Study design

This was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly allocated to the Shenyi capsule group (n = 200) or placebo group (n = 200). The treatment lasted for 6 months, and the expected duration of follow-up was 10 years. After follow-up, symptoms, quality of life, TCM syndromes, recurrence, and metastasis were evaluated. The 1-year, 2-year, 5-year, and 10-year survival rates and overall survival were also recorded. The study was conducted in accordance with the GCP guidelines with strict supervision. Before the study, a random number table was generated using the Statistical Analysis System (SAS) at the Guang'anmen Hospital of the China Academy of Chinese Medical Sciences to ensure the double-blinding of drugs to patients and clinicians. Patients were recruited in February 2002 and followed up for 10 years. Investigators supervised these centers once every 3 months and followed up with all patients.

Patient selection

All enrolled patients had stage I–IIIA NSCLC; received surgical interventions within 2 months; had normal heart, liver, kidney, and hematopoietic functions; were 18–75 years old; had Karnofsky performance scores of at least 70; did not receive radiotherapy or chemotherapy before surgery; and volunteered to participate. Informed consent was obtained before enrollment, and all patients complied with the treatment and volunteered to undergo follow-up. Regarding TCM syndrome type, patients with characteristics of qi deficiency were evaluated.[8] The exclusion criteria were concomitant heart, liver, kidney, or hematopoietic dysfunction, pregnancy, breastfeeding, mental illness, and allergy to the study drug. All enrolled patients procedures were carried out in compliance with the guidelines for scientific procedures approved by the ethics committee of the Xi Yuan Hospital of China Academy of Chinese Medical Sciences, and the approval number is No.2019XLA028-3.

Therapeutic protocol

Treatment was initiated within 2 months of surgery. Patients in the treatment group were administered Shenyi capsules (Ginsenoside, Rg3, Jilin Changchun Yatai Pharmaceutical), and patients in the control group were administered placebo capsules (Jilin Changchun Yatai Pharmaceutical; mainly starch) that were identical to the Shenyi capsules in shape, taste, and smell. Two capsules (drug or placebo, 10 mg/per capsule, 20 mg, twice per day, taken with warm-boiled water 30 min before meals) were administered daily. The treatment was free and lasted for 6 months. Other therapies were administered according to the 2002 National Comprehensive Cancer Network guidelines for lung cancer, and patients who received concomitant chemotherapy or radiotherapy were also observed. All drugs were obtained from the same lot number and were certified by the local Institute of Biological Products Examination.

Evaluation of therapeutic efficacy

The primary endpoint was survival time. The following data were recorded: (a) median survival time and 1-year, 2-year, 5-year, and 10-year survival rates; (b) recurrence and metastasis (time and site) after treatment and during follow-up; (c) TCM syndrome, scored according to the standard criteria;[9] (d) quality of life (Karnofsky Performance Status [KPS], body weight, pain, and other parameters); and (e) immune function (measured using carcinoembryonic antigen [CEA] levels and other parameters). Immune function was classified as elevated if the serum CEA level increased by at least 10%, reduced if it decreased by at least 10%, or otherwise as stable. The KPS was classified as elevated if it increased by at least 10 points, decreased if it declined by at least 10 points, or otherwise as stable.

Data management

A third party (Beijing Maidekang Pharmaceutical Technology Co., Ltd) managed the data. According to the standard protocols for clinical trials and medical reports, a database was established using EpiData software, and all data were entered and double-checked. Unclear medical record reports were further investigated to gather sufficient data. Finally, the database was revised and locked based on the results.

Statistical model

Third-party statisticians (Statistics Department, School of Medicine, Peking University) performed all statistical analyses and reported the results using SAS version 8.2 (The SAS Institute, Cary, NC, USA). A two-tailed P < 0.05 was considered statistically significant.

The intention-to-treat analysis included randomized patients who received at least one treatment with the drug or placebo. If information was incomplete, data from the last follow-up were used. The full analysis set (FAS) comprised data from patients who were randomized, received at least one treatment, and underwent evaluation after treatment. Missing data on therapeutic efficacy in the FAS were supplemented using the last observation carried forward method. The per-protocol set (PPS) consisted of all patients who completed the study, had good compliance, took no prohibited drugs, completed the case report form (CRF), and received 80%–120% of the drug for analysis of therapeutic efficacy. The safety set consisted of patients who were randomized, received at least one treatment, and underwent a safety evaluation after treatment.

The data from this trial were primarily obtained from the PPS statistics. Owing to a large number of subject centers and wide national coverage, some CRF secondary efficacy indicators had missing data. After the statisticians excluded dislodged and missing cases, statistical analysis was performed mainly on the nonmissing data while ensuring a consistent baseline for both groups of patients. Among these, there were no missing data on the subject's primary efficacy index of survival, which was counted according to the FAS.

Statistical analysis

For quantitative data, numbers, means, standard deviations, medians, maxima, minima, and 95% confidence intervals were calculated for comparisons of the treatment and placebo groups. First, normal distribution and homogeneity of variance were tested. If the data had a normal distribution and the variance was homogeneous, an analysis of variance was used; otherwise, a nonparametric Kruskal–Wallis H-test was used. For qualitative data, contingency tables were used for processing, and the Chi-square test was used for statistical analysis. When the theoretical frequency was lower than 5, Fisher's exact test was used to calculate the exact probability. The numbers and percentages of categorical parameters were calculated and tested using a center-stratified Cochran–Mantel–Haenszel test. The scales used to evaluate the quality of life were analyzed to assess reliability, validity, and responsiveness.


  Results Top


General characteristics of the treatment and placebo groups

We enrolled 402 patients; 361 individuals met the inclusion criteria and were willing to participate in randomized controlled trials. Of these, 185 were in the treatment group, and 176 were in the placebo group. Eleven patients in the treatment group and 18 patients in the placebo group were lost to follow-up, corresponding to a dropout rate of 8.1% [Figure 1].
Figure 1: CONSORT diagram of patients' recruitment and analysis. FAS: Full analysis set, PPS: Per-protocol set

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The treatment and placebo groups had similar demographic characteristics and vital signs (P > 0.05). The two groups were similar in terms of the methods used for diagnosis, tumor location, pathological type, body weight, cancer stage, use of chemotherapy and radiotherapy, KPS score, and quality-of-life score [P > 0.05, [Table 1]]. The treatment and placebo groups had significantly higher serum CEA (P < 0.001) and CD3+T lymphocyte levels (P = 0.008). Thus, the treatment and placebo groups had comparable baseline demographic and clinical characteristics.
Table 1: Patient clinicopathological characteristics in Shenyi capsule and placebo groups

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Recurrence, metastasis, and survival

The median follow-up time was 54.6 months. The treatment and placebo groups showed similar rates of recurrence and metastasis [Table 2]. However, according to the subgroup analysis of patients with stage II or III disease, the treatment groups were superior to the placebo group [Table 2]. Survival analysis [Table 3] and [Figure 2] indicated a mean survival time of 29.26 months and a median survival time of 31 months in the treatment group, and a mean survival of 23.55 months and a median survival of 22.3 months in the placebo group. The Wilcoxon analysis indicated a significantly better survival in the treatment group (P < 0.0001). The 1-year and 2-year survival rates were also significantly longer in the treatment group, although the 5-year and 10-year survival rates were not statistically different from those of the placebo group (P = 0.008 for the 1-year survival rate in PPS and FAS; P = 0.001 for the 2-year survival rate in PPS and FAS; and P > 0.05 for the 5-year and 10-year survival rates in PPS and FAS). The results of the multivariate analysis of variance on the overall survival showed that the interaction of age, sex, body weight, pathological type, and Karnofsky performance score did not have a significant impact on OS (P > 0.05), while the interaction between stage and age had a significant impact on the overall survival (P < 0.05). Patients at a later stage and older age had shorter overall survival.
Table 2: Recurrence and metastasis of patients in the Shenyi capsule and placebo groups in the per-protocol set and full analysis set

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Table 3: Survival rates of patients in the Shenyi capsule and placebo groups in the per-protocol set and full analysis set

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Figure 2: The overall survival of patients in the Shenyi capsule and placebo groups

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Therapeutic efficacy

Evaluation of therapeutic efficacy in the PPS and FAS indicated that the treatment group had a significantly better outcome than the placebo group according to TCM syndrome, KPS, and body weight (P < 0.05) for all comparisons, except for P = 0.054 in the PPS for body weight [Table 4]. However, the treatment and placebo groups had similar NK-cell functions and CD4+T/CD8+T cell ratios [P > 0.05, [Table 4]].
Table 4: Therapeutic efficacy in the Shenyi capsule and placebo groups in the per-protocol set and full analysis set

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Safety evaluation

The treatment and placebo groups showed similar hemograms and heart, liver, and kidney functions before and after therapy. Moreover, these parameters remained unchanged after therapy in both groups. No serious drug-related adverse events occurred in the 361 patients.


  Discussion Top


NSCLC is typically systemic in the diagnosis. Therefore, researchers have focused on the development of adjunctive therapies after complete resection. The use of adjunctive therapies such as radiotherapy and chemotherapy is controversial because they may be ineffective. A meta-analysis by the NSCLC collaborative group examined 8147 patients who received postoperative chemotherapy and showed that patients with stage II or III NSCLC benefited from postoperative radio- or chemotherapy (absolute risk reduction of 7%), but patients with stage I NSCLC received no significant benefit.[10] Hui et al. studied 364 patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy and found that postoperative radiotherapy did not improve disease-free survival.[11] In 2014, Wu et al. published a Chinese multicenter, prospective, and noninterventional study (ICAN) of 568 NSCLC patients.[12] The results indicated that adjuvant chemotherapy provided no benefit and that the 3-year disease-free survival rate was mainly determined by the pathological stage. In addition, for patients with stage I or II NSCLC, postoperative radiotherapy did not significantly prolong survival or improve the quality of life and reduced quality of life in a small number of patients who experienced severe heart and lung toxicities. At the same time, an open-label, randomized, phase III trial involving 501 patients showed that postoperative radiotherapy was not associated with an increase in disease-free survival, and it is not recommended to use conformal postoperative radiotherapy as the standard treatment for patients with stage IIIA N2 NSCLC.[13] However, in recent years, the clinical research on postoperative targeted therapy has also made advances: the results of a randomized, open-label phase III clinical study (EVIDENCE) of icotinib for postoperative adjuvant treatment of stage II–IIIA operable Chinese NSCLC populations showed that the median DFS of the first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) reached 46.95 months, which was significantly better than the 22.11 months of adjuvant chemotherapy, and the risk of disease recurrence was reduced by 64%.[14] The 2021 ASCO meeting announced the results of the phase III clinical study (ADAURA) of osimertinib. A total of 682 NSCLC patients with EGFR gene mutations and postoperative adjuvant chemotherapy were enrolled from more than 200 centers in more than 20 countries/regions. In patients with stage II or IIIA, osimertinib reduced the risk of disease recurrence and mortality by 83%. In all (IB, II, and IIIA) populations, osimertinib reduced the risk of disease recurrence and death by 79%.[15] This trial successfully explored the efficacy of osimertinib as an adjuvant therapy for patients with early (IB, II, and IIIA) NSCLC (carrying EGFR gene mutations) after radical tumor resection. This is another study on the successful adjuvant treatment of (ADJUVANT) Iressa (for patients with EGFR mutation-positive lung cancer after surgery, the use of gefitinib as adjuvant therapy can significantly prolong the recurrence time of the disease by approximately 10 months). These findings provide a basis for the postoperative adjuvant treatment with EGFR-TKIs.

Some researchers have previously examined whether TCM provides a therapeutic value by prolonging survival or reducing recurrence and metastasis in patients with NSCLC. Our center has used therapies that strengthen antipathogenic qi and cultivate the root since the 1990s to prevent recurrence and metastasis of lung cancer after surgery, and the findings have been promising.[12] Based on our previous findings, we reviewed the literature on the treatment of lung cancer with TCM and solicited opinions from other experts to design the present study according to the principles of EBM. Thus, this multicenter, randomized controlled study with a large sample size investigated the therapeutic efficacy of postsurgical Shenyi capsules in patients with NSCLC. The main ingredient of the Shenyi capsule is an RG3 monomer from ginseng, which can strengthen the antipathogenic qi and cultivate the root. The State Food and Drug Administration classifies the Shenyi capsule as a State Category I New Drug. Our previous studies confirmed that Shenyi capsules could inhibit the angiogenesis of tumors, prevent cancer recurrence and metastasis, and prolong survival[16] as shown in studies supported by the national “fifteen” key programs. The combination of Shenyi capsules and TCM can reduce blood flow perfusion volume and improve vascular permeability in mid-late-stage NSCLC.[17]

Our results showed that after complete resection of NSCLC, adjuvant therapy with TCM can strengthen antipathogenic qi and cultivate the root, thereby prolonging survival and reducing cancer recurrence and metastasis. In addition, this therapy modulates the immune function, which may explain its therapeutic effect. The safety analysis showed that this therapy had no serious adverse effects. Thus, we recommend the use of this therapy for more than 6 months for the postsurgical treatment of patients with NSCLC.

This study has some limitations; all of which are attributable to the limitations in terms of workforce and resources. First, the sample size was too small to perform a subgroup analysis. Second, owing to the limited time available for the study and the different locations of the medical centers, the duration of the herbal intervention for the patients in this study was 6 months. Longer periods of herbal intervention and subsequent treatment modalities were not performed in either group of patients. Therefore, no significant differences were observed in the 5-year and 10-year survival rates. Third, the conditions used for radiotherapy and chemotherapy were not strictly controlled owing to the limited research budget and Chinese conditions, and only baseline conditions were subjected to statistical analysis. Fourth, although cancer tissue and blood samples were collected, biological examinations were not performed. Fifth, TCM-specific and individualized treatments according to syndrome differentiation were not employed due to operability concerns. We plan to conduct a multicenter randomized controlled clinical trial with a large sample size to investigate individualized TCM treatment in patients with NSCLC after surgery. This future study will examine therapeutic efficacy and use a TCM-based evaluation system for the systemic evaluation of efficacy, safety, economics, and ethics.


  Conclusions Top


The results of this multicenter, randomized, placebo-controlled, double-blind clinical trial with a large sample size indicated that adjunctive therapy with Shenyi capsules (which strengthens antipathogenic qi and cultivates the root) significantly prolongs survival, reduces recurrence and metastasis after surgery, reduces clinical symptoms, increases KPS and body weight, improves the quality of life, and regulates NK-cell and T-cell subsets. Moreover, there were no serious adverse events, and the safety evaluation indicated a favorable safety profile. These results indicate that this therapy should be promoted in clinical practice.

Authors' contributions

DL and WH presided over this study. DL, QM, and HL drafted the protocol, and BH, PZ, and LX revised it. DL, QM, HL, LX, and HW assisted the subcenters in recruiting patients, and QM conducted the data analysis. HL and BP provided summaries. All authors participated in the design and read and approved the final manuscript. DL and HW contributed equally to this study.

Acknowledgments

We thank the Beijing Municipal Health Bureau and the China Academy of Chinese Medical Sciences for funding this study. We also thank all the people and groups for their great contributions to this research, including Hong-Chao Xiong, Li-Jian Zhang (Beijing Cancer Hospital), Xin-Xin Ma (Beijing Anzhen Hospital), Yan-Ning Shou (China-Japan Friendship Hospital), Xian-Li Meng, Hong-Yan Wang, Bao-Qing Li, Rui Wang, Jing Li (The Fourth Hospital of Hebei Medical University), Lian-Ya Zhou (The Second Hospital of Hebei Medical University), Jin Shi, Wei Chai (Bethune International Peace Hospital), Ying Chai, Ying Wang, Yu-Feng Yao (The Second Affiliated Hospital Zhejiang University School of Medicine), Xin-Ming Zhou, Hong Jiang (Zhejiang Cancer Hospital), Jun Hua, Guo-Qin Ren (Second People's Hospital of Wuxi City); Ru-Lin Qian, Feng-Lan Song, Xue-Fang Lin (Henan Provincial People's Hospital), Gao-Feng Zhao (The First Affiliated Hospital of Zhengzhou University), Zai-Qin Yang, Zhi-Song Xing (The Fifth Affiliated Hospital of Zhengzhou University), Shi-Qing Jiang (The Third Affiliated Hospital of Henan College of Traditional Chinese Medicine); Ping Lu (The First Affiliated Hospital of Xinxiang Hospital); Zhen-Hai Zhang (Xinxiang Central Hospital), Jiang-Feng Cao, Jing-Fu Du (Anyang Tumor Hospital, Henan Province), Hong-Xin Sun (Traditional Chinese Medicine Hospital of Henan Province), Guo-Fan Wang (Shandong Cancer Hospital), Yi-Ren Luo (Qingdao Medical College), Guo-Jian Tang, Hai-Jian Zhou (The Affiliated Hospital of Qingdao University Medical College), Jun Liang, Zhuang Yu (Qingdao Medical College), Qing-Yu Zhang, Shi-Hui Song, Peng Zhang (Tianjin Medical University General Hospital), Guang-Ru Xie (Tianjin Tumor Hospital), Jin-Ming Zhang, Hui-Min Zhou (Tianjin Chest Hospital), Ying-Jie Jia, Ying Zhang (The First Affiliated Hospital of Tianjin Medical University), Zhen-Ming Zhang, Li-Jun Lu, Hong-Tao Li (The First Affiliated Hospital, Zhangjiakou Medical College), Xiu-Fang Liu, Chang-Fu Xu (The Chinese People's Liberation Army [PLA] DiErWuYi Hospital), and the medical staff of the Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences.

Financial support and sponsorship

This study was financially supported by the Capital Medical Development Fund, the Innovation Project of China Academy of Chinese Medical Sciences (ZD199902).

Conflicts of interest

There are no conflicts of interest.



 
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