The Role of Carbon Nanoparticle in Lymph Node Detection and Parathyroid Gland Protection during Thyroidectomy- a Meta Analysis

Objective To assess the efficiency of the carbon nanoparticles (CNs) in lymph node identification and parathyroid gland protection during thyroidectomy. Methods A systematic literature search for relevant literatures published up to December 2018 in PubMed, Embase, Web of Science and Cochrane Library was performed. Both English and Chinese literatures were retrieved and analyzed. Randomized controlled trials or nonrandomized controlled trials on the use of CNs during thyroidectomy were enrolled in this study. The primary outcomes included the number of lymph nodes harvesed, rate of lymph nodes involvement, and the rates of accidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Weighted mean differences (WMDs), odds ratios (ORs) and risk differences (RDs) were calculated for the dichotomous outcome variables. Between-study heterogeneity was tested using the Q tests and the I2 statistics. All analyses were performed using Review Manager (version 5.3.5). Results 25 studies comprising 3266 patients were included in this analysis. The total number of lymph nodes harvested in the groups of carbon nanoparticles was significant higher than that in the control groups (WMD, 2.36; 95% CI, 1.40 to 3.32; P <0.01). Administrating carbon nanoparticles was associated with a lower incidence of accidental parathyroid gland removal (OR = 0.30, 95% CI = 0.23 to 0.40, P <0.01) and lower rates of both postoperative transient hypoparathyroidism (OR =0.46, 95% CI = 0.33 to 0.64, P <0.01) and transient hypocalcemia (OR =0.55, 95% CI = 0.09 to 3.43, P =0.52). There was no significant difference of identified lymph node metastatic rates between the patients with and without use of carbon nanoparticles. Subgroup analyses indicated that the application of CNs in thyroid cancer reoperation also decreased the rate of transient hypoparathyroidism (OR =0.20, 95% CI = 0.36 to 0.04, P =0.01) and the possibility of accidental parathyroid glands removal (OR = 0.19, 95% CI = 0.05 to 0.73, P<0.05). Conclusions The application of CNs for thyroidectomy results in higher number of lymph node harvested and better parathyroid gland protection during initial surgery and reoperation for thyroid cancer.


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Thyroid cancer is one of the most common types of cancer in the world, the incidence of which 38 increased dramatically in recent two decades(1). Cervical lymph node metastases are common in 39 patients with papillary thyroid carcinoma (PTC), the most common subtype of thyroid cancer(1).

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Total thyroidectomy combined with levelⅡ-Ⅵ neck dissection for clinically N1b cases or central 41 compartmental dissection (CND) for cN0 case is widely advocated as one of the standard treatment 42 protocols for thyroid cancer, whereas lobectomy is only accepted for T1 cases without high risk 43 factors(2-4). However, it's a challenge for a surgeon to perform a total thyroidectomy plus CND 44 due to the potential risk of postoperative hypocalcemia or hypoparathyroidism, whose incidence 45 ranges from20% to 60% based on the previous reports and even higher for those who undergo a re-46 operation(5, 6).

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Carbon nanoparticles (CNs) have been successfully used for sentinel lymph node detection in breast 48 carcinoma, gastric carcinoma, and etc. (7,8). The CNs, with a diameter of 150 nm, can easily be 49 captured by macrophages and penetrate the lymphatic capillaries with an endothelial cell gap of 50 20-50 nm rather than the capillary vessels whose endothelial cell gap is 120-500 nm, and they 51 ultimately accumulate in the sentinel lymph nodes. This is the hypothetic basis that CNs can be used 52 as a tracer to detect the sentinel node. In the past decade, CNs had been successfully attempted as a 53 negative developer to protect parathyroid gland during initial thyroidectomy (9). Although a couple 54 of meta-analyses had been published on evaluating the value of CNs in initial thyroid surgery, the 55 data need to be updated (10,11). Furthermore, there are still doubts about the efficiency of CNs in 56 re-operation thyroidectomy due to the hypothesis that the lymphatic capillaries may be destroyed 57 during initial surgery(12, 13). Therefore, we performed a meta-analysis with more comprehensive Figure 1

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The quality assessment details for the RCTs and NRCTs are presented in Tables 2 and 3.

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Surgical procedure

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The CNs were provided by Chongqing LUMMY Pharmaceutical Co., Ltd. The details of the 116 injection method are shown in Table 4. In most of the studies, the CN injected underneath the fibrous 117 thyroid capsules at two or three points around the neoplasm, 0.1-0.2ml for each point. And 5-10mins 118 later thyroidectomy or lobectomy and neck dissection were performed.

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Lymph node removal 120 All studies regarding lymph node dissection are showed in Figure 2. The total number of lymph 121 node(LN) harvested in the CN group was significant higher than that in the control groups (WMD, 122 2.36; 95% CI, 1.40 to 3.32; P＜0.01, Figure 2). There was no difference in total metastatic rate 123 between the two groups (OR = 1.07, 95% CI = 0.75 to 1.57, P=0.71, Figure 3). The rate of LN black-7 124 staining varied between 73.3% and 95.3%.

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Thyroid cancer is one of the most common types of cancer in the world, with a rapid increasing 140 incidence in recent two decades(1

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Hypoparathyroidism is a common complication after thyroid cancer surgery, especially reoperation.

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The incidence of transient hypoparathyroidism after surgery is reported to be 20% to 60%, while 173 that of permanent hypoparathyroidism is 0% to 7%(5, 6). Our study revealed that application of 174 CNs during lobectomy or CND reduce the rate of PGs accidental removal by approximately 30%.

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But there were still doubts about practicability for parathyroid protection during thyroid surgery.

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Liu and Shen reported that CNs play important role in identifying and preserving PGs, but not

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The current meta-analysis has some limitations and the results should be interpreted with caution.

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First, all of studies including in this meta-analysis were performed only in