Chao-Qun Bi, Han-Han Chen, Miao-Miao Liu, Jing-Wei Li?▲

1. College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014

2. Department of Mammary Gland Thyroid Surgery, First Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014

3. First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014

2?.Department of Mammary Gland Thyroid Surgery, First Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014

Keywords:

ABSTRACT

1. Introduction

Granulomatous mastitis (GM) was first proposed by Kessler[1] et al in 1972. It has the characteristics of suppurative granuloma with the terminal lobular duct as the center. It destroys the structure of the lobule of the breast and forms caseless necrosis. In the necrosis, it can form lipid absorption vacuole and micro abscess[2].GM usually occurs in childbearing women, especially in the first five years of pregnancy[3].In recent years, with the increasing incidence of GM, the clinical understanding of the disease is deepening, the concept of treatment is constantly updated, and a variety of treatment methods are gradually adopted.At present, GM can be divided into several types, such as mass type, abscess type, refractory type, etc. the treatment of GM varies from person to person, according to the conditions of the type. At present, the combination of hormone surgery is the main method to treat this disease.It has been reported that autoimmune diseases, prolactin elevation, chest impact, fullterm pregnancy in recent 5 years, taking contraceptives and non double breast alternative breastfeeding are independent risk factors for IgM[4].At present, many RCTs show that the combination of traditional Chinese and Western medicine has a good clinical effect on GM, but due to the small sample size, different scales of effect and lack of systematic evaluation, there is no summary conclusion.Therefore, this study systematically evaluated and meta analyzed the effective rate and recurrence rate of GM treated with integrated traditional Chinese and Western medicine, in order to provide basis for clinical treatment of GM.

2. Data and methods

2.1 Inclusion and Exclusion criteria

2.1.1 Inclusion criteria

(1) study type: clinical randomized controlled trial (RCT); (2) language: Chinese and English; (3) study object: Patients with clear diagnosis of GM regardless of age; (4) intervention measures: the test group was treated with combination of Chinese and Western medicine, and the control group was treated with single western medicine; (5) outcome indicators: effective rate, recurrence rate.

2.1.2 Exclusion criteria

(1) data missing or repeatedly published in the literature; (2) animal experiments or basic experiments; (3) the design of research scheme is not rigorous and cannot be studied; (4) there is no clear diagnosis.

2.2 Retrieval strategy

Chinese Journal Full-text Database (CNKI), Wanfang, VIP, PubMed, EMBASE, China biomedical database, web of science were searched. The retrieval time limit was from July 2019 to July 2019. In addition, the references included in the study were also checked to supplement the GM literature related to the study. Key words are "granulomatous mastitis", "combination of Chinese and Western medicine", "randomized controlled trial".

2.3 Literature screening and quality evaluation

In the process of literature selection, the two researchers should follow the principle of cross discussion and check. If there is a score, the two researchers should follow the principle of cross discussion and check Otherwise, it needs to be discussed. If there is still no agreement, it needs to ask the third party for opinions. If necessary, it needs to contact the original author to determine the test data and implementation process. Then, according to the biased risk assessment of RCT in Cochrane manual, including 7 items, including random grouping, assignment concealment, blind method, data integrity and standardized report, the included study was assessed with high, low and unknown risks.

2.4 Statistical analysis

In statistical analysis, Revman 5.3 software was used to meta analyze the extracted data, and odds ratio (or) and 95% confidence interval (CI) were used as analysis statistics. When I2 ≤ 50% or P > 0.1, it is considered that there is less heterogeneity and better homogeneity between the studies, then fixed effects model is used for meta analysis; when I2 > 50% or P ≤ 0.1, it is considered that there is greater heterogeneity between the studies, random effects model is needed Model) to analyze the sources of heterogeneity. If there is greater heterogeneity between groups or the reasons for heterogeneity cannot be explained, descriptive analysis can be used.

3. Results

3.1 Document retrieval process and basic information included in the study

Computer searches 2570 literatures about the combination of traditional Chinese and Western medicine and the treatment of GM by western medicine. According to the inclusion and exclusion criteria, they are carefully selected and finally included in 9 RCT studies [5-13], all of which are Chinese literatures without English literatures. The flow chart of literature selection is shown in figure 1, and the basic information table of inclusion is shown in Table 1.

Figure 1 Document selection process

Table 1 Basic information of included documents

3.2 Basic characteristics and quality evaluation of the study

Nine studies were included. Although they were all RCTs, none of them mentioned the specific method of random sequence generation; none of them showed the withdrawal or loss of visit of subjects or researchers or the absence of research data; none of them mentioned the patient's detailed condition; none of the studies mentioned the registration information, so the specific study scheme could not be obtained. Using the bias risk assessment tool to make the bias risk map, red stands for high risk, yellow stands for unclear risk, green stands for low risk, and the quality assessment map is shown in figures 2A and 2B.

Figure 2 Quality evaluation chart

3.3 Meta analysis results

3.3.1 Efficiency

Seven studies [5-11] mentioned the effective rate, a total of 456 patients, including 235 cases in the experimental group and 221 cases in the control group. As there was no heterogeneity between the studies, there was homogeneity (P = 0.74, I2 = 0), so the fixed effect model was used for analysis. The results showed that from the effective point of view, the experimental group (92.3%) was higher than the control group (75.5%), and the difference between the two groups was statistically significant (OR = 4.09, 95% CI (2.28, 7.36), P < 0.0001], see Figure 3.

Figure 3 Forest chart of effective rate

3.3.2 Recurrence rate

Three studies [8, 12-13] mentioned the recurrence rate, a total of 208 cases, including 111 cases in the experimental group and 97 cases in the control group. Because there was no heterogeneity among the studies, there was homogeneity (P = 0.64, I2 = 0), so the fixed effect model was used for analysis. The results showed that from the angle of recurrence rate, the recurrence rate in the experimental group (21.6%) was lower than that in the control group (55.7%), and the difference between the two groups was statistically significant [OR =0.19, 95% CI (0.10, 0.37), P < 0.0001], see Figure 4.

Figure 4 Forest chart of recurrence rate

3.4 Evaluation of publication deviation

Published bias analysis of 9 randomized controlled trials showed that, as shown in Figure 5 and Figure 6, in funnel plot, 6 of the efficiency studies were in the middle and upper part of 95% confidence interval, and 1 was in the lower part; in the recurrence rate studies, 2 were in the middle and upper part of 95% confidence interval, and 1 was in the lower part, and all the studies were basically symmetrical and centered The location concentration indicates that there is a small publication bias between the two groups, and the results have good authenticity.

Figure 5 Efficiency funnel

Figure 6 Recurrence rate funnel

4. Discussion

Clinically, GM has a variety of manifestations, most of which are sudden mass in the early stage, abscess in the middle stage, followed by rupture and purulence, and sinus tract or breast scar and deformity in the later stage due to failure to heal. Therefore, most experts and scholars divide GM into three stages according to the course of disease, including tumor stage, abscess stage and sinus stage.

At present, there are many ways to treat GM in clinic. Traditional Chinese medicine and Western medicine have different opinions. Western medicine believes that hormone combined surgery is the main treatment of the disease, but this method has the disadvantages of trauma, breast shape damage and long-term hormone use complications.Xin Lei, Chen Kai et al. [14] found that the CR rate of surgical treatment of GM is high, and the recurrence rate is relatively low. For patients who care about breast shape, oral steroids can be considered.Patients who have requirements for breast shape can also consider using ultrasound-guided vacuum assisted minimally invasive rotary cutting technology or breast reconstruction technology to retain the beauty of breast shape [15-16].Xie Xinmei [17] pointed out that the total effective rate of the study group (treated with surgery and antibiotics) was 95.00%, significantly higher than that of the control group (treated with surgery) 57.50% (P < 0.05).

At present, there is no clear record of granulomatous mastitis in ancient Chinese medicine books. According to the development characteristics of GM course, most doctors believe that this disease should belong to the category of "mastitis" and "galactorrhea". In the long-term clinical work, each doctor has summed up unique diagnosis and treatment experience and formed a unique treatment theory.Professor Liu Lifang[18] and Professor Zeng Yi[19] think that GM always belongs to Yin Syndrome, which should be treated mainly by Warming Yang, and adding and subtracting Yang and decoction;Professor Liu Sheng [20] thinks that GM is mainly composed of phlegm and blood stasis, and the treatment is mainly based on "elimination method", which advocates combination of internal and external treatment and treatment by stages; Professor Ma Hongbo [21] thinks that the disease is related to the malaise of liver qi and the obstruction of milk collaterals. In the treatment, it should be mainly to soothe the liver, regulate qi and promote blood circulation. Professor Sun Yujian [22] believed that the occurrence and development of GM was closely related to emotion, spleen and kidney deficiency. In clinical treatment, he was good at using the theory of "shujianbu", and advocated to dredge the liver and regulate qi, invigorate the spleen and replenish qi, and tonify the kidney and regulate Chong.

At present, the combination of traditional Chinese and Western medicine is a common treatment for GM. Lan Shuying [23] pointed out that the total effective rate of self blood therapy combined with hormone treatment for GM (86.7%) was significantly higher than that of the control group (73.3%) (P< 0.05), and there was no significant adverse reaction. Shichuanke [24] and Wanggang[25] found that the combination of traditional Chinese medicine and minimally invasive circumcision has a better clinical effect in the treatment of pyogenic granulomatous mastitis. After treatment, compared with the control group, the treatment of the experimental group significantly shortened the GM operation time and postoperative incision healing time, and maintained a good postoperative breast shape. The data of the two groups were statistically significant (P＜0.05).Zheng Jinzhou et al. [26] believed that traditional Chinese medicine should be applied internally and externally, and the whole process should be carried out; according to the clinical stages, hormone therapy, antibiotic therapy and surgical treatment should be flexibly used, and the operation evidence should be strictly mastered, and the appropriate operation mode should be selected, and the better clinical effect has been achieved.Wang can [27] found that the combination of traditional Chinese medicine sloughing and hormone therapy can not only reduce the size of GM patients' focus, but also reduce the degree of local pain, so as to improve the treatment effect. Qixing [28] study found that local injection of safflower Xiaoyao tablet combined with triamcinolone acetonide can not only significantly reduce the C-reactive protein in GM patients, but also reduce the viscosity of abscess blood in the stage of mass and abscess.

In this study, there were 9 studies, 664 patients with GM, including 456 in the efficiency study and 208 in the recurrence rate study. The study found that in terms of efficiency, the combination of traditional Chinese and Western medicine treatment of GM was significantly better than that of Western medicine alone, and in terms of recurrence rate, the combination of traditional Chinese and Western medicine treatment was lower than that of Western medicine alone. Therefore, in the future clinical work, the combination of traditional Chinese and Western medicine can be considered in the treatment of granulomatous mastitis.

In addition, in this study, there are some limitations due to the limitations of relevant conditions: searching authoritative database, only Chinese literature is collected, in order to collect English literature, and the number of literature collected is small; some literature does not describe the specific method of random sequence generation, and the sample size is small; different severity of patients in the study, different age and so on may lead to biased report, etc . Therefore, in the future research, we should pay attention to large sample collection, as much as possible to select randomized clinical control trials and random sequences have specific methods to improve the quality of literature, reduce the impact of other factors, so as to improve the quality of evidence-based medicine.