Efficacy and prognostic factors of neoadjuvant chemotherapy for triple-negative breast cancer

lNTRODUCTlON

《山西省水利水電工程設(shè)計概（估）算編制規(guī)定》（晉水規(guī)計［2003］716號）、《水利建筑工程預(yù)算定額》（2002）、《水利工程施工機械臺時費定額》（2002）、《水利工程概算補充定額》（2005）、《晉中市工程建設(shè)標準定額信息》（2015年2期），實地調(diào)查的材料價格及其它相關(guān)資料。

MATERlALS AND METHODS

Baseline data

A total of 118 patients with TNBC from January 2016 to January 2020 in our hospital were selected. The inclusion criteria were as follows: (1) Patients who were pathologically diagnosed with TNBC; (2)patients with tumor-node-metastasis (TNM) stages III–IV; (3) patients who were all first-treated; (4)female patients; and (5) patients or their family members who provided an informed consent. The exclusion criteria were as follows: (1) Patients with an estimated survival period of ＜ 3 mo; (2) patients complicated with other systemic malignant tumors; (3) patients complicated with liver, kidney, and other important organ diseases and immune system diseases; (4) patients with mental illness; and (5)patients with incomplete clinical follow-up data. Patients were divided into the observation group (

=60) and the control group (

= 58) according to therapeutic regimen.

Treatment and follow-up methods

Recent therapeutic efficacy[7]: Complete response (CR) was defined as complete disappearance of the lesion, partial response (PR) was defined as tumor shrinkage ≥ 50% compared with that before treatment, stable disease was defined as tumor shrinkage ＜ 50% or increase ＜ 20% compared with that before treatment, and progressive disease was defined as tumor enlargement ≥ 20%. Total effectiveness was achieved using the following formula: CR + PR.

Inspection method

Patients in the two groups received chemotherapy on the first day after the admission. The control group received routine chemotherapy: on the first day of chemotherapy, intravenous cyclophosphamide(Baxter Oncology GmbH, batch no. 20151211) (500 mg/m

), intravenous fluorouracil (on day 1 and day 8) (Shanghai Χudong Haipu Pharmaceutical Co., Ltd., 20151022) (700 mg/m

), and methotrexate [Pfizer(Perth) Pty Limited, 20151103] (35 mg/m

) were administered. All patients received granulocyte colonystimulating factor support therapy on the second day after chemotherapy in a 21-d cycle. After four consecutive cycles of chemotherapy, surgery could be performed if the effect of chemotherapy was significant.

The observation group received neoadjuvant chemotherapy for the epirubicin-paclitaxel (ET)regimen. Epirubicin [Pfizer (Wuxi) Co., Ltd., 20150724] (75 mg/m

) and paclitaxel (Hainan Haiyao Co.,Ltd., 20151202) (75 mg/m

) were administered intravenously for 21 d. After four consecutive cycles of chemotherapy, surgery could be performed if the effect of chemotherapy was significant.

Cancer antigen (CA) 125, CA19-9, and carcinoembryonic antigen (CEA) levels were detected using a Roche Cobas E601 automatic electrochemiluminescence immunoanalyzer, which was purchased from Roche. The next day before and after treatment, 5 mL of the patient’s fasting venous blood was collected and centrifuged at 3000 r/min for 5 min, and the serum was separated. Electrochemical luminescence automatic immunoanalyzer and corresponding reagents were used for detection. All operations were performed in strict accordance with the instructions to avoid hemolysis and contamination.

滑模負荷頻率控制器設(shè)計包括切換面設(shè)計和控制器設(shè)計兩個步驟,以保證系統(tǒng)在有限時間內(nèi)達到切換面并穩(wěn)定在滑模面。根據(jù)柴儲混合電力系統(tǒng)負荷頻率協(xié)調(diào)控制結(jié)構(gòu),將式(4)、式(6)和式(7)分別修改為

The monoclonal antibodies karyopherin A2 (KPNA2), protein 53, and KI-67 were purchased from Roche, and BenchMark ULTRA was used for immunohistochemical staining. The experimental procedures were performed according to the provided instructions. Known positive tissue was used as the positive control, and phosphate buffered saline was used instead of a primary antibody as the negative control. Organization immunohistochemical staining results were provided by two senior pathologists using the semi-quantitative method, according to the density of dyeing (negative = 0,weakly positive = 1, moderately positive = 2, strongly positive = 3) and the positive cell percentage (0:negative, 1: ＜ 25%, 2: 25%-50%, 3: 51%-75%, 4: ＞ 75%), and five high-power electric field immune response scores (IRSs) were calculated. The final results were as follows: negative (IRS = 0) (-); weakly positive (IRS = 1–4) (+); moderately positive (IRS = 5–8) (++); and strongly positive (IRS = 9–12) (+++).

Statistical analysis

The Statistical Package for the Social Sciences version 22.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. Normally distributed data are expressed as mean ± SD, and

-tests were used for comparisons between groups. Counting data are expressed as

(%), and the

test was used for comparisons between groups. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional risk regression analysis was used for multiple factors. Spearman rank correlation analysis was used to assess correlation. Inspection level was set at an α level of 0.05.

中心靜脈置管術(shù)是危重病人搶救、急救復(fù)蘇以及重大手術(shù)中監(jiān)測和治療必不可少的技術(shù)，它作為一項基本臨床操作技能是麻醉醫(yī)學繼續(xù)教育的重要內(nèi)容之一。中心靜脈置管術(shù)通常采用頸內(nèi)靜脈和鎖骨下靜脈穿刺兩種途徑，但由于鎖骨下靜脈穿刺導(dǎo)致氣胸的發(fā)生率（16.0%）高于頸內(nèi)靜脈（0.5%～5.0%）[2]，所以常首選頸內(nèi)靜脈穿刺途徑。右側(cè)的頸內(nèi)靜脈和上腔靜脈幾乎成一直線，并且右側(cè)沒有胸導(dǎo)管，而頸內(nèi)靜脈中路的穿刺方法可以避開頸總動脈，誤傷動脈的幾率降低，所以臨床上常選擇右側(cè)頸內(nèi)靜脈中路進針的方法，即本研究中盲穿所示的方法，更適合用于臨床教學。

Breast cancer has several types, and each subtype has different biological behaviors and clinicopathological and molecular characteristics. The corresponding treatment methods and prognoses of breast cancer are also different[1]. Triple-negative breast cancer (TNBC) is a type of breast cancer with no expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2,and its incidence accounts for approximately one-fifth of the incidence of breast cancer[2]. TNBC has high morbidity and shows an upward trend annually. However, due to the lack of effective targeted endocrine therapy, only conventional treatment can be provided in clinical practice. However, the curative effect of conventional treatment is poor, and its local recurrence rate is high, which has become one of the areas of interest in breast cancer studies in recent years[3]. For the past few years, drugs(anthracyclines, taxanes) are often used for TNBC treatment in clinical settings, although the therapeutic regimen for TNBC remains unclear. Some patients are drug-resistant, which can influence the treatment effect[4]. Currently, neoadjuvant chemotherapy is one of the most ideal treatments for locally advanced breast cancer, which can effectively improve the overall efficacy for breast cancer[5]. According to a previous study[6], tumor markers are consistent with the biological characteristics of breast cancer, and cytokines can predict the occurrence and development of tumors and the prognosis of patients. Patients with TNBC in our hospital were selected to explore and discuss the effects and prognostic factors of neoadjuvant chemotherapy in TNBC.

RESULTS

Association between karyopherin A2 and SRY-related HMG box-2 expression and clinicopathology of patients with triple-negative breast cancer

The KPNA2-positive expression rates of patients with TNBC with intravascular tumor thrombus and TNM stage IV were significantly higher than those of patients with no intravascular tumor thrombus and TNM stage III (

＜ 0.05) (Table 1). The SRY-related HMG box-2 (SOΧ2)-positive expression rates of patients with TNBC with intravascular tumor thrombus and TNM stage IV were significantly higher than those of patients with no intravascular tumor thrombus and TNM stage III (

＜ 0.05) (Table 2).

Correlation between the expressions of KPNA2 and SOX2

The expression of KPNA2 was positively correlated with the expression of SOΧ2 (

= 0.514,

＜ 0.50)(Table 3).

Comparison of clinical data between the two groups

There were no significant differences in CEA, CA19-9, and CA125 Levels between the observation and control groups before treatment (

0.05). CEA, CA19-9, and CA125 Levels in the observation and control groups were lower after treatment than those before treatment (

＜ 0.05). CEA, CA19-9, and CA125 Levels in the observation group were significantly lower than those in the control group (

＜0.05) (Table 6).

Comparison of short-term therapeutic effects between the two groups

The short-term therapeutic effects of the observation group were better than those of the control group (

＜ 0.05), and the total effective rate was 58.33% (Table 5).

Comparison of tumor markers before and after chemotherapy between the two groups

The clinical data of the two groups were compared (Table 4).

Comparison of survival curves between the two groups

The median survival time of the observation group was 33 mo (95%CI: 31.21–34.79), which was significantly longer than that of the control group (22 mo, 95%CI: 20.69–23.31), and the difference was statistically significant (

= 15.994,

= 0.000 ＜ 0.05) (Figure 1).

Cox proportional risk regression analysis

Cox proportional risk regression analysis showed that TNM stage, differentiation degree, lymph node metastasis, KPNA2 and SOΧ2 expressions, and treatment plan were prognostic factors of TNBC(relative risk = 1.575, 1.380, 1.366, 1.433, 1.411, and 0.581, respectively,

＜ 0.05) (Table 7) (Figure 2).

DlSCUSSlON

The ET regimen uses neoadjuvant chemotherapy before surgery, and its main target population is patients with locally advanced breast cancer[8-10]. The paclitaxel used in the regimen was a taxane antitumor drug, which can bind to free tubulin, accelerate the assembly speed of microtubules, inhibit the aggregation of microtubules, and effectively inhibit the growth of tumor cells[11]. The chemical composition of epirubicin, an anthracycline antitumor drug, is similar to that of adriacin, which plays an anticancer role mainly by inhibiting nucleic acid synthesis. The drug is inserted directly into the double strand of DNA, stopping the process of cell division and killing tumor cells. When used in combination,the two drugs have significant antitumor effects with few side effects[12].

According to the study results, the short-term curative effect of the observation group was significantly better than that of the control group, and the median survival time of the observation group was significantly longer than that of the control group (

＜ 0.05), indicating that the two chemotherapy regimens can all achieve good treatment effects, and the efficacy of the neoadjuvant chemotherapy regimen is relatively significant. The mechanisms of action of the two regimens are different. Cyclophosphamide mainly inhibits the proliferation of breast cancer cells by inhibiting the expression of the key protein pKAT in the PBK pathway. Neoadjuvant chemotherapy can control micrometastases in the body and effectively reduce the clinical stage of breast cancer. Paclitaxel binds specifically to specific parts of tubulin in cancer cells, preventing it from depolymerization, so that the division of cancer cells will always stay in the G2 and M phases, leading to the inability of the cancer cells to replicate and ultimately to the death of the cancer cells. Epirubicin can inhibit DNA replication and RNA synthesis, inhibit the division of cancer cells, and can affect the DNA superhelical DNA replication and transcription process by inhibiting topoisomerase II. It also chelates iron ions, producing free radicals that damage DNA, proteins, and cell membrane structures. KPNA2 is a member of the nuclear transport signal superfamily, transporting mRNA, DNA, and RNA polymerase andtranscription factors into and out of the nucleus, thereby promoting cell proliferation and differentiation, and participating in cell development, apoptosis, migration, and DNA damage response.

Studies have shown that[13,14] tumor markers are closely related to the biological behavior of tumors, among which CEA, CA19-9, and CA125 are common. As a common type of hormone in humans, CA125 is a marker for ovarian cancer and can be highly expressed in breast cancer. CEA is elevated in advanced breast cancer, and CA19-9 can indicate the nature of the tumor. The combined detection of three tumor markers can improve the diagnosis rate of tumor, with high prognostic value,and the change level of cytokines after treatment is also of high value in predicting the prognosis of breast cancer[15-17]. In our study, CEA, CA19-9, and CA125 Levels in the observation and control groups after treatment were lower than those before treatment (

＜ 0.05). CEA, CA19-9, and CA125 Levels in the observation group after treatment were lower than those of the control group (

＜ 0.05),suggesting that neoadjuvant chemotherapy with the ET regimen can significantly reduce the levels oftumor markers and cytokines in patients with good therapeutic effect. According to the literature[18],patients with TNBC have the worst prognosis and a short survival time and are at risk of developing distant metastasis. Cox proportional risk regression analysis in this study showed that TNM stage,differentiation degree, lymph node metastasis, KPNA2 and SOΧ2 expressions, and treatment plan were prognostic factors of TNBC, which could be used as important indicators for clinical observation of efficacy and prognosis and may be related to the reduced sensitivity of tumor cells to chemotherapy drugs.

The study was approved by the Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University (SWYΧ: No.2021-223).

現(xiàn)在看來，事實已經(jīng)很清楚了。李老黑請我喝酒的目的是想把我灌暈，灌暈我的目的是制造我企圖強奸李金枝的假象，制造假象的目的是逼我娶李金枝。可弄清這點絲毫無助于問題的解決，反倒讓人更糊涂了。說實話，像我這樣一無所長的民辦教師，在李老黑眼里基本就是個廢人，這么多年來恐怕李老黑沒拿正眼看過我。現(xiàn)在他忽然腦子進水似的，一門心思要把閨女塞給我，心甘情愿讓李金枝嫁過來當晚娘，這種做法實在太離譜，太讓人無法理解了。

CONCLUSlON

In conclusion, neoadjuvant chemotherapy for TNBC treatment can achieve good curative effects.Moreover, TNM stage, differentiation degree, lymph node metastasis, KPNA2 and SOΧ2 expressions,and treatment plan are prognostic factors of patients with TNBC.

ARTlCLE HlGHLlGHTS

Research results

The short-term curative effect of the observation group was significantly better than that of the control group, and the median survival time of the observation group was significantly longer than that of the control group (

＜ 0.05). The epirubicin-paclitaxel regimen can significantly reduce the levels of tumor markers and cytokines in patients with good therapeutic effect.

Research conclusions

幾何模型取對稱半結(jié)構(gòu)，地基寬度取60 m，加寬前路面結(jié)構(gòu)層厚度為79 cm，加寬后路面結(jié)構(gòu)層厚度為85 cm。地基處理措施：采用復(fù)合地基樁網(wǎng)結(jié)構(gòu)處理，樁體采用三角形布置，樁長15.0 m，樁間距2.0 m，樁徑0.4 m。處理范圍：原有路基邊坡開挖的最后一級臺階內(nèi)緣至加寬后路基坡角處；填筑路基時在最下一級臺階和路床底部(位于地表以上4.0 m左右處)分別鋪設(shè)一層土工格柵，格柵長度8 m。

Research perspectives

Next, we will investigate the mechanism of neoadjuvant chemotherapy for TNBC.

Neoadjuvant chemotherapy for TNBC treatment can achieve good curative effects. Moreover, tumornode-metastasis stage, differentiation degree, lymph node metastasis, karyopherin A2 and SRY-related HMG box-2 expressions, and treatment plan are prognostic factors of patients with TNBC.

FOOTNOTES

Dong TY and Ding F designed this retrospective study; Dong TY and Chen RY wrote this paper; Dong TY, Chen RY, Hou J, Guo J and Ding F were responsible for sorting the data.

HRD弱凝膠鉆井液性能穩(wěn)定，抑制能力強，操作維護簡單，保護儲層[7]。該體系所用處理劑不含有對環(huán)境有影響的磺化處理劑，在瑪湖氣田、環(huán)瑪湖水平井具有一定的推廣前景。

In the comprehensive treatment of breast cancer, neoadjuvant chemotherapy is no longer limited to breast preservation, staging surgery, and other advantages. It can evaluate the sensitivity of chemotherapy, realize personalized treatment, and develop targeted drugs[18-20]. There are many studies on the side effects of chemotherapy drugs, but few studies on the factors that affect the prognosis of patients after chemotherapy have been conducted. This study had certain reference valuefor clinical treatment. However, due to the short follow-up duration of this study and considering that influencing factors were not assessed in this study, larger multicenter study sample sizes to explore the clinicopathological characteristics and prognosis of elderly patients with TNBC are required in the future to develop a standard treatment plan for better prognosis.

Patients were not required to give informed consent to the study because the analysis used anonymous clinical data that were obtained after each patient agreed to treatment by written consent.

No conflict of interest.

譯文：《美國科學院院報》在本周一發(fā)表的研究報告中指出，那些渴望垃圾食品的人愿為它們付出更多錢，可見這種感受多么強烈。

式(2)和式(3)中，b、c、d、e為方程的回歸系數(shù)，反映自變量對因變量的影響程度，表示當P、A、T1、T2任一自變量變化1%，則會導(dǎo)致 I相應(yīng)地發(fā)生b%、c%、d%、e%的變化。

No additional data are available.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

由表4可知，蔗糖濃度為0，2%，1%，3%的泡菜中亞硝酸鹽濃度在第4天時達到頂峰，蔗糖濃度為0，3%，2%，1%的泡菜中亞硝酸鹽濃度頂峰值依次降低，到12天時含量已經(jīng)很低并穩(wěn)定。4%濃度的泡菜液在第8天就達到頂峰，然后開始下降，到12天時含量已經(jīng)很低并穩(wěn)定。亞硝酸鹽濃度降低說明產(chǎn)亞硝酸鹽的微生物含量減少。由此可知2%濃度的泡菜最適合食用，0，3%，1%次之，4%最次。第4天的泡菜最不適合食用，第12天后即可食用。

Feng Ding 0000-0003-3865-1768; Ru-Yue Chen 0000-0002-0847-4740; Jun Hou 0000-0003-2273-1421; Jing Guo 0000-0002-3234-1876; Tian-Yi Dong 0000-0002-7394-1704.

Wang JL

特別是在教學中能夠較好地和物理學知識相結(jié)合，從學生實際出發(fā)，讓學生領(lǐng)會技術(shù)動作后再因地制宜設(shè)置練習，通過教師和學生的共同努力，一定能夠提高教學效果。

A

Wang JL

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