lNTRODUCTlON

Breast cancer is one of the most common malignant tumors threatening women[1]. In recent years, the incidence of breast cancer has increased year by year, topping all types of cancer in Chinese women[2].Magnetic resonance imaging (MRI) has become an essential examination method to diagnose breast lesions due to the avoidance of ionizing radiation, high soft-tissue resolution, multi-parameter imaging,multi-sequence imaging, and high sensitivity[3,4]. Nevertheless, the specificity of MRI in detecting breast is relatively low, leading to many false-positive results and high rates of re-examination or biopsy[3,4].

Novel functional MRI techniques, including diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and other non-invasive detection methods, have enabled the detection of pathological conditions of tissues to reach on a molecular-level, as well as the detection of functional status and change in mechanisms of organs, tissues, and cells[5]. DWI is considered the most effective modality for malignant tumor screening and therapeutic effect assessment for breast cancer[6-9]. PWI can be applied in detecting blood perfusion in tissues, where the perfusion imaging pattern is closely related to the density of newly-generated microvessels in tumors[10,11]. Nevertheless, these techniques have not been widely validated in clinical practice since they mainly act as auxiliary roles for assessing suspicious lesions[8,12,13]. DWI can also monitor the treatment response to neoadjuvant chemotherapy[14] and help to determine the subtypes of breast cancer[15].

According to the MRI breast imaging reporting and data system (BI-RADS) (5edition), potentially malignant breast lesions are classified as the 4category (BI-RADS 4) with a wide variation with regard to the risk of malignancy, from 2% to 95%[16]. BI-RADS 4 lesions could be anything from benign to malignant, resulting in the difficulties for clinicians to distinguish between them[17-20].

Therefore, the present study aimed to investigate the diagnostic efficiency of the apparent diffusion coefficient (ADC) combined with PWI in determining the nature of lesions categorized as BI-RADS 4.The results help to decide the exact nature of breast lesions before the patients undergo biopsy.

MATERlALS AND METHODS

Study design and patients

智慧課堂作為新型的教學模式和教學手段，以培養(yǎng)具有高智能和創(chuàng)造力的素質(zhì)型、技能型人才為目標，依賴于數(shù)據(jù)挖掘、虛擬現(xiàn)實、人工智能分析等技術(shù)，實施學情診斷分析和資源智能推送，開展“云+端”學習活動與支持服務(wù)，進行學習過程記錄與多元智能評價的新型教學模式。[1]本研究依托安徽省級質(zhì)量工程智慧課堂試點項目，開展了基于超星學習通的智慧課堂研究和實踐，應(yīng)用于高職高專汽車類“汽車裝飾與美容”課程的教學改革中，探索適應(yīng)社會和企業(yè)需求的新型課程教學模式和人才培養(yǎng)手段。

The inclusion criteria were: (1) Age over 20 years old; (2) BI-RADS 4 based on mammography only;(3) Lesion ＞ 5.0 mm; (4) The MRI examination of all lesions was completed before needle biopsy; and (5)The MRI examination included DWI and dynamic contrast enhancement imaging (DCE-MRI) in addition to the conventional plain scans. The exclusion criteria were: (1) Received neoadjuvant chemotherapy which might affect the MRI readings[14]; or (2) Clinical or pathological T4 lesion.

應(yīng)該說這是一種非常合乎情理的推理，是一種常規(guī)思維。從多種結(jié)果的觀察與比較中總結(jié)出規(guī)律，并形成結(jié)論。再通過中間這條線的變化，從側(cè)面的例子進一步來說明這個結(jié)論的正確性，結(jié)論似乎已非常完美，這也達到了題目事先設(shè)計的要求，即本題解答過程的第二個階段讓學生形成一個統(tǒng)一的結(jié)論。

MRI acquisition

All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

MRI analysis

The collected data were transmitted to the General Electric Assistant Diagnostic Workstation 4.6, and the image data were analyzed. Then two radiologists with more than 5 years of experience in breast lesion diagnosis provided an independent analysis and assessment without knowing the clinical and pathological results. A consensus was reached through discussion in case of any inconsistencies between them. Regions with enhancements in DCE-MRI sequence and high signal intensity in the DWI sequence were considered to be lesions. After obtaining the ADC map by post-processing, the ADC values were measured by manually placing the elliptic in the lesion area, and covering at least four minimum pixels, with the average value based on three measurements. Meanwhile, the volume transfer constant (K), rate constant (K), and extravascular extracellular volume fraction (V) in this region were measured (Figure 2).

BI-RADS 4 breast lesions at mammography only appeared a wide range of risk of being malignant (2%-96%)[17-20]. DWI and PWI could help discriminate benign from malignant lesions[6,10,11], but thosetechniques are mainly considered as accessory to standard imaging modalities[12]. Therefore, this study aimed to evaluate the efficiency of DWI and PWI in diagnosing breast lesions categorized as BI-RADS 4 at mammography. The results suggested that DWI, combined with PWI, might possibly distinguish between benign and malignant BI-RADS 4 breast lesions at mammography.

Pathological features

The lesion samples gained from needle biopsy were sent to the Department of Pathology at the Hospital to obtain the pathological results. The lesions were divided into benign and malignant groups according to the classification of histopathological results. The benign group included non-hyperplasic,hyperplasic, and atypical hyperplasic lesions. The malignant group included ductal carcinoma in situ and any type of invasive carcinoma[21]. For samples with mixed pathological characteristics, the more severe lesion prevailed (Figure 3). Surgical resection was performed for all patients whose pre-surgical needle biopsy results demonstrated either malignant lesions or atypical lesions.

The study was reviewed and approved by the First Hospital of Hebei Medical University. The need for individual informed consent was waived by the committee.

Statistical analysis

All data were analyzed using SPSS Version 18.0 (IBM, Armonk, NY, United States). Continuous data were presented as means ± SD or medians (range), according to the results of the Kolmogorov-Smirnov test for normal distribution, and analyzed using the Student-test or the Mann-Whitney U-test, as appropriate. Categorical data were presented as numbers (percentages) and analyzed using the chisquare test or Fisher’s exact test. Differences with＜ 0.05 were considered statistically significant.

RESULTS

Characteristics of the patients and lesions

This study included 95 breast lesions in 83 female patients, of which 36 patients were in the benign group, and 47 patients were in the malignant group. All women were Chinese Han. There were no statistically significant differences between the benign and malignant groups in terms of age, family history, history of benign breast disease, history of marriage, history of delivery, long-term use of exogenous estrogen, alcohol abuse, and age of menarche, but there was a statistically significant difference between the groups in terms of the age of menopause (= 0.021) (Table 1). As for the 95 lesions detected, 46 (48.4%) lesions were in the benign group, and 49 (51.6%) lesions were in the malignant group. The average size of the lesions was 2.2 cm (0.6-5.8 cm); the lesions were larger in the malignant group than in the benign group (median, 2.4 cm1.5 cm,= 0.007) (Table 2).

在穿越高鐵橋梁樁基期間，建立足夠的土倉壓力平衡刀盤前端水土壓力，以保證掌子面穩(wěn)定，利用5個土倉壓力傳感器數(shù)據(jù)綜合控制土壓，上部土壓控制在0.17MPa；將刀盤轉(zhuǎn)速控制在1.4r/min，以減小掘進對周邊土體和橋梁樁基的擾動；掘進推力控制在11 000kN，掘進速度控制在20～30mm/min[2]。

Perfusion parameters

Table 2 shows that the Kand Kvalues were both larger in the malignant group compared with the benign group (both＜ 0.001), but there were no significant statistical differences regarding V(=0.866).

Diffusion parameters

The ADC values in the parenchyma and lesion area of the normal mammary gland were 1.82 ± 0.22 ×10mm/s and 1.24 ± 0.16 × 10mm/s, respectively (= 0.021). The mean ADC value of the malignant group was 1.09 ± 0.23 × 10mm/s, which was lower than that of the benign group (1.42 ± 0.68 × 10mm/s) (= 0.016). Based on the literature[22], an ADC value of 1.20 × 10mm/s was used as the threshold for malignant lesions. Lesions with an ADC value lower than the threshold were considered malignant lesions, and those with an ADC value higher than the threshold were considered benign lesions(Table 3).

Diagnostic efficacy of DWI and PWI

We evaluated the diagnostic efficiency of PWI and DWI and combined examination techniques compared to the pathological results. The sensitivity and specificity of combined PWI and DWI were higher than those of PWI or DWI alone. The accuracy of combining the two test methods in predicting pathological results was also significantly higher than that predicted by PWI or DWI alone (Table 4).

DlSCUSSlON

關(guān)于山水畫的研究，成果豐碩，角度眾多，有的從藝術(shù)社會學角度來分析山水畫風格與社會深度之間的關(guān)系；有從形式轉(zhuǎn)變角度來研究藝術(shù)家及藝術(shù)流派的風格。尚輝以為，“從自然科學的角度入手，不僅在方法論上將自然科學與社會科學有機聯(lián)系起來，而且在一定程度上論證了中國山水畫風格及流派的形成與自然山水視覺效應(yīng)在內(nèi)的辯證統(tǒng)一聯(lián)系”①。韓長生認為，“通過山川地理、地貌考察聯(lián)系比照，為范寬《谿山行旅圖》找到了‘寫山真骨’之依據(jù)”②。從這一角度出發(fā)分析李唐的作品《萬壑松風圖》，可以發(fā)現(xiàn)山水畫皴法與自然地貌之間確實有特定的聯(lián)系，皴法是認識與表現(xiàn)物象的形的一種技法，也是區(qū)分不同時期、不同畫派之間繪畫風格的重要因素之一。

To improve the accuracy of combining PWI and DWI in predicting pathological results.

Many studies have been conducted on the threshold point of the ADC value used to distinguish benign lesions from malignant ones, and their conclusions differ[28,30,31]. By referring to the methods used in the literature[22] and diagnostic tests, the present study used 1.20 × 10mm/s as the critical ADC value to distinguish benign lesions from malignant ones in the DWI examination of breast lesions.The accuracy obtained by comparison with the pathological results was approximately 73%. Using a relatively high ADC value as the critical point can effectively avoid over-diagnosis of BI-RADS 4 Lesionsat mammography. Except for 5.5% of the cases in this study, which were mucinous carcinomas (with an ADC value of 2.20 × 10mm/s), all lesions with ADC values ＞ 1.74 × 10mm/s were nonmalignant, as indicated by the final pathological results. This critical point is close to the average of the critical values ranging from 1.60-1.81 × 10mm/s, as reported by previous studies[22,28,30]. Ren[31] showed that the ADC values could be used to evaluate breast lesions’ malignancy. Spick[32] also stated that DWI might partially eliminate the need for MRI-guided biopsies. They revealed that when the ADC value of 1.58 × 10mm/s was used as the threshold, no false-negative occurred.

PWI is an imaging method that can clearly display microvessel density[33] and reflect the neovascularization of tumors, which is a necessary condition for tumor growth, progression, and metastasis[7,8,12,34]. The hemodynamic information that it provides has enabled quantitative analysis. The parameters include K(which refers to the rate of the contrast agent diffusing from the inside to the outside of the blood vessel), K(which refers to the rate of the contrast agent in the extravascular tissue space returning to the blood vessel after diffusing for a period of time), and V(which is the volumetric ratio of the extravascular extracellular space to the total voxel). These parameters are able to quantitatively evaluate blood perfusion in the diseased tissue[7,35], thereby enabling quantitative and differential diagnoses of lesions. In the present study, there was a significant increase in the number of blood vessels throughout the breast in sequence of PWI. The reason may be that tumor blood vessels face smaller growth resistance, and the high metabolism level of tumors gradually stimulates the regeneration of blood vessels throughout the breast. In addition, studies have shown that breast cancer with multifocal lesions, large masses, and axillary lymph node metastases have also exhibited pronounced neovascularization throughout the breast, suggesting a poor prognosis[36]. It can thus be inferred that the significant increase in the number of new blood vessels in the breast with cancerous lesions will suggest the progressive growth of malignant lesions and intramammary metastasis.

Conventional MRI scanning techniques combined with DWI and PWI can provide information on the internal structure of the breast[27], reflect the pathological characteristics of the tissue more accurately,and improve the diagnostic accuracy for breast lesions by measuring ADC values and quantitative parameters of PWI[7]. This method achieves the transition from qualitative diagnosis to quantitative diagnosis, thereby associating BI-RADS 4 lesions with corresponding histopathological grades. By using a DWI sequence combined with the quantitative parameters of PWI, a pathological classification of potentially malignant lesions, which were diagnosed as BI-RADS 4 lesions by mammography, was performed in this study to improve the accuracy of imaging diagnosis and provide different clinical recommendations. The present study proved that the sensitivity and specificity of DWI combined with PWI were higher than that of DWI and PWI alone. Nevertheless, additional studies are necessary to further confirm those results. Follow-up observations with imaging methods should be performed for those diagnosed with benign lesions, and needle biopsies should be performed, if necessary, for those diagnosed as malignant lesions.

This retrospective study included patients who underwent breast MRI examination, including symptomatic patients presenting to clinic and patients detected abnormalities in regular screening,between May 2017 and May 2019 at the Department of Radiology of Hospital. The diagnostic criteria were the 5edition of MRI BI-RADS[16].

This study has limitations. Firstly, the purpose of this study was to group BI-RADS 4 lesions at mammography based on their histological features by dividing them into two groups. Including atypical hyperplasic lesions in the benign group may result in bias, and different histological subtypes are included in the same group. As a result, the ADC values of the group may vary greatly. Secondly,two radiologists independently evaluated the slides, but the concordance was not examined. Thirdly,ultrasound data were not available for many patients because the physicians decided not to perform it,the patient refused, or it was done at another hospital, and thus could not be analyzed. Fourthly, the sample size was small, and receiver operating characteristics and multivariable analyses could not be performed. Studies with larger sample size are necessary to determine the real diagnostic value of DWI combined for PWI and determine the adequate cutoff values for the different quantitative parameters.

現(xiàn)實主義為了解國際社會提供了真實的一面，但其更側(cè)重于描述以國家間相互實力的對比為核心的層面，在這種無政府狀態(tài)下，國家之間并非完全處于一種無政府狀態(tài)下的混亂局勢，各個國際組織、國際法會對主權(quán)國家間的行為進行相應(yīng)的約束和遏制。但現(xiàn)實主義并未對國際關(guān)系中各國之間的合作與發(fā)展作出必要的解釋和分析，建立在對現(xiàn)實主義批判基礎(chǔ)之上的自由主義將從理論層面對這些問題進行相應(yīng)的彌補和梳理。

CONCLUSlON

In conclusion, DWI, combined with PWI, might possibly help distinguish benign breast lesions from malignant ones and provide clear diagnostic results for patients with potentially malignant BI-RADS 4 lesions at mammography.

變量相關(guān)性分析表明，Sub與Own、Inst都是顯著正相關(guān)，這在一定程度上可以說明政府補助對于社會投資者具有信號效應(yīng)。Da與Own、Inst顯著負相關(guān)，說明社會投資者對于會計信息質(zhì)量較為重視。而Rem與Own、Inst無顯著相關(guān)說明真實盈余管理較應(yīng)計盈余管理更加隱蔽。另外，Roa、Lev與Own、Inst顯著正相關(guān)說明社會投資者偏好績效良好、有適當財務(wù)杠桿的企業(yè)。通過檢驗，變量的VIF值均小于2，多重共線性不會影響回歸結(jié)果。

ARTlCLE HlGHLlGHTS

Research conclusions

The sensitivity and specificity of combined PWI and DWI were higher than those of PWI or DWI alone.DWI, combined with PWI, might possibly help distinguish benign breast lesions from malignant ones and provide clear diagnostic results for patients with potentially malignant BI-RADS 4 lesions at mammography.

由于林芝市特殊氣候的影響，每年降雨量特別大，導致青稞倒伏以及發(fā)生銹病等農(nóng)作物病蟲害。對此，要采取切實可行的方法加以應(yīng)對，如選育抗倒伏品種、適合林芝市的青稞優(yōu)良品種，采用科學技術(shù)進行統(tǒng)防統(tǒng)治，做好病蟲害的預(yù)測預(yù)報及防治指導工作，將災(zāi)害造成的損失降至最低。

Research perspectives

DWI has the advantages of short acquisition time, unnecessary for a paramagnetic contrast agent, and high sensitivity[23]. Therefore, DWI is widely used in the differential diagnosis of breast diseases, with the scanning parameters and diagnostic specificity being constantly optimized[24]. Among the new MRI techniques, DWI is considered a useful diagnostic method in differentiating benign from malignant lesions and assessing the therapeutic effect[2]. Studies showed that the ADC values of typical malignant tumors are lower than those of benign hyperplasic tissues and normal tissues[25,26]. This finding is partly attributable to the small extracellular space resulting from the high cell density of malignant tumors, which leads to the restricted diffusion of water molecules[25]. This complicated microscopic phenomenon can be partially converted into quantifiable parameters by measuring ADC values, which can thus be applied in distinguishing between different tissue sources[25,26]. In the present study, the mean ADC value of the observed lesion areas was lower than that of the normal breast tissues, and the mean ADC value of the malignant group was the lowest (except for necrotic areas). This finding is consistent with the results reported in previous studies[27,28]. Tsushima[29] found that DWI is extremely helpful for diagnosing breast cancer, which its sensitivity and specificity achieved 89% and 77%, respectively.

FOOTNOTES

Zhang H and Wang Y designed the experiment. Zhang XY implemented the experiment;Zhang H and Wang Y drafted the manuscript; Wang Y was responsible for the paper.

The study was reviewed and approved by the First Hospital of Hebei Medical University Institutional Review Board, No. 20210907.

All examinations were performed with the patients in the prone position. MRI was performed by a 1.5-T MRI scanner (Signa Excite HDxT; GE Healthcare, Waukesha, WI, United States) and a 3.0-T MRI scanner (GE Silent Discovery 750W; GE Healthcare, Waukesha, WI, United States) with an 8-channel phased-array bilateral breast coil. The scanning sequences and corresponding parameters were: (1)T2WI fat-suppressed fast spin-echo (FSE): Repetition time (TR) 6079 ms, echo time (TE) 85 ms, flip angle(FA) 111°, field-of-view (FOV) 36 × 36 mm, matrix size 320 × 256, number of excitation (NEX) 1.0, slice thickness (ST) 5.0 mm, scan time 2.44 s; (2) T1WI FSE: TR 697 ms, TE min full, FA 111°, FOV 36 × 36 mm, matrix size 320 × 256, NEX 1.0, ST 5.0 mm, scan time 1.05 s; (3) DWI: TR 2881.4 ms, TE minimum,FOV 36 × 36 mm, matrix size 128 × 128, ST 5.0 mm, b values 0-800 s/mm, scan time 2.01 s; and (4)T1WI dynamic perfusion: TR 5.5 ms, TE min full, FA 12°, FOV 34 × 34 mm, matrix size 160 × 150, ST 5.0 mm, 40 phase scanning, scan time 7.12 s (Figure 1). The contrast agent was gadopentetate dimeglumine(Jiangsu Hengrui Pharmaceutical Co., Ltd., China) and was administered at a dose of 0.2 mmol/kg with infusion rate of 3.0 mL/s. The intravenous injection of contrast agent began 30 s after the start of the scanning.

The authors have no conflicts of interest to disclose.

詞之過片也可以另辟新境。如呂渭老《卜算子》中上闋寫眉為愁鎖，并用疊詞“千千”修飾淚的何其多來言作者心中無限愁。下闋首句“莫唱短姻緣”，筆鋒一轉(zhuǎn)，另辟新境，把上闋的哀愁一掃而光，加之尾句“誰信”二字，又將上闋的愁情推開置去。

Technical appendix, statistical code, and dataset available from the corresponding author at wy80868@163.com. Participants gave informed consent for data sharing.

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/

張愛玲的短篇小說《色·戒》寫于1950年，故事發(fā)生在抗戰(zhàn)期間的上海，一群進步青年為刺殺漢奸特務(wù)頭子易先生，派出最漂亮的女子王佳芝實施“美人計”。但在刺殺就要得手之際，劇情卻戲劇性地發(fā)生逆轉(zhuǎn)——王佳芝在老易為她買鉆戒的過程中深受感動而改變初衷。

China

Hui Zhang 0000-0002-2971-5216; Xin-Yi Zhang 0000-0001-8705-4308; Yong Wang 0000-0001-5869-2044.

Fan JR

A

3) 基于反雙曲正弦函數(shù)的自抗擾控制的參數(shù)為：R=10，a1=2,a2=2，b=5,β03=10,β1=5,β2=25,b0=0.002 3。

也被稱作《DOTA2》，由《DOTA》的地圖核心制作者Icerog（冰蛙）聯(lián)手美國Valve公司研發(fā)的一款游戲，于2013年4月28日開始測試，發(fā)布中文名為“刀塔”，是該系列的第二部作品。

Fan JR