妊娠相关乳腺癌诊断问题的现状

全文:

BACKGROUND

Pregnancy-associated breast cancer (PABC), or gestational breast cancer, is first diagnosed during pregnancy, in the first year after childbirth, or during the entire breastfeeding period [1]. Literature provides several definitions for PABC. While some references include the 2–5-year postpartum period in this definition [2], others define PABC as a condition that can be diagnosed during pregnancy or at any time thereafter, or at any time while the patient is lactating [3].

Although PABC is rare, it is typically aggressive and associated with adverse prognostic factors, including high nuclear mitotic activity, lymph node involvement, drug resistance, and HER2 positivity [4]. The long treatment duration and poor prognosis for PABC may be explained by delays in diagnosis and treatment due to low physician awareness, as well as challenges in interpreting the findings of breast status assessment. The Russian literature on the PABC diagnosis is extremely limited, so further discussion of this issue is relevant.

It should be noted that the majority of breast neoplasms detected during pregnancy are benign [5]. However, careful examination of suspicious or persistent breast lesions remains crucial for early PABC detection. Accurate and timely diagnosis is necessary to avoid undue stress to the patient and to minimize adverse effects on the fetus. Breast ultrasound examination is the preferred imaging modality for pregnant and lactating women who have a palpable lump [6, 7], regardless of age.

STUDY AIM

The aim of this study was to review literature data on the PABC diagnosis.

METHODOLOGY OF STUDY SEARCH

The authors searched the electronic databases PubMed, eLibrary, and Google Scholar for scientific publications. The following keywords and combinations thereof were used in the search: “gestational breast cancer,” “breast cancer,” “pregnancy-associated breast cancer,” “breast cancer associated with pregnancy,” “pregnancy,” “breastfeeding,” “lactation,” “MRI,” “CT,” “mammography,” “ultrasound,” “biopsy,” and “diagnosis.” The search was conducted for studies published before July 2024. Each author independently reviewed the titles and abstracts of the articles found and, if relevant studies were found, received the full text of the article. Duplicates and incomplete versions of the articles were excluded. Full-text versions of the articles were reviewed for compliance with the following inclusion criteria: the study was published in English or Russian; the study was published in a peer-reviewed scientific journal; the study enrolled human subjects; the study described the diagnostic value of a specific diagnostic modality for PABC.

EPIDEMIOLOGY AND RISK FACTORS

PABC is a relatively rare diagnosis. Some studies have reported that PABC is diagnosed in approximately 15 to 35 per 100,000 births [8–10]. PABC corresponds to less than 3%–5% of breast cancers, but up to 20% of breast cancers are diagnosed in women under the age of 30 years [11]. The mean age of women diagnosed with PABC is 32–34 years, which is significantly lower than the mean age of women diagnosed with breast cancer [12]. A study conducted in Sweden between 1963 and 2002 reported similar incidence rates in 1,161 cases of PABC in women aged 15–44 years [8]. The overall incidence was 2.4 per 100,000 deliveries during pregnancy, 10.6 in the first year postpartum, and 15.0 up to two years postpartum [8]. The incidence rate decreases during pregnancy, with most cases being detected in the first six postpartum months [11, 12]. Study findings are inconsistent due to the lack of a clear definition of the postpartum period, which ranges from one to five years [2, 3].

Although PABC still needs to be better understood, some potential risk factors are identified, including age at first pregnancy, lack of breastfeeding, and adverse family history [13]. Late maternity predisposes to PABC more than early maternity [13, 14]. Women over the age of 35 years have a higher risk of breast cancer during their first pregnancy than nulliparous women [14]. Parous women have a transient increased risk of breast cancer of approximately 5% in the first few postpartum years compared with nulliparous women; however, this risk decreases over time [13, 14].

Women with germline mutations in breast cancer–susceptibility genes, BRCA1 or BRCA2, have a high risk of PABC, possibly because breast tissue is exposed to elevated levels of estrogen and progesterone during pregnancy [2, 13, 15]. Some studies show that a family history of breast cancer is also associated with a higher risk of PABC, but others report that the majority of patients diagnosed with PABC do not have a family history of breast cancer [2, 10, 12, 13].

A meta-analysis of 50,302 women with invasive breast cancer and 96,973 controls demonstrated a 4.3% reduction in the lifetime risk of any type of breast cancer for every 12 months of breastfeeding [16]. Breastfeeding may be an effective way to reduce the incidence rate of breast cancer, although no studies found specific correlations between breastfeeding and PABC [13].

CLINICAL PRESENTATION

Diagnosing PABC in pregnant women may be challenging due to the physiological changes that occur during pregnancy and lactation and can mask the early signs and symptoms of breast cancer. In pregnant and postpartum women, breast cancer usually presents as in non-pregnant women, with a painless palpable mass, breast thickening, and/or bloody or purulent nipple discharge [11, 17]. Lymph node involvement is often observed at the time of diagnosis [10, 11]. Breast cancer is often diagnosed at a late stage when the tumor is large and has metastases [4, 11, 17]. The delay in diagnosis may be attributed to the physiological changes that occur during pregnancy and lactation, as well as the delay in appropriate examination due to the risk of adverse effects on the fetus. Several studies reported lower rates of estrogen and progesterone receptor expression in PABC compared to non-pregnant patients [18, 19]. Suspicious lesions or clinical manifestations should be evaluated promptly and thoroughly due to the PABC’s aggressive nature.

THE ROLE OF IMAGING MODALITIES IN THE DIAGNOSIS OF PREGNANCYASSOCIATED BREAST CANCER

When breast cancer is suspected, breast ultrasound examination is the first step in diagnostic imaging. Locoregional imaging, including mammography and ultrasound of the affected breast and ipsilateral axilla, is required to diagnose PABC. The goal is to determine the size, extent of the primary tumor, and regional lymph node involvement. This information is used for treatment planning [20]. Additional imaging may be chosen depending on the clinical stage of the cancer and the overall pregnancy status.

THE ROLE OF MAMMOGRAPHY

Mammography is used in addition to ultrasound to assess the condition of a pregnant or lactating woman when a palpable lump is detected. If ultrasound does not identify the tumor origin, mammography may be considered to evaluate features such as suspicious calcifications or distortion of the breast parenchymal architecture [6]. Mammography is recommended for pregnant or lactating women with a suspicious ultrasound finding and for patients with a verified diagnosis of PABC [6, 21]. The ability of ultrasound to detect tumor invasiveness in PABC is complemented by the ability of mammography to detect microcalcifications associated with cancer in situ, providing a global assessment of disease extent [2, 22, 23].

Mammography is effective in detecting malignant tumors in pregnant and lactating women [21, 24, 25]. Available data show that the mammography sensitivity for PABC is 63%–91%, and a mass with or without concomitant calcifications is the most common mammographic sign [21, 24–30]. Even if the mass cannot be detected by mammography due to tissue density in this population, it may still demonstrate abnormalities such as malignant calcifications, asymmetry, axillary lymphadenopathy, changes in skin thickness and trabecular structure, and architectural changes [21, 25, 30]. Suspicious mammographic findings and signs of malignancy in PABC are the same as in non-gestational breast cancer [2, 31].

THE ROLE OF ULTRASOUND EXAMINATION

Breast ultrasound is the preferred imaging modality in pregnant and lactating women with a palpable mass [5, 6], regardless of age. A breast lump is the most common clinical manifestation of PABC, with 100% ultrasound sensitivity in most cases. Ultrasound also effectively evaluates benign breast lesions in pregnant or lactating patients [6]. Ultrasound helps differentiate between normal glandular tissue and a neoplasm. If a neoplasm is present, its type (solid or cystic) can be determined to decide whether a biopsy is needed [6, 21].

Numerous published studies show that breast ultrasound has 100% sensitivity for diagnosis of PABC [21, 24–29]. Doppler ultrasound visualizes PABC as an irregular lesion with poorly defined margins and internal vascularization [21, 25, 26, 28]. In addition, complex cystic lesions on ultrasound indicate rapid growth followed by tumor necrosis [2, 28]. PABC may or may not produce shadowing artifacts [21, 25]. This is in contrast to the acoustic artifacts typical of invasive breast cancer. Some sonographic PABC features are similar to those of benign lesions, including parallel orientation, complex or anechoic appearance, and acoustic enhancement [25, 26, 28].

Breast ultrasound can detect multifocal, multicentric, and bilateral lesions [21], which can guide surgery planning. Yang et al. suggest that in patients with confirmed PABC, breast ultrasound findings should be considered to rule out carcinoma in the contralateral breast [21]. In the general population of women with newly diagnosed breast cancer, whole breast ultrasound increases the detection rate by 15.5% in the ipsilateral breast and by 3.9% in the contralateral breast [32].

In addition to demonstrating malignancy of the primary tumor in patients with PABC, ultrasound can evaluate regional lymph nodes, i.e., axillary, subclavian, internal, and supraclavicular ones [21]. Ultrasound of regional lymph nodes may reveal their clinically silent involvement [21]. Based on the American College of Radiology (ACR) criteria, axillary ultrasound is considered appropriate for the locoregional diagnosis of PABC [5].

Ultrasound is helpful not only in the initial clinical evaluation of patients with PABC but also in the follow-up of women who receive neoadjuvant therapy to improve the patient’s condition prior to surgery [21].

THE ROLE OF MAGNETIC RESONANCE IMAGING

The role of magnetic resonance imaging (MRI) in the PABC diagnosis is to assess tumor extent and local staging, guide surgery planning, identify silent malignancy in the contralateral breast, and evaluate response to neoadjuvant chemotherapy [23, 33]. The US Food and Drug Administration (FDA) classifies gadolinium contrast medium as a pregnancy category C agent [23]. Dynamic contrast-enhanced breast MRI (DCE-MRI) is not recommended for pregnant women due to safety concerns because gadolinium can cross the placenta [5, 33]. Contrast-enhanced breast MRI is an appropriate modality for assessing the health status of women after childbirth or pregnancy termination [5] and is safe for use in lactating patients [2].

Contrast enhancement of lactating breast parenchyma occurs rapidly after contrast administration, in contrast to non-lactating parenchyma, which tends to enhance gradually [22]. DCE-MRI has excellent sensitivity (97–100%) in diagnosing PABC in both lactating and non-lactating patients, despite moderate-to-severe underlying breast parenchymal enlargement [22, 27–30]. Espinosa et al. found that in five cases of breast cancer, the change in signal intensity was significantly greater than in lactating breast tissue 1 minute after the contrast administration [22]. Taron et al. reported that enhancement kinetics were effective in distinguishing tumor from normal tissue, with tumors demonstrating a contrast washout pattern that could be distinguished from plateau or sustained enhancement of lactating breast tissue [29]. Neoplasms in this study were also visualized on non-contrast-enhanced T2-weighted images as low signal intensity lesions in diffuse T2-hyperintense parenchyma of the lactating breast [22]. This was also observed in five of nine cancer types in the study by Oh et al. [28]. Therefore, breast changes associated with pregnancy and lactation do not significantly affect the diagnostic value of MRI for PABC.

PABC, which usually presents as invasive ductal carcinoma, is most commonly detected as an enlarging lesion with washout kinetics on DCE-MRI [22, 26, 28, 29]. MRI most commonly visualizes PABC as a lesion with irregular shape and margins [27, 28] and may show homogeneous or heterogeneous enhancement as well as rim-type enhancement [22, 26, 28]. Some areas appear to be sites of contrast enhancement rather than neoplasms [26, 27, 30]. DCE-MRI may also show signs that are unrelated to the primary lesion, such as skin thickening, edema, and regional lymphadenopathy [26].

Myers et al. performed MRI in 53 women and found a confirmed multicentric lesion in 6% of subjects, a lesion in the contralateral breast in 4%, and previously undiagnosed metastases in 4% [27]. Based on these data, medical or surgical treatment strategies were changed in 28% of patients, while biopsy confirmed the MRI findings in 33% of cases [27]. In a study published by Oh et al., MRI detected PABC in three (33%) of nine lactating women, and this diagnostic test was more accurate than mammography or ultrasound in determining the tumor extent [28]. Taron et al. found tumor lesions on MRI in six (31%) of 19 patients, of whom 4 underwent biopsy and 2 were confirmed to have malignant tumors [29]. Task et al. reviewed the MRI findings of 47 women with PABC; 18 women were found to have previously undiagnosed cancer in the contralateral breast, and one patient was found to have 5 lesions that were not detected by ultrasound [30].

MRI may show a larger than expected tumor size or extent than mammography or ultrasound. However, in rare cases, MRI may overestimate the disease severity [26, 27]. Taron et al. evaluated the correlation between imaging and histopathology findings in five patients. The authors found that ultrasound was the most accurate modality in determining tumor size compared to mammography and MRI, and MRI tended to overestimate tumor size [29].

In addition to diagnostic use, MRI can be used to assess the response to neoadjuvant chemotherapy (NCT). Oh et al. evaluated MRI findings before and after NCT in six patients. In all patients with confirmed residual disease at surgery, MRI showed partial response or stable disease. Notably, the rate of contrast enhancement after NCT decreased from significant to moderate or minimal in this study [28].

THE ROLE OF OTHER IMAGING MODALITIES

As mentioned above, mammography and ultrasound are used for locoregional staging of PABC because these modalities can be potentially used to evaluate both the primary tumor and regional lymph nodes. Digital breast tomosynthesis (DBT) is shown to improve lesion detection in dense tissues, thereby improving the diagnostic value of mammography, so it may be helpful in the PABC diagnosis [6, 34, 35], but there are no studies evaluating DBT in PABC. The value and reasons for DBT are the same as for mammography in pregnant and lactating women, according to ACR criteria [6, 36].

Additional imaging modalities that may be used for staging PABC in pregnant women depend on the clinical stage and include chest radiography with an abdominal shield, liver ultrasound, and possibly non-contrast-enhanced MRI of the spine [37–39]. Computed tomography and bone scintigraphy are generally not recommended for pregnant patients due to the high risk of fetal radiation exposure [37]. Positron emission tomography (PET) is also not indicated [37, 40]. If the risk of distant metastases is considered low, a possible strategy is to wait for the postpartum period to perform the necessary evaluation [40]. In lactating patients, staging imaging may be performed according to the National Comprehensive Cancer Network (NCCN) guidelines [38].

DIAGNOSTIC CHALLENGES

Breast tissue is difficult to evaluate clinically and radiologically in pregnant and postpartum women [6, 23], which contributes to late diagnosis of PABC [24, 25]. A palpable mass is more difficult to detect during and after pregnancy due to tissue hypertrophy and other changes in the breast, including increased elasticity and nodularity, so it may sometimes be mistaken for a benign lesion [24, 25]. It is important for patients, clinical teams, and radiologists to understand the risks and safety issues associated with imaging in general and breast imaging in pregnancy in particular. The ALARA (As Low As Reasonably Achievable) principle can be applied when considering appropriate imaging modalities, dose reduction strategies, and protection of pregnant patients when ionizing radiation needs to be used [40].

Based on ACR criteria and NCCN guidelines, mammography is safe in pregnant or lactating women [6, 38]. With abdominal shielding, fetal radiation exposure during conventional mammography is negligible [6], by an order of magnitude lower than fetal exposure to background radiation during pregnancy [26]. In pregnant patients, ultrasound and mammography are the key modalities for locating and assessing the extent of PABC, as contrast-enhanced breast MRI is contraindicated.

There are special requirements for breast imaging in lactating women. If mammography is performed in a lactating woman, it is currently recommended to perform it immediately after breastfeeding or expressing breast milk to reduce breast density [5, 6, 23]. This is also recommended for lactating patients undergoing DCE-MRI [23]. Lactating women may ask if they have to stop breastfeeding after the administration of gadolinium for DCE-MRI. According to the ACR manual on contrast media and the American College of Obstetrics and Gynecology guideline, there is no need to discontinue breastfeeding after gadolinium administration because the excretion rate in breast milk is less than 0.04% of the administered dose, and the expected dose that would be received by an infant through intestinal absorption is less than 0.0004% [41, 42]. If a patient is still concerned, milk can be expressed and breastfeeding can be avoided for 12–24 hours after the scan; in this case, milk expression the day before the scan should be considered to ensure that milk is available for the baby after the scan [41].

The risk of ionizing radiation in mammography is negligible, and the advantage of mammography is that it visualizes features such as calcifications and architectural distortions that are not visible with ultrasound. The diagnostic challenge in mammographically detecting PABC is that most patients have heterogeneous or extremely dense tissue, which is a known limitation of mammography in general as it may mask malignancy. In women, mammograms show increased breast density due to pregnancy-related changes, accompanied by an increase in glandular tissue and water content [24]. These changes may reduce the sensitivity of mammography and limit its ability to detect additional subclinical non-calcified lesions in the ipsilateral and contralateral breasts [24], which is critical for accurate staging of established PABC.

The advantages of using ultrasound in pregnant and lactating women include the absence of ionizing radiation and 100% sensitivity to PABC. The diagnostic challenge in ultrasound detection of PABC is not to confuse it with a benign neoplasm. PABCs have typical benign sonographic features such as well-defined margins, parallel orientation to the skin, and acoustic enhancement, mimicking benign lesions such as galactocele or cysts [6, 25, 26]. A complex cystic lesion visualized by ultrasound may also present a diagnostic challenge, as the differential diagnosis may include abscess and galactocele in addition to PABC, requiring aspiration and possibly biopsy for differentiation [2]. The advantage of MRI in the PABC diagnosis is its ability to simultaneously evaluate the affected breast, contralateral breast, and regional lymph nodes. Identifying PABC within a moderately or significantly elevated range is the diagnostic challenge. In addition to standard diagnostic modalities, subtraction imaging can be used to examine breast tissue by DCE-MRI [29]. When using DCE-MRI, subtraction images are typically created in post-processing by subtracting each post-contrast dynamic series (typically 4 series) from the pre-contrast data. Subtraction images are created by subtracting the last dynamic series of post-contrast images from the second dynamic series of post-contrast images, rather than from the pre-contrast series [29]. Taron et al. reported that these images better demonstrate a malignant lesion with poorly defined margins [29], which helps a radiologist to assess the extent of the disease. This modality should be used with caution because it may not always visualize a malignant lesion with a constant kinetics of increase or plateau, similar to lactating breast tissue. This was observed in one patient (5%) in the study by Taron et al. and in over half the patients in the study by Taskin et al. [29, 30].

BIOPSY

Indications for breast biopsy do not consider pregnancy and include solid or complex cystic lesions, suspicious microcalcifications on mammography, and refractory inflammatory changes [21]. If inflammatory changes are observed on imaging without suspicious lesions and persist after antibiotic therapy, a skin biopsy is indicated to evaluate for inflammatory carcinoma [40]. Although mammary fistula is a possible but rare biopsy complication in this patient population [43], biopsy is safe in pregnant and lactating women and should not be delayed or avoided in the presence of an indeterminate or suspicious lesion [3, 26]. Pregnant and lactating patients should also be cautioned about the potential for increased bleeding or infectious complications with needle biopsy.

When a suspicious neoplasm is detected in a pregnant or lactating patient, ultrasound-guided biopsy is preferred if the neoplasm can be visualized with this modality [23]. For suspicious lesions visualized only by mammography, stereotactic biopsy or mammographic needle localization can be safely performed in early pregnant or lactating patients [23]. For suspicious breast lesions visualized by DCE-MRI in a lactating woman, MRI-guided breast biopsy may be performed [23].

Lidocaine for local anesthesia during percutaneous biopsy is safe in pregnant women [23]. Lactating women may be cautioned that their milk may contain blood or lidocaine after a biopsy. This poses no risk to an infant, but patients should be informed as they may choose to express milk or not breastfeed for up to 24 hours [23, 34]. Before a breast biopsy, a lactating woman can be advised to express milk or breastfeed to open the ducts. After the procedure, a patient should continue to express milk or breastfeed to guide milk from the ducts created by the biopsy to the nipple [33, 34]. A healthcare provider may consider reducing the size of the needle, shifting the needle insertion site away from the nipple, limiting the distance between the insertion site and the target lesion, and limiting needle movement during the procedure [33, 34]. However, these changes should not affect the accuracy and adequacy of biopsy material collection.

Breast cancer can be diagnosed with a needle aspiration, fine-needle aspiration, or surgical biopsy. Needle aspiration is the most common choice because it is the standard diagnostic procedure for suspected breast neoplasms [44]. Ahn et al. [25] found that fine-needle aspiration was the most common diagnostic modality for malignant tumors. Surgical biopsy was the less common modality, which was used to diagnose all six cancer cases in the study by Son et al. [45]. In some patients, the initial diagnosis is made by fine-needle aspiration, core biopsy, or axillary lymph node biopsy on the same side as the breast tumor.

FOLLOW-UP EXAMINATION

Breast ultrasound is used for both the initial evaluation and the subsequent monitoring of response to NCT [21]. Since the sonographic features of a breast mass are common in normal patients, ultrasound can be used to determine if a malignant lesion changes during treatment and to classify it using standardized criteria. In women with known metastatic disease, ultrasound may also be used for regional lymph node monitoring to assess treatment response.

CONCLUSION AND POSSIBLE DIRECTIONS FOR FUTURE RESEARCH

PABC presents unique diagnostic and treatment challenges that require continued research into new technologies. Gegios et al. describe several advances in imaging that can be used in routine breast cancer screening and treatment, including ultrasound elastography, contrast-enhanced ultrasound, and hybrid PET/MRI imaging. The use of non-contrast-enhanced diffusion MRI in pregnant patients is another area of interest in PABC imaging research. Diffusion modalities, including diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI), are based on the movement of water in tissue, which is abnormal in many malignant tumors, including breast cancer. DWI was evaluated as part of non-contrast-enhanced whole-body MRI for systemic staging of breast cancer in a study of 14 pregnant women. Breast DTI was shown to be feasible in pregnant women with PABC, but its low spatial resolution and other technical characteristics, including artifacts, were limiting factors. DTI was also evaluated in lactating women as an adjunct to standard DCE-MRI to improve visualization and quantification of PABC. Therefore, despite progress, further research and development are needed to improve the diagnosis and treatment of breast cancer, especially in the context of the unique challenges associated with pregnancy and breastfeeding.

ADDITIONAL INFO

Acknowledgments. The team of authors is grateful to Aida Ulfatovna Hamadyanova, Associate Professor, Department of Obstetrics and Gynecology No. 1, Bashkir State Medical University, Candidate of Medical Sciences, for scientific revision of the manuscript and counselling during its preparation.

Authors’ contributions. R.F. Sadrtdinova developed the concept and design of the study, edited the manuscript; E.V. Malikova provided scientific editing of the manuscript, collected and analyzed literature sources, prepared and wrote the text of the manuscript; A.V. Ponomarev collected and analyzed literature sources, prepared and wrote the manuscript; A.A. Agzamova performed literature review, collected and analyzed literature sources, wrote and edited the manuscript; D.I. Kireev performed literature search and analysis, wrote the manuscript; D.S. Ramazanova performed literature review, collected and analyzed literature sources, wrote the manuscript; Y.V. Amirova performed data collection and analysis, participated in manuscript writing; Z.I. Tajibova performed data collection and analysis, edited the manuscript; I.I. Ibragimov performed data collection and analysis, edited the manuscript; E.A. Akhmetova performed data collection and analysis, edited the manuscript; V.R. Kagramanyan performed data collection and analysis, edited the manuscript; N.A. Zeynalova performed data collection and analysis, edited the manuscript; M.M. Khashegulgova performed data collection and analysis, wrote the manuscript. All authors confirm that their authorship meets the international ICMJE criteria (all authors have made a significant contribution to the development of the concept, research and preparation of the article, read and approved the final version before publication).

Funding source. The study was carried out within the framework of inter-university collaboration on the base of the scientific student group of the Department of Obstetrics and Gynecology No. 1, Bashkir State Medical University.

Competing interests. The authors declares that there are no obvious and potential conflicts of interest associated with the publication of this article.

作者简介

Ruzilya F. Sadrtdinova

Bashkir State Medical University

编辑信件的主要联系方式.
Email: sadreit@rambler.ru
ORCID iD: 0009-0004-9484-2256

Student

俄罗斯联邦, Ufa

Elizaveta V. Malikova

Rostov State Medical University

Email: malikova1344@mail.ru
ORCID iD: 0009-0005-5051-2615

Resident

俄罗斯联邦, Rostov-on-Don

Aleksei V. Ponomarev

Far Eastern Federal University

Email: ponomarev.avi@dvfu.ru
ORCID iD: 0009-0000-9966-703X

Student

俄罗斯联邦, Vladivostok

Alina A. Agzamova

Bashkir State Medical University

Email: agzalina05@gmail.com
ORCID iD: 0009-0007-2522-6478

Student

俄罗斯联邦, Ufa

Daniil I. Kireev

Bashkir State Medical University

Email: daniilkireev2204@gmail.com
ORCID iD: 0009-0009-0709-0954

Student

俄罗斯联邦, Ufa

Daniya S. Ramazanova

Bashkir State Medical University

Email: Rrramazanova.daniya@gmail.com
ORCID iD: 0009-0002-6242-0863

Student

俄罗斯联邦, Ufa

Julia V. Amirova

Bashkir State Medical University

Email: Ignis2015@mail.ru
ORCID iD: 0009-0008-3872-0296

Student

俄罗斯联邦, Ufa

Zalina I. Tadzhibova

Astrakhan State Medical University

Email: tadzhibova.z@mail.ru
ORCID iD: 0000-0001-7662-5427

Student

俄罗斯联邦, Astrakhan

Ilyas I. Ibragimov

V.I. Vernadsky Crimean Federal University

Email: ilyasibragimov2002@mail.ru
ORCID iD: 0000-0001-9169-5597

Student

俄罗斯联邦, Simferopol

Elizaveta A. Akhmetova

Bashkir State Medical University

Email: maklizi@mail.ru
ORCID iD: 0009-0004-1943-4033

Student

俄罗斯联邦, Ufa

Veronika R. Kagramanyan

Astrakhan State Medical University

Email: veronikakagramanyan716@gmail.com
ORCID iD: 0000-0002-6410-9000

Student

俄罗斯联邦, Astrakhan

Nazrin A. Zeinalova

Astrakhan State Medical University

Email: nazzzrin2424@gmail.com
ORCID iD: 0009-0009-6013-3263

Student

俄罗斯联邦, Astrakhan

Madina M. Khashegulgova

Bashkir State Medical University

Email: m.khashegulgova@bk.ru
ORCID iD: 0009-0001-6408-7796

Student

俄罗斯联邦, Ufa

参考

补充文件