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Axillary lymph node dissection is not required for breast cancer patients with minimal axillary residual disease after neoadjuvant chemotherapy

World Journal of Surgical Oncology volume 22, Article number: 286 (2024) Cite this article

Abstract

Background

Sentinel lymph node biopsy (SLNB) is widely used in patients who receive neoadjuvant chemotherapy (NAC). Still, axillary lymph node dissection (ALND) is recommended for patients with any axillary residual disease after NAC. The necessity of ALND in patients with minimal axillary disease is unclear. We aim to investigate regional recurrence rates in patients with limited axillary residual disease after NAC underwent SLNB + image-tailored axillary surgery and adjuvant radiotherapy (RT).

Methods

Patients with clinical stages were T1-3 and N1 at the time of diagnosis, clinically good or complete axillary response after NAC, and limited axillary residue (≤ 3 pathological lymph nodes) with favorable response to NAC in the final pathological examination were included in the study. All patients underwent SLNB + image-tailored axillary surgery. Peripheral lymphatic radiotherapy was applied, and no further surgery was performed in patients with compatible radiology and pathology results.

Results

Our study, which evaluated 139 patients with a median age of 47 years, found that the median number of excised lymph nodes was 4. Notably, 46% of patients had between 1 and 3 lymph nodes excised, while 45% had between 4 and 6. Only 9% of patients had ≥ 7 lymph nodes. 83(60%) of the patients underwent breast-conserving surgery (BCS), and 56(40%) underwent mastectomy. The study’s median follow-up period was 44 months. During this duration, one breast recurrence (0.7%), one supraclavicular recurrence (0.7%), and six systemic recurrences (4.3%) were observed. No axillary recurrence occurred within the follow-up period.

Conclusions

Patients presenting with pathological-suspicious ≤ 3 lymph nodes on imaging and showing a good response to NAC can be considered suitable candidates for SLNB + image-tailored axillary surgery, followed by adjuvant RT instead of ALND.

Introductıon

In recent decades, there has been a shift towards personalized treatment approaches for breast cancer patients. The traditional one-size-fits-all surgical methods are being reconsidered, and more tailored minimally invasive interventions are being developed. In the 1990s, Giuliano et al. first described sentinel lymph node biopsy (SLNB), demonstrating that axillary lymph node dissection (ALND) is unnecessary for SLNB-negative breast cancer patients [1]. Landmark trials such as NSABP B-04 and NSABP B-32 have shown that the extent of axillary surgery does not improve survival for clinically node-negative patients [2, 3].

The evidence overwhelmingly supports SLNB as the preferred treatment for axillary surgery in early breast cancer, considering its proven benefits in terms of morbidity, quality of life, and oncological safety [4]. Notably, clinical studies like ACOSOG Z0011 and AMAROS have shown that even in cases of limited axillary involvement with a positive SLNB, axillary dissection does not offer lower axillary recurrence and survival benefit when axillary radiotherapy (RT) is applied [5, 6].

The extensive use of neoadjuvant chemotherapy (NAC) in locally advanced breast cancer and the remarkable rates of pathological complete response (pCR) have sparked a new debate on how to approach the axilla after NAC. While SLNB is commonly used in patients who initially present with no signs of cancer in the lymph nodes and are treated with NAC, its use in patients with positive axillary nodes before NAC is controversial [7]. Prospective studies have been conducted to resolve this controversy. With current chemotherapy treatments, axillary pCR rates have reached 50%, making ALND unnecessary in almost half of the patients. Consequently, the option of SLNB has become more prominent in patients with a positive axillary status before NAC [8, 9].

In light of current guidelines, ALND is recommended for axillary residual disease after NAC, irrespective of disease burden, due to insufficient evidence. Nonetheless, there is growing scrutiny around the necessity of ALND, particularly in cases of limited axillary residue [10]. Magnetic resonance imaging (MRI) and ultrasound (USG) are widely used to evaluate response to neoadjuvant therapy, with an approximately 60% success rate in predicting complete pathological response. However, the accuracy improves when comparing the presence of axillary response (shrinking) to baseline images [11, 12].

Our study sought to evaluate the efficacy and the safety of image-tailored axillary surgery in combination with SLNB as a substitute for ALND in patients exhibiting limited axillary involvement and demonstrating favorable responses to NAC.

Methods

In this prospectively designed study, we evaluated patients with clinical stages of T1-3 and N1 at the time of diagnosis, who showed good or complete clinical response to NAC for both the breast and axilla and exhibited favorable changes (> 50% fibrotic) in the final pathological examination. The study was conducted at the Breast Surgery Unit, Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, between January 2011 and December 2023.

Patients with T4, cN2-3, and M1 stages at admission, no clinical axillary response to NAC, more than three pathological lymph nodes on imaging, and complete axillary pathological response as per the final pathology report were excluded from the study.

All patients underwent evaluation by a multidisciplinary team before and after NAC. The tumor stage, NAC response, and the number of pathological lymph nodes with their location were determined using USG, mammography (MMG), MRI, and positron emission tomography-computed tomography (PET-CT) by a breast specialist radiologist. Patients who showed a significant or complete clinical response in their axillary lymph nodes after NAC were included in the study, while those who showed progression or no regression were excluded (Fig. 1). Before surgery, it is important to identify the locations of pathological lymph nodes. For instance, level 1 in the inferior axilla can be close to the breast tail or lateral to the pectoralis minor muscle. In the superior axilla, level 1 can be lateral to the pectoralis major muscle, close to the axillary vein, or near the latissimus dorsi muscle. This information helps surgeons to target and remove these nodes more effectively during the operation, which is referred to as image-tailored surgery. During surgery, the surgical team checked the locations identified by radiology through palpation while performing the SLNB. Any suspicious lymph nodes found in these areas were removed as non-sentinel nodes. For example, if radiology indicated a pathological lymph node at the lateral border of the pectoral minor muscle, the surgical team would check this area during the operation and remove any suspicious lymph nodes found there.

Fig. 1
figure 1

Study design flow diagram

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All patients underwent neoadjuvant chemotherapy, including anthracycline and taxane. Patients with HER2-neu-positive disease received additional trastuzumab therapy. Adjuvant hormonal therapy was administered to all hormone-positive patients. Of the 18 triple-negative patients who underwent surgery after 2017, 10 received adjuvant capecitabine treatment, and those with HER-2-positive disease had trastuzumab or trastuzumab emtansine.

Patients underwent SLNB in conjunction with image-tailored lymph node excision performed by dedicated breast specialist surgeons. In a minority of cases, dual mapping (lymphoscintigraphy + blue dye) was employed (17%) and targeted axillary dissection (TAD) was carried out as per surgeon preference (7%). Lymph nodes were meticulously dissected from the excision material by an experienced pathologist. The presence of blue dye was noted during macroscopic evaluation. At least four sections were obtained from each lymph node block at 250-m intervals and stained with hematoxylin and eosin (H&E). Sentinel lymph nodes containing tumor cells detected by H&E or cytokeratin immunohistochemistry staining were considered positive, according to the AJCC 8th edition. Pathologic findings regarding chemotherapy response were also recorded, including regressional fibrosis, fibrohyalinization, and reactive changes.

The study investigated the relationship between the number of radiologically suspicious or positive lymph nodes and the number of lymph nodes removed. The number of lymph nodes removed was at least equal to the number found to be suspicious or pathologic. The multidisciplinary council reviewed patients’ final pathology results. Evaluation encompassed assessing the number of lymph nodes removed, the number of pathological lymph nodes identified radiologically before NAC, and the number of nodes with residual disease pathologically. No further axillary intervention was scheduled for patients with consistent radiology and pathology results.

Patients who had breast-conserving surgery (BCS) received RT to the entire breast, while those who had a mastectomy received RT to the chest wall. All patients also received RT to the axilla (level I-II-III), which includes the supraclavicular lymph node regions with or without the internal mammary lymph node region.

Patients with high-load axillary residual disease, unable to undergo adjuvant RT, and having inconsistent radiologic and pathological findings regarding the number of positive nodes underwent ALND. This group of patients was also excluded from the study (Fig. 1).

Demographic, clinicopathological, and radiological data of the patients were analyzed. According to the current guidelines, patients were regularly examined and evaluated for local recurrence or systemic disease.

Statistical analysis

The assumption of normality of continuous variables was tested with the Shapiro–Wilk test. Categorical variables were presented as frequency(%), continuous variables as mean ± SD, median (IQR: P25-P75), and range. Comparisons between groups in continuous variables were made with the Mann–Whitney U test, and comparisons between groups in categorical variables were made with Chi-Square tests (Pearson Chi-Square Test, Continuity Correction Test, and Fisher’s Exact Test). Diagnostic tests (sensitivity, specificity, PPV, NPV, and accuracy) were used to compare clinical findings and pathological results. Statistical analyses were made with SPSS software version 25 (IBM Corp., Armonk, NY, USA). Results were evaluated in the 95% confidence interval, and p < 0.05 was considered significant.

Results

Out of the 308 patients assessed for eligibility, 28 patients with four or more pathological lymph nodes in the preoperative evaluation were excluded. Additionally, three patients declined to participate, and nine patients were excluded due to disease progression during treatment. Breast surgery with SLNB + image tailored axillary surgery was performed on the remaining patients. Furthermore, 85 patients with pathological complete response, three with incompatible pathology and radiology results, 28 with high-load axillary residual disease (four or more metastatic lymph nodes) in pathological evaluation, and one with contraindication for adjuvant radiotherapy were also excluded from the study (Fig. 2). A total of 139 patients with a median age of 47 years (IQR, 39–54; range, 21–73) were included in the study. Of these, 128 patients had T1-2 stage tumors, while 11 had T3 stage tumors. Breast-conserving surgery was performed on 83 patients (59.7%), while 56 patients (40.3%) underwent mastectomy. Non-luminal subtype was found in 30 patients (21.6%), whereas 109 patients (78.4%) had luminal subtype. Prior to neoadjuvant chemotherapy (NAC), MRI and USG imaging of all patients were examined by a breast radiologist. The imaging revealed a single pathological lymph node in 76 patients, 2 in 41 patients, and 3 in 22 patients. Pathological features of the lymph nodes were confirmed through fine-needle aspiration biopsy (FNAB).

Fig. 2
figure 2

Flow chart of study inclusion and exclusion criteria

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During the study, sentinel lymph node biopsy (SLNB) was carried out using blue dye in 115 cases (82.7%) and with the combined method of blue dye and lymphoscintigraphy in 24 cases (17.3%) (Table 1). The identification rate of SLNB was 97.3% when using the single tracer (blue dye) and 100% when using the dual tracer. In only three patients, no blue dye was observed in the axilla. In these cases, lymph node excision was conducted based on palpation findings and radiological imaging.

Table 1 Patient characteristics
Full size table

A total of 64 patients (46%) had 1–3 excised lymph nodes, while 62 patients (45%) had 4–6 excised lymph nodes. Thirteen patients (9%) had seven or more lymph nodes removed (Table 2). The median number of excised lymph nodes was 4 (IQR, 3–5). Five patients had only one lymph node excised, as radiological findings suggested only one pathological node and no other palpable or suspicious node was found during the operation. Pathological examination revealed that 101 patients had a single metastatic lymph node, 32 patients had 2 metastatic lymph nodes, and 6 patients had 3 metastatic lymph nodes. Macrometastasis was observed in 80 nodes, micrometastasis in 43, and isolated tumor cells in 16. pCR was detected in the breast in 26 patients (18.7%).

Table 2 Comparison of radiological lymph node involvement with the number of excised lymph nodes
Full size table

The study compared the number of radiologically positive lymph nodes, pathologically positive lymph nodes, and positive sentinel lymph nodes, as shown in Table 2. All patients with one radiologically positive lymph node were found to have one metastatic lymph node. In this group, all patients had metastasis in the sentinel nodes and no metastasis was detected in non-sentinel lymph nodes. Among 41 patients with two radiologically positive lymph nodes, 17 (41%) had one metastatic lymph node, 22 (53%) had two metastatic lymph nodes, and 2 (5%) had three metastatic lymph nodes. Two patients with inconsistent pathology and radiology results were re-evaluated in a multidisciplinary council, and it was determined that axillary lymph node dissection (ALND) was not necessary. Radiology revealed three positive lymph nodes in 22 patients, of which 8 (36%) had one metastatic lymph node, 10 (45%) had two metastatic lymph nodes, and 4 (18%) had three metastatic lymph nodes (Additional file 1).

The median follow-up period was 44 months (IQR, 29–56). One patient experienced breast recurrence in the 31st month, and another patient had lymphatic recurrence in the supraclavicular area in the 39th month (Table 3). Systemic recurrence was observed in 6 (4.3%) patients. No axillary recurrence occurred during the follow-up period (Additional file 2).

Table 3 Characteristics of patients with local or regional recurrence
Full size table

Discussion

The efficacy of chemotherapeutic agents in the treatment of breast cancer is progressively on the rise. Following NAC, the incidence of axillary pCR may escalate to 50%. Notably, rates of pCR are even more pronounced in HER-2-positive and triple-negative patients [13]. The notable efficacy of NAC warrants deliberation on the necessity of ALND in cases of limited axillary residual disease, thereby advocating for the adoption of less invasive techniques in axillary surgery. Particularly, SLNB is the preferred approach for patients who are converted from cN + to cN0 post-NAC.

Although SLNB is often performed in patients who have converted to cN0 after NAC, some surgeons are concerned about the potential for false-negative results of SLNB. Caudle et al. suggested targeted axillary dissection for this concern [14]. Boughey et al. also showed that the false negative rate (FNR) can be reduced to less than 10% with TAD [15]. In clinically node-positive (cN +) patients who were converted to clinically node-negative (cN0), various prospective studies have demonstrated that FNR of the SLNB was higher than 10%, and if the dual mapping is used and ≥ 3 Lymph nodes are excised, and FNR can be reduced to acceptable rates of < 10% (4.9%-9.1%) regardless of TAD [16,17,18]. In the SENTINA trial, the FNR was 24.3% for patients with one sentinel node removed and 18.5% for patients with two sentinel nodes removed [17]. Three or more lymph node excisions and dual methods are recommended to reduce FNR [19].

In contrast, Galimberti et al. published 10-year follow-up results of patients who were initially cN + and became cN0 after NAC. Inclusion criteria were SLNB alone (one node is enough) without TAD, single tracer (no dual mapping), and nodal radiotherapy was not mandatory. Axillary failure occurred in 1.8% of the initially cN1/2 patients and 1.5% of the initially cN0 patients [20]. Although there is a risk of false negativity of SLNB, nodal recurrence rates are not increased in patients with negative SLNB who do not undergo ALND [21, 22]. Despite the lack of evidence regarding the negative impact of FNR on axillary recurrence and survival, the surgical community is actively pursuing strategies such as dual mapping and targeted axillary dissection to reduce FNR. It is recognized that despite diligent efforts, the FNR of SLNB cannot be reduced to zero, resulting in the presence of minimal residue in the axilla of a subset of patients. For patients undergoing upfront surgery, we have substantial evidence from prospective trials with 10 years of follow-up, such as ACOSOG Z0011 and AMAROS [5, 23]. It is established that even if there is a limited residual disease in the axilla, ALND does not decrease axillary recurrence rates or extend overall survival as long as adjuvant RT is administered.

Now is the time to discuss avoiding ALND for N + disease following NAC. Reports of ongoing prospective trials, such as Alliance 11,202 and NSABP B-51/RTOG 1304, are expected to clarify this topic [24, 25]. A trial including SLNB + patients after NAC was presented in ASCO 2023. The study evaluated cN1 breast cancer that became ycN0 but remained node positive following NAC, according to findings from a retrospective analysis of patients treated in phase 3 prospective NSABP B-40 and B-41 trials. Results showed that more intense axillary surgery (ALND) was not associated with better cancer outcomes when compared with SLNB. 5-year loco-regional recurrence was 9% in the ALND group, compared with 12% for those who underwent SLNB (I = 0.790) in unselected patients. 5-year risk of metastasis was 31% and 26%, respectively, and 5-year risk of any recurrence was 33% and 32%, respectively [26]. Similarly, in a few recently published studies, the superiority of ALND in oncological terms could not be demonstrated for neoadjuvant breast cancer patients with limited axillary residual disease [27,28,29]. In a multicentric registry trial, Cabioglu et al. showed that ALND could be avoided in selected cN ( +) patients who underwent SLNB after NAC having low-volume residual nodal disease with luminal pathology, as long as axillary radiotherapy is provided [29]. Almaharic et al. analyzed a total of 1617 patients from the National Cancer Database to compare survival following SLND and ALND in breast cancer patients with residual LN disease. Subgroup analysis demonstrated that SLNB was comparable with ALND in patients with luminal A or B tumors with a single metastatic lymph node [28]. Unlike these studies, Our study showed no difference in local recurrence rates between luminal and non-luminal subtypes. In the database study of Kantor et al., 6554 HR + /her- cN0 patients receiving neoadjuvant endocrine therapy were evaluated, and > 90% of patients had less than three positive lymph nodes. No survival difference was found between SLNB and ALND in these patients [30].

Axillary involvement is generally defined as N0 and N + without considering the volume of nodal disease (number and size of pathological nodes). The absence of image-tailored localization of suspicious lymph nodes places all N + patients in the same category and prevents individual decision-making (one size fits all). Our aim should be to determine precise, tailored surgical (need for ALND) and medical treatment (need for additional systemic treatment) approaches for every patient. To achieve this, we need to determine the extent of axillary involvement before NAC and assess the response after NAC using imaging to identify cases with minimal axillary residual disease.

In our study, we observed no axillary recurrences in 4 years of follow-up, despite expecting a high recurrence rate in patients with axillary residual disease after NAC. This suggests that minimal axillary residual disease may not necessitate ALND as long as radiological and pathological findings are consistent. It’s worth noting that current guidelines recommend ALND for patients with any axillary residual disease, regardless of tumor burden and NAC response [10].

Our practice is based on multidisciplinary councils where we evaluate the clinicopathological features of patients, pre- and post-neoadjuvant imaging, and pathological examination results. Based on this evaluation, we devise a personalized treatment plan that goes beyond the current guidelines. It’s important to note that we focus on the compatibility of imaging findings and pathological examination results. This approach allows us to initiate a personalized treatment for patients with limited axillary involvement without compromising oncological safety.

Most patients had an average of 6 or fewer lymph nodes removed (95% of patients with one pathological lymph node, 87% with two, and 82% with three). The number of lymph nodes removed in our study appears to be higher than standard SLNB. This is because we also removed palpable and suspicious lymph nodes guided by imaging. Excising more lymph nodes helps obtain a better correlation between imaging and final pathology, leading to safer decisions to avoid ALND. The number of excised lymph nodes could be decreased, but this may cause an increase in second axillary surgery rates.

Radiological evaluation of post-neoadjuvant axilla can be challenging. While imaging techniques are effective in identifying axillary involvement, they may be insufficient, particularly in assessing the complete response to NAC [31, 32]. Our study focused on differentiating between high-volume axillary disease and limited disease (< 3 lymph nodes). Our objective in evaluating post-neoadjuvant response was not to discern complete response, and we included patients with a good partial response, so the constraints of imaging methods did not impact our study.

The study’s main limitation was the absence of a comparison group. Additionally, interpreting the palpation findings requires experience. Our team consists of breast specialist surgeons and radiologists, and our center deals with a high volume of breast cancer cases. A comprehensive multidisciplinary tumor board evaluated all patients and determined individualized treatments. Therefore, conducting this prospective study in a tertiary referral center is feasible.

Conclusion

In patients with minimal axillary residual disease, SLNB + image-tailored axillary surgery and adjuvant radiotherapy may be sufficient for local control of the axilla as long as radiological and pathological correlation is ensured. ALND may be considered in patients suspected of having a high-volume residual disease. This study also confirmed that the belief that “chemo-resistance is equal to radio-resistance” is not valid in patients with minimal axillary residual disease (3 or fewer nodes) who exhibit a favorable response to NAC.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

SLNB:

Sentinel lymph node biopsy

NAC:

Neoadjuvant chemotherapy

ALND:

Axillary lymph node dissection

pCR:

Pathological complete response

MRI:

Magnetic resonance imaging

USG:

Ultrasound

MMG:

Mammography

PET-CT:

Positron emission tomography-computed tomography

TAD:

Targeted axillary dissection

H&E:

Hematoxylin and eosin

BCS:

Breast-conserving surgery

FNR:

False negative rate

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Acknowledgements

The authors are grateful to Atilla Bozdogan, MSc, who helped with the preparation of the statistical analysis

Funding

No funding was received for this study.

Author information

Authors and Affiliations

  1. Department of General Surgery, Istanbul Faculty of Medicine, Istanbul University, Capa Fatih, Istanbul, 34090, Turkey

    Mahmut Muslumanoglu, Baran Mollavelioglu, Neslihan Cabioglu, Selman Emiroglu, Mustafa Tukenmez, Vahit Ozmen & Abdullah Igci

  2. Department of Surgical Oncology Unit, Institute of Oncology, Istanbul University, Istanbul, Turkey

    Hasan Karanlık

  3. Division of Gastrointestinal and Oncologic Surgery, Harvard Medical School, Boston, MA, 02115, USA

    Tolga Ozmen

  4. Department of Radiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Ravza Yılmaz & Rana Gunoz Comert

  5. Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Semen Onder & Aysel Bayram

  6. Department of Nuclear Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Duygu Has Simsek & Melis Oflas

  7. Department of Radiation Oncology, Istanbul University Institute of Oncology, Istanbul, Turkey

    Kamuran Ibis

  8. Department of Medical Oncology, Istanbul University Institute of Oncology, Istanbul, Turkey

    Adnan Aydıner

Authors
  1. Mahmut Muslumanoglu
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  2. Baran Mollavelioglu
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  3. Neslihan Cabioglu
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  7. Tolga Ozmen
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Contributions

Design of the work: Muslumanoglu M., Cabioglu N., Tukenmez M., Emiroglu S., Mollavelioglu B. Acquisition of data: Karanlık H., Ozmen T., Muslumanoglu M., Cabioglu N., Tukenmez M., Emiroglu S., Mollavelioglu B., Ibis K. Analysis and interpretation of data: Yılmaz R., Gunoz Comert R., Onder S., Bayram A., Oflas M., Has Simsek D., Drafting: Yılmaz R., Gunoz Comert R., Onder S., Bayram A., Oflas M., Has Simsek D., Ibis K., Mollavelioglu B. Important intellectual content: Karanlık H., Ozmen T., Aydiner A., Ozmen V., Igci A., Muslumanoglu M., Cabioglu N., Tukenmez M. All authors have approved the publication of the final version of the manuscript.

Corresponding author

Correspondence to Baran Mollavelioglu.

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Ethics approval and consent to participate

The study was approved by the ethical committee of Istanbul University, Istanbul Faculty of Medicine (08.08.2023–1981986), by the ethical standards of the institutional and national research committee, and with the 1964 Helsinki Declaration. Informed consent was obtained from all individual participants included in the study.

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Muslumanoglu, M., Mollavelioglu, B., Cabioglu, N. et al. Axillary lymph node dissection is not required for breast cancer patients with minimal axillary residual disease after neoadjuvant chemotherapy. World J Surg Onc 22, 286 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-024-03547-7

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Keywords

World Journal of Surgical Oncology

ISSN: 1477-7819

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