scholarly journals Characteristics and prognostic values of traditional pathological parameters and advanced molecular subtypes in women in Beijing with operable breast cancer: a retrospective analysis

BMJ Open ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. e021819
Author(s):  
Qin Li ◽  
Li Li ◽  
Xiaoyue Jiang ◽  
Qi Du ◽  
Yingrui Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Risk Group ◽  
Histological Grade ◽  
Recurrence Risk ◽  
Operable Breast Cancer ◽  
Her2 Overexpression ◽  
Luminal A ◽  
Luminal B ◽  
Relapse Rates

ObjectivesThis study investigated the characteristics and prognostic values of traditional pathological parameters and advanced molecular subtypes in women with operable breast cancer in Beijing.DesignA retrospective study through case information enquiry or telephonic follow-up.SettingBeijing Friendship Hospital.Participants1042 patients with primary operable breast cancer between 2008 and 2012 were enrolled in the study.MeasuresThe characteristics and 5-year relapse rates according to the Nottingham Prognosis Index (NPI) and molecular subtypes were analysed.ResultsIn 1042 patients, the percentages of high histological grade, N1+N2, T2+T4 were 7.3%, 24.2%, 46.9%, respectively. In patients with invasive breast cancer, the percentages of auxiliary staging, positive margins, vascular invasion and nerve infiltration were 65.0%, 2.8%, 10.5% and 1.1%, respectively. The missing percentages of auxiliary staging, margins, vascular tumour invasion and nerve infiltration were 14.2%, 31.4%, 46.5% and 97.4%, respectively. The percentages of ER-positive, PR-positive, HER2-positive and Ki-67 high expression were 64.3%, 43.8%, 18.8% and 62.7%, respectively. The percentages of luminal A, luminal B, HER2-overexpression and basal-like breast cancers were 10.5%, 54.2%, 8.2% and 11.2%, respectively. Luminal A, luminal B and basal-like breast cancer subtypes were more common in the >60 years group, the 41–60 years group and the 20–40 years group, respectively. The 5-year relapse rates according to NPI were as follows: 6.2% in the low recurrence risk group, 10.4% in the moderate recurrence risk group and 12.9% in the high recurrence risk group. The 5-year relapse rates according to molecular subtypes were as follows: luminal A 4.0%, luminal B 7.0%, HER2-overexpression14.2%, basal-like 15.6%.ConclusionsReasonable analysis of traditional pathological parameters and advanced molecular subtypes in women with operable breast cancer in Beijing may be useful to guide precise treatment and predict prognosis.

scholarly journals The Analysis of bcl-2 in Association with p53 and Ki-67 in Triple Negative Breast Cancer and Other Molecular Subtypes in Ghana

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Charity Ameh-Mensah ◽  
Babatunde Moses Duduyemi ◽  
Kweku Bedu-Addo ◽  
Elijah Atta Manu ◽  
Francis Opoku ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Histological Grade ◽  
Her2 Overexpression ◽  
Luminal A ◽  
Ki 67 ◽  
Cross Sectional ◽  
Luminal B ◽  
Protein P53

Background. Little is known about the role of apoptosis in the tumorigenesis and prognosis of breast cancer in Ghana. Chemotherapeutic drug efficacy partially relates to apoptosis induction, rendering it a vital target in cancer therapy with unique biomarker opportunities that have not been exploited. Aberrations in this pathway are central to tumorigenesis, tumor progression, overall tumor growth, and regression during treatment therapies. Antiapoptotic bcl-2 (gene) and p53 are known to play roles in apoptosis while Ki-67 is a proliferative marker. The aim of our study is to determine the association of bcl-2 (protein) with p53 and Ki-67 in 203 consecutive breast cancer cases over a 10-year period. Method. A retrospective cross-sectional study on archival FFPE tissue blocks over a 9-year period with abstraction of clinicopathologic data. Two hundred and three consecutive and suitable FFPE blocks were selected for tissue microarray (TMA) construction, and IHC (bcl-2 (protein), Ki-67, p53, cyclin D, pan cytokeratins A and E, ER, PR, and HER2/neu) was done. Expressions of bcl-2 (protein), p53, and Ki-67 were related to histological grade, lymphovascular invasion, and molecular subtypes. SPSS version 23 was used to analyze results. Results. Most of our cases were in the fifth decade of life (31%); invasive carcinoma of no special type (NST) was predominant (87%); histological grade III (38%) was the highest; and Luminal A (19.8%), Luminal B (9.9%), HER2 (16%), and TNBC (54.3%) constituted the molecular classes. bcl-2 expression was found in 38% of the cases. Our cases also showed mutation in p53 (36.7%) and ki-67 expression (62.5%). bcl-2 (protein) and p53 significantly correlated with Luminal B and TNBC ( p < 0.01 ). Ki-67 also correlated significantly with Luminal A and B and HER2 overexpression ( p < 0.01 ). Premenopausal age (40–49) and histological grade inversely correlated with bcl-2 (protein) expression. p53 statistically correlated with Ki-67 ( p < 0.05 ). Conclusion. Our results show high expression of bcl-2 (protein) suggesting an important role of apoptosis in Ghanaian breast cancer cases. bcl-2 (protein), p53, and Ki-67 expressions emerged interdependently from this research and can thus be manipulated in prediction and prognosis of breast cancers in our setting.

scholarly journals Cancer stem cell markers ALDH1 and CD44+/CD24- phenotype and their prognosis impact in invasive ductal carcinoma

2018 ◽  
Author(s):  
Iris Rabinovich ◽  
Ana Paula Martins Sebastião ◽  
Rubens Silveira Lima ◽  
Cícero de Andrade Urban ◽  
Eduardo Schunemann Junior ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Ductal Carcinoma ◽  
Molecular Subtypes ◽  
Histological Grade ◽  
Clinical Aspects ◽  
Stem Cell Markers ◽  
Luminal A ◽  
Luminal B

Breast cancer is a very heterogeneous disease. The intrinsic molecular subtypes can explain the intertumoral heterogeneity and the cancer stem cell (CSC) hypothesis can explain the intratumoral heterogeneity of this kind of tumor. CD44+/CD24- phenotype and ALDH1 expression are the major CSC markers described in invasive breast cancer. In the present study, 144 samples of invasive breast carcinoma, no special type were distributed in 15 tissue microarrays (TMA) and then evaluated for expression of the CD44+/CD24- phenotype and ALDH1 to understand the importance of these CSC markers and the clinical aspects of breast cancer. The samples were classified into four molecular subtypes according to clinicopathological criteria: Luminal A, Luminal B, HER2, and Basal-like. A statistical association was found between the molecular subtypes and the CSC markers, with HER2 the most frequent subtype for both markers. ALDH1 was also associated with other poor prognostic variables, such as a high histological grade and larger tumors, but it was not associated with the patients’ prognosis in this sample and nor was the CD44+/CD24- phenotype in a multivariate analysis. There are still many controversies about the role of these markers in breast cancer molecular subtypes. The identification of these populations of cells, through immunohistochemical markers, can help to better understand the CSC theory in clinical practice and, in the near future, contribute to developing new target therapies.    

scholarly journals Triple-negative breast carcinomas as tumors untraceable by conventional radiological methods: a retrospective cohort

Mastology ◽  
2020 ◽  
Vol 30 (Suppl 1) ◽  
Author(s):  
Vanessa Monteiro Sanvido ◽  
Morgana Domingues da Silva ◽  
Patricia Zaideman Charf ◽  
Gil Facina ◽  
Afonso Celso Pinto Nazário
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Young Patients ◽  
Screening Tests ◽  
Molecular Profile ◽  
Rapid Progression ◽  
Her2 Overexpression ◽  
Luminal A ◽  
Luminal B

Introduction: Invasive breast carcinoma represents a heterogeneous group of lesions that differ in their molecular and histological characteristics. Perou et al. evaluated breast tumors using the DNA microarray technique and classified them into four molecular subtypes: Luminal A (LA), Luminal B (LB), HER2 overexpression (HER2), and triple-negative (TN). Immunohistochemistry approximately identifies the subtypes. The TN subtype is negative for estrogen and progesterone receptors and HER2 protein. This subgroup is comprehensive, with 75% of them being basaloid, that is, cells with a molecular profile similar to that of myoepithelial cells and a high expression 5, 6, 14, and 17 cytokeratins, vimentin, and P-cadherin. These tumors tend to be more aggressive, have higher rates of cell proliferation, and, therefore, a worse prognosis. Clinically, triple-negative carcinomas are more strongly associated with younger patients, early local and distant recurrence. Given their rapid progression, they can be clinically diagnosed in the interval of screening tests. Objective: To compare clinical and radiological aspects of TN and other molecular subtypes of breast cancer at diagnosis. Method: The study retrospectively evaluated data collected from medical records of patients diagnosed with breast cancer and treated at the Hospital São Paulo from 2013 to 2016. Results: In the study period, 235 cases of breast cancer were diagnosed. The incidence in patients under 39 years was 4.2% for LA, 4.9% for LB, and 8.3% for TN. At diagnosis, 83% of patients with TN tumors had clinical complaints, of which 96% were nodules. In mammographies, TN presented as nodules in 100% of cases, LA in 68%, LB in 71%, and HER2 in 50%. Microcalcifications were identified in 14% of LA cases, 21% of LB, and 50% of HER2. TN had no cases of microcalcifications or asymmetries. Among the other subtypes, the diagnosis by physical examination represented 35% to 53% of cases. As to the staging at diagnosis, TN cases presented ≤2 cm tumors in 25% of cases. The LA, LB, and HER2 subtypes presented as ≤2 cm tumors, respectively, in 61%, 49.4%, and 43% of patients. Lymph node involvement by neoplasm at diagnosis occurred in 3.35%, 17.5%, 14.3%, and 33.3% of LA, LB, HER2, and TN cases, respectively. Conclusion: TN carcinomas affect a greater number of young patients, outside the screening age group. In our sample, TN tumors were diagnosed based on clinical complaints and showed no association with non-palpable breast lesions. TN is the subtype with the highest probability of interval tumors, untraceable by conventional exams, and, as a result, other screening options, such as serum assays, have been discussed.

scholarly journals PROFILE OF SURROGATE MARKERS OF MOLECULAR SUBTYPES USING THE EXPRESSION PATTERN OF ER, PR, AND HER2/NEU RECEPTORS IN OPERABLE BREAST CANCER

2021 ◽  
pp. 148-151
Author(s):  
VISHAL VERMA ◽  
HIREMATH RN ◽  
SHARANJIT SINGH BASRA ◽  
NIRAJ CHOUREY ◽  
POOJA SINHA
Keyword(s):  
Breast Cancer ◽  
Expression Pattern ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Operable Breast Cancer ◽  
Surrogate Markers ◽  
Nodal Involvement ◽  
Luminal A ◽  
Luminal B ◽  
Significant Difference

Objective: The present study was planned with an aim to study the profile of surrogate markers of molecular subtypes using the expression pattern of ER, PR, and HER2/NEU receptors in operable breast cancer so that most effective and advantageous treatment can be offered for better surgical outcomes. Methods: A cross-sectional observational study was carried out in one of the tertiary care centers in Central UP. All patients presenting to the center with early and locally advanced breast cancer with age bracket between 18 and 75 years during 2-year period and willing to participate in the study were included in the sample size. Clinical staging was done using the standard TNM criteria and all the specimens were subjected to immunohistochemical evaluation for surrogate molecular subtyping Results: Out of 94 cases enrolled in the study, a total of 32 (34.4%) were identified as luminal A, 3 (3.2%) were identified as luminal B, 35 (37.6%) were identified as HER2 positive, and remaining 23 (24.7%) were identified as triple negative. Statistically, there was no significant difference among groups with respect to age (p=0.958) and BMI (p=0.332). However, there was a significant difference among groups with respect to clinical stage (p=0.031), clinical nodal involvement (p=0.014), pathological staging (p=0.006), and pathological nodal involvement (p=0.023). Among those with nodal involvement, all the cases had involvement of one node except for one patient in Group I who had involvement of thrMost of the luminal A cases (81.3%) were clinically Stage 1 or 2. All the luminal B cases were clinically Stage 2 or 3 (100%). Almost half (48.8%) of Her2-negative cases were Stage 3 or 4. Majority of triple-negative cases were Stage 3 or 4 (65.2%). Clinically, nodal involvement was seen to be maximum in Her2-negative and triple-negative groups (54.3% and 52.2% of cases, respectively). Pathologically, most of the luminal A (83.9%), Her2 negative (81.8%), and all the luminal B cases were Stage 2. Pathologically, nodal involvement was seen in 16.1% of luminal A, 42.4% of Her2-negative, and 50% of triple-negative cases. Conclusion: The findings of the present study provided a glimpse of expression pattern of ER, PR, and HER2/NEU receptors in operable breast cancer based on which most effective and advantageous treatment can be offered for better surgical outcomes.

scholarly journals Is There a Correlation between Multiparametric Assessment in Ultrasound and Intrinsic Subtype of Breast Cancer?

2021 ◽  
Vol 10 (22) ◽  
pp. 5394
Author(s):  
Magdalena Gumowska ◽  
Joanna Mączewska ◽  
Piotr Prostko ◽  
Katarzyna Roszkowska-Purska ◽  
Katarzyna Dobruch-Sobczak
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Profile ◽  
Her2 Overexpression ◽  
Imaging Features ◽  
Luminal A ◽  
Luminal B ◽  
Post Surgery

Molecular profile of breast cancer provides information about its biological activity, prognosis and treatment strategies. The purpose of our study was to investigate the correlation between ultrasound features and molecular subtypes of breast cancer. From June 2019 to December 2019, 86 patients (median age 57 years; range 32–88) with 102 breast cancer tumors were included in the study. The molecular subtypes were classified into five types: luminal A (LA), luminal B without HER2 overexpression (LB HER2−), luminal B with HER2 overexpression (LB HER2+), human epidermal growth factor receptor 2 positive (HER2+) and triple negative breast cancer (TNBC). Histopathological verification was obtained in core biopsy or/and post-surgery specimens in all cases. Univariate logistic regression analysis was performed to assess the association between the subtypes and ultrasound imaging features. Experienced radiologists assessed lesions according to the BIRADS-US lexicon. The ultrasound scans were performed with a Supersonic Aixplorer and Supersonix. Based on histopathological verification, the rates of LA, LB HER2−, LB HER2+, HER2+, and TNBC were 33, 17, 17, 16, 19, respectively. Both LB HER2+ and HER2+ subtypes presented higher incidence of calcification (OR = 3.125, p = 0.02, CI 0.0917–5.87) and HER2+ subtype presented a higher incidence of posterior enhancement (OR = 5.75, p = 0.03, CI 1.2257–32.8005), compared to other subtypes. The calcifications were less common in TNBC (OR = 0.176, p = 0.0041, CI 0.0469–0.5335) compared to other subtypes. There were no differences with regard to margin, shape, orientation, elasticity values and vascularity among five molecular subtypes. Our results suggest that there is a correlation between ultrasonographic features assessed according to BIRADS-US lexicon and BC subtypes with HER2 overexpression (both LB HER2+ and HER2+). It may be useful for identification of these aggressive subtypes of breast cancer.

scholarly journals Diagnostic performance of superb microvascular imaging combined with shear-wave elastography in distinguishing invasive ductal carcinoma molecular subtypes

2022 ◽  
Author(s):  
Fengjiao Chen ◽  
Hui Jing ◽  
Haitao Shang ◽  
Haoyan Tan ◽  
Haobo Yang ◽  
...  
Keyword(s):  
Ductal Carcinoma ◽  
Molecular Subtypes ◽  
Histological Grade ◽  
Shear Wave Elastography ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Luminal A ◽  
Luminal B ◽  
Superb Microvascular Imaging ◽  
Microvascular Imaging

IntroductionTo explore the diagnostic value of combining superb microvascular imaging (SMI), shear-wave elastography (SWE), and Breast Imaging Reporting and Data System (BI-RADS) to distinguish different molecular subtypes of invasive ductal carcinoma (IDC).Material and methodsA total of 239 surgically confirmed IDC masses in 201 patients underwent conventional ultrasound, SMI, and SWE examination, the information such as echo pattern, posterior features, margins, SMI pixels, and hardness of the masses was recorded. According to the St. Gallen standard, breast masses were classified as Luminal A, Luminal B, HER2 overexpression, and triple-negative subtype. We further explored the differences between different molecular subtypes of IDC.ResultsLuminal A subtype had the following characteristics: low histologic grade, posterior acoustic shadowing (p= 0.019), spiculated margins (p<0.001) , and relatively soft. Luminal B subtype was characterized by low histological grade (p <0.0001), posterior acoustic shadowing or indifference, and indistinct margins. HER2 overexpression breast cancers were characterized by high histological grade, enhanced posterior acoustics or indifference, calcifications (p= 0.005), spiculated or indistinct margins, vascularity (p=0.005), and relative stiffness. Triple-negative breast cancers had the characteristics of high histological grade, posterior echogenic enhancement, lack of calcifications, circumscribed or microlobulated margins, low blood flow signals, and stiff tissue (p=0.013).ConclusionsOur study demonstrated the significant differences and trends among the IDC four subtypes by the combined application of SMI, SWE, and BI-RADS lexicon, which are of great significance for early diagnosis, selection of treatment methods, and evaluation of prognosis of IDC.

scholarly journals Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

2021 ◽  
Vol 107 (1_suppl) ◽  
pp. 12-12
Author(s):  
D Aissaoui ◽  
M Bohli ◽  
R Ben Amor ◽  
J Yahyaoui ◽  
A Hamdoun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Inflammatory Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

scholarly journals Diffusion-Weighted Imaging of Different Breast Cancer Molecular Subtypes: A Systematic Review and Meta-Analysis

Breast Care ◽  
2021 ◽  
pp. 1-8
Author(s):  
Hans-Jonas Meyer ◽  
Andreas Wienke ◽  
Alexey Surov
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Diffusion Weighted Imaging ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Diagnose Breast Cancer ◽  
Luminal B ◽  
Diffusion Weighted ◽  
Adc Values

Background: Magnetic resonance imaging can be used to diagnose breast cancer (BC).Diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) can be used to reflect tumor microstructure. Objectives: This analysis aimed to compare ADC values between molecular subtypes of BC based on a large sample of patients. Method: The MEDLINE library and Scopus database were screened for the associations between ADC and molecular subtypes of BC up to April 2020. The primary end point of the systematic review was the ADC value in different BC subtypes. Overall, 28 studies were included. Results: The included studies comprised a total of 2,990 tumors. Luminal A type was diagnosed in 865 cases (28.9%), luminal B in 899 (30.1%), human epidermal growth factor receptor (Her2)-enriched in 597 (20.0%), and triple-negative in 629 (21.0%). The mean ADC values of the subtypes were as follows: luminal A: 0.99 × 10–3 mm2/s (95% CI 0.94–1.04), luminal B: 0.97 × 10–3 mm2/s (95% CI 0.89–1.05), Her2-enriched: 1.02 × 10–3 mm2/s (95% CI 0.95–1.08), and triple-negative: 0.99 × 10–3 mm2/s (95% CI 0.91–1.07). Conclusions: ADC values cannot be used to discriminate between molecular subtypes of BC.

Association between molecular subtype of local advanced breast cancer with Ca 15-3 level

2021 ◽  
pp. 1-4
Author(s):  
Dony Ruswendro ◽  
Salman Ardi Syamsu ◽  
Rudy Thabry ◽  
Arifin Seweng ◽  
Andi Nilawati Usman
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Tumor Marker ◽  
Molecular Subtypes ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Tissue Growth ◽  
Advanced Breast ◽  
Luminal A ◽  
Luminal B

BACKGROUND: Neoplasm is an abnormal mass of tissue that grows excessively and not coordinated with normal tissue growth and continues to do so even though the stimulation that triggered the change has stopped. Breast cancer can be known by using tumor marker, which has been used is mucin-like glycoprotein Carcinoma Antigen (CA 15-3) which is a tumor marker that is specific to breast cancer. METHOD: This study is a cross-sectional study to determine the association between molecular subtypes of locally advanced breast cancer with CA 15-3 level at Abdul Wahab Sjahranie Samarinda Hospital. The population in this study were all breast cancer patients that were confirmed by histopathological examination. RESULTS: A total of 75 patients were included for this study, 29 patients (38.7%) known as Overexpression HER2, 18 patients (24.0%) were Luminal B with HER2 (+), 11 patients (14.7%) were Luminal B with HER2 (−), 11 patients (14.7%) were Basal-like/TNBC, and 6 patients (8,0%) were Luminal A. From the ANOVA test, the value of p = 0.045 (p < 0.05) means there was an association between Ca 15-3 level and molecular subtypes in patients with locally advanced breast cancer at the Abdul Wahab Sjahranie Hospital in Samarinda 2017. In this study Ca 15-3 levels were obtained on average for Luminal A 16.98 U/mL, Luminal B with HER2 (−) 42.41 U/mL, Luminal B with HER2 (+) 73.75 U/mL, Overexpression HER2 47.73 U/mL, and Basal Like /TNBC 63.50 U/mL. CONCLUSION: Statistically, it was found that there was an association between Ca 15-3 levels and molecular subtypes in patients with locally advanced breast cancer at the Abdul Wahab Sjahranie Hospital in Samarinda 2017.

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