Annals of Oncology Advance Access originally published online on September 17, 2007
Annals of Oncology 2008 19(1):62-67; doi:10.1093/annonc/mdm440
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
breast cancer |
Screening mammography for young women treated with supradiaphragmatic radiation for Hodgkin's lymphoma
1 Division of Medical Oncology and Hematology
2 Department of Biostatistics
3 Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
4 Division of Medical Oncology and Hematology, Massachusetts General Hospital Cancer Center, USA
* Correspondence to: Dr M. Crump, Princess Margaret Hospital, Room 5-108, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada. Tel: +1-416-946-4567; Fax: +1-416-946-6546; E-mail: michael.crump{at}uhn.on.ca
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Background: Female survivors of Hodgkin's lymphoma (HL) treated with supradiaphragmatic radiation therapy (SRT) are at increased risk of breast cancer (BC), but there is little data on the optimal screening strategy.
Patient and methods: We report a prospective surveillance study of women treated for HL with SRT before age 30 participating in a high-risk screening clinic. Starting 8 years after treatment, women received annual mammography and clinical follow-up from 1997 to 2006. Method of detection and characteristics of BCs were identified.
Results: In all, 115 female HL survivors attended at least one clinic; 100 participated in annual surveillance. The majority had mammography alone; adjunctive magnetic resonance imaging (MRI) was used more frequently in women with high breast density (P = 0.025). Median age at first mammogram was 36 years and decreased with more recent year of diagnosis. Twelve of the 100 participating women (12%) were diagnosed with BC after a median of 5 years of surveillance (range, 1–9). Seven BCs presented as palpable masses [six invasive, one ductal carcinoma in situ (DCIS)], five were detected by mammography (one invasive, four DCIS).
Conclusions: Despite earlier initiation of mammographic screening, most BCs were detected clinically and had unfavorable pathologic characteristics. Evaluation of more intensive screening and the contribution of MRI for earlier detection is warranted.
Key words: breast cancer, Hodgkin's lymphoma, late complications, screening
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Successful treatment of early-stage Hodgkin's lymphoma (HL) has led to a 15-year survival rate of >80% [1]. However, survivors are at risk for long-term treatment complications including increased incidence and rate of death from secondary malignancies. Breast cancer (BC) remains the most common second malignancy among female survivors, particularly in those treated at young ages with supradiaphragmatic radiation therapy (RT) [2–6]. Cumulative risk increases with radiation dose, time from treatment, and attained age at end of follow-up and approaches 29% in a women at age 55 who were treated for HL at age 25 [7]. The increased rate of secondary BCs emerges following a latency of 10 years and persists beyond 25 years of follow-up [3, 8, 9].
Thus, many of these women are at significant risk for BC at a young age, before routine screening mammography is recommended for the general population. There is a current paucity of prospectively collected information on the optimal surveillance frequency and screening modality. Practice guidelines vary widely in their recommended use of screening mammography for selected female HL survivors [4, 10, 11]. In young premenopausal women, denser breast tissue limits the sensitivity of screening mammography [12], such that the effectiveness of mammography in young HL survivors is uncertain. Based on expert consensus opinion, the American Cancer Society recently recommended magnetic resonance imaging (MRI) as an adjunct to mammography in this high-risk population [13].
We report the results of a prospective BC surveillance program based on annual mammography for female HL survivors at our institution, focusing on the method of detection and characteristics of secondary BCs in a screened cohort.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
study population
Four hundred and fifty-three female patients with HL were registered at Princess Margaret Hospital (PMH) from 1 January 1968 to 31 December 1997 and received supradiaphramatic RT for HL before age 30. A prospective high-risk screening clinic was started by one of the authors (PEG) in 1997 for 8-year survivors of HL who had no prior diagnosis of BC [14]. A total of 360 eligible women were identified and invited to participate by mailed letter. Direct referral from their primary care physician or PMH treating oncologist was also accepted. Women completed a consent form and baseline treatment and risk factor questionnaire. At initial clinic visit, BC risk was discussed. Minimum recommended surveillance consisted of monthly self-breast examination and annual follow-up at PMH with clinical breast examination and screening mammography at each visit. All breast imaging was carried out at our institution. Conventional four film/screen mammograms (mediolateral oblique and craniocaudal views) were interpreted by dedicated breast imaging radiologists, and additional screening with breast MRI or ultrasound was carried out as required. Digital mammography was introduced in 1999, and routine annual screening with concurrent mammography and MRI was initiated in January 2006. Pregnant or lactating women deferred mammography, but continued to have annual clinical follow-up.
The Research Ethics Board of PMH approved this study.
data collection
Chart review was conducted to collect information on patient demographics, HL diagnosis and treatment, and BC diagnosis and treatment. Reproductive risk factors and BC surveillance history were obtained from self-administered questionnaire at the time of study entry. Mammogram reports were reviewed and breast density was evaluated semiquantitatively on a four-point scale based on the American College of Radiology Breast Imaging and Reporting Data System reporting lexicon [1 = fatty; 2 = scattered fibroglandular densities (mildly dense), 3 = moderately dense, 4 = extremely dense] [15]. If breast density changed over time, breast density at last follow-up was recorded. Use of additional imaging either for regular screening or to clarify lesions was noted. Last follow-up was defined as date of last clinic visit, BC diagnosis, or death. The occurrence of BC among HL survivors not screened through the high-risk clinic was ascertained through linkage with the Ontario Cancer Registry (OCR), which captures all cancer diagnoses in the province of Ontario. Based on data from 1997 to 2002, age-adjusted BC incidence rates for women between age 15 and 59 were obtained from the OCR.
statistical analysis
Descriptive statistics were used to describe clinical features of the cohort, methods of breast surveillance, and breast density. To determine whether there was a relationship between age of first mammography and year of HL diagnosis, Wilcoxon rank sum was used. The associations between other categorical variables were tested using the Fisher's exact test. The cumulative BC incidence in the screened cohort and of the unscreened cohort were calculated accounting for competing risks of death [16]. To estimate the number of expected BC cases, age-adjusted BC incidence rates were multiplied by person-years at risk. Relative risk was expressed as the ratio of observed to expected numbers of secondary BCs.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patient characteristics
A total of 115 of 360 (32%) eligible female HL survivors agreed to be seen in the high-risk clinic (Table 1). Median age at HL diagnosis was 22 years (range, 9–31) and median age at time of inception into clinic was 35, representing a median period of 13 years since HL diagnosis. Initial treatment for HL consisted of RT alone in 53 (46%) and combined modality treatment in 61 women (53%). The majority of women (91%) received extended-field (mantle) RT with a median dose of 35 Gy. Nineteen women had been treated for recurrent HL, but all were disease-free at entry. Mechlorethamine, vincristine, procarbazine, prednisone (MOPP)-containing chemotherapy was used during the treatment of 45/115 women (40%). Treatment-induced amenorrhea occurred in 15 (13%) women at median age of 38. Twenty women (17%) had a family history of BC in at least one first-degree relative.
|
breast cancer screening
At the time of enrollment of 115 women, 39 (34%) had no prior screening, 53 (46%) carried out breast self-examination, and 23 (20%) had at least one prior mammogram. Of the women who had a mammogram, 10 were between age 40 and 49 and five were older than age 50.
One hundred of the 115 enrolled women returned annually to PMH for BC surveillance. Seven women deferred radiographic screening >1 year after their first visit due to pregnancy or lactation, but continued to have annual clinical breast examination. During this period, two of these women developed BC. Of the 98 remaining women who received annual radiographic screening, 82 were screened with mammography alone, 12 with mammogram and MRI, three with mammogram and ultrasound, and one with breast MRI alone (due to age <25).
The median age at first mammogram decreased with more recent year of HL diagnosis. Among women diagnosed with HL before 1985, median age at first mammogram was 40, compared with median age of 33 for women diagnosed after 1985 (P < 0.0001). The median interval between HL treatment and first mammogram was 13 years (range, 6–27).
In the screened cohort, mammographic breast tissue density was described as extremely dense in 10 (10%); moderately dense in 41 (42%); mildly dense in 39 (40%); and fatty in seven (7%). Combined screening using mammography with breast MRI occurred more often in women with moderate or extremely dense breasts (P = 0.025). Even before the initiation of routine screening with mammography and MRI, women with high breast density received additional MRI more often than women with less dense breasts (P = 0.0036).
breast cancer detection
In the surveillance cohort, 12 BCs were diagnosed in 12 women after a median of 5 years of active surveillance (range, 1–9). Median age at BC diagnosis was 40 years (range, 32–51) following a median latent period from completion of HL treatment of 16 years (range, 13–28). No incident BCs were detected at first clinic visit or on first screening mammogram.
Method of detection and clinical characteristics of the BCs are listed in Table 2. Seven BCs were detected by physical exam and five were detected by mammography. Of the seven palpable tumors, four women had a negative screening mammogram within the preceding 6–12 months, two had deferred mammography due to pregnancy and lactation, and one had an indeterminate lesion screening mammography which appeared benign on second-look ultrasound (Table 2, case 3). Subsequent diagnostic mammograms were abnormal in 6 of 7 cases, with the majority demonstrating a focal mass. In one woman (Table 2, case 2), diagnostic mammogram was normal and invasive cancer was detected by diagnostic MRI. In the BC cases detected by screening mammogram, suspicious calcifications were seen in four cases and a mass was evident in one case.
|
breast cancer characteristics
As shown in Table 2, six of the seven of the clinically detected cancers were invasive ductal carcinomas while four of the five mammogram-detected BCs were in situ carcinomas. Of the seven invasive cancers, all had a tumor size >1.5 cm, six were intermediate or high-grade lesions (the other one presented clinically as inflammatory cancer), and six had lymph node metastases. Five of eight tumors tested were hormone receptor positive. All six BCs tested for Her2/neu were negative.
In these 12 women, 10 were premenopausal, one had HL treatment-induced ovarian failure, and one surgical menopause. Three women (25%) had a family history of BC in at least one first-degree relative.
breast cancer incidence and mortality
In the entire cohort of 115 women, the 12 BCs were diagnosed during 855 person-years of follow-up. As shown in Figure 1, the 5-year cumulative BC incidence from start of screening in our study cohort was 3.8% [95% confidence interval (CI) 1.4–9.9]. During the same time frame (1997–2006), the 5-year cumulative BC incidence in the unscreened cohort of 245 women was 3.3% (95% CI 1.6–6.4).
|
At 20 years from HL diagnosis, the cumulative incidence of secondary BC in our screened cohort was 10.9% (95% CI 5.3% to 18.8%). Compared with the expected incidence of BC in the age-matched general population in Ontario, the relative risk of BC in this cohort is 18.5 (95% CI 9.5–32.2).
At time of last follow-up, 111 patients were alive. One patient with invasive BC developed metastatic disease and died 24 months after diagnosis (Table 2, case 7). The three other deaths were attributed to lung cancer (n = 1), recurrent HL (n = 1), and unknown cause (n = 1).
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
It is recognized that female HL survivors are at high risk for secondary BC, yet the optimal screening strategy is not well established. Our study evaluated a BC surveillance program for 8-year survivors treated with supradiaphragmatic radiation before age 30. Mammographic screening was initiated at median age <40, which is earlier than recommended for the general population. During 855 person-years of follow-up, screening mammography detected five of the total 12 BC cases (42%). The seven other cases presented with palpable cancers and six of these were large, invasive ductal carcinomas with nodal involvement. These results indicate that screening mammography may be effective at detecting ductal carcinoma in situ (DCIS), but may be inadequate for early invasive BC detection in this high-risk population. The fact that two BCs were diagnosed in women who deferred mammography because of pregnancy or lactation highlights the problem with radiographic screening in this group of susceptible women.
Before the start of this program at our center, 73% of HL survivors with secondary BCs presented symptomatically or with palpable masses [14]. Retrospective studies of diagnostic mammograms in HL survivors revealed radiographic abnormalities in the majority of cases, which indicated that screening mammography may allow earlier detection in this high-risk group of women who otherwise would not be screened due to young age [17, 18]. There is only one other prospective screening study reported that suggested screening mammography could detect small, node-negative BCs [19]. However, excluding two cases of incident BC on baseline mammogram, five of the secondary 10 BCs in that report were detected clinically during a median follow-up time of 3 years. Similarly, our study shows that active screening with mammography detects some secondary BCs, but a substantial proportion of cases continue to be detected clinically.
The utility of screening mammography in our HL survivors may be limited by the young age and premenopausal status of this population. In the screened cohort, 52% of women had moderately or extremely dense breasts, comparable to the prevalence reported in another cohort of HL survivors [19] and to that of premenopausal women in general population [20]. In our study, these women received annual MRI screening or second-look MRI to clarify indeterminate lesions more frequently. At the preclinical (i.e. nonpalpable) stage, the majority of early BCs have subtle mammographic findings, such as architectural distortion or asymmetry [21], that may be obscured by surrounding normal dense breast tissue. Four of the five mammographically detected BCs in our study were DCIS detected as calcifications. Although calcifications are less likely to be masked by high mammographic breast density, they are more common in in situ carcinomas than in clinically occult invasive carcinomas [21, 22]. Breast MRI has been shown to be more sensitive than mammography for early BC detection in high-risk young women due to BRCA mutations [23] or a strong family history of BC [24, 25]. However, breast MRI generally has lower sensitivity for detection of microcalcifications [26]. The value of screening breast MRI for earlier BC detection in women at high risk due to HL treatment is yet to be determined, although a prospective randomized study is not likely to be feasible.
Alternatively, the interval diagnosis of BC despite annual screening mammography may reflect more rapid tumor growth in radiation-induced BCs. In our study, four cases of interval BCs were stage II at time of detection illustrating the need for improved screening in this population. Sanna et al. [27] indicated that secondary BCs may have a higher proliferation index (Ki-67), but their overall pathological characteristics and rate of nodal involvement appears similar to those of sporadic BC [18, 27, 28]. Further investigation is required to determine whether HL survivors would benefit from more frequent radiographic screening, at 6-months intervals, to improve BC detection rate.
While derived from a single center, this is the largest prospective study with the longest follow-up reported to date evaluating annual mammography for BC screening in female HL survivors, using a protocol that meets or exceeds the minimum screening recommendations endorsed in current consensus guidelines [4, 10]. One limitation of this study is that many patients were lost to follow-up after the long latency from HL treatment. As only 32% of eligible women were enrolled, our results could be affected by participation bias. However, the clinical characteristics of the screened cohort were comparable to those of the entire eligible HL survivor population reported from our center [14], and cumulative BC incidence for the screened and unscreened cohorts were similar. The small size of our screened cohort limits our ability to determine whether breast density is associated with secondary BC risk in this population. Recently, Boyd et al. [29] reported that high breast density is independently associated with increased BC risk in the general population and may be an indirect marker of exposure to hormones and factors that potentiate neoplastic growth [30]. Additionally, we are unable to determine the impact of mammographic screening on mortality from secondary BC.
Modern therapy for early-stage HL employs combined modality therapy with involved-field RT at lower doses [31], and investigation of strategies using chemotherapy alone is in progress [32]. A meta-analysis of individual patient data from randomized trials indicates that the risk of secondary BC is significantly lower for women treated with involved-field RT compared with extended-field (mantle) RT [33]. However, there exists currently a large population of women previously treated with extended-field radiation who require vigilant BC surveillance. Our results indicate that annual mammography can detect DCIS in this population, but may miss early invasive BC. This underscores recent American Cancer Society guidelines recommending use of screening MRI as an adjunct to mammography in these women [13]. The incremental benefit of a strategy using both modalities, and whether the imaging should be done concomitantly or at 6-month intervals, is unknown. We have adopted a BC screening strategy incorporating annual MRI in addition to mammography for female HL survivors and are evaluating the increased detection provided by interval breast MRI screening.
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
We thank the members of the Lymphoma Site at Princess Margaret Hospital for contributing patients to this screening program: M. Gospodarowicz, R. Tsang, W. Wells, A. Sun, I. Quirt, and J. Sturgeon and the radiologists in breast imaging for their expertise: K. Bukhanov, M. Dill-Macky, S. Kulkarni, and S. Pantazi.
Received for publication July 10, 2007. Revision received July 30, 2007. Accepted for publication August 3, 2007.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger. J Clin Oncol (2002) 20:2101–2108.
2. Hancock SL, Tucker MA, Hoppe RT. Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst (1993) 85:25–31.
3. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma. J Clin Oncol (2007) 25:1489–1497.
4. Mauch P, Ng A, Aleman B, et al. Report from the Rockefellar Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease: July 9–16, 2003, Bellagio, Italy. Eur J Haematol Suppl (2005) 68–76.
5. Swerdlow AJ, Barber JA, Hudson GV, et al. Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol (2000) 18:498–509.
6. van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol (2000) 18:487–497.
7. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst (2005) 97:1428–1437.
8. Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol (2002) 20:3484–3494.
9. Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol (2003) 21:4386–4394.
10. Jost LM, Stahel RA. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin's disease. Ann Oncol (2005) 16(Suppl 1):i54–i55.
11. Ralleigh G, Given-Wilson R. Breast cancer risk and possible screening strategies for young women following supradiaphragmatic irradiation for Hodgkin's disease. Clin Radiol (2004) 59:647–650.[CrossRef][Web of Science][Medline]
12. Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology (2002) 225:165–175.
13. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin (2007) 57:75–89.
14. Gervais-Fagnou DD, Girouard C, Laperriere N, et al. Breast cancer in women following supradiaphragmatic irradiation for Hodgkin's disease. Oncology (1999) 57:224–231.[CrossRef][Web of Science][Medline]
15. The American College of Radiology. Breast Imaging Reporting and Data System Atlas (2003) Reston, VA: American College of Radiology.
16. Kalbefleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data (2002) New York, NY: Wiley-Interscience.
17. Dershaw DD, Yahalom J, Petrek JA. Breast carcinoma in women previously treated for Hodgkin disease: mammographic evaluation. Radiology (1992) 184:421–423.
18. Yahalom J, Petrek JA, Biddinger PW, et al. Breast cancer in patients irradiated for Hodgkin's disease: a clinical and pathologic analysis of 45 events in 37 patients. J Clin Oncol (1992) 10:1674–1681.
19. Diller L, Medeiros Nancarrow C, Shaffer K, et al. Breast cancer screening in women previously treated for Hodgkin's disease: a prospective cohort study. J Clin Oncol (2002) 20:2085–2091.
20. Kolb TM, Lichy J, Newhouse JH. Occult cancer in women with dense breasts: detection with screening US—diagnostic yield and tumor characteristics. Radiology (1998) 207:191–199.
21. Sickles EA. Mammographic features of 300 consecutive nonpalpable breast cancers. AJR Am J Roentgenol (1986) 146:661–663.
22. Gajdos C, Tartter PI, Bleiweiss IJ, et al. Mammographic appearance of nonpalpable breast cancer reflects pathologic characteristics. Ann Surg (2002) 235:246–251.[CrossRef][Web of Science][Medline]
23. Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA (2004) 292:1317–1325.
24. Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med (2004) 351:427–437.
25. Lehman CD, Blume JD, Weatherall P, et al. Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer (2005) 103:1898–1905.[CrossRef][Web of Science][Medline]
26. Bazzocchi M, Zuiani C, Panizza P, et al. Contrast-enhanced breast MRI in patients with suspicious microcalcifications on mammography: results of a multicenter trial. AJR Am J Roentgenol (2006) 186:1723–1732.
27. Sanna G, Lorizzo K, Rotmensz N, et al. Breast cancer in Hodgkin's disease and non-Hodgkin's lymphoma survivors. Ann Oncol (2007) 18:288–292.
28. Wolden SL, Hancock SL, Carlson RW, et al. Management of breast cancer after Hodgkin's disease. J Clin Oncol (2000) 18:765–772.
29. Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med (2007) 356:227–236.
30. Harvey JA, Bovbjerg VE. Quantitative assessment of mammographic breast density: relationship with breast cancer risk. Radiology (2004) 230:29–41.
31. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol (2003) 21:3601–3608.
32. Meyer RM, Gospodarowicz MK, Connors JM, et al. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol (2005) 23:4634–4642.
33. Franklin J, Pluetschow A, Paus M, et al. Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials. Ann Oncol (2006) 17:1749–1760.
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in Ann Oncol:
- in this issue
Ann Oncol 2008 19: 1.[Extract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  K. C. Oeffinger, J. S. Ford, C. S. Moskowitz, L. R. Diller, M. M. Hudson, J. F. Chou, S. M. Smith, A. C. Mertens, T. O. Henderson, D. L. Friedman, et al. Breast Cancer Surveillance Practices Among Women Previously Treated With Chest Radiation for a Childhood Cancer JAMA, January 28, 2009; 301(4): 404 - 414. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||