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Breast Cancer Awareness Month, and Vitamin D by Jeffrey Dach MDPerhaps a better name for October Breast Cancer Awareness Month would be October Mammography Screening Awareness Month. We live in America, a country dedicated to capitalism and corporate profit, therefore marketing for cancer screening is to be expected. A prominent radiologist, Lenard Berlin, MD informs us marketing mammography sets unrealistic expectations in the consuming public. The reality is that mammography misses many cancers, which are seen only in retrospect years later. My previous article, raises a few more questions about mammography screening.
Upper left image: Iodoral
Mammography Screening for breast cancer is fiercely defended by radiologists, oncologists and breast surgeons, who cite the medical literature showing a 15-40 % reduction in mortality from breast cancer depending on the study cited. However, screening mammography also has critics such as Samuel Epstein, Nortin Hadler, Michael Baum and David Plotkin.
One of the more outspoken critics is Peter C Gøtzsche, director of the Nordic Cochrane Centre of Copenhagen, Denmark. Dr Gøtzsche’s recent article in the British Medical Journal highlights overdiagnosis and overtreatment, two failings of mammography screening. See the accompanying BMJ editorial.
Screening mammography suffers from the same drawbacks found in prostate and thyroid cancer screening, namely a high rate of overdiagnosis and overtreatment for a large reservoir of biologically insignificant cancers that do not cause clinical disease. Autopsy studies for all three cancer types reveal a large reservoir of latent cancers, that do not cause disease during the patient’s lifetime. For the thyroid, this is called papillary cancer. For the prostate, this is called well differentiated or low Gleason score cancer. For the breast this is called DCIS, or ductal carcinoma in situ.
After twenty years, and a million overtreated men, prostate cancer screening with PSA testing, was found to be a failed medical experiment.(link) Thyroid cancer screening with ultrasound guided needle biopsy of nodules has been seriously questioned.(link) Will breast cancer screening suffer the same fate as its two cousins, the prostate and thyroid glands? Only Time will tell. Check back in about ten years after we learn more about the biology of cancer, and more studies come in.
Marketing programs mistakenly assert that Mammography is a cancer preventive measure. It is not. Mammography is a detection method, and not a preventive measure. What measures should be regarded as preventive? As Dr Cristiane Northrup has said in her Huffington Post article, an excellent way to prevent breast cancer is Vitamin D supplementation. She cites Dr. Garland’s 2006 article finding individuals with higher Vitamin D levels (above 52 ng/ml) had 50% lower risk of breast cancer than those with lower vitamin D (serum <13 ng/ml).(3)
Another useful preventive measure is Iodine supplementation, the main pillar of any breast cancer prevention program.
Links to articles with related content:
Breast Cancer Prevention with Iodine Supplementation
Breast Cancer Prevention with Iodine Part Two
Jeffrey Dach MD
http://www.drdach.com/
http://www.truemedmd.com/
Links and References:
1) http://www.thorne.com/altmedrev/.fulltext/13/1/6.pdf
Cannell, J.J., Hollis, B.W. 2008. Use of vitamin D in clinical practice, Altern Med Rev, Mar;13(1):6-20.
2) http://www.ajcn.org/cgi/content/full/79/3/362
Holick, M.F. 2004. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis, Am J Clin Nutr, 79:362-71.
3) http://www.direct-ms.org/pdf/VitDNonAuto/Breast%20serumSBMB2747.pdf
Vitamin_D_prevention_breast_cancer_Pooled_analysis_Garland_2006
Garland, C.F., et al. 2007. Vitamin D and prevention of breast cancer: pooled analysis., J Steroid Biochem Mol BiolMar;103(3-5):708-11.
Background: Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose–response relationship in individuals has not been adequately studied.
Methods: A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose–response association between serum 25(OH)D and risk of breast cancer.
Results: The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend < 0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to
intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D3.
Conclusions: Intake of 2000 IU/day of Vitamin D3, and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.
http://www.huffingtonpost.com/christiane-northrup/protect-your-breasts-with_b_265642.html
Prevent Breast Cancer with Vitamin D By Dr. Christiane Northrup
A study conducted by Cedric Garland and other prominent vitamin D researchers determined that women with vitamin D levels above 52 ng/ml have half the risk of developing breast cancer as those with 13 ng/ml! [footnote 7] Garland (et al) estimates that 58,000 new cases of breast cancer in the United States could be prevented per year by raising vitamin D levels to 52 ng/ml. Imagine what the global impact could be!
http://cebp.aacrjournals.org/content/18/10/2655.abstract
Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study Lars Rejnmark1, Anna Tietze2, Peter Vestergaard1, Line Buhl3, Melsene Lehbrink2, Lene Heickendorff4 and Leif Mosekilde1+ Author Affiliations
Departments of 1Endocrinology and Metabolism C, 2Radiology, 3Pathology, and 4Clinical Biochemistry, Aarhus Sygehus, Aarhus University Hospital, Aarhus, Denmark
Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor–positive and estrogen receptor–negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2655–60)
http://carcin.oxfordjournals.org/cgi/content/full/29/1/93
Oxford University Press
Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer—results of a large case–control study Sascha Abbas, Jakob Linseisen, Tracy Slanger, Silke Kropp, Elke Jonny Mutschelknauss1, Dieter Flesch-Janys1 and Jenny Chang-Claude*
Various studies suggest that vitamin D may reduce breast cancer risk. Most studies assessed the effects of dietary intake only, although endogenous production is an important source of vitamin D. Therefore, the measurement of serum 25-hydroxyvitamin D [25(OH)D] better indicates overall vitamin D status. To assess the association of 25(OH)D serum concentrations with post-menopausal breast cancer risk, we used a population-based case–control study in Germany, which recruited incident breast cancer patients aged 50–74 between 2002 and 2005. Information on sociodemographic and breast cancer risk factors was collected by personal interview. For this analysis, we included 1394 cases and 1365 controls, matched on year of birth and time of blood collection. Conditional logistic regression was used to calculate odds ratios (ORs) for breast cancer adjusted for potential confounders. Serum 25(OH)D concentration was significantly inversely associated with post-menopausal breast cancer risk. Compared with the lowest category (<30 nM), OR [95% confidence intervals (CI)] for the higher categories of 25(OH)D (30–45, 45–60, 60–75 and 75 nM) were 0.57 (0.45–0.73), 0.49 (0.38–0.64), 0.43 (0.32–0.57) and 0.31 (0.24–0.42), respectively (Ptrend < 0.0001). Analysis using fractional polynomials indicated a non-linear association. The association was stronger in women never using menopausal hormone therapy (HT) compared with past and current users (Pinteraction < 0.0001). Our findings strongly suggest a protective effect for post-menopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D measurement, with a stronger inverse association in women with low serum 25(OH)D concentrations (<50 nM).
http://edrv.endojournals.org/cgi/content/full/29/6/726
Endocrine Reviews 29 (6): 726-776
Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice Roger Bouillon, Geert Carmeliet, Lieve Verlinden, Evelyne van Etten, Annemieke Verstuyf, Hilary F. Luderer, Liesbet Lieben, Chantal Mathieu and Marie Demay
The antineoplastic activity of 1,25-(OH)2D was shown both in vitro and in vivo in a wide variety of malignancies, such as leukemia (266, 267) and colon (268, 269), breast (270, 271, 272), and prostate cancer (273, 274). In a number of cell types, induction of programmed cell death contributes to the antineoplastic activity of 1,25-(OH)2D, but inhibition of angiogenesis and invasiveness may also contribute to its antitumor activity.
http://annonc.oxfordjournals.org/cgi/content/abstract/mdn550v1
Annals of Oncology 2009 20(2):374-378;
Vitamin D intake and breast cancer risk: a case–control study in Italy M. Rossi1,*, J. K. McLaughlin2,5, P. Lagiou3, C. Bosetti1, R. Talamini4, L. Lipworth2,5, A. Giacosa6, M. Montella7, S. Franceschi8, E. Negri1 and C. La Vecchia1,9
1 Department of Epidemiology
Conclusions: This study adds to the existing evidence that vitamin D intake in inversely associated with breast cancer risk.
http://carcin.oxfordjournals.org/cgi/content/full/29/1/93
Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer—results of a large case–control study
Sascha Abbas, Jakob Linseisen, Tracy Slanger, Silke Kropp, Elke Jonny Mutschelknauss1, Dieter Flesch-Janys1 and Jenny Chang-Claude* Division of Cancer Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
Our findings strongly suggest a protective effect for post-menopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D measurement, with a stronger inverse association in women with low serum 25(OH)D concentrations (<50 nM).
Mammography Screening
http://www.junkscience.com/consumer/jan00/mammo.pdf
Is screening for breast cancer with mammography justifiable?
Peter C Gøtzsche, Ole Olsen Lancet 2000; 355: 129–34
http://www.bmj.com/cgi/content/abstract/339/jul09_1/b2587
9 July 2009: BMJ 2009;339:b2587 . Overdiagnosis in publicly organised mammography screening programmes: systematic review of incidence trends Karsten Juhl Jørgensen, researcher, Peter C Gøtzsche, director . The Nordic Cochrane Centre Copenhagen, Denmark
http://www.bmj.com/cgi/content/full/339/jul09_1/b1425
9 July 2009, BMJ 2009;339:b1425 Editorials: Overdiagnosis and mammography screening, The question is no longer whether, but how often, it occurs
http://www.epicentro.iss.it/problemi/tumori/reslet.pdf
Cochrane review on screening for breast cancer with mammography
Ole Olsen, Peter C Gøtzsche In 2000, we reported that there is no reliable evidence that screening for breast cancer reduces mortality. As we discuss here, a Cochrane review has now confirmed and strengthened our previous findings. The review also shows that breast-cancer mortality is a misleading outcome measure. Finally, we use data supplemental to those in the Cochrane review to show that screening leads to
more aggressive treatment. Lancet 2001; 358: 1340-42
http://www.ncbi.nlm.nih.gov/pubmed/17054145
http://www.cochrane.dk/research/Screening%20for%20breast%20cancer%20with%20mammography%20(Cochrane%20review).pdf
Screening for breast cancer with mammography (Review) Gøtzsche PC, NielsenM. Cochrane Database of Systematic Reviews 2006, Issue 4. Art.
Authors’ conclusions: Screening likely reduces breast cancer mortality. Based on all trials, the reduction is 20%, but as the effect is lower in the highest quality
trials, a more reasonable estimate is a 15% relative risk reduction. Based on the risk level of women in these trials, the absolute risk reduction was 0.05%. Screening also leads to overdiagnosis and overtreatment, with an estimated 30% increase, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged. In addition, 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. It is thus not clear whether screening does more good than harm.Women invited to screening
should be fully informed of both benefits and harms.
Journal of the National Cancer Institute, Vol. 94, No. 3, 167-173, February 6, 2002
All-Cause Mortality in Randomized Trials of Cancer Screening
William C. Black, David A. Haggstrom, H. Gilbert Welch
Background: The most widely accepted end point in randomized cancer screening trials is disease-specific mortality. The validity of this end point, however, rests on the assumption that cause of death can be determined accurately. An alternative end point is all-cause mortality, which depends only on the accurate ascertainment of deaths and when they occur. We compared disease-specific and all-cause mortality in published randomized cancer-screening trials to indirectly assess the validity of the disease-specific mortality end point.
Methods: We examined all 12 published randomized trials of cancer screening for which both end points were available (seven of mammography, three of fecal occult blood detection, and two of chest x-ray screening for lung cancer). For each randomized trial, we subtracted disease-specific mortality observed in the screened group from that observed in the control group and all-cause mortality in the screened group from that in the control group. We then compared the differences in these two mortality measures.
Results: In five of the 12 trials, differences in the two mortality rates went in opposite directions, suggesting opposite effects of screening. In four of these five trials, disease-specific mortality was lower in the screened group than in the control group, whereas all-cause mortality was the same or higher. In two of the remaining seven trials, the mortality rate differences were in the same direction but their magnitudes were inconsistent; i.e., the difference in all-cause mortality exceeded the disease-specific mortality in the control group. Thus, results of seven of the 12 trials were inconsistent in their direction or magnitude.
Conclusion: Major inconsistencies were identified in disease-specific and all-cause mortality end points in randomized cancer screening trials. Because all-cause mortality is not affected by bias in classifying the cause of death, it should be examined when interpreting the results of randomized cancer-screening trials.
http://www.ncbi.nlm.nih.gov/pubmed/12881373
Mammographic screening: evidence from randomised controlled trials.
de Koning HJ. Department of Public Health, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
BACKGROUND: All randomised breast cancer screening trials have shown a reduction in breast cancer mortality in the ‘invited for mammography’ screening arm compared with the ‘control arm’ for women aged 50 years and older at randomisation (overall 25%). However, individually published point estimates differ and concern has been raised about methodological quality and outcome measures. Materials and Methods Review of the evidence on breast cancer mortality reduction and discussion of the causes of difference in point estimates in the five Swedish and Canadian trials. A summary of the prerequisites for methodological quality and its available evidence from the trials is given. Data to support breast cancer mortality as a correct outcome measure are presented.
RESULTS: There is no reason not to use breast cancer mortality as an outcome measure for trials intended to reduce breast cancer mortality, both from a clinical and a methodological point of view. Everything possible was performed in these trials in order to determine this outcome measure as accurately as possible. The fact that a few of the trials showed a relatively large breast cancer mortality reduction and others far lower reduction rates is irrelevant, if one does not consider the background situation in the region before the trial started, the design of the trial or quality of screening.
CONCLUSIONS: There seems no reason to change or halt the current nation-wide population-based screening programmes. Nor is there any justifiable reason for negative reports towards women or professionals.
http://www.ncbi.nlm.nih.gov/pubmed/16703451
Breast Cancer Res Treat. 2006 Oct;99(3):333-40. Epub 2006 May 9.
Assessing the impact of screening mammography: Breast cancer incidence and mortality rates in Connecticut (1943-2002).
Assessing the impact of screening mammography: Breast cancer incidence and mortality rates in Connecticut (1943-2002).Anderson WF, Jatoi I, Devesa SS.Biostatistics Branch, Principal Investigator, DHHS/NIH/NCI/ Division of Cancer Epidemiology and Genetics,
BACKGROUND: Randomized controlled studies demonstrate that early detection and intervention reduce breast cancer mortality by approximately 25%. Though the ultimate goal of screening is to reduce breast cancer deaths, the immediate goal is to detect and treat early-stage tumors before they pose a threat to life. MATERIALS AND METHODS: To assess the impact of early detection and intervention in the general population, we analyzed breast cancer incidence and mortality rates in the NCI’s Historical Connecticut Tumor Registry (1943-2002).
RESULTS: Though breast cancer rates increased for the entire study period, overall incidence rates rose faster than previously following the initiation of mammography screening in the early 1980s in the United States. Of note, stage-specific incidence rates increased 152% (53.2-133.9 per 100,000 woman-years) for early-stage tumors and fell 16% (56.1-47.2 per 100,000 woman-years) for late-stage breast cancers. Period- and cohort-age-specific incidence rates rose dramatically for early-stage tumors among women targeted for screening (ages 40-80 years), whereas rates for regional and distant stages declined modestly among women ages >50 years. Breast cancer mortality rates fell 31.6%.
CONCLUSIONS: Along with increases in incidence rates for early-stage tumors, rates for late-stage disease and breast cancer mortality declined following widespread screening mammography, consistent with effective early detection and improved treatment over time. However, the disparity between the dramatic rise in early-stage tumors compared to the more modest declines in late-stage disease and mortality suggests that many mammography-derived early-stage lesions may never progress to late-stage cancers and pose a threat to life.
———————-
http://www.ncbi.nlm.nih.gov/pubmed/15111759
Breast Cancer Res Treat. 2004 Jun;85(3):219-22.
The full potential of breast cancer screening use to reduce mortality has not yet been realized in the United States. Schootman M, Jeffe D, Reschke A, Aft R.
Department of Pediatrics, Division of Health Behavior Research, Washington University School of Medicine, Saint Louis,
OBJECTIVE: Breast cancer mortality has been declining in European countries and the United States since the early 1990s. Based on breast cancer screening programs in western European countries, the reduction in mortality results from a predictable pattern of increasing early-stage and subsequent declining incidence of late-stage cancers. The purpose of this study was to determine whether changes in the incidence of early-stage and late-stage breast cancers has occurred in the United States to suggest that a reduction in breast cancer mortality is the result of screening.
METHOD: The analyses are based on women 50-69 years of age using 1990-1998 Surveillance, Epidemiology, and End Results data. Five indicators that are precursors to reductions in mortality are described: in situ breast cancer, T1 tumors (< 2 cm), stage II-IV tumors, lymph node-positive cancers, and locally advanced breast cancers (LABC). RESULTS: The rate of in situ tumors increased from 37.8 to 67.0 per 100,000 population and that of T1 tumors increased from 143.5 to 163.5 per 100,000 population during 1990-1998. The rates of stage II-IV tumors, lymph node-positive cancers, and LABC remained unchanged at about 120 per 100,000, 76 per 100,000, and 17 per 100,000 population, respectively.
CONCLUSIONS: Although there has been an increase in early-stage breast cancers (in situ and T1 tumors), the prerequisite decline in late-stage cancers has not yet occurred in the United States–a pattern that was observed in European studies. Possible explanations include the lack of widespread mammography use during the 1980s and, therefore, insufficient elapsed time since mammography use has become more widespread.
http://www.ncbi.nlm.nih.gov/pubmed/8096941
Lancet. 1993 Apr 17;341(8851):973-8.
Breast cancer screening with mammography: overview of Swedish randomised trials.
Nyström L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Rydén S, Andersson I, Bjurstam N, Fagerberg G, Frisell J, et al. Department of Epidemiology and Public Health, Umeå University, Sweden.
Despite encouraging results from screening trials the efficacy of mammography in reducing mortality remains somewhat controversial. Five studies have been done in Sweden. This overview, based on 282,777 women followed for 5-13 years in randomised trials in Malmö, Kopparberg, Ostergötland, Stockholm, and Gothenburg, reveals a 24% (95% confidence interval 13-34%) significant reduction of breast cancer mortality among those invited to mammography screening compared with those not invited. To avoid the potential risk of differential misclassification causes of death were assessed by an independent end-point committee after a blinded review of all fatal breast cancer cases. The mortality reduction was similar, irrespective of the end-point used for evaluation (“breast cancer as underlying cause of death” or “breast cancer present at death”). There was a consistent risk reduction associated with screening in all studies, although the point estimate of the relative risk for all ages varied non-significantly between 0.68 and 0.84. The cumulative breast cancer mortality by time since randomisation was estimated at 1.3 per 1000 within 6 years in the invited group compared with 1.6 in the control group. The corresponding figures after 9 years are 2.6 and 3.3 and after 12 years 3.9 and 5.1. The largest reduction of breast cancer mortality (29%) was observed among women aged 50-69 at randomisation. Among women 40-49 there was a non-significant 13% reduction. In this younger age group cumulative breast cancer mortality was similar in the invited and control group during the first 8 years of follow-up. After 8 years there was a difference in favour of the invited women. There was no evidence of any detrimental effect of screening in terms of breast cancer mortality in any age group. Among women aged 70-74 years screening seems to have had only a marginal impact.
http://www.ncbi.nlm.nih.gov/pubmed/17626708
J Med Screen. 2007;14(2):87-93.
Service screening with mammography in Northern Sweden: effects on breast cancer mortality – an update. Jonsson H, Bordás P, Wallin H, Nyström L, Lenner P.
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
OBJECTIVES: To study the effectiveness of service screening with mammography in Northern Sweden. SETTING: Two counties which invited women aged 40-74 years to service screening with mammography were compared with two counties where service screening started 5-7 years later. There were 109,000 and 77,000 women in the study and control counties, respectively. METHODS: Cohorts in the study group were defined to include only breast cancer cases diagnosed after their first invitation to screening. Two outcome measures for breast cancer mortality were used; excess mortality and underlying cause of death (UCD). Detection mode was used to estimate the efficacy of screening for those women who actually attended screening. The cohorts were followed for 11 years. RESULTS: The relative rate (RR) of breast cancer death as excess mortality and UCD for women aged 40-74 years invited to screening, compared with women not yet invited, was 0.70 (95% confidence interval [CI] 0.56-0.87) and 0.74 (95% CI 0.62-0.88), respectively. The largest effect was seen in women aged 40-49 years (RR = 0.64 and RR = 0.62 for excess mortality and UCD, respectively). RR in age 40-74 years for women actually screened was 0.65 (95% CI 0.51-0.84) and 0.70 (95% CI 0.57-0.86) for excess mortality and UCD, respectively. The number of women needed to screen to save one life was 912 after 11 years of follow-up. CONCLUSIONS: This study confirms previous findings in the earlier follow-up and indicates a long-term reduction of breast cancer mortality by 26-30%. The efficacy among those who actually attended screening was about 5% larger.
http://www3.interscience.wiley.com/cgi-bin/fulltext/97015455/HTMLSTART
Volume 95, Issue 3, Pages 458-469
Published Online: 22 Jul 2002 Copyright © 2002 American Cancer Society
The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties A collaborative evaluation Stephen W. Duffy, M.Sc. 1 *, Laszlo Tabár, M.D. 2
http://www.biomedcentral.com/1472-6947/9/18
http://takingnote.tcf.org/2009/04/mammography-screening-a-double-edged-sword-1.html
Jeffrey Dach MD
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