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Program Written Summary
Audio-Digest Internal Medicine
Volume 60, Issue 04
January 28, 2013

Cancer Screening – Richard C. Wender, MD
Risks and Benefits of Folic Acid Fortification – Caroline M. Apovian, MD

From The 2012 Update In Family Medicine, Presented By University Of Michigan Medical School And Michigan Academy Of Family Physicians
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Internal Medicine Program Info  Accreditation InfoCultural & Linguistic Competency Resources

<p class="Title2">Cancer Screening/Folic Acid Fortification</p> <p class="EOsh">Educational Objectives</p> <p class="EOs">The goals of this program are to improve cancer screening and to review the benefits and risks of folic acid (FA) fortification. After hearing and assimilating this program, the clinician will be better able to:</p> <p class="EOsl">1. Implement screening protocols for cervical cancer.</p> <p class="EOsl">2. Offer screening for prostate cancer using shared decision making.</p> <p class="EOsl">3. Identify patients eligible for screening for lung cancer.</p> <p class="EOsl">4. Summarize the role of folate in one-carbon, nucleic acid, and amino acid metabolism.</p> <p class="EOsl">5. Advise patients on the risks and benefits of folic acid fortification.</p> <p class="EOsh">Faculty Disclosure</p> <p class="EOs"><span>In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.</span></p> <p class="Lectureh">Cancer Screening</p> <p class="Lecture"><span class="char-style-override-1">Richard C. Wender, MD, </span><span>Alumni Professor and Chair, Department of Family and Community Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA</span></p> <p class="Boldf"><span class="char-style-override-2">Cervical cancer: </span>accounts for <span class="char-style-override-3">≈</span>4000 deaths of women each year in United States; second leading cause of cancer-related deaths in women worldwide</p> <p class="First">Cervical cancer and human papillomavirus (HPV): association between cervical cancer and HPV extremely high; HPV-16 most carcinogenic type and HPV-18 second most carcinogenic; 90% of cases of HPV infection transient (virus becomes undetectable within 2 yr); <span class="char-style-override-4">associated risks</span> — persistent infection with HPV-16 or -18 associated with substantial risk for grade III cervical intraepithelial neoplasia (CIN3) or worse conditions; untreated CIN3 associated with substantial risk of developing invasive cancer over 30-yr period</p> <p class="First"><span>New guidelines for screening from American Cancer Society (ACS) and United States Preventive Services Task Force (USPSTF): all women should begin cervical cancer screening at age 21 yr (no screening before then); women aged 21 to 29 yr should have Papanicolaou (Pap) test every 3 yr (HPV test can be used to triage abnormal Pap test); women aged 30 to 65 yr should have Pap test and HPV test every 5 yr; women with normal Pap tests can stop screening after age 65 yr </span></p> <p class="Boldf"><span class="char-style-override-2">Prostate cancer (PC): </span>in May 2012, USPSTF gave screening for PC grade D recommendation (<span class="char-style-override-4">ie</span>, harms outweigh benefits); relatively few of men diagnosed with PC each year at risk of dying from disease, but number of deaths substantial</p> <p class="First">Data from randomized trials: <span class="char-style-override-4">update of European Randomized Study for Prostate Cancer (ERSPC)</span> — men aged 50 to 75 yr randomly assigned to being offered prostate-specific antigen (PSA) test or usual care; Schröder et al (2012) reported substantial increase in benefits at 11 yr of follow-up, compared to results at 9 yr; data suggest peak benefit of screening not seen until 15 to 20 yr of follow-up; <span class="char-style-override-4">Göteborg trial</span> — screening reduced mortality from PC by <span class="char-style-override-3">≈</span>50% over 14 yr; risk for overdiagnosis <span class="char-style-override-3">≈</span>50%; benefit of screening for PC compares favorably to other cancer screening programs; <span class="char-style-override-4">reduction in mortality</span> — Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed no reduction; ERSPC showed modest reduction; Göteburg trial showed significant reduction; key reason for different results length of follow-up (<span class="char-style-override-4">eg</span>, PLCO published findings at 7 yr)</p> <p class="First">Recommendation from USPSTF: D recommendation does not mean clinicians and patients cannot discuss screening for PC; clinicians and patients should discuss possible benefits and harms, as well as patient preferences, before deciding to start or continue screening</p> <p class="First"><span>Making sense of disparate results: shared decision making recommended by all guideline organizations; offer screening for PC to men age </span><span class="char-style-override-3">≤</span><span>70 yr, healthy, and motivated to prevent death from cancer; perform biopsy on all men with PSA >4 ng/mL (consider biopsy if PSA </span><span class="char-style-override-3">≥</span><span>2.5 ng/mL); convincing evidence that screening for PSA best way to avoid death from PC</span></p> <p class="Boldf"><span class="char-style-override-2">Lung cancer (LC): </span>each year, <span class="char-style-override-3">≈</span>226,000 patients diagnosed and <span class="char-style-override-3">≈</span>160,000 deaths occur</p> <p class="First"><span>National Lung Screening Trial (NLST): </span><span class="char-style-override-4">criteria for eligibility</span><span> — age 55 to 74 yr; 30-pack-yr history of smoking; current or former smoker (must have quit within 15 yr); </span><span class="char-style-override-4">design — </span><span>53,000 participants randomly assigned to low-dose computed tomography (LDCT) or chest x-ray; LDCT performed at time zero, 1 yr, and 2 yr from enrollment </span></p> <p class="First">Benefit of screening for LC: results of NLST show 20% fewer deaths from LC in LDCT group; <span class="char-style-override-4">adenocarcinomas</span> — seen in slightly higher percentage of cancers found on LDCT, compared to those found on chest x-ray; possibly more curable form of LC; identification main benefit of LDCT</p> <p class="First">Fleischner Society guidelines for evaluation of lung nodules: nodule <span class="char-style-override-3">≤</span>4 mm in low-risk patient requires no follow-up; for nodule <span class="char-style-override-3">≤</span>4 mm in high-risk patient, initial follow-up at 12 mo recommended (for nodule 4-6 mm, initial follow-up at 6 mo recommended; for larger nodules, positron emission tomography [PET] scan may be appropriate)</p> <p class="First"><span>Additional benefits of screening with LDCT: results of NLST showed 7% reduction in all-cause mortality in LDCT group; most reduction due to decrease in deaths from LC; other reduction in deaths due to heart disease (abnormal results of LDCT encouraged cessation of smoking; speaker recommends attaching smoking cessation program to LDCT program in hospital)</span></p> <p class="First">Risks of screening for LC: <span class="char-style-override-4">risk for major complications</span> — patients not diagnosed with LC have only 0.06% risk; patients diagnosed with LC have 11.2% risk; <span class="char-style-override-4">premature</span> <span class="char-style-override-4">deaths in NLST associated with diagnostic work-up — </span>10 deaths in chest x-ray group in patients with cancer; 6 of 10 deaths in LDCT group in patients without cancer; deaths most likely associated with wedge resection</p> <p class="First">Emerging guidelines: <span class="char-style-override-4">ACS interim guidance statement</span> — adults aged 55 to 74 yr who meet eligibility criteria of NLST can consider screening; individuals interested in screening should weigh benefits, limitations, and risks, and make shared decision with physician; <span class="char-style-override-4">National Comprehensive Cancer Network (NCCN) guidelines</span> — patients who meet NLST criteria and individuals aged >50 yr with >20-pack-yr history of smoking and one additional risk factor other than exposure to second-hand smoke should be screened annually with LDCT for 3 yr; for all others (including individuals at moderate risk), screening not recommended; additional risk factors include exposure to radon or occupational hazards, personal history of cancer, family history of lung cancer, and history of chronic obstructive pulmonary disease or pulmonary fibrosis</p> <p class="First">Online tools for estimating risk for LC: option for assessing patients who do not meet NCCN criteria for screening; if calculated risk comparable or higher than patients meeting criteria, acceptable to offer screening</p> <p class="First">Unanswered questions: best recommendation for high-risk individuals who do not meet screening criteria; whether yield and safety seen in NLST can be reproduced outside of dedicated centers; whether screening for LC cost effective</p> <p class="First"><span>Proactive discussion of screening for LC with eligible patients: </span><span class="char-style-override-4">reasonable if</span><span> — colleagues (in radiology, pulmonary, and CT departments) prepared to follow NLST diagnostic and therapeutic approach; other high-priority preventive goals addressed</span></p> <p class="Bold"><span class="char-style-override-2">Colon cancer:</span> offer annual stool blood testing (preferably fecal immunochemical test [FIT]) in addition to colonoscopy; reach out to patients not regularly coming to clinic; if using FIT, track whether test returned and remind patients to do so; help patient schedule colonoscopy (make call from office during visit); rectal examination unreliable for screening (not recommended)</p> <p class="Lectureh">Risks and Benefits of Folic Acid Fortification</p> <p class="Lecture"><span class="char-style-override-1">Caroline M. Apovian, MD,</span> Professor of Medicine and Pediatrics, Boston University School of Medicine; Director, Center for Nutrition and Weight Management, and Director, Clinical Research of, Obesity Research Center of Boston Medical Center, Boston, MA</p> <p class="Bold"><span class="char-style-override-2">Water-soluble B-complex vitamin:</span> <span class="char-style-override-4">folate</span> — exists in metabolically active forms in foods and in body; <span class="char-style-override-4">folic acid</span> <span class="char-style-override-4">(FA)</span> — more stable form; not found in foods or human body; commonly used in vitamin supplements and fortified foods</p> <p class="Bold"><span class="char-style-override-2">Function of folate and FA:</span><span> </span><span class="char-style-override-4">one-carbon metabolism</span><span> — accepts and donates one-carbon units in variety of reactions critical to metabolism of nucleic and amino acids; </span><span class="char-style-override-4">coenzymes of folate in nucleic acid metabolism</span><span> — necessary for synthesis of DNA from precursors; required for synthesis of methionine (required for synthesis of </span><span class="char-style-override-4">S</span><span>-adenosylmethionine [SAM; one-carbon donor used in methylation of DNA and RNA]); </span><span class="char-style-override-4">amino acid metabolism</span><span> — synthesis of methionine from homocysteine requires folate and vitamin B</span><span class="char-style-override-5">12</span></p> <p class="Bold"><span class="char-style-override-2">Function of Vitamins B</span><span class="char-style-override-6">12</span><span class="char-style-override-2"> and B</span><span class="char-style-override-6">6</span><span class="char-style-override-2">:</span> <span class="char-style-override-4">pathways to metabolize homocysteine</span> — synthesis of methionine from homocysteine; conversion of homocysteine to cysteine (2 vitamin B<span class="char-style-override-5">6</span>-dependent enzymes required); amount of homocysteine in blood regulated by vitamins B<span class="char-style-override-5">6</span>, B<span class="char-style-override-5">9</span> (folate), and B<span class="char-style-override-5">12</span></p> <p class="Bold"><span class="char-style-override-2">Homocysteine and cardiovascular disease (CVD):</span> elevated levels of homocysteine increase risk for CVD (possibly due to effects of homocysteine on clotting of blood, dilation of vessels, and thickening of arterial walls from corrosive action); decrease in plasma homocysteine level of 1 <span class="char-style-override-3">μ</span>mol/L results in 10% reduction in risk; not yet clear whether lowering homocysteine levels reduces risk for CVD; American Heart Association recommends screening for elevated levels of homocysteine only for individuals at high risk</p> <p class="Bold"><span class="char-style-override-2">Folate essential for synthesis of nucleotides:</span><span> critical predecessor for synthesis and repair of DNA by 2 pathways; efforts to decrease incidence of cancer and improve cardiovascular risk factors may not be apparent because folic acid (rather than folate) used in fortification of food; </span><span class="char-style-override-4">5,10-methylenetetrahydrofolate essential cofactor for DNA synthesis</span><span class="char-style-override-2"> — </span><span>required for conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP); if absent, normal cells can progress to colonic adenomatous dysplasia, which leads to cancer </span></p> <p class="Bold"><span class="char-style-override-2">Deficiency of folate: </span><span class="char-style-override-4">causes</span> — dietary insufficiency; alcoholism; pregnancy; medications (<span class="char-style-override-4">eg</span>, sulfonamides, valproic acid, methotrexate); <span class="char-style-override-4">symptoms and signs</span> — no obvious symptoms in early stages, but increase in blood levels of homocysteine may occur; <span class="char-style-override-4">pathology</span> — when folate supply to dividing cells of bone marrow becomes inadequate, division of blood cells becomes abnormal, resulting in megaloblastic anemia (MA) and hypersegmentation of neutrophils; progression leads to decreased capacity of blood to carry O<span class="char-style-override-5">2</span>, resulting in fatigue, weakness, and shortness of breath; MA resulting from folate deficiency identical to MA resulting from deficiency of vitamin B<span class="char-style-override-5">12</span> (repletion of folate may temporarily mask deficiency of vitamin B<span class="char-style-override-5">12</span> [<span class="char-style-override-4">eg</span>, restoration of neurologic deficits])</p> <p class="Bold"><span class="char-style-override-2">Dietary recommendations:</span><span> </span><span class="char-style-override-4">dietary folate equivalents (DFE)</span><span> — reflect higher bioavailability of synthetic FA found in supplements (in contrast to folate occurring naturally in foods); 1 </span><span class="char-style-override-3">μ</span><span>g folate from food equals 1 </span><span class="char-style-override-3">μ</span><span>g DFE; 1 </span><span class="char-style-override-3">μ</span><span>g FA in fortified food provides 1.7 </span><span class="char-style-override-3">μ</span><span>g DFE; 1 </span><span class="char-style-override-3">μ</span><span>g FA taken on empty stomach provides 2 </span><span class="char-style-override-3">μ</span><span>g DFE; </span><span class="char-style-override-4">recommended dietary allowance (RDA)</span><span> — 400 </span><span class="char-style-override-3">μ</span><span>g DFE/day for most adolescents and adults; pregnant and breastfeeding women require more DFE; </span><span class="char-style-override-4">sources of folate</span><span> — fortified breakfast cereal (200-400 </span><span class="char-style-override-3">μ</span><span>g DFE); green vegetables (</span><span class="char-style-override-4">eg</span><span>, spinach, asparagus); beans (</span><span class="char-style-override-4">eg</span><span>, lentils); fortified grain products (</span><span class="char-style-override-4">eg</span><span>, bread, pasta, rice)</span></p> <p class="Bold"><span class="char-style-override-2">Genetic variation in requirements for folate: </span>variation in gene for methylenetetrahydrofolate reductase (MTHFR) known as C677T <span class="char-style-override-4">MTHFR</span> polymorphism results in less stable enzyme; 50% of individuals may have inherited one copy of abnormal <span class="char-style-override-4">MTHFR</span>, while 5% to 25% may have inherited 2 copies (enzyme less stable); MTHFR required to form methionine from homocysteine; <span class="char-style-override-4">individuals homozygous for C677T MTHFR</span> — when intake of folate low, blood levels of homocysteine higher; improved folate nutritional status stabilizes MTHFR; unknown whether requirement for folate higher than RDA in homozygotes (may have ramifications for development of cancer); studies show increasing serum folate to adequate levels results in reduction in risk for colorectal cancer (CRC)</p> <p class="Bold"><span class="char-style-override-2">FA fortification in food:</span> in January 1998, Food and Drug Administration (FDA) required addition of 1.4 mg FA per kilogram of grain to products enriched with other B vitamins and iron, to prevent neural tube defects (NTDs)</p> <p class="Bold"><span class="char-style-override-2">Benefits of FA fortification: </span><span class="char-style-override-4">prevention</span><span> — prevalence of NTDs in United States reduced from 10.8% to 6.9% (United States Public Health Service recommends 400 </span><span class="char-style-override-3">μ</span><span>g FA daily during periconceptional period); </span><span class="char-style-override-4">protective effect</span><span> — 40% to 60% reduction in risks for CRC and for precursor lesion and adenomatous polyp in individuals who consume greatest quantities of dietary folate and have highest levels of folate in blood; effect more pronounced in heavy consumers of alcohol (inhibits metabolism of folate)</span></p> <p class="Boldf"><span class="char-style-override-2">Risks of FA fortification:</span> <span class="char-style-override-4">dual effect of folate on risk for cancer</span> — inadequate intake of folate increases risk for certain cancers (<span class="char-style-override-4">eg</span>, colorectal, breast); for individuals with cancerous or precancerous cells in colon, overabundant intake of folate may increase risk for cancer</p> <p class="First">Risk of excessive intake: <span class="char-style-override-4">common scenario for 60-yr-old man</span> — daily total intake of folate equals 2623 <span class="char-style-override-3">μ</span>g DFE; studies show total intake of folate higher for men than women between 2003 and 2006; <span class="char-style-override-3">≈</span>5% of people (mainly older individuals) exceed tolerable upper level of intake</p> <p class="First"><span>Intake of folate and risk for cancer: </span><span class="char-style-override-4">Mason et al (2007)</span><span> — incidence of CRC in United States between 1996 and 2002 declined; after FA fortification introduced, trend shifts upward and to right by </span><span class="char-style-override-3">≈</span><span>5 cases per 100,000 individuals (may represent population with unknowingly excessive intake of folate); </span><span class="char-style-override-4">Sanjoaquin et al (2005) — </span><span>meta-analysis of 7 prospective cohort and 9 case-control studies found low association between dietary folate and risk for CRC in individuals who take extremely high amounts of folate; </span><span class="char-style-override-4">other studies</span><span> — show supplementation with folate may enhance risk for cancer in some settings (</span><span class="char-style-override-4">eg</span><span>, risk for breast cancer slightly increased in women taking>400 </span><span class="char-style-override-3">μ</span><span>g FA in daily supplements); </span><span class="char-style-override-4">randomized controlled trials (RCTs) — </span><span>slight increase shown in overall risk for cancer in </span><span class="char-style-override-3">≈</span><span>38,000 patients; 6 RCTs found slight increase in risk for PC (only type of cancer in which increase in risk shown to be associated with supplements of FA)</span></p> <p class="First">Comments: association of supplementation with FA and risk for cancer controversial (because many studies do not show significant risk); use of FA to lower homocysteine levels does not have significant effect on CVD in <span class="char-style-override-3">≤</span>5 yr</p> <p class="First"><span>Concerns: many common cancers (</span><span class="char-style-override-4">eg</span><span>, CRC) evolve through dysplastic phase that typically does not progress to cancer unless “enticed” by additional factors (</span><span class="char-style-override-4">eg</span><span>, colonic polyp, prostatic lesions); sizable segment of United States population consumes far greater quantities of folate on habitual basis than recommended (likelihood of excess consumption increases with age); fortification of foodstuffs and supplements use pharmaceutical form of vitamin (</span><span class="char-style-override-4">ie</span><span>, FA) not found in nature; FA may promote some cancer cells even more rapidly than natural folate</span></p> <p class="Bold"><span class="char-style-override-2">Dilemma of FA fortification: </span><span>level of intake of micronutrient safe and healthful for one person may be potentially harmful for another; </span><span class="char-style-override-4">unlimited quantities of FA available in United States</span><span> — through fortification of grain products and vitamin supplements (result of 1976 Vitamin-Mineral Amendment, which prohibits FDA from limiting potency of vitamins and minerals in food supplements); small increase in incidence of CRC seen; hence, delay in other countries to embrace FA fortification, which has led to more NTDs; </span><span class="char-style-override-4">solution in United Kingdom</span><span> — fortification of cereal grain mandatory but other sources of FA (</span><span class="char-style-override-4">eg</span><span>, supplements) curtailed; </span><span class="char-style-override-4">recent study — </span><span>showed mandatory fortification of grains comprises only </span><span class="char-style-override-3">≈</span><span>20% of total consumption among high consumers of FA (>1000 </span><span class="char-style-override-3">μ</span><span>g/day); high blood levels of folate from supplements </span></p> <p class="Bold"><span class="char-style-override-2">Conclusions:</span> people vary widely in need for folate; folate from food more important than that from supplements; adults (particularly aged >40 yr) advised to limit intake of FA to <1000 <span class="char-style-override-3">μ</span>g/day (from Institute of Medicine)</p> <p class="EOsh">Acknowledgements</p> <p class="EOs"><span>Dr. Wender was recorded at the </span><span class="char-style-override-4">35th Annual Eastern Shore Medical Symposium</span><span>, held on June 18-22, 2012, in Rehoboth Beach, DE, jointly sponsored by Jefferson Medical College and University of Delaware. Dr. Apovian spoke at </span><span class="char-style-override-4">Controversies in Internal Medicine 2012</span><span>, held May 7-11, 2012, in Hilton Head Island, SC, and presented by Boston University School of Medicine. For information about upcoming CME events presented by Jefferson Medical College, please visit their website at For information about </span><span class="char-style-override-4">Controversies in Internal Medicine 2013</span><span>, scheduled for May 6-10, 2013, presented by Boston University School of Medicine, their website is The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.</span></p> <p class="EOsh">Suggested Reading</p> <p class="EOs"><span class="char-style-override-2">Bailey RL et al:</span><span> Total folate and folic acid intake from foodsand dietary supplements in the United States: 2003-2006.</span><span class="char-style-override-4">Am J Clin Nutr</span><span> 2010 Jan;91(1):231-7; </span><span class="char-style-override-2">Boone JD et al:</span><span> New insights into cervical cancer screening. </span><span class="char-style-override-4">J Gynecol Oncol</span><span> 2012 Oct;23(4):282-7; </span><span class="char-style-override-2">Clapin HF et al:</span><span> Dietary and supplemental folate and the risk of left- and right-sided colorectal cancer. </span><span class="char-style-override-4">Nutr Cancer</span><span> 2012 Oct;64(7):937-45; </span><span class="char-style-override-2">Clarke R et al:</span><span> Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010 Oct 11;170(18):1622-31; </span><span class="char-style-override-2">Croswell J, Costello A:</span><span> Screening for cervical cancer. </span><span class="char-style-override-4">Am Fam Physician</span><span> 2012 Sep 15;86(6):563-4; </span><span class="char-style-override-2">Hudson SV et al:</span><span> Physician recommendation and patient adherence for colorectal cancer screening. </span><span class="char-style-override-4">J Am Board Fam Med</span><span> 2012 Nov;25(6):782-91; </span><span class="char-style-override-2">Klabunde CN et al:</span><span> Lung cancer screening practices of primary care physicians: results from a national survey. </span><span class="char-style-override-4">Ann Fam Med</span><span> 2012 Mar-Apr;10(2):102-10; </span><span class="char-style-override-2">Leader A et al:</span><span> Measuring informed decision making about prostate cancer screening in primary care. </span><span class="char-style-override-4">Med Decis Making</span><span> 2012 Mar-Apr;32(2):327-36; </span><span class="char-style-override-2">Liu AY et al:</span><span> Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk. </span><span class="char-style-override-4">Mol Nutr Food Res</span><span> 2012 Sep 7 doi:10.1002/mnfr.201200180 [Epub ahead of print]; </span><span class="char-style-override-2">Mason JB et al:</span><span> A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. </span><span class="char-style-override-4">Cancer Epidemiol Biomarkers Prev</span><span> 2007 Jul;16(7):1325-9; </span><span class="char-style-override-2">Miser WF:</span><span> Cancer screening in the primary care setting: the role of the primary care physician in screening for breast, cervical, colorectal, lung, ovarian, and prostate cancers. </span><span class="char-style-override-4">Prim Care</span><span> 2007 Mar;34(1):137-67; </span><span class="char-style-override-2">Moyer VA:</span><span> Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. </span><span class="char-style-override-4">Ann Intern Med</span><span> 2012 Jul 17;157(2):120-34; </span><span class="char-style-override-2">Pollack CE et al:</span><span> Primary care providers' perspectives on discontinuing prostate cancer screening. </span><span class="char-style-override-4">Cancer</span><span> 2012 Nov 15;118(22):5518-24; </span><span class="char-style-override-2">Reddy C et al:</span><span> Lung cancer screening: a review of available data and current guidelines. </span><span class="char-style-override-4">Hosp Pract (Minneap)</span><span> 2011 Oct;39(4):107-12; </span><span class="char-style-override-2">Sanjoaquin MA et al:</span><span> Folate intake and colorectal cancer risk: a meta-analytical approach. </span><span class="char-style-override-4">Int J Cancer</span><span> 2005 Feb 20;113(5):825-8; </span><span class="char-style-override-2">Saslow D et al:</span><span> American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. </span><span class="char-style-override-4">CA Cancer J Clin</span><span> 2012 May-Jun;62(3):147-72; </span><span class="char-style-override-2">Schröder FH et al:</span><span> Prostate-cancer mortality at 11 years of follow-up. </span><span class="char-style-override-4">N Engl J Med</span><span> 2012 Mar 15;366(11):981-90; </span><span class="char-style-override-2">Ulrich CM:</span><span> Folate and cancer prevention: a closer look at a complex picture. </span><span class="char-style-override-4">Am J Clin Nutr</span><span> 2007 Aug;86(2):271-3; </span><span class="char-style-override-2">Wender RC:</span><span> Colorectal cancer screening: don't just do it, do it right. </span><span class="char-style-override-4">Am Fam Physician</span><span> 2006 May 15;73(10):1707-8; </span><span class="char-style-override-2">Wien TN et al:</span><span> Cancer risk with folic acid supplements: a systematic review and meta-analysis. </span><span class="char-style-override-4">BMJ Open</span><span> 2012 Jan 12;2(1):e000653.Print 2012; </span><span class="char-style-override-2">Williams EA:</span><span> Folate, colorectal cancer and the involvement of DNA methylation. </span><span class="char-style-override-4">Proc Nutr Soc</span><span> 2012 Nov;71(4):592-7; </span><span class="char-style-override-2">Yang HT et al:</span><span> Efficacy of folic acid supplementation in cardiovascular disease prevention: An updated meta-analysis of randomized controlled trials. </span><span class="char-style-override-4">Eur J Intern Med</span><span> 2012 Dec;23(8):745-54.</span></p>
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