}vPg!؟I'F걺뗆.~z^MifK^c[dQo=(\⿛g˒٭,oI_^307lz֧hvcfhosk勶0a+Tn4ca&m_nqF*E9 ɒ>A-mZYz%{x4*om80G|`9:4[iT֧Ջ7oZQuۭj}ӱsb+,Knf}n=͕>}q}X!tS59DaU*Xo.{pC;8JT1(20Z 48Z2tTu^߮:yݵs@y=+O ?+=b m#5?'3& ʫyWf9 q+NN&蛖|Z&@QXH૽,V)``=9VST^@>Yz)dX88'I6][T溎+<_@tgXicdio97'K;oN.i1z!"ɋZK5 )[DŽIØeIU<>Z+Wt'[ׂV?Y7ф8(k&`F|TsX&,e p83f8XX Zk r~-ŃaDN+:jp(%%4omv$0LYihB='puC iw8Y޶˪Va|fVBpkF'୉o-csl_1j/ˊl1bּ^h2 ʼtKKܗpV11L .FZY+2P7`مxfeB0bSKJd ThbBYFhh6q`mCNVfu[%IM)OSXx /1ę:+qhbv%uxZ7;v|`ɼ%,H ' NH4rIx8)ˮ(i&KGB6$#K&ӆGN &R^*}Vz jr7Cb|{ZnHq(8|T0 lI`@Xk-NH@R&Vm5s L }F'2Kԙz :L9OAaC&96i!XZkۆvۣk{k҄mVC<^gnX!$ƑD5tMΣE9Ks9hFqk:Qai!ϑv"d(}JJ)Sb}ȃCJp=^MG6l5YAQ C@Iltfj8Ph57dF:adᐈGh ki` |AWn>A .P~R5뤼b!J4.X Wk@%DΔO09=pVß;lЙf)yM 04M*Q]KT#E~ێQcq^3$s.U; ۉ%\h~M"HwrNG49@kdA<@)^ Sh3 7T8FXll+=xvl>7;G]@02xH:,/aK[Vbׂ@-U@o-@e1tT=OjzL)da"m IA~f4}`hV;HZ.s>VmӶѺoPgCv}hK+;yF>긒=5x#}7##59Zd4#9y0 VULp| U8;s*\106`,J5$e)[ Z\_,@`#A0#wLZpс&xh QŁr|()1*AqvH;.aQK4EI7{WA깮+Xֺs%pt- GEF>锖)SLԏ`,6} W n4s/:,IM!oTC-r9Rӻ}8t-{42JΙ!=vx]XkE^3k&ܸIH-<R;`rEV0glf~ 2 p/+ O$% ‚K5\oU=EQӌ8dNl b>BVMW|/ráaDIչGG"ehڢHoEqJhNL)\%-!77V Ul%+c#㍖uJ+ (A읖3bh\7,>:݇GmrZ*2(3*"h/yAf0sx[X!cd Kkp6(@c2(RP!q8r `*VcQ ; hR+l-Ưy6&SgE0CN4eѸSЕ$8|H ii$[a3^Ro$ w^tr^Q@gb ^{iH\F!tREz362+俗%B/ oMg4w,07ǩ֢l۪\rmm$֐m!;TJȩ$ 0 砳3/톯d0B@eR64ش#$OH0خ}a\U$!(.߲sjޮF] <49p_"npseXnńjsQ -K|,SCE\GEFO-@ Q0DQgPq6(MS̖LqP{|kSaUN:k]$N,:#Nك~V<>Z䗒MЄ;M3:L%ï"[Aљ/0ɀ:xGdCIU Sh |a8:]i+ nDMmd6sBi*L'I#lybb?^OEثfk=[LJ0<"]8کM(fŅ=^%ftA Q "4$gN"g?Jh]kM/jFv7x=G8,W@2m$le\q*): h\j53]ɺ̀|0#L+hG]E :ًr(t~!Hwf`\.Q}Ν#C<f?T, !eS;m1 mCP7p<)3q&U`mZ  S] 6ѐJ;)h"z*=E; ;E(Y. `5n="ހSsӋbA2H>OZA JO O+ gcu)XvcAPlpM|9) uݾe߁>xO-z>y6k%In:UrIYQA|]+oCb҉KHRZ[Sw&n"/x7y I0a5ٰ=&(Kt!F6˛}\m9th_&:R5 -iYL@7,;u៶vV8^?b"w,;~eA*$-ӽd7]n@ ٭ܫIXTluD{ ~IKM^)#S5XL`'EPMX,^ (Y6;=4&-?j!G@t5KZr%En4XBQ]V+V-VU[9pMo `*(`˘  xl&UN`2߯˒4Ӵ_۠ޭoC;HM^ ]%03ZCEoz2T=m eJw{oeV2 \>q8,IE..//s$hhM͕p"Z 8J'AuLCl6FHiiRJ4&X)hq&+@S /;)`Ӛk]CFPS&jrZx'4=,Vg';ɣ\>EGkV2&)' 5flZ0S׌jաYl^o|ptuwzf~_:m^Uh]7]_|>8+L.ovV_'zmJ'A_/1Ox־]Zk]_Q^ Jh#*Wn:6˛'K}pR(]|u_Zm^o{﮾|X/]]y糕4OՃ?wJkK;qT3f3h|=T\r>/{=tuRKumel^[yw؛qQ~޸U9@X;כVݗzCoΝ;th1o6>\>lXƧiǶK8ysgKG-KkikWwo]U]چ\S{noاӓ7;ߛ ~u_wKoz?5njO<wο]{kucby5X; uٷfy߻:Nl7oo˗UGouWқ]iL?[v5Vݭ}[/Yi\_S/}ؗ73\OJQ_?jwJCgޚ5\ ם~o[ƾ4owoupYW۝wէiݭH`[aPRDq"픮zm#|uؽ8<\ i{P+fşj89pHT ]A/ }jiRkRr-2t.pT,nN 50y;A!2c[Ub=NpXKƇ HnZ>jxx1\eL)ɑ4*Dm:aMTU*ojfi߀Veba#;b &-7 F&oqN4:DBUQx ܪQGhhb *~Lƌy*9,X;0Zq/oHreiR^:RO ű P7@P+p! 'Z&[ȉf13ODB`&%^,Ψd1IT4IDm"]GD{IT&(Je#~OL1ק [/r˿%*\ӈԲ,5@Z2 #x^Exm>AtvN@9hc na&~=)3/~ 9^U% 8rXV_~!kƱӭJ̲2ta1OHAo/߅.gDtKɒSA*"g xu4ul!Jk6A")6DLF!-v4l3<ŮEOOvornq(h.N2 @Ÿ3B;Mln5@=T'&h9O , +ZH}BKӒ6uQ,ol 楍.b t=?Ov;=% vvy8x,)&~}Ho&l,$O*Ђ8q:-ՁBg~N@0xo6,8jRӂ:^]eTpMGq|Rۄr^mkC3Z 6N>=UU_  i o%VY]IK1.XŠpה$$GbkK]DWt'.pfsWNtbR0dwJ` yb|6*j^ST>Ni|8?8, h*A I#|w }`!q ? C*EPS{Νu:ټ ڱApY\_I%6~:M5`GpXC)ØN68 ERy3q@Kx.gdmf?HK6}@`8Ց#K$=PL.6φ (p@%Ӥ3Hw/w:0HB{*?AwSI{ŸD,&׵AV;8|h$JeJV˫ryU.u{\ʥހ"w﫡%xA\uAʱ1ZBۍ;v1Tb$-_슶؍6?bB̙ݦJtM; Q+>DD{s= &JM?,|a$.5lYv0Qdsjk\Q$5vERˬ-\iڅhxMBj'mlKo M0c655tc&:AW!ГpJj8ROwD䊠PP3oq̝G䲝R ?p;RDb?㮴t!hc5?F`ZF {es`ߙW;ߗ;Ǜwǝrw>x{9zf=gڝW,8>NT,Lq $mLUW? i}4})-"f0W⭈Q9v (|//Sjx32F-;^hy^dHl\KG 124B!cȬA'$q34OyE$؋T [zߗ2y&M~8p#66 3?5Xҙx?xCr' 4]htt[Nm?_; Sӫ,J99 ?ZN($$$ď3i%$wnfE%7Qb²@gu=:HIJ5[gq*:KXz'gYZbjXNNDYzjBWIPu{-$HW i.-ТhKq# )mi1֮+e L@R_;ge:XmQ{o`|kGQ\*WN>TFTLСDp5nHy<17\N9?m6q %4)‰lܾ$pa9]  Tsb@ xJ=B4w7 !JҌ~6;8*Hm|⵪Ȧ;ctS<5Ѥ9 IO'}ޝKkMP]aE=Fl;#IʆYXZ| XA 2_+?&f%D"~) Ū 5Qz8,=zLHk`e0֮HTcWZi[ѕ@CG(ʼnӷ[^J~6@ixk{=$i(8oTls4el/-Yw#xw` %PdxSo0w; *$p9|uspGMcyb9LkS,2[sdAZǀZ0LvrSŏQڎ؟J$˨įFL-惮:]+2ҐyKIŝtU'P1'P)e2 \~Jga >W:;d|{ #JHr'-iV[TCm^&~GI'YOOj$4rf>QVض7|?*8뗷Cג`Zg8hH>Z64'.FwH;_$Z0h2P}٣tBZ2Rt| `r m4IQTJq֙27{|{逹O偅 D00i(|;C‚DVt<+I4Dp/ 4j P -"Ba["L3c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9M#籜汜汜汜汜汜~rrrrrJ!v 41(L~?Etb*.03D #^8q&Ü9e{'y[UB2KE[SPgzfuE-F*#,mt.furd˲&CUG|rRߎG}k /5 @fAQ ˲P(<ݎ8AR҈dyu 2#zc$tq 8"[N'̘co.97TWtC*gpr$jGNK$vq9q:N4Ƽ|&)q1jT#A 7`Wjp~p:K7ƵZz"RZQ:<jSs\Cᝆ l:v4-bsCݣäu/.Q KxfD<1ӬG9CKAVr@J qs*B"H𤷙~px›}rҚ X7FTO~9 }PqkT9]zV s"!8蠻)=7ZT݋˃ipp(&[xEUS 4')ޞ1J282j+ZdtkH o^[tQ#y"N{?мd8skSt+n/֧ǫ.MD[AQfe]m]TzvZ:H0ITnF )J%3,Nwftr!?z*mGm'=h SO)~[)7sd{"M$Y-x =Fn0`$tDvA[sv;Y[c 4 o(!s"7Ev|n;xҴySH`>ИٱX&ɾHjhAo BڡB hQ(T\;XR,FHe6JպbA j:oB&ؑ ]bjn1<τ4#깃]ǴS> cw6s};r<1N7}jJޙ3Է}e,d?9$>)sJ%aAyGw~e ׆u_mHȷgGD?xPG}tg{WnʼnC7UKu 4Kf֡HJ+tC4@mNj] z37;5bThkRHZŸj+t NUAQo%Y24_PQAŦȎD_6=rJU1rA+2/}I4&eH$'P"r5,? N5#+/NU"Xާ+i]hR{귑yzi'mͧ<\fwokQBz]43>O-)+;"<}#ݩ47`繶zE.G>8+ܷqzͿ_b(x'Ads I^zxX4$P)oG~b~#Gyj򦜻].ns˹nEF̥}C羡sйo7t: }C羡sйo7t: }C羡sйo7t: 9D #|t[ԟfV~ozǥ;ѹU?}_e-Yu߯+'{=}G]_~vi{vڻc~վ zoϖ/߽kjwz~w^}]ߗXk߮h/ܒ&2<5rbIu/r&V3Oq*?vxwڸe_s{S?aT9Ô·onsm?*i=%j5bw`9yD;Z'Cu馪4o`2<ᴶsP1 Kas8|C8}*@"sfF.ˏ7"49_mi9 )vյ5ZqLlEFCY>Y>V|7` Tӈ"`dRֱYY]oވ7"rMÝ,12 əy C{1 UNR;jW Ž=o1Aw3n c2LWxj\z+uW'͕WrKfG-fdV3J (EᏔRZ6&p5,kjt@8#{~. -; t TePt;1@/빹A=UܺϏtn}o];Wrpx=zjk}WKqhtk}99]쮸'f^goֿjoOKW{Ukݯ՛s{[X?Pxci>}kwJÏ'7#?gpǖ &N-]4Sݵ͋W?0+7Fc8Ó]}beoXvqOIۏsܾt5 ֢O@ʃ<W[i3X= ; :ɕ—C/bZ;fC>X=pʥ[bOGkt}EIh6_E~#- *SV&BǛd጗B+7#z Uʡ x,<}qBN^6PKTAUM>O{a ZuM4{ծ S/ӵ4[gwjxLY.6 3U K?Z;0fG-/p?ڙqVA\5sBNh0fhfw߁4W|--C@ R_n+ZXP ڸ T plDP/]f`=M,Ш>[(9}dw%ArԐ5h(𾩫뀎lcƒmo- lBc$o}hDJ9@l9ӷqSж["j>\w;Լ&j=s06<ݳa [fs7ol5nni<\{~qz9Aݎg¿k4vvְ Ft^ueWݹ~;CWu.$yL1}|\?ka?{6޽{c a0r3c`T0uuݶAt;. w26 &i%]x =!>fӤO'4_q #dQ}6XcT cRՓ %_qHk;}ފt`(x"n˷ hCDITi8.6dvY>})CAXh 'zϹ> RՎa./nNk'GQ+ɉOGBƑ-A ir ޙ^zxO1,pj}@ղ\">Z.q܄ԁmBgO`)dbg<`$_# y ^G+͘/^uˋ'Y-3 OKBNPŘ( 3wS^!fU=+ L"%H&*nݴMt/0="!3+c nل7&QߑZYZY[Y(9MO@mK%d4oxᾮ$/ʑKA<`Uwm$}؅ĀIY9?t<mS%ZAn0 ?[t "@G:E {s:)nr?ڇR+Dw @U>zw痒vӧ/uujUxv/ߝ_1~x|AKR o݋5Iߝ<&E!ˏ1+bdx8oGuw

EDITORIAL

Vitamin E Supplements: Good in Theory, but Is the Theory Good?

E. Robert Greenberg, MD

Ann Intern Med. 2005;142:000-000.

Much of the U.S. public has a deep, and seemingly unshakable, faith in the health benefits of nutritional supplements (1). Use of these products has increased so rapidly in recent years that a third of all adults, and half of those older than 55 years of age, report taking at least 1 supplement daily (2). The shelves of pharmacies, grocery stores, and "nutrition centers" are well stocked with a dazzling variety of nutritional supplements, and for sound business reasons; supplements accounted for an estimated $18.8 billion in sales in the United States in 2003 alone (3). Many of these supplements are promoted to the public as "antioxidants," a fuzzily defined category that includes vitamins C and E, some carotenoids, and many other phytochemicals and plant extracts. Vitamin E is the most widely used of the individual products, and it is taken daily as a specific supplement (usually containing 400 IU of -tocopherol) by 22% of U.S. adults older than 55 years of age (2).

The touted benefit of antioxidants is prevention of the major chronic diseases that affect modern adults. Belief in the preventive value of antioxidants rests largely on 2 bodies of evidence. The first is epidemiologic observation, which has been interpreted as showing a decreased risk for disease among persons who consume relatively greater amounts of antioxidants in their diets or as supplements (4). The second is laboratory experiment, which has implicated oxidative chemical processes in the pathogenesis of such conditions including as atherosclerotic cardiovascular disease, cancer, neurodegenerative diseases, and chronic lung disease (5, 6). Clinical trials of antioxidant supplements have not shown a clear benefit from taking these agents. Nevertheless, they continue to be widely used, even by physicians (7, 8). Many doctors may share the view of a cardiology researcher who told me his reason for taking vitamin E: It won't hurt and might help, so why not take it?

But could antioxidant supplements actually be harmful? Two large clinical trials reported in the 1990s showed a statistically significant increase in risk for death among participants (mostly men with a history of heavy smoking) who received -carotene, an agent previously thought to be nearly free of serious toxicity (9, 10). More recently, the authors of a meta-analysis of clinical trials of antioxidant supplements and gastrointestinal cancer concluded that random assignment to supplements may have increased overall mortality (11). And now, in this issue, Miller and colleagues (12) report the results of a carefully conducted meta-analysis of clinical trials of vitamin E supplementation. They conclude that high doses of this agent increase the risk for death. Their meta-analysis involved data from 19 randomized trials, which recorded 12 504 deaths. Overall, being randomly assigned to receive vitamin E had no effect, either positive or negative. However, the data suggested a decreased risk for death associated with vitamin E in trials that used lower doses (<400 IU) and showed a statistically significant trend toward increased risk at doses of 400 IU and above.

The finding of possible harm with higher doses of vitamin E is surprising and has serious implications for the tens of millions of people who regularly use vitamin E supplements. Yet, how firm is the conclusion that the risk for death is increased? The wide range of vitamin E doses used in the various trials and the large number of study participants and deaths enabled detection of possible dose-related health effects that any single study could not identify and previous reports from meta-analyses have not addressed. Although Miller and colleagues excluded 17 trials from their meta-analysis, all were relatively small studies, and I doubt that inclusion of their data would have materially altered the principal conclusions of the report. However, I am not totally convinced that the authors have isolated the effects of vitamin E from those of other supplements, since 10 of the 19 trials included in the meta-analysis involved provision of vitamin E together with other nutritional supplements. Of particular concern, most of the evidence for an elevated mortality risk at high doses of vitamin E comes from 2 trials (13, 14) that administered vitamin E together with -carotene, a supplement previously associated with an increased risk for death. Miller and colleagues controlled for the possible effect of other supplements (apparently considered together, not as separate agents). Likewise, much of the data on low doses of vitamin E comes from trials (15, 16) of multiple vitamin and mineral supplements in Chinese populations whose nutritional status and causes of mortality differed profoundly from those of the North American and European participants in the other trials. Miller and colleagues acknowledge the difficulty of drawing broad inferences based on results from poorly nourished populations. Nevertheless, one cannot fully discount the possibility that the effects of specific supplements, nutritional status, or the conjoint effects of these factors underlie at least part of the dose--response relationship observed between vitamin E and mortality. Thus, while Miller and colleagues' report provides intriguing evidence suggesting that higher doses of vitamin E cause death, the case is not ironclad.

The lack of a benefit associated with vitamin E supplements in this meta-analysis accords with the published results of individual trials and previous meta-analyses. Despite my uncertainty about the finding of harm in this meta-analysis, I fully agree with the authors' conclusion that high-dose vitamin E supplementation is unjustified. Ample evidence indicates that taking high-dose vitamin E in later adult life (when most use of vitamins currently occurs) has no favorable health effects, and Miller and colleagues' meta-analysis raises the possibility of harm. Thus, our message to the public must be clear on this point: Vitamin E supplements won't help, and might harm, so save your money. However, many users of nutritional supplements report that they would continue to take the supplements even if they were shown to be ineffective in scientific clinical studies (1), so basing our advice simply on evidence of no benefit may not have much immediate effect.

The public's faith in vitamin E, and in antioxidants generally, reflects the strong belief of scientists and health professionals in the theory that exogenous antioxidants prevent chronic diseases. Ten years have passed since publication of the first large trial showing that vitamin E supplementation had no effect in preventing cancer and cardiovascular disease (9), and subsequent trials have repeatedly confirmed this result. The story is similar for other presumed antioxidants, such as -carotene and vitamin C. Yet the notion that consumption of antioxidants in diet and supplements can prevent disease appears to have drawn strength, rather than been weakened, by contrary results from clinical trials. Investigators have called attention to isolated findings of possible antioxidant benefits for subgroups of trial participants, or for secondary end points, when the overall results of a trial were clearly null. After -carotene, initially viewed as an extremely potent antioxidant, was shown to be harmful in clinical trials (9, 10), some scientists opined that the result represented a pro-oxidant property of the agent under certain conditions; thus, they made the seemingly perverse outcome fit the antioxidant theory. Meanwhile, research based on the antioxidant theory continues apace; a recent search of the 2004 National Institutes of Health funding database produced more than 700 hits for the term antioxidant. Most funded studies are basic research, but they include many clinical trials testing vitamin E supplements in tens of thousands of patients, with dosages ranging from 400 to 2000 IU/d, for prevention of a variety of conditions such as dementia, heart disease, and prostate cancer. These research projects have all passed a rigorous peer review, and I do not question the scientific merit of any one of them. But isn't it past the time for the scientific and public health communities to loosen their ties to a theory that lacks predictive ability for human disease?

Author and Article Information

From Dartmouth Medical School, Hanover, NH 03755-1404.

Disclosure: The author led the research group that conducted one of the trials whose data are included in Miller and colleagues' meta-analysis, and provided the unpublished data to the authors of that report.

Potential Financial Conflicts of Interest: None disclosed.

Current Author Address: E. Robert Greenberg, MD, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North M4-B402, Seattle, WA 98109-1024; e-mail, E.Robert.Greenberg@dartmouth.edu.

References

1. Blendon RJ, DesRoches CM, Benson JM, Brodie M, Altman DE. Americans' views on the use and regulation of dietary supplements. Arch Intern Med. 2001;161:805-10. [PMID: 11268222]

2. Millen AE, Dodd KW, Subar AF. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc. 2004;104:942-50. [PMID: 15175592]

3. Supplement Business Report. Nutrition Business Journal. San Diego, CA; 2003.

4. Stanner SA, Hughes J, Kelly CN, Buttriss J. A review of the epidemiological evidence for the 'antioxidant hypothesis'. Public Health Nutr. 2004;7:407-22. [PMID: 15153272]

5. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239-47. [PMID: 11089981]

6. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239-67. [PMID: 14744246]

7. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002;162:1472-6. [PMID: 12090883]

8. Frank E, Bendich A, Denniston M. Use of vitamin-mineral supplements by female physicians in the United States. Am J Clin Nutr. 2000;72:969-75. [PMID: 11010939]

9. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029-35. [PMID: 8127329]

10. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-5. [PMID: 8602180]

11. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364:1219-28. [PMID: 15464182]

12. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LA, Guallar E. Meta-analysis: high-dosage vitamin e supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:000-000.

13. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23-33. [PMID: 12114037]

14. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119:1439-52. [PMID: 11594943]

15. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483-92. [PMID: 8360931]

16. Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, Ershow AG, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993;85:1492-8. [PMID: 8360932]

}vPg!؟I'F걺뗆.~z^MifK^c[dQo=(\⿛g˒٭,oI_^307lz֧hvcfhosk勶0a+Tn4ca&m_nqF*E9 ɒ>A-mZYz%{x4*om80G|`9:4[iT֧Ջ7oZQuۭj}ӱsb+,Knf}n=͕>}q}X!tS59DaU*Xo.{pC;8JT1(20Z 48Z2tTu^߮:yݵs@y=+O ?+=b m#5?'3& ʫyWf9 q+NN&蛖|Z&@QXH૽,V)``=9VST^@>Yz)dX88'I6][T溎+<_@tgXicdio97'K;oN.i1z!"ɋZK5 )[DŽIØeIU<>Z+Wt'[ׂV?Y7ф8(k&`F|TsX&,e p83f8XX Zk r~-ŃaDN+:jp(%%4omv$0LYihB='puC iw8Y޶˪Va|fVBpkF'୉o-csl_1j/ˊl1bּ^h2 ʼtKKܗpV11L .FZY+2P7`مxfeB0bSKJd ThbBYFhh6q`mCNVfu[%IM)OSXx /1ę:+qhbv%uxZ7;v|`ɼ%,H ' NH4rIx8)ˮ(i&KGB6$#K&ӆGN &R^*}Vz jr7Cb|{ZnHq(8|T0 lI`@Xk-NH@R&Vm5s L }F'2Kԙz :L9OAaC&96i!XZkۆvۣk{k҄mVC<^gnX!$ƑD5tMΣE9Ks9hFqk:Qai!ϑv"d(}JJ)Sb}ȃCJp=^MG6l5YAQ C@Iltfj8Ph57dF:adᐈGh ki` |AWn>A .P~R5뤼b!J4.X Wk@%DΔO09=pVß;lЙf)yM 04M*Q]KT#E~ێQcq^3$s.U; ۉ%\h~M"HwrNG49@kdA<@)^ Sh3 7T8FXll+=xvl>7;G]@02xH:,/aK[Vbׂ@-U@o-@e1tT=OjzL)da"m IA~f4}`hV;HZ.s>VmӶѺoPgCv}hK+;yF>긒=5x#}7##59Zd4#9y0 VULp| U8;s*\106`,J5$e)[ Z\_,@`#A0#wLZpс&xh QŁr|()1*AqvH;.aQK4EI7{WA깮+Xֺs%pt- GEF>锖)SLԏ`,6} W n4s/:,IM!oTC-r9Rӻ}8t-{42JΙ!=vx]XkE^3k&ܸIH-<R;`rEV0glf~ 2 p/+ O$% ‚K5\oU=EQӌ8dNl b>BVMW|/ráaDIչGG"ehڢHoEqJhNL)\%-!77V Ul%+c#㍖uJ+ (A읖3bh\7,>:݇GmrZ*2(3*"h/yAf0sx[X!cd Kkp6(@c2(RP!q8r `*VcQ ; hR+l-Ưy6&SgE0CN4eѸSЕ$8|H ii$[a3^Ro$ w^tr^Q@gb ^{iH\F!tREz362+俗%B/ oMg4w,07ǩ֢l۪\rmm$֐m!;TJȩ$ 0 砳3/톯d0B@eR64ش#$OH0خ}a\U$!(.߲sjޮF] <49p_"npseXnńjsQ -K|,SCE\GEFO-@ Q0DQgPq6(MS̖LqP{|kSaUN:k]$N,:#Nك~V<>Z䗒MЄ;M3:L%ï"[Aљ/0ɀ:xGdCIU Sh |a8:]i+ nDMmd6sBi*L'I#lybb?^OEثfk=[LJ0<"]8کM(fŅ=^%ftA Q "4$gN"g?Jh]kM/jFv7x=G8,W@2m$le\q*): h\j53]ɺ̀|0#L+hG]E :ًr(t~!Hwf`\.Q}Ν#C<f?T, !eS;m1 mCP7p<)3q&U`mZ  S] 6ѐJ;)h"z*=E; ;E(Y. `5n="ހSsӋbA2H>OZA JO O+ gcu)XvcAPlpM|9) uݾe߁>xO-z>y6k%In:UrIYQA|]+oCb҉KHRZ[Sw&n"/x7y I0a5ٰ=&(Kt!F6˛}\m9th_&:R5 -iYL@7,;u៶vV8^?b"w,;~eA*$-ӽd7]n@ ٭ܫIXTluD{ ~IKM^)#S5XL`'EPMX,^ (Y6;=4&-?j!G@t5KZr%En4XBQ]V+V-VU[9pMo `*(`˘  xl&UN`2߯˒4Ӵ_۠ޭoC;HM^ ]%03ZCEoz2T=m eJw{oeV2 \>q8,IE..//s$hhM͕p"Z 8J'AuLCl6FHiiRJ4&X)hq&+@S /;)`Ӛk]CFPS&jrZx'4=,Vg';ɣ\>EGkV2&)' 5flZ0S׌jաYl^o|ptuwzf~_:m^Uh]7]_|>8+L.ovV_'zmJ'A_/1Ox־]Zk]_Q^ Jh#*Wn:6˛'K}pR(]|u_Zm^o{﮾|X/]]y糕4OՃ?wJkK;qT3f3h|=T\r>/{=tuRKumel^[yw؛qQ~޸U9@X;כVݗzCoΝ;th1o6>\>lXƧiǶK8ysgKG-KkikWwo]U]چ\S{noاӓ7;ߛ ~u_wKoz?5njO<wο]{kucby5X; uٷfy߻:Nl7oo˗UGouWқ]iL?[v5Vݭ}[/Yi\_S/}ؗ73\OJQ_?jwJCgޚ5\ ם~o[ƾ4owoupYW۝wէiݭH`[aPRDq"픮zm#|uؽ8<\ i{P+fşj89pHT ]A/ }jiRkRr-2t.pT,nN 50y;A!2c[Ub=NpXKƇ HnZ>jxx1\eL)ɑ4*Dm:aMTU*ojfi߀Veba#;b &-7 F&oqN4:DBUQx ܪQGhhb *~Lƌy*9,X;0Zq/oHreiR^:RO ű P7@P+p! 'Z&[ȉf13ODB`&%^,Ψd1IT4IDm"]GD{IT&(Je#~OL1ק [/r˿%*\ӈԲ,5@Z2 #x^Exm>AtvN@9hc na&~=)3/~ 9^U% 8rXV_~!kƱӭJ̲2ta1OHAo/߅.gDtKɒSA*"g xu4ul!Jk6A")6DLF!-v4l3<ŮEOOvornq(h.N2 @Ÿ3B;Mln5@=T'&h9O , +ZH}BKӒ6uQ,ol 楍.b t=?Ov;=% vvy8x,)&~}Ho&l,$O*Ђ8q:-ՁBg~N@0xo6,8jRӂ:^]eTpMGq|Rۄr^mkC3Z 6N>=UU_  i o%VY]IK1.XŠpה$$GbkK]DWt'.pfsWNtbR0dwJ` yb|6*j^ST>Ni|8?8, h*A I#|w }`!q ? C*EPS{Νu:ټ ڱApY\_I%6~:M5`GpXC)ØN68 ERy3q@Kx.gdmf?HK6}@`8Ց#K$=PL.6φ (p@%Ӥ3Hw/w:0HB{*?AwSI{ŸD,&׵AV;8|h$JeJV˫ryU.u{\ʥހ"w﫡%xA\uAʱ1ZBۍ;v1Tb$-_슶؍6?bB̙ݦJtM; Q+>DD{s= &JM?,|a$.5lYv0Qdsjk\Q$5vERˬ-\iڅhxMBj'mlKo M0c655tc&:AW!ГpJj8ROwD䊠PP3oq̝G䲝R ?p;RDb?㮴t!hc5?F`ZF z6/~cv?ok;Mqkv8zf=gڝW,8>NT,Lq $mLUW? i}4})-"f0W⭈Q9v (|//Sjx32F-;^hy^dHl\KG 124B!cȬA'$q34OyE$؋T [zߗ2y&M~8p#66 3?5Xҙx?xCr' 4]htt[Nm?_; Sӫ,J99 ?ZN($$$ď3i%$wnfE%7Qb²@gu=:HIJ5[gq*:KXz'gYZbjXNNDYzjBWIPu{-$HW i.-ТhKq# )mi1֮+e L@R_;ge:XmQ{o`|kGQ\*WN>TFTLСDp5nHy<17\N9?m6q %4)‰lܾ$pa9]  Tsb@ xJ=B4w7 !JҌ~6;8*Hm|⵪Ȧ;ctS<5Ѥ9 IO'}ޝKkMP]aE=Fl;#IʆYXZ| XA 2_+?&f%D"~) Ū 5Qz8,=zLHk`e0֮HTcWZi[ѕ@CG(ʼnӷ[^J~6@ixk{=$i(8oTls4el/-Yw#xw` %PdxSo0w; *$p9|uspGMcyb9LkS,2[sdAZǀZ0LvrSŏQڎ؟J$˨įFL-惮:]+2ҐyKIŝtU'P1'P)e2 \~Jga >W:;d|{ #JHr'-iV[TCm^&~GI'YOOj$4rf>QVض7|?*8뗷Cג`Zg8hH>Z64'.FwH;_$Z0h2P}٣tBZ2Rt| `r m4IQTJq֙27{|{逹O偅 D00i(|;C‚DVt<+I4Dp/ 4j P -"Ba["L3c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9c9M#籜汜汜汜汜汜~rrrrrJ!v 41(L~?Etb*.03D #^8q&Ü9e{'y[UB2KE[SPgzfuE-F*#,mt.furd˲&CUG|rRߎG}k /5 @fAQ ˲P(<ݎ8AR҈dyu 2#zc$tq 8"[N'̘co.97TWtC*gpr$jGNK$vq9q:N4Ƽ|&)q1jT#A 7`Wjp~p:K7ƵZz"RZQ:<jSs\Cᝆ l:v4-bsCݣäu/.Q KxfD<1ӬG9CKAVr@J qs*B"H𤷙~px›}rҚ X7FTO~9 }PqkT9]zV s"!8蠻)=7ZT݋˃ipp(&[xEUS 4')ޞ1J282j+ZdtkH o^[tQ#y"N{?мd8skSt+n/֧ǫ.MD[AQfe]m]TzvZ:H0ITnF )J%3,Nwftr!?z*mGm'=h SO)~[)7sd{"M$Y-x =Fn0`$tDvA[sv;Y[c 4 o(!s"7Ev|n;xҴySH`>ИٱX&ɾHjhAo BڡB hQ(T\;XR,FHe6JպbA j:oB&ؑ ]bjn1<τ4#깃]ǴS> cw6s};r<1N7}jJޙ3Է}e,d?9$>)sJ%aAyGw~e ׆u_mHȷgGD?xPG}tg{WnʼnC7UKu 4Kf֡HJ+tC4@mNj] z37;5bThkRHZŸj+t NUAQo%Y24_PQAŦȎD_6=rJU1rA+2/}I4&eH$'P"r5,? N5#+/NU"Xާ+i]hR{귑yzi'mͧ<\fwokQBz]43>O-)+;"<}#ݩ47`繶zE.G>8+ܷqzͿ_b(x'Ads I^zxX4$P)oG~b~#Gyj򦜻].ns˹nEF̥}C羡sйo7t: }C羡sйo7t: }C羡sйo7t: 9D #|t[ԟfV~ozǥ;ѹU?}_e-Yu߯+'{=}G]_~vi{vڻc~վ zoϖ/߽kjwz~w^}]ߗXk߮h/ܒ&2<5rbIu/r&V3Oq*?vxwڸe_s{S?aT9Ô·onsm?*i=%j5bw`9yD;Z'Cu馪4o`2<ᴶsP1 Kas8|C8}*@"sfF.ˏ7"49_mi9 )vյ5ZqLlEFCY>Y>V|7` Tӈ"`dRֱYY]oވ7"rMÝ,12 əy C{1 UNR;jW Ž=o1Aw3n c2LWxj\z+uW'͕WrKfG-fdV3J (EᏔRZ6&p5,kjt@8#{~. -; t TePt;1@/빹A=UܺϏtn}o];Wrpx=zjk}WKqhtk}99]쮸'f^goֿjoOKW{Ukݯ՛s{[X?Pxci>}kwJÏ'7#?gpǖ &N-]4Sݵ͋W?0+7Fc8Ó]}beoXvqOIۏsܾt5 ֢O@ʃ<W[i3X= ; :ɕ—C/bZ;fC;xs|q /}z9?|r&(05LYXoR=_3^ (/ W1*zk6A C:yA`f@-RU5<?)7`jߺ5UN7%󴮩Q(axhQ#SS_3CxJz7c?(~'H%Q i^_sa, Zc MԐ yT[bOu Y=rN?OX.K[cE GRF*\vL!uL:B?]:^LkOLnT]x`cרӇ~nO2ǙkNOS SR((#.~0=U$iAjڙ;H:>S5s_t 䚞ߙU^0agC﮺T(,\W.V.,hhgn[]sz̕ ;=B&]7_| ^PP}-6tHK|ħ[@kbnBu6h6.<.K8PՒ+ùR:v@ݾta7e@^la (QCVowe[h뻧}̟{]Z^?gт&0F2(\M; އIc Ė;}'l<m*CCk¿3 ^oh8z~oÓ/=6ްe6;lj˶[[o斆Õ!3x&Fsmwan ݰnIEOZgYx۝7=t\gBǴ!|wȅnþ;߮1a[7x.;#G8C=FZ S\x A1Ouj-U>i7iz eq]m{DI=ͽ# Rkhz'3HOh` Pޅ3`6My» /I57;BAg5=&jA ]0&uX=Z7XA*6_|[hlT]K)t'P7znRM*V6Kw*FWmy^EVR:!"<@ɬ{L? CnpZ46rNI`¿%_f(6tKDズoCVlkIӗ8Vp' @Q [b68NNvzB|tT1X+tpaT&[Eַ D^Z]_-U)BsMHH?&tiQxCFi$뤏UQ@Q( ~ ’'l[Y2:,X/>WC5MsB&v, S F5Ҽ ޑuیUzbX8mmȍ`!@T\. D 5YBi}z[WVlq헏WT4z)O[ZYTM{q_ՠ&Ǥh6d1f|Edw