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. r. ' Eh'wx IT Oscar (Diseases of the Chest ~.-- 020

, , L'FFFt~T ; t1F CIi,/,F *-Cl"~. StNJ~TYf IfPCJ;~ Df~:S Puliarn:nry Yeopl;so:c.a - •- .- ~ ' -" ~ : i ~ Auerbach, Pi.D,, E. .r;uylrr h:1,smond, Sc.D., Dr.F;ed. h.c.. 3 . 4 DeviC Kimar., B.S. and Ls*"ence ~.ar.`tni:r:l, H.A. _.. Saot Orsnge, Now Jersey and New York.'Hcv Yortc : An exporir,ent v'ns mdertaken to deterniac tahar.her mol;ieg; c:isurettatt filter ct2arettec; and to de3tezaaine 4tr?ther, zfter sufficier.t durAtion of eqttipped with an efPf.cient ' filter iti any lefa harrful tlegn amoKing nan- oxpooure, inhalation of cigarette t-noke will pro-d2+ce Irmt; cas;cer in dogo. Y£ndinga in recpect to raortnlity, ccuacs of decth criG tliCtoi- ology of the Iune vartncltirra have Llrtadv Lern rPnnrrnrl in rt.& Ff rr.F eaf v61"e _ 1 . - . . . Eet. In tkia pcritr ve will report findingc in recj.ect to tit: occurrcrce -of r.on-invFCire and £nvanirc brohchir~Io-elvevicr te:;or& and early invcaive broi:chiaI c€retncr~s. dtt:er findirigo will ba reported st a lAter df-te. New York, lieer ioi•t;. Supportcd in part by a reeenrch grcnt frc;fa the Arx.rir.an vocfety. the Y}epartc:ent of l:pideaiology and Staticticr. of tha Azerf,ccn Cancer Society, €rcra tho Vctorrr%~ h,=LniEtr.?tfo-n Horpitr.~1, Esct Urr,abe, Now Jersc:y And Profcuror of Potholo-y, New York 1•TdS.c-cl Co11<:Pw. 2-~'ictt ire.^.ic:,nt for f'cipi~ie<:.iolo,;y c!nd Steatictictt, f,r.:erican Cancer Socicty, Z•Srrnior h:cti¢r.l Envcr;C4~c~ear, V. It. Kc-r?frel, rs:t t1ta:-Zc, New .Iere.cy and Inc., I:cu Yrrk, I:er+ York. StattatLcG, ls:erican Cancer Societ}, Lnc.., tr'-ew 1'ot-1:, I:eti I'orl;. 3-1'roject DirGcto-, Animal I:ece.arcl, SecticYa, i.-.F:oretory of the f'eaor t-:cd.ceL Yn'reetii;;.tor, V. A. :rospiral, Grct Orrnge, 1'_tr J: rcey 4-Chief, iricld cnd Sf-ecirS. P&eearch Prnjects, ~c,~ar*.~n4nt of I:pldo~ic~faC}~ and W N . ._

TYacbto-3tmcy was perfonwad cisz r..nlh bo.Agle 6o,;a; diGht vero btpt so ao=-5r-_kiag cc-atroLg (CrG:tn, C) . All ott:ror do-'-'a ct-'s'xed cit;r;;-etta® Gaily t#7 =aua of tahing caagccting the trcchao:Jtc;.a to a ciaarottc ho26xir. Aftar a 55-4-ay trntning 1-criosl, the =&-,inII Gogc y~ra ~?:.v4dcd into fmr grc;6psi thrccsgii day f€75, Crc~p F OaZs rc-_AYad filccr -tip ctZeratito© cmd grc,--? e Lp 13 ctzd heoMv Fmikrd mas-fi.tcr cigercttca. Gro4s-9 L dfG cE~.eked t~1t' eo tj._nr_y cf€cr-,ttes ea tLe at!~*r Zb-;,a. to -dog in grc-<? C Gicd; 2 r;tc~ 19, 2 12 Lrcn:2 P. Lnd 12 :-rc:W h d~~8 Zicd. 11r.e reM, ri~:riC gro-,7,c C, P, L cwi 41&a-r. were 6ACr`sfieaa ctertia,- an dcy P876. l2oa-inraoiva brc-mchioLcs-clreolcr tum-or6 u-cre fc-:.xnd in ca-~ 4na of eract; of tho fire gro;.pa. rr.vcaiL.e tunora %:-ere net fc--jLd iw lungo of any of cIra gro~.? C, F cud L doKgn. Tm.msivc broachfolo-n1voolar tc_atto t~:sge fc,Ltp4 in 2 of tho 12 grcirp h clo; a Vaich ltcd, 2 of the 3.2 gro:rp 11 c;c-ge vMch Gied, cud fi of tha 12 grct:Q 1; dno viifch w-rf cccrsficcu. I`£vo of to tsei-c: r,&crifLccd. inve cfra tmc-Tc exCenGcd €r-te tM p1cLre.. F.'t:r1y fuviscivc aqu3::c~~ co11 ct;rtiutc;;, uoU fe---d ia thc treactii of to of ti.r 12 ,r.,r") 1' Lc--e uhiclt

Trucedures ..Since tiie deefgn of the cxporiercnt vas dcocribed In detail in the firat from 1,7 to 3.3 yenTa, The trachenstuva woe krpt open by e hollqrw tuhe uade Trachcoetony vaa perfo;tred on pedSgrced male bengle dogp ranRing in ago paper, an abrLdqed det,rr(ption v1I1 sufficc. of Teflon. In cmoking biteiona, the doge voluntarily inhaled cigaYetto amoro throvgh tubing connzcting:.t{u Teflon tube to a cigarette holder. Attho ^tart 8 doge were oeleetei by random numbera and retcintd ao non-cr`r+kinL cootrol .All of the other doga cc~oked filter-tip efgarettea daily for 56 consecu- tive dnye. The firot day of smoking vill be called day 01. On day 657 the tsokir.o dooc were divided Into fovr groups: F, L, H tnd h. The 38 heeviaet wrs nnr inorp,hrnn raFanf..fno dnon (whfch w~rw Ifchror 1nvafrhf) divided by rnndcea ninbera into groupo F, L and H. Ytirelve doge were put were grcduclly trancfcrred from filter-tip to non-filter cigarettes, and frozs fLlter-tip cigarettes throughout the ezperirr_nt. The group L, Hand h dogs in group F, 12 in group L and 24 in group H. The group Fdog: csokcd only then on, caolced non,flIter cigarettee in the -eornina a;-ij af:ernoon of each dey, eevFm deya•a ueek. The daily number of cigerettea wac gradually increauad un- -.day 057 to day [E75 the group L doga amoked covcwhat leac than half no tzany ,'til each of the group F, H and h dogs w~:e anol:ing 9 cigarettea a day. Froe2 cigrxetteo an the group F, H r:nG h doEa. Sao`ka frc= each filter-tip cigprette contr.it ed 17.8 Pg. of tar and 1.17 tsg. I of nicotine. tean-Gil2cr cigarettec vere obtLiined by re-oviug the filter fro:a tigarcttoc of tho eace brand. Y,ithout the filter, the rr.uke contc+fned 34.8 r`g. of tar and 1.C5 ng, of nicotine. The total tcr end nicotine concuredfu 875 daye by each of the tun•i•ring doLC vac: 109.3 S. of trtt and 7.19 C. of nico- tinefor group F doLr+; 103.5 g, of tar end 5.56 E. of nicotinc :or group L.

207,8 g. of tar and 11,12 g. of nfcotino for trouip B; nnd 2M7.8 Z. of tor and 11:12 g, of nicotine for group h. Althoudh or rrp A snd aroup h CcVa ro- I ceived the same t.ital s.nounF af tar anJ nicotine, 2,roop h doRo recoivod a I ' or dotn`e that group N doar, in relatton to thc(r bod~w~ht. Yvaotq-eitfa of the taookdng dogs died betceen day 457' nud dnq, 6RL'i. Theoe fn~ luA~d: tvn of t!.e 12 group F dogx, two of the IZ group L dnra, 12 of thr: 24 group H Any,p an4 12 of the 38 group h logs, gone-of the 8 graup C control d-,a died. All of the recaain- ing group F, L and P dogo, and all of the grnup C dngs were oacrificod bottmeen day WS and dny frR06. The group h 3o•ga cere not tacglficed end ccntincad to t:S:e non-filter cigarcttes. Findin.-a on group h dogo Yhich died at a later EBte will bo repqrtod in a later L&gcr. Avta?op raa perfcrrn°d at eoor; no poccible oftOr tho Lseth of each dcd. After czrrsir.^.tioa of the pleural sxrfaceo, th^- lur.go~ core reaac-ed cud infictod by gravity-fed inctillt:ticn of forz4l2n into the trcc.hce, The itmra of tk.o tica f,1e do,Zo have eaven lob~en, foar on the rit;'at eide cnG tt•reo on the left nid<.. A c£izsn of lung pcxrenchl:,a aac ramcrvod frc: each of theee *rteven 1a%.ae end or~ at sG eier"cc»ically„ ;4io reaaining pertioxe of the lunge vcra cearched for groaaly vicible raacea of e•:y kind; ond thocs r.ecnd were aoctioaed end nicroaca;ticclly en- tsaieod, The trache:.breachiel trca nsa then diar.e•:ted out ef the It-n;,a and diviind into 131 porticno, each of u°tieh raa ambxdded in purofYin. A hiatclo;;ic r-ectie:: 1i^a L,,-:an Frol-.nred frm onch cf the 22 Farnffin Llk-ck.a coQtcicie8 the epaciL~-nn 4ren the rper r.~in btnpche.a cnd frc~m the right cnd left c;eiccl lo•ra br3nch£, rrMra twra boon rUcraecc;.iealir eecrchad for brcx.crcial tr_-orR. In odGitioca, r.ca--plra of t.-t:-la of the re=iran8 lrng tiscti^!o uct'e prtpcred for r.fcrc,cc;4c oxc~Srstfc-n, LL r2* at inctmeoa, abaet 40 cuch SGCtSC.nG l'erc prefar4d in'cGditic:s to the t;ee;.~n ro:tit--) ltm3 p,rcach^L1 rocticr.a end tLe 22 branchinl cectic_*_n cccntioaad ci ~-Ye, • All or 'haca eGatfc-:c tperc aoerched t_lcroecopi:cally fcr- (--a11 tc:rnrc seSich c.iEI~t L^.ca l•.~w°o avorlc..-ly,d by rtQcr: em:inAtitr'.. 1".•.w-cectic*nn fro= each tr'.~r uad the ourrnTadinL if.lcrz tcero tjicrn-

•seopicalby esenineat to debeM!ne --br_hJ'ctolo;,ic type, utte of orlEir'ond rlndtn~r " . tmaors veet• Iutmd, the nuab.rr at at:f..*-,rLLea -okcd, the age uf the do& at tims :_ vf death, the type*of tuoor and the loce;ion in which the tweor aoo found. For _Tbe maJority of trrnors, both non-lnvcnii•e and iaveaive, tcore found in the Tfndines it, re:poct to ttxors are e.ir+y.rtted In Tn41e 1. It ehouo the vt our, {r~ 9, 1 N or h), the day of de&th of ea.:lt doik ta vhilcii onc or more luos dogo will be referred to by group and day of' death._. DoEo vhich, were aacrificed tao:fng doga, the dAy of death r®e•na the number of -ay,o of aooiCir.g. Individisal after day A)S (includimg one dog which dteA after dep-{•075) are further identi- fled by the letter "a" or For ezawple, '118192o identifieo one gro-up 11 doII vhieh was eacrfficed on day f892; and "H692b'' identiffeo another crovp 11do3 spicel lobe (rJ.), apical lobea, sore being found in the left apical lobe (IA) thcn in the right Treralence of Tumorc = l,2 !la Che-vn in Tab:e 11, cca,e of the dogs with tu~,orc had only non-invccivc . I L L ttraors, oo" hadonly invaaive tumorc and cor;e had both invaeive end non-invasivo ' - tcnors. The relctlvs prevclence of tuaora in different grmtpa of do6s raay b~a coa- -_pared by diartgardinl, prer.ence or rtbccnce of invcaion of the Table 2 Chowa the nunber of dogs In which one or uore tv:.ora -nuaber of lobeo in which one or more tv.nora were found. The cao hf&hect in dogc of group B end loa+eat In doga cf groip C provolenco wae eo.-teehet htLher in group L thsn in group 1'.. underlying otroc~. Here focnd cnd the prevclence of ttnord (contsol dogc). inc 4

rion -Invrsice fironchiolu- Alvonlnr Ttn.arr. I t l+on-fu-safve tuaRors vare fout.d in the l~tt:ga of 24 doQe. SEnco they were :.xeurrallv mnltfcentrt~. it ic difficult to ctFte thc nuaber of truly ind*pendent uooro. Rorever, in soce dogs auch tunore were foaind in tuo or three difierent - ..•lobes; and it a,av Jr nsstmrJ that nun-f~rvr,c!vr toaora fownd in different lobec are lodependtnt. hon-invcsive tu:eura vcrr Cnun& It, 41 of the 1 x 29 ~ 203 lobeo Invaefve ttmors ware found In the-1 w go of tvr- of the 12 Sroup 1: aon-filter ., eeokerc that died before dAy E87G, and in it of the 12that.uere cocrfficed aftor i 1 of the 29 doga. :doga were very eatall and a3ght va11have been wfteed except for the fact that vo It Is of inrereet that auch Lunoro were found in tuo of the eight coa-t~moking group C control doge. T1sis was aurprisfug to ue in the light of thair rarity in 2,3,4 doge sa roported in the literature. Penczpo they are not ea rare e.e in gen- erclly 66elBed. It ahouid be pointed out*that thocc fo•.atd in the tvo'non-ECwking ntcro9copically exetcined a great esany oectfone of lung tieeua frc:n er-eh dog. Invaaive Tasora The tera "iovasion" as used here, &~eana penetrAtion of the ttror into the : Ifo inviceive ttratora were found in the langa of any of the S group C control -doga. in none of the 12 Srovp F filter-tip emofxra, nor in any of the 12 group L noa-ffllter =oNcra. day fFi75. Inveoive tmore were nlao fotmd in the 1unEo of two of the 12 group 11 nca-filter mokere tlLt dicd before dap C-F.75. (l:me of tha group It dcEe voro eaerificed and-noao dicdbetucen dny'(97G and dtq Tcble 3 provic'ea a brief deecriptioa of oGch of the invcofvc tc-)or(r,) fox.~cl in the luoLe of the 12 group II and It doLC a.:ntioncu.~tbovc. th= [v.:or eao found in indicatcd by 1. , LD, LC, etc. i^ne loccticn in Ohicn

r .t SquarAaun ccll -iuvasfve bronchit+l carcinazaa of aicroocopic aizc Hc~o . in two duge (r,37: a a-ld E1E185a). t?aa of thcof cRrvin,maa aKa in s brcnch of the left apical lobe broncbnc. The other w6s .a tl.e.le.ft r«af.n'h~r~e-cl~~sa. InvQeive brocchiolo-a1vcoIxr t-xvorc yerr: found in 12 d8So. Six (h626, n644', H7 53 , HS ; 6-k, of t ~38;re and Ei892i,) itud such rmsora in t%co or nore . end it cppeara that these were indej>endent prijzary t%wors rathcr than orie ed the plevrn , one cho,--ed eFrlj involvem-,~ant of the pleurr;, and 15 did not . iavolve tw--or with neteatuaeo to other lobes. Mder thia coauzptioci; at leact 20 indepcn- _ - , _ . _ .. c:ent inYcciYe brvc,cblolo-nlveolcr tt,"sors were fo-snd. Four of th.cse ttcxora invO'.v- It ahould be noted - that r•~ny vAcroccopic cacticn s caere prcpcred froa each of the pleure, the inrEnive bronc:,iolo-alveolcr t"more and the aurrc,ursdin'" tiooc-t. T°ne hictol,>gic typr of eQllc vcriell conciderablj frcca one part hf c~ ti~ar to another part or tho acns tmor. Squmoum cell foci vere found in all of tlM1eae tu...rirc. If ject cmnl~ t•oetioa had bocn proparod frca each of the tu:yorn, sc~x of then QiE;ht hAres boen elacoified eithcar ac cSufmwH m^trplacin vith cd.rcenced ctrpim, or cq,~ ~r,onc cell ccrcinczta. Th e yotuzf;oat do; uith an in~~cniCe t~mor (Go~ P 753) tTct: 3.C ycaYEs old cC lic~ roup li and h, vhich diod erirlier. of r 7~,2 firat invAaivc tc--*or mte found in a d.og (h626) c.~hich diet~ on C.ny 26 after havinr, rz-;,:6d 3,928 ciCA crettca No iavoaivE tt-3orn sTere fp-snd in the 15 dogr. - of death, - the oldeat (do;, 1,877f~) the 14nCo In des,a are raroly ovccrvRd at rutojsy Lcforo the nCe of ccveu yr.&rti. Wnc 5.4 yec.rn old, and the coAn 80Q at dcatl._ of the 12 doZa t:itl. invacivc tiLmora vr.n 4.9 yebrt . _' In contrc:r.t, tt7-:.or:: of - CIA ~- dctniled ecr,criptioq; of the tz.m-oro follo=•tt:

ation. ooas of theet vere found to bQ bronchopncusonia in ortnai.oticn z;hi1e tf2ay aannea vera foimd in the lunfe of the dogo. Upoo cacroaccYpic exe=tn- otGere were found to cmtain foci of neoplnotic celia. Fnc vord "tvaor° aaad hare arpliee only to thoce aaaecs vhScc conteiuod foci of neoplcotic ce11a; but tTse do3o, up to to twny ea 20 tcrsro t~ero foecnd in th.: e=o loba oafiicScQtly in t3o®t iaotcneeo, ouch aaoaao s]s+c.~~taincG non-neo?lcctic tLosng. Ia ot= of olly eoparoteb frc= othcr foci by areas of noa-ncopleotic tisac2.• The rulaCieo- -centrie in tl;2 oens,t that oo9a roci of uacQlactic cclic rare e=posateG or pr:rti- ol.art to n:kc it ap;loar'thati car} usa indapendcnt. Each oxpsroto ttoo: aso eu2wi- hrom.-iiiolc-hlveolcr Tt-coro "ohip eamg the vrriona naoplsetic feci vithin tl3 oc:~o tuoor rnaeo to often t5a- eertaS4. In iainp ir-tcnceo it cp;aorcd that one focca o:i-~t::atod by 4ir4ct cs- _c4_~ '-- .--~c-r s., ,.r~..,. tr.ntr:nceo. it np"cro6 to li.'-.ely th.at tao d:f- -foreat faei of nQo,?lcotic colic eco;.o indepcol._nt_y. The grwoly viciblo Lroachiolo-alvoolor tu--oro faznG in the dwgo vat:cd cr.c'sLns.tiaa, each tuch tt~or uaa feY.:6 to be ccmpcoe6 of nmororz fcrf of tGo- ¢lootie cello to~cfl~r with arco9 of noa-n.r,lcatic ticcra. €=I1 fcei of r.^o- eisa from one eillf~zter to 3 ca. x 3 cn. x 2 co. (?ig. 1). Lpm aicrcucc=-?:c plabtic ce11u aithS,n a tt':or voro nolvlLr and, to the rat:od eye, rco=bied uiltrAry tut;rrclo6, T-trrj often tc: Ccd to r_er;;e ir;.¢rcop : iyly with the ea.rrc ;d- ing li.•-~; pcrc-ac5T-_i. The oo~-~,ict lar^or foci of no6-, laCtie cello e•zra Lc•nortll:ry coro LLffa3e, grcy, fir_- and flc.t. The 1.:rfent foci c.r,-re Lcrerclly ;ellce ews t1«) ctc^o of 3ray t~~tSCCticr, r.er .irid f3ceG of tl:s :v vro fcraod fa t'.::a do;;o rcam'Ao@ oit~er lc~nr raa~.nfo 1A i f.crc~ccr.<_c t.s~ac_ -c~ V_io lrietotc,.ic p£ctc:e ~~Yiue frc,4 o r t1-_3or to It elc:o c:....cr. fYC-i c---o Eo-aa to cuoct:.er in the tcaz r_icrc:rcc?ic f<_cld. S.ne r.ocplc:e::.e frxi 4ro Sr.e~rir:bl;~ aare<iztcd uith n b:<.ac:;to.c• (i'it. 2). T:w U:c_caiGlc. csy he G ^II

Ksny wsaoovere foauid in the lunrc of the daao. ation, 00-ne of thece --othcro cmro fo-mrd to were found to be bronchepntwic•nia contain focf of ncuploctic coitc. tfpon nitroacopic cxe--ta- ia orthufcatfo;y cl+ilo The vord "tmor" r.sad hore opplieo only to those cssasec chich comtoined foci of aaoplcctic cellc; but in teast iooteneEO, such r.meGOO'sloo coatoinod noa-neo.,~lactie t1o5rf3, in oo= of :tF.o dotye, up to no way as 20 tu~2oro tirro fo%md in tho ea'sa lobo onffLcto:=tly ap-rt to nshc it cplirnr that eaeti c,ce inZey*cndcnt. Erreh oepsrato t=zvY erso ou2tL- tentric in tba aeoce that amo f,ici of raopteottc collc e.-cre osporatacu trc Isa.Ct- " aily sats..a.~reted fr(m othcr foci by areas of aon-«ea~leat.c ifcac2, 743 rolat€ca- ahip cta..-~g the vcrt-cz~a r_soplantic fec£ rita£n t-h* no tuaoz csea it oftcn ~s- certai-r;. In usny ir.atEncco it cp?aarcd t?at c.~o facca osi-~faoto6 by Ci:-cc-, os- «,;-; sn othor iGCtcneen. it cpls rod ra.~ o lil;cily thAt iroo ~,if•- - forcnt faci of tt¢o-eleotic collc sro;.o £ndcfc5?_!•nt2y. The grcwnly viAible brr,chiolo-alvoolr,r ttm-orc focs«4' in t'.a dcuo vEr.cC in ett;o frou one mfllis~ater to 3 m, x 3 cm. x 2 c:~. (Vip. 1). L`rp,= o-crcccc:)_c osrainatios. oach ouch tw.er vao far.d to bo ecFaacG of nimoro-oa foci of eoo- Vaotic cellc to~,CthEr with arcna of noa-nzcnlcctic ticcr,, yr~2l foci of r.oo- l+lastic cella suithia a tc:Aor verc aciuler r.nd, to t;o noG.ed cye, reac`'a=ed cailicry t~e..'~,srcle+t. 'M.af oftca teaCcd to ccr ;o i-^,erca~; .ibly nith two r.,srcw~~ ing I^t;, parcnchs:a. 7he oc~ atet lar„er fo=i of ncvploottc ccilo v--~ra „PCacruliy av:b Giffo.e. Erey, fir,: cad flct. -ne Lcr~ at f.c-ci r.\zrc l;ci+_crcllq ,<s.1ou ©c,~ Viotblc t5rc;la the pler,ra. Gm-o of t-,,s ':c:cro fo•ae4 fn t:a doca roer..r3loC citltcr lc?-ar r~~.;afn LR tha etno of Brey taT-:tir.ctLcn noi IZ7,id f; v~cz2G. . tiicraccc-,ic 7ao 1:£ctoLa;,ic ~;.ct.crc v`r.oa fr.-:-~ ors tc_or to ac.ot:•3:. It aloa vcvLao frc . cco ¢c~.~ to c actLcr in t~o cr~a aacreseo; tc: fic1G. 71c naonlcc:ie foci

I r r - eci3pIotelp or uSnoot c=plctoly ourr,o-ac.eCl by the focvs, thoc: fomirg a c~ ~ro. in other tnr.t©ncen the ttnor ertcn6a tomcrG the p1esaLO in A l.near fc3obim acPzet{raaQ abutting it (Fig. 3). ' The plemrA over2yin; the foccuo ic thickeneL. The clooe relctionnhip betWcen the broachio2e r.nd vur rcK,-ndiitg t~.-zoz in seQZ in the n_E>er of opa,ninha In the eozaunicctiona bete+een the bronchiol4r lt--,en cnd . . ~- . ~ •. S tH,2 ourrounding ocini in the tv.ot (L:.rcSert'c cersr:2o). In cscr~o arm8 the naegicsstic ce119 are srrengod on aci,:i tclhiYE in otbcF -epithelial cella of t'':e;o ccini cwd p:; Ellary forndt.i.ccac vc~r, froa c~©iCel iirc:jo (psrtScalerl; in tho porip"sery) thoy c:~~ }~'+~9t.?&T,+ fc~r~cit4c~a. `:ae to colv=ar. Fn t.l-e oore beniCn cr7oear6na for<-~o thc rc its a nir:;;1Q rc"S of ct:~~id ~l cQIIo, ::`10 nuclei cre aYS.'-'htly cu2.rre'cd r;tld the c;tcrpIcrm is "fncrcased cnd paler than unt~a?. AC the eitc of cc^:~Sc~ tten lsctc.~cc~rs the two (y i~,, The ctrG~- in tl:eco ne brracMc,%a. in the ccr.tcr of tS-rs ttmor ofCc3o t%a-w:a the cew'- tyl-a of e-'>it::e i Ln1 ts--cr co' Za co c;po rroQCht in the e.cini, T,,-nrticvlctrTy -amcn to cc-ano epci Sc cc=paeod of vc_•ic!>2e e~~cr.~.to of ccr<::ectie-e tir;E=E:t t:~ic4a rre otrendc of mrse th vnta_~clo bcsr-?Ivo, i'haro t:.sy bo n ciz}l•.cn, or d biuaE trcan£tioa frc-- the tz;:or to tho s~c~xr~l 1u:,t; Y_tenchy~lc (r i"g. 5A, L) . 55;e _tc.:r ccllo often i;rr;c az3t cmt© t2=~n Bc:~;-c~rtin~ o2roa2ar ce,ata. in the te=,.--r ,<.:o-reorcn, ti;ercr to an increcpc in the era'C'Jr of cell:a v4tt3 on cslterotica of their c7to7o-'ic c5nrrctericticc. The luncFic at t~e acin£ in tlfe t-L.!,-or hemma =~,e19, an a rcoe:lt of or. ircrcracQ in tho tF~~'~~r of ceSl gezrt. T`~;s r.c1Za L ro oftcn err.r:ncd ia r,t-, cc tc 131 . The ton,~,<rtcy tc:serda c c:vc+a gr46tcr in the 2:Zt;i11nr} fc-o::~tic~©, ~io r?zeto4 'rrct Iatger cr:4 cc-tcin prc;i.ncllt .VcZcVEi. G:cnci~Zl:l r.Atotic fQ_7,ksrcrp at:u pi-ctk:r:t. r:.tcoatro i:ribrci:chS.olc6 ffbx-a,+ir: to c,ft4~.;+ prccc-at. rca tYso rore aGvtrcad otegan thtira Sc nGroctcu vr.riotic-ri iu the cicte~ cN:p and otaiitfn- c?:orcctcr of t:ie nuclci. rtitclculi nrc c-ore prc.19incr,t encl ; taftotic UM.raa are c.cro froqunut. SqL,aeme ctoQfes with b-e1l l./'

I iutarcof 1falnr bridgen ere =oro cxtec~ai :e€, i,¢ nteclei in tl-,vQ o4n,=cLo 2enzeo I i obcu aoelenr at)-pirn :L~i1ar to that ceen in the scini (Fig, 111, 0. Cincit nucle£ alco bec~-~ tso:a Qro-~,ineat in the ttn-or foci_, Concccitent with the taore florid proccr,e which caac fo.und only ia.tho uot g of rro---? F and h there ia an extcncion of the tuinor cello throvgh the baecc=-tat - tboobrana into tt-* u.-~dcr7.ying otrr_ss.(Fig. Sh). T.zie occurrod in 12 dc;Sc, -CC= of which ;,%zd tw-orc of thic type in t•ao or na:e 1rr~ce, A1tbors':: tha celln ere t_o'-`o bizcrta c.~ith raoro Cir,nt nuciei; more ca;tot..c fLf;crce rresont; st~d e,wr~-.;~ ereco aro aQre ;SrcnLcent. if G-al}' CZti? Goct'.c3 had tioeln teben . :.- . t=ora-nro ch1t.pZe, thcy ore ~cr, raL;~ ccncentrctc: in cne area, To t%=-,&,r frca~7 t%ir^, t'+3 Of tt:'~2oi , G QvCZr-C~:JeO of 13qt='.r--u0 cG U r'r tcp~[ O~A E3L.~ fi&S$C6d' aty-pic~, or cqc:^:o<c3 co11 cprcinc--z mii;.lt hcve toen r4:Lo. CCiGCJ:&ic.l1:.V.1 ti.i Zitc 1. C;. ~ C'~ Ll'ut~-_.~, ~.- t ~:i• 1. .o n ncsat e:r~.(1. t1P>:a ~ C.F] t'i."1 Q ob^crvnZ in a; r,ts~uer of th3 tv=o_-e, slthouph this e•sc tee;: st3 frGe,ti•sntZy 6 c3be:vtd co in h--,zn Iun~3 rcported b7 Licbc~. _Ia five of t?-o cEceo critta L:;.II3ioM of th'::~ underl.yir=a t~ttc ~a tha:o afco en £nrecicz- of tine overlyio;; picur&. In me of tha tfva rccc;9 tire ttnzrz~ r cc1lo v--rQ cntansLc?e in the elLCtic_ fiLb=ra at t" SL:.ctic~a. :- In thc~ otr5r £o;!r cc:La[a the tt:7,or ca1ln frcra the vndcrl}^ir:s tc:~aon ce~, aztene-cd thre^_;'~t tca e1o^tic tsoun%cry Lnd c:-oro prccczt tteyc;lci tt;c plaurc~ulrorary lc::'ctf_ca fFE~. G's t!r~d ~') . A p::st of tc-~or co1Lc in vac of tl:coo ccc4,6 c-a~c i:~~c~o~ct fu h r.;,zeu r~; ich t,Yd thi ccafiEurctf.o:t of 0 Iy::; haeic vGCC:I; but In omQ of tha cot:aa c:rie th~;ro ev%d,w, co of tntnr,tc.cea to tho trac::ec-bcG:~ci?inl

rcnl_r.y ctiRCYwrft; 0? Yf.r tRC++CIICS Itrveota/e oqcmouu- co11 carcino,.a of atcroccopic 6ito was fo..od tn a broocuua of each of tt-c do3e. In both, an area of urcinc*•ia in eito voo fau--d in the hroucktmi epitheliua; and tnvacion into the uud.orlyinII ctrcca occurred fn thke oita. We have uoed the oarte criterie for carcin.n,~n to citn ond~ qarly invaaicn • 7 in tbo®e 4oso co we provicroely aaed inotudying human natortal . in _ eoreineaa in citu thara is a ccllulcr diaorgcairatioa utth loca of the r.e"l Inq- crinS; the enclet chu;;i grect vartation in oico, ohcpa sad chro~ltin ccetent;• nucleQr 6aperchrc.3~etin to frequent; thcreto an LBcreenod n=ber of mitccen t-ad -In eo^- c¢ee (do8 11II77a, eecrificed m Gay l877 after e-moking 6.13n ei0et- otteo) an invauicfl of the vsll of a brmiohuo vcn fata:,d in the area of a carefn.,_-ra in aitu (ri8o. 107.,10y). Tiro ir:vas4c-: eztcntcd throuun tac .~~:.. .... :.` =Lc brmchen into the pErit,rmci:£sl tiocue (Ftg. 10c). In thia ccoe, n/:oto of equ~e.3 opithalial ta:car cellts c~ero fomd in othcr parto of the ecmo 1aS¢. A ointler irzvacive cq~_-,Qwtoua ccll ccrcinc.::c woo fcr,md in the eoctLo,:it frc-a the lofc t~io bronchua of Gon Ii885a; :hich t•co cacrificod a1 ewy G~;SS nftcr hsvLcg ~d 6,210 e£;;erottoo (f'ig. 11). The depth of the ircteic.n eao not ao crcat ctt Lu Cc3 1~377a; ur:vorthelc€c, the eilvor c~.~•tbaruainc ateic of thtc coct.am ohEood the the ir<terrcr:tioa of,,L.ecor4at >xembrcrn at the etto of inrocicn. AISCI~: STOP9 tlrc:ul:;cilo-tarcolcr 1ir~~orc litatlu tl:?j rr.s jc rity of 1mf, eencer.r, to hL=n Uatr.ro 4ro r.4u ~--a:ra cr_11. unC rn- diffcrentictcG ccrcinc-ue, brcachiolc.al.vc,olor cr:vcir--r;•zto ai•c not rnr3. ll:.fficc I.Cy in ectiratinC the propvrtic,r Nf the lctcer ariacc fro,3 th~ fl,ct that rtr.£e^.ln totr.9 arc ct~cd hydifforcnt petholocirtr.. For exr_,p1c, nc-:.^ tt:_.orc of tlaa typc, ray L3 rc:rartel ea "r:(^rocsrcinnrxpo"; rin! tt,tc to not u7reaccal.blC ei.nce in. uc:i+; crcco tlof s+re Ller-fulor It, aypccreace. In n ncriGO cf 7,454 1-ri::ac7 1u;~,~, cnacorc ftt- ---- 9

r cludcd in ths 1lwrwria1 lYioptcal Canccr R4btatry, 1,759 t.-oro roeorl•od oe er.xcicrcao -'of spacffied hiatoleII£c type. Of the lctter, 214 (11.9X) ncro clersificL to "tcr- ninal broncbiolar carc`nocae". Art additional 162 (9,)x), LCro;claeuifiod On "eEoQO- eerelaocw", and a fenr of thece may hcve LEOU bro:+chio1ar in origin. ^'.; `• Is a proapcctive spidedtolosicel srudr, of lmig cancer, e dofinito eceoci- ntiua taaa frtcad ltetvsdtt ci&nrett,e avokt„g and dec(h rotao frcn ~adCY.oearcicaoa" of hi d i " " " " G n t l~Lofl laclt.:a brac+chtolar carcfc,rrs w olveolcr corcinaaa and CW ItML ( • $ 10 coto%j;rrp,) R4anezel, Lovelrnd cnd SirLoa toesad a oiAilar coaocictica, the ston&rd- i.eoc' rsortalit7 ratio for "ader,ocarcinc•-....a" of the lunt; bainE 26 tima ec loio twj,;.v. ms>a voo omked over a pacti of ciEarettoe a dap cn cs%*na n:o c:no acvvr tzd:.od. In 11 ecot[ror prospaetiae el•udp, over oobsecto rore trccod for c? to eir gecrr, _"Tn a reeent rerica of the rccordc of thot studp, c>o fouad thet 47 of the ewle euS- jocto uero reccrd,sd as dpirg of "r.lveolcr cercii:c.;.g", "c1rreoler cell carcitccas" or . "bre_c'aieler ecrcinc,~a", and ercthnr 1S9 nsle ouhSa-tc usrc recorde6 co uTs.nT oi "edenocarcir,c~a" of tho lumge. Stendcrdired for age, the t.octh rato fr= "brm- ehtolar" snd "elrer,ler" cErcina:a eac czer thr::o tL,sae to h1& Q:,mg t•_^_n rdjb ccro ecrrant citarette tmc,kors at the ctcrt of the ctudy ca t_~g t:-2n tis;+o hcG mmer cssoknd reCulcrly, Yl:e -&-atl, rate from "cc:cnoeercir,sw^ of the '_,,-as vuo orcr tivo timao ca hirh ner.g ccrrcnt cigcrctto rma*crrn co Ez,mg r.a. -r„okera, tfo can only nprculoto CO to whp,-in r-..okLnS doto, t-^o fc-nrnd cxrp roro isccr=.ro hraaclrio1o-alroolcr tu._.=oro then leacc+i~n equLr_,Dua coll cnreir:oade of the tvrcncl_cb. Ao cicaretto cz=kc l,cacoa tlrrauth the bronci::, rs~_a of the Lf'rtfcaicto cat;tor to Cc;oefted a:1ca the cpi:cl:cJ.irr_•, i'fiea, tno!~e cntorina the hmn::lriolee 1;Lo e reGnced e<SOeentratYcu 0 r*rtfeclr.te r-.ttter, Sfaco tl:t2 1:YC.xchi of t':o;;ti aro fvr tFa:rtor thcn thebrcvc hi of e:n, it rsp ti:s cuy:pocscd thst• lce.n of the s-':rticvlrtt eattcr S.c ciq:.rctto cza':o it q%parited ca the hronclriall oi,itliotiu:w of t.o-~-,o or._ c:r;reup2 Gic~,iy i~_u to dclrccdtcd ca tlfi apt`h~lktct of tia ttcncltolca. If no, ti-3 rctio of UrcicLiol:o-aFvcolor. tr__'~'rc to 00>.r '.tma ttT.orc L•r. c:.:~Latt~ t6;a r.u cr~ctl^G 003 the retio in ran cce:lC, to c~ l+ac_v? vZI tl; : 1•Lci3 of e C ~e-r rr•~ ~:c9 rrlatLc~ t:ro;,, 10

Efo hevo cg?liod tho ec:w criterjr-1ec brooci:folL-e.Icncler tm-trre no r.c4d by Licbew for ooet: trsorc occcrriag feo hc:-~ea Datann c-.d tCzicl3 ho GLeeoaCOo -- 6 tmEor ttds titlo GroZR-Alveolar C.crcit--s", wa have used t.ha torfl, ure. ehiolo-alveolar t=or" rattnar than "hrocc-h£oto-r,lveclar carcirnw", fcr tl:a 12 ..t r ruaeoD efate y kroaa tad /:I1CA .. • thot thia torsn lo•ru not c=e1-(;u t o o 'arorop to a bcs£Gn or rwelit,r.c,nt,G-aei&oFiivn. of the Icn; that tlvap scsct be tss;aad a Grcaaly roc:~uzicebla brc.etrrz with a 6 . .. •. :... f2-1~ f.tabom'e critcr{o , V%icF: hIIvo taea L,OaoralLy occepted, ero tF=C tiw t~ors aro ~11 dif€omeWtictoC Af,~aoccrcir.cre o:cerrfflg £fl tSzo rorirlearg tocLascy to cp reab ch2efly Littst"t:a con:" cf t!~ ltz-~ by "c+crb~t4s,c" c-r BsMcrtfea ctrczka for tha caopl6stic ccl.ic. G peL2n.-y c"rcc: "tetGo tbo Es~, 17r;hatfc rccatea. Ip edditic^_, the 9--ZIlo of tUo Eictoi cir nptcco oftc:o cct to r= c--- hafore a Zic,-neeis of L rcacklmlo-e2,racier tcicz cco Fs,3 cz;- fa, li2th~b th-z hicto1c; ic c1l2rcctcrs:Gtic4 of tFa bnsacktoto-ALve~l.ci~ Lc~c:c - fc--m-d In tr.9 c..~tir.3 Zefo aro r.ac iPtcticel to tF-r.s Urc:Qcl:lolo-cl.darlsr tm~-sro Ln {=ssa baiu;a cs 4--scri4ed Lq L£et5cra* , the o•rcrcll F:£ctcro Ssa*_ifios- ttx£r in• a css~artic~ ctrutc:ro for tF-.s trara; but tuia f:r. c~t as ctcJeiV: an c sa £n = fato Lf tFa dc-p tad not t~_-c, cscrificcd. Y`"o taLYc of the circclce c-apta Ccra' cZasie-a in thin catugorq, Vlore are ceticrol LLfrcccncoa. In the ttm--,.°a fG.rid in che- dcy;a, "c3rcqgeracc~ rprcaG f.c prorcr.t; E-_t FS-~7317tic apracd to not ca foaturo. Tt cay or r. p not harc c-:..cc;rrad at c tESoc A Htrii:Ln- recc-,'r,lc.lca to ~L_.c {c3 Ln tt;o rCeco of C~rily Fatht£:tcef:c~ cd 1t;rSC ~r~-~ie fa ;`ich ~~br.e£aca c c•~cr r:?ee ~ae~t osrcn fre:, tr-~ c~i.re.c~ £~ G Q.cecxZ£c,q to l,toloaa c:=.tc: tr.cca c.:cr.re to ct i:car: S'i'7~ af t~ = et•c ~. . . E4ra~ rie;ce cv--ra prc,!,_ctic•x to e. c~t~t £u tt3a t:r.~:zLtclc-clv::cic tc_~~o Lc C:^ .. A c~trctt Iieo £r~ tLa ui£f-ere:~co ot 2y;.~. L<.c ~r.d F:^_ tci?caC^~ fftC~:'r.rt:4Lv:~. L'a h,w:, not o'uc.rvcjO t-l:to is, a:rr t;r.•F:iL;~ C: ,Za e.;+ to., tL:d T:rOG-:t ttf:c.

Liebqv alco atetoo that there in a frequant lnvae(aa of tk,o 1?ulcvsaory artorioo area in the we1l-difforentfated tumorc. Diatant involvte*nt euch no the broin, lircr aud other orglt.ro in eom~e of the ho:3cn casee rf bror.chiolo-alvcolar tisore. •hao not been found in any of our doga up to the prunrnt tiae. Extenaiva otudy frcqurnt iind{ng In the tUe»orn of naoking dogy and accura vith groater freqvaocy of theee orgnna will be donc at o lntrr dato. Gqur."oua catcplceia to an extrec+ely to the more r„alfCnont foree. Liebav r.teteo that equououe r.utaplr.oia in broachiolo- =.alveolar taaora in lcu~sa befng;e i6 rare, havinf, bcer preoent in three of hio 20 Patho;eneaie of Brosichiols-1:1vcolar ?u_horn The applicetion of cigerctta rnoko to the luaCo over a period of over 075 daye Lavc us the nniSuo oprortunity to observe u ecriee of progreceitic+ petbolr-gic chcegee 1kahich ran frao: a'non-invacive charecter to that of eztencion i£to the c+wor.- 1Fin;, hltwra. Sere:rr.i qu--etiouo bt"lhe, V etoor.-cut ancvar can b~j Cfver.. TheEe aro; 1) Since th.eee tu_--nro ore ceyTabla of cutcnding Wyond the coflfinxt of tlk lung into the Plouro, thoul:d tfie5 all, 1,3 c4F0Ci4ied on canceroY 2) EincE the oboorvedcerieo of proerecLive chac£Oo occurred urdsr tko it my be celled 'S:gli,pnsut"1 Since the civ_•ngcc crc prnratnive to imvncic•a of tha tixro a poiEt at w1:ich ono may aap the tu:.or in "tsr.i{a", nnd snothRr 1•+oin[ ct v-;mictr - influ02c8 of Cigart:tto t'_ohe, can all cuch tvzerc be cecigned to one grcrapY 3) Lc platqif. liffcrEnt obcervccrti may app1y the terti tencer at different nait:ta in thi0 co,tir.raia rtro:coo. The microacopic air t~ntlcno of the bronctiiolo-altool.cr tL:aorr lcu4 tuppfrt to brar,ei`iclc6. eertrel bromehpalc fcwnd no froqc•.:!ntly in the fc:i of thcoe tu-oro, nei! tho rra:.cnco of rz"-ath ru.acle tuadicr. conf the ccini cnd p=rilt;cry fon=tiana e-yeclc ctr(Y)f;1y for thi6 arioin, knnth;r patnt itr fovar of thia vit,-cr in the tnparinC off of (;j.1th^Iir,l. tt~ar cc11c in th, pzril.l~ery, Epitl:elial prolifcrntiona in t.+e IininL of the tr.11c of the alvaole:r c',7: ccic t:are not fcu:iG in cbt:cncc of l:rolifcrcticn in thc t,d}r.•lcrt - the Lenerelly hold vicv thct thoco t...~orn erino in •tho bronchiolcr cpitLclit.~, lha

Elcctxcn nicroccogic etcdtea of thEne tsc-nrta nci Lwina ro.forr.->£! in cor 'latwratorica ooy eaexcr-thQ queati-oa of +e4ct4er olvaolcr 1iAir.U ce11o aro o teoaaible oo.:rco of thece t~~oro. rvaturT11,}L Oeencrirv~ £uL.r.aarY Tc ore In Dowa 3,4 of thaao tm-zore verfoe frc:i 0,2X to C,61~ at cyto;:y• - lnlaoyary tt=Dra In co Ghavo. Sern dcocritizd' by netiorol t.u[horo. S°:o prcYalcnce 4 12ieloon Eouad the average eGC ct cleath to be 9 resro for doCs with oacv trmoro. The ercroCe nao of the dcgo with 1w^:C cczccr in ttn r•ozica rcForto3 by F~ e~cy 40z6 17 • Cra-,Q - rea- 1J.a ye.err , one, tho yok---sGat eog in the iorioo mo e2ron ycara old. Y.c lettcr au.horo atrooo the feet tkat cnrcrn^n-a of the 1x:a3 fo e dYclaoo ef old Zo,r; 'A FCYioif of the litcroturo i.y i.rc::cp c:; C:::C Cicc<ccc~ 109 ceai" icng t~tira, 63 c: v'hie5 s::e .C.;nec-areinccxao. Scb~ and t:er.necy ea the oth.er Eztd, ac;y end cp;;roro to bo :ttre in thcae anc,~,r oe.e3 ycara of er~3. Ch+t 75% of c_imary tt:u2ro of -the Cof; are arr.zct;<uao-r;,-..1_- _t=^^- t`;e3ticcrtric tr.-oaro G+.:y occur In cmo or both 1t~,2-; but tTpicclly it c c:olitcsp rc..'>;:to c"lic5 cris-eo 12 the pari;,bary of the dirFtirc~:.:tlc lobc. Crcwth of thece timorn c,ccora by t+fca AAd iDf(ltrct:on. Mctolo;iec1ly they cro act-ler tz=orn of ret;w: L-oni;n c;,esx- s=o in thich the nzo2S:netSc col_s C;tc•c ralin'•y ea the cra"tio of the ri:vaoli. G:yly a [°^...ai: f:c;~°GAca vE thoro tr_~ro natecteozgo. s°':.c a; croscna£c a~t,eFprs c of the tt=ro is einilor to the re:ro tc-uoro obcervtd io our cotioo. fr^.arlnacecl~, :'ro~3ucad T~~ern in Uo;rn, S~u.:o o ccll ccrc£sa-a of the hraacF~i, in dcfo hr.o b ca t~rc~ucr.G t.ry the et n~i- 14 cctfca of tamcco MCao condooccte, Sir-iir,r czncc:ro hfrc been yrc'ccod• by dL-,cttiy- I£L~s.aeetbrcaa aiid r_ctli7Lc2.o1ncthreno, 21- CFt.rtie cn~i tGncr_it_tco r,r. £r,ir.teaed '?u 02 c;:rc--?ctn to 43 Gcza. L'i,ta of ten lo; 3; nh£ch,. ckmircG frc:a 2; to 56 oc.:c;;c icvclof,c4' 1.rc-nchfc:.o•~lY^L1.RI car-

_olvooler tworo uith rubanqw:nt r.alfpant r"rectcr, cre in +aeny t"eFo, Bi+ailar to The uicroecopic fiodinsa doceribed hs ,t',].erka e:,d oeeoeictas of bronehioto- the more edvr:nced ttisnc,ra in our aerico. The eeteanf to plccwprphicw of rt,e calln, . the rreaence of giaat nuclei. rsitoeeo, uvcoi4a of thra u-.dc:rlying otro:*A cad •'finallp, imxofon of.the plcurn; cre aAj=~.~:1o in the tuo etc6iFC. Oar atudy ~,- differed in that v® did aot obuoire natestc'r:co to the trnct.cobre~chiol lpr>ph ceoG..o aar did ao find dictcGt wtectneea after 875 dapo at r.~olicg. Cc+r1S Inacr+ivo Lraacl.iel Ccrcinc-..r .. - , . . 71 Inraoiro Eqramcmc cell carcinano of uicrGeea•;ie aiee usR CaEVd to krsaci:£ = of tro dose rfiich aaoti.c:d aori-filtcr eiLGrcttce, 'n _oe tr-e cnrcinm2pac aro in- dietinEviaheblc fmi thoto a.hick t.-© h.avo obacrved S.si bzo3chi of ht.>.`~`an bair.~a cho rxokrd ci~erettcs,

a1wo16r ts"ora vtth enbseqer:ut ;: -ihe eiccczcs?ic' Eindinga dmccribed by.Clari:o cad Eceociatca of bronchiolo- the roore advancc3 tmnora i-n our nRlit;nsnt c~Aractcv, are in cccq ragc, of.z.Llr.r to eeriuo. Sjso crtoi:uiro ploe<aorj::tibrca of tbo co11c, L3S8 pr'PaQacO of Ciant nNClni, CitoG@o, £6'VGcica Cftm C':aC.Crty'i[2b`6trc.^..nG'£A, f4c:.ISy. iuvoaic+n of tta plcurc, are ec:j.srcblo tu tt:9 tre e:tt>Gioa, Q4e ataGg • difforef ;a tMt vo did c.t oboorro e~tc+otccae to tha trncS cacarcoct~ial 1y'zTA c6Zas oar eud we tissd diatact t~tr.atacea cfcor 015 Gayo of mokinC, . - Y.~r1g Znvaoico rzrca :Mol Ccrc£LF:--A IsraelYa cell cgrcics..-. of eicrs-scctfc also ia+a fEr.sd £t3 brcachl - of tvo do;;e t<'aich r-ked ron,-filtor ciCaretteo, ~'r:recr [to cnrc€ri=a cra ia- diotirCuickcbla frrrs tkoeo ea£ev t`a hc:uo oboorrwd in bresctt of l:cWu l*ieLo C„9 ~c~ cf~tettac. -Tho euthore cro Cratefr.l: to the follc-: LnC e;io rcuiet~v-d s£erc-,cej,ic c1iG;fl aced in tbis ctudy; tiet£c_.eI Iuctitutca of i:etiitti, 6sthecc<e. :.arp,lcLd To~a 14. %srC. U. D., t`'"ad. Ei.iGc-`sLcaio~fc Pr.thoEory LI-n£t, t'attoaqt Ccccec F.tret€tato Er=Lo Carctt, 31, U„ Ct;fef, LeborctcL-Y t<-ccv£ee, t'cterera f.d_tnictrctfca 1:_L;3ita1 : . . . . . 21 Souad t:. 13iGZLOfl, t*..~portr--nt of Ar-ir.al f)ircococs, UY:£vero£tp of C.ou-n-ecticeF Tbo cett:neo Srctc fuity r.c4:r. -r_loL~r c1; vnr4ctr.rc~ of l.z. L. J. t'altcc•r EcL* Fimy-m-2a3 lcr,~3r, t:. 1?., C?sfef of Stt.ff enf: Ci11cf F ~:.raco:y, £ar+f.oo \'ctcronn Gc:::.lrfotrcaiua t'or.t:facl, 11t.tt {sr-cU, C -,tre. Poto Alto, Ccitfc:fmiu Storro, Ccnnocticut . •- _ Lhi~2G2 i~arr::a, N. C., F'aK LY~alcnd ccrr~ar.o,GcLnitol, L~ccr3, i'~ccceNLC~tit3 prcp--irr:eic-a of ol I(; c.c,:rcp.~ic r:4tcr;.al.

Table I.Dala on dogs with Iung,tunora indicating typc of tumor an! lulc iu vt,rut, til.' `•'-••' was found, I I , Fi h t.26 3,928 ].A L h G49 4,143 5,0 GI 11,,}L'~ 7S~i 5,/;L3 5.1 LA,l4 Lt., left :,pic;.l ]ube; LC, left rrcrdi:.c; 1.D left di'::]1r;sL~natic; PJ.'Fri;;nt apncal; :. y, ri,;ht cardiac; 1:1, righl in-cnaed'iatc; RU, ri11Lt dir.phrtg;,aGte;' Li~1:6, left apical liranci:Drom:hus; L]!L, left catn 6ronc;,• s. For swoling,doTs the ;.y of death indicates the nu;zbcr of d'4ya sLncc rCart of rTokiitg, 1hc ]CCitcrF "'ot "A" Dotloss thc dny,~~G ccntli of to car-rificcd after lay .'t75, Lobes with Gronchiolo- alveolar Ti~ora Early Squr-oua Croup Day of Dcath No. of Cigar- ettea A,^;e at Death (Yearc) Non- Invasive Invaaive Ccll Bronchial Carcfnora Group C (Controls) C °04n 5.1 LA C yU4h Group F(Filter-tip)F 878i 6,161, 5.1 1.A F 879: 6,170 4.7 IA F 885a 6,224 5.2 l.A F 890a 6,269 5.4 LA Group L(No Filter) L 347 1,055 3.8 LA,I1C L 812 2,847 5.1 FA I. 876. 3•1~03 5.1 LA,R4 _ L 877a 3,107 5.2 LA,Li , L Pr7a 3,127 5.2 IA,1.D L 896a 3,183 5.3 LA,R9 L 894a 3,195 5.4 LA Group H(l:o Filter) H 135 5118 2.5 P.C H 259 1,342 3.3 LA,kA,P;D H 563 3,404; 4.7 LD„^A H 716 4,689 5.0 LA S 753 5,030 3.8 Rl 11,,FjrP.D H 760 5,038 4.2 LA .H 858 5,570 5.3 LA U P76a 6,129 4,9 LG,LD,P.A H 877a 61138 5.4 LA I~.i;3 11 87Fa 6,147 5.3 SA LA II E82a 6,183 5.4 LA 11' PF3a 6,192 4.7 TApSRl ].A H FPSa 6,210 5.0 1.A,Ph L H 8E9a 6,246 5.0 LA H 890a 6,755 4-9 i LA :• H 692a 6,273 5.7 LC,£.A IL I 1: 892b 697,E E97b 6y273 6,31E 6,3U5 5.3 5.2 4.5 i:A LC LA,RA I11 Group 1~(I~o Filter) h 60t, 3,769' 4.f. L,1

able 2'. Number of dogs in uhich one or more tumors (Non-invasive or ittvasive) were found; and the number of 1oUes in which one or more such tunors 'were found. Controls Filter-tip No 1'ilter No Filter No Filter Croup C Group F Group L Group l! Group h A. Dogs uhiclL died befnre doy fi876 Number of Dogs -. 2 2 12 12 Number aith Tusnor(s) 0 2 7 4 Number of Lobes 14 14 84 84 Number with Tumors - 0 3 13 8 I B; Dogs szcrificed after day i875 12 C. Tota1. All group C;,F, L and11 dogs. hwaber of DoFs, 8 12 12 24 *. Number with Tuaor(a) 2 4 , 7 19 . ~' 7. with Tumors 25.0 33:3 58.3 79.2 * Number of Lobes 56 84 84 168 * Number wiCh Ticr.or (s) 2 4 12 35 * 7.° v itli Twaors . ~ 3.6 4.8 14.3 20.8 ie * FiEures omitted because no group h dogs were sacrificcd'. . Nu.-sber of Dogs $ _ " * Number with T tw~or(s) 2 4. 5 12 7. with Tumors 25.0 40.0 50.0 100.0 * Number of Lobes 56 70 70 -84 ~- Number with Tumor(s) 2 b 9 22 * 7. ~:~ith Tumors 3.6 5.7 12.9 26.2 1 i

_--; ---~ - Table 3. 'jypes of,invasive lung tumors in•12 dogs that smoked in Daientheais r:on-filtcr indicate the location(s) in which the tumors yere found. Deacrihtion of Invasive Tumor bop, and Location of Tumor invasive 6ronchiolo-alveolar tjn„~,%1- v{th squamous cell foci iind pleural Involvement Invasive bronchiolo-alveolar tt~ur r•i~l~ ~y_,G....,,.,. _.. . _ - - and early pleural invol!vement Invasive bronchiolo-alveolar tumor with squamous cell foci 11877a (Left Tidin Bronchus) 11885a (Left Apical Branch Bronchus) 11878a (I.A) h626- (LA,BY) h649 .(LA,RA) 1171G (IA) 11753 (1-4,F.D) 1187f a (LA,LD,RQ 1187 *, a (LA) 11885.3 (P.4) 11889a (LA) 118921+ (RA) 11897b (I-A) Hotc: Do~;s H877a and 11885a, each of ~:1iich had, an early sqi~amous also had an invasi.ve brorcchiolo- cell bronchial carcinor.~a, aJveolar tui1or. 171/

0 ~ l ~ ` 2r-~-~ N<`~ Fii .. ER f ~ j ° ~ x9 @ (!/? L.S A r~Y ClGARETYES) 24

0 V 9