THE APPARENTLY BE EFIGAL EFFECTS OP GONG RRENT INFECTIONS

INPLAMMATIO OR FEVER A D OF BACTERIAL

TOXI T TIIER \PY O EUROBLASTOMA

*

GEORGE A . FOWLER, M .D. AND HELEN C. NAUTS

MO OGRAPH # 11

NEW YORK CA CER RESEARCH I STITUTE, I C. 1225 PARK AVE E EW YORK, .Y. 10028

E W YORK 1970 INDEX

I TRODUCTIO1 . I

CONCURRENT I FECTION, I NFLAMMATIO , FEVER

SERIES A, 18 CASES Table I IO Detailed Histories 16

TOXIN TREATED CASES \0 SERIES B, g CASES Table 2 . 48 Detailed Histories 52

BIBLIOGRAPHY 79

We are indebted to C. Everett Koop, M.D. for his thoughtful review of this manuscript and for his helpful suggestions. INTROD CTTO~

THE APPAREi\'TLY BE~EFJCL\ L EFFECT ' OF CO.'.\ RRE~T I FEC- TlON , I~FLA?llllfr\TJO:\' OR FEVER, A.:'\D OF BACTERIAL TOXl THER.\PY 001 ~E ROBL.\ 'TO;\L\ This LUdy of neuroblasLO ma compri e Lhc kno\\·n ca es of Lhi Lypc of tumor in whom baCLerial toxin Lherapy was admini tcr cl (eiglu), or m "horn oncurrcnL acuLe infecL ion, inllammaL ion or lever o urred, (cigluecn).

01\IE CLINI AL FACTS ABOUT ~Fl"ROBLASTO.\IA Ncuroblastoma is found in infancy and cJ1ildhoocl and originate from Lis ue from which- Lhe adrenal medulla or oLher ponion of the y.m pa the tic nervous system develop. Approximately 15 per cent of all ancer in chil- dren are ncurobla LOma . In the majority of patients with untreated neurobla ·LOmas, rneLa La cs develop oon and there i a rapidly downhill cour e re ulting in death in a few month. Because of the rapid growth of this LUmor, a hilcl well 12 to 14 month after LreatmenL wiLh no evid nee or re urren c, probably may be on idered cured. (M) fL er biop y or incomplete urgical remornl, an infection, fever or with• out known cau c, chi lllmor may undergo pontan ou hemorrhage and necro­ is and regre · compleLcly or may undergo maturation Lo become a benign gang I ioneuroma. 1 • urobla toma was [ir t de cribed by l\larchand in 1 91 as beino· derived from neural structure. (43) lt wa not until 1910 that the) were e ·tabli hcd as a eparate and di tinct clinical entity by the hi LOlogical ob crvation o[ \\ right. (77) 'I hey are neurogenic in origin and are om Lime rel erred to a ncurobla LOma or a sym1 athcticobla LOrna , as they ari e from the undif. ferentiated cells o[ the sympathetic nen-ou ) Lem. Th ir origin i not con­ fined to adrenal ti uc. They may al o arise in the sympathetic gangli ons along the ·pine, e pe ially in the ce rvical area. They are more 0111111011 in males. tmren grouped the tumors of the ympathetic nervou y tem imo the f llowing: congenital n urobla Loma, neurobla ti ar oma, ganglion urobla • LOma and ganglioneuroma. (67) The first two are indi Linguishable anatomi• ca Ji y blll must be separated bccau e of difference in bi logical behavior. Ii congenital ncurobla toma probably alway occur within the first six years of life and i fatal in 70'.fi: of the ca c. The neurobla ti aroma occur with random frequency throughout life and is invariably fatal. The ganglioncuroma i a benign LUmor of mature Li ue. It occur mainly in the adult age group. The ganglioneurobla Loma i a tumor which combine fcaLUres of both nor­ mal ganglionic ti ue and neuroblas torna. It i · c cntiall y only a histological de ignation rather than a distinct entity. He reported that 69% arc fatal. (67) I ncidence of Ne11roblasto111as: l oop Lated that neurobla Lom a was Lhe mo t common tumor treated at the Children's Ho pital in Philadelphia. (39) Dar• geon Lated that it is one of the more 0111111011 cancer ob erved on the Pediatric Service at Memorial Ho pita!. From 1926 to 1958 a Lota! of l ,49 ch ildr n uffering from neopla tic di ea e were aclmiLLecl Lo Lhi ervice, I 0 of whom had neuroblastoma. (12) Initial ymptom: The iniLial ympLOrn may be pain referred to the spine or legs, but in at lea t half the cases an enlarged palpable abdominal mas will be the mo t prominent ob en·ation. The clinical s •mptom produced by an expanding retroperitoneal ma in infants and children include gastro­ inte Lina] disturbance, debility, anemia, blo d changes, and signs uggestive of acu te abdominal condition . "\\'hen an abdominal mas is felt it should i INTRODUCTION

be co nsidered maligna nL unLil p roved o Lh erwi e. (54) Less often symptoms are !referable ini Lia ll y LO Lhe che t, perip heral nodes, kin or a ingle bone. tumor of the orbit or eye itse lf is not uncom mon. In some the metastati c le ions first attract attention. Loss of weight i u ually prese nt, there may be emes is and when first seen the child i pale, uncle rnouri heel and irritable. Jn ome ca e swelling about the face or skull is noted; proptosis o( one or bo Lh e es with di co lorati on o f li d is om mon d ue to increa eel intracrani al pre sure and orbital metastases. In all uch cases choked discs are prese nt. Enlarged lymph node occur ea rl y or late. Bone pain from meta ta cs may be the predominant fea ture a t thi ti me. The clinical cour e i usually a rapid decline with death in a few month .

Structure and Jl istolog;y : Structu ra ll y the5e tumors arc rather o(t, h emor­ rh agic growLhs, Lh c cu t surf'aces of which are white or ye ll owish in olor, with necroti c and hemorrhagic areas, and which d i pla a distin ct lobulati on. i\Ii­ croscopica ll y thi lobula Li on is fo und to be cl ue to the d ivi ion o( Lh c tumor growth by strands or bundle of connec ti ve ti sue; the heavier tra ncls are continuous with mallcr stra nd of conne ti,·e tis uc fiber whi ch further su b­ divide the lobules. Hi tologi ally these lobules vary in appearance : so me may he extrc111 cly cellular, co n isting of ce lls with sma ll round h ypo hromati c nu lei and urrounded by an ex treme! narrow rim of cy topla m which tend · to fl ow o uL into processc . Often there are LO be seen tran itional tages in their development wi th neurobl a t , ga ngli on cell , nerve fiber and cap ular ce lls. T he more acl va n eel tage of diffe rentiati on the le s malignant the g rowth, the less cellular the area and the more abundant the intcrcellular n twork of fibrillac, some of which may be traced to Lh ei r nerve cell . The fo m1a ti on of ro ettes by the cells i one of the characteristic, but some authors have een ro cttcs in onl y a third of their case . T he ro ette con i t of a ircular arrangemen t of cell about bundles of fibrillae. The charactcri ti c cell is similar LO the primitive migrating ce ll s of the sy mpa theti c nervo us ys tcm. ome authors believe that the e tumors are moderately radio- cnsitive, others do no t. Certa in pathologist bcli e,·e Lhat neuroblastoma and retinobla LO ma are essentially imilar neoplasms. Cu hi ng and 'i\Tolbach were the fir t LO report that a malignant neuro­ bl a toma may matura te into a benign ganglioneuroma. (11 ) T hey described such a ca e in " ·hich thi oc urrecl fo ll owing pro longed ad.m ini trati on of Coley toxins alone ( ee below, erie B, Ca c 1). Other reporting ca es of mawra ti on of Li te e tumors include Eyrebrook and H ewer (18), GrecnEielcl and Shell ey (29), McFarland and appington (42) and W ya tt and Farber (7 ). T h latt r a l o ob en ·ed tha t neurobl a LO ma may undergo spontan­ e u hemorrhage a nd necro ·i · and di appear witho uL any trea tment other than bi ops .

fliffere11t ial Diagnosi Willi (74) and a few other authors have noted the imi larity of neurobla torna meta tati c in bone to Ewing' sarcoma: both m a ha,·e roset Le mi roscopically. However, Ewing's sarcoma u ually occur in later hildhoocl and ha the characteri tic oni n kin appearance roen tgenologically. hcrman and Leeming n oted that neopla m said to be confused with neuro­ bla toma are Ewing's arcoma, primary reticulum cell sarcoma of bone and rare! even certain o teogenic arcoma . Thi i an added rea on why the ro lllg nologi t hould be fam ili ar with the x-ray a ppearance of this tumor. (60) In the pre en t tud , eries B, Ca ·e 3 and 4 were initially regarded as E wing' ar oma and a e 5 a nd 6 " ·ere regarded a reticulum cell sarcoma.

2 INTRODUCTION

THERAPY a) Surge1y: Farber ( I 9) and Koop (39) have sla Led that the first Lep in the treatment of any solid intra-abdominal mas in early li[e should be urgical removal. Bodian (2) observed that a triking feature o[ neuroblastorna is that by the time they are fir t seen the majority show x-ray ev idence that the tumor has already invaded adjacent strucLu res or meta Lasized. l ndeed, metas­ tases may be the first indicati on of the tumor and in e the primary tumor may not be obviou , this feature may lead to an initial error in di,wno is. Be­ cause these wmors are highly invasiYe, thi frequenlly makes any auempL al adequate surgical removal out of the question, specially in intra-abdominal growths where retroperitoneal spread frequently involve adjacent vi era and urrounds major ve els. b) Radiation: As to whether irradiation should be u eel in these cases, opin­ ions differ. Koop concluded in 1955 that x-ray is not as importan t in the urvival of these cases as has hitherto been upposed. (39). ln J 96·1 he slated that x-ray therapy is not given routinely after surgery. I[ it i · given he recom­ mends a total dose o( a pproxim;i tely 1200 r rn th r th;i n the higher do age pre­ viously in vogue (40a). ·wittenborg stated: "The limiting dosage factor in the treatment of in­ fa nts and small children is not the skin , but the respon e of the hemato­ poietic tissue. Vertebra ex;i minecl postmortem which were within th e dire t field of therapy showed evidence of bone marrow depression to the degree of complete hema topoietic tasis and fibrou di placement of marrow. This wa true of calculated tumor do age of as little a 600 r in 10 day repeated tw ice or a m onth apart. It is axiomati c that the total amount o[ hemawpoietic tissue irrad iated or the dosage to which it i subjected are the decisive factors in determining recov ry o[ an infant or small child from the radiation effect." (75) He cited two ca es that died of clinical pancytopenia a nd co mplete marrow uppres ion confirmed at a utopsy. In the group that survi ved none had received x-ray to both ch es t and abdomen. This experi ence would indica te that deep x-ray therapy directed to the media tinum and a bdomen in ti ue doses up to 600 r, if justifia ble at a ll , should be undertaken with co n ·id erable reservation. Complete regression of tumor with cures has been ach ieved with as little as 400 r delivered in 16 clays. A number of investigators h;ive repor ted on the deleterious late effects of irradiation in children treated for neurobla Loma or \\ ilms' tumor. King, et al reported three ca cs of radiation induced osteochondroma in infants irradia ted a t the age of from five month Lo three years for neurobla torna. (38a) Severe skeletal deformity, incl uding scol iosi , may o cur in these children as a result of radiation changes. (-1 b; 57a: 73a). Other have observed severe radiati n nephritis which. may ultimately prove fata l. Two su h cases are included here as Case 7 and 12 in Series A. (1; 18). c) Vitamins: Beginning in 1950, Bocli an attempted to determine whether Vitamin B-12 could bring about matura tion of neuroblastoma. That this icle;i was erroneous was evidenced in his Cases 1 and 3 where uccess ive biopsies were obtained. (2, 3) There was progressive shrinkage of tumors in 50 per cent of the cases, compatible with de truction rather than simple d ifferen­ tia tion of the neoplastic tiss ue. Encouraging results occurred in a group of patients con idered unsuitable for or thodox methods of treatment, and in whom the prognosis was considered h op eless . The dosage he u eel was I 000 micrograms of the crystalline product (Squibb) given intramuscularly on al­ ternate clays. In some cases this was continued for two years, Boclian's Cases 1, 2, and 7 had survived 30, 13, and 14 months when he published his fir L INTRODUCTION report, and the di ea e appeared to be arre ted. (2) In Case 3, although the child finally died, there wa triking regre ion of extemi\'e liver metasta c~ over a period of nine months, proven by succe ive liver biop ie . a"·itsk and Depo ito collected the re ult obtained by American ph) i ian with itamin B-12 alone or combined with x-ray or other agent for advanced neuro­ bla\toma. (5 ) ~o in rea c in rcmi ion rate wa een in tho e reccivino- the vitamin. Po sibly it effects may be more apparent if it i admini tered prior Lo other mo lalitie and earlier in the course of 1.hc di ea c. ][ it i g iven after concurrent infection or fever po sibly the re pon e may be greater. ( erie Case 14 , 15) cl) flacte,ial Toxins: Recent rc\ear h had indicated that bacterial infection or their toxins may timulate hematopoi tic and reticulocndothclial function and protect these radio en itive ti ue against the lethal effect of radiation ( , 3·1, 63). Al o bacterial toxin appear Lo potcntiate the re pon e of the tumor Lo the irradiation. C, 49). Thee findings ugge t that it ma , be advi - able in treating neurobla toma in the fuwre to admini ter bacterial toxin prior to irradiation and to reduce the do age of x-ray. incc many ob rvers have reported that urgical strc~. or trauma markedly i ncrcascd the number or i, of Ill ta ta c in variou t) pc of tumor , it wotil;I seem ad\'i able to aclmi ni Lcr toxin before and after all ·urg ical procedures, including cxpl ratory operation, to counteract thi cffe t. Progno i: Iany authors, e pe ially prior to 1940 believed the progno i in neurobla toma wa ab olutely hopcle s. Poore (55) and Goldring (2 ) quoted Redman a . ta ting that the "clinical cours in thee a e i almo t uni\'er all , rapid, progre ing Lo a fatal te1·mination. The average duration of ymptoms and ign i about two to five month . lrradiation produce only light tempor­ ar • re pon and urgical intcn·ention i u ually followed by death "·ithin evcral months." Koop et al. reported in 1955 that 39 per cent of their . cric (10 out of 17 ca cs) . urvived even though half of them had meta ta e . (39) Their method of hoi e wa urgery, even though only an incomplete removal ould be effected. " ya Lt and Farber and other have concluded that a one 1ear un·ival in childhood neuroblastoma i equivalent to a fi\·e year urvival from the average form of adult ancer. (77) 1\Io t of the ca e in the literature died within a few week following di cover of the di ea e.

FACTORS \V111 .H ;\fAY .o:--:TR11H ·TF To Dr. REA. FD RE. 1 TAJ\CE To 1\'FOPI.A. L\ l :\'Cl.l' l)]:XG ~El'ROIH.ASTOMA In reviewing the fa tor which appear to timulate or inactivate re istancc Lo ncopla. tic di ea cs it may be possible to elucidate some of the cau es for the apparent in rea e in the incidence of neopla 111 a well as leukemia in chil­ dren in the pa t 20 year.

D('Cr('a ed timuli to /11111111111• He ponw : Before infectiou di ea e were marked! · urtailcd. the rcticulocndothelial and 1 •mphoid ti sues were re­ peatedly timulated b • a \·ariety of infection and infectiou di ea e , from early infancy onward . mith (62) has pre ented evidence which ugge t that can r and allied di ca e are till comparati\'el rar among the Indians of the nitecl tate, who till have a much higher incidence of infection and in( tiou · di ea e than the \\'hite p pulation. ,\ imilar tucly ha been done of the anaclian Indian, with imilar finding. The in rea ed responsivenes of . frican children with Burkin's lymphoma to chemotherapy may be due to INTRODUCTION the fact Lhat most of the e d1ildren had a great deal of prior in(ecLion. Of course, in these ethnic groups, genetic facLor may a l o play a role in Lheir relatively greater host resistance to neoplastic di ea es. ot only have children and adults been expo e I to infinitely fewer ba - teria in the las t few decades, but when an infection d id develop, an antibiotic or ulfanilamide ,ras u ually given. ln addition to making it unnece ar for the natural immune respon es to deal with tl1e infecti on, some of these drugs may have a damaging effect upon the hematopoietic system, and po sibly lead to decreased resi tance to neoplastic diseases. As Meyer and Ben jafielcl have stated: " If. . .ca ncer is due to a viru, may we not co nclude th at by damaging the tis ues in some subtle manner the antibiotics may ab olve the body of the need to bring the .normal immunological mechani m into u e - a mechani m that has been acquired and perfected through millions of years of evolution and which seldom fa ils - and furthermore may up et the bacteria-virus balance and so predispo e th e ti ues Lo invasion by ca n er cell -?" (44a). A11ti-i11flammato1y drugs: .-\n other group of drug whid1 shout I be u eel with great caution are the anti-inflammatory drug , for there is con iderable evi­ dence to indicate that the ability of an animal or patient to eli cit an acute inflammatory reaction is one of the powerful inhibitor to succes ful trans­ plantation of tumors or to the formation of meta ta es. , 1Vith cortisone it was po sible for the first time to grow human neoplasms in animals su ce fully (67-69) . There i evidence to ugge t that tl1e depre ing effect of co rtisone on inflammation can be completeiy aboli bed by adequate h line admini - tra tion (32-33). Since the intlammatory reaction seem to be an important factor in the hot' re i tance to cane r, it i interesting to find tl1at a few investigators liaYe observed tl1at the ability to invoke such a reacti on seems to be absent in many advanced cancer p atients. (65) ngar made a statistical cudy of all the pa tient admitted to a ho pital in Ba l , witze rland, in a 20 year period ending about 1947. The prior incidence of acute infections or of acute inflammatory episodes wa almo t nil in the ca n er group. (70) Toxin therapy, concurrent infection (48) and choline (32-33) appear to stimulate the host' ability to invoke acute inflammatory reactions. It may be ,.·orthwhile to study the po ible effect of induced inflammation (vesica­ tion, fixation abscesses) on cancer pa ti ents since it is known that inflam­ ma tory exudate de u·o neopla tic cel l in vitro (4 1). It may be that tl1e exudates produced by severe erysipelas infection played a salutary role in the defen ive proce ·es wh ich re ulted in regression or remi ion of cancer or leu­ kemia following such infection . (48,53) One must al o consider that the his­ tamine liberated by acute inflammati on appears to be a physiological acti­ vator of the RES (25,36). In this co nnection it is of intere t to cite the ca e of Dargeon (11 , 49). This patient was admitted in very grave condition having been operated upon in Ch icago a short time before for abdominal neuroblastoma. H e deteri­ orated thereafter with meta tases in the abdominal region in and about the laparotomy scar. H e then leveloped h rpes zo ter and the vi ible tumefac­ tions dimini heel 75 percent in size. The boy expired before any definitive treatment ould be started . Po tmortem studie of the regre sing les ions showed some necrosi in parts of the tumors. (49) A tudy wa made in Germany of the incidence of neopla tic clisea es among bee keepers, who e immune reaction are co nstantly being stimulated by exposure to bee tings. It ,,·as found tint in over l ,000 German bee keepers, there was an as tonishingly low incidence of neoplastic diseases: 0. 36 per thousand (23).

5 INTRODUCTION

Irradiation: Thi a carcinogen i and leukemogenic agent to which the modern world is being exposed in seriously increa ing amounts. A great many authors have cited the de tructive action of x-ray or radium upon the hema­ topoietic ystem. Simpson and Tf emplemann (6 1) co ncluded that therapeutic radiation of infants may be an etiologic factor in thyroid cancer of children and adole cel1ls. Its role in the production o[ leukemia or other lllmors in chil­ dren i Jess !car and await further data. They uggestecl that the practice of irradiating chi ldren on a large ca le hould be abandoned, pani ularly in the case o[ the thymus, for ·which there is meager evidence that the treatment has an benefit. Jn other ca es the benefit to be deri\'ed hould be carefully ''°eigh d again t the po sible clangers. Fluoroscopy as well as therapeutic ra­ diation should be included in su h onsiderations. Pelner analyzed the effect of radiation on hot-tumor antagonism. He concluded: " review of both old and recent work on the effect of ionizing radiations of the tumor and the host suggests that our con ceptio n of proper dosage ma have to be revi ed. Large do es of radiation may have a salutary effect on the local tumor but a detrimental effect on the res istance of the hosL." (5 l). Further evidence which confirms thi view is indicated by the inve tiga­ tions of To Ja n (67-69) and W eeler et al (73) who found that heterologous tumor, including human neopla ms will grow readily a[ter the host ha been conditioned with x-ray or corti one. The e finding corroborate the earlier work of ~furphy (45) and hi group who stressed the vital role played by the l)mphoid ti ue in natural re i Lance against tuberculo i and again t neo­ plasti di ea e (41) .

'po, T ,\ NFOUS R.EGRFSSION AND FACTORS 'iVH! C: 11 J\lAY JNCREASE R.ESI TANCE R ecent report on pontaneou regre sion of cancer indicate that the ma­ jority of such ca e had some form of acute infection, fever or inflammation, oft n not considered by the r eporting physician to have been of any conse­ quen e, becau e little wa under tood until very recently about the various ho t-resi Lance mechanism which may be activated by such complications. (15- 17 ; 47; ,JS). It is now known that streptococcal organism and their toxins appear to ·timulaLe a ho t re ponse to ub Lances or ti ue which do not normally elicit uch a re pon e in an animal or patient. For example, Glynn and Holborrow (27) found that four trains of treptococci (three Group A and one Group C), and a train of taphylo occu a ureus, when grown on agar media, gave rise to agar a11tibodie in anti era prepared again t them. Burky found that by combining taphylococcu with lens sub tance, rabbit were ensitized to lens and cl vclo1 eel high pre ipitin titre for lens ti ue. A diver e gToup of bac­ teria in addition to treptococci and Staphylococci show thi property, i.e. higell a higas, almonella typhi, Bacillus anthraci , H oemophilus influenzae and ~ei ~eria mcningitidi . ('J) Jn order for thi to occur the organi m do not need to be a live but they mu I come into significant con/art with the target tisrne. Thee [indings sug­ ge t that in treating patients with toxin therapy in the future, some of the initial injection houl I be made in or near the tumor. Inter( ron now appear to be one of the mot ignificant medical discover­ ie relatino- Lo man' re i tan e to a great many disease, especiall y those of ,·iral orig in. Interferon production i stimulated by viruse , bacteria and other mi roorgani m a well as by bacterial a nd fungal extracts and synthetic

6 INTRODUCTION polyanions. (55a) This remarkable ub tance act in one to four hour , much fa ter than other immune re pon c . R ecent studies in licate that stimulation of interferon producti n in tumor­ bea ring rat and mi e markedly incrca ed the re i tan c o[ the c animal~ to their tu mor. There were no urvivor in the untreated control . All the treated animals were alive with no eviden e of their wmor two month a ft er ce a ti on of treatments. Since certain microbial infection or their toxin and probabl y :-\n in­ omyc in D, through variou mechanisms described above, a ppear to in cr ase ho t re i tancc LO neoplas ia, it i e entia l that we lea rn how be t to protect and activate any ti ucs re ponsible for thi re i la nce and that we a\oicl prior use of chemotherapeutic drug, amibiotic or h ca \'y radia tion.

0 E ND R r:: LTS J;s; Tin: A. E ,O:'IIPR1s 1:s: c T111 TL'DY SERIES A . Concu rrent in fectio 11 , fe ver or inflnmmntory e/Jiso des: 18 Cases. Eleven patients were traced , ell, 5 to 40 yea r after on ct, t"·o were traced \,·ell three and four year (Ca e l and 3). One wa ali\·c with di ca c when reported four years after onset (Ca e 5) ; two died o f their di ease, 7 Lo 29 m onths a fter onset (Ca es 11 , l ) ; one of thee patient recei\'ccl a grea t dea l of radiati on, the other had chemotherapy prior to infecti on for generali,ecl disea e; two died of uremia 23 and 10 year a fter on et (Ca es 7 and 13. Case 7 had received 4050 r of x-ray therapy re ulting in con iclerabl c thra r[ing and chronic radiation nephritis which fin all y proved fatal) . ERIE B. T oxin T reated: 9 Cases. 1in e case of neurobla Loma received toxin therapy (Co ley toxin.). Although terminal (quadriplegic) the only ca e to re eivc olc y t0xin alone recovered and i ali\'e in 1969, 5 year a fter on ct. This fa rn ou case, o often cited at medical meeting in which neurobla torna is di cuss I, ha · u u­ a lly been inco mpletely reported. It ugge ts the need for further clinical trial of host-s timula ting llli crobi al product uch a thee tox in . as a primary method of treatment in neurobla toma. The second toxin treated ca e had multiple meta ta e. O\'er hi · entire body wh en Coley toxin ,,·ere begun. nine cla •, a[tcr radia tio n. The many concurrent infection he developed ub equently may ha\·c played a rol in his recovery. 0( specia l interc t i the fac t that ex ploratory laparotomy for an a ·mptomati c residual ganglioneuroma 20 ear la ter wa foll owed about a yea r later by reactivation of the neurobla toma ·which pro\·ccl fa ta l 25 year. a ft er on et. The third ca e had multiple tin) ubclllaneou meta ta e. . Ile received small radium plaque to one or two of the nodule \,·ith no a ppar nt ffe t. Ile also re eived a few injecti on of Coley tox in , re O\'Cred and wa trac cl well o\·er (i ve vear later. In th;.ee of the other six ca e a brief co ur c o[ toxins " ·a g i\ n con­ currently with x-ra th rapy before meta tase had occurred (Ca e l, 5, G) . T,,·o of thee patient had recurrence. In all three there " ·a dramatic, com­ plete rcgre sion: no evidence of di. ea e within four Lo ix week. . J lowever, reactivati on occurred promptly. In the la t three ca e the di ea~e wa~ meta ta ti .. I n a e 7, the toxin were begun two day after x-ray and g iven concurrently ( 16 do es) . Complete regre ion occurred in fo ur weeks with reacti\'a ti on of the di ea e four month · later. In Ca e 8 th e toxin ,l" cr not begun until a great deal of radiati on hacl

7 INTRODUCTION been given (8038 r) and only 15 do es were administered. There was com­ plete regression in a few week , but the di ea e reactivated following a fall and progre ed rapidly. These ix a es indi ate the extreme importance of more prolonged toxin therapy in order to produce a permanent result. Ca e 9 wa terminal with "·ide pread di ea e when the toxins were begun, having received 7200 r of radiation (although only 21 months old) as well as two cytotoxic chemotherapeutic agent . There was rapid deterioration rather than improvement. Thu it would ccm that toxins arc not helpful if begun after mas ive irradiation and chemotherapy have destroyed the immunological re ponsive­ ncs of the patient. Burchenal, in a per onal communi ation to H.C. 1auts stated in 1968: " It ertainly appears to many people working in the area of acute leukemia and Burkitt's lymphoma th at stimulation of host defense is needed in addition to chemotherapy to produce long term remission ."

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9 0 SERIE A T \BLE I :'\' 1·.l"ROBI..\ I () \f \ \\' I 111 CO,(TRRE,T I,FEC 110'\'. l:'\'FL.\:'-nr \ TO RY OR FEBR ILE El'L'ODE. : C \ E Physician or ex 'i te , J:.xtcnt l'rior oncomitant I Subsequent JnCeetion Immediate & Final R es ults Hospital .\ ge Prior to Infection Therapy Therap~ Therapy Inflammation Year Traced After Onset R cfercnces 1 Dale of On Cl Fe,er ~ facFarland l·emalc neut obl11st0ma appar• none Februal') 1\:1::SI x-ray (2) fo l•1 February 1\:13 1 pharyn - complete recov ry; pulmonary & appington 5½ yrs. c ntl y prim ary in cer­ 5 x-ray treat• lowing surgery geal ab cess tempera- lesions regre eel; :s/ .E.D . alive. 42 "ic;1l region; multiple ments: ab cess :'-l ay 1932 ture continl!ccl 10 ri e well late I 935. almost 4 yr . af­ pulmonary meta 1a es; inc-iscd. drained; occa ionally; ;'If a y ter onset onset J anuary 193 1 tonsilc tomy 1932: li gh t postopcr- 1932; Jemo'n- atil'e fe\'Cr for I wk. izcd lesion ex- cised from cer• , ical region: neuroblastoma ma!Uring into gangli oneuroma

2. Dcbrc Female inoperabl_c neu r_ob las­ December incisional biop· none pertussis. ru beola_. De- by J anuary 1935 abdominal mass 13, 14 7 mos. toma pnmary 111 rt. 1930: S)' of knee le ion cember 1930 urticaria! had regressed % ; tumor on back Ihypochrondrium. me­ x -ray (7) October 193 1 rash on legs (allcrg • h,1rcl. painles . \'Cry mobile; by tastases 10 knee, hemi- 10 eggs?). further SC· 193 abdominal ma still large, 1horax. eyeball &: sup­ , ere, extcn i,·c bullous hard. indolent. back tumor re· raorbital region (the c, urticaria. pruritis, su p• grc sing. complete recover y, all regressed spontaneous p uration traces o f primary &: mc1as1a1es ly in I mo.) di ·appeared, married, 2 children 19~ , . 1954: in perfect health 1969. 40 yrs. a ft er onset I 3. R ocher Female inoperable congenital exploratory x-ra to none few a ttacks bronchitis no further retention of urine; 56 newborn neuroblastoma appar- operati on , pelvic \\'hile hospitalized st eady complete regres ion in entl y arising in the, condition region 3 mos. 1.E.D. thereafter; a li ve presacral sympa thetic, hopeless (2880 r) & well 1937. 3 yr . after onset Itrun k, ex tensive mas obstructing entire hol- low of pelvis from po terior acrum al• mo t to posterior pu• bi : retention of urine 8 days a [tcr hi1 th , slight erosi on I vertebra 1. FcvTe m ale neuroblastoma w i t h none none biopsy of tu­ diaJThea at 4 mos. at time of diarrhea explosive 21 infant meta tasi canthus rt. mor near rt. de,elopmcnt multiple tumors (born pre­ eye; onset apparent at eye: massive in soles or feet. groin, but­ maturely 4 mos. (lesion on eye) dose of tocl..s . large t deep 111 rt. scro­ at 8 mos.) vitamins tum. back. It. thorax, inner canthus It. eye; only I other tumor developed later on scalp; progno i grave; com­ plete r ·gression all lesions in 2-3 mos.; alive & well Decem­ ber I 957, 22 yr . after on et 5. Roussv male in operable neuro­ none none biopsy, July June I 937: enteritis, metastatic mass appeared on 57 , 22 yTS. hlastoma ize of fe­ 1938; x-ra ; di;irrhea; after x-ray, It. ·idc after x-ray, evere con­ tal head in rt. iliac cl iscase pro­ I 939, febrile pul­ ·tipation, wt. lo s; di ease re­ fossa hypochron- gres eel; fur- monary ep isode activated, violent abdominal drium (1st noted ther x-ray, (pneumonia?) Nov­ pains fall 1939; during pro­ cl u r i n g enteritis, Feh. 1939; ember 1939, cystitis, longed C) titi recutrent ma June 1937) tumor in- hcmawria, lasting 6 slowl)' but completely disap­ cre:1sed slow­ mos.; several epis­ peared; other lesion develop­ ly; August taxi ed with neurological symp• 1939: prim­ toms, severe pain: 05 verte­ ary ma s dis­ bra. ran1us lower jaw, rib, ccr­ sected free, ,·ical · cpiga tric regions; gen­ 2nd mas in­ eral condition declined; Octo­ volving me­ ber I 910 cephalagia, edema of socolon in­ eyel id ·. exophthalmos; cereb­ operable; ral symptom cleared up further x­ rnmpletely each Lime epistaxis ra y (5800 r); occurred; alive with disease I 9~0. x-ray "·hen rcpo1 ted 194 I, 1 )TS. to bladder, after onset lumbar, cer­ , ical. epi­ ga 11ic reg­ ion (poorly tolerated) 6. \ anCreveld female inoperable abdomin­ none none 3 x-,ay treat­ ,·aricclla at yr; gained weight, grew normally, Van Dam newborn al ncurobla toma, ments (no wbc. 9,600 1t1111or slowly rcgre sed in next 49; 71 apparent from birth, effect); ex ­ few 1rs.; married. had normal ;\[a 193 ; Ii v er plored. biop- d1ilcl ; aliH:. well 1969, 31 )l"S. lightly enlarged, hemorr­ after onset abdomen greatly en­ hage, di rri ­ larged cult Lo con­ trol Ph)sician or ex ite · Extent Prior oncomitant ub cquent Infection I Immediate and Final Re 11lts '" !lo pital Age Prior to Infection Therap • Therapy Therapy l11flamm a1 ion Year Traced After Onset References Date of On ct Fc,·er , 7. Beck &: male congenital, apparent- none biopsy, 1945; none concurrent comedos, li,cr re cdcd to co tal margin, Howard newborn ly inoperable neuro- x-ra (1 ,400 r infected acne, leuk- wmor ma rcgres ed. no long­ I; 49 blastoma It. adrenal tumor doe) 2 oc '10 is ( 11 ,100 wbc); er felt at 1-1 mos.; small indi • hepatomegal )', ascites, mos. later 1,250 acne cleared after x- 1inct ma palpable in upper 1944 r t. d.; 194 : ra ·; 19-15, influenza; abdomen I 94 ; in good health 1,400 r t. d. 19-19 another u. r. i.; thereafter, e ·cept for dwarfing 1951, 01i1is media due to radiation · chronic rad- i:uion nephritis requiring hos­ pitali,ation 3 times, finall can eel death, February 2, 196 , 23 }I". after on ct.

8. Vigorelli male congenital generaliz­ none biopsy of nodule x-ray, 700 fever at 5 mos. &: again became afcbrilc, quieter, better 17, p. 154; infant ed neuroblastoma: at Iin pectoral reg­ r, then in July 1946 (to 102.2° appetite; no new nodules; those 49; 72 I mo. least 50 subcutaneous Iion July 1946 200 r lO F.): lcukocytosis to in checks decreased in size; irra-j meta ta cs over entire cervical 20,000 wbc, decreased diated nodule then dccrca ed, body except hands region; to 6,000 after x-ray other un hanged al 1st, later · feet, I t apparent epigastric con iderably flaller, all but 3 of in acral region at I I mass excis­ the 50 Ir ·ions disappeared; in Imo., others appeared ed 1952: excellent health thereafter, nor­ in next 5 mos.; ane- reported mal dc\'clopment; married, fa. mic, undernourished; I as ganglio­ thered a child; alive, .E.D. 1945. neuroma 1967. 22 TS. after on et

9. Goldring male inoperable neuroblast­ none antibiotics 3 blood mild otitis. pharyn- proptosis more marked after x-1 28; 49 4 mos. oma rt. upper kidney for otitis transfus­ gitis just prior 10 ray, requiring celluloid shields region, extending into ions; x-ray known onset; then for e ·cs; striking improvement rt. upper abdomen, rt. kidney rhinitis; leukocytosis shonl , after final tran fusions, numerous me1asta es region; ex- to 15.550 wbc; fever continued stcadil ; complete re-I 10 liver, proximal rt. plored; liv­ twice after x-ray: to covcry by ept. 194 , proptosis, humerus, skull, cxten- er extensive- 101 °F.; u. r. i. .\pril abdominal mass sub idcd; ivc proptosis, bilateral/ 1y involved, 194. high fever, :'\' .E.D. th reaftcr, normal men­ pcriorbital con juncti­ biopsied; 2 cough, hronchiti tal · ph , ical development, in 1 val hemorrhages; 1947 more blood excellent health, active in sports, tran fusions 1969, 22 yrs. after onset x-ray stopped due to leuk­ opcnia (4350 I wbc); ane­ mia 4 more transfusion I (total of 9) 10. Greenfield female inoperable ne uroblast-' none none inguinal i nterm i tten t complete recovery; .E.D. when & Shelley 2 yrs. oma w i t h inguinal biopsy; fever las t traced 18 yrs. la ter. 29 lymphadenopathy & untreated hepatomegaly; onset at 21 mos. II.Haber& female inoperable congenital laparotomy none none po t-operative . course further growth of abdominal Bennington newborn neuroblastoma I. u. q. x-ray, 2100 stormy: ubfasc1al ab - wmor not cl after cyclophos-, 30 infant of abdomen, numerous r; many les­ ccss ~ trep .. fccahs, phamide; death about 29 mos. subcutaneous metas­ ions excised E. colt , E. 111tern:ie- after onset, in recovery room ta c · (primary unre­ at 8½, 10 &: 1dun_1); gangrenous 111-, 5½ wks after excision; autopsy scctable clue to in­ JI mos.; cy· tesune rup~ured, en- showed well d ifferentiated gang- l'Oh ement of intestines, clophospha­ 1 terococcu f1stul ae lioneuroblastoma, with foci of great vessels) mide; x-ray 1 apparent differentiation to gan­ to rt. thor- , glioneuroma, f o ca I necrosis, ax; metas­ small areas o f calcifica tion tases excis­ ed from It. knee, ingui­ nal region; laparotomy; dumbbell I shaped lll­ mor excised

12. Eyre­ female inoperable mas i v e none explored Dec. none cvsuus (co li form ba-1within mo . after biop ) brook &: infant neuroblastoma rt. lum­ 19-19, large cilli); pu in urine, complct rcgre sion of abclom­ Hewer bar region, abdominal piece remov­ some urinary retcn• inal ncuroblastoma occurred 18 ma s deformi ng blad· ed for biopsy tion; cystitis contin - but residual paralysis of legs der; marked foot drop, ued 10 yr .; gross py- remained with impaired bladder some para! is of feet; oncphritis pre ent at function due to compression of progno is hopclc s; on-, death cauda cquina; progres ive de- ct noted at 3 mos., terioration of kidney function, cpt. 1949 death from uremia, almo t JO / yrs. after onset, June 1959; au-j top y howed peripheral por· tion of extensive ncuroblastoma of lumbar spin e had regressed remaining dumbbell shaped tu­ mor in spinal canal had ma­ wred into a ganglioneuroma '

<.,c Physician or ex ·ite Extent Prior Concomitant ubsequent Infection Immediate and Final Re uh Hospital Age Prior to Infection Tberap · Therapy Therapy Inflammation Year Traced :\fler On et References Date o[ Onse t Fever 13. Ochsner female congenital inoperable, vitamin K H:-.1 , for 4 3 remaining mother de\'eloped in- gradually began to improve fol- Clinic newborn generalized neurobla - gi\'en a her da) ; blood le ions in It. fluenza, brea ts wol - lowing 11. r. i., penicillin; li,·er 49 torna, abdomen abnor­ blood did tran [u ion; thigh,· groin !en. almost absce ed. rcccckd; ;s;,E.D. b)' October mally large at birth; not coagu- rnuch worse ex i ed April but continued to nurse 195 1. keletal urve,· normal ex- widespread subcutane­ late proper- 1951 infant during I c mo.; cept for monled calcification in ous meta ta es appear­ ly, biopsy, (neuroblas- diarrhea, C\'ere diap- region o[ li\'cr grew normally

ed following Vitarnin ?-fay 1950; toma); H:-./ 0 er ra h; light fever; in e,ery wa~·; in excellent K over pubes, groins, for 4 da)S 11. r. i., penicillin; health 1969. 19 )rs. after onset distal abdomen, chest, repeated; furunculo is; runny back, head; hepato­ jNov. 195 1 nose, penicillin a[tor m e g a I y; prognosis n. quadrant H :\' ,. I 951, severe al- Ihopeless mass excised I lerg1c reaction, entire I (ncuroblastoma body covered by red with clifcr- rash. e)'e w o Ile n entiation to shut: ,·aricella at 3 ganglio ncu- ) rs. ; rubeola at -1 yr . roma): peni- cill in again

j for I H:\'2 D c., J an.

x-ray, 1500 r lll· concurrent fever (104° definite improvement within al 14. Woorls infant extensive inoperable none explored; jmor dose; per- F.); leukocytosis ( 19,- wk. after Vitamin B-12 was be- 49; 67 female retroperitoncal neuro­ biopsy 15 mos. hlastorna; vascular. fix­ istent Ieukope• 000 whc), no apparent gun: COn\'ale cence uneventful ed mas 17x7½ cm.; nia, pale, apath- cause thereafter; wbc decreased Lo i in extremis; l 954 etic, inert, re- 8700 with I •mphocyt0sis (76% fu ed all food; then 43 01,,); became subthyroid, chloromycetin, corrected by thyroid xtract; no improve- complete regression, in excellent ment; Vitamin health thereafter, no abnormal- 812 i.m. every itics: :\fay 1962, developed dia- 4 hrs. then l a hctcs; alive and we ll 1969, 16 wk. fo r 2 yrs. yr . after on ct th\Toid extract (0'.5 gr.) 15. Knudsen female congeni tal, inoperable, e;plored_ at \ none Vitamin Bl2 latelectasis, pneum~nia, masses in It. neck, swell ing of ,\ mromin newborn ver large neuroblas- 2::i days liver 1.m . for 2 1 mos., recurred several tunes It. arm apparent after x-ray; 38; 49 infant Loma, involving liver, almost com­ !biopsy It. axilla, in few mos. after x- abdominal mass regre sed in 9 primary site unknown; pletely re- \fay 1956: char- ray; fever, 101° - mos. after vit~_min B-12 was be- 1955 placed by tu- acteristic neuro- 104°F. gu n; stigmata of Re hlinghau- n1or; X•ray, fibroma; July scn·s disease, 1956; 1.£.D., nor- 1600 r, stop­ I 956: explora- mal intelligence, in good health ped due to tor)' thoracoto- except for scolio is of spine with lcukopenia, my: lobulated convexity (radiation hanges) anemia; ch l­ mass in medias- hy I 969 mental development orambucil, tinum connec t- sub-norma l; fall 1969 2 spinal no effect Iing via apex lt. fusion to relieve pain and im- chest with mass prove cosmetic appearance; in It. neck, arm, :'\ED. 1970 , 15 yrs. after onset. adherent to ribs encircled It. thoracic &: cer- vica l sympathe- tic chain; por- tions removed fo r biopsy: gan- glioneu roma; I I 957 : liver biop- j sy: no residual : disease Ph)sician or ---~ -- itc: - Extent Prior Concomitant ' ub cqucnt lnfection Immediate and i:'inal Results HospiLal :\gc Prior Lo ln[cction Therapy Therap Therap' In[lammation Years Traced .\her On et References Date of On et Fe\'cr 16. Hornstein female congenital, inoperable le ion ex­ antibioti x­ 195 , 3rd bi­ 1·ecurrent episodes p . ·mall area neuo i , calcilica­ · ~Hilke 3 wks. neuroblasLOma rt. a- ci ed £or ray 10 l mctas- opsy; infla­ oderma, refractory 10 Lion in region rt. adrenal; me­ 35; 49 clrenal; multiple me- biop y; 1asi , no effect; mmatory re­ therapy; also nutri- 1:1 ta e rCtITe cd notably after ta Lase over entire prednisone 2nd biopsy; di- action pre · tional di turbanccs; ,·aricclla, in 3 mos. many mall trunk, proximal lower 2 wk . 10 etary re trict- ent, tumor varicella at 3V2 mos. I ·ion , e peciall · tho e that bad 10 ion ; ulfona- no longer I extremiti s, bean mo-.0 dail appeared la l. di appeared; • ·1 pigeon size; 1957 I midc malignant; E.D ., normal ph) ically ,· men­ 1965, 4th bi­ tally; in excellent health 1969. opsy of in­ guinal mass: 12 ,., '''" '" CL I completely differentia­ ted gangli­ on uroma I 17. Cochran male congeni ta! neuroblas- plum i,ed none x-ray re­ 11. r. i .• throat diffuse- complete regic- ion; 2 yr . later 6, Case 4; newborn toma in rt. abdominal wmor biop­ sumed a[tcr I) inflamed, bronchiti }ano1ic heart di case, hepaLOm­ 49 infant S) mpa1he1ic ch a in, sicd at I u.r.i. (3000 r C"aly; laparoLOmy revealed sim­ persi Lent bile-stained wk.; l cla)S in 60 da ) ple cholangioma, no Lracc of vomitus from birth; later x-ray neuroblastoma; alive, well 196 •1 I 960 in Lcrru ptcd 8 yrs. after onsel. b LI . r. i. 1 I 18. Cochran male inoperable neuro~las- cyclophos- none vincristine Xovcmber 1966, fairly disea e arrc·1ed but without 49 2 yrs. l toma rL adrenal, wide- phamicle for for tibial severe rubella; mild signi[icant regrc ·sion unLil cy­ sprc~d metastases 1_0 2½ mo .; meta ta i ,aricclla 3 wk. later dopho phamide sLOpped; more ~elv1s, low_er extre_m1 -jblood trans­ (some tem­ rapid regression dated from uc . cervical spme, fusion· vit­ porary re­ concurrent infections; grossly cranium, sca lp; head am ins' B-12 grc ion) ·wollen head decrea cd 4 cm., gro l swolJen, ane- . A scalp irregularity di appeared, mia; on ct April 1966/ cranium, tibiae recalciCied, ane­ mia ceased; N.E.D. for a mo. April 1967, sudden recurrence of tibial metastasis, 2 mos. la- , I ter ma ivc rccrudc cen,ce; death few day later, June 1967, 14 mo ·. after onset. I ERIE .\ , co;s:c RRE::--:T ]l'\FECTlO:\ .. DET,\ ILED HI TORIE

CA. E l: ;s:eurobla Loma maturating into ganglioneuroma appar ml · prima, , in the cervical region with multiple pulmonar) meta a ( cc b - low f r hi ·tologic report).

Previous liisto,y: .\. C.. " ·hitc female. aged 51 ,2. The hild' parent were both li\'ing and well. he "·a dc:Ii,·ercd b) 1101111al labor weighing 9½ pound at birth. ' he wa brea L (eel for one month. The first tc th erupted at three month , but all her baby teeth were poor in quality. lnfancy and early chi ld­ hood were uneventful. Onset, at the age ol 5½ )e,11-- a \\'Clling appeared in the region o( the cervical l)mph node. Thi ominucd LO enlarge and \las diagno eel a luberG ulous adeniti ·. Radiation: ric o( five x-ray treatm nt "·ere gi\'Cn. Clinical Course: On Februa1·y l 6, J931, three \l'Cek · after the la t x-ray treatmem, the d1ild wa admiLLed to Hahnemann Ho pita! in Philadelphia. he appeared pale, though apparcmly well nouri heel. The breathing \\·a lightly ob tructed and the ton ·il were enlarg cl. A larg , moo th, nodular, non-tender ma wa pre ent in the right side ol the ne k. lL did not nuctuale. Blood examination showed Hg. 70%; rbc 3,500,000; wbc 1\900 . .,\ ccond ex­ amination on i\Iarch 1J, I 93 I h wed Hg. 72 % ; rbc -1,290 000 and \\'bc G,200 of ,,·hid1 58% ,,- re pol) morphonuclear , :15% l) mphoC) lcs and 7% tran itionals. Conwrrent Infection: (Ab cc ·) The temperature varied b tw ·n 9i 0 and 99. °F., the pul ·c between 76 and 11 ' . . \ phar) ngcal ab ce de\'elopcd. 11rge1y: On February 23, 1931 a ton illcltomy wa pcrlormcd and the pharyngeal ab cc wa incised. Clinical Gour e: The general condition then impro,cd, though no ap­ parclll change occurred in the welling o( the neck. The temperature { n­ tinued LO ri e occa ionally. An xamination o[ the chc t on .\larch 5, .1931 showed bronchial breathing, more LUbular than u ual in the mid-portion, pos­ teriorly, with bronchophony and well tram.mill d ta tile l'remitu and m ies. he heart wa · normal. A ;\ lantollx LC,L on the right forearm \\"a reported po itive . he L [ilm on ;\larch 10, 193 1 hcn,·ed di tinct thickening o[ the root o[ the Jun~ ,,·ith exten ion to both ba e and to the right upper lobe. There were a fe\\' calcilicd area at the root ol the lung~ and ,ome mouli11g of both upper lobe. The di turbance in the lung root~ \\'a thought to be in the bronchial lymph node. On ;\Ianh l'.Z, J!) '.{I another .\Iantoux 1e t and Von Pirquet tc t \\'ere performed and both \\Tie reported a negative. The d1ild ,rn di charged on .\ pril ·l, 1()3 1 al the mother· reque L, \\'ith a diagnosi o[ tuber u lou aclcni ti . 'he was readrniucd on .-\ pril 23, 1932 "·ith at mpTaturc or 100 °F. Blood exami nation gave 7400 I ukocytcs or wh ich GI~~. were pol n1orpho11uclcars, 3 o/c lympho ytc and J ~ ba ophile. Two day · later the hemoglobin wa 91 lcukoc Le 6,200 of \\"hi h 2% were pol) morphonu lcar , 131/o I) mphoq tc , 2o/c tran itional and 37£ co inophil. Alter L\\"O more day ther e were 6.5.5 pol , (55';fc maw re, 7% immature and 3% mctaleukocyte); 2 '% lympho ytc, 4.5% tran itional and 20-~ co inophils \l"ith abunclam platelet , man · broken, poor! taincd and degenerated white cell . Che t film on Ap1 ii 27, 1932 howed the condition pre,·iou ly reported xcept for pul ation in the right inf,ada, ic­ ular region thought to be characteri tic of tuberculou infe tion. urgery: On May .f, 1932, the hilcl wa operated upon and a firm cn­ ap ulatecl LUmor about the size of a lemon was removed from a po 1uon deep down in the neck. At the upper pole it app ared to be atta heel to some long tructure, el e\\"here it was free. The ~ -o appearance wa not charactcr- 17 SE RIES A: I :\T FECTlON CASES, DET ILED HI T ORIE

1st1 c of any recogni Led condition. T here were no a reas of casea ti o n and no suggestio n of tuberculos is. la Farland a nd Sapping to n reported the histologic findings a fo llows: "The tumo r con ists of a [ibrilla r background or stroma in which are ca ttered cel ls a nd cells in groups. "The fil ers that ma ke up the greater p art o E the tumo r present con­ sidera bl e di versity o( a ppearance. Some arc extremely [in c and wavy, o thers coarse a nd coll ageno us. T he indistinct bundle o( fibers intertwine so tha t th ey a rc a lways cut both long itudina ll y and trans,·crse ly. Some have their res pcnive fibril s widely sepa ra ted, a · in edema, o thers a rc compact. There is a n occasio na l tcnclen y to hya lini1a ti on, and a t many points a granular break­ ing d own foll oll'cd by co lli q ua tion necro is leading to the forma ti on of minute definite , p aces. "The nucle i of the fibrillar t iss u a re elo ngate, ova l and ves icular where the fibers arc coa r:e; e lo ngate, sl nder and rnore uniform where they are fine a nd wavy. In many places distinct pali ades of nuclei show indubita bl y th a t th e fi bcrs be long to n ervous ti ss ue. Few de(i n i te n rve fasc icu Ii a re seen, but m ay belong to a ntecedent nerves about whi h the tumor h as grown. Ex­ ce pt in them, no rn edullary she·Hhs were fo und. "'Th e cells distributed through thi backg round o f fibers eern to form an ascending sc rie th a t begins with sma ll ce lls no t unlike lymphocy te and ends in t ·p ica ! g,1ng li o ni c nerve ce ll s. T he vari o us fo rms - neurocy tc, ncuro­ bla ts, ympa L11 obla t a nd gang li on ce ll s - occur together. Jndividua l cells in all or an y or the tag s o[ dev lopm nt are a ll r tl ingly or in group · th roug ho ut th e \\'ho le tumor. "Sma ll ce ll group of spindle h ape, and composed of a few large un­ mistabt bl c nerve cells, w ith abunda nt cy toplasm, beautiful ves icul ar nuclei and la rg distin ct nucleoli , fl a nked by smaller cells ta pering of( to very ma ll o ne. at the end · o ( the spindle, no t infrequently occur in the intervals be­ t wee n the fi bcrs. " La rge rn ll cctio ns o ( cel l. co nstitute a striking pi cture. A good m a ny corres po nd with the gang li onic nerve ce ll g roups baractcristic of ga nglio­ ncuronn a nd adjacent to them palisa de arrangemen t of Sch wa nn ce lls. There is no do ubt but tha t the wmo r is a gang li oneuroma. But it i no t witho ut its ccc n tricitics . i\fan y of the ce lls a r imma ture forms closely o r loose ly massed togcth r in a ,·e r de li ca te or Ioo c trorn a, or in indefinite SJ aces in the stroma. The c ell aggregati o ns, o nurnerou , so large a nd ·o indefinite, mis­ led some o f those who fir t examined the ti ss ue into the erro r of believing tha t they were I o king· a t some fo rm of malig nant epitheli al tumor. "The cells rcprescn t all of the tages o f cl evelopmcn t, but in stead of each progrcs ing regul arly to the ganglion cell stage, tho e of a ll stages seem to mul t ipl y a t random, th n degen rate or liquify. "Scarcely a nen ·e cell, primitive or adva nced in develo pment, appear to b in a state of good health. Large ganglionic cells with bea utiful ves icula r nuclei comm nl haYe finely o r coar cly vacuola ted cy topla m or they po e·s two, th ree o r [ ur nuclei, unifo rm! de\'elo pccl and healthy, or one or several nu lei may a ppear norma l while o th ers m ay be mi toti c, pykno ti or vacu­ o lated . ,\li to is, not frequent, may be fo und in the ell s of the ame g roup. In adjacent grou p there may be none. Judging by this criteri on the growth of the tumor houl cl ha,·e been low a nd sho uld h ave progressed by multi­ plicati on of cells, now here, now there. "The retrogrc io n a nd colliqua ti o n of the gangli o n cell s was a ttended by fin er, then oarser ,·acuola ti on, then fraying a t the edges. Jn ome cases, th r 11" as 'lopyknos is and karyo pykno is in 11"hi ch the nucle i beca me small, SERIES A: JNFECTlOl\' C E, DET lLED lllSTO RI E.S dark colored bodies eccenLrically . i1uaLccl LO\\'ard Lhe urfacc or the cell " ·hose cytoplasm was solid, uniform a nd eo in phili . The general imprc io n rc­ sulLin g from the sLucl y of e Lions tainecl by hematoxylin and co in , iron hcrna­ LOxylin, " eil's a nd Bielschow ky's method ma be ummccl up a fo llow . The neopla m is a gangli o neuroma 1,·hose cl ,·e loprnenL began wiLh the rnul­ Liplica Lio n of embryo n a l n eurocyte, a nd continued Lhrough th o nLinued mulLiplication of those primiLive celJ ·i ncl Lh e ir crnh ·ing d es endam up LO Lh e stage of ganglion cell s. 'i \ heLl1er perfected ganglio n cell s ca n mulLipl i unccna in, but many which seem Lo ha ,·e reached perl'cnion conLa in LW0, three a nd four nuclei a nd sh ow a n o ca ion a l miLo Li c figure. Th sc gangli o n cell s probably g ive o ff' nc uraxons, which ac o unL for the nerve f ibr il s brought o ut by the Biel chow ky stain, and seem to cxciL c Lhe proli[craLion of the S hwa nn cell whi h . how the palisade of nucl i. Then Lhc ga ng li o n e ll. , and m a n y of the ympathoblasLs not yeL LhaL far developed, lose Lh c ir viwliL), retrogres a nd dissolve into the jelly-like accumula Lion s w iLh ,,·hich the col­ leCL io n of dying cell a re surrounded . In a few in Lances Lh e dead e ll ca l­ cify so Lh at occa ion a l, sm a ll , irregularly rounded aggrcgaLio n · o( lime sail 0c ur in the Li ·sue. The genera tions o f ce ll Lhat h a,·c nm LU reel , proclucecl fibrils and di appeared , account for the n e urofibro m aLO us Lro m a or m atrix o r Lhe Lumor." Postoperativ e Fever: After o peratio n the tc mperaL ure rose Lo a bo ut 100°F. for a week o r so, then gradua lly returned Lo no rmal o n M ay 20, 1932. Furllzn R ad ia lion: . \ dcl i Li ona I x-ra) Lre:1L111 111s " ·ere g i vcn o n r-.Iay 24 a nd 27, 1932 as a prophylacLic again t recurren e. Cli11ical Course: T h e child 11·as di charged o n June 18, 1932. Two year · laLcr h e wa seen again a nd appeared to be qui Le well. IT r m oLher staL d, ho11"cvcr, LhaL be coug hed during the clay a nd was n n ·o u during Lh e nig hL. She a lso turned her h ead to o ne ide w hen wallowing, which was considered clu e Lo Lh e operative car. Careful exam inaL io n revealed no evicl n ee o f re­ currence of Lhe wmor in Lh c car. C he L film howed 11 0 ev icl nee of the mctasLatic wmor in Lh e lungs pre ent two year before. JT O\l'evcr, there was a curious oft rnclling pre enL, harply limited to Lh lcfL si d e of the to ng ue, Lhoug ht b y Lh e moth r to have develo ped a (Ler leaving the ho pital. The case wa published in NoYembcr 1934, over fo ur years al'Ler onseL. r\ttcmpLs to Lrace he r in ce h ave failed. R eferences: 42.

C E 2: Inoperable nc urobla toma with meLasta e confirmed by microsco- pic examina Li o n, fo ll owing inci. ional biopsy of o ne or the meLas­ LaLic tumor . Pre11ious fl istor,•: C. , female in lanL, born al l' ull term on November 2,J, J928, an o nly child whose develop111ent appeared normal until Lhe age of se,·e n mo nLh . AL Lhi time Lhe 1110Lher firsL noLccl a LumdacLion in Lhe ri g ht h yoch o ndrium while bathing Lh e child. This wa considered by Lh physician to be h ipertrophy of the li ver. AL the eighLh monLh, Lhe hild being ll'ith a wet nur e, Lh ere appeared a nd then spontaneously di appeared a meLastati les ion of the left eyeball , h aving the appeara nce of a palpebral hcmatoma. Shonly thereafter, Lhere appeared a lllmor the i1c of a nut in the supra­ o rbita l region. Thi a lso regressed pontaneou ly in about a month. ~cvcr­ the le s Lhe tumor in the h ypocho ndrium graduall y in reased in siz . T he ch ild " ·as firsL seen aL the age of one year aL Lhe l fopital des Enl'a nLs-J\faladcs, P aris. 19 SERIES A: 1 FECTlO r C SES, DETAILED HISTORIES

Rad ialion: ,.\ L Lhi 5 Li me a se ri es of 7 x- ray Lreatmen t were given over Lhe abdom in al Lumor, wiLhout ev idence of diminution in ize. Cliniral Course: The child' genera l health rema ined good, and her phy­ sica l and psychic development was norma l: first tooth at e ight monLhs, first wa lked a l 18 mo nLh s. Co11c1nre11t l11 fectio 11 s: .\ L Lhe age o[ t,\·o he develo ped whooping co ug h and Ill easies, wi Lh o u L co m p l icaL ions. Clinical Comse : AL Lhe age o[ 2½ years. in .\ pri l 1931, there a ppeared a sma ll subcuLaneous nodule o n Lh e inLernal asp ect o[ Lh e left knee. Conc1nrf 11t Urticaria : In mid-Se pLembcr 193 1 a n unica rial rash appeared o n th e child's legs. The moLh er a LLribuLed it to an all ergy to eggs, wh ich were th en omit Led (ro111 Lh e di et. The child ,\·as een in co n ulLaLion by D ebrc a l Lh e I li'> piL a l Bea ujon o n O cwber 19, 193 1. AL Lh is Lim e Lh ere wa al so a meLa LaLi c mobile tumor in the posterior right hemithorax. The abdomen was enlarged , sLreLc hed, wiLh slig ht colla teral circu latio n below the umbilicus. Palpation revealed a deep-seated tumor in the right h ypochondrium reaching from the umbilical region a nd not a llached to the li ver. lt wa hard and painless. On percussion it was dull, in contras t to Lhe tympanism of the ne ighboring regions. The spleen was palpabl e. There was a sma ll umbilical hernia. There remained a trace of the urtica ria on the child's legs, which had clevelopecl a month pre,·io usJy. On the edge of the left orbit there , as a sli ght irr g ula rity prese nt. The examina tion was otherwise negative. Su rgny : J\n in ci ·ion a l biop,y ,ms performed on October 26, 1931 of the nodule o n the left knee. Conrnrrrnt !11 [/ammalio11 and l 11fl'Clio11 : The child then developed seri­ ous and e Lensive cuta neou le ion , with pruritis and uppuration, having the appearance of a bullou uni aria. new rnetastaLic nodule also clevelo1 eel on th e a nLerior ape t of the rig ht thigh. This was in Tovember 19 31. No treatment was given. Cli11ical Course: The child 1\·as een at interva l . In June 1932 no hange was apparent. In April 1933 the general condition was excellen t. The ab­ domina l tumor had noL increa eel in si1e, but seemed Lo con ist of two masses, 0 11 e above, limited at its lower edge by a clear-cut margin, the lower one behind it in th lumbar r g ion. The nodule on the back also persisted. The spleen wa · ti ll pa lpable. By J a nuary 1935 the ab lominal tumor had appar­ ent! regre eel o ne third - b ing the ize of a fist. The little tumor on the back rema in ed hard, painless, very mobile, and was th size of a cherry pit. :\'eurological exam in a tion wa n ega tive. In January 1936 the condition re­ mained un hanged. No new nodules had appeared. ( t this time the father was first examined . It was found that although he was in good health he had suffered from pytirias is ince the age of 12. Two subcutaneous nodules \\'ere pre ent a bo,·e the left elbow, one the size of a hazel nut, the other even mall r. ,\ 1 o there were two little naevi and a rnollu cum o n the la teral ches t wa ll.) In 1938 the abdo111in a l tumo r till appeared to be very volumin o u , but wa inclol nt and hard. H owe,·er, its form eemed to have changed a li ttle. The tiny tumor o n the back eemecl to be in the proces of regres ing. The child wa again examined by Debrc in February 195 a nd in June 1960. He found h er in perfect health. The abdominal tumor present in 1938 was no long r palpable, and there was no evidence of a ny metastatic les ions el e-

20 SERIE ' A: INFECTJ ON C.\SE ', DET.\ J LED J llSTORI ES where. The patient had married and had two healthy children born in 19-18 and 1954. he was la t traced in good health in April l 969, 40 year · after onset.

Comment: ln this ca e it is impo ible LO determine what fac tor may have produced the pontaneou regre sion of the l sions of the left eyeball and of the upra•orbital region at the age of eight months, whi le she was with her w t nur e. The ab orption o( thee two le ion may h;1ve increased the natural res istance f this child to her neoplasm. Fortunat ly he received onl y sev n X•ray treatment over the abdom in al mas, ·o 1h at her resistance was not depressed by heavy radiation. It is difficult to e,·aluate the po sible inlluence of the pertu is and rubeola on the course of the disease. However, the development of urticaria followed by suppuration coin ided with the ar­ rest of the disease in tbi ca. e. R eferences: 13; 21; -19; 71 . CASE 3: Inoperable neuroblastorna, apparemly an lll g in the presacral sym­ pathetic trunk, confirmed by micro copi exa mination by Pro(es­ or Bonnard. Previous History: H . C., female, aged 6 months, of Dorcl ogne, France. The baby ·was born at full term, a normal delivery, of complete] healthy parents. She had one sibling, aged JO. The infant developed retention of urine on the ei0 ·hth day a fter birth, requirino- catheterization. There was no fever or nausea. She was referred to Dr. H.L. R ocher o( Bordeaux by Dr. Lagorce of Exideuil on J anuary 15, 1935. \t thi time the ch ild wa a little co n ti pated. R ectal examin ation re\'ealecl a firm, fibrou ·, voluminous tumor obstructin g the entire hollow of the pelvis, extending from the posterior sac­ rum almos t to the posterior pubi . The examinin g fin ger in the rectum could not be pas eel beyond the tumor. One got the impres ion that the tume[acti on fe lt on biman ua l exam in a ti on below the urnbili u was the blad­ der, which was greatly distended. On turning the child on her swmach a tumor was seen on the right border of the sacrococcyx. lt cau ed the skin to protrude without being adh rent to the deeper structure . There was n o change in the co lor of the tis ues and no (luctuation wa pre ent. The general hea lth appeared good. The chil d was not tired. X-ray exam in ation revealed a slight erosion of the anterior a pect o( the body of the fir t sacral vertebra. At fir t the condition was believed to be a tumor arisin g in the b ne or cartilage which in developing had ca u eel ob truction o( the ureter b pres• sure aga in t the pubis. Surgery : An exploratory operati on " ·as performed. The condition was absolutely inoperable. A segment of the tumor was removed which gave th e d istinct impression of being a fibroma: the mass wa uniform, the consistence firm, the cut urface a p inkish grey. The wmor did not bl cccl . The post­ operative co urse was uneventful. The wound healed per primam. The prog­ nos i , however, was regarded as hopele · . Concurrent I nfections: \\' h il e the child wa lll the ho pita! she had a few attacks of bronchiti . She did not aga in have any ympwrns o[ retention of urine after the day she was admitted and catheterization was not again require I. Radiation: X-ra therapy wa give n at the clin ic of Pro(essor R e hou: 16 treatments between J anuary 16 ancl March 4, 1935, usuall y at 48 hour intervals, alternating the posterior and anterior pelvic region: 180 K.V., 10 x

21 SERIES : INFECTION CA ES, DETAILED HI TORIES

10 cm. port, totalling I 00 r to the po tcrior and 1080 r to the anterior portal. At the ncl of this tr atmen t the tumor appeared to be regressing, and there were no local or general symptom . By March 11 , 1935, when the baby was di charged, rectal examination revealed that the tumor seemed Jess hard and le s vo lu m in ous. The operative scar was perfect and there was no recurrence al the site o( the biopsy. Clinirnl Co11st: The ch il d was (ollowecl regularly every two months. At each exami nation it was fou nd that the tumor had di.mini h eel progressively. In .June 1935 there was no (urther pelvic tumeCact ion. X-ray examination early in September 1936 revealed calcium deposits or o si(i ations on the mar­ g in of the base of the sacrum, especially on the right side, and on the side of the hollow of the pelvi ·. On May 20, 1937 the child was 'tga in seen and appeared Lo be in perfect h a lth, apparently cured. She had developed nor­ mally. Bimanual pelvic exam ination revea led absolutely no evid ence o( dis­ ease in the pelvi ·. X-ray examination revealed nothing abnormal except the alci(ied mass mention cl above, but on the right side only, opposite the sacroili ac not h. This was about three years after on et. R eferences: 56.

CASE 4: Inoperable neuroblastoma, ,vith multiple superfici-t l metastatic lesions, co nfirmed by microscopic examination of one of the nodule removed f r biopsy from the external canthus of the left eye, by P rofessor Oberling. l'rcv io11 s llislo1y: i\fale inl"anl. The ch ild wa born prematurely in the eighth month in 1935. He was the grand on and nephew of physicians. The parents and two sisters, ev n and ix years old, were in perfect health. Ho\\·­ e\'er, the child's mother died of multiple myeloma in the summer of 1957, 22 yea rs later. Conrnrrrnl Enteritis: The baby had an atta k o( d iarrhea at four months wh ich cau ed him to be a little tired and pale. Shortly thereafter th e mother noticed a maJI ubcutaneous tumor at the lateral corner of the right eye which 11·a~ hard and mobile. IL rapidly increa eel in ize. During the next few cla ys many similar small tumors developed on the plantar surface on the feet, the right groin, buttocks, scrotum, e pecially the r ight side, back, left ide of the thorax, and th external ca nthus of the left eye. These small tumor remained the ame size. However, the mother noticed that the prin­ ipa l wmor on the crotum varied in siLe. Only one other tumor appeared after the (ir t outbreak, on the scalp, near the anterior angle and to the right of the fonta nel le. The general condition and appearan e of the child was xcell ent after h i reco,·ery from the diarrhea; there wa no loss o( weight, I uL a normal weight in rea e. H e wa happy and gay, with a normal appetite a ncl no fe,·er.

11rgcry: The child was fir t examined I y P rofe sor M o quet and Dr. R aoul i\Ion cl. smaJI tumor wa removed, near the external ang le of the eye, a m mh after its appearance. The histological examination, fir t at Pa - teur In. titute, then co nfirmed by P rofessor Oberling tatecl, "The tumor tis- ue is form cl of mall round ells, quite regular, crowded one against the other and constituting membrane in the cen ter of which often appears a finely fibrillar ub tance. Here and there are true sym patheticoblast clus­ ter. I t i a ca e, !early of ympatheticobla toma." SERIE INFECTlO:'\' 'ASE. ', DET'AILED I lJSTORlE. '

Clinical Course: The author, on examination of th patient, de cribed the case a having a central tumoral region, that of the rotum and it multiple acces ory nodules. The principal tumor ,ra. cl eply irnbedded in the right scrotum, being an agglomeration of sma ll round tumors, resembling h ard green grapes, sharply dcfin cl, and not ad herent to the scrotal sac. Les we ll -defined, there was neverthele an exten ion of the tumor toward the med ian raphe of the scrotum and, apparently in the le(t scro tum. Further up, the tumor gradually extended towards the inguinal ca nal. The neopla m was very hard , and painless. round the principal m as, the i1 e of a small plum placed vertically in the crotum, ther were apparently small i olatecl tumors. There was a lso a smal l, hard utaneo us tumor on the right crotum. The other tumor, much smaller, were in the inguino-a bcl ominal region of the right groin (in the z ne of the subcutaneous abdom in al artery), and de­ scended towards the perineum and the buttock particularly on th e right side. The tumor ituated nea r the right eye " ·as under the kin an l wa not ad­ herent to it. It was about the size of a lentil. The tumor on the scalp wa. the size of a pea and in the thi ckness of the ca lp. On the back, the small nodule was deeper, and seemed to be attached to the rib , being so mewhat mobile. The overlyin g ti sues moved free ly over this mas . T here wa s a very mall and hard nodule on the forearm, which seemed to adhere to the skin. How­ ever, the nodules on the plantar urface of the foot, particularly numerous on the right, involved the superficial ti sue and protruded on the urface, being purple in co lor. The general hea lth of the child rema ined I erfe ct. The temperature varied from 9t' .6° to 99.5 ° F. onl y very occa ionall y re,1cbi:1g 100.4 ° f . The child wa rosy and ga in ed weight regular!) . . \ blood test r . veal d nothing abnormal. The excell ent genera l hea lth contra ted v1 ith the tumors, " ·hich, from their quantity would make one think of a generali za tion of malignant tumor. The authors noted also that after the imultaneous ap­ p ea rance of the multiple tumor , only one new tumor appeared, that on th sca l1 . Also, only one had rapidly increased (the tumor by the external angle or the eye, removed for histologica l examination) . Given the clinical and patholog ical cliagno is of neuro blastoma, the au­ thors sea rched very carefuly, both clinically and by x-rays, for the primary tumor. There was no perceptible tumor, either lumbar or abdominal, alt­ though the left lobe of the liver, both on the x-rays and clinically, appeared to be a little increa ed in si7e. But the earch for the primary tumor was nega tive. The tumor on the ri ght s rotum remained preponderant in rela­ ti on to the others. The authors stated: "We were confronted with two alternatives: either the multiple tumor were benign, and we had only to wait, and perhaps re­ move the unattractive or annoying ones; or the multiple tumors were malignant, which was probable, in which ca e their multiplicity excluded the poss ibility of removing them, as it wouldn't have been of any use Lo remove the tumor on the scrotum, even if it had been the primary and principal tumor. Profe sor Oberling advi eel again ·t x-ray therapy. v\T ith a di agnos is of neurobla toma, we naturall y gave an extremely guarded prog­ nosis. H owever, we gave the I aren t a mall gleam o[ hope, clu e to the excel­ lent hea lth of the child and the lack of knowledge or certain infantile tumors. \ 1\ e would not in any case have regretted giving them thi hope, but were extremely a toni heel and happy to discover that the tate o[ the child re­ mained stationary and then improved." Vitnmill TheraP)' : The onl y treatment comi~ted o[ ma ive doses of Yitamins. "Finally, we h ad the joy of ee ing thi · child, . ix years later, en­ tirely cured, and in perfect health. There is no more trace of superficial

23 SERIES A: INFECTION CASES, DETAILED HI TORIES tumors. The large tumor in the scrotum h as entirely d isa ppeared. Perhaps, and it is the only clinical ob ervation, the left lobe o[ the liver is sli ghtly larger than usua l. The mother told us that the tumors had di a ppea red pro­ gressive ly, in two or three month a[ter our fir t examination. The explos ion o[ the multiple tumors had onl y la tcd about five months. "This suq rising case, this cure of ma lignan t multiple tumor , gives mat­ ter for reflection. One must envisage the poss ibility o( the sp ntaneous dis­ appearance of neuroblastoma, the degree of its malignancy, particularly in the superfi cia l form o[ multiple tumor ." The patient rema ined free from further evidence of the disease. H e was la t traced in good hea lth in December 1957, 22 yea rs aft er onset. C:omm en l: Th is ca. e resembled that of Ro u sy et al (194 1) in which an acute enteritis also developed early in the co urse of the di ·ea e. It is possible tha t if more cases of this type of tumor were left untreated in ·tead of being given large amounts of x-ray therapy, wh ich is now known t depress the na tural res istance factors such as reti culoenclothelia l and lymphoid tissu es , that many more such "spontaneous" regressions migh t have occurred. T his child appears to have had co ngenital suprarenal primary tumor which remained undete tecl until it a pparen tly r gressc cl during an attack o[ enteritis at four months. T his was not a severe or prolonged attack, and it did not stimulate nawral resista nce sufficiently to preven t rapid temporary dissem inati on o[ the disease. Children appear to re pond more dramaticall y to co ncurrent bacteri a l infection or to tox in therapy than lo older pati ents. It has b en noted in a e receiving toxin therapy that inadequate initial dosage may at fir t a ll ow meta tatic les ions to develop during the initial dis­ solution of the primary tumor. H owever, if further toxin treatment is give n th ese metasta cs may al o di appear \Yith complete and pennanent recovery. H efercnres : 21; '19.

ASE 5: Inoperable neuroblastoma confirmed by microscopic examination at the In titut du Cancer, Paris, France, fo ll owing b iopsy in July 1938, of two sections of the tumor; and of the tumor mass re- 111 0,·ed at the operati on in ugust l 939. Prc11 io11s Tlistory: i\l a lc, aged 22. The famil y history was difficult to as­ certain with exactitude. His parents were alive and hea lthy. One grandfather had been operated upon at 77 for a lesion on top of hi head, sa id to have been lupus, but two yea r later a mas appeared in the neck, which wa till pre ent five ears later. vVh ether it was cancer or not was unknown. The paLient had bronchopneumoni a and convulsions at Lh e age of three, and a ut rheuma Li sm at 17. H e ·wa s serving in the French M arines. About J anu­ ary 1937 he f ll about two meters landing on the abdomen. The exact date of on ct i not known. Co11rnrrrn/ Enttritis: In June 1937 he was eizecl with intc tinal coli c and diarrhea, with ye ll ow liquid stools. The patient then noticed in the iliac fos a and ri ght h 1 pochondrium a harcl fixed tumor. X-ray examination o( the intcsLine. ves ica l ca theteri zation and urinalysis were all negative. Ex/Jlorato1y Operation: The urgeon in the i\Iaritime Hospital at Brest, France decided to attempt oper:llion in July 1938. H e found a voluminous Lumor in Lh c mescntery which appeared to be inoperable. A biopsy was taken from a nodule auached Lo the tumor mas . The cliagn os i remained uncertain huL it was noted that no lym pho id ti s ·ue wa fo und in the nodu le.

24 ERIES A: I t .FEC IOI\' CA ES, DET,\lLED HJ TORlES

R adiation : X-ray therapy wa g i,·en for a month (no d Lail were re­ ported). H e wa di charged from the i\farine in September 1938 beca use o( hi m se nteric tumor. Clinica l Course: The patient \\·as fir ·t seen in the lnstitut du Cancer six months later, in January 1939 . t this time he had lo ·t weight a nd su[­ [ered from evere constipation, and pa inful ymptoms a. well as po llakiuria. Examination revealed a prowberant, ha rd, sm oth, fixed wrnor in the right internal ili ac fossa, reaching onl y sli ghtly abo\'e the horit0ntal umbilical line, and a pparently a ttached to a tumor ma s that h ad de,·clopecl a month pre- iou ·ly immed iately to the left o[ the median line, but lc ·s protubera nt a nd less a pparent tha r:i the primary growth. There existed a light coll atera l ir­ culation. Digital examina tion per rectum re,·ealed a hard, fixed, mooth ma. s the ize o[ a fetal h ead adherent to the anteri r wall, but not to the acrum. R ecto copy was impossible. Fu rt her Radia tion : H av ing obta ined the sections removed in July 1938 from th e M aritime H ospital in Brest, a nd h a,·ing di agno ·cd th condition as neuroblas toma, it was de ided to give another course o [ x-ray th r;ipy (two abclomin;il port anter iorl y and two posterior] , 200 r L\\'i ce dai ly 200 K.V.) This " ·as given between February 5, 19 39 and March 3, 1939. The tumor in creased li ghtly a nd slowly in volume. Clinical Course: Jn i\fay 19 ~9 Lh e patient co mpla in ed or pa in in the thoracic region which ,vas intenniucnt as to ite a nd intcn ity. Chest films revealed nothing abnormal. The general health remained good until the end o[ July 1939. Then suddenl y in early Augu L 1939 the patient de\' elopcd \'io­ lent pains in the abdominal region. Examination revealed two very hard suprapubic ma ·ses a nd an a bdominal mass a l iule higher up in the left ·idc. Surgery: On August 7, 1939, Dr. Barbier operated. l lc [ound that nex t to the ·upcr[i cial m a s th e tumor extended deeply ba ·k\\'ard a nd laLcrally, and wa not very mobile. In the front it was encapsul a ted , whi ch made it pos­ sible to spl i L it. There ex i tecl another mass a llach cl LO the left me ·ocolon , whi h it was po sible to eparate from the (ir t, a nd there were adhes ion on it pos Lcrior portion e pec iall y to the peh·ic iliac ,·csse ls. l t was detached Crom the front a nd ba e of the bladder. The po terior-infcrior pole was harder to free. The entire mas, which extended behind the rectum, was finally di - sected free. few mall granulations remained on the sma ll intes tine. The second mas , involving the me ocolon co uld n L be removed . Immediately after opera tion Lh e constipation cased entirely, and the sLool were no longer fl a tLcn ed. Furth er R adiation : Another co ur c o[ x-ray therapy wa th en given be­ twee n August 30 a nd September 30, J 939. (1 00 r to each o[ two posterior abdominal ports, and 2200 r to the two anterior port ) . Conc11rrenl Pneumonia (?): A few day after the fin a l treatment, in Octob r 1939, the patient had a pulmonary epi ode with fever, a nd signs in the left base ,rith slight dullne s. Thee symptoms improv cl rapidly, although the patient became thinner, lost appetite a nd felt tired. At first these acute sympwm " ·ere con icl ered LO be due to pulmonary meta La cs. Che L [ilms revealed nothing abnormal. The patient left for the ountry to convale cc. Clinical Course: Examination on :'\ ovember 15, I 939, showed that the a bdomin al in ision formed a cord, hard on the deeper plane a nd enlarging at the umbili us inLo a ma the size o[ a n orange. There till exist d the other mass in the left la tero-vertebral region. The stools were again [] a u ened, a nd rectal examina tion (digital) revealed a hard mas 4 or 5 cm. above the 25 SERIES A: INFECTION CASES, DETAILED HISTORIES anus which compressed the rectum backwards. This mass was irregular and lobula tecl and did not a ppear to be adherent to the mucous membrane. It a ppeared to be either a recurrence of the tumor removed in August 1939 or a new growth. There were no urinary symptoms, although cy tosco1 y revealed that the bladder wall were very much deformed . The muc us membra ne ap­ peared normal on th e upper part but the lower p nion could not be seen. The general h ealth was good. \ (ew days la ter the pa tient again had viol ent pains in th e a bdominal and left lumbar regions wh ich persisted and prevented hi s sleeping. At a bout this time h e developed a sli ght intercostal neuralg ia or the left sid e. (011 c11i-rent Cystitis: For the nex t six months the patient suffered per­ sistent cys titis a t first acute with h ematuria, ancl the paroxysms rapidl y ,ttten- 11 ated, but there wa pus in the urine for a Jono· time. Further R adiation: On .J a nuary 17, J9,JO a n x- ray treatment was o·iven O\·er the blaclcl er region. Co11c11rre11t l nflam111atio11 and F11rt/1 er 111/ection: T here followed an epicl ydimitis of the left sid e wh ich lasted a few cl ays. Progress ively the symp­ toms of cys titi and hem a turia improved a nd finall y clea red up entirely by th e encl of April 1940 and n ever recurred. It is signi(ica nt to note th at during the period in w hi ch the p a ti ent u([ered from a persisten t cys titis the indur­ atecl area along the cicatrix in the mid-line became co nsid erably so(ter and l"in a ll y appeared to be only a fibrou s ·ar. T he subjacent ma ·s pre n t in i\'ovcn1ber slowly regressed during this period unt il it was no longer present in late April l 9,10. H owever, immed ia tely a bo\·e the umbilicu a sma ll hard nrn tl1e siL e of a nut had appeared in the cica trix; also in early pril there ;ippearcd to be diminution in ensa ti on o( the left ha lf of th e lower li p. The stool were ·till fl a ttened and the dig ital examin a tion of the rectum revealed a harcl (ixed ma s apparently attached to the pubis. Clinical Course: In e;i rl y J\f ay the pati ent felt tired, the constipation be­ ca me more per ·istent and one cla y intercostal pains developecl , of such severity as to ca use dysp nea a nd a sense of uffocation. t the sam time generalized a bd ominal pa in s developed with n a usea a nd emesis. The tempera ture rc­ m;1ined at I OI .7°F. An enema insta ntly stopped Lhe pain but they returned a nd las ted three cl ays. An x-ray examin ation revealed p artial obstru ti on be­ tw ee n the sigmoid a nd Lhe d escending colon which wa situated a bove it. This obstruction seemed LO be clue to a n external mass pressing on the lumen of the bowe l. "Suddenl y everything stra ightened itse lf out" and the pa tient re­ ma in ed well for a time. On May 29, 1940, he first experi enced formication , stiffening and burning involving the lower extremeties . Soon he developed cl il"ficulty in oorclin ating, h aving an inebriated, staggerin o- walk. At examina ti on on June 5, l 940, there ·was spasmodic incomplete p araplegia with hyper­ acti \'e rdlexes. Babin, ki ign was pos itive, bila terally. The left remasteric ref] x was diminished. H ypoes thes ia was present over the entire lower part or the trunk up to D5 accompanied by disturbance of deep se nsibility and pain on pre sure of the muscles of the thigh and legs. X -ray examination reveal cl onl y a n ero ion of the L S vertebra. Further R ad ia lion: An x-ray treatrnen t was give n to the vertebral les ion. (200 r d a il y for 15 clays, totalling 3000 r, 200 I<..V.). The patient felt tired a t the encl o( thi treatment, but he wa a ble to walk better. The tumor above the umbilicus to the left of the vertebra l column did not completel y disappea r. (;/i11ica! Cou rse: The di turbance in de p se nsibility disappeared and

'.2G SERIES A: I1'"FECT1ON CASE , DET ILED 11 ISTORLE hypoe Lh e ia was Jc s m arked. H o" ·e,·er, there wa cl ecrea e in th cuta n o us sen atio n o f the upper left extremiLy, very m a rked in the inner side o f the left a rm, \l'ith a burning en a tio n in Lh e ulna r regio n o f th rig hL a rm. ,\ t the sa m e Lime there were acute pa ins a t the site of the ramus o f the lo \\' er jaw. Fu rther Radia tion : On July 8, 19-J0 x-ra) Lh era py \\' as 1-c · u111 ed and g iven to the lumba r lesio n (200 r daily, totalling 1200 r) . The pa ti e nL conLinued to suffer se,·ere pa in irradia ting Lowa rcl the bo ulder · a nd a rms. X -ray therapy ,ms th en gi,·e n to the cervica l regio n (2 00 r d a ily alterna ting rig ht a nd left, totalling 1400 r) . The pa Li ent to lerated Lh e Lh era p , poorl y. J lo 1,·e,· r, o n ug u t I, 1940 x-ray thera py was g ive n to the epiga-Lri c regio n (2 00 r) . Cli11ica l Course: During July a nd .\ug ust l 9·10 Lh e pa ti ent a ppeared to be in good general conditio n altho ug h a LUm or a ppeared a t the ra mus o f the in fe ri o r m axilla which in crea eel ra pidly LO Lh e size o f a sm a ll nut. Further R adia tio11 : .\ no ther cour e o f x-ray therapy was given to thi a rea (2 00 r daily, to talling 1200 r) which " ·as concluded o n Se ptember 26 , 1940. This tumor did not d ecrease in size as a re ult of radiation. Clinicn l Course : The pa ti e nt rem a in ·cl jusL a, constipa ted , the stools still be ing n a tten ed , a nd h e was asthenic, w ith no a ppe tite a nd suffered ,·io le nL headache as well a pa in in Lh e che t. Ches t film reveal ed n o e,·id e nce o f pa tho logy in the lungs, ribs or , ertebrae. In O cto ber 194 0, Lh e genera I con­ dition d eclined, the a ppe Lite being irregula r. A L this time a tumor m ass a p- pearetl Oil ' llle 'Jeh ~ th 1'lb al ·t il e a n rer1or a xlll,rry 1i111 e. Th \\";\S 11rarl l, ' ]Jcl lllt '. ~ a nd comple te ly adherenL to the bo ne. Jn the a bdo mina l regio n , to Lh e left o f the umbilicus, the re till rem a ined the e pigastric m a , which ha d been irracli a Led a nd which was still Lh t ize o f a m a ndarin orange, ha rd, ro unded a nd on I sl ig h tl y mobile. Thereafter th is m ass regre sed com plcte l y. The pa­ ti en L continued Lo be co n tipated a nd to have headache that ca m e at no fi xed ho urs, also he ome times h ad vertigo ancl proje tile vomiting a n hour a ft er eating . On October 22, 1940, upo n awa k ning he fo und tha t th e upper eyelid was edematous and then the lo wer lid o f the rig ht ey , wiLh extrem e] · ,evere headach e. This edem a was arcompa niccl by exo phtha lmos a nd this yncl rom e a ppeared to represent a ra pidly growing m etasta is, but examina­ Li o n revealed Lh a t the eye wa no rm a I. S/Jon tn 11 eo 11 s R egression Fol/owi11 g E/Jilnxcs : On O cLO ber 2 , 1940, with­ o ut a n y treatment, the ed em a, exo phtha lmos and cepha lg ia comple Lel y d isa p­ peared. These phe no m ena recurred evera l ti mes, som e ti me las Lin g longer, others brieC ly, som etimes o n the ri g· ht side, som etimes o n L11 e I fl, a nd were a lways accompanied by epistaxis of the h omologous na ris. (;/i n irn l Course : .\ few d ay, la ter a . h a rp pain d eve lo ped benea th the rig ht ribs posteri o rl y, w ith thickening in this regio n. ,\fter a few d ay this p. e udo-m eta,ta i di. a ppeared spo nta neously witho ut trace. On November I 0. J9 40 a thoroug h ex a mination was made o f the p a ti e nt. IIis we ig ht ha d in­ crca ed a bo ut 3 pound . A n eu rologi al exa mina u o n r vea led no rma l egm en­ ta l musc ula r form; there was n o di LUrba nce of the m obility, except tha t h e had a few muscu lar sp asm s of the legs which cam e o n a t a n y time o f Lh e d ay o r nig h t, a nd la tecl a few seconds. R eflexes were norma l. Exam ina ti o n o f e nsi­ bilitv re,·ea led the fo ll owing seque ll ae to his o ld di t urba n res: there was pa in­ ful h ypere thesia in the zon e b elow a nd insid e the left nipple over a n area o f a fe 1I' cenLim e ters, also o n th e a nterio r a pen o [ Lil e left kn ee. The re were painful phenom ena a t nume rou poinLs especially m a rked a t the left h emi­ t ho rax, irradia ting to th e upper I ft a rm a nd al o LO the lower and o uter

27 ERIE A: INFECTION C SES, DETAILED HISTORIES

portion of Lh e right capula. At this area there was a light degree of thick­ ening. The rig lH knee was pa inful Lo palpati on, and the pa ti ent could not fl ex the leg onto the th igh without pain. This pain radia ted toward the sole of the feel. The. e pains were \'ery va rial 1 in in tensity, with brusq ue crise, coming on a nd cc,1, ing wi thou t a ppa rent c, aus , las Ling a few hours or a (ew days, cha ng ing site, from one arm LO the other, without clinical or x-ray examina tion being a bl e to d eterm ine the cau se. i\Iostly they were of a burning type, occasiona lly o ( pinching, or o( t0rsion. They were exaggerated by ex­ a m ina tion , a nd by pressure and a ppea red to b e Jes enecl by heat. T he consti­ pa tion persisted with fl a ttened tools. R ectal exarn ina Li on revealed the same mass in the r ight pehis. ln mid-December l ~N O the meta,ta ti c tumor " ·hiclt had de,·elopcd in O t0ber ancl ,1·hi ch h ad remain ed a lm os t imperceptible for two months uclcl enly rapid ly increased in size. bout J an uary l , 1941, an­ other ha rd, pa in f u I m etas tatic noel ule the size of a sma II n ut developed on the extern al a ·pect o( the fifth rib. In reporting thi case on J a nuary 9, 19-11 the a u th ors noted th at the prima ry tumor histologically h ad a stru turc quite characteristic of neurobla - toma, very li ghtly fibrillar. H owever, exam ina ti on o( the tumor ma s l 1.5 x 8.5 x 7.5 cm. in d iameter removed from the abdom ino- pelvic region in August 1939 rc1·ealccl a ornpletel different tructure. The tumora l stru ture were ,carcc a nd ,rere covered with fibrillar tis ue more or less elonga ted .. . the neurobla ts had ju t a bout disa ppeared. The a uthor co ncluded tha t the g- reater pa rt o( the tissu e con isted of adult ganglion ic cells. They also found ,ill the tra nsitions betwee n these elem nt and neuroblas t . I n n ne of the e t) pe · of ce ll s was a mitoti c divi ion seen. The fibrillar zones were remarkable b, their a bunda nc . ln a few i ola Lecl area one found betwee n the fibers little a1'. ca o( a l i(ica tion. Between thee cellu la r a nd fibrillar tis ues were va t a reas formed by necroti c ti ssu es urrouncl ecl by hemo id ero ic macrophages or or very \'ascu la r connec tive tis ue with not very dense co11 agenous fibers. T h ese areas s11rrouncl ecl hemoi-rhagic suffu. ion a nd more or le s cl ea rly lim ited a nd ca lcified ti sue. Jn a f w area the alcification wa more diffuse a nd calcarious gra in wcr i o latccl among the c,o ll agenous fiber. The author earch ed th e tumor ti ss ue for th e po. i bl c existence of Jc · ions cl u e to the irracl iation done . ix month prior to opera tion. Absoluely no degenerative cellular alteration cou ld be a ttributed to radia ti on. The presence of necrotic a rea a ncl ca lc ified area being the u sual observation in this type of tu mor, the author d id not a ttribut the c to the radia tion. Jn ummary, histological exami nation of the tumor removed fir t revealed a neuro blastoma pres nting all the u ual character i ti s of fra n k malignancy. Although the ccond tumor removed a year la ter wa also unquestionably n uroh la toma certa in im portant modification h ad taken place. This tumor rcvcalccl a t ndency to evolve toward a more adu lt form (pre ence of ganglion cell or to a gangli oneurom a); in thi ase there was a transition in termed iate bct,1·ec n a n embryona l neuroblastoma and a n adult ganglioneu roma. The au thor cited th e li tera tu re of ·upra renal tumor . They no ted tha t Frew di:tingui bed t\\'O d i tinct types, with d ifferent symptoms and routes of meta ta cs, those a rising in the right ide u ua lly presen ting painful phenom­ ena loca li?ecl to the abdomen and u u al1 y confined to the ki dneys a nd liver, nc,·er to the cra ni11m or rib . Exo1 hthalmos wa rare. The econcl type, where the tu mor i~ pri mar on the left icl e, i · cha racteri ,ed by pa inful ·ymptom in the lm1·cr extremi tic, by o eou mera ta e, a y toli c murmur in the ca rd io­ ,·as ular area, a nd exophthalmo u ually of the left side. The pain and ys toli c murmur are cl 11 e partly to compression by a neop la ti c mass of th e lu mbar plexu and part! , to enlarged rn edias tinal ve els.

2' SERIES A : I NFECTION CASES, DET ILED HISTORIE

The author then point d out that in th e above case at onset th re was a mas on the right side which pre en ted th e classic symptom outlined above for uprarenal tumors on th at icl e. Howe\'er, when this ma ,,·as r mo,·ecl at operation in Augu t 1939, leaving only a small er re idual mas on th e le[t ·icl e, th e cla ·, ic ~) mp tom found in tu11 1or. a1 i i11 g on th at side soo n devel­ oped. (S li ght ev idence of ome of these s mptom first developed a few months prior to this operation) . They also noted that in th eir case th e prim ary tumor on the right side d id not rapidly spread to th e liver, d iaphragm or lungs, con trary to the usual our e of th disea e in such a es : " By its diverse characteri ti c, by it sl ow evolution, marked by recurrences, by sue essive locali za ti ons which were nevertheless ca pabl e or regress ion, the neurobla toma of our patient thus i d istinct from the grea t d a sic types ." They then cited fo ur cases in th e literature in wh ich th e co urse of the disease had been remarkably slow or completely arrested. Commen t: In the li ght o[ pre enc kno,decl o-e regarding th e timulus which bacterial toxins give to the r ti cul oendotheli al, hematoipoietic and lymphoid tissues, each of which appea rs to play a significa n t role in res istance to malignancy, one should note that this patient had a severe nteritis at the time a tumor in the right h ypochrondrium was first noted. T his epi ·od may have increased his natu ral resistance enough to delay th e usual metas tases which occur in such cases, and to produce the hi tologi a l changes seen. The authors noted that no apparent benefit was der ived from the radiati on, as evidenced by the lack of regress ion occurrin g after x-ray and the lack of changes een in the irradiated tumor which ould be attributed to the treat­ ment. T his tumor did not show complete tran ition [rom neurobla toma to gangli oneuroma. The ca e of neuroblastoma reported by Cushing and vV ol­ bach , treated by the child' father in 1911 , had Col y tox in s a lone g i,·en over two years, without radiation, and in this case the widespread involve ment of the ce ntral nervou system cleared up, including th e ce reb li ar symptoms and this patient remained well when last traced over 59 years later (see below Series B, Case I) . In publishing that case in 1927 Cushing and Wo lbach sta ted: "A very th orough examin ation of the tissue removed in 192 1 reveal ed no trace of cells similar in struclure to those 11·hich in 1911 apparently con­ stituted th e entire growth. It 1,·o uld appear without que ti on th at the proli fer­ ative activity of the former growth sub icl ecl coincidentally with the admin ­ istration of Coley' toxins. The les ion was origin all y an a tive growin g symp­ atheticoblastoma whose cells, co i ncicl ent with loss of pro! i [era tive acL i vi t y, ca me to be differentiated in tim e in to ga ngli on cell s a ncl in Lo heath and ca psu lar cells ...Th e ca e from a pathological standpoin t is a unique one." (l 1) Un­ fortunately no other case of neuroblas toma was treated by toxins alone. R eferences: 57.

CASE 6· Inoperable neuroblastoma, confirmed by microscopic examination after exploratory operation. Previous History: Female infant. The first child of healthy parents. The fa mily history was negative for ca ncer, tuberculos is, diabetes and all erg ic . During pregnancy the mother had not been ill. The child was born spon­ taneously at full term, but she had a swollen abdomen from birth in fay 1938. Growth and development were normal d uring the first year. Concurrent I nfection: The baby developed varicella at th e end of her first year, in May 1939. This was h er only illness.

29 SERIES A: INFECTION CASES, DETAILED HISTORIES

Clinical Course: She was admitted to the Children's Clinic of the funi­ cipal U ni vers ity of Amsterdam in October 1939. She did not appear to be ill or suffering l u L Lhe abdomen was greatly swollen and did not move with respiration. There was a clear net of ve ins visible on the pale wall of the abdomen. On palpaLion Lhe abdomen was rather taut and deep l ressure seemed to cau e pain. At the right lateral side below the sli ghtly enlarged li ver a round wmor Lhe ize of a ta ngerin e could be pa lpated. It was of firm consisLcncy and clearl y co nfined es pecially below and at th e medial side. Blood cou nt showed 9,600 wbc, with a moderaLe shi[t Lo the left and no anemia. X-ray findings suggested hydronephrosis. o treatmen t was give n. Three months later, in J anuary 1940, Lhe child wa readmitted. Her weight had diminished so mewhat, but the general condition remained fairly good and there were no special compla ints although the tumor had grown some­ what. Physical exam ination revealed a superficial tumor palpable in the up­ per righ t abdomen, about 9 x 6 cm. in d iameter. U nder this tumor wa a larger mass of firm consi tency which reached to about 2 cm. below the umbilicus. Radiation: Three deep x-ray treatments were g ive n in 13 days, to the side o( the abdomen, J a nuary 30, February 6 a nd 13, 1910 ('JOO r each). This did n ot cause any diminution in the size of the tumors. The child did not look well, had no appetite and her weio·h t wa steadil y decreasing. S11rger),: A t operation on February 20, 1940, Dr. Van Cappillen, the urolog ist, found "a n inoperal le vasc ul ar Lumor in Lh right renal region, firmly grown LOgeLher wi th the under layer." H emorrhage: 'When a small part of the tissue was removed for histo­ logica l exam in ation a hemorrhage. occurred whi ch was controlled with diffi­ culL y. The pathologic report at Lhis time was small round cell sarcoma. The prognosis was regard cl a · unfavorable. 1o treatment was given . Clinical Course: Abou t 18 months later the child was seen in the out­ patient department. She had gained a great deal of weight. The cicatrix was healthy and t.he tumor in the abdomen had regressed to the si ze o[ a tangerine. T here was no anemia. A year later she was again seen and the tumor re­ mained the same size. Four and five years after the operation the child re­ mained in good health and there was no evidence of tumor on palpation. he had clevelope I well. At this time ( 1945) the sections " ·ere re-examined and were pronoun eel "neuroblastorna, an extremely mali gnant ty pe of tumor, cl ue to the hi tologic p icture." The child developed splendidly and remained in excellent health; he married in 1960 and had a normal child. Both ·were las t traced en ti rely we l I in December 1969, 3 1 years after onset. (The au tho rs cited the cas so( Cu ·hing and W o lbach, R ou y, Fcvre and Debrc'. ). Com111e11t: In this case the concurrent vari cella infection prior to the three mall do e of x-ray therapy a ·well as the shock of hemorrhage at exploration, may have timulated the reticuloendothelial and hematopoietic Li ·ues to elaborate re istance fa tors uffi cient to cause complete regression. R eferences: 49; 71.

CASE 7: Apparently inoperable neuroblastoma of the left adrenal gland, confirmed by micro copic examinati on fo ll owing biopsy by Dr. F. W. Hartman, Department of Pathology, Henry Ford Hospital, D e­ troit, Michigan who reported: "Sections of bits of tis ue removed

30 ERIE A: E\'FEC 10;\ C,\ E , DETAILED 111 TORIE

show d den e, pink- ta ining, parsely nucleat ti troma supporting large ma e and column of deep! · ta ining o, al or round (ell . Thee had little C) topla m, but the nucleu "·a h -per hromati c. There was a tendency toward whorl fo rmation in .ome pl ace, but no typical ro ettes were found. The diagno is was mali gnant neu­ rocy wma of the left adrenal g land.'· Prev ious Histo,y " . ., male in fa nt. The child wa born normally on .'\O\ ember -1, 19·14 and eemed to be in excell ent condition. l lc " ·a~ cxa!ll in ecl at the age of three ,reek for occa ional ,·omiting and a olitary mas wa · relt 2 cm. below th e left cos ta l margin . X-ra) exalllin a ti on rc\'ca lecl a quc,­ ti onable ma s in the left upper quad rant of the abdomen and the Ii,· r eemed larger than u ua l. A comp! te blood count ga,·e norma l rcwlts . . \ fasting bl ood ugar level wa 9 mg. per 100 cc. and after admini\ trati on of 2 mini1m o[ J:1 ,000 ephedrine ubcutan ou ly it roe to JO ' mg. per 100 cc. Th \\'a - erman was nega tive. Chole terol content o( the blood wa 222 mg. per I 00 cc. The tuberculin reaction wa negati,·e to 0. 01 mg. of o ld wberculin. Concurrent Infection: Comedo and acne, with ma ll infected pimple cl e­ ,·elop d over the cheek and thi was regarded a clu e to stimulation or ex hormone . t the age of nine week the mas in the l ft upper quadran t of the abdomen was more definite and the infant· · weight ,,·a 12 pounds (5,4 ·10 gm.) The rn ea urement were: head circumfe rence 3, cm. , che t cir­ cumferen e 37 111 ., and abdomen 47 cm ., a gro nlargement o l the lau er. At this time he wa referred to the H enry Ford H ospital by Dr. Ruth Kraft of Detroit and was admitted. The bl ood ount showed I lg. 11. 2 gm .; rbc. ·l,000,000: wbc. 11 ,100: 33 pol ·morphonuclea r ; ·1% cosinophiles. 50°~ m ;1 ll lymphocyte and 7% mononuclear ce ll . T he phenol ul[onphtha l in-ki dney functi on te t ho" ·ed 35° ~ excreti on in the (ir t hour and 15% in the econd hour. L abora tory data ,rere blood ,·an len Bergh tes t, n gati,·e: inen1 s index, 5 mg. per 100 cc.; blood protein nitrogen, 30 mg. I er 100 .; fa sting bl ood sugar, 72 mg. per 100 cc. ; ugar level following admini tra Li on o f" 2 111i11ims of I :1,000 ephedrine, 77 mg. per 100 cc. Urinaly i ga,·e normal re ults and L11 e tool ho\\·ed a 3 plu guiac reacti on. Che t fil111 bowed norma liL~ exce pt for moderat elevation of the left dia phragm. Flat film of the abdom 11 re­ veale I onl y a slight increase in den ity in the upp r abdomen, ,l"ith down ­ ward di pl acement of the inte Lin e. Intra\'enou pye logram · how d no ex re­ tion of dye inLO the right kidney. The left kidn y wa \'i ~uali,ed and appeared normal. Examina tion of kull and long bone howecl no abnormalities. urge1y : biopsy wa performed and reported as abo,·e.

R adiation: X-ray therapy \.\"a begun immediately and 20 were g i\'en in 38 cl ay, an e timatecl doe of HOO r LO the tumor ite in the upper a bdomrn. Two month later he wa given a second course o( J 6 treatments in 20 day , an estimaLe I 1250 r tumor dose (200 JZ.V. , 50 cm. dist. 25 ma., It a l[ \' ct lu , layer 1.0 mm. cu. ; fi eld ize varied from x IO cm. to J5 x 15 m.) . The child' kin remained in good condition, and he im proved genera l] '. The acne did not rema in on the face fo llowing radiation. Clinical Course: By July 2 , ]9,15, one month after radi a ti on wa s com­ pleted, the liver had re ed ecl to the co ta! m argin, but a sma ll firm mass could till be felt in the left u p per quad ra nt of the abdomen. _\ t the age o[ 11 month he weighed 19 pound and eemed well. t the age of 1·1 month the ma in the left upper quadrant could no longer be felt and the Ii,· r wa of normal size.

31 SERIES ,\: l:'\FECTIO:\. C ES, DET\ ILED LI I ' ORIE

C.011c111-re11t Infection: In :\o,·ember 1915 he had an attack of influenza. C/inirnl Course: .\t 1 momh complete roentgen wd · wa made of all th long bones and the ~kull for po . ible meta ta e, and the on ly finding wa "a uggestion of se,·eral cal ified glands in the upper abdomen." t the age of two )Car the child "·a a happ) normal boy, eating a regular diet and howi ng no e, idence of 1c:< un encc. In . \ ugu t 191 at the age of 3 ½ ,ear , a ~mall indi\tin t, firm ma ~ "·a palpable in the upper pan of the abdomen ju. t below the xiphoicl. The left lobe o( the liver wa palpable and smooth. ffe ,rn 1cadmiued to the ho pita! at thi tim for retrograde py lography. Thi re\ealecl the left kidney to be lo\\·er than the right, but no e,·idence of tumor wa cen. Further Radiation: 1 Iowe,·er, with the evidence of a palpable mas and di~plac.ern ·nt or the kidney a third cour e of roentgen therap · wa gi,·en. Thi con. i. ted of 13 treatment in 16 da) (1400 r tumor doe) . Further l11fcctio11.1 : In October 1919 he had another re pirator · infe tion. In ,\l arch 1950 he had a f w clay of abcl minal pain and ,·omiting. In Janu­ ary 1951 he had a right otiti media "·ith ton illiti. Clinica l Course: The child remained in good health thereafter. Hi de­ \Clopment wa normal. There \,·c. re no palpable ma e and the liver " ·a not enla,ged. The ca e wa reported by Beck and llo,,·ard in 19~1. Jloward tated that the b · had not been e peciall) ubject to a ute infection. lie apparently had rem a, kably good re i tance ao-ain t the type of infe tion common in of the \ Crtebral bone marrow (lumbar); evere pul­ monary d ma and ono· tion; ana area; al o econda,·y parathyroid hyper­ pla ia and fibrinou pericarditi . Death occurred over 23 year after on et.

lfrfC'fl'IICC : I ; 19.

CA E <: Inoperable general iz cl neuroblastoma, fir t noted in the sacral region. with at lea t 50 meta la e ( ub utaneou) on the calp and mire body exc pt the face and hand , onfirmed by micro- opic examination following biop ie of two of the nodule , by Profe ·or avallero, Director o[ the In titute of Pathological .\ natomy, Univ r ity of Pa,·ia, and Profe or irtori, of the Can• cer In tilllte . \lilan. ltaly. SERIES : I NFECTJOK ASES, DETAILED HI TORIES

Previous History: A.B., male, infant. The chi ld "·as born prematurely at home in the cvcn th month of pregnancy, a[ter a normal labor. At one month of age a small ubcu taneou tumor in the sacral region and another on the hairy sca lp were fir t noted by hi mother. Although the infant co n­ tinued to grow atisfact0ril y, new ubcutaneous nodule kept appearing which rapidl y increa ed from the size o[ a lentil grain to that of an ;:i lmond or larger. Concurrent Fever: During his fi[th month fever set in. Clinical Course: Tumor then appeared on the right cheek wh ich inter­ fered with sucking._ On June 25, I 9-16, at the age or (i ½ month the baby wRs adm itted to the Pediatric Division o[ the Di trict Hospital of Busto r\rsizio, ltaly. Phy ical examination revealed a pal , fragile, underdeveloped and un­ cl crn ouri heel child we ighing 6-100 gm. Scattereci subcutaneous nodules, rang­ ing in size from a lentil LO a walnut, were pre n t in the ha iry sca lp and a ll over the surface o[ the body except for the hands and feet. The nodules were rounded, somewhat o[t and [leshy to palpation. Some cemed Lo have no attachment to the overlyin g sk in , other. were definitely fixed to the deeper strata of the kin. The nodule on the scalp and abdomen were sli ghtly violet 1 in color under the emitransparent kin, po ·sibly due Lo va cul arit • Ther " ·ere about 50 tumors, mostly on the back. One nodule was present on the scrotum. Surgery : A ubcutaneou · nod ul e in the left pectoral region was biop• sied on July 1946. The report at this time was " highl y irnmaLUrc round ce ll sarcoma." Fmther Fever: The child wa hospitali zed for 30 day during which time hi temperature ranged from 98.6° to I 02.2°F. (l7° to !l 9° C.). I Tc lost l 00 gm. in weight. Four new nodules appeared, two on the sca lp and two on the trunk. R adiation was recommended, but in vi ew of the hopeless prognosis, the parents re[u eel and took the child home. T hree weeks la ter th y recon­ sidered and had the infant readmitted. t thi time there w·is no fever, he was quieter and had a beuer appetite. Blood count ·howed a leukocytosis (20,000 wbc.). It was noted that no new nodule had appeared and that th s on the cheeks had dec reased in size spon tancou ly. R adiation: . Five x-ray treatments were given (100 r each). The white blood oun t dropped to 6000 wbc. Clinical Course: By September 22, )9'16, when the baby was again seen, it wa noted that the irradiat cl subcutaneous nodules were rcgrcs~i ng wh ile the other remained unchanged. Clinical Course: Beca use o[ the contras t between the favorable genera l condition and the unfavorable hi tologic cliagno i , the child wa se nt to the • ational In titute of Tumors in i\Iilan. Further Surgery: A biopsy was then performed of a subcutaneo us nod ul e in the left axill a. This was again di agnosed a sarcoma, a nd continuation o r radiation was advised. Further R adiation: On an utpaticnt basis two additional x-ray treat­ ments were give n (100 r each), this time to the nodule on the neck and the nape. Clinical Course: \Vhen the infant was next seen, on February l 6, 1947, at the age of 14 month , he looked well and the ub utanco us nodules had uncler- 33 ERIE A: I NFECTIO"N CASES, DET AILED HI TORIE

gone a general regression, th ose on til e neck a nd calp h aving disa ppeared en tirely, while tho e on the back, a lthough le s palpa bl , had fl a ttened con­ sidera bl y, a nd had acquired a fibroelas tic firmness. Only the nodules on the abdomen preserved their ori gin al features. No further treatment was give n. The boy was readmitted at the age of six years because one of the three re­ lll aining nodules had become more noti cea ble. At this Lime the child a p­ pea red LO have developed sa ti fa ctorily, but h e was somewha t a nemic ancl ttndernouri ·hed . Concurrent Infection: There were a fe w impeti gous spots on his face. The th ree old subcuta neou n odules were still p resent: one in the epigastric region, one a ppended under the scrotum and one on the outer side of the ri ght foo t. R adiological examina ti on of the sk eleta l sys tem revealed nothing a bnormal. Further Surgery: A n exci ional bio psy of the epigastric nodule wa per­ fo rmed on eptember 6, 1952. On gross examina ti on the ti ss ue had the a p­ pea ra nce of white scl erotic connecti ve ti ss ue. This was sub equentl revi ewed I y P rofe sor Cavall ero who reported it to be a ganglioneuroma. The secti ons removed earlier were also revi ewed as sta ted above a nd the diagnosis o [ th e lesions removed in 19'16 was neuroblas toma. Clinical Course: During the following yea rs the two rema ining nodules did not change in a ny way. The boy enj oyed excellent health therea fter. H e was thoroughl y reexamined a t the age of 12 , a nd in 1962, when Vi gorell y r 'pon cl the case. H e remained trong a nd h ealthy, ma rried and had a nor­ mal ba by by \ug ust ]967. T here was n o further evidence of neuroblastoma. Th is wa 22 yea rs after on et. R eferences: 17 , Case 29, pp. 154-159; 49; 72.

C..\ SE 9: Inoperabl e neurobl a toma of th e right upper kidney region ex- tending int the upper ri ght abdomen with numerou m etastases to the liver a nd to the right proximal humerus and skull, includ­ ing both peri orbi ta1 regions, a usi ng extensive prop to is, confirmed by microscopic examina ti on of a biopsy from the liver taken :i t 1Iercy Ho ·pital, Chicago, Illinois, fo ll owing explora tory o pera tion. ( ee below for details) . P revious J-1 isto ,y: G .S. , male, aged 4 months (in March I 947). The in­ fan t was born of h ealthy parent , and the pregna ncy h ad been normal. His mother had no a n tibioti c, antihistamines or r adia tion during I regnancy. t birth he " ·eighed 6 pound, 7 ounces, and on feeding of eva porated milk supplemen ted by vitamins his weight a t four months wa 13 po unds, his height 2·1½ inche . Concurren t h1 feclio11, /\lild Otitis and Pl,a1y ngiti : H e was first seen by Dr. Da vid Goldring on i\Iarch 4, 1947 because of a mild upper re pira tory infection and wa fo und LO h ave a mild o titis and pharyngitis. Phy ical ex­ :1mina tion was otherwise negati ve. Hi only m edicati on was a ntibioti s. H e was aga in o b ervecl a m onth la ter, a t the age o f five month , with a mild rhinitis bu t no oth r a bnormality. Iis blood count on pril 22, 1947 was rbc. 4,5 10,000; wbc 15,500 and h emoglobin 65%. On et: On pril 2 , 1947 he ucldenly developed bila teral hemorrhage [ the eyelid and when examined wa found to be definitely anemic and to have a palpable m as in the upper right abdomen. Thi was [irm, not too

'.l ·l ERIES A: INFECTION C SES, DETAILED HISTORIES sharply outline I, but slight] movable and appeared to b beneath the liver, ,\·hi ch \\"a pushed somewhat up,l"ard and forward. On fluoro cop y, a rad i­ opaque ma s wa seen in the right upper abdomen, and the right diaphragm was considerabl y higher than the left. After admission to St. Catherine' H o ·­ pitaJ, \ Vhiting, Indiana, th e fo ll owing laboratory l"inclin gs were obtain ed: Blood - hemoglobin 7.4 gm.; erythrocytes 3, 040,000; platelets 60 ,800; leuko­ cy te 7,500 with a d if ferential of I basophile, 2 eos in ophil s, I ju,·enile, 2 swb c ll s, 20 s gmentecl cells, 68 lymphocy tes and 5 normobla t per l 00 I uko ytcs. Bleed in g time was 11 minute · and cl ouing time -J ½ minutes . Blood chem i. try - non-protein nitrogen 3 mg., chlorides 569 mg., total se rum protein 6.6 gm., with album in 5.3 gm. and globulin 1. 3 gm. per JOO cc. An intn n·eno us pye lo­ gram showed the -right kidney pelvis m uch JO\,, er than the left a nd x-rays re\'eaJed, in additio n LO the mass in the right upper quadrant not ·d on flu or­ o copy, an area of localized rarefaction in the upper r ight humerus, ,i ncl a suggestion of irnilar areas in the kull. Tran fusions: The child was given three whole blood tran fu ions o[ 100 cc. each. R adia tion and Concnnent Fever: H e was given six deep x-ray tr aunems to the ri ght kidney region in clividecl dose of 200 r ror a total of LOO r. This caused m ild erythema. T here was fever Lo IOI °F. on Lw o occasions fo ll owing the x-ray treatment. urgery: .. The patient wa then tran ·[erred to Mery H o ·pital, Chicago, [or surg ica l explorati on. \t this time the periorbital and co njunctiva ! hemor­ rh age · am proptos i were rather nnrked ("ee 28, Fig. l [or photograph taken on admiss ion) . T he infant's abdomen wa explor d on i\Iay 2-1, l 9,17 by Dr. John Keeley. The liver was fou nd to be exten ively in vo lved with nodul;ir meta, ta es; orn e soft, som e hard, which varied in color from l igh L ye ll ow to orange. Some were whitish in color. There were nodules up over the lome o r the right lobe o( the I iver, and upon palpating the region or th e ri gh L kidney the lower and middle portions were entirel y normal. The upper por­ tion of the kidney wa · in continuity with a rcLrop ritonca l mass wh ich cemed to come upward a nd anteriorly to involve the li ver in a nodular manner. biopsy wedge of the li\·e r was taken. Microscopic examination or this ti ss ue showed the li ver Lo be involved by extensive depos its of a neuroblastoma. T h · LUm or revea led ver y well-defined rose tte formation · over wide areas, and else­ where it grew in more so lid or co rd -like closed packed masses o f ce ll s in a ft ­ brous Lrom a (28, Fig. 2, 3) . Further Transfusions: T he pati ent was give n two more whole bl ood tran fu sions of 120 cc. each and wa d ischarged. Concurrent l11fection: On May 7, 1947 the child again developed rhiniti , wiLh a L mperaturc o[ 10 1°F. No treatmem was given. Further Radiation: During June 1947 five more x-ra y trea tm ents we re g ive n Lo the right kidney region (or a total of 750 r. X-ray was stopped becau ·e he developed a m arked leukopenia and anemia (w bc 4,350 on June 30, 1947) . Clinica l Course: The hilcl eernec.1 to be getting more pronounced prop­ to i · d uring radiation therapy, o that protective ce lluloid shield s had Lo be con tructecl for his eyes. Further T ransfusions: During June, the six th and eventh tram[usions were given and during July 1947 he was give n his eigh th ancl ninth tram -

35 SER.JES r\: IN FECTIO,:-,J CASES, DETAILED HISTORIES

fusions o[ whole blood (120 cc. each) ; none caused reactions. His co ncliLi on remained grave. Clinical Course: He was again seen on A ug ust 16, 194.7 and surprisingly e11ou gh showed raLher triking improvement. His weight was 15 pounds eight o unces. The ma s in the right ide of the abdomen was smaller and the prop­ LOs is was not a · marked. He showed no ev id ence of a nemia, Lh e wbc being 6,400, the hemog lobin GO % . . \ monLh laLe r he was seen aga in . H e h ad gained Lwo pounds, the propLOsis was very slight and the mass in the right abdomen was smaller. The chi ld was een periodically and continued to improve. f'urlhr'r Co11rnrrenl I nfection: On pril J 2, 194 he developed a n upper respiratory in[e tion, with high fever, a coug h and bronchiti ·. C:/i11icol Co11rsr' : By SepLernber 8, J~JtJS he weighed 25 pound and his heig ht was 34 in ches . t this time he showed no clinical eviden e of the origi­ n,tl LUm or, his propw ·is ·was absent, as was Lh e mas in Lhe right abdomen . Sk eletal x-rays taken on November 24, 1948 a nd September 15, 19,19 revealed no metasLases. B lood examinatio ns were w ithin normal limits. illfec tious Diseases: In l 95 1 h e had measle and varicell a. Clinica l Course: The child is be in g seen periodically by Dr. J i\ [. Troy o f 'Whiling. Hi last keletal l'ilms taken in 1957 were no rmal. He remained we ll a nd free (rom funher ev idence o( disease. On September 22, 19G l aL the age o( 15, hi we ighL was l 00 pounds, his height being five feet two inches. (1 Ii · parenLs are small). By ugust l 961 he had grown fou r inches a nd weighed 136 pounds. Ilis menLal developmen t was normal a nd he was in his normal grade in school. H e remained in excell ent h ealth, quite active in spons in .J an uary 1969, almost 22 years a(ter onset. (49) Co111mn1L: 1n Lhis case, the child developed a series o( raL her mild in­ r n ions beginning w ith the otitis media, but he developed a leukocy Los is of I r:: ,500. Some o[ Lilese infecL ions occurred before radiation ·was given. There .v,1s fev er on two occasions during the radiation, and hig h fever on one oc­ casion, in Lh e spring o[ 194 fol101l'ing his final upper respiraLory infecti o n. During 195 1 be had mea ·Jes and varicella. It i of interest that in 1952 his wbc. wa . Lill J,1,350. It is possible Lhat in Lhi s ca ·e Lbe e episod es a ncl the nin Lra 11 s[11 ions help to stimulaLe Lhi · child's n atural resi tance, so that the radiation and xploration were fo llow cl by complet regrcs ion of a ll the wide ·pread cl i ea e. R ef(')ence. . 28; 49.

No de La ii cl his Lory is avail able for C SE 10.

C \ ' E 11: ]noperable congeniL al extra-adrenal neuroblasLoma, confirmed by microscopi examination fo llowing laparotom y. Pr!'v io11s History: Female, newborn infant. A mas in Lbe left upper q uacl­ rant was discovered Lwo days a[ter birth. n intravenou pyelogram revealed downward di ·placement of a normal left kidney. urgcry: . At laparotomy four clays later the tumor was fo und to be un­ rese Lable becau ·e it invol\'ed the intest ine and great Yessels. Radiation: .. The infant received x-ray therapy postoperatively over a four ll"eck period totalling 2100 r.

36 SERIES : INFECTION CAS ES, DETAILED llIST ORlES

Further ' 11rgcry: ,\L the age or ,½- 10 a nd 11 111 011th · nurncrou:, s11 bc 11 ta­ eou · 111 tas ta es were excised. Chemoth era py: AL 11 mon ths cyclop ho pbamic!e (Cywxan) ,ns g i\'en.

Further R adia tion: At th i time x-ray thera py \\·as g i \'en to the ·u bcu La n­ eous m etas ta tic nodules in the rig ht p o terior thorax (2 022 rads in l 0 cl ays.) Fu rth er Surgery: Funher subcuta neous m eta Lase · were exci eel from the left knee and ing uinal region. F11rt!t er R adiation: A so lita ry nodule in the rig ht lung received 84 0 rad, ( in g le dose). Further C: /1('111ot !t na/J)' : Se\' era l additio na l cour o l q 1oxan \\' ere g- i, (·11 until the child was 27 month o ld, when further g rowth o f th abdominal LUm or was no ted. Further 11rge1y and Pos to/Jera tive Infec tion: At la paroto my a dumbb II ha ped LUm or was seen to ha ve extended superi orl y in the retro periton um ; approxima te ly 50% o r i1 wa s excised be l'ore ·pasrn o f th uperi o r me enteri c artery with res ultant ischemi a o( the sma ll intes tine forced the urgeon · to stop. Examina tion o( the specimen revealed gangli oneuro ma. The po t- opera­ tive co urse wa sto rmy. Two " ·eeks la ter a ruptured gangreno us segment o r jejunum was excised. Numerous enterocutaneous fi stulae were exci ed on two occa io ns: 51/'?. week a[Ler a ttempted e ·ci ion o( lle a d on i1n\ lu 11or, :\tldi- ti o nal gangrenous segments o f i nte tine were exci ·ed , n L rococcus fi LU la were losed, and cl ehiscence o ( the abc! mina l wo und co rrected . The arterial supply to the inte tine was found to be o clud cl. The pa tient died in the recovery room. A utofJsy : Numerous sub utaneous m etas ta e · " ·ere no ted . There " ·as in ­ fa rcti o n from the proxima l jejunum to the h ep a ti c rl exur o f the colon (a p­ proxima tely 10 cla ys old) . umcrous cl ef ct in the wall o f th e small inte ·tinc were no ted. Escheri chia coli, E. intermedu.m a nd Strep tococcus [eca li s wcr cultured [rom a sub(ascial a bsce which communica ted with the perito neum. The LUm or comple tely urrouncled the left a ncl ri ght rena l and adrena l a ri cr­ ies a nd ,·eins a nd the celi ac artery but did not o bstruct them. It surrounded the superi or mesenteri c an cry a nd appea red to ompress it around a ·I mm thrombus which was adherent to the intima a t the ite o f a fin e black suture in the a nteri or wall. The left kidney was di placed in fe ri orly a nd posteriorly by the tumor, but was not invaded by it. There were no o eous or vi sceral metastase . Histologica ll y the LUm or was a well differentiated gang li oneu ro­ bla tom a. Focally the tumor wa necrotic and there were sma ll areas o r a l­ cifi ca ti o n. ln co ncl usion the a uthor ~Lated tha t differentia ti o n o f thi, ex u :1- adrenal ncuroblastoma to gang li oneuroblas toma a nd fin ;i ll y to gang li o neur­ oma suppo rts the c nccpt tha t the cmbryogenes i o f sym patheti c gang li a a nd that o f the adrena l medulla are imilar. n r•ferrnces: . 30.

c.; E 12: Ino perable m asst\'e neurobla tom a arising from the rig h t lumba r regio n, d eri ved fro m p ar<1\'e rL b1 --'l l ympa theti c nerve ti uc, con­ firmed by micro co pi c examina ti o n fo ll o \1·ing bi o p. y in December 1919. Previous H isto1y: Fem a le, in fan t, born June 6, 19-19. On ct, at the age of three mo nths the child was no ted LO ha\'C a hard we lling in the ri gh L

37 SER.JES A: 1NFECT100.' C SE , DETAILED HI TORIES lumbar mus les. ·within the next month there was weakne s of the left ca lE .mus Jes and the lumbar swelling had grown. An abdominal swelling on the ldt side was read il y palpable ·within another four week . The child was ad­ mitted to the Bristol R oyal H ospital for Sick Child ren at the age of 5 months in early November 1949. At this time there was a mass below and to the left o r the umbilicu and a firm ovoid mass about 4 cm. long in the right lumbar region, just to the side of the pine. The left leg was flexed at the knee and there was marked foot d rop. There was no m ovement of the foot, but sli ght power of exten ion of the knee. In the right lower limb there was no move­ ment or the root, but normal control of knee and hip. X -ray examinati on showed a so ft tis ·ue mass in the pelvis and right abdomen with calcifica tion in the right sid e of the pelvic av ity. Intravenou pye lognq hy showed that the right kidney wa high but probably n ormal. The left kidney was "full" with stasis in the left ureter. The bladder was cl formed by an extrinsic mas lying ma inly to its rig ht side and above it. Co11c11rr('nt Infection: The urine co ntained pus cells and co li form ba­ cilli . S11rge1y: An incisional biopsy was performed in December 1949 through an in cision paral lel to the right iliac crest at the level o( the th ird spin ous proces, and a hard grey lobulatecl mass was expo eel. The tumor was adherent to th e iliac cre ·t and surrounding tructures and extended anteriorl y. A large pi ece was removed ror hi stologic examination. The tumor showed a white ce llular appea rance with area or hemorrhage. It onta inecl the classica l rose I te · of neuroblastoma, but w::is more highly cl i fferentiatecl than many neu­ robla toma ee n at this age, in that the rosette were numerous, and there were no ga ng li on cells. Sin ce treatment wa thought unlikely to benefit the child she was a ll owed to go home. Further Inff'Clion : here ,ms so.me urinary retention and consequen t cys titis. (This continued over the next decade). Cli11i ca / ,011rs(': She was . een a year later and appeared to be in good genera l health apart from deformity of the feet and the urinary retention and cy titi . The ma s wa no longer clearly felt, and the abdomen was much less cli 1cncl ecl. There was no evidence of metastas s. The abdominal neuro­ bl astoma di ·a ppearecl completely in the 18 month fo ll owing exploratory oper­ a Lion. During th e n xt 8½ years the hilcl was reaclrn ittecl on 12 occa ions for treatment o[ paraly i of the legs and the impaired bladder fun Li on caused by co mpres ion of the ca uda equina. This led to progre sive deterioration in kidney (unction and the ch ild died of uremia at the age of 10 in June 1959 l'rom urin arv inf ction clu e LO a persi tent neurogcn ic bladder. Limited necrop­ s ' re\·ca lecl no abnormality in the abdomen other than gros pyonephrosis and dilati on o( the bladder and ureters. The lumbar p ine and sacrum were re­ mo\·ecl for detailed examination and ga\·e hi tological confirmation th at the pcri ph ral portion of th is extensive neu roblastoma had regressed and the re­ maining dumb-bell tumor in the lumbosacral ca nal h ad m aturated to a small ga ngli oneuroma. The proportion of tumor to fibrous tissue was very low. Ifrfne11 ce: 18.

A E 13: Inoperable neurobla toma, present at birth, confirmed by micro­ copic examinations by Dr. J hn Godwin and another pathologist at the Och ner Clinic o( biop ie from everal di[erent metastati c nodule removed in i\Iay 19 0, pril and 'ovember 1951. SERIES A : INFECTION C \SE , DETAILED HJ T ORIE

Previous H ist01)': M .B., fem ale infa nt, of ake Charl e, Loui iana. T he fa mily history was essen tially negati\'e. T he child' mother cl c1·elop cl an itch­ ing rash or irritation of the vagina a few week prior to her co nfinement, but thi was treated locall y and cured in a r w days. She did not re eive any radia­ ti on (cli agno ti c or therapeutic) during her preo·nancy or confinement, both of which ·were entirely normal. T he baby was born at full term on February ~. 195 0 and weighed six pounds. T he m other n oted that "at birth the baby's abdomen wa abnormall y large, and po inted thi out Lo th ph ician, but he sa id it was nothing." T he child was brea L feel fo r two month . \\/hen he was a week old the moth er co ntra Led flu , " not e ·pccia ll y severe.· · The other children also had influenza, but the infant r ema in cl as •mptomati c. The mother also had . some ma titi during this flu in [cction. Vitamin K TheratJy : The hild seem ed well d uring h er fir L month, but at that time the local doctor gave her four injec ti ons o[ Vitamin K, beca use he aid her blood did not eem to coagul ate p r perl y. Clinical Course: At the age of t\\·o mon th mall masses began Lo a ppea r under the skin over the abdomen, groin s, back and on the head. These were ra ised, hard and some seemed bluish in olor. Th e con tinued to ;i ppear and then the local physician noted a mas in the abdomen and referred the child to the Ochsner Clinic in ew Orlea n . Phys i al examinati on on admiss ion fay 26, 195 0, a t the age of thr e months, showed an in fa nt 56 cm . in height, weight 12 pounds 4 ounce . The baby looked p;i le, chroni all y ill , with a protuberant abdomen mea u ring 45 cm. in circurn(erence. here were n1~T iacl · of wides pread subcutaneous mases 5 Lo JO cm. in d iameter in the groin , over the pubis, over the lower abdomen and le numerou ones ca ttercd over the ch es t and back. In the abdomen a large mass, a pparently the li ve r, was felt on the right extending from th e costa l m arg in to below the ili nc ere t, and medially '"ell beyond the rni cl line in the upper abdomen. notch could be felt in the vi cinity of the umbilicus resembling the notch between the right and left lobe of the liver. T he blood count on ad mi s ion . how cl hemoglobin 8.5 gm. Intravenous p yelograms showed both kidneys displ aced downward , and the right kidney rotated outward and pu heel mediall y until its ureter lay in the midline of the abdom en. X-ray o f the long bone and ches t were nega Live. Suro-e1y: On i\Iay 29, 1950 a bi opsy o f t1 rn subcutaneous nodules was performed and the diagnos i wa neurobl a ·toma. Concurrent I n fection: While the baby was ho pitali 1ccl he had a ca c of diarrhea (not e1·e re) , but it caused severe di aper ra h, also she ran ;i slight tern pera ture. Chem otherapy: Beginning June l , 1950 he was give n nitrogen mustard intravenously once daily for four day in doe of 0. 56 mg. She wa gi,·en a blood tran fusion fo llowing thi therapy. Clinical Course: The bab y was dis harg cl June 4, 195 0 with a hopeless prognos is. H er o ncli Li on deteriorated. Concurrent I nfections: bou t two weeks later she developed a cvcre cold and wa given penicillin by the local p hy ician. T he mother La ted : " I oft n wondered if this did n ot have omething to do with her cu re, 1 ecau e she hacl seemed to get o much wor e ,._,-hen ,eve first came hom e from the hospita l, then after her spell of cold she began to get better graduall y."

39 SER.JES t\: INFECTION CA ES , DETAILED HI ORIE

Clinical Course: The baby wa again seen in the O ch ner Clini on O cto­ ber 22, 1950, at the age o f eight m onth , a t which time h ,ra readmitted fo r tud ) . She then " ·cig hcd 18 po und . The li ver \\' as [e lt ' cm . belo w th rig ht costa l marg in, no longer reaching to the umbilicus. Only two or thre \ 11bcuta ncom nodu les co uld be fell. The blood co unt was n ormal a nd kclewJ x-rays were ncgati\'C. Intra \·eno us pyelogram showed tha t both kidney h ad I \.! turned Lo a norma l po itio n. T he sli de o f the prc\'i o us bio p y were r e\'iewed by two path logi ts a nd the diagno i o f neuro bl a tom a " ·as confirmed. The child was di charged witho ut further treatment. F11rlher Concurrent l11fectio 11 s: v\lhen the child w a abo u t a yea r old she d c\·clopcd "a kin condition re cmbling boil ." The o nl y trea tment recom­ m ndccl ,rn the u e of hexachloro phene instead of soap fo r ba thing. Clinica l Course : The hild was sc n in the clinic a t m onth! interval~ from December 19-0 to .\pril 19- I. She ·o n tinued to do well a nd gain " ·eight Jiowcvcr, there were three or four n odule p a lpa ble a t ca h \'isiL. She wa rcadmi1tcd o n .\pril 9, 195 1. F11 rth n 11rgery: t this time three subcuta n ou. n odule were remo\'ed from the left thig h and g roin . The pa thologi ts re1 orted n curobla toma, "\\'ith n o cha nge ince pre\·io u bio psy." Be a use of the hi to logic a ppearan ce o f m a lig nancy the bab " ·a readmitted ;\fay 15, 195 1. t this time the liver was ,1½ cm . belo,\· the cos tal margin a nd it ll'a no ted tha t a prominent sub­ n1ta ncou nodule previously rcpcaledl y palpa ted in the rig ht la bium majus had di a ppea red . X -ra o r the ·kull, pine a nd lo ng bon e were negati\'C. Fur/her Chemotherapy: The bab ,ra g i\'en nitrogen mu ta re! intraven­ o u I , o nce d a il y for fo ur day, then a three d ay re t peri od and ano ther four da cycle. (llcr m o ther . tatcd tha t after thi therap y she cl evelo pe I a cold, a nd wa aga in g iv n penicillin) . Cli nical ,0 11 rse : T he child " ·a followed in the cl inic, where she wa een dming Jul y, Aug u t a nd eptember 19- 1. ln O to ber 19- 1, the liver wa no lo nger pa lpa ble, a nd there were no pa lpable ubcutan cou le ions except one on the rig ht thig h. Complete kclcta l survc a t thi time was negative, but x-ra , f the a bdomen showed m o ttled calcification in the region o f the liver. Further urgery: he wa therefore readmitted to the ho pita! on i'J o\·em­ bcr 26, 195 1 for urg ical cxci ion of thi m as in the rig ht quadri eps femorus musc le. Pa tho logi report on this m a s wa neuro bla Lo ma with differentia­ tion towa rd gan o- lioneuroma. Concurrenl Acute l nfla111malio 11 : h \\·a given penicillin d a il y for about a mo nth a ncl a fter 3 ½ " -ee k cl c\·elopecl a e\'ere a ll ergy to it; her en tire body l\' a co,·cr cl with a red ra h a ncl h er eye were wo ll en hut. The rash di a p­ l ca red when the penicillin wa slopped. Fur/her Che111olherapy : In December !95 1 a nd in J anua ry 1952 the baby 1eceivccl further cour e o f nitrogen mu ta re! , each consisting o f J. 5 mg. intra­ \'Cno u I ' on c d a il y fo r (our cl ay . Clinica l Cour e: The child was seen on Februa ry 15, 1952 a t which time h " ·c ighecl 25 pound and exhibited no ubjecti,·c or objecti\·e eviden ce of d i ea e. Further In fec tions or Infectio us Disea e: At the age of three he h ad chi ken pox a nd a t the age of four or five she had mea le .

40 SERIE I FECTlON C ES, D ETAILED HI TORlE '

Clinical Course: There has been no funher e, idence of neuroblaswn1a. The patient graduated from high school in June 1968 . he rema in ed in excelle1,L healLh in 1970, 20 years after on el. Com111e11l: This case i · of great interest. ~ole LhaL the congen ita l n. c·uro­ bla Lorna appeared LO metastasize \\"icl cly , ·ery shonly after administration o r ViLamin K. Note Lh a L Lhi child was nurse d by h er m oL hcr during an in[lu­ cnza infecti on and ma Lili . The baby h ad diarrhea, ·e,·erc diaper ra h, [urun­ culos i a nd finally a very severe a llergic reaction to penicillin (unicaria and edema) in the period in which the tumors were rcgres ing. ·wi th in the nex t two years or more she had variccll a a nd rubeola. These concurrent infcc·tio ns and acute inflaminawry episodes apparently Limulatccl thi chilcl "s resistance, po si bly aided by the nitrogen mu tare!, resulting in complete a nd permanent regre s10 n. R eference: 49; 66a.

CASE 14: ExLensive in operable reLropcriLo nea l neurobla ·Loma, confirm cl by microscopic examinaLion fo llowing biopsy b Lh e Patholog ical Lab­ oratory, DeparLrn ent of Public H ea lth, Sydney, AusLra li a. (See be­ low). Previous H istory: A.H., female, aged 15 mo nLh s. The family history was negati,·e for ca ncer or tuberculosis. Iler paternal grandfaLher (dccca eel ) was a diabetic. H er mother did not rccei,·c radiation, antihistamines or oL h r anti-inflammatory drugs luring h er pregnan y. The child ,l" as brca t fed for 12 mo nths. The da le of on CL wa not recorded. Concurrent Infec tion: She was admitted to the Goulburn Base Ilo pit a ! on .July 21, 1954. She wa pale, thin, very irritabl e a ncl o[Lcn sc reamed as if in evere pain. H er weight was 19 pound 5 o unce . 1 Icr tempera Lure was J0-:1 °F., th pule rate 138 per minuL . ExaminaLion rev alccl a large firm , tender, oval tumor in the lower a bdomen. !Ls lower border " ·as palpable by recta l examinatio n. S11rge1),: On July 2·1, 195·1 Dr. G. l-1. Kennell performed an xplor aLo ry laparo Lom y. A large, vascular, fixed, retroperitoneal wmor ''" a found ext nd­ ing acros the posterior abdom inal wall from flank LO flank. IL measured 12 by 7½ cm. in diameter, iLs longer diameter being Lran ver e. B cause of iL extent and fixity, removal was inpracticable, and cxarnin aLion of the liver and adrena ls wa not feasible. A tentative diagno i of retropcritoneal arcoma was made and a secti on was tak n for biopsy. "Sections showed the tumor to consist of a scanty h emorrhagic sLroma supporting ma cs o r rounded ce ll ·wh ich vary somewhat in size and how frequent mitoses. SomcLimes the cell s are arranged in "rosette" formation. The tumor is mali gnant a nd the appear­ :1. nces are tho e of neurobla Lorn a." Chnicol Course: Following Lhi exploratory operation the child "·as in rxtremis for a week. However, keleLal x-ray · did not reveal a ny meLasLase. \\'i th ca reful nursing she lowly improved suffi cienLly LO be taken to the R oya l Prince lbert H o pital in Sydney (120 mile away). R adiation Therapy: he wa then gi,-e n x-ray therapy ca l ulatcd as 1500 r (tumor dose). Becau e of the per i tent leukopen ia Lhi was spread over a period of 53 day .

41 ERIES A: JNFECTlOt\' C \ E , DETAILED HI ORIES

Further Fever: On ,'(o,·ember 25, 195°1 she reLUrned home and was re­ admiued to Gouburn Bae H o pita!. She was pale, apathetic, inert, but re­ se nting interference, refusing food and drink., but apparently not in pain. AJtl10ugh her temperature was I 05°F. a nd her blood count showed lcuko­ c tosis (19,000 wbc), no physical igns oE intercurrent disease ·were apparent. Empirica ll y, ch loromycetin palminate wa give n, without any impro,·ement in her ondition. The prognosis seemed hopeless. Vitamin Therapy: On December 3, 1954 Dr. Robert G. Woods decided to try mas i ve do. es of vitamin B-12, having read Wayne's article (1954) . A dose of 1000 mi crogram was given intram uscul arly e e1 r 4 hours (or 16 da 1s. Thereafter, this close wa given once a week. ·within one ,,vee k there was de­ finite improvement in the child' condition. She began to take food willingly and he lost her listlcssnes . From then on her convalcsce nse wa uneventfu l. he gain ed weight - from 3 to 26 ounces a week. Serial blood count showed that the rbc remained a t about 4,000,000, the hemoglobin a t 10 per ml.; the wbc diminished from 19,000 to ,700 by J anuary 1955. The differential was characterized by a lymphocyto. i , at fir t 76 % diminishing to ·13 % by January 1955. On December 19, 1954 she was discharged - a happy, miling child who was learning to walk ( he could not walk prior to admission). ·wood believed that the vitamin B-12 therapy h ad apparently a is ted the co nvalescence re­ markably. s an out-patient the close wa reduced to l 000 micrograms weekly. The onl y pos ible ill effect of the therapy was that in about three months he became ub-thyroid: dull, apathetic, with dry crackling hair. Thyroid extract, gr. 0.5, ·oon orrectecl thi . Vitamin B-12 therapy wa co ntinued weekly for two year . Clinical Course: he exten ive inoperable retroperitoneal tumor disap- pear cl. R gular follow up examinations failed to reveal any significant ab­ norma li ties in an apparen tly normal, healthy child. By August 1957 she weighed 39 pound ·, having doubled her weigh t in three years. In l\Iay 1962 he developed diabete, requiring 65 unit of Lente in ulin dail y. The diabetes was very labil e with everal hypoglycemic episodes, but otherwise the child remained very well and normal in every re ·pect, including skeletal develop­ ment. At Lhe age of 10 yeai-s her weight was 74 pounds, her height four feet even in che. h remained in g od health in November 1969, o er 15½ years after on et. R eferences: 49; 76.

Comment: T\;ote tha t 111 thi a nd the following ca e infection and/ or fe er occurred prior to the admini traLion of Vitamin B-12. Po sibly thi com­ bination i more effeCL ivc Llian ei th er o ne alone.

C: E 15: Inoperable neurobla torn a of the liver (primary site undeter­ term inecl), confirmed by micro copic examination following biopsy of the li,·er (3 , Fig. 1) . The tumor con i ted oE small round cell with cant cytopla m, often grouped into ne ts or ro ettes and char­ acteristic of n eurobla toma. The child also had Von R echlinghau- en's di ea e (neurofibrornatosi ) and ga nglioneuro.ma of the thor­ a ic ympathetic chain, all co nfirmed by variou biop ies . Previous Hi tory: V.D.H., female newborn in fa nt. The family hi tory was non-co ntributory. The baby wa the sec nd-born of a 23 year old father and a 21 year old mother, the fir t child being a healthy boy of two year . Both parent were healthy and did not have the tigrnata oE neurofibromato is. The SERIES A: I NFECTION SES, DETAILED HI TORI E patient was born on J anuary 15, 1955 following a normal uncompli aled preg­ nancy and delivery. She weighed 9.7 pound . Per i tent Yomiti ng began at the end of her fir t week and at two weeks he was d iscoYered to haYe a Yery large a bclomi nal mass. Surgery: . Surgical exploration on February IO, 1955 re ealed a liver al­ most completely replaced by white nodular tumor ti sue. No primar · oulcl be seen or felt. R adiation : co ur e of x-ray therapy was begun po t-OJ eratiYel but wa d iscontinued becau e of leukopenia and anemia, after 1600 r had been give n. Clinical Course: About thi time a mas in the I ft ide of the neck and swellino· of the left arm were noted. The baby wa then referred to the City o( I-lope :\Icdica l Cemer in Duane, C;il ifornia. On adrnis~ ion in June 1955 she was poorly nourished and weighed 12.3 pounds. A mooth, poorly demar­ cated firm mass was fe lt in the left supraclaYi cular region and the entire left arm except for the h and was swoll en, smooth, firm and non-pitting. The in­ fant did not u e her left arm a much as the righ t. The li ver, which had an irregular, nodular surface, was palpated 6 cm. b low the osta l margin. A ches t film revealed two large masse , one in the up rior media tinum. The intravenous pyclogram was negative a were the skeletal survey and a bone marro\ aspiration for metastase . Che,nothera/J)': A course o[ hlorambucil wa instituted, without appar­ ent benefit. Concurrent I 11fectio11s: In July 19"5 sh e had a temperature of J0 l°F. for several clay as ociated with a bout of a piration pneumonia. At this time Beta hemolytic streptococcu and taphylococcus a ureus were cultured from her throat. Treatment co n i ted of erythr mycin and terramy in . In Septem­ ber 1955 she had an upper respiratory infection and again in December 1955 she had a recurrent pneumonia with a t mperature or l01 ° F. In the two yea rs fol lowing surgery she had several other respiratory infecti on with fever and cough. Vitamin TherajJ)': In September 1955, the child was tarted on Vitamin B-12 (IOOO mcg. daily intrarn u cu l;irl) .) Cr;iclually during the next nine month. her general condi tion improve I. 'I he abdomin al ma s receded and by June 1956 it was no longer palpable (the li ver metastases had entire! , regre sec! .) During thi period the other ma e seemed to grow in proportion to the ch ild's growth. left Horner· syndrome cle\·eloped. Further Surgery: In May 1956 a biopsy of the welling in the left axill a revealed the h;iracLeri ti neural and co nn ctive Li sue elements of neuro fi ­ broma. (38, Fig. 2) In July l 9r-5 exploratory thorac tomy revealed a large lobulated mass in the superior and left media ti num connectin g via the apex of the left che t with the mass in the neck and with the welling in Lhe arm. It was adherent to the ribs and vertebral bodie. and enveloped the lcl't thoracic and cervical ympathetic chain. Portion of Lhese mases were removed. i\Iicro- copica ll y Lhe mas in the arm wa characteristic of neurofibroma, whereas the thoracic mas al o had clusLers of ganglion cells a ob ervecl in neuroblastoma. R ecovery from this urgery \\"a uncomplicated and the hild ""a discharged home. Further Vitamin Therapy: Vitamin B-12 injections were continued until June 1958, a total of 21 months.

43 SERLES A: 1:-.:FECTJO:\' C SES, DETAILED HJ TORIES

F11rlher Infections: Jn Ocwber 1958 she again had pneumonia of the left lower lung, 1rith a te111perature or IOJ ° F. , which respond cl LO penicillin. Jn .f a11u <1ry 11) 59 she wa ho pitali1.ed because of pneumo occa l pneumonia of the right middle lobe. Three month later he had a nother bout of pneumonia (lcf't lower lobe) w ith a tcmperaLUre or 10·1°F. Both were treated with peni­ cillin. Cli11i ca l Course: The lesions rema ined tatic. An a nterior bulg ing de[ormity of the left che t developed. A previous fa int pigmentation over the left shoul­ der area became very prominent. Large 11umber or cal'c-au-lait spots cl evel­ opecl a ll over her body. A fracture o ( the left humerus in J960 h ealed well. Jn 1962 enl argement o[ the clito1 is was first noted by the child's mother. This 11·as presumed to be clue to neurofibromatosis. Further Stirf{C I) •: About .June 1965 she underwem surg ica l recoll'tructi on o l 1he chest wall deformity without complication a nd with a good earl y re ult. Clinirn l Course: The ch ilcl auencl ed chool regularly and seemed to be ,vi thin the normal rate of intell igence. By J 966 she weig hed 62.9 pounds, h er h e ig h1 being 53 in ches. Jn 1967 the Homer's sy ndrome, swelling of the a rm and intrathora cic rn a~s es persisted, and there was ever e scoli os i o r the cl or al spine with corvex ity LO the ri ght, but there was no further evidence o( the neuro­ bla torna. I !er ni ajor clil'l'i cult ' has bee n pain in various pan of her keletal ys tem, pa nicula rl y the chest a ncl back. By 1969 i L was ev icl en t that her mental d evelopme11t was ubnormal. Becau ·e o r per ·istent ba k pain he wa referred to the Orthopedic I lo,pita l in Los .\ ngeles 11·h ere two spina l fu ion o pera tions \\'ere performed in :--.'o\'emb 'r and December 1969 in order LO reli eve the pain a nd impro1·e the co~metic effect. \fenarcbe had not occurred by .J a nuary 30, 1970, 15 yea rs a[ter onset of' the neuroblastorna. H e[(' rences: 38; ,19_

C.\ SE 16: lnoperabl neurobla toma of the righL suprarenal g land, with multiple cutaneous metastases, confirmed by microscopic examina­ tions f'ollowing biopsies of two meta tatic le ions. Pl'l'v io11s I-listo1y : .K., female infant, aged 3 weeks at onset in July 1957. The pregnancy and labor were norma l. The child weighed 7.3 pound a t binh. She wa the econd child of hea lLh y parent ancl wa breast fed. A a nell'born she had a ore in th oral ca1·ity, otherwi e there had been no Tio us illnes and the inf'ant developed well. t the age of two to three weeks the mother first noted mall tumors under the kin in the genital area and in both hip ·. J\t the age of three weeks the child was admitted Lo the 'iVurzburg Children's Clini . H er we ight on admi sion was almost 10 pounds. Examina­ tion rel' aled a '"ell developed infant with numerou LUrn ors over the entire trunk a nd proximal lower extrem iti es. These were in the deep cutaneous a n I ubcuta neou. ti sues and ranged in ize from a bean to a pigeon egg, being of coa r ·e con istency. They were m o tl y movable on the underl yi ng tissues, omell'h aL aclh rent to the over-lyi ng skin and painles to pre ure. The over­ I ·ing ~kin in many pl aces wa rnoderately ti g ht and reel. (See 35, Fig. 1). The spl n a nd li\'er conta in ed no palpable tumors. The uperfi ial lymph nodes were not enlarged on palpation. The peripheral blood picture, edimenta tion rate, marrow puncture, bacteriological culture of the blood, tuberculin and \ Va crman reanion and side reanion, feces, urine, all skeleta l a nd medias tinal x-ray. 11· re 1\'itli out pathological finding .

,JI ERIES \: Ii\'FECTlO~ C \ ' ES, DET.\TLED HJSTORIE

Surgery: A single tumor wa exci cd for bi op y. T h e hisLO logica l linding · were reported a foll ows: " Epidermis and cuta ncou appendag 'S in compi cuom. 1n the lower corium a nd adjacent fa tty ti ··uc there are num rou ne t a nd tra nd, o f und ifferen tiated tumor ti , uc ol re la ti\·c h ~ma ll ce l­ lular lymphocytoid to mo nocyto id tructure. They rc\'ca l !earl y in­ filtra tio n tendcn ics . The d ense cel lular c lemen t- arc poor in cytoplasm in the m ajority, ometirnes their nuclei arc a lmo L bare a nd they are only m od erately differen tia l d from each other as far as form a nd size of the nucl u. i con ernecl . 1 ola tccl mi toses a mo ngs t them, a l o pa th o logica l sha pes, and ma rked P) knos i~ o r the nuclei are ·conspicuou in sc \'era l place . 1o typical fo rma tio n o f psc udo-roseu es. H owc\'cr, . ma ll spo llcd 101 1cs o r fin e fila111 e 11t s, weakly ba ophilic m a terial, frequently urrounclcd b y tumor cells in wrea th-like arrangem ent. Silver impregna tion according to Gom­ o ri , hows no reti culum fib r ils cha racteristic o r the tu111 or pro per. H erc a nd there a light m etach rom a ia o f the trorn a o r the co n­ nective ti ssue. Hi tological Diagno i : E vidently m etastasis o f a sma ll cell neurogenic tumor, \'Cry probably o[ a ncuroblastoma ympa theticum. No d efinite indicati on o [ re ti culo is or o f other sys temic disea~e o r th e REs.·· (755 157) . Clinical Course: Thi clinically unexpected diagno is, which was in strong contradi t ion to the sati factory general well be ing o[ the infant, ac ordin!!; ly ,, as m et with consid erable kepticism. fore x-rays o f the abcl omcn were d on , without a t fir L a ny further pa thologic cha nges be ing cli sco vcrccl. Concurrent Infections: At the age o ( abo ut three m onth. there was per- istent p yoderma in\'olving the bead and neck "hich \\'as re franory to treat­ ment a nd which r urrccl e\·ery ix or seven weeks without the genera l con­ dition o[ the child becoming cs cntia ll ) cl eterio ra tccl a ncl withou t the d evel­ opment of cachexia from the tumor. The hild wa trea ted loca ll y a nd sys temicall y by antibio li cs (acrom ycin . L tranclinc, penicillin a ncl , 1rcptrn11 y­ cin) . She then d eveloped nutritional di turln nccs which were fi rs t treated b y cli eta r re tri cti o ns a nd la ter a l ·o ,,·ith sulfonamide ( I11t cs tin-eu\·e1nil ). H ormones and R adiation: Prcdnisonc was gi\'Cn d a il y fo r two week · ( 10 mg. o ral). ,\ t the age o r .!J½ months a trial :-.- rav trea tm ent was g i\·cn to a m etastatic lesion on the rig ht thig h (4 00 r x 6 d elivered in six week ) . N o a pparent benefit was no ted. The genera l h ealth rem a in ed sa ti sfactory a part from slight a nemi a, although new tumor ontinued to cl \·elo p subcuta ne­ ously. F11.rther u rgery : Ano ther biopsy was performed and hi tolog ic stud y a t the University Skin Clinic gave the sa me diagnos is. (35, Fi g. 2, :l, 4) "Now, ho,..,·ever, there wa con picuou ly a certa in incrca,e and spr ad o f the fila­ m entous mucoid , but no metachromati c [oci \\'Iii h ,rcrc round a t the fi rs t biopsy in whi h ome o f the cell ne ts were embedded. '.\fo rCO\'C r, mall i~o­ la ted a reas o r necrosi a nd ca lcifi ca tio n were no ted . .\no th cr :-.-ta) examina­ tion reveal cl numcrou calci[ications in the area o f the right ad renal so tha t the primary tumor could be a ·urned to be there.'' (35, Fig. 5). R.evi w or the fir t x-rays r evea led cal ium d cpo its in the ame area w hi ch h acl not been recog nized with cer tainty due Lo ma rked mctco1 ism. F11rtli er I nfection: :\t th age o r 5½ months the ch ild developed vari­ cella. Conspicuou ly from tha t time on the cuta neous tumor becam no ti ce- SERIES r\: L\ ' FECTl O;\1 CASES, DETAJLED HISTORIES a bl y sma ll er. ,\ t 6½ months many small node, particul a rly the one which had a ppea red las t, hacl disa ppeared. During thi entire tim the chi ld h ad onl y been under ob erva tion, her onl y therap y ha ving been 6 x-ray treatments to one me tas ta ti c le ion ancl predniso ne for two week , neither of wh ich had a ppeared to alter the cour e of the disea e. F11 rth f'r Surge1y : In J anua ry 195 a third bi opsy was p rformed a nd histo log ic study a t the nive rsity kin C li n ic showed a co mpletely cha nged picture: " nclea rly delimited nes ts without signs of a tu morou prolif­ eration , however, ,,·iL11 exten iY e regre ion cha nges. There were hya line amormou or fin e fibrillar irregularl y di persed foc i recall­ ing coagula ted tiss ues or 'ne uro hya lin e' modera tely ba ophile partl free o[ cell or surrounded by ce llula r elements at the border which took dye poorl y. Also in the miclst o f thee degenera tive foci there were pa rse 'vercl am.mernde' cell ula r elements (fig. 6) . I n the sur­ rounding troma of connective ti. ·ue there ,rn a pot haped Iymphohi ti ocyti c in fl amma tion with ingle foreign bod y type g iant ce ll inter per ed . (Fig. 7) . On the basi of thi finding the h i - tologi a l d iagnosi o f a n orig in al neuroblas toma mpa theti cum was no longer poss ible." (35) Clinical Co urse : The con i tency o( the continuously regre ing tumor became les5 and le h omogeneous. X -rays revea led ma n y . ma ll ca lcific,u ions. \\'hen the case wa publi heel ea rl y in 1960 only very ma ll i olatecl remnant ol tumor were pre em: "at the out icl e of the left thigh, in the lcfL n 1h·a, h re of very ha rd con istency. (35, Fig. 8) . \Vhen the ligh t fa ll a t a n ob li q ue ang le the original contours o f th e cu ta neou~ tumor show ome fine unevennes of th e kin on the back and on the anterior icl e of the trunk, otherwi e ou r little pa ti en t. now ~½ ear o ld , a pp a r. hea lth y a nd i not retarded in a n " ·ay." ,\ fourth b iop y o f the e tumor wa made in the summer of 1965 a nd re ported a comple tely d ifferen tia ted ga ngJioneu roma, with no evidence of 111 a li gnanq. The cl1ild rema in ed norrn a l a nd ha pp>' a nd do ing well in chool, entirely h a ltl1 y and ~) 111jHOm-I'ree, in O ctob r 1%9, 12 year after on CL R ef<' r<'1nr's: :15; ·19.

C.\ SE 17: Congenital neurob la Lom a a ri ing from the rig hL abdom ina l sym­ pa theti c chain, confirmed by micro cop ic examina ti on fo llowing biop y. Previous l-li to,y i\lale, aged one " ·eek. The infa nt had p ersi Lent bile­ ta in ed vomiting [rom birth in 1960 .

. 11rgl'1y: .\ rig ht sided a bdomina l Ill a \\'aS explored a nd found to be a firm Lum or the i1e of a p lu m ari sing from the righ t a bdom inal sympathe ti c chain a nd extending aero · the m idlinc into the le er ac. A small biops was ta ken a nd thi howecl the hi tologica l picture of la ica l neurobla toma. R ndiatio11 and Co ncurrent I nfec tion: X-ray therapy was begun 18 day aft r operati on but wa interrupted by a re piratory infection. The throat wa diffu ely reel and inflamed, th re were ca tterecl adventitia l ounds in the che t a nd the radio logica l picture wa tha t o( m ild bronch iti c changes. tumor dose of :1000 r wa cl eli\·crecl in 60 d ay . Clinica l Course: Three week a ft er radia ti on wa completed the tumor Illa wa no longer p alpable. Two year la ter the baby pre entecl with cya-

·16 ERIE A: L',FECTIOi\' CASE , DET.\ILED 11 L T OR LE no Lic heart d isease a nd a la rge liver with a p ro mincn L nodule 111 the r ight Jobe. Further urgery : L aparotorn · rC \'calecl Lh e nodule LO be a sim pl e hol- angiorn a wiLh the conLi g uou li,·er hi tologi ally n ormal. 1 0 Lnt c o ( Lhc ncu roblasLO ma was fo uncl at opcra Lio n. Clinica l Course: The child remained well and free from funhcr C\'i ­ cl ence of disease in 1968, over eight year a fL er o n ct. R eferences: 6; 49.

CASE 18: \\' id ely di emina Lecl ncu roblastoma prima ry m Lh c left adrenal gland with ,ride pread bo ny .rne tasLa cs Lo Lh e pe lvis, lower limbs, cervical spine, · a lp, cranium a nd lungs. Previous History: M ale, aged Lwo years. T h e child wa · see n b a suc­ ce sion of phy icia n , wiLh n onspcciCic illness beginning in 1\ pril 1966. The Lru e nature o f his disease did no t be ome apparent unLil July 1966, when ca lci(ica Lion in the region of the lc[L adrenal a1 pea recl associa Lccl wiLh nodular les ions in the scalp. The child was first seen by Mr. William Cochra n, F.R.C.S. (Edin.) when Lh e disea ·e was genera li1ed a nd there wa a large a bdomina l tumor, also an emia "clu e in p art to pace oc upa Li on of bone marrow by tumor. " T reatm nt was unclen a ken a t the p anicular reques L o( Lh e parcnL and lini ian altho ug h Cochran per ona ll y felt Lh a L Lh c condition wa. too far gone, the progno is h opele s. Chemotherapy, T ransfusion ancl Vitamins: Cyclophos phamidc wa admin­ isLered supplem nLecl by blood Lran fu sio ns and ViLa min H-12. The course o[ the disease was h alted but wiL11 out ignifica nt regr ·ion unLil cyclopho pha­ micl c wa to pped a L Lh e encl o f 2½ mo 11L11 s. Co ncurrent I nfection: "R egressio n suddenl y be amc rem ark a ble in N ov­ ember 1966 following a fa irly e\'crc a u ack of rubella, foll owed wiL11in Lhrcc \\'ee ks by a brief aL tack of " ·haL a ppeared Lo be chi cken pox." Clinica l Course: '\ViLhin a .rno1nh the gro sly woll en head decreased 4 cm., the alp irregularity and the Lum or in Lh c left adrenal " ·as no lo nger palpa bl e. The cranium, whi h wa largely eaLen away by mcLas tases, con~id erabl re­ ca lci[iecl and laro-e translucencic. in bo Lh tibiae bad a lmos t com p lcLcly fill ed in by February 28, 1967. T h e hemoglo bin ,,·as a l o a l a norm a l level al thaL da le. H e rema ined free from any funber e\'idence of disease l1nLil Apr il 1967, ,rhen b e prese 11Led wiLh a udden swelling o r the leg, Lhi s being a recrudes­ cence of the pre-exisLin g tibial mcLas tasi which h ad Lra n icnLl y disappeared wiLhin two m o nLhs after his in[ecLi ons. Further Chemothera py : H e was then treaLed with Vincri tine (Lill ) with o m regression until June 1967. Clinica l Course: H e died in June 1967 \\'iL h in a Iew da s fo ll owir,g m as­ i\'c recrudescence of his neopl asm. ln rcponi ng Lhi~ case Lo us Cochra n sla ted this was "one in tancc in hi experience where Lh ere may have been an inflam mawry trigger to ho t re istance." R eference : 35; 49.

,17 Table 2: :'sE .ROBL.\ " I 0.\1 \ I RU'J ru 13Y C:OLEYJOXK .\LO~R ()\IB! :S: l~D \\'l rH -;-l. RC l~RY\ :\D1 0R R \ DL\l'JO:'s: 9 .\ E - l'h) ician or ·ex --_-{ic-:-:-£xtent Prior Concomitam ubscquent-- Infection I )PC of- Toxin Immediate & Final Result l lo pita I ,\gc Prior to Toxin Therapy "l hcrapy Therapy Inflammation ite. Duration Year, l raced .\fter On ct Ref -renn· _ ____ Dale of On ct ______---,-- Fc,er Reaction I. \\ . B. Colq male inoperable par• exploratory none 10 HS. later none I racy XI into cercb<:llar S\lnptom cea: 9, 10, 11 :-13 mos. a,cncbral ncu- inci ion of Cushing rcmo,- tumor and i.m. ed. no trace of 11) tagmu , 12. 17. 49 rnhla toma al paraverte- ed remaining \\ilh interl'al diplopia, etc.; regained 6 a, 7 scapular I c ,. c I bra! ma ganglioneuroma. of re l for 2 ·r . bladder control ,· con ·id- with extensi,e (biop yon- spine · laminae beginning Jul) ' erablc muscular power meta ta e in- ly); no other of 5 ,enchrae 1911 but required cnuche for ,oh ing central therapy in auempt to 1.-alking: after ushing's nen·ou · ntem impro,c his mo• operation. walking great· ny tagmus' dip'. bility ly impro,ed. dro,e car, lopia, pto is; \ worked in lore; N.E.D. complete quad- 1970, 59 )r·. after onset 1 iplcgia; prog- no i rcga rdcd as 2 mo . 1911 2 . .\ lemoria l male inoperable me• biopsy of x•ray con'd; ra• 20 ) rs. later ex- peculiar ra h on Parke Davi 31 1., mo . afier toxin Hospital 4½ mos. ta tatie nc11ro ­ le ion in It. dium packs to plored at N.C.T. buuocks. abclo• X III t0xin be- , \\'e~·e begun many small er 2-1; H; 16; blasloma with ·capular re­ le ion on back. because of ilcnt minal wall. cv• gun 9 day af· (Unirradiated) nodule -19; 54 multiple sub• gion x·ra~ thigh, forehead area calcifica· ere de quamat· ler I t x-ra); 21 had disappeared, in ex· tlltaneou le - lO rt. di tal (500 mch each); tion n. 11pra• ing rcaCLion on i. m . in 49 da , cellcnt condition; ;\farch ions over entire he t (326 no apparem cf. renal region; rt. thigh (irra• febrile reaction 1937. 2 new lesion ap• body, c pccially r), to n. feet mas 12xl0x dialed area); 10 103.8°F. pearcd. then rcgre cd; trunk; onse t thigh (327 cm incomplete- broncho - p11eu• :S: .E.D. by early October :\l ay 1936 r), lo It. I remo\'cd, ,ilso monia 1937; 1937, in \'Cry good hea lth; proximal ubctuancou badly disea eel I 951 became hypcrten• che l (326 ma in rt. tonsil remo\'ed i,e; 1956 con ulled l\'.I. r); no ap­ flank: both o-an• 193 ; poison i\'y H. for hypcrtcn ion; spon• parent et­ gliorcuroma; annually; 5 taneou pncurnothorax feet re•explored more bouL after surgery there 1957; 1959, retroperi• pneumoni a, neurobla 1oma reactivat· toneal mass 12x none very seri- eel 14 mos. later, progres­ x6 cm remov• ou sed. cau ing death 196 1, eel: ganglioneu• 25 F . after onset. roblastoma; 1other ma in• operable 3. ;\fcmorial male inoperable ncu- I nodule biop­ none none none Parke D avis Discharged with hopeless Ho pita! infant roblastoma mu!- sicd; small ra­ XIII (no details progno i ; nodules then 66a few mo. , tip le, tiny sub- dium plaques a to technique) began to disappear; com­ old cutaneous a pp! icd to I or plete regrc sion; in per­ mctasta cs 2 nodules with­ fect health I 952, over 5 out effect. ) rs. after on ct. (66a) 4. i\fcmorial m a le 3 time recur- excision De cm- December none June I 946: very Nov. 2 , I 946: remarkable regression cvi­ llo pita! 3 yrs. 1. rent inoperable bcr 1944: then 1946 IO x- scverc measles, Parke Davi dent during 1st 2 wks. of 44; 49 , ncurobla Loma x-ray. (600 r); ray; 2 blood 1 high [ever; 3rd XIII: °17 i. v. in toxin therapy; >i .E.D. in It. thigh invol- re UITencc re- tran fusions re un-ence then 3 day ; rcac- 4 wk ., gained 2 lbs.; 2 ving pelvis, ab- moved Novcm- penicillin; ' developed, very Lions averaged , wks. la ter d i ca c rcacti- dominal avity; ber 19•1j; p.o. reactions to rapid growth, 103°-106°F. vated. progrc eel very onset, :'\'ovcm- x-ray. (600 r); both. oon involved rapid!\·; meta ta c 10 ber 1944 2nd recurrence · abdominal cav- pleurae. trachiobronchial removed :\fay I i1y, pelvis; acute lvmph node , It. Jung; 19.J.6; further x­ strep. pharyngi- d ·a th February 8, 1947, rav 6i50 r to It. ; ti during x-ray over 2 yr . after onset. thigh fall I 916.• fa II I 946, fever LO I 05°f.

5. i\lcmorial female ncurobla toma x-ra · to rt. I x-ray (2700 . inci ional biop-: J ul)' 1948, spik; ,\ ug. 21, I 9-1 111 better health for 6 Hospital I mos. of rt. thigh; on­ thigh. Aug. 1948 r) Aug. 1918; y, Oct. 194 : 1ng. fever 10-1 Park Da,·is wks. after toxin than in 44 ct :\[arch 191 , (600 r) further x- ~.E.D.; aspira-, F., 111flamcd Xlll, 13 i. 111. previous )r.; :'\'.E.D., full during u. r. i.; ray during ti on biopsy, throat; June in 15 days. very ani\i1ies; w('II until cpl. quic cent 4 mos; 2nd course cpt. I 949: ncu- I 919, van cell a mall doses. 1919 pain. mass recurred. 1 recurred during toxins, cpt. robla Loma, fur- sligh t or mod- improved a fter further [ebri le cpi ode I 9-J.9 thcr x-ray crate reactions toxin ; then pain in ( 1200 1·); trans­ (a,·cragc 101.2°- It. leg, metastases to fusion ; x -ray to I 02°F. once lung . inguinal lymph spine; . K. I. 10.'5°F.): ept. nodes. rt. distal leg, wt. 11 33 (25 mg) . 19.J.9, J 3 i.m. in lo ; much heller after Feb. farch 13 days, large 4th close of final toxin , 1950 doses. similar co u rs c; mc1a~1asi to reaction plus spine, D 11; paraplegia urticaria on during radiation; rapid arm , face: Ja11. downhill course. death I 950 large do cs . \ pri I 22. 1950, 25 mos. daily i. v. after on et. Phy ician or ex ite& Extem Prior oncomitant . ub equcnt I nlection I ,pc of Toxins lmmcdialC & final Re ult Ho pita! Age Prior to Toxin Therapy Therap, Therapy Inflammation ' ite. Duration Yca1s Traced .\her Onset References Date of On ct Fever Reaction 6. ~lemorial male inoperableneu- d ia th~ relic­ ~la, 1951: Octobt'r 1951 a - .\ugu l 1951 P.irJ..c Oa,i in nccllcnL «u1diti(ln lull Ho pita! 14 }TS. robla toma in- ,ed pain hricf­ , -rav pir:uion hiop ~; grippe 'OH hcchills x-ray, good appetite; pain 1,·cu1Tecl. unh,•arnble; ,kath J uly 30. 1952, 15 mu . af1cr on L

7. ~I morial meta tatic neu- ept. 1950. clia ­ , •r:t\ LO codeine for pain none Parke Da,·i pain r-clicn:d. 0% re­ Hospital roblastoma pri- thern1y; region­ capula due to recur­ X 111 eptember gn•,,ion 2.t d:t) a her l l 44 marr in rt. sea- al procaine 4184 r rence; ca pu lcc­ 195 1. 16 i. v. in injl'rtion toxins: returned pu la onset ep- ncn·e block tonw :\larch 16 clay; reac- tu "'orl.. a · dc111i t; com­ u:mber 1950 June 1951; a · 1952 re,ealecl lion a\'eragecl plclc rcgrc · ion in 4 wk ., piration, inci - meta tatic neu­ 104.6° - 105.6°. gi:ncral condition excel­ ional biop ie of robla toma: pal­ maximum 107° lent: pain recuned 4 mos. scapular mass; liati\'C X-ray lOI F., paroxysmal l:lll'r, petsi. tcd. increased; I x-ray begun 2 spine. 6150 r; to cough during di,l·ase widclv disscmin- da) prior LO peh•i . 5650 r; rea~Lions; 2nd atcd hv )fav' I 952: rib toxins H:-;, ; 3 blood course begun 7 ternuni, pine, pelvis, tran fu ion : days after ur- fcmora; temporary im­ further pallia­ gcry; 15 i. v, in provem ·nt from palliati e tive x•ray to 15 days; reac- radiation; then lost 35 ,·ariou 1nctas• tions a\'eraged lb . .. Icukopcnia, became tase totalling 103..J 0 -104..J °F. drug addict: paLholo!ric 6400 r; amino• fracrnre rt. di ml femitr; an fol, tilbes­ death. \p.-il 1-1, 1953, 2½ trol, estrogen, ) r . alter onset. androgen 8. Memorial male metastatic neur-! J an. 1952 I part of x-raylDcccmber 1952 January 1952, loan Kcucring excellent resu lt, thigh! Hospital 2 yrs. oblastoma in• aspiration, given during x-ray to skull bilateral tonsil-\ In titutc XIV completely normal, ch il d 44 volving cmire incision al tox ins 2250 r, no ap- Jar aclcnopath), toxins begun 10 very active; 1 .E .D. until shaft of It. fe­ biopsies; x­ parent effect abundant mu- days after x-ray December 1952, then me­ mur, probable ray, 4538 r amethopter in, Icopurulcnt dis- 15 i.v. in 15 tastasc to skull; fell Feb· primary para­ to femur, 6- mcrcaptopur- charge, fever, clays ruary J 953, clisca c then vertebral reg­ 2500 r to inc, Pl64, fur- . 100.2 °F., naso- reactivated, pain, ccrc- ion; on et at IO chest as thcr x-ray, cor- pharyngitis; eel- Ibra ! metas tasis, also to mos., J an. 1951 . prophylac­ ti so ne, testost• luliti in arm; mand ible, vertebra L2; pain, limp; re- ' tic crone, transfu. u.r.i. June 19"2, pa raplegia; di case pro- current transi­ ions, adrenalin, meas les, prompt grcssccl, very widespread ent attacks dur­ also received \ recovery; Feb. metas tases at death, Sep- ing teething penicillin twice 1953, influenza, tcmbcr 1953, 32 mos. af- fo r u.r.i. intes tin al grip· tcr onse t. pe, diarrhea, fe - ver to I 02 °F.; cervical adcni tis 9. Johnston male terminal gencr- biopsy, x-ray I none none none John ton XV no improve ment, rapid 37, Case 80 21 mos. Ia li zed ncuro-, 7200 r; am- I toxi ns: 12 i.m. dct rioration, death 5½ blastoma, each- cthopterin, I in 21 days mos. after onset, 3 wks. exia, a cites su- thio-TEPA I a ft cr tox ins were begun pcrior mcdiast-1 inal syndrome, mass in It. ; Ishou lt.le r I ERIE B, TOXJN TR.Et\ T ED, DETAJLED HI TORIE

CASE J: 1 nopera bl e neuroblas Loma (para vertebral ympa theti oblas torna) of th e right transvcr e proces of the si xth thoracic ven ebra, of the hourglass type, with exten ·i\'C involvement of the central ner­ vous system, based on careful swdy o[ the biopsy mat rial from Lh c original tumor (19 11 ), by Drs. H arvey Cushing a nd S. Burt Wolbach who reported: "At first glance Lh c resembla nce of the LUrnor LO a (ibrosarcorna (the original diagno is in 1911 ) with ver y little intercellular sub­ sta n e might be conceded. H owever, a peculia riLy is irnrnediaLely n o Li ced in Lh a t Lh e ti ss ue is p artitioned b y connec Live ti ss ue ba nds h aving all the rela Li on hi ps o( a stroma in an epithelial tumor. 'il\lith the Lain employed (hcm aLOx ylin and eosin), it is impos ible Lo sec cell outlines, and the impres ion of spindle-s haped cell is obta in ed wholly through the outlines of the nuclei. The nature of the tumor, however, i m ade apparent by the presence of an in­ tercellular substa nce consisting of extremely deli cate fibril whi h a re sta ined a faint bluish pink. These fibril · o cur in bands o [ considerable width separa ting cell m as es from the sL roma, a nd as large ba nds joining widely sepa ra ted group of cells. The size and grouping of the cells, the connective tis ue sLroma a nd th e pr sence of the cl eli caLe fibrils which resemble cy to1 las rni c proce ses of tu­ m or cells, agree perfect! y with the characteristi c of th so- ailed 'ympa the ti c neuro blas torna' ...Th ere a re no cell of a more m a ture type such as h ave been frequently described in n euroblas Lomas a ri sing in Lh e adrenal gland. (sec 11 for microphotographs, Fig. 9) . Pres umably thi lide is repre enta ti ve of the tumor as a whole as it existed in 19 1l. Thi tumor disa ppeared or diminished (c i a­ trizcd) under the influence of Coley's toxins. Symptoms of pinal pre urc persi tcd , a nd years la ter (19 12) the intra pinal les ion which rema in ed was identified a a gang li oneuroma, the more co mpact ex­ tra pinal remna nt of the tumor howing the same characteri ti cs. "A very thorough examina ti on of the ti ues removed in 1921 revealed n o trace of cell similar in tructure to those which in 19 .11 apparently constituted Lh e entire growth. Instead we find a n eopla m compo eel chie(ly of two el ments, one representing ga ng­ li on cell s and the other representing growth of ca psul ar and shea th o[ Schwann cells, which is the usua l combina tion recorded in gang li on uromas o[ sy mpa th eti c ori gin. T herefore, one is forced t co nclude Lh a t the ells of thi tumor as a whole h ave responded to the in(luences of facLor governing the normal d i[[erentia tion of the nervou y tem .. .It would appear " ·ithout ques ti on that the proliferative acti vity o[ the norma l growth ubsidecl coinciden­ tall y with the admini tra tion of the bacterial toxin . It is safe to pre ume, from the study of the original Lum or and its co mpari son with the tumor after a ten-year interval, that the lesion wa origi­ nall y an a tively growing sympatheti coblas toma whose cell , coinci­ d ent with lo s of prolife ra ti,·e activity, came to be lifferentiaLcc.l in time into ganglion cells a nd into sheath and capsula r cells . . .Th e ca e from the pathological sta ndpoint is a unique one." (11, p. 211 - 212). P revious H istory : 'i\l. 'i\ ., Jr., male, aged 21 months (at onset), of L acrosse, Virg inia. The fa mily hi Lory wa not recorded a regards fa milial disease in I 9 11. (The child's father died of m alignant m elanoma in J9 53) . In February l 911 the father wa Lhrown from a wagon while holding the infant in his

52 ERIES B : TOXIN TRE TED CA E , DETAILED I I ISTORl E arms. On et, it was no t known a t the time th a t the child h ad b en injured in any way, but a m onth la ter the f ir t ·u picion " ·a aroused b , progre ivc weakne of the legs, associa ted " ·ith a p aravcn cbral sw lling oppo it the middle o f the sca pula o n the r ig h t icl c. The welling in crca. cd in . i,c a nd by April 19 11 muscula r weakn e s h ad so in reasecl th a t the child could no t h old up his head. The diagnosis at this time wa poli omyeliti to which the p a ra­ verteb ral swelling was unrela ted. T he child wa taken to a " ' II -known sur­ geon, Dr. Stuart M cGu ire, in Richmond, '7iirg inia. By i\Jay I , 19 11 the weak­ ness had gradua ll y progressed up the trunk, the arms could no t be moved . oon there wa fever, na u ea, vomiting, a nd tupor, a we ll a Joss o f phin ter control. The eyes b ca m e cross cl and there was p t0s i . In view o f thee sy mp­ toms, Dr. H. Allis'on Hodges, a neu rolog i t, aw the child in the con ulta ti on with fcGuire a nd the o pinion was then expressed th a l th . ) nd romc was due LO om e intradural exten ion o f a cli sea e which wa po ibly tuberculo is, though a lumbar puncture \\'a nega tive and there was neither stiffness o [ the neck n or Kernig's sig n. Since the para vertebra l swelling wa incrca ing in ize, it was cl ecicl ecl a t the fa ther's r eques t, that an explora tory incision be made to d etermine th e na ture o r th e loca l les io n . C t1 shing a nd \ Volbach (1927) emphas ized in reporting the case tha t " this pre limina ry story is important in howing tha t there was wide prca cl invoh ·em cnt o f the centra l nervous sys tem, which cxtenclecl above the level o( the welling in the back." ( 11 ) The para­ ,·ertebra l tumor was by this time pla inly palpable a nd scmi-nt1 ctuant. It sug­ ges ted either li pom a or a tubercular ab cess.

Sm gery: In June 191 l, M cGuire, by an x ploratory in i ion parall el 10 the rib , exposed the growth a nd round a w 11-cl cfin ecl tumor a pparently spring ing from the lamina or right tra n verse process o f the sixth thoracic vertebra. The les ion was in o pera bl e and a fter r mo,·i ng a piece o( 1 i sue for histo logic examina tion, the wound wa clo eel. This ti s uc wa. diagnos cl as f'i brosa rcoma.

Clinica l Course: The surg ical incision h ea l cl promptl 1, bu t the tumor in crca ed in size . IvI Guire rega rded the prog nos is as a l out two m o nths but o n the advi e o [ Dr. \Villia rn B. Cole ' it wa cl e idecl to try Coley toxins. T oxin Tliernpy (Trac) XI ): lnjcnio n ll'Cre beg un late in July 19 1 I, by the child' father, a phy icia n. The ini tia l d ose wa I / 5 minim, which caused a febril reacti o n o ( 102°F. They ,,-ere g i,·cn e\'Cr o ther cl ay, o ne a week being m ade in to the tumor, the r em a inder intramusc ul a rl y r mote from the tumor. The maximum intra tumoral d ose wa 2 minims, the max imum intra­ musc ula r cl ose wa .m inims, a nd o n one occa ·ion this cl ose ca u eel a good d ea l o f shock, a nd th ercaf'Lcr the in tra rnu,cul ar do,e wa kept a l 2 ½ to 5 minims. The child' · weight steadily increased during treatment, from a low o f 21 po unds, until b y i\farch 191 2 he weighed 29 po unds, a ga in o f eig ht pounds in even month . By thi time h e h ad rega in ed considera ble musc ul a r power, o tha t he could mo ve bo th hand. we ll , hold up his h ad a nd mo"e his legs, altho ugh he co ul l no t walk without upport. lt wa a t this time tha t Co ley fi r t aw the hilcl and that Dr. J ames E,\'ing exam in ed the orig in a l slides. Ew­ ing la ted that the growth wa " ungue tio nably a m aligna nt LUm or which might Yery well be ca1lecl a arcoma .. . I am inclinecl to thin k it is either a n encl otheli­ oma econdary Lo the cerebra l gro\\'th . or po sibl y a ne uroq Lo ma cl crivecl from misplaced nerve tis ue in the crani u m." C ushing a nd \\'o lbach noted tha t this tatement indicated tha t " the vi ew still p rernilccl that there h ad a tuall y been a n intercra ni a l proce · and that the loca l Jc ion in the back was no t the so le cau e o f the clinical picture." (11 ) On M arch 19, 1912 Dr. Foster Kenned y, o f

53 ERIE B: TO IX TRE TED Cr\ E , DETAILED HI TORIES

~cw York City, made a carc[ul neurological exam ination of the hild and reported: "On examination the child ho"· marked cereb li ar allitude of the head, though the attitude referable to one lobe i not con tant. Frequently there is a marked ti cmor of the head. prcci el) of the a me character a that een in athanccd ca e of di eminated clcro i of the cerebellar or medullar t ·pe, or of achanccd ca ~ of Fricdreich' ataxia. Th pupil arc bri k, the light and auomoclation equal, central ancl regular in o utline. There i no pto is. There is marked ny,tagmu on lateral conjugate movcmcm, either to the right or to the left. Query, wcakne s of the left ixth nerve. Jaw dc,·iatc al­ ways to the right, therefore, query, right motor fifth nerve affe ted. The ma - , eter on the right idc contracts le well than that on the left. hild apparemly hears on both . ide . There i ob, iou ly no defe ti,·c vi ion, no change in the nnsibility of the face, nor i there any facial pal y. The tongue come out traight, and th re i no tremor or wa,ting. Palate normal. ·' · /J/J<'r I~x/remitics. There i marked motor ataxia in both arm of definitely cerebellar type. (:"\'.B. Thi ataxia i not in an) '"ay dependent on an) \en or) clckn.) Diadochokine. ia right and left. Th ,1rm are very strong for all movement. There i no wa ting. ~o paraly i in the leg. All mo,·e­ ment an be performed, but the ataxia manife tee\ in the arm i. pre ent in the lower limb al o. The sensor condition i e,·e11·whcrc normal, that is to s·1y, the child appreciates pin-pri k, touch and tcmperatur ever where. Th('re i~ 110 C'g111e11t of ane thesia or hypcrc thcsia in any way corresponding to the 1il11alio11 of the tumor in the mid-dorsal region. ''Hcflexes. ,\rm jerk normal. .\bdominal reflcxe right and left, pre ent and equal. Knee jerk incrca~ed equally. l oubl cxten or re p n e . O"·ing to inauention of the hild combined with gro s ny tagmoicl movement of the ·cba ll , it wa difficult to get a cl ar view of the optic di k. The vein· in each ocular lundu were ,·cry large. Outer edge of di ks were een in glimp e and "·ere apparently clear, and did not pre ent the inuou it · o( outline nor the blurring u ·ually f>Ccn after th ub id nee of a neuritic proce ·· \\'e are told that the child ha impro\'ed ,·e1;· greatly in the pa t 1x month not onl , a regard weight and general nutrition, but in regard to po"·cr and abilit to perform mo\'Cmcnt. Jt i ob,·ious, however, that there i ;ti ll a ?;10, · crebellar le ion." (11 ) Cu~hing and \\'olbach oncludcd: "The c note made by a highly compe­ tent ob cncr urely indicate that the cerebellar ymptom at the time were pre­ dominant and that the pinal paraplegia had largely di appeared. Did the tory end h re. one might well enough a ume that the ymptom had been pro­ duced, a Dr. E"·ing· qualif) ing remark ugge ted, by one of the common tumor (mcdullobla toma) of the fourth ventricle which had ino ulated the ccrcbro pinal . pace and au ed a spinal implantatio n with paraplegia, which in certain rare ca. e i kno,rn to di appear pontaneou ly. ·'ft ma) be pointed out, howe,·er, the child wa then under 3 year of age (2 )Car, 9 month,. LO be cxa t): a l o that the renex movement of the lower e"-ucmitie in tran ,er e le ion. of the cord were at that time imperfectly un­ d r tood, and c,·en today when ob er\'ecl in infam may be cliffi ult to dis­ tingui h from ponta11 ou 111 0\'Cm nt. It would appear, ncvenhele s, that th intracranial and cerebellar ymptom "·ere more pronounced at the time than were tho e referabl to the ·pine." (11) ,\!though the child had imprO\'Cd mark ell in the prc,·iou nine momh, Kenned · reg-ardcd the prog,10 i · a hopelc . and wa o imere tee! in the ca e that he offered to go to Virginia to do the autop y. The child' father con-

51 SERIE B: TO IN TR ·ATED CA E , DETAILED HJ TORIE tinued the toxin injections with interval of re L, a nd fu rther impro\'emenL o - curred. Ile wrole Coley on November 23, 1912: "There i n o indication of return of the growth on the back, and hi general health i good, hi mind eern s bright. H e h as never regained the u e of h i leg , though he ca n move them beuer and they how no ign of wa ting o r contraction . J li C)e ymp­ toms are al o better a nd h e i hea rty and well cl e,·eloped, doc n ot eem to suff r an y a ncl i · bright a nd full of life." (10) During 191 2 a ·J minim doc of toxins was g iven every third day. Cushing a ncl \\. olbach n oted that during the first year in which toxin therap y was admini tered " the cerebell ar ymptom , if such they were, eem to have fallen into the ba kground of the picture." ( 11 ) The wxins -\\·ere continued with inter\'als o f res t fo r a lotal o( O\'er two year. Clinical Course: For the en suing eight ye·irs the child, though rema ining paraplegic, thrived a nd developed in all o ther respect. 1 l e a quired a uto­ m atic control of the bladder and rectum, a nd by 1912 h acl learned to bal­ a nce himself awkwardly on crutches. The father fin all y came to the conclu ion tha t a n exploratory laminecwmy houlcl be underta ken. "H ence the child \\·a adrniuecl to Peter Bem Brigham llo pita], Bo ton, ;\fa . achuse LL., on i\lay 18, 1921, 10 years after the fir t explora tory op era ti on. Al thi time he a ppeared well nouri heel , coop erative a nd h ad n o discomf arts w hatsoever." (11 ) N eu rological examina ti on on May I , 192 1 " h " ·ed a b olutely no igns of in olvement of the bra in or upper pinal cord . T here wa not a trace of the n y tag-mu , diplopia, plosi and ·o on, de cribed in the prcvi ou hi ·w ry. ln the back was the scar of the old operation (11 , Fig. 1) . T hi wa s ft a nd m ova ble, and palpati on revealed no eYicl ence of an under!) ing tumor. T h e x-ray of the spine, howe,·er, howed a cl oud a rea repre ·cnting either dense fibrous ti sue or o i fi cation a t the i Le of th e orig in al 1c ion. The ou ti in s o[ the la minae, spines, a nd tran ver e procc e were clear a nd without evidence of h a,·ing been involved in the cli sea e. "The child was powerle s to move the lower extremities but the li ght ·t ·timulu ervccl lo throw them into refl ex 111 O,·em ents which Lro ngly ugge tecl voluntar y movemenLs and even the pa ti ent was under the impr sion tha t he h ad some voluntary control. H e could sland a lone with the support of crutches and b ta king advantage of a u taincd adductor pasm which h eld the knees together, the fee t being ep ara ted a nd turned in. \\'hen this pa 111 re laxed he would fa ll unless supported. "Sensa tion wa apparently complete! Jo t up to the level of Lh ·ix Lh thoracic skin-fi eld, but the en ory tc Ls were cl i[[icult lo interpret becau e a pin-prick or e,·en a light Lou ch would e,·oke ponta neou reflex movements which gave sen ory impre sion refetTed by the child to hi s leg . "The deep reilexe both a t knee a nd ankle howed an ea il y Ji cited a nd u ta inecl clonu . There was on both ide an active clor al toe r e ponse LO almost any form of stimula tion, even uch as the mere expos ure of the legs by removing the bed covers. The crem a leric refl exes were a ti ve. R efl ex erection were ea ily provoked by p ri cking the glans or p i king u p the kin of the groin. nder these circumstance the legs would fl ex and th bl adder which could retain about 200 cc., would be emp ti ed wiLh out se nsa ti on. " (11 , Figs. 2 a nd 3) . "" ha tever m ay have been th e condition Len year previou ly, c n ainly a t thi time there wa nothing to be ecn but the evidence of a tota l transv r e pin al le ion a t abou t the level of the ixth thoraci egmen t which corre - ponded lo the ite of the original paraverteb ral tumor. ;\foreo,·er, the x-rays di cl o eel a somewha t den e h adow in the region of the former tumor which, however, did not affect the normal oulline o f the adjacent lam in ae or tra ns-

55 ERIES B: TOXIN TREATED CA'.SES, DETAILED H1STORIES tumor ti ss ue. Th is mass encircled and constricLed the meninges and cord and verse processes. I t would appear from the hospital hi tory Lh at no preoperati,·e diagno is wa ve ntured. No lumbar punclure was performed. It would almost ccnainly have shown a complete block with xanthochromia." (1 1). "May 21, 1921. Opera Li on (Cushing) . Lamin ectom y with disclosure of ·harply ddincd extradural mass of d ense non-infiltra ting and non-adherent apparently communicated wilh the relic of the orig in al les ion through a n en larged intervcn ebral foramen. " WiLh the po ition o[ the old cicatrix as an indication of the original tumor site, the spines and laminae of the three adjacent venebrae were at first removed. T here wa no apparent le ion of the bones but, on scraping o[[ the pcriostcum from the laminae of the right side, a dense scar-like ti ss ue was encoun tered in the spinal m us les wh ich was taken to be the residuum o( the original lc ·ion. On Lhe removal o[ the spines and laminae, instead of the usua l exLradural cuffs o[ fauy ti sue, the ca nal wa fo und LO be [i!Jecl with the arnc kind of den. e s ar-like Lissu e. A n in cision, made into this firm tissue, wa carried clown to a considerable depth without disclosing dura. The tissue ·was quite vascular. "R eali zing Lh at the exposure was in ufficient, the aclcl itinal spines and laminae of the two preaxial venebrae were then removed. This brought into view Lhe upper margin o[ the les ion with normal appearing dura headward LO it. Similarly the !amine tO,ITiy of an additional postaxial vertebra exposed the normal dura ca udal to the lesion. It therefore extended over approximately (ive spi nal segment . "The cxpo ·ccl growth was then tilted up and li fted by blunt dissecti on away from the dura Lo which it was not adherent. s the fairly rig id posterior shell of tumor was broken away from its lateral a uachments, it was ev ident that it extended Lo the amerior aspect o[ the canal on the right idc where it be- anie much thinned ou t. "A [ragrn nt of Lhis intraspinal ti sue was immediately exam ined ('Wo l­ ba ·h) and wa reported as probabl y a ga ngli oncuroma. 'W ith thi sugges ti on [ a pos ible seat o[ origin [or the tumor in a po Leri or root gangli on, which might account for its hourgla h ape by coincidental exlension into the para­ vcnebra l mu cl es and spina l canal, the wound before clo ·urc, was reinvesti­ ga Lcd. The exLravertebral mas which had been taken to be icatricia l tiss ue was found to li e .ma inly between the lamin ae of the fifth and sixth thoracic segmen ts ju t opposite the thickest portion oE the res iduum of the intras p inal growth. The two masc apJ eared to ommunica Le by a narrow neck through the region of an enlarged in tervertebral fora men. A fragrnen L of the dense cxtra-verLcl ra l Li ss ue was then removed for compari on with that whi ch had been removed from within the canal. "Following the removal of the tumor Lhe greatly compressed dura [illecl out its normal dimensions and resumed it pulsations. It was not opened. In the hope that the procedure would suff ice LO release the cord from its co n­ striction and perm it a return of function, if such a thing were po si bl e after o many y ars of comprc ion, the wound was loscd as cust0mary in uccessive layer. "Po !operative R eport. The child ma le an excellent re overy from the pcration. H ealing was perfect (11, Fig. 1) . The preoperative symptoms re­ mained unchanged at the time of his di charo-e." (11 ) Cu hing wrote Coley regarding this case on i\Iay 23, J92 1: "He had a ve1-y extraordinary tumor which 'Wolbach thinks ·was a gangli oncuroma .. .It is ex­ traordinary that the le ion should have been o unmistakably benefited by your toxin ." (10)

56 SERIE B: TOXIN TREATED CA E , DET,\lLED 111 'TORIE

There was light improvement fo llowing Lhi o peraLion as regard walk­ ing. However, the boy's father soon ,,-role Cu hing that he had impro eel g reatl y and had much beuer phinCLer conL rol. Aga in in 1923 some Lenotomies were performed whi h helped him greaLly. In Augu L 1926, five ye;1r after Lhe larni nectomy, the father reported Lhat phincLer conLrol had co11L inued Lo improve. I-I e added Lhat Lhe boy co uld get up, dre him el[, walk around the room without a crutch, though m o t of Lh e time he u eel one ruL h ; that he o uld " hiLch his pony himself and d rive around anywh re he pi ca eel ." (10, p. 209). His only illne during the next few year wa appendiciLis, for which an appendectomy ,ras performed (abou t 1931). Early in 195 1 he de­ Ycloped hypenhyroidi m, with lo s of weight, and he wa g ive n iodine, wiLh som e improvement·. L a ter he was giv n a thorough chc k-up in Richmond, Virginia, including basal rn eLa boli m Le t, and wa puL on propylLhi o uracil. Thereafter he improved very much. t Lhi s Lim e he was able Lo drive a ca r and " ·ork sLeacl il y in a drug tore. During 1957 he wa asked Lo go Lo Lhc National JnstiLUte of Il eal t.h in BcLhescla, ;\Jar ,]and. for revie"· of hi ca , a they were intcres Lcd in following a group of ca ncer paLienL with long su rviY al . They found a sLo ne in the kidney a nd following operation for its removal, he d eveloped septice mia, and later osLeomyeliLis of Lh e cervica l spine, buL recovered. In Lh e (all o [ 195 he again developed a bladder infecti on a nd reLUrn ccl LO Lhc N.I.H. for Lreatment. The thyroid condition ecmed Lo be normal a nd medica Lion wa discontinued. ln D ecember 1958 he was being maimained on i\Icndalamine, I gram t.i.d. He remained well and free from a n y evidence o f neurohlasLOma in 1970, 5~) years al'tcr on.el. R eferences: 9, JO, 11 , .1 7. 2-1. ·19 , S·l, 77.

CASE 2: Metastatic generalized neurobla toma, confirmed by microscopic examinaL io n in 1936 by Dr. Jame Ewing, following biopsy o( the nodule in the capular region; the ections were revicwe l in 195l"i by pathologisL at i\femorial Center, a nd al Lhe NaLional C;111 c r In titute, Bethesda, faryland. Previous T-l istrny: P.\\ ., male, aged ½ monlir, or Frankf"on, Kenwck . The child' paLernal great aunt died of ca ncer. Onset, in i\Iarch 1936, when he was abouL 1I ½ monLhs old his mother first noticed some Jumps under Lh e le ft arm, apparently in the axilla. Thereafter oLher nodule appeared over the body, es pecia ll y o n the Lrunk. Th re was fr quenLly a slig hL ccchymos is preceding the a ppearance of new nodules. The mother b li e, ed ome of Lhese had regre sccl or disappeared. The baby rema in d in good hca lL11 and ap­ parently had no pain nor discomforts. Surgery: biopsy was performed of Lhe nodule in Lhe left laLeral s apu- lar region which was reported as "probably an adrenal neurocyLOrna." Cli11icnl Course: The baby wa examin d by Dr. Lloyd D. Craver on eptember 3, 1936 at whi h time he appeared healLhy and films of Lh c sk ull, chesL and abdomen howed no di tincL e,·icl ence of wmor. r\t numerou poinLs about the child's trunk were soft, subcutaneous tumor nodules varying from ½ to 3 cm. in cliameLer, ome entirely subcuLaneou , oLher elcvaLcd about l cm. above the skin. Several were slig htly bluish in color. There was no ulceration or alta hrnent of Lhe sk in. Some of Lhc larger ones "·ere in Lh e right infrascapular, the left uprascapular regions and below Lhc right thigh near the perineum. At Lhe left Hank, below Lhc co Lal border a (lauened nodule wa fell on bimanual palpation somewhat re ernbling a low plcen. R adiation: Low volLage x-ray trcaLmcnl "·ere g iven between September 57 SERIE B: TOXl 1 TREATED CASES, DETAILED HISTORIES

3 and l 0, J936 as follows: the n odule on the right lo,ver chest posteriorly received 163 r x 2 (160 K.V. 3 mm a l. filter, 30 cm. d istance, 3 cm. cone; 5 m illiamperes [or 5 m inutes) . The nodule in the righ t upper thigh anteriorly received 327 r (sa me facLO rs except [or time: 10 minutes). The left upper ches t posteriorly received 16 3 r x 2 (sa me factors as the lower chest). He ·was admitted to femorial Hospital on September l l , 1936. H e appeared to be bright, large and very active. T oxin Therapy (Parke D,l\·is XJJI): injections or Coley tox ins were be­ gun on September 12, 1936, nine clays after the fir t x-ray treatment. A total o[ 2 1 were g ive n in 49 cl ays intram uscul arly in doses of ½, ¼, ½, ½, ¼, 1, I½, 2, 2½, 3, 3½, 4, 4, 4 ½ , 5, 5½, 6, 6½, 7 and 7½ minims. T hese cau eel febrile reactions averaging 100 °-l0l 0 f. (m inimu111 or 99.2°, max imum 103.8°f .). No ch ills occured but it wa · no ted tha t the ba by wa ro s, or restless duri ng the reactions on several occasions, and once he had a "rash on his face." By October 8, 1936 th ere had been " no change in the size of the tumors." Fu rther Radiation : On October 17, 1936 the patient was given a radium pl aque trea tmen t of 500 mch. to the tumor on his back. It was noted that cl ay that his "general co nd ition was excellen t." A second radium plaque treat­ ment was g iven (500 m ch.) on October 2 1, l 936 to the tumor on the u pper inner right thigh at 1 cm. distance. These caused a good reaction in the sk in bu L no de[ini te regress ion in size of the tumors. On October 27 , l 936 a rad iu m plaque treatment was given to the les ion on the forehead. Clinica l Course: s Dr. Norman L. Higinbotham did not feel he should receive any further toxin therapy for another two or three months the baby was d ischarged on November I, l 936. Craver stated at this time: "Clinicall y th is cl isease is behaving as though· it was neither radio-sensitive nor highly m alignant. The subcu taneous nodules that have been treated (each with 500 111 h. at J cm.) show no regression. " 111 /lam.mation: The baby subsequen tly developed a peculiar rash all about the bu Lto cks and on one or two spots on the lowe r abdominal walls consist­ in g o[ red areas of apparently superficial denudation of skin, rather clean cut, varying in d iameter from 0.5 cm. to 2 cm.; suggestion of impetigo was made by the local physician and a sa lve co ntaining mercury was u eel. At xamination on November 17, 1936 the lesions seemed somewhat softer and fl atter. The large nodule in the right in terscapular region seemed to have rema in ed tationary r was perhaps a li ttle small er and the one on the fore­ hea d was slightly mailer. There was no evidence of new tumors and the child was in exce ll en t co ndition. Clinical Course: At examination on J anuary 1, 1937 the child remained in excell ent co ndition and there was no evidence of rec urrence. The exam­ ining phy ic ian Lated: "Apparen tly many of the smaller untreated nodul es have disa ppeared." At examination on March 29, 1937 the baby remained in excellent condition. H owever, the mother had rece ntly noticed two new lumps; one in left axilla and one over the left sca pular region. They were at fir t di co lored blue, but the co lor soon disappeared. On that date each lump w·1s onl y a small movable subcu taneous soft nodule 0.5 cm. in d iameter. There wa no other evidence of di ea e. t examination on June 25, J 937 when the baby was l months old both Ewing and Stewart raised the q uestion of the baby being- somewhat precocious: he had 16 teeth. Craver did not agree. By 0 Lober 8, 1937 all evidence of disease had regre sed completely. The boy SERIES B: TOXI T TREAT ED CASES, DET AILED HI T ORIES had been hea lLh y except for a tendency to large Lonsils and sLU[[in e s in co ld weather. Infection: ln December 1937, Lil e child had bronchopneumoni a from which he recovered co mpletely. Clinical Course: In December 1938, a ton illectomy wa perfo rmed. The tonsils were said LO be "badly di eased." At thi time the child weighed 40 pounds. Further Infections: During May 1939 he had mumps. That fa ll he had a "croupy cough." Clinica l Course: A sm all m ovable subcutaneo us mass was discovered over the left sca pula. The child was readmitted on October 22, 1939 for excision of this nodule for diagn os ti c purposes. Examination on admis ion revealed an unusually well developed and well nourished child who did not appear ill. The nodule was removed and showed only fat. During J 94 l a pea-s ized nodule appeared in the right ches t or abdominal wall which di appeared sponLan­ eously. In fection and Further Inflammation: In J anuary 1942 he had measles. H e also had poison iv y annually. Clinica l Cou.rse: On May 25, 1942 th e mother noticed small nodule in ·til e r 1gl1 t a11l.l 1leh occ11jrni1 .. reg1011 ·. 'lte chlll.l 'hall CO l1 Cllll1 Cl.l ' to 'have p,!lpa lJ Je pos terior cervi al and inguinal nodes . ..Wh en seen on AugusL 25, 1947 he was 5 fee t 2½ in che · in heig hL and weighed 127 pounds. T he examining phy ician reported: "H e has been in very good healLh except for poiso n iv y annuall y, ev id ence of whi h i prese nt now. i\Iother no ted mas in right lumbar region ... believed to be of a few weeks duration." H e was then in the sixLh grade at chool. H e did not exercise very much; h e was not a behav ior problem. Ex­ aminaLion revealed a very develc ped, rather obese boy o[ 12, with at least ave rage intelligence. There were several lesions of poiso n ivy on the r ight h and and leg. Pubic hair was appearing. There was a nodule about 1 cm. in diameter on the right lumbar region 5 cm. la teral to Lh e micl-ven ebral line, which was not movable. Further In fec tions: The boy then h ad "fi ve bouts of pneumonia, none of which were very serious." Clinical Course: Thereafter he ·was well until 1951 when he developed hypertension (at one time to 180). He also complained of headaches at in­ tervals. H e was considered a hypochondriac by his mother. H e was not par­ ti cularly interes ted in athletic and was only moderately "sociable." There was co nsiderable di sparity betwee n his pos itive achi evemenL and his poorer one ·. His memory wa very capricious. Examinati on on J anuary 1, 1954 showed a fairly well developed, well nourish ed boy of 18 whose re ·pon es wh ilc in tell i­ gen t were somewhat variable as to perceptiveness. Craver and Dargeon felt that the questi on of hypertension should be more Lh oroughl y ex plored, es­ pecially with the consideration of a pheochromocy to.ma. There was hyper­ Lension in the paternal branch of the fa mily. (ApparenLl y nothing was done during the next two years.) The patient was admitted to the Clinica l Center of the Tational Institute of H ealth in August 1956. His fa Lh cr had died of h ypertensive cardiovascular disease a few months prev iously and at this time the patient became interes ted in his own h eart problem, having been h yper­ tensive himself for fi ve years. His only other symptom on admiss ion was parox-

.59 SERJES B: TOXI I TREATED CASES, DET ILED HISTORIES ysmal headache , associated with excitement. The h ypertension had been paroxys111al in the past. These episodes were a sociatecl with palp itation, headaches at times, aml characteristically a low back p ain. There had been no anginal co mplications or ym ptorn s. The patient had been ee n in another hos pital where a fl at plate of the abdomen revealed an area 0£ ca lcification of the r ight suprarenal region. The ques tion of whether or not this could have been a pheochrorn ocy toma was ra ised and Jed LO his admi sion to the National Cancer InstiLUte. Examina tion on admission revealed an area of post-radiation fibros is and a telangiectasia situated in the m id-frontal region of the scalp, the right lower dorsal region of the back and the inner aspect of the thigh. In addition, there ,,·as a 3 x 1 cm. firm mas in the subcutaneous tiss ues of the right (lank. There was one area in the mid-lower lumbar region that was tan-brown in colo r resembl ing a cafe-a u-lait spot. His blood pressure on ad­ miss ion mea ·urecl 160 / 90 in both ar111s. Blood and urine catechols were wi thin normal limits. Suro·ery : An excisional biopsy of the subcu taneous mass in the right fl ank was perfonnecl . H isto /o

CASE 3: Ino perable neuro bla Lo rn a with multiple tiny ubcuLa neou nodules confirmed by mi roscopic exarnina Li o n a fL er bio psy o [ one o f the nodules a l M emori al H os piLa l by Dr. Fred Stewa rt. Se Li ons were la ter r eviewed b y sev ral o ther pathologists who concurred ·with the diagnosi . Previous Histo1y: :\Ialc infa nt a (cw mo nths o ld . Surge 1y: One o f the subcllla ncous les io ns wa bi op ice.I.

R adiation: Sma ll radium plaques were applied 10 o ne or two o ( th e nodule Lo see if they exhibited eno ug h en iLi,a ti o n to wa rra 11L who le bod y irradiation. They di l not. T oxill Tli erajJ)' (Parke Da\·is XIJl): 11. e also received a (cw injecti ons of wxins (no deta il s arc ava il a bl e a to technique) . Clinical Course : Al'Ler being di cha rged with a ho peless p rognosis, the nod­ ule bega n to disappea r. Corn plet reg ression occu rred a nd the hild rema ined in perfe L h calLh in 1952, more tha n fiv e years later. R ef ere11 ce : 66a.

61 SERIES .B: TOXlN T R EATED CASE , D ETAILED Hl T ORIES

CASE 4: J nopcra blc recurrcnL n curoblasLoma o[ the lcft thig h , confirmed by microscopic examina Li on by Dr. F.'iV. } ooLc, .J r., pa thologist at M emoria l H ospital, o f Li sue removed at each of the three opera­ ti o ns. Previous H istory: O.'ii\1., m a le, age 3, of 'i,Vat ontown, Pennsyl\'ania. The child's m aLcrnaJ grandmo Lh cr diccl o f can ce r o r Lh e pa ncreas, a nd his m aterna l g reat a unt had skin cancer which wa "cured." There was no hi ·tory o [ tuber­ cu lo is o r diabeLcs. A materna l g reat a unL becam e a comple te in valid after the binh of her la ·t hilcl (p a raplegia) . The child' · mother had several aller­ g ies whi ch were worse in spring a ncl sum.m r (hay fever). be was m a rried aL 20 a nd the patient was born 5½ years laLer. T he pregna n cy a nd b irth were norma l, altho ug h Lhe patient'· m o ther staled she " h ad n a usea for seven m onth , a nd L11ree bad fa ll s," al o a very bad old a nd a n a nnoying coug h during Lh c six th a nd cvcnlh rn onLh o f her pregnancy, during wh ich p er iod she lo L 10 po unds. T he child weighed nine pound at binb. H e wa breast feel for 10 ½ m o nLh s a nd ga ined ,,·e ig ht rapid ly. H e was very alert a nd bright, a nd walked a nd talked b (ore h e was a year old. His m other sla ted that " he never slept a nig h t thro ug h ; he would la ug h a nd play all cl ay a nd cry al nigh L Jt wa · not temper. 1one of several doctors could expla in it." H e received Lh usu a l diphLheria a nd scar let fever immuniza Li on sh Ls beginning prior Lo Lh e age o[ one year. H e was a n onl y child (and only gra ndchild) . His mother LOOk c;i re o [ him un t il he was a year o ld a nd then ·he went to work a nd h e was cared for by her parent. At a bout 14 m onth h e became very hoa r e w ithout any sig n o f a cold. H wa tak n LO a d octor wh o aid Lhat i[ Lh e con d i tion did not dear up in a week, the chi lei shou lei om e back. IL cl eared up then, but would re1urn occa ion ;i lly for a da y o r LWO. He ne ver bad a ny contagious cli case, ;i ]L11ough h e pl ;iyecl with children who were con tra ting a t variou s Limes m e;is les, mumps a nd w hooping cough. H e seemed a nd looked very hcalLh y. On ct, in Nov mber 1944-, without an y known a nteced ent local tr;iuma, a lump was [irst no ti ced o n L11 e left thigh. The child was then 18 months old. Surgery: On D ecember 12, 19-14, this " ·as rem oved urg ica ll y, a wide ex­ n . 1011 " 'a 111;:id c. Further operations for recurren ce were performed on 1 ov­ r. mbcr 9, 19·15 and ?\Ia 23, 1946. R adiation: H e a l o received 1200 r of d eep x-ray Lh erapy, g iven in two course ·, from _J ;:i nua ry 5 Lo l l , 1945 a nd November 16 to D ecember 14, 1945. Th cl ise;i e was not con trolled. Conrnrrent l11 fe ction : Three d ays a fter his re turn home from the third opcra Lion he developed mea les a ncl h ad a very evere case w ith high fever. I le h;:id la rge patche, n ot spoL , his mother stated. During this a ttack of measle, while cha nging the dre sing, she noticed a nother recurrent m ass had appeared in the in cision. She sta ted: " It seem ed to grow li ke wi ldfire from thaL time on ." Cli11iral Course: In Lh e early u.mmer of J946 Lh ere was in\'Olvem enL of the pelvis and a bdominal avity. The patient was admitted to M emorial Hos­ pita l on Aug u L 23, I9,J6. ExaminaLion revealed a la rge lllmor involving the outer aspect of Lh e left thigh a nd extending through Lh e pelvis into the left low r quadrant. The pro,·isio nal diagnosi inclucl ·cl the fo llowing po sibilities : Ewing' tumor, fibrosarcoma, n c uro bla Lorna, a nd rhabc!om ysarcom a . Fwtlier R odiatio11 Civl' 11 Co11011-r1' 11liy ]Viti, F11 rll11'r J11 fec tio11 , l11flam- 111a tio11: Further d eep x-ray Lh crapy wa begun on 1\ ug u L 26, 1946 and SERIE B: TOXIN TREATED CA E., D ET lLED HISTORIE was u suall y given da ily August 2G , 27, 28, 29, 30, 3 1, SepLember 3, 6, 7, 9, 10, 11, 12, l 3, 16, 20, 2 l, 24, 2·1, 25 (250 r each over Lh e lc [L thigh, le i\ pelvi , anterior a nd po ·teri o r). On Aug ust 30. 19 1G the pa ti ent h ad a fever of J05°F. Ile h ad no compla inL except th a L o n vari oll' occas io ns hi e)e · hur t. The Lo nsil were large a nd lig hLl y infe L cl. The re,·er wa · l05°F . Lh e next day and Lh e ca u e ·was undetermined: m ala ri a, m n i ng i Li s, Lr ep tococ al infection a nd p yeliti were ruled out. H e had no ti[( n ck o r heacl::i ch , no a bnormal pain or tenderness . His ches t ,va cl ear a nd there " ·as no ra h or adenopa thy, no lethargy. The refl exe were normal. The final diagnosi s was acuL e pha ryng iti , and a culture sho\\'ecl no n-hemo l) Li e ·trepwcoccus. By Sep­ tember 2, 1946 the child was m oderately ill, hi throat acutely in(lamed, look­ ing like a viru infection. H e was g iven penicillin in b e " ·ax, but the infec­ tion did not respond to it. The next day Lh e tonsilhr nodes were slig htly but definitely enlarged. By eptember 16 the L mpera lllre wa till ele,·at cl ( l 02.4 °F.). At th is ti me there were ro u r erythema to us area - o n the bu Ltocks fro m the p eni cillin injecti o ns whi ch \\'ere po sibl a b cesses. :\ Lra n fu sio n wa given on tha t clay. The child h ad had a n allerg ic reaction Lo p eni cillin prior to admission. He had a quiLe generalized ras h by SepLember 17, 19-16. On SepLernber 26 he was "scratching furiously" and h e h ad four loose tools. X-ray Lh erapy was g iven during mos t of this I:cbrile peri od . When h e h ad re eived a toLal kin dose of 2250 r x 3 Lo each p ort Lh e skin apparenLl reached its Lol er­ a nce a nd there seemed Lo be Olll e rcgrc sio n of Lh e proce s. (Thi Lo Lal lcd 6750 r. tumor dose) . On N o\'elllber J, J9,J6 th e family ph ·sician, Dr. L. i\f. JioIT!ll a n, re­ ported a new nodule just a bove th e crest of th e ilium, the i1e of a mall m arble. The o ther nodula r areas had appa rently di appea red. The child " ·a · rcadmiuecl o n N ovember 27, 1946. T oxin Therapy ( loan Kettering JnstiLulc XI ): Injecti o ns were begun by D r. C ordo n i\IcNeer o n November 28, 19-16, the initia l doe be ing I/ 100 minim given intra ven o u ly. Thi · ca used na usea, eme is a nd a fever of J 05. °F. The child received a total of 17 intra veno us injecti ons during the next 38 days. These u ually cau eel mark ed r bri le reaCLi o ns ( 10 3°- I0G °F.) and the chills occurred at least four Limes la ting from 5 to 45 minute. By D ecember 11, 1946, two week after the injecti o n were begun, l\ l N eer r p on ed: "R e­ m arka ble regr es ion o[ m ass in suprapubic region a nd ld t upper quadra nt. l do n o t believe tbi can in a ny way be attributed to Lh e x-ray Lrea tment as (t.h e) lesio n bowed no uclt re ponse prev io usly to x-ray thera py." The p a ti ent re eived x-ray therapy on D ecember 3, 5, 9, l l, J 3 ornbined with toxin thera py. He al o had blood transfu ion of 25 0 cc. on December 11 a nd 12, 1946. Fu 1' /li er Radia tion: Further x-ray therap y wa g iven on D ecember 16, 18, 27, 30 and 3 I, a total o[ 10 treatment given on the days toxin inje Li o ns were no t g iven. By De ember 26, 1946, M cN eer reported: "Suprapubic m as · not palpable; left upper quadra nt m a s n o t palpable; some r siclu al indura­ ti on (umbilica l); right fl a nk m a not palpable; left Lhig h mas not palpa ble; left iliac mass no t pa lpa ble." A complete skeletal x-ray examina tion wa made o n December 30, and showed no eviden ce of c!i sea e. Clinica l Course : The pa ti ent wa a llowed to go home on J anua1 6, 194 7. H e was to return in a few week for (unher toxin therapy, buL beca use of a mump epidemic in the ch ildren ' wa rd, n o bed wa obta in able. Hi moth er sta ted that "on his return h ome he was wonderful, ha ppy, healthy a ppetite, but I noticed that he tired ea ii . H owever, h e gained two po unds in one week. About January 17, I no ticed his brea thing was sh all ow a nd n q id, a t

li3 ERIE B: TOXl T TRE TED C E , DET ILED Hl TORIE times becoming almost labored. Ther, I noticed a lump on his back." The child wa admiucd LO SL. Luk 's H o pita! in New York on January l , 19,17, in great di omfon, complaining everely of pain in the abdomen. H e wa pale, with a hot dry kin. There wa marked dullne and upprc ion of breath ounds th roughout the lower left che t. R adiographic and fluoroscopic examination o[ the ch t showed marked widening of the media tinal had w. The heart was d isplaced to the left ide which showed homogeneou den ity throughout, suggc ting atelccta i of the lung, probably with om overlying fluid in the pleural spa e. There was no ev idence of respiration fluoroscopical­ ly in the left lung. The patient wa treated by upportive therapy, penicillin, tran fu ion , thoraceme i and edation. The di ea e progre sed rapidly, caus­ ing death on February 8, 1947 . Po t mortem examination of th e chest con­ tent were permitted. Thi showed meta ta e in both pleural ca\·itie, medi­ a tinum, tracheobronchial l) mph node , and I ft lung; hydrothorax bilateral; partia l a tclc t a ·i , both lung. Dea th occurred 26 months after onse1. R eferences: '14, 49.

C E 5: Neurobla toma of the ri ght thigh, confirmed by mi roscor ic ex­ amination at i\lemorial H o pital fo llowing a piration biop y (on clot) : "on mear alone could be neurobla LOma, Ewi ng tumor or reticu lum ce ll arcoma." Previou bi op i s had bee n reported as "inadequate material" or a howing no ev idcn e £ tumor. Previous Iii to1)•: i\I.G., female, aged 2 year, of Oueen \ illage, Long land. The baby's mat rn al grandmother had diabetes. he h ad a brother of 4 ½ and a ·i Ler a •car old, both in good health. he wa born on i\Ia • 31, 1946, after an un omplicated full term pregnancy. Deli\·ery wa pontaneou after a ix-hour labor. he wa not brea t fed. he was in good general health until on ct, in i\farch 194 when he had an upper r pirator • infection and com­ plained of "ore leg ." Infection: In three days he wa entirely asy mptomatic and remained well until _111I • 13, 191, wh en he piked a temperature of l0·1°F. and wa gi \·en penicillin for a red throat. Clinical Course: Two clays later a lump wa fe lt on the anterior portion of the right thigh abo\·e the knee. Five cla · later the \1·c lling eemecl to de­ er a c. H owever. about Jul · 2 , 194 the " ·elling became markedly larger and the child wa taken to the Immaculate H o pital in J amaica. X-rays of the xtrcmitie and chc t were taken and the hilcl wa referred to Dr. Theodore ;\tiller who made a cl ia!Tno i o[ Ewing' tumor of the right femur. The ch ild did not complain of an pain but he wa kept off her feet during the three week prior Lo admission to ,\femorial I los pital on Aug u ·t 20, 19·18. Examin a­ tion at thi Lim ho\1·ed a petite. friend!), wh ite hild " ·ho did not appear to b acute!) ill. There wa. a fmi[01 m firm light! tender . \1·elling of the lO\l"er third of the right thigh. i\ fo,·c n1 nt of th e right knee joint a nd hip were not limit cl. Radiation: X-ray therapy wa begun prior to acl mi ion and by August _o, 19·18 he had re eivcd 600 r. fter admi ion radiation wa continued con­ comitant! ' with Cole toxin , a total of 1'100 r being g i\·en to ea h of two portal .

Toxin Thcrnpy (Parke D,n·i~ XIII): Injection " ·ere begun on .-\ugu t 21, 194 and were gi\·en daily intramu ularl · in very mall clo e for 11 days,

64 ERIE B: TOXI TRE \TED Cr\. E , DETAILED III TORIE lhen eYery 4 hour for Lhe I. t Lwo injection . The do age u ·ed wa ½, ¼, '½ , I½, 2, 2½ for Lhe ncxL ·ix do. e., . , 3112 niinim . :\' one of Lhc e au ed an ch ills, allhough lhe Lcmperaturc roe lo 102 °- I0 '.~°F. on four occa ion, 103. °F. once, the Olher febrile reanion bei nrr \ e,·) lirrlu (99.5 -l OJ.2 °F.). . \ n a pi ra­ tion biop y was performed by 1'1iller on Augu t 30, 194 and wa r poned by Dr. Sophia piLz a : "Inadeq uate material. Faint ro elle pauern ugge - tiYe of neurobla toma." The final injection in lhe our e ,rn given on ep­ Lember 4, 194 . Concurrent Fever: On the da the child returned home, eptember 4, 194 , he had a fe ,·er of 10~ 0 f. Thi ub ided with a pirin. Clinical Course: During t11e next six weeks the child was at home and the mother ·Lated he wa in beuer health than he had been for a year. H er activity wa restricted until eptember 23, 19·1 , but thereafter he ,rn all owed full acti ilie . H er appelite wa good. he slept well, her bowels and bladder fun ction were good. urge1y he wa readmitted on October 14, 191 and an inci ional biop y was performed. A oft grayish "neoplastic" tumor was found in the marrow cavity of the rirrhl femur. at Lhe junclion o[ the middle and lower lhird . The Li ue remoYed for biop y wa report d a howing "no eviden e of tumor." The ch ild wa di harged on Oclob r 21. I 4 . The growth ap­ parently regre eel a in licaLed by the x-ra s. Infection: In late June 19°19 he de,cloped \'ari ella. Clinical Co urse: It was noted in ugu t 1949 th at iliere had been "no hange in her condition." he continued to do well until ptember I 949 when he had re urrent pain in the right thigh. Ther had been no weirrht gain from April to ept mber 1949. Chest film Lak n at thi Lime howe I pul­ monary meta ta in boili lungs. Examination revealed e\·era l matted firm inguinal node. The kin howed radiation change in the di tal half of the r ight thigh and a firm tender w lling of t11 e lower part of the right upp r leg in th e anterior porlion, ov rl ying both co ndyle · of the femur. The hild's appetite had nu lUaL cl " ·ilh febrile epi od of 100 °-101 °f (r ctal). urge1y: On September 21, 19-19, an a piration biop y wa performed by Miller. Thi wa · reported as neurobla Loma on clot. Further R adiation: X-ray lherap · wa given between ept ml r 23 and Ocwber 8, 1949 (25 0 K.V., 300 r x 7, LoLalling 2100 r ea h to th e anterior ancl po terior right thigh). he "·a al o gi ,·en a tran fu ion. 2nd Gour e Toxin Therapy (Parke Da\i , ·1 11 ): lnj nion were begun on eptember 2-1, l9•J9 and were g iY en lail y f r 13 day. illlramu cularly in closes of 1/ 10, 1/5, ½, l, 2, 4, 6, 12, 16 minim . . \ new boLLlc wa obtained and a doe o[ 3 cc. o-i ,·en, another boule ,,·a lhen u eel and -I cc wa gi ,·en. Thi · doe produced pain in the I g, a mild ch ill la ling 30 minutes and the maximum febrile reac­ li on (105.2°F.). The final doe on O wber G, 1919 wa 1.5"cc., cau cd a moderate chi ll of J05°F. and hi,·e on both am1 and lhe lace. The maximum 1eaction of 0 the fir t JO doe. (up LO 2 cc.) wa~ 103 °F., the average being 101. -102.2°f. The final do e in th e co ur e wa given on October 6, 1949. Clinical ourse: The child wa di charged improved on October 9, 19,J9, but he still had pain in her leg. She wa readmitted on J anuary 16, 1950. Three " ·eek previou ly while rawlino- on the floor he omplainecl of pain in lhe le/ t knee. he wa examined by :\Ii Iler who found pa m and . ugge led re L. ERIES B: TOXIN TRE TED CA ES, DET ILED HISTORIES

Pa in in Lh c: left leg was consta n t day a nd night prior to admiss ion and was relieved for a few ho urs by codeine, a nd barbiLUra Les . IL seemed to start a l Lhe ankle and go up Lhc leg. Pain was a lso Lill prcsenL in the r ight leg buL much less Lh an prior LO LreaunenL (x-ra y and toxi ns). The temperature h ad been around 100°- 10 2°F. The chil d had lot omc weight. H er highe t weight, in ug usL a nd September 19..J9 had been 29 pound. By J anuary 1 it was 27 po unds a nd li y .J an ua ry 18 ii was 25 ¾ . F urt/1cr T oxin Thr' ra/J)' (Parke D avi. X f11 ): lnjcn io ns were resumed on .J anuary 17, 1950, and were g iven d a il y for 12 d ays by the in tramuscular route in closes o f 0. 1, 0. 3, o.~, 0.75, l, 2, 2, 2, 2.5, 3, 2.5, 4 cc. Thee cau ed only fo ur febril rcacL io n5 of 103 °-10-l. 6°F., Lh e OL hers be in g from 100.8° to 102.2°F. Slig ht chills o curred bric[ly af'Ler Lhrce doses a nd lasLc cl 45 min11Les on one occasion. /\f'Ler o nly fo 11 r clays' Lrea Lm e nL it was noted tha t the child appeared much bc Lt cr a nd wa. eating w II. fL was noted a l'tcr the la t fo ur doses tha t she com­ plained o f cvere pain in the back. Tra11sf11sio11 s: Transfusion "·ere g i\'en o n February 2 a nd 3, 1950. These were adm inistered with difficulty clue to lack of coop eration. F11rt/1 cr R adiation: X-ray therapy was g iven over the Jdt tibia between February 3 and 17, 1950 (250 I<..V., 300 r ea h, totall ing 2100 r.) Between February 6 and 18, 1950, x-ray therap y was also g iven over the lumbodorsal pine a x- ra y cxami nation had reveal eel d estructio n of the bod y of the 11th dorsa l vertebra w ith abou t 75 o coll a pse. This area received 25 0 JC V., 300 r c;1r h, touilling 1800 r. Durin o- ho pitali zation it was fe lt tha t at times there ll'as an emotio na l component LO the recu rrence of pain whi h was usually during the evening and night onl y. be also h ad o ca ional involuntary mic­ turi1 ion prior to d ischa rge, which h ad been attributed to pcevi hne until x-ray exam in ation s h ad revealed metastases to the 11th dorsal vertebra. On Fcbruar 5, 1950 a fter two or three cl ays at h ome he d eveloped paraplegia with incon tin ence of urine and extrem e constipation . (During this period she \\'as rccci\'ing thera p y to th spin a a n o ut-pa Li nt). By Fe bruary 16, there was ed ema o ( the lower extremitie , r1nd almost constant pain c pecially in the back a nd lower extremities. The ch ild was rea dmitted on Febn.1ary 16, a ppearing hro nicall ill and in p a in (whenever e ither leg was moved he cri ed o ut in pain). Examina ti o n re\·ea lccl cldinitc para lys i o[ the right lower xL rcmity and pro bable m arked paraly i of the left leg. The anal sphincter was a tonic, the bladder wa palpable. R adiation was completed on February I , 1950. Chemothna/Jy : Sloan-Kettering 11 33 " ·a administered (a ub titute nitro­ gen mu Lard) on February l , 19, 20, 21, 24, 25, 28, 1950 in close of 2 mg. to '.Z.5 mg. in 11 ,0 (by n1outh). The genera l co ndition appeared Lo be Jes good on J\f arch 7, 1950. The child compla in ed o[ headaches a nd pain in the back of an indd ini Lc na wre. T he li ver wa enla rged about 4 to 5 cm. below the costal marg in. }ou r more do e o[ .K. 11 33 were gi\'en in dose of 2.5 m g. a cl ay. By ,\larch 13, 1950 the child had rece i\·ccl a Lo ta! o( 25 mg. of .K. 11 33, which ll'a reported to have bad no bene[icia l effect on the n eurobla toma. The di ca c progre sccl ra1 idly ca using d eath on April 22, 1950, 25 months a fter o n et. Com111r·11t: Compare re ult in this cas with Ca. e l in wh ich toxins were given a lo ne and co nLinucd tcad il y for a longer period. This child h ad only 1hrcc bric[ co u, .. e o-i \·en during and fo ll owing heavy radiation. R eferences: 44. 66 C E 6: ".\Ieta tatic neuroblastoma of the left femur, confirmed b · micro­ scopic examination by Dr. Fred "\\'. Stewaa fol lo\\'ing biop I on November ', 1951 (51-1537-:l). The diagno i following a piration biop y on i\Iay 15, 1951 had b en reticulum c II arcoma (51-7692) . Previous 1J isto1y: ].7\I. , male, aged l ·J, of Brooklyn, N.Y. The boy" father had died of heart clisea e. lle was an only chi ld. Ile had hi · ton~il and aden­ oid rernO\'ecl at the ao-e of l months. l le had a streptococcu throat for which he was ho pitalized at the age of three year . H e al o had a thma a · a child. II fracwred hi left upper femur at the age or li,e and had it in trac­ tion fi\'e or ix week . At the age of 7 and J l he fractured hi left forearm. On­ set, about the rnicldle of April 1951, he fir t developed a dull Leady pain over the lateral a p ect 0£ the lower le[L thigh. t thi ti me he noticed a local " ·elling. Heat: . The day after his local phy ician was onsulted and he adm inis­ tered three diathermy treatment, with relief of symptom . Two week later " ·hen pain recurred the boy received a econd cour e of diathermy with fur­ ther irnpro\'ement in the pain and om diminution in the welling. Clinical Course: On 7\Iay 10, l 951 marked pain recurred, being e peciall y snere at night, and the patient '"a referred to ' t. Catherine' I Iospital in Brooklyn, where x-rays were taken. The patient wa then rderred to Dr. Brad­ ley L. Coley and '"as admitt d to l\femoria l Ho pita! o n ;\fa ' 15, 195 1. Exam­ ination on admi ion reYealed a wcll-de,eloped, well-nou1 i hcd (obe e) ado­ Jc cent white male, in no a uLe di tre . (1 Ii s ,,·e ight was I, 7 pot111ds, and had been graduall y increa ing). He wa alen, cooperati,·e and intellig-ent. Ther wa (ullne in the di ta! part of the left thigh. The preliminary clinical diag­ no i wa o teogenic arcoma. X-ray examination wa reported a howing a le ion in the di tal femur JS cm. in length " ·hich " 'a· "regarded as a periosteal fibro arcoma or po sibly a an aneuryw1al g iant ce ll tumor." Che t film were negative. Co111bi11 ecl R adiation and Toxin Tl,ernpy (S K[ X J ) : X-ray therapy was g iven to the left thig·h between Ma 1 18 and June 2, 195 1 ( 1000 J ., ., 3 16 r each, totalling 2092 r to po terior and anterior portal,). Thi, \\'a~ calculated i a tumor doe of 3000 r. Injection were begun on the same day as x-ray therapy a nd gi\'en daily for 15 clays intravenou ly in dose of 1/100, 1/50, 1/30, J/15, 1/3, ½, 1/3, 2½, 3½, 4½, 6, 7½, 9 ½ and 11 minim. Thee caused febrile reaction a,eraging J0-1., 0 -105.J °F. (minirnum JOI.2°F., maximum 106.2°F.). Th re wa also headache, and occasional I) nausea and erne. is dur­ ing the reaction . Clinica l Course: The boy " ·as di harged on June 2, 195 1. The kin wa. in good condition, and he had full range of motion withouL pain. He was told that he could do mild exerci e uch a wimming and 1,·a lking. H e re­ mained in ex ellent condition until September 1, 1951 " ·hen h e developed pain in the treated kn e. Physical examination that day re,eal d no objective finding. X-rays ho"·ed continued healing. The bo , was ach·i ·ed lo re t. H e wa again een on eptember 12, 1951 and again howed no e1·idence o[ di - a e. The pain appeared Lo be mu cular and came on following an allach of grippe. The patient wa reaclmitLed bccau e of continuing pain in the antero­ lateral a pect of the lower left thio-h. Examination on reaclmi ion howed an obvious welling and comparative measurements howecl a 4 cm. differenc :i.t the uprapatellar level. This had noL been pre ent t11·0 we k pre iou ly. An a piration biopsy was performed on October 1, 1951.

(i 7 SERIES B : TOXI TREATED CA'SE , DETAILED HISTORIES

Further Toxin Therapy ( loan Ketlering XIV): Inj ctions were resumed on OcLOber 2, 1951 a nd 18 were given in 20 day, all but one intravenously in dose of 1;,10, J/ 20, 1/ 15, 1/ 7, ½, I, 2, 3, 4, 5, 6, 7, 8½, 9½, 10½, 11½, 12½. The 13th injeCLi o n ( 15 minum ) wa give n into the tumor a nd cau eel no chill a ncl sl ig h L febrile reaction, l 00.2° F. The febrile reacti o ns from intravenous therapy averaged J0,J.6 °F. to l05°F. (minimum 103°F., maximum 105.6°F.) with ch ills lasting 20 to l 20 minute occurring after all but one of the intra­ venou injections. Radiation: X-ray therapy was begun o n O ctober 23, 1951 and wa given to the left anterior and posterior thigh (JO00 K.V., 348 r each, totalling 2088 r to each portal). The lateral femur received one treatment on 1ovember 7, 1951, 369 r. It was noted on O ctober 24, 195 1 that the patient's mother con­ tinued to interfere w ith his progress a nd a ttempted to dire t all procedures. (Actually she was d esperately worried about the child, as her life wa centered about him) . The patient compla ined of pain onl during vi iting hour, a nd the mother's daily calls were becoming quite irritating. !\lea urements taken on 1ovember 2, 1951 showed a definite slight decrease in the size of the tumor in the femur. t the time of his discharge on November 8, 1951 it wa noted by Coley that his appearance sugge ted there was probably disea e elsewhere a nd his enlarged liver uggested that the organ might be involved. Clinical Course: On November 26, 195 1 the patient's mother called a nd tated he wa om1 laining of trouble in his skull a nd that he h ad a lump on hi skull. Phys ical examina tion by Coley revealed no evidence of irregula rity of the contour o( the calvarium. X-ray examina tion was also negative. At ex­ amina tion on D ecember 27, 1951 Coley reported that the affected limb at the 11 prapatell ar level measured 0.5 cm. le than the normal one, a decrease of 5 m. in a period of three months. Coley added: " the tumor has certainly responded remarkably to the recent x-ray treatment. Patient ha surprisingly little yrnptom, gets about well on crutches and has a good appetite. He looks well altho ugh perhaps a tri[le a nemic." No further treatmem was given. The patient died on July 30, 1952, "after months of unbearable pain." This was 15 month after on et. Comment: This pa tient received only two courses of toxin therapy total­ ling 35 days given during radiation (totalling over 7500 r). R eferences: 44.

C E 7: 'i',Ieta tatic neurobla LOma wa the final diagno i in thi ca e, al­ Lhough it was first regarded as a reticulum cell arcoma of the right apula, ba eel on microscopic examination by Dr. . Purdy tout following a piration and incisional biopsie . Dr. H enry L. J affe al o examined thee sections and reported: "I be li eve ...i uffering from a malignant tumor of the scapula which is rather difficult to pigeon-hole cytologically. I do n t beli eve it repre ents a reLiculum cell arcoma. It eems to me in vi ew of his per istent cough that th ere may be tumor in the lungs or omewh ere el e within the thoracic cavity. There i no ab olute certainty that the tumor in the capula i a primary tumor ..." Dr. Fred ·vv. Stewart favored pla macytoma from examination of the a piration and in­ ci ion al bi psy ti ue, but tated that a chonclrobla tic le ion could not be eliminated. L ater tewart reviewed the case and stated it wa a meta tatic neurobla toma."

6 ERIE B: TOXI:'\ TRE TED .\ E , DET,\ LLED Ill I ORI£

Previous H ist01)': !\U,I., J ewi h male, ager! 3 l, a dentist, f ~ w York Cit . The patient' mother had diabete , hi [ather died of hea1 L di ·ea~ . Two uncle had can er, one of the lung, one of the face. he famil) hi LOry wa negative for tuber ulo i. The patiem had bronchopneumonia in 1912, and an appendectomy in 19cl'1. nset, in eptember 1950 he fir L notic d vague pain in the po terior right hould r. Thee la t cl everal day · and th n ub- icled. Heat: In June 1951 the patient had a e, re auack of thi hould r pain which limited motion o[ the arm. Ile ,,·a treated twice week! · for 10 week ,..-i th procaine i njcnion (region a I proca inc nc1, e block) " ·i th moclerat relief. hortly after · the e inje Lion were topped, about . \ uo-u L 30, I 951, he fir t noti cd a welling above the right capula. X-ray examination wa, made about eptember 12, 1951 whi h re,ealed a le ion o[ the uperior border of the right capula. Thi welling progr i,·el enlarg cl. Ph · i al examination on admi ion Lo Memorial Ho pita! on eptember 19, 1951, was negatil'e ex­ cept fo r a definite firm ne approx imately 4 x 6 cm. i n diam l r wh i h ap­ peared to be fixed to the capula. It wa not hot, tender or flucwant. The overlying kin " ·a not fixed or reel . .\T otion o[ the right arm wa limited only a regard rai ing it behind hi back. he patient wa w 11-de,·elopecl and well-nouri h cl. Ile . lated he had had a marked dry cough for t"·o "·eek prior to admi ion. The provi ional diagno i was eo inophilic granuloma due to the long duration of mptom . or hondro ar oma. urge1y: ,-\n a piration biop y wa performed b ' Dr. Bradle ' L. ole' on eptember 20, 1951. The ti . ue wa . reponcd b) unclerland a being . ugge ti, e o[ pla ma cell myeloma. Lerna! marrow tudie wer made and bowed no evidence of p la ma cell m 1eloma. An in i ional biop y wa performed b ' ole ' on eptember r, 1951. The ti ue wa examined b ' tewart and Jaffee, and both regarded it a probabl · a reti ulum ell arcoma. Radiation and Co11c11rrc11t Toxin Tliera />y (.. K.T. X I\') : X-1ay therapy (1000 K.\ .) wa given betw en eptember 29 and October 20, 1%1. The whole capula wa tr atecl through two tangential port, medial and lateral, a total tumor do e of 11 "1 r being deli,·er d in thi period. The patient toler­ ated the radiation very well. At the encl of treatment there wa a li ght ery­ thema. Injection of ,oley toxin were begun on Ouober l, 19.51 (LI\" da)\ after the fir t x-ra treatment) and were gi,·en dail · oncurrentl with radia­ tion for 16 day intravenoul · in doe of 1/ 0, 1/30, 1/15, 1/10, 1/ 10, 1/ 3, ½, l y.;, 2, 3. 4, 5, 6, 7, , minim . The febrile reaction a\'eraged JO l.6°F. to l 05.6° F. (maximum 107°F. following the final do c). Chill occ lll reel Ia ting 5 to 30 minute and u ually tarted within an hour after injection. Oc a ion­ ally the patient wa nau eatecl or ,omited during th reaction. B) 0 Lober 3, 195 1 after the third inje Lion, the re pone wa regarded a "satisfactory, w ith li gh t d iminution in i1e of the capular wrnor." D uring the r anion Lo hi ~ toxin injection he de\'eloped paroxy m of coughing whi h requi1ed codeine for relief. By October 11, 19· l he had recein·d 15·0 r LO the , ight ~houlclcr. On October 13, 1951 it wa noted that the pain had largely but not completely ub ided. n October 16, it wa n ted that there had been "ob\'iou re~c - ion of tumor," and that the general tatu wa ati factory. On that clay he had an exce i,·e febrile rea tion to hi toxin inj nion ( 107 °F.) from a close of 5 minim gi,·en intra,enou 1 ·. Therefore it "·a de idecl Lo di cominue toxin Lherap · and to allo"· the patient to ha,e hi la t four x-ray ueatment a an out-patient. He wa di charged on October 17, 1951.

69 SERI ES B: TOXli\' TREATED CA E , DETAILED HISTORIES

Cli11ical Course: .\ t examination on October 2·1, 1951 it was noted that there had been 'O p r cent regrc: ion of the tumor ma in the apula and relief or pain. Tie had no complaint and wa eating and Jeeping oundly without medica ti on. llis general condition was good. lTe re turned to work. a ncl on O ctober 3 1, 195 1 .,ta ted that he had a va ue i nde[i ni Le cirt o( pain, mainly cli comfort in the region oE the capula and houlder ince re urning " ·ork. I le wa rca med by Cole). On Xovember 7, 1951 he again Lated that he ould not work withou t pain, but ··when ...loafing he had no trouble." Examination that cl ay showed still further diminution o[ the fullness beneath th ar over the right suprascapular region. The o·eneral condition was ex­ cell ent. By NO\·ember 21, 195 I the welling had completely disappeared o that the affected s apula pre ented a normal appearance. H e cominuecl to ha,e light ,·ague pain in the whole houlder region while "·orking. ole · rel t the c ) m ptom were not ign i rican t. X-ray examination o( the right ca­ pu la on Dccern bcr 12, 19 I rcvea led consicl era ble cha ng : " i ncr ase in den i L in the area of destru tion and the border now appeared well-cle(ined and de­ limited. The appearance " ·a con i tent "·ith healing fo ll owing treatment of a 1etirnlu111 cell arcoma (100-27 1) ." H e appeared a ympwmatic on February 6, 19r'.?, bin when ccn on February 20, b , Coley he tatccl he had had ome pain in 1h affected h o ulcl r for a week. Coley noted that hi s range of motion was im proving and ta ted: "l ca n ee nothing on in pection or reel a nything on palpation that sugge t local a tivit , here a nd the film made two ,,·eeks ago "·ere indicati,·c of impro,·ement rather than otherwi e." H e "·a again . e n b · ,oley the next clay ha,·ing called twice the previou e,·en ing on ac­ count of the persistent p<1in and lo,r-grade fever. The pa in wa · located right in the 11 praclavicular area <1 nd had recentl y increased in ev rity. Phys ica l examination on February 22, 1952 rcvcalecl onl · the lightc t ugge tion 0£ fullne s in th treated area, particularly the upper portion. X-ray taken on F b1 uar) 6. 19~~ by Dr. Pear on had been rcponccl a "fa,·orable." However, Cole) a5ked Dr. :'\01111an l l iginbotham lO ec him in con ultati n on February 26, at ll'h ich time th patien t st,it cl that the pain was now "requiring empirin ,i nd codei ne pra ti all y ever , night" for relief. H e ailed attention to a swell­ ing. ,,·hicl1 "·a confirmed by palpation by Higinbotham, that ,rn pre ent -in the 11pra,pinou lo . a jmt abO\ e the biop ~- car. Thi · "·a lightly tender ·and th ma ,rn fixed. From thee findings I liginbotham w,pected local re­ currence altl'r radiation therapy that hould have b en adequa te for reticulum ce ll arcollla. I le appro,·ed or Coley' deci. ion to perform a n as pi ration biopsy. \\"hether 01· 1101 the biop) re,·e:t!cd tumor. he felt that a capule tom, houlcl b c1 iou I) comidcrcd on the ba is o[ ~ mptomatology and ph · ical finding . l le added: "' J ha,·e alw;i) leaned to,,·ard a cliagno is of r ticulum cell arcoma in this a,e. l lo"·e, er, there ,,·a con id crabl equivo ation among t patholo­ g ists a5 lO th e exact na ture or this tumor a nd for this reason I suspect it is cer­ _tainl) not a L) pica! r ticulum cel l. and ma) not b a reticulum cell at all. If it ,HTC the u ual t~ pc I would have anticipated complete regre ion for a long p 1iod of time following th adequate therap) giv n.·· Therefore in tead of further radiation, he belie,· cl capulecwmy wa · probably the b st method of trea tment a t th at time. T he pa ti ent ''"as readmitted on i\Jarch 2, 1952. Exami­ nation on adrni ~ion rc,·e;i led a firm hard tumor ma over the right upra capul <1 r region whid1 ould not clcfinitel) be mea ured. X-ray examination h0\1·ecl a I~ tic le ion o,·er the I ight upra·pinou region and pinou proce . The patient appeared to b ". II nouri heel and health). 11rgcry: \ rio-hL capulc tomy ,ras performed b Coley a nd Higinbotham on i\Iar h 3, 19-'.?. tewart examined the pecimen a nd reported it wa "meta .

70 ERIE B: TOXJ;\' TRE.\TED .\. E DET.\lLED 111 T R.IE tatic neurobla toma." The gro pecimen was rC'ported a follow b , Dr. C.L. Butler: "Ari ing in the region of the capula i a tum~r appareml~ im oh ing the capula extending out\\·arcl in both the upra p1nou ancl intra pinou area and al o xtending beneath the perio teum 011 the central ~urracc of the apula. The tumor in\'olve the bon of boL11 the pi11ou proce · and the body of the capula widening it at the upper margin to a maximum width of l .7 m. in thickne . Thi upper margin o( bone ho"· an irree;ular trabecular pauern with ome o teobla tic and clcrotic area and the marrow filled with a oft gTeyi h yellow tumor ti ue .. . (ha,·ing) ...the con i ·tency of a firm lymph node ... (and extending) out\\'ard to inrnlve the 111u le adjacent to the tumor. The glcnoicl fo a i lined by mooth gro ly normal articular cartilage... The LUmor i in mo t area " ·ell demarcated from the mu cle; in ome portion in the upra- and intra pinou area there i ap­ parent light infiltration .. .llowe,er, the remainder of the rnmcle appear gro ly normal and no eparate foci of wmor arc not cl either in the mu cle or auached fat or tenclonou ti sue." A total o( I I sections were prepared from the pe imen (52-3556) . On March 5, 1952 he fir t complained of light tcnderne o,· r the rio-ht groin, whi h wa better the next day. Further Toxin Therapy ( ' .K.l. XIV): Injection of Coley toxin "·ere begun on the seventh po toperati\'e day and a total of 15 intravenou 1113e - tion were gi\'en in 15 day, in do,c of 1 60. I 40, I ~O. I Io, 1/10. 1/5, ½, ½, 1 1/3, 2, 2 2 , 3, 3½, 4 and ·1 2 minim . he e cau ed febrile rea Lion a\'eraging 103.1°F. LO 101.1 °F. (111inimum, no 1i eat all: 111 ;n.i111um J05.J °F.). hill occurred after ea h inje tion except the one on ?\larch 16, I 952 when no rea tion whatever wa elicited from a doe of 1/5 minim). Clinical Course: The wound healed uneYemfully and the patient wa di - hargecl on :\larch 27, 19~2 feeling extremely w ak. "·ith a guarded progno i. . He wa een in the office of ole b April 15, 1952, and app arecl 10 be virtu­ ally yrnptom-free except that he still complained of ome di comfort in the abduct r region of the right thigh high up near the groin. (Thi wa. fir t noted in the ho pital d1an on 'i\rar h 3, 1952). Coley found nothing abnormal on palpation, and Lated that the }mptom were ··not of lon° tandino- 01 ,·er noti cable.'' Function of the shoulder wa "about what one w uld xpect ( ix week ) following a total apulectomy." The patient wa r admitted on i\ra) 5, 1952. He Lated that he had developed pains in the legs ,,·hich were a utc and severe and were u ually a ociated with mo, emcnt. Th e "occu1 reel in mall area and would la t a few day at a time." On one o ca ion pain devel­ oped in the left buttock of four day' duration. In micl-.\pril 1952 the patient, while rea hing high, de\'elopecl "a kink in hi back," and could not bend over. Thi di appeared in about thr e clay. A " ·eek later h de,elopcd pain in the right ankle, whi h remained more or le onstant, a dull aching of a hronic nawre. Thi required hypnoti for lcep. He then de,eloped a dull con tant pain in the right thigh and calf and occa ionally the I ight an_kle. On M ay l, 1952 he de\'eloped pare thesia of the lateral a~pe t of the right foot la ting two day . On i\Iay 3, he developed lumbago la ting 12 l_1our . On J\Iay JO, 1952 he developed a "kink" in the inner ape t of th left tl11 gh in the pelvic area la ting 2½ clay . On \fay 15. 1952, on reaclmis ion, he had pain in the left thigh, tenderne in the left cal[ and numbn in the lateral a peel of the left foot. There wa an area on the left buttock which wa en itive LO touch. The right and left acroiliac joint were al o en iti\'e. The patient

71 REATED ; E., DET · JLED H I T ORIES

tated he had limited motion of the hip joint which wa con idered a prob­ abl volunlaf) due to pain on motion. Conc11rre11t Fever: He al o stated that he had had a pikin;< temperature of 10l.°F. every few day for the pr ·vio u f w wee k , no chill , na usea or headache,. On May 11 , 1952 the tempe1aLUre piked to l01.6°F. On i\Ia 15, I 952, the ca e was 1 vie,,·ecl by Dr. I I.J.Tagnon, who noted that the pain mov cl from one place to another, being at that time in the left groin, left alf, right ankle and lower back. General neurological examination, including mobil ity of all the lim bs and fa e, wa negative. All tendon re[lexe were prc ·ent and equal. The liver and plcen were not palpable. On palpation mu cle ma e in the left cal[ were tender, al ·o on palpation the lower gluteal mu. cle po teriorly on both icle were tender. Ela tic nodule of the con i - Lene , of tendon, were palpable in the gluteal mu cle in the acral region bilaterally and were very t nder. Palpation and percus ion of bone in te nder ar as wer negative for pain. Pa in ecrned lim ited to the oft ti ue. Tagnon Lated that if th re wa no roentgenologic evidence of bone tumor, the po i­ bility of ock a kie viru myo iti should be con idered. X -ra · were then taken and re,·ealed di e.rn inated di ea e in the che t, femora, pelvi - quite ·w ide pread. On l\Iay 22, 1952 tewart reviewed the section and stated he beli eved th e pati nt had ncuroblastoma. Further Radiation: Between i\Iay 20, and June 19, 1952 uper \'Oltao-e x-ra · the1apy (1000 K. \ .) wa admini tcred to the left para,ertebral o-uuer (T '-12, anterior and po terior), 350 r ead1, totalling 3100 r t the anterior and 3050 r to th po tcrior portal. (The included both the meta ta es in th e 'I th rib and th e area in the ternum) . T he pelvis wa give n 2850 r an teriorly and 2 00 r po tctiorh. h 1c wa omc improvement e\'ic.l nt by June 4, 1952. he pati nt wa di charged on fay 2·1, 1952 and ontinued hi radiation a an outpatient. Clinical Course: Ile was readmitted on June 23, 1952. H e tated he had rec ntl y had tencl erne · in th e tempero-occipital ar a and in the apular vert ·bra! bord r. He did not appear Lo be in di tre and wa well developed and well no u1 i heel. ln the left founh rib area, in the anterior axilla1 , and nipple ar a th re "·a a diffu e but light enlargement of the rib. There wa a L nder area along the ,·ert ·bra! bord r of the capula. There wa a ugge - ti on of a cl eply ituatecl paravert bral ma s in the left abdomen, but this was q uit incl finite. Firm non-tender node were palpable in both axi ll ae. hemothera/JY: The patient '"a given H:-.: , (urethane), intra,·enou ly (the total do e wa 2 .4 mg.) . Clinica l our e: IJ was di charged on Ju ne 28, 1952. During th e first two week of Jul · he complained of pain in the ba e of the neck on the left ide. X-ra ' examination on Jul · 10, 1952 howed that the po terior inferior poni n of the b cly of -6 appeared light! · radiolucent and a portion of the articular rtex could not be identified, indi ating the p ibility of a ·mall, ill-d fined meta la i in thi reg ion. At thi time the patien t looked very anem i , and hi hemoglobin was found to be 9 gram . O n July 16, 1952 a mall ma · in the oft part of the right arm in the region o( the bicep wa noted. Three blood tran fu ion were given prior to July 23, I 952 and the patient lo k cl a great deal better and felt better by that date. Further R adiation: X-ra treatmen t wa given over the left malar bone (25_0 K.\ ., . 300 r x 5) between ugu t 12 and 19, 1952. The right temporal region re e1ved 1200 r (300 r x cl): the right fifth rib recei,·ed 1600 r (-100 x 4)

72 ERIE B: TOXIN R EA · D CA ' £, DETAIL · D Jll O RIE and the right upraclaYi ula region recei, eel 1200 r (·IOO x 3). Thi radia­ tion wa completed by ugu t 29, 1952. Clinical Gour e: At xamination on .\ ugu t 26, 195~, the chic! omplai nt wa extreme fatiguability and weakn s, m derate malai e and anorexia. H had gained four or five pound ince hi d i harge two momh previou l •. Ile al o complained of rather dull continuou pain in the ri ht boulder which had not re pond cl LO radiation therapy. Chemotherapy: .mino-anfol therapy \l a begun on Augu t 26, 1952. The initial cl ose was 20 mg. ·incl th rea fter 110 mg. wa g iv n da il y. Ile had tw bouts of nau ea and vomiting between .\uo-u t 29 and eptember 2, 1952. I le tated that pain in the rig-ht ant rior rib area wa better. but for three cla · he had noticed "pain of left boulder radiatino- clown oc a ionall to the finger tip with om re tri tion of motion." Thi~ wa ontrolled b1 co­ deine and a pirin, and on eptemb r 2 a ppeared a mor of a dull a he. The white ell co unt wa · beginning to fal l. On 'eptemb r 14, 19r2 the pa­ tient had le pain in the houlcler, but that afternoon devel peel an inten c pain at the ba e of the o iput in the mid-line. If he remained p I fenly till the pain wa not pre en c. The pain was le C\'ere next clay and gracluall it ub icl ed. he doc of amino-anfol wa increa eel 10 60 mg. dail y. On .,eptember 23 the patient stated he f It better than h had f r sev ral week . Ile did omplain of ome pain in the left kn ee recurring at periodic intcn·al which di app ared when the \\'Cather wa le damp. Ile cominuecl on 60 mg. of amino-anfol dail · until ~ O\'cmber , 1952 wh n the do~e " ·a rai eel tO 0 mg.

Further R adiation: X-ray therap 1 \l a · given to th right hip (25 0 J<.V., 500 r x 3); t the po terior right femur totalling 700 r; to the left hip po terior, 500 r, amerior 300 r; to the right houlder 300 r; LO the I ft h t po t rior 600 r; to the left femur, anterior and po terior 250 r ea h. Thi wa completed on November 21, 1952. Clinical Gour e: The patient continued to fe el improved during rov m­ bcr, but b i\" ovember r, 1952 wa pending mot of hi tim in bed. ( here had been an increa ed amount of nau. ea and yomiting incc the doe of anti­ folic had b en increa ed). At thi time the pati nt had double , i ion, om­ plained of pain in the region f the left orbit, pain in the right boulder, and a tend r area in the lower hemithorax. The amino-a nfol was di co ntin­ ued in late OYember becau e of leukopenia (bone marr ". ho"·ed no m galobla ts). TT e w:1 readmitLccl on l ecember 3. 19~2 . . \ t thi time he had pain in the right capular region where there wa a hard, firm, irrep;ular non-tender ma . The chi f complaint "·a ' t g nerali, cl feeling f wcakne and pain in the righ t shoulder xce1 t when lyin g on his back. Ile hacl cliplo­ pia, and rnocl rate anorex ia and bouts of pain at various meta tatic ·itC\ in the keleton, la ting one or t\\·o cla · . H e had lo t 3~ pound ince on ct. (Ili normal weight in 19~0 had been I 70 pound). · xamination 1 ,·cal cl a tumor in the left orbit and upper lid which indented and displaced the globe. Tran - fu ions \\·ere given to improve the anemia. Further R adiation: During December 1952 palliative x-ray therap · wa given to thi area and to the meta ta. in the D-\ 'I , fir t dor al \"Cl t bra and the left perietal reo-ion, al o the right lateral rib and the right knee and the right o cipital re!!ion. B · December 27, 19~2 the patient wa comp! tel) free of pain, the diplopia had ub ided even on extrem e lateral gaze, though there wa till ome blurring of vi ion in 0 .. The patient was di charg d on De-

73 SERIES B: TOXI~ T RE TED C ES, DETAILED Hl TORIES cember 27, J952. He was readmitted on March 2, 1953 for transfu sion. H e had lost 15 p uncls in the previous two month, but tated he had ,·ery liule pain. Hormone Thera/Jy: tilbesterol wa administered, but caused nausea and vomiting. Th refore es trogen and androgen were given intramu cularly. By March 31, 1953 the pati ent was th in , anem ic, almost cachetic in appearance. Ile had be ome a drug addict and he had a pathologi fracture of th e right lower femur. His condition rapidly deteriorated. Death occurred on pril 14, 1953, 2½ year after omel. Comment: In this case the fir t cour~e of toxin on istecl of only 16 intravenous inje tions give n in a ]6-day period co ncomitant with heavy radia­ tion. This ca e is of interest because of the difficulty in establishing the diagnosi . R eferences: 40.

C E 8: Neurobla torn a first found in the left femur (probable primary site, paravertebral region). The diagnosi wa only arrived at fol- 10\ring post mortem. Ea rlier opinion of di[[ rent pathologi L fol­ lowing biop y of th e les ion in the femur were reported as follows: Dr. H enry L. J affe ca ll ed it a malignant tumor but co uld not tate with ce rta inty whether the les ion wa Ewing's sarcoma or me­ La tatic neurobla Loma . H e adclecl: "The ca ncer ce ll s are omewhat compres eel in some places being rather rounded in other. There i some os ifi ation going on in connection with the presence of the tumor, but I do not think the bone formation is indigenous to the lesion." Dr. Fred VV. Stewart: "Not neurobl astoma; neither do I think it typi al Ewing' . ells too spindly and bone production it elf may be n oplastic. i\Iaybe thi i proof of the relation be­ tween Ewing· and osteogeni c arcoma." (#52-17 7) Previous History: G .G., J ew ish male, aged 2, of Flushing, 1ew York. The family bi Lory was negative for ca ncer, allergy, metabolic disea e or tubercu­ lo i . Th patient' aunt had a nervou breakdown at the age of 35 . The child wa born a[ter a normal pregnancy. I e had one ibling. aged 4½ years wh o wa li\'ing and well . H e weighed ix pound (ive ounce at birth. H e had no illnesse, injuries or operation prior to on et, whi h occurred in J anu­ ar 195 l at th e age o( L n month . t thi time pain and a limp in th e left leg developed which recurred at intervals of about a week and la ted several days at fir t. Thee attack graduall y recurred at longer imerval up to everal month apart, and la t cl only a few hour. There was no fever or other consti­ tutional ympt ms. The pain was relieved by taking th e child off his feet. The con ultant noted a ociation of periodic ymptoms with active teething. On J anuary 15, 1952 the con ultan t first noted tenclerne in the left hip. X-ra examination ,\·a reported a howing bony de truction and production im· lving al.mo t the en tire haft o( the left femur, mea uring l4 cm . in length and a o iated with parallel perio teal and endocortical erosion. Surge,)': An incisional biop y of th e le ion was per(orrnecl at Kew Ga r­ den General Ho pita] on J anuary 21, 1952 and reported by J affe and tewart as tatcd above. finical Course: The patient wa adm itted to i\ Jemorial H os pital on J anu­ ary 31 1952, a year after on et of left leg limp and pa in. Phys ica l examination on ad mi ion revealed a well-developed, well-nourished 22 month child in no apparent cli tre . 7-l: ERIE B: TOXI:'\ TRE.\TED C \ E . DE AILED HI ORIE

Concurre11t Infection: There ,ra bilaLeral ton ill ar adenopathy, the lym ­ phatic being otherwi e negati,·e. There ,rn inflammation of the na,al muco a, with abundant mu opurulent di charge, cru ting, partial na al ob truction, po L-na al cli charge; the pilla1 and phar) nx w re inflamed. The left anterior thigh wa wollen in th mid-portion. The temperatu1e ranged from 9 ° Lo I 00. 2°F. during th first we k. Antibiotic Therapy: Cr Li cillin wa gi,·en dail · for four da) for the arnte na oph;11-) ngiti (300,000 unit imramu cularl ) . R adiation and Conrnrrent Toxi11 Tlinapy (.'. K.I. XIXV): Between J anu­ ary 31 and February JS, 1952 x-ray thera py was gi, en LO the I ft f mur ( 1000 K.V,. , 2234 r anterior and 22 11 r po ·terior). H e L leraLed the tr atm nL well. P roph)la tic x-ray therapy ,rn · g i, en LO the che~L ( 1250 r ach, ant rior and po terior) ben,·een February l 9 and M ar h I, l 952. Inje tion of oley toxin were begun on Fcbruar) JO, 1952, JO cl;1) a[tcr the fir L x-ray Lreat­ mc:nt a nd " ·ere g iven during x-ray th rapy. he initial inLraveno 11 injc tion of 1/ 70 minim ca u ed a febrile rcanion or 102.l ° F., 110 chill and a pul e of J52. The injc tion were usually g iven dail y (14 in 17 day), increa ·ing the doe a follow: 1/60, 1/50, 1/30, 1/15, ½, I, I 2. 2, 2½, 3. 3½, ·1. 4½. Chill · oc- urred only after the la·t four inje Li on, la ting 15 to 40 minute. Febril reaction a\'eraged 100° to l03° F., (mi nimum I00.1 ° F .. maximum 105°F. which o curred when x-ray therapy was being g iven to the che L). Foll owing the final i njc ti on on February 26, I 952 the patien l de,clopecl cellu Ii ti in the upper arm at the iLe of the imravenou injection . Thi area wa tr ated with hoL oak . H e al o had an upper re pirator) infection aL thi time. Further Antibiotic Thera/J)': He wa given penicillin for a f " day . The in[lammation a bout the arm ub ided lowl y. Clinical Gour e: The child wa cli charged on i\farch 3, 19"2. Ile was een by Dr. Bracllc L . oley on ;\Jar h 17, 1952 who reported: "Ex cll em re ult thu far ...parent are deliglucd . .. boy act normally, run about and play 0 11 a fl cned leg " -i1h o ut difhrnlt)··· B ) .\ pril I l, 1952 u1 thigh hacl "a LLa ined compleLe normal ouLward appearance." The child wa lked, ran a bout and pla)Cd v ry a Live] · with virtually no re trinion. :X -ray examinati on that day bowed there had been a definitely fa,·orable re pon c LO 1ecent ombined x-ray and LOxin Lh erapy. Periodic phy ical and , -ra · examination in i\[a and early June howed no ev idence of disca e. Ilo" · vcr, on June 23, 1952 the child app a red LO limp a little and Lh e parents became pan icky and brought him for another check up which revealed no cvid nee of limp a nd n hange. Concurrent I nfection: hortl thereafLer he de,·eloped mea Jes, from whi h he promptly re O\'ered. Clinical Course: t examination on Jul 15, 1952 Lhe hild a ppeared in excellent health: "Lot~ of motion. 1un; around on leg, ha no limp, ha good appetite and look robu t." Phy ical examination reYealed slight ign of enlargement of the left femur, in keeping with the x-ra) examination " ·hich revealed no e\'idence of di ea e un Li I De ember ] I, 1952 when Coley noted tha t the veins in Lh c calp were prominenL Th child was readmiLLCd Lo Memorial Ho pital on D ecember 15, 1952. Ph · ical examinaLion on admi. ion revealed a well-nouri heel, ,,·ell developed 2 ¼ year old boy with prominenL calp vein and di Len ion of Lhe e on the forehead. H e wa in no di tre ancl did not appear ick. There had been no s,mpwm prior LO admi ion u h a headache, eme i , res Lless ness, per onality change or tendency to

75 SERIES B : TOXI 1 TREATED CASE , DETAILED H ISTORIES brui ing, al o no evidence of recurrence in the femur. X-ray examina ti on re­ vealed o. teolyti c metasta cs in the skull. R adiation.: X-ray therapy was gi en over the lesions in the left and right lateral ·kull between December 15, and 23, 1952 (250 J<..V. , 225 r each, or 11 25 r in air to ea h of the two pon s) . This was ca lculated as a tu mor doe of 1185 r. The child tolerated the treatment well , although the appetite was \'Cry poor. There appeared lo be no change resulting from the treatment. H e was di harged on December 21-, 1952. Further Infections: He remained well unti l the m iddle of February 1953 when he dev loped inUuenza with a fever of l01.5°F.-102.°F., fo llowed by in­ t sti n-d grippe and d iarrhea. The whole episode las ted a bout 2-1/2 weeks. Clinical Course: On February 20, 1953 th e child fell off a sofa landing sq uarely on his back on a con crete fl oor. For a week ther after he complained o[ pa in in th e buttock . X-ra exa mination of the pelvi s, femur a nd knees showed no fractures. Pain continued, but by M arch 17, 1953 it ·wa difficult to determ ine th e ite of pain, which was localized only to the left side. The child refu sed to it on a hard ch air or to lie or it on his left ide. H e al o cried a gTca t dea l and one co uld not move or touch him. H e was readm itted to Memorial Ho pital on March 17, 1953. He appeared to be irritable and acute­ ly ill with symptoms of increa eel intracr ani al pre ure. H e was dehydra ted, had a tiff neck and could not be moved without pain. As he did not void for about 24 hour , he wa ca th eterized. Thereafter a pina l tap wa made and howc

A 11 tibiolic Tliera /Jy: H c \\'as given Lcrramyc i n origin all y beca use catheter­ iLati on wa nece ary, and during the third week 0£ March beca u e of fever ( 102°F.). On :\ I arch 2 , I 953 th e hi Id complained of omc pain in the left lower jaw and examination revealed the left submaxillary nodes were pal­ pabl and tend er. H ot comprc c were appli ed and the lymphadenitis sub­ sided. On pril l , 1953 it was noted that metas tasis had developed in the rig- ht id e of the mandible. Further R adiation: X-ray therapy wa given to this area ( 00 r). On A pril 14 , 1953 the child deve loped paraplegia and x-ray examination revealed ollap c of the e on l lumbar vertebra. T hi area received 2560 r, followed by grad ual improvement and low return of motion of the extrcmeties . Ch emotherapy: One do e of -methoptherin and 6-MP \\'as given on April 15, 1953. No fu rther do e were give n for 10 day and then from April 25 through Ma 20, 1953 the child received 1. 25 mg. of -methoptherin dail y, 25 mg. of 6-MP daily and 25 mg. of P-16'1 daily. Fu rth er Radia tion and Chemotherapy: Du ri ng thi chemotherapy, on May 7, 1953, he wa no ted to have a well ing on the left sid e of the scalp, which wa treated by x-ray therapy on 7\,fa 30, 1953 (300 r) . On 7\Iay 27, 1953 cortisone \\'a tan ed, and 12.5 mg. wa given daily. On June 26, when seen in the linic, the patient co mplain d of interm iuent abdom in al pain of fo ur days duration. The co rti one and -methoptherin were di co ntinued temporarily. n Jul , 2, l 953 the corti one wa resumed (12.5 m g. daily). The child was

76 SERIES B: TOXIN T R EATED

readmitted to 1femorial H o p ita! for the fo u rth Lime on July 3, 195 3, com­ pla ining of epiga tri pain and anorexia of two week ' duration. h e lump on the left scalp had b een in cr as ing in ize a nd "over-night" two new mas e · a ppeared in the same area. Breath ounc.I s were d imini heel in the ri ght he. t. On July 7, 1953 A- methoptherin wa re urned (2.5 mg. dail y) and th doe of corti one wa increased to 50 mg. da il y. Further x-ray therapy wa g iven to the left po terior pa ri etal region from July 10 through .July 2 I, I 953, a tota 1 cl ose of 243 0 r. On July 23, 1953 it was noted that knee j rk were ab nt. On July 31, 1953 th e child spiked :1 rev r or l02°F. and was hanged from terra­ mycin to erythromycin. H e developed complete parapleg ia with cord bladder at a pproximately the wa it line level. X-ray examination on r\11 gu t l , 195 re­ vealed coll a pse of the second lumbar vertebra. Further x-ray th era py was g iven over the pine (D 11 to S 2) , 154 0 r tumor cl o ·e between Augu L 5 and 17, 195 3. On August 5, 1953 there was p itting edema of the extremities and the nex t cl ay there was hema turia, considered to be hemorrhagic cys ti ti , which was trea ted with ga ntrisin. A metas ta tic lesion appeared on th e le[t check on u­ gust 12, 195 0. The next clay the pa ti en t had trismu a nd x-ray thcrap wa given (750 r) to th e left ma ndible. On Augu t 17 , 1953 he bega n having intermittent d ys pnea. N ext cl ay a le ion wa noted allached to the ma nubrium sternae. che t x-ray on Augu L 21, 1953 bowed minimal pleu ral effu sion without parenchym al disea e. U rine cultured showed B. proteus mira bilis a nd hemolyti c cnterococcus, mos t en itive to chloromy etin. T h is drug was tarted. On Augu t 25, 1953 he was noted to ha\·e petechiae over th e abdomen. During the 1a t weeks th e child receiYecl t to teron , tran [u ion and adren alin. T h di ease progre se c! , ca using dca Lh on September l , 1953 after a gradua l a nd low course of progress ively evere ym ptomatology cl u e to the metas ta ti c tu­ mor in voh ·ement. Dea th occurred 18 months a fLer onse t. His weight at dea th was approxima tely 30 pound . Autop y revealed " ncu roblastoma, fir t found in left femur and meta ta izing to skull, manubrium, bod o( ternum, multiple rib , multiple vertebrae with oll ap e o( L 2, left mandible, right ilium. retro­ pleural and retroperitoneal regions, left upracl avicular and c. ophag al lymph no le , . ca lp, lungs, liver, right kidney, pleen, pancrea , dura ma ter, with pa raplegia secondary to cord compress ion a t level of D 3 a nd 4, a nd L 2. Pro bably prima ry site pa ravertebral region." There wa al ·o acu te bronch o­ pneumonia, pulmona1·y cong-e ti on and eel ma; bila t ral erosa nguinou pleural effu sion; fa tty infiltration o( Lh e liver; foca l acute congesti on of the rena l m ed­ ulla, bila teral; focal subrnucosal hemorrhages a nd calculi in the bladder; gen­ erali zed edema; x-ray necrosis of the kin over the upper lumbar vertebra; a nd a acral decubitus 6 cm. in diameter. Comment: This pa ti ent had only one course of 15 toxin inj cti ons fo l­ lowing antibiotic a nd x- ray thera py. Compare wiLh Case l in which tox in thera py alone was g ive n with interva ls o ( rest fo r two years. The case is of pecial interest due to the difficulty in es ta bli hing a correct diagno is until po tmortem. N ote also the extremely wide pread d isease at cl a th , whi h may have been lue to the repea ted x-ray Lhera py a nd to administra Li on of corti­ ·one. (67-69) R eferences: 44.

CA E 9: The deta il ed hi story of Lhi ca e was not ob ta inable.

77 SERIES B: TOXIN TREATED CASES, DETAILED HISTORIES

SUMMARY ,\ D CONCLUSIONS The incidence, symptoms, hi tology, differentia l diagnosis and therapy of neurobla toma ha\·e been reviewed. Factors which may favorably or deleteriously affect na tura l res ista nce to neoplas tic diseases, including neuroblas to ma have been di cussed. T he l 8 known cases of this tumor with concurrent in (ection, leu kocytosis, febril e or in(lamma tory episodes were presented in the fo rm of a table fo l­ lowed by complete histories for those wish ing to study them in detail. In some o( thee ca es the factors wh ich m·:1y be re po n ·ible fo r increased host resis­ ta nce are le s evident tlrn n others and may a lso in clude blood transfu sions and pro longed admini tra ti o n of Vitamin B-12. The only nine cases of neuro bla Lo ma who received bacterial toxin thera­ p y (Coley tox ins) were a lso presented in brief and deta il ed form. ltho ugh term ina l, with guadriplegia, the single case who received Coley toxins a lo ne recovered, a nd is a li ve in 197 0, 59 years after o nset. H e received 1ox ins with in tervals of rest f"or two years. This fam ous case suggests th e need for further clinica l tria l of microbial products such as the Coley toxins as a primary method of trea tment for neuroblas toma, thus avoiding the possible la te effect o[ radiation in children, such as dwarfin g or nephriti . The second toxin treated case might a lso be a li ve today hacl he not been subjected to a n explora to ry la parot0m y a nd pan ial excision o r the residua l ga ngli oneuroma 20 yea rs after recovery for a ymptoma ti c ca lcifica ti ons seen o n x- ray examination. The disease reactiva ted about a year later, ca using dea th 25 years a fter onset. Fa ctors a rr cting p rognos is in the other six cases were di cussed. The m ost important factors appea r to be the duration of toxin therapy and whether the injections were begun prior to or subsequent to radiation or chemotherapy.

7' BIBLIOGRAPHY 1. BECK, . ivI. & H owARD, P . J.: 1euroblas torn a. Review o[ the literature and report o[ a six year cure by roentgen therapy. A.M.A. mer. J. Di . Child. 82: 325-334. 195 1. 2. BoO IA N, M.: Prelimin ary ob ervations on the Lreatrn ent o[ neurobla toma with Vitamin B-1 2. 31 L Annual R eport of the British Empire Cancer Campaign. 1953 . pp. 174- 179. 3. BooIAN, M., \\ HITE, L. L. R . & JACO, N. T.: Neuroblastoma. general review. 32nd Atnnua l R eport o l the Briti h Empire Cancer Campaign. 1954, p. 195. 4. B RKY, E. L.: The production in the rabbit o[ h ypersen itive reactions to lens, rabbit muscle and low rag\ eed extracts by the action o [ taphylococcus toxins. J. Allergy. 5: 466-475. 1933-34 . 5. CHANDLER, J. J., STARK, D. B., ALLEN, C. V. & Fu:TC II ER, V/. S.: Treatment o[ cancer wi th ba terial toxin s. Arner. Surg. 31 : 4-:13-449. 1965. 6. COCHRAN, \ 1\1.: 1 eurobla Loma (sy rnpa the ticoblas torn a) in northern Ire­ land. A review over a ten year period. U l ·ter i\ L J. 82 : 82-98. 1963. 7. Co1-1EN, L.: l mmunity and res istance in clinical cancer. South African M. J. 30: 16 1-167. 1956. Cou:, D . R., DREYER, B., R o ssr-:LoT, L. M. &: TENDLER, M.D.: The radio­ protective a nd a nti-tumor effect o[ mixed bacterial toxins and anthramy­ ci n. Amer. J. R oentg., R adium Therapy e :\'t1clear i\Jedicin . 97: 997- 1002. 1966. 9. COLEY, vV. B.: The treatment of malignant in operable tumors with the mixed toxins of erysipelas a nd Baci llus prodigiosus, with a br ief report of 80 cases uccess[ull y Lr a ted with toxin from 1893- 19 14. Brussel ·, M. vV eis­ se nbruch, 1914. JO. COLEY, 'W. B.: OHice R ecords. 11. CUSHING, H . & \,Vo u 3AC I-I , S. B.: The transformation o[ a malignant para­ vertebral sy mpatheti cobla storna into a benign gang li oneurorna. · 111. J. Pa th. 3: 203-2 16. 1927. 12. DARG EO , , H. \ I\T.: Pro blems in the prognosis o[ neuroblastoma. Aim. J. R oent. R ael. Ther. & Nucl. Med. 83: 55 1-555. 1960. 13. D En RE, R ., l'HERJ\ffn"E, .J., U HR Y, P ., PARI. , R., et OEMIGIIEN, MLLE.: Tu­ m eur sy rnpathique embryonna ire chez un en(ant. Ann. cl' \nat. path. et cl 'Anat. norm. 15: 1-8. 1938. 14. Do n, H.P.: The roentgen a pect of sy mpathetic neurobla torna. J. A. M. 109: 11 88-1191. 1937. 15. EvER o , , T . C. & Cou:, \ V. H.: Spontaneo us regression of ca ncer: preli m­ inary report. Ann. Surg. JN: 366-383. I 956. 16. EvERS0N, T. C.: Spontaneous regression of ca ncer. Conn. Med. 22: 637- 643. 1958. 17. EvER ON, T. C. & Cou:, \ V. H.: Spontaneous regre sion of cancer. \IV. B. Saunders Company, Philadelphia and London, 1966. I 8. EYRE-BROOK , . L. & H i::wER, T. F.: pon taneou cl isa ppearance of neuro- blastom a with maturation to ganglioneu rorna . .J. Bone J o int Surg. (Brit.) 44-B: 886- 90. 1962. 19. FARBER, S.: eu roblastom a. Amer . .J. Di . Chil d r. 60: 749-751. 1940. 20. FA VET, .J., CAMPAGNE, J., CHAVY, . . , PI ET, G.: Guerison , regressions et remis i ns pontances de ca n ers. R evue du Prat. (Paris) JO: 2349-2384. 1960.

79 21. FEVRE, i\f., LAMY, i\I., i\[OG(,i ET BA DOIN, J.: Gucrison spontance d 'un yrnpathomc embryonnaire ;t foyer · superficicl multiples chez un nour- 1 ison. Arch. franc. de Pcdia trie. 1: 195- I 99. 193 22. FEVRE, ~r. · I--IL'c 1-.;,; 1;,; R . : :.\Iallormati on Tumorale et Tumeurs de J"Enfant. ;\J a on et Cic, Editcur. Pari . ]954. p. 23. 23. FoRSTl,R, .\. K .: ' tatistiche Iller u hungen i.iber den h emmenden Ein[lu von Biencng i(t auf En,tchung von I r b bi e lmkern. Leipzig Bienen Ztg. 57 : 101. 1942. 24. Fox, F., D 1\\'JO ON, J. c· T110.\IA , L. B. : :.\Iaturation of mpa theticoblastorna into gangl io neuroma. R eport of t,rn patielll with 20 a nd ,J6 year urvi als respectively. Cane.er. 12: I0 '- 11 6. 1959. 25. GABRI ELI, .E. R. · J Iou1CIU.N H.: Effect of a nti-hi ta mine on the reticu­ loi ndo theJia l y tern as demonstra ted by Lh e u ·e of radioactive hromium pho phatc. :\'ature. 16 ': 467--16 . 1951. 26. GABRI ELi, E. R. · At: K.\P , .\. A.: The effe t of whole body irradiation on the reticulo-e nd thc:lial ,y tem a d mon tratecl by th u e of radioactive c.hromium pho phate. Yal e J. .Biol. · M ed. 26: 159-169. 1953- 1954. 27. GLYNN, L. .E. · lloLBORROW E. J. ; The produ tion of complete antigens from poly a · haridc ha ptcne by trepto o i and oth r organi ms. J. P a th. · Ba t. 6-1: 775-7 3. 1952. 2 . GoLDR1;-;c, D. L .: .\"eurobla wma ) mpatheticum ,\·ith meta ta e ; report of a ca e with apparent recovery. J Ped ia tric. 3 : 231-234. 1951. 29. GR EE, FJELD, L. J. · II ELLI::Y, \\'. i\l.: The pectrum of n eurogenic tumors of the ympa theti c ncrv u ·y tcm: maturation and adrcnergic function. J. Nat. Cancer In L. ,5: 2 15-226. 1965. 30. lI ABER ' . L. · B E:-;;>; I:-.: GTo :-;, J. L.: .\faturati on of congenita l exLra-adrenal neu r bla torna . . \ rch. Path. 76: 12 1-125. 1963. 31. lIACl·R, .E. B. , BAILI-.Y, C. L., 11A:\IPERS, ;\I. D. · MERRILL, J. P.: ImmuniLy against Ehrlich a -c ites c:1 rcin oma produced by ba terial e ndotoxin ·. Proc. Tran planLaLi on ·o . 1: 124- 12". 1969. 32. H ELLER, J. J l. : R cacti \ a Lion o[ coni one-clepre eel reticulo-endothelial ys­ Lcm. F dc1aLion P roc. 13: 69. 1951. 33. I II::LLER, J. I I.: Effect o( corti o ne, holine a nd radiation upon the reticulo­ cndo th lial y L 111. FcdcraLion Pro . /-/: M arch 1955, #726. 34. 11 0LLCR FT, J. \ V. · S.\Irr11, \ \'. \ \'.: Endotoxin treatment a nd x-irradiation in mi c b aring Lran planted tumor. J. ~at. Cancer In t. 21: 311-330. 195 . 35. llORN TF11', . c· :\I LKF, G.: Kutan meta La ierendc ?\eurobla toma sym- pa thicum mit " ponta n" regr i\'ern Ver! u[. DcrmaLO logica. 120: 35-53. 1960. (a l o Z. I indcrklinik 83 : 40-83. 1959.) 36. JAN co M. : lli ta minc a a phy iolog ical a tivator of the re Li ulo-endo­ thelial · L m. :'\a ture. / 60: 227-22 . 19':17. 37. Jo11x TO:--, B. J. · ·o\',\LE ~.: Clini a l cffe t of oley' to xin II. even ar tudy. 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The following case has recently come to our attention. It should be added to the series of nine cases in Series B known to have received Coley Toxin therapy.

DIAGNOSIS: Congenital generalized neuroblastoma, confirmed by microscopic examination at the Children's Hospital of Akron, Ohio, following biopsies of two skin nodules: the pathologist reported "sheets and nests of plump or poly­ gonal neuroblastoma replacing dermal and subcutaneous con­ nective tissue and infiltrating adjacent fat . . . There was no evidence of neuroblast maturation into ganglion cells or of hemorrhage, necrosis and dystrophic calcification. Focal interstitial collections of lymphocytes and plasma cells were prominent. In many areas of the tumor, clumps and masses of degenerate and dying neuroblasts were found."

PREVIOUS HISTORY: L. C., female infant. With the exception of their first child, the family hi story was negative for tumors, neurofibromatosis, skin nodules or cafe au lait spots. (Abdominal x-rays of the entire family in 1969 re­ vealed the presence of a small focus of adrenal clacifica­ tion in the 15 year old sister . ) The patient was the fifth child of these parents. Their first child had also been born with neuroblastoma and had died following extensive radiation therapy at the age of 15 months in 1949 . The patient was born in November 1954, weighing 6 pounds, 9 ounces, after a full term pregnancy and uneventful delivery. At birth there were approximately 40 subcutaneous non-tender lumps all over her body, varying in size from 2 mm . to 3 mm.

SURGERY : Two of these lesion were biopsied.

CLINICAL COURSE: Because of the experience with their first child the parents refused treatment . During the next two months the skin lumps became larger and marked hepatomegaly developed. The child vomited constantly and had to be fed every hour in order to prevent dehydration. (She was not breast fed.) The parents then took her to the Cleveland Clinic in January 1955.

TOXIN THERAPY (Sloan-Kettering XIV}: Injections of Coley 2toxins were administered there. ( ·o details are available as to technique.)

CLI 'ICAL CORSE: Gross hematuria was noted at eight months of age. By 15 months she appeared to be doing very well.