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The Apparently Beneficial Effects of Concurrent Infections, Inflammation

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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.
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