THE 1lECHANTShT O F THE CANCER DEATH AWD

CANCER THE RELATION O F PERNTCIOUS hNEb4Th TO

JACKSON RTJAlR

Bland-Sutf on (1 ), in writ iiig 011 the parasitic theory of eaiiwr, stated that tlierc ~ r c many who arc thorouglily ac- (painted wi tli tlic clinical and pathological features of car- cinoma who feel strongly that this disease will ultimately come to lw clefiiicd as ;I “chroiiic infective disease due to a inici+o-parasit c wliicli selec

Opposed to the parasit io theory, a i d used as ail argument against it, is the well-(1st ~ ld i shcd fact tliat epitlicliomas map hc produccd by c*Iiemical means, as by repeated applications of coal-tar 1jrepan.atioiis t o the skin. In addition some years ago I’eyton Rous (2 ) WIS able to transmit a spiiicllc-crll sarcoma in cliic*kt.ns with ii (*ell-free filtrate. Gye’s ( 3 ) work has s c ~ v e d to call further attention to the fact that ccrtaiii types of cancer may be t riiiismitted by crll-free filtrates. Thcsc facts which seem to oppose the parasitic theory simply serve to confirm tliu tjcliclf that the iiormal cell map be iii-

flueiiced by many possiblc iiicit irig agents which cause i t to assume tlic c1iar:ictcr or qualitp of growth and divisioii typical of the (Jallcelb cell. Foi+ some years it lias beeii my privilege to Iiave studied

clinically many cases of 21 pathological condi t ion in cliildrcii aiicl adults wliicli appears to throw light upon some of tlw problems of cancer, with particular rcferciice to the mech- anism of the caiiccr death, mid also to point to ,a tlicory of the chtiology of e m c w itself mid to w e n suggest a mealis of cancer prevcntion. This clinical study began with tlie study of pyelitis in children. Tlic obscrvution was made that oiic of llic common symptoms of pyelitis in c~hilclrcii w a s a cle- grce of aiicmin, aiid tliut a similar anemia w~ also often

an epithelial cell.’’

142

THE MECHANISM O F T E E CANCER DEATH 143

present in adults with pyclitis. The observation was made concei*niiig palor of the skin, but was checked by blood cleter- miiiatioiis in a sufficient number to verify the prcscncc of an anemia in many of these cases. The outstanding disease fcat- nred by extreme anemia is pernicious anemia and a study of this disease showed that pyelitis was present in all the cases it has beeii my privilege to see. Ti1 il report soon to be pub- lished (18) I liave presented my findings aiid stated my belief as to the ct iology of the disclase a id the mechanism of tlie pro- duction of the anemia. Briefly summarized, the conclusions arc that the primary etiology of pernicious anenlia is Coca1 infection and the mcc~hanism of the production of the anemia is the con1 inued chronic destructioii of blood corpuscles in the uriiiary tract, as a result of urinary tract infection, hem- otogcnous in origin, and arising from focal infection. The frequent occurrence of a blood picture identical in certain cases of cancer of the stomach aiid pernicious ancmia was of interest cspecially as anemia is also present in other types of Callcel'.

With tlie idea of determining d i e t h e r tlie anemia in cancer might be due to a similar came as the anemia of pernicious anemia, a study was undertaken to t ry to either confirm tlie

The re- siilts were sucli as to strengthell my theory as to the common clause of the aiicmia in all three conditions and to give a n adequate explanation of the cwliexia in cancer, t o explain the mechaiiism of cancer dcath, and to offer an hypothesis as to the cause of cancer itself.

The records of cancer patients seen by myself in general practice were reviewed and in every case pus had been fonncl in the urine aiid with one exception all had become more caclicc>tic, more anemic, tended to run a higher elevatioii of temperature aiid had died in coma. The one exception, al- though losing some in weight, remaiiied fairly well nourished but died presnmably from metastases to the brain. Brief case histories of the esseiitial features of this small series of cases a re presented :

sion that such w t ~ s the case or to disprove it.

144 J A C K S O N BLAIR

('rise 1. S.(" . , tige 42. ('arci~iomrl of prostrate with metastasis to p ~ l v i s , vertebrae and ribs. Mother died of ctincer of breast. IIad been failing in health, and pains in back had bren growing

worse for past 8 moiiths. Progressive m m i a , emaciation and wealmess with moderate eleva-

tion of temperature until the development of a terminal pneumonia. ITrintl : Alb. F.T. OCC.

cpith. cell and w.b.c.

Many crowntd and carious teeth.

Iioatleci with grandi l r and liyalin casts.

('nsc' 2. Inoperable carcinoma of stomach. Tms of wt. and wcakn Mastoit1 operation 4 y 1)reviously. Extensive nodular mass i n

epig ast rium. IIad many crowned teeth and pyorrhea. 13tlcame progressively

anemic ant l rmaciated. 1Jrine: Alb + +. IIyalin and fine gran. casts.

('asc 3. M.B., age 58. Iteeurrent carcinoma of brmst. Gave history of frequency of urination every half hour for years.

wei~e extenrive and presumably there were

T.W., niale, ape 64.

fo r past year, with stomach troitble.

Sug. o Pus + +.

The metastases in this c extensions to the braiii.

Tlwrt. wiis loss of wt. but cachexia not niarked. lrrine: All) + + Pus f + f. ( 'ase 4 . cJ.M.l uge 5!1. ('arcinonlii of p:increas. ('onsultetl in(' eigli t montlis before his death o n account of weakness

a i i d inipottliicy (Iiatl just married for third time.) At this time therr wits a large llliihri in abdomen which proved to bc a carcinonia of the pancreiis. Twth \wre few, with crowns and bridgework antl one iibscess. Progressive course with intermittent fever (97.6' to 103.0" ) , increasing tinrmia and emaciation. Irrational and died i n coma.

Hloud: ITb 2.5 per ce11t. W.B.C. 11,500. Rbc. 2,976,000. lirinc : Alb. V.F.T. Pus +. Fine gran. casts.

C ' U S P 5 . Caricw of liver secondary to carcinoma of sigmoid.

N.Ii., female, age 44. Intrrval of

t h e e years between resection of sigmoici and final illness, tlien rail rapidly downward course with daily interriiittciit fever (96" to 102" )

THE MECHANISM O F THE CANCER DEATH 145

and marked emaciation. Towards the last, irratiorial and in coma. I was infornied by physician who had previously treated her that she l l i ld had attacks of cystitis for a t lcast 15 years.

Blood: IIb 60 per cent. W.B.C. 21,000. Rbc. 3,130,000. Much degeneration of red cells. ITrine : Alb. V.F.T.

Case 6. Carcinoma of tongue. Arthritis defnrmans. Chronic arthritis fo r 6 years. H a d serous

nasal discharge for inariy years. Numerous crowned teeth with epithelioma developing at sitc of ill fitting bridge. Emaciated, ir- rational, d i d in coma.

Poikiloeytosis, anosicytosis. Many epith. cells-numerous pus cells.

O.N., male, age 72.

Urine: hlb. +. (’ase 7 . Carcinoma developed in field of operation of cholecystectomy a t

Anemia

Epith. cells and few W.B.C. occ. hyalin cast.

Pus +. Few epith. cells and fine gran. casts.

E.F., female, age 47.

which time only eholeeystitis and cholelithiasis were found. and emaciation.

Urine: Alh. tracr.

(“USP 8. Malignant papilloma of ovary with recurrence. One year previously hat1 been operated for sinus infection.

J.Z., female, age 46.

Teeth only fair. Tonsils large. (’onsiderable improvement after operation with later typical tlownward course.

l lr ine: Alb. o. Pus + $+ + +. Tlicse cases, with tlie cxceptioii of Case 3, were typical ex-

amples of the cachexia present in canper and were typical of the usual cancer death. I n considering this as the usual type of canccr death other factors arc recognized in certain other cases of cancer, such as mechanical obstruction to the ali- mentary passages, pressure on vital orgaris, pain and mental depression leading to distaste of food, a limitation of the diet, and also the abnormal loss of hloocl in hemorrhayc and pro- teiiis in exudations. All of these latter factors may play their part in hastening death aiid in producing cachcxia. It is with cachexia and the usual cancer death that we a re concerned. Wilbs (4) in 1863 from a study of 2,000 antopsies a t Guy’s Hospital concluded that cancer as such docs not

Extreme emaciation.

146 JACKSON BLAIR

calisc cachexia. Ewing (5) claims Wlks ’ conclusion has stcadily gained support arid states that from careful clinical stncly, from observat ion at autospy arid finally from chemical iiivestigatioii that a peculiar toxiii scwetcd by cmcer cells and Ieadiiig to cachexia does riot exist.

A, febrile dcstructioii of proteins ocwirs very often, especi- ally in low grade forms of infection, aiid in liyperpyrexia a similar destruction of f a t f akcs place. Irrespective of I h e controversy as t o the selective action of fever o n fat or pro- tciii tlcstructioii it is t i clinical observation that the loss of weight arid emacaiat ioii is in proportion to the extent and dnra- tioii of the fever. Fever is present i n caricer patients during tlie course of the progress of emaciation, iiitcrmittcnt, abscn t a t times, but always prcsiiiit at intervals. In those cases wlicre fever i s higher tlie cachexia i s more marked. There a re probably other causes of elevation of temperature than infection, but fever is usually considered an evidence of in- fection. Lcucocytosis is usually coiisidercd an evidence of infection arid leucocytosis is usually present, except in those cases of caiiccr, wlicre the clinical picture and the blood pic- ture approaches that of pernicious anemia and there the leu- caopenia or ahscnce of lcucocytosis map he cxplaiiicd by the following reasoil, i.e. that while iiifcction jxeseiit in caiiccr is essentially c*hroiiic and is measured in years, it is more :icntci t 1i:ui that in pernicious anemia wlicre the time element is measured in (lccdos and the infection is milder. The lcs- ser ilcgrec of iiifcctioii and the smaller clcvation of temper- ature in periiici oils iriicmia supplies an explanation for thc lesser degrcc of loss of weight aiid the greater preservation of the fatty tissues.

I n Smilliics’ (6) analysis of 261 cases of caiicer of‘ the stomach he fouricl the average wliite count was 11,270; illat of 23 cases aiialyzed by Da Costa tlie wliite count averaged 8,100; that in 235 of Cabol’s cases the average was 10,600; aiicl lie also fo~uicl that four out of five of all eases had lcuco- caytcs between G,000 and 14,000. The laboratory findiiigs of one of my cases of pyelitis in aii adult male, presenting him-

THE MECHANISM O F THE CANCER DEATH 147

self with stomach difficulties, is instructive with regard to what might be expected in pyelitis : Urinalysis, only abnor- mality, pus in clumps ; X-ray of teeth, five apical abscesses ; blood, Hemoglobin 85 per cent, R h . 3,700,000, W.R.C. 9,400.

As evidenced by the fever, the leucocytosis, the delirium commonly present and tlie death in coma, we are led to con- clude that the mechanism of the death in cancer is by an in- toxication, caused by the infection of the upper urinary tract present in these caseb.

Further evidence of tlie presence of urinary tract iiifection in a series of cancer cases was presented by an analysis of 64 consecutive history charts of cases of carcinoma from tlie wards of the Lutheran Hospital. There were 17 cases of caiicer of the l ) rwst , 18 of tlie uterns, 3 of tlie stomach, 6 of the prostate, 9 of the coloii and 10 of otlier organs. Of 64 cases of c~axicc~r 60 were positive for tlie presence of p s in the urine and only 4 negative. The high percentage of posi- tive results are 110 doubt due to the ability of the well-trained laboratory technicians wlio made these examinations.

Wetzel, ( 7 ) who has had considerable cxpcrience with pye- litis in children states that one of the most scvcre cases of pyelitis which he has seen occurred in an adult who died and wliose autopsy showed a cancer of the pancrcas.

Certain experimental work in cancer while leading to other conclusions yet off ers coiisiderable support to the conclusions a t which I have arrived. With reference to the detailcd work of Maucl Slyc (8), which has no doubt established certain facts as to an hereditary factor in cancer, the charts of mice families which she pi*esents are very interesting with regard to other pathological conditions than cancer. I believe 1 have heard her state that mice a re subject to the same diseaso to which man is subjected. I n her twenty-first report, the in- cidence of uriiiarp infections and other infections in her can- cer families, is striking. In her 21st Report, Chart 5 there a re reported scveii cases of cancer, six cases of nephritis, acute aiid chronic, aiid thrcc deaths f rom unknown infection. I n Chart 6 there are iiiue cases of cancer, five cases of ne-

148 JACKSON BLAIR

phritis, m(l sis cases of niikiiown infectioii. In Chart 9, three of miicer, two of iiephritis. In Chart 10, four of cancer, one of fihroma, one of nephritis, two of unknown infection, one of ~)neiimonia, oiie of puerperal infectioii, one of intestinal infection. T n (’hart 1 3 , three cases of cancer, one of nephritis, one of pyelonephri t is, iwo of pulmonary infection. Cliart 1, eight cases of cancer, six of infections and five of nephritis, analyzed as 011e each of R right ’s disease, sub-acute ascending nephri t is, cliroiiic nephritis, sqpi i ra t i i ig nephritis and chronic nephritis with uriiiary calcnli. (’hart 4, six of can- cer, o i i ~ of aciite nephritis, one of urinary calculus, one of septicemia, aiid one of mcseiiteric abscess.

In ,Ilantl Slye’s 25th report relative to sporitancous Iliproicl tumors in mice the cases of urinary disease are still more striking. I11 Chart 3 there is one case of stireoma-Carcinoma of thyroid and six cases of chronic nephritis; (’hart 4, two cases of s;wcomr2-c;Zrcinoma thyroid and six cases of chronic nephritis : (’hart 5, two of sarcoma-carcinoma, oiic of carci- noma, aiid eight of clironic nephritis ; Chart 6, two of sarcoma- carciiioma, oiic’ of carcinoma and five of chronic nephritis ; Chart 7, one of carcinoma, and seven of elironic iiephritis. Wlietlici. tlic cases of cancer also liad iiepliritis is not stated.

of infection in mice ~11d how frcqnently the urinary tract is involrccl. I believe Rliss Rlye’s conclusion that “110 observa- tioiis w c ~ r made during the eighteen years of this work has ever been consistent with tlie germ theory of caiicer” to be i8c4ut ed by her figures given above. With another conclusion, bnt differing slightly in the interpretation of inherited susccp- tibility we are in agreement, i.e. that “there are apparently two ftictors nc~cessary for the production of canccr : first the inherited susceptibility (i.c. susceptible soil) and secoiid, ir- ritatioii or elironic stimulation o r trauma of the type fitted to produce it.”

With regard to heredity it may be of interest to report seven families uiider my care with three generations of each with pyelitis, or pyelocystitis. In one of these, a fourth gen-

r 7 llic figures a re of interest in showing the great prevalence

T H E MECHANISM O F TIIE CANCER DEATH 149

<>ration, the great grandmother is said to have died of cancer of the bladder, one daughter lias a chronic cystitis with chronic infected toiisils aiid a lipoma of back, her sister has pyelocystitis and has had a n ampiitation of the breast for carcinoma, and a. granddaughter and grcat grand-daughter both have pyelitis. Pyclitis is not inherited, hut the tendency may lie; the tendency, however, probably being in the in- herit;ince of a similar physical cliaracteristic such as cryptic tonsils, If infected tonsils causes pyelitis in one generation i t is quite lilaly that similar tonsils in the iiext generation may likewise caiise pyelitis.

There is plenty of clinical and experimental evidciice of tlie coirriection between focsal iiifection aiid disease of varioiis organs of the body remote from the site of the focus of in- fection. Billings (9) in 1912 reported the etiological relation of chronic focal iiifection to arthritis and nephritis. Grulee and Gaarde (10) in 1915 reported a series of cases of acute liemorrhagic iiephritis in cliildreii following an acute tonsil- itis mid showed that cultures from the blood, throat and nrine were identical. Rosenow, Aleisser aiid Rumpus (1 1, 12, 13, 14) of the Rlayo CXnic a i d others have established experi- mentally and cli iiically the relationship between dental infec- tion and various systemic diseases. They were able to pro- diic*e iiephritis experimentally by the devitalization and in- fection of teeth in dogs. Pyeloiiephritis was produced by them in similar manner.

Pediatric literature is replete with cases of pyelonephritis due to diseased tonsils aiid adenoids. Persoiially within the past year I have had under my care 33 cases of pyelitis in adults each one of whom showed X-ray evidence of infection about tlie teeth.

William Hunter (15), to whom we owe milch of oiir knoml- edge of oral sepsis, arid whose name is iiiseparably connected with tlic study of pernicious anemia, was insistent that the anemia was of an infectious nature and that oral sepsis was the etiological came. Recently Craver (16) stated a suspi- cion that the dental history was of coiisiderable importance in caircer.

150 JACIZSON BLAIR

Gyc (3) has ~vell stated the geiieral opinion that the malig- iiailt cell is one wliicli uiiclcr the influeiice of many possible exciting causes, has assumed a character or quality which enables it t o grow aiicl divide steadily and persistently be- yond the needs of tlie rest of the body. Ewirig ( 5 ) states that clinical experieiice strongly impresscs the importaiice of chem- ical and mechanical irritants and various disturbniicw of nutrition as the exciting cause of tumors. He has suggested that some hypeiylastic prowsses, owing their iiiceptioii to the influence of parasites, become at length established and pro- gress without the stimulus of the parasite aiid he emphasizes tlic fact tliat inflammatory hyperplastic: processes pass by iii- sciisiblc gradation into neoplastic growl h. One has oiily to examine, 01' read the report of a microscopic examination of, such tissues as those of oliroiiic mastitis and beginning cancer of the breast to have difficulty in deciding where inflammatory process ends and caiicer begins.

Ewiiig (5) has noted the difficulty in obtaining bacteria. free caiicer tissue. Nuzum has isolated an aiiacrobic COCCIIS oc- curring in pairs and chains from human and moim tumors. Rliimeiitlial 1ia.s f omicl polymorphic organisms which he be- lieved to be specific in cancer aiid asks whether the initial cause of caiicc~* might not be purely chemical, the parasite serviiig to set up a reaction analogous to the process cle- scribed by Erwin Smith in plant tumors. Burrows (17) at- tributes the cause of caiirer to the result of a local imhalnnce in the organism with a diminution of vitamin A a i d an iii- crease in vitamin R aiid states that various substances as X-ray, radium, aiiimal parasites or bacteria map increase tlie vitamin R and disturb tlie vascular supply to a part so that the vitamin A call not be supplied to it.

One of the primary results of trauma and clironic irrit a t' ion is the disturbance of the local vascular supply. It is only iiatural that bacteria coiistaritly circulating in the hlood stream from a chronic focus of iiifectioii would tend to lodge in such an impaired vascular system, there to actually set up a chronic inflammation, temporarily perhaps but con-

TEE MECHANISM O F THE CANCEE DEATH 151

stantly repeated and therefore chronic. Further work is necessary to decide the exact nature of the growth stimulus in cancer and this is in the province of the bio-physicist, the chemist, the biochemist, and the pathologist.

SUMMARY

A connection between anemia and pyelitis is noted and case reports of cancer cases seen in general practice are presented. An analysis of a series of hospital charts of cancer patients is presented, a large proportion of whom showed the presence of pus in the urine. The generally accepted beliefs as to the hematogenous origin of pyelitis from focal infection are noted and a portion of the literature of cancer is reviewed with particular relation to leucocytosis, febrile reaction, anemia and cachexia.

The similarity of many of the general symptoms of cancer and pyelitis is noted and an explanation offered for these sim- ilarities and for the manner and mechanism of the produc- tion of cancer cachexia and death.

CONCLUSIONS

1. It would appear that there is a relation existing between pyelitis, pernicious anemia and cancer by reason of an ap- parent common origin and by reason of their possible co- action in the same individual.

2. It seems evident that the usual mechanism of death in cancer, not due to starvation or hemorrhage or pressure on vital organs, is by the toxemia and drain of urinary tract infection.

3. As it appears evident that urinary tract infection is com- monly present in cancer, and as it is my belief that this uri- nary tract infection is hematogenous in origin it would seem n reasonable hypothesis that other tissues in the body would be subjected to the lodgment of micro-organisms in them by way of the blood and that this bombardment of traumatized or irritated tissues by hematogenous infection, from a chronic

11

152 JAUKSON BLAIR

focus of low grade infection, be indirectly the cause of cancer. It may well be that the actual energizing factor in the con- tinued growth of the cells be chemical in nature and that it be partially influenced by certain toxins given off by the chronic focus of infection, also by the lessened alkalinity of the blood in this condition, and also by chemical substances set free by the destruction of the blood born micro-organisms at the site of the cancer, this chemical substance either being derived from the destroyed bacteria or from the body of the leucocyte or macrophage that may be destroyed while de- stroying the micro-organism. 4. From review of the literature and especially from ex-

perience with focal infection it seems evident that in all cases of a chronic focus of infection such as abscessed teeth, pyor- rhea, diseased tonsils and adenoids, chronic sinusitis, etc., that a secondary hematogenous infection is set up in the urinary tract, and therefore, that pyuria of any degree of chronicity, recurring or failing to respond to treatment, is a strong indication of a chronic focus of infection outside the urinary tract.

5. Dependant upon acceptance of the foregoing conclusions, the prophylaxis and prevention of cancer embraces the dis- covery of urinary tract infection and the search for, discovery and removal of chronic foci of infection.

REFERENCES

1. BLAND-SUTTON, SIR JOHN: Tumors Innocent and Malignant. Wsel l &

2. Rows, PEYTON: J.A.M.A., 1910, lv, 1805; 1911, lvi, 198, 741. 3. GYE, W. E.: The Cancer Problem. Brit. Med. Jour., 1926, 11, 665. 4. WILKS: Guy’s Hospital Report, 1864, 4. 5. EWING, JAS.: Neoplastic Diseases, W. B. Saunders Co., 1922. 6. SMITHIES, FRANK: Cancer of the Stomach. 7. WETZICG, N. C.: Personal communication. 8. SLYE, MAUD: Borne Observations in the Nature of Cancer. J. Cancer Res.,

1927, xi, 135. IDEM: Inheritance Behavior of Cancer, 21et Report. J. Cancer Reg,, 1926,

IDEM: The Relation of Heredity to Spontaneous Thyroid Tumors in Mice.

Co. Ltd., 1917, p. 272.

W. B. Saundera Go., 1916.

x, 15.

J. Cancer Res., March 1927, xi, 54.

THE MECHANISM O F T H E CANCER DEATH 153

9. BILLINQS, F.: Chronic Focal Infections and Their Etiological Relations to Arthritis and Nephritis, Arch. Int. Med., 1912, ix, 484.

10. GRULEE, C. G., AND GAARDE, F. W.: Involvement of the Urinary Tract as a Result of Focal Infection in Children, J. A. M. A., 1915, Ixv, 312.

11. BUMPUS, €1. C., AND MEISSER, J. G . : Focal Infection and Selective Local- ization of Streptococci in Pyelonephritis. Study I. Arch. Int. Med., 1927, xxvii, 326. Foci of Infection in Cases of Pyelonephritis. Study 11, J. A. M. A,, 1921, lxxvii, 1475.

12. MEISSER, J. G., AND BUMPUS, H. C . : Focal Infections in Relation to Sub- mucous Ulcer of the Bladder and to Cystitis.

13. ROSENOW, E.C.: The Etiology of Acute Rheumatism, Articular and Mus- cular, J. Infect. Dis., 1914, xiv, 61. The Pathogenesis of Focal Infection, J. A. D. A., 1918, v, 113. Focal Infection with Special Reference to Oral Sepsis, J. Dent. a s . , 1919, i, 205.

14. ROSENOW, E. C. AND MEISSER, J. G.: Effective Localization of Bacteria Fol- lowing Various Methods of Inoculation, and the production of Nephritis by Devitalization and Infection of Teeth in Dogs. Jour. Lab. and Clin. Med., 1922, vii, 12.

15. HUNTER, WM.: The Pathology of Pernicious Anemia. Brit. Med. Jour. 1896: I, 320. The Infectious Nature and Etiology of Pernicious Anemia. Lancet.

1903; I, 283. Severest Anemias. Brit. Med. Jour., 1922, I, 421. 16. CRAVER, L. F.: Medical problems in the diagnosis and treatment of Cancer.

17. B-ws, MONTROSE L.: Nature of the Growth Stimulus in Cancer. J.

18. BLAIR, JACKSON: The Nature of Pernicious Anemia and the Underlying

J. Urol., 1921, vi, 285.

Am. J. Med. Sci. 1928, clxxvi, 679.

Cancer %s., 1926, x, 239.

Basis of its Production. Med. Jour. and Record, 1929.