No. 3511.

DECEMBER 13, 1890.

LectureON

KOCH’S TREATMENT OF TUBERCULOSIS.Delivered at King’s College Hospital, December 3rd, 1890,

BY SIR JOSEPH LISTER, BART., F.R.S.,PROFESSOR OF CLINICAL SURGERY IN KING’S COLLEGE.

GENTLEMEN,-Having just returned from a visit of a

few days to Berlin, where I have had the opportunity ofwitnessing Koch’s treatment of tuberculosis, I will relateto yon some of my impressions regarding it. I need notmow describe the method of procedure further than to saythat it consists in the injection of a few drops of a dilutionof Koch’s fluid into the subcutaneous tissue, the part usuallyselected being the back between the scapulas or the lumbarregion. The effects of this treatment upon tubercular,disease are simply astounding. Take, for example, theoase in which its results can be most readily observed, inconsequence of the superficial position of the affected part,upus of the face. I saw in Berlin a patient with extensivelupus of the cheek, in whom an injection such as I have de-scribed had been performed two days previously. The’cheek was enormously swollen and red, and the affectedpart of the skin covered with crusts of dried serum whichbad exuded as the result of the intense inflammationthat had taken place. Meanwhile, no inflammationlhad been produced in any other part of the body.It is only the part affected with tubercle that is in theslightest degree influenced. Similar inflammatory effectsare produced in other tubercular affections, wherever they’may be situated. Thus in strumous glands of the neck,:swelling of the glands, with redness of the skin over them,and pain, follow the injection. In gelatinous degeneration,of the synovial membrane of the knee the same thing occurs.Again, in tubercular disease of the larynx, where also wehave the opportunity of seeing what takes place, corre-

sponding inflammatory changes are observed. But if thepatient is affected with any disease other than tuberculosis,such as cancer or syphilis’, no more effect is produced than’on a healthy person. Tubercular tissue only is affected bythe treatment. Meanwhile the effects on the system gene-TaUy are scarcely less striking than the local ones. An injec-tion which in a healthy person would produce no symptomswhatever is, in a tubercular subject, followed after a few’hours by a more or less severe, though transient, feverishattack, characterised usually by pains in the limbs, shiver-ing, prostration, nausea, and perhaps vomiting, while the I’temperature undergoes a considerable rise, it may be- even to 105° or 106° F. The quantity of the materialwhich produces these effects is extremely small. One- Ithousandth of a gramme of the fluid is the usual dose 1for the first injection in a case of phthisis. Now, Dr. Koch .’informed me that the undiluted fluid contains probably 1- only about a thousandth part of the really active in- 1.gredient. If, therefore, one-thousandth of a gramme of (

the fluid is employed, only a millionth of a gramme of the iactive substance is used ; yet this almost inconceivably fminute quantity, diffused throughout the circulation of 1the human body, gives rise to these remarkable changes. t

But no such results occur in persons affected with dis- E’orders other than tubercular, such as cancer or syphilis. EA precisely similar train of febrile symptoms may, indeed, <

’be induced in persons who are not affected with tubercle by ittsiag a sufficiently large dose of the fluid ; but for this i(purpose about a tenth of a gramme is required, or a s

hundred times the quantity that exists in the first injection t=in a case of phthisis. Thus in its general, as well as in itsqocal effects, this substance picks out and renders manifest gtubercular disorders as contrasted with other conditions. c

It thus comes to have the highest value for diagnostic a

purposes. A case occurred lately in Berlin, in which there a

was a doubt whether an affection of the larynx was vsyphilitic or tubercular; an injection with the fluid cleared gup the diagnosis at once in favour of the latter hypothesis. v

The substance seems to be wonderfully searching in its s

effects upon tubercle. In a house which I visited, a young dmedical man had an injection performed upon him as a 11matter of experiment, not having the slightest suspicion o’?t.T- oriv

that he was the subject of tubercle. A violent feverishreaction followed, which led to a careful examination by a

physician, and this revealed a slight but unmistakabledisease of the apex of one of the lungs. A similar resultoccurred in the case of a lady with phthisis, who hadformerly been under treatment elsewhere for a smalltubercular ulcer of the larynx in the inter-arytenoid fold ofmucous membrane. This ulcer had been for six monthscompletely healed after scraping and the application of lacticacid ; but after injection with Koch’s fluid a red granulationmade its appearance, projecting from under the left vocalcord, showing that tubercular disease was lurking where ithad not previously been suspected to exist. I also sawcases where tubercular joints had been excised severalmonths before, and all had appeared perfectly sound ; butinjection being practised on account of fresh tubercle else-where, the scar and surrounding parts became red, swollen,and painful, whereas scars of other kinds are absolutelyuntouched by the treatment. This would appear to indi-cate that some remnant of tubercular affection was presentin the seat of excision, although no other means at our dis-posal would have indicated its existence.But while Koch’s fluid has this searching diagnostic

value, there can be no doubt that it has also a powerfultherapeutic or curative influence. In lupus of the face, forexample, which may have long obstinately resisted othermeans of treatment, the crusts that form on the affectedpart as the result of the injections fall off in due time,leaving a more or less completely sound scar. This hasbeen known to result from a single injection, although morefrequently a repetition on several occasions is required.

In tubercular disease of the synovial membrane of theknee-joint the swelling caused by the injection soon sub-sides, and leaves the part smaller than before. The samething occurs after each injection, and though I had not theopportunity of seeing any cases of this kind in which acompletely natural state of things had been brought about,I was informed that such had been observed. I also learnedon trustworthy authority that patients in the early stage ofphthisis had under the treatment lost all their symptoms.The pumlentsputa, after diminishing in amount, had becomemucous in character, at the same time losing the tuberclebacilli, and had finally ceased entirely. Nigh t sweats haddisappeared, progressive lossof weight had given place to gainof flesh, while the physical signs ot the disease had vanished.But, it may be asked, how far are these effects

likely to be permanent, and what limits are to beanticipated to the curative agency of the method? Inseeking for an answer to these questions let us returnto the case of lupus of the face. It is found that someparts of the diseased tissue lose their vitality altogetherunder the violence of the local action, and are dis-charged as sloughs. There are other situations wherenecrotic portions may be so disposed of. I saw a patientwho had coughed up from his larynx a considerable pieceof necrosed tissue; and dead portions of lung substancemay be expelled with the sputa. But there are manysituations in which parts deprived of their vitality bythe remedy cannot be thus discharged externally, and Ihave seen it argued in print and heard it maintained inconversation that it is impossible under such circumstancesfor the dead portions of tissue to be got rid of. To you,gentlemen, such an idea would probably hardly occur. I&uacute;is now many years since I observed that dead portions oftissue, if preserved from septic agency, are not necessarilyseparated en masse from the living body, but are gradu-ally absorbed. This it was that led me to employ thecatgut ligature, which, though composed of dead tissue,is eliminated by absorption. The tissue of tubercular partsis not irritating in ttie sense in which a piece of putridslough is irritating. It would seem that the tubercle bacilligive rise to the production of some poisonous substancewhich modifies the nutrition of the parts in which theygrow ; but the tubercular tissue which arises from thiscause is not incapable of absorption. This we know from

ample experience. Thus in the ordinary strumous form ofantero-posterior curvature of the spine the bodies of thevertebrw have become so softened under the influence of thegrowing tubercle bacilli that they have yielded beneath theweight of the upper parts of the body. But if a patient withsuch an affection is brought under our care before abscess hasleveloped, even although the curvature is already stronglypronounced, we have only to enforce the strict maintenance)f the recumbent posture, so as to place the affected part at

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rest, giving at the same time good nourishment with suitabletonics, in order to ensure a spontaneous cure. The tuber-cular tissue and its contained bacilli alike disappear. Andthere is no reason a priori for supposing that the death ofany portion of tubercular tissue through the agency ofKoch’s fluid would render it unfitted for absorption. Hencethis theoretical argument against the possible eflicacyof the treatment falls to the ground. As a matterof fact it is completely refuted by experience. In thoseportions of a lupus patch where there is no actual sloughingas a result of the injections, but only inflammatory swell-ing, the tubercular tissue gradually disappears, althoughthere can be no doubt that necrotic portions are scatteredthrough its substance. Similarly in laryngeal disease whereno ulcers are present, but merely tubercular infiltration ofthe affected structures, the swelling has been observed tosubside steadily under repeated injections without theoccurrence of either sloughing or ulceration.’While the tubercular tissue is got rid of by this treatment,

it appears to be clearly established that the tubercle bacilliare not killed by it. It does not, however, at all followthat the tubercular disease may not be cured, although thebacilli are not directly affected. If the special diseasedtissue which they inhabit is eliminated, the bacilli will beturned adrift among the healthy tissues in the vicinity, andmay be quite unable to maintain their ground there. In a

public hospital like this we are doubtless all of us frequentlytaking tubercle bacilli into our bodies; y et even in those whoare hereditarily predisposed to tubf-rele, the healthy tissueswage successful war against the microbes unless some acci-dental circumstance gives them an unusually favourablenidus for their development. It is the living tuberculartissue on which Koch’s remedy directly operates; yet thebacilli are affected indirectly. But what shall we say ofcaseous masses and sequestra in which tubercle bacilliare lodged ? Koch’s fluid cannot touch such bacilli, directlyor indirectly, and the necrotic masses may remain assources of future infection, like potent inoculations of atubercle culture. In many cases, no doubt, we may com-bine surgical procedure with Koch’s treatment, and operate,we may hope, with greater success than heretofore ; becausewhile we as surgeons clear out the dead infecting masses,Koch’s injections will cure the surrounding living tubercle.But there are, I need hardly say, situations where thesurgeon’s knife cannot penetrate; and when extensivecaseation or necrosis affects parts thus inaccessible, andwhere spontaneous expulsion outwards is impossible, Koch’streatment in its present form affords little prospect of cure.

- Perpetual fresh infections might, indeed, be combated byoften-repeated injections. But as the absorption of exten-sive necrotic debris must be at the best a most tediousprocess, the treatment would, under such circumstances,have to be indefinitely protracted. What we here wantis immunity from tubercle infection. If we could gainthat; if, while the existing tubercular tissue was destroyed,the healthy tissues round about were rendered incapable ofaffording growth to the bacilli, or, rather, capable ofresisting their development, the caseous or necrotic masseswith their bacilli in them would remain harmless as sourcesof further infection, and the tubercular disease would bedefinitively cured. That is what we want in order to makethis treatment perfect. Now, Koch himself has thrownout, in a footnote to his paper published in the DeutscheMedicinische Wochenschrift of Nov. 13th, the possibilitythat immunity may result in consequence of the treatment.Hitherto, however, it does not seem to have been attained.We read of cases-in TIlE LANCET of last week there is onereported-where, lupus having been apparently cured by acourse of injections, a recurrence had taken place. We canwell understand that if immunity has not been established,some necrotic piece remaining unabsorbed with its livingbacilli may start the disease afresh.The immunity of the whole system, which is so desirable,

does not therefore seem as yet to have been attained. Inthe concluding passages of Koch’s address on Bacteriologyat the International Medical Congress, he revealed the factwhich astonished the world, that he had succeeded in find-ing a substance which, when injected into tubercularguinea-pigs, cured them. Before mentioning this wonderfulcurative effect, however, he stated that the substance inquestion produced immunity of these highly susceptibleanimals against inoculation of tubercle.The immunity, gentlemen, seemed at the time a less

1 Vide Lublinsk : Deutsche Med. Wochenschrift, Nov. 27th, 1890.

striking thing than the cure, because ib wa only in harmonywith what we had already known in the case of diseases suchas anthrax and chicken cholera as the result of Pasteur’s"vaccinations." But the immunity is that which we nowlong for. It has not been attained in man as it has in theguinea-pig. Why should there be this difference betweenthe guinea pig and man as regards immunity? Itstrikes me that it may perhaps be due to the fact that theguinea-pig is capable of taking much larger doses of Koch’sfluid without bad effects. In a healthy guinea-pig 2ce.-that is to say, practically, 2 grammes-of Koch’s fluidundiluted produce no effect in the way of general reaction,whereas in a healthy man 0’2ce., just one-tenth of thequantity, would probably cause serious febrile disturbsance. koch, having experimented upon guinea-pigs, triedlike a hero the effect of an injection upon himself. Heemployed 0’25 cc., which, as we have seen, would have pro-duced in a guinea-pig no general disturbance at all, andthe results in him were serious, and, indeed, alarmingA guinea-pig, then, will take fully ten times as large iidose as a man to produce the same effect upon the generalsystem. But if we consider what the weight of the guinea-pig’s body is as compaied with that of a man, we find thatthe guinea-pig requires, weight for weight, at least 150()times as much of the fluid to produce any effect upon th&;general system. And it seems to me very likely thatthe immunity in the guinea-pig results from the corn"paratively large dose of the fluid which it receives.If this be so, it might perhaps be possible to produce-immunity in man also, if we could sufficiently increase the,dose of the remedy. Now it is a remarkable circumstancewith regard to the injections in tubercular patients that,beginning with a small dose, one-thousandth of a gramme itmay be, producing considerable fever, the fever having sub-sided, twice as much may perhaps be injected next daywithout causing as much fever as resulted from the-first injection, and in the course of two or three days a con-siderably larger quantity may be used without producingany general effect whatever. It has been known that,after three weeks of the treatment, 500 times the originaldose has been borne. How is this to be explained? Thereseem to be two conceivable explanations. One is thatthere may be an acquired tolerance of the remedy, thesystem becoming accustomed to it, as it does to morphia orto arsenic. The other is that the fever is caused, in part atleast, by the inflammation of the tubercular tissue inducedby the remedy : and that as the tubercular tissue is progressively eliminated, there is less and less tissue to beinflamed, and therefore less fever. I confess I cannot thinkthat the latter is the true explanation. It seems to me -

inconceivable that, in a patient with a considerable massof tubercular disease in the lungs, the tubercular tissue canbe reduced by one-half in the course of twenty-four hour%Yet this it seems necessary to assume in accordance withthe hypothesis. It is also a significant fact that the degree-of fever caused by the first injection is by no means strictlyproportioned to the amount of tubercular disease present inthe patient. It may be said, indeed, that we have no analogyfor such rapid accommodation of the system to such a powerfulremedy. But the principle of acquired tolerance is familiarto us, while the remedy is of a totally novel character.Acquired tolerance, then, seems to me to be by far the morelikely explanation. If this be the true state of the case, it,seems to point to the possibility that the tolerance might becarried still further, and brought up to a considerably higherdegree than obtains in the healthy subject. We have seenthat the fever which is induced in tubercular patientsby Koch’s remedy is identically similar to that which iscaused in healthy persons by larger doses. As regards thefever, unlike what occurs in the local phenomena, the

. tubercular patient differs from the healthy in degree, not inkind. It seems, therefore, a priori not improbable thatincreased tolerance might be induced in the healthy person

i also, and that in the tubercular, if instead of stopping shortat the dose ordinarily borne by the healthy, the quantity

j were pushed steadily further and further, a degree oftolerance might be attained which might be attended with

. immunity. If this has not been already attempted, it,l seems to me worthy of trial.l But there is another line of inquiry from which I csumot?i help hoping for good results. Through Dr. Koch’s great

2 It would appear from recent publications that eases now and thenoccur in which little or no fever is produced by the ordinary injections,in spite of the presence of a considerable amount of tubercular disease.Vide Deutsche Medicinische Wochenschrift, Dec. 4th, 1890, p. 1134.

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kindness I had the opportunity of penetrating into thearcana of the Hygienic Institute of Berlin and seeingmost beautiful researches being carried on in that in-stitution, of which Koch is the inspiring genius. Isaw things which, while they excited my admiration,made me also feel ashamed that we in this country,from one circumstance or another, are so greatlybehind our German brethren. The researches to which Idesire specially to refer are still in progress, and fresh factsare accumulating day by day. As they have not yet beenpublished, I am not at liberty to mention details, but therecan be no harm in my saying thus much, that I saw, in thecase of two of the most virulent infective diseases to whichman is liable, the course of the otherwise deadly disease cutshort in the animals on which the experiments were per.formed by the injection of a small quantity of a materialperfectly constant in character, an inorganic chemical sub-stance as easily obtained as any article in the materia medica.And not only so, but by means of the same substancethese animals were rendered incapable of taking the-disease under the most potent inoculations ; perfectimmunity was conferred upon them. I suspect thatbefore many weeks have passed the world will bestartled by the disclosure of these facts. If they I<can be applied to man-though our experience of the Idifferent behaviour of Koch’s Huid in guinea-pigs andun the human subject makes this a matter of uncertaintyuntil tested by experiment-but if they can be applied toman, the world will be astonished, and the beneficence ofthese researches will be recognised on every hand. At thepresent time Koch is engaged in the earnest endea-vour to produce his remedy for tubercle by some processwhich could be divulged without the risk of the publicbeing supplied either with material useless from its inert-ness, or, on the other hand, with deadly poisons. Koch, Ibelieve, would not have published his method at all, had itnot been for great pressure brought to bear upon him, untiltle could have produced it in a form capable of being re-vealed in every detail. It is nothing but the fear that, bypublishing now the precise mode of preparing this material,he might do immense harm instead of good that preventshim from making it known. And I must say that thecarping against Koch on account of what is spokenof as a "secret remedy can only proceed from absoluteignorance of the beautiful character of the man. But if itshould so happen that, as with the other diseases to whicht[ have referred, so with tubercle, complete immunity shouldbe obtained by means of some inorganic chemical substancewhich anyone can prepare, then would be achieved the com-plete triumph of the treatment of tuberculosis. And, forrny part, I rejoice that we are permitted to look forwardwith hope to that glorious consummation.

ABSTRACT OF AN

AddressON

THE CHARACTERISTIC ORGANISMOF CANCER.

Read before the Pathological Society of London on Dec. 2nd,and the Medico-Chirurgical Society of Edinburgh

on Dec. 3rd, 1890,BY WILLIAM RUSSELL, M.D., F.R.C.P.E,

LECTURER ON PATHOLOGY IN THE SCHOOL OF MEDICINE, AND PATHO-LOGIST TO THE ROYAL INFIRMARY, EDINBURGH.

DR. RUSSELL stated he had been occupied for some yearsin tracing the mode of growth of cancer in different organs.By this study he hoped to map out the steps of the process,and by learning the manner of its growth to perhaps obtain.an insight into the factors, determining the departure ofthe tissues from their normal behaviour and arrange-ments. He bad found appearances which lie could not>fit into modes of cell growth and nuclear proliferation,and these had so puzzled him in one case that he asked hispathological assistant, Mr. W. F. Robertson, to experiment on’7t with every possible combination of stains with a view tothe possible differentiation of some of these structures.His attempts were soon successful by the following method:A. Saturated solution of fuchsine in a 2 per cent. carbolicacid in water, 2. 1 per cent. solution of iodine green

(Griiber’s) in a 2 per cent. carbolic acid in water. Placesection in water. Then stain in fuchsine for ten minutesor longer; wash for a few minutes in water. Then wash forhalf a minute in absolute alcohol. From this put thesection into the solution of iodine green, and allow it toremain well spread out for five minutes. From this rapidlydehydrate in absolute alcohol, pass through oil of cloves,and mount in balsam. By this method it was found thatcertain structures stained a brilliant purplish-red, while thetissues stained green. Similar bodies were found in anumber of cancers then examined, and these, for laboratorypurposes, were called " fuchsine bodies."With this discovery all kinds of possible errors suggested

themselves. That they were not accidental impurities inmaterial, bottles, or stains was shown by the fact thattissues from the same bottles and cut at the same time gaveno indication of this. That they were not the nuclei oftissue cells in exaggerated reproductive activity was testedby the cells in organising inflammation of serous membranesnot giving the reaction, nor the cells in tubercle, in typhoidlesion, in inflammatory affections, or in the organs of anembryo. That they were not globes of some degenerativesubstance was proved by the examination of a greatvariety of tissues showing different varieties of degenera-tion. Further, they were not present in the sarcomata,nor in simple tumours, such as fibromata, papillomata,myomata, &c., nor in venereal warts and condylomata, nor inprimary syphilitic sores. Sections of a tumour labelledadenoma of the mamma, and rich in adenomatousstructures, and a gumma of the dura mater showed the

bodies, but of the history of these cases he was ignorant.Another syphilitic case which had defied treatment, andin which there was extensive destructive lesion of thefauces and larynx and the bones of the vertebra behindthe fauces, showed a few fuchsine bodies in sections ofthe larynx. Altogether tissues had been examined fromfifty to sixty different cases selected with the purposeof subjecting the positive observations to the severestpossible tests. The result was that fuchsine bodies werefound in one case of chronic ulcer of the leg, one of tuber-cular disease of a joint with old sinuses, one of phenome-nally severe, destructive, and intractable syphilitic lesion;and in two other cases, of which he had no record, one acase of mammary adenoma, and one a gummatous tumourof the meninges. He indicated possible explanations ofthese, and that they could not be regarded as sufficient tooverthrow the other evidence.Turning to the positive side of the question, forty-five

cases of cancer had been examined, which includedmalignant epithelial growths of various structure, as

epitheliomas of the lips and face, rodent ulcer, scirrhus ofthe mamma, both primary and recurrent; malignantadenoma of cervical glands, cancers of the stomach, liver,spleen, abdominal glands, supra-renal capsules, uterus, andovaries. The pathological position of one of these wasstill uncertain; another was represented by sections dated1885; in these two no fuchsine bodies were found, but inthe remaining forty-three they were present. In individualsections they varied greatly in number, and it was notedthat they occurred in special abundance in foci. Theymight be present in the small-celled infiltration at themargin of the cancer, amongst or in the epithelial cells, inthe stroma, or in the lymphatics. As a rule, they occurredin clusters or groups of two, ten, twenty, or more, and theyalmost always showed a clear space round them. In shapethey were perfectly round. The commonest size was 4c,but chey might be much smaller or larger. Examined bydaylight they appeared homogeneous and structureless.As there seemed to be no escape from regarding these

structures as special organisms, which--so far at least ashis pathological material was concerned-were practicallyconfined to cancer, the question was, Were they animalor vegetable, and what was their mode of growth andreproduction ? To answer this question it was neces-

sary to consider the work which had been done,especially on the Continent, in the study of cancer.

He then referred briefly and in detail to the various paperswhich bad appeared in French and German literature, inwhich it was contended that an animal parasite bad beenfound in some cases of cancer. Summing this up and ex-cluding molluscum contagiosum, it was found that Albarran,Darier, Thoma, Wickham, and Sjobring had found incancer an organism which they described as belonging tothe protozoa, while Thoma did not commit himself, andonly Wickham and Sjobring give figures to aid in forming