The Treatment of Malignant Tumors by the Toxins of the Streptococcus of Erysipelas. Read in the Section on Surgery and Anatomy, at the Forty-sixth Annual Meeting of the American Medical Association, at Baltimore, Md., May 7-10, 1895. N. BENN, M.D., Ph.D., LL.D. PROFESSOR OF PRACTICE OF SURGERY IN RUSH MEDICAL COLLEGE; PRO- FESSOR OF SURGERY IN THE CHICAGO POLICLINIC; ATTENDING SURGEON TO THE PRESBYTERIAN HOSPITAL; SURGEON-IN- CHARGE TO ST. JOSEPH’S HOSPITAL. CHICAGO. REPRINTED FROM THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, JULY 27, 1895. CHICAGO: American Medical Association Press, 1895. THE TREATMENT OF MALIGNANT TUMORS BY THE TOXINS OF THE STREPTO- COCCUS OF ERYSIPELAS. N. SENN, M.D., Ph.D., LL.D. It has been known for a long time that in excep- tional cases an attack of erysipelas has exerted a curative effect on malignant tumors. A number of years ago Billroth reported a case of inoperable sar- coma of the pharynx cured by a severe attack of facial erysipelas. The tumor mass sloughed and the large defect healed rapidly by granulation, leaving a healthy scar upon the site occupied by the tumor. Isolated cases of this kind have been reported from time to time, but the diagnosis was not always estab- lished by sufficiently careful clinical observations and microscopic examination of the tumor tissue. The discovery of the microbe of erysipelas by Fehleisen, and the cultivation of the streptococcus upon artificial nutrient media outside of the body enabled investigators to produce erysipelas artifi- cially in the uncomplicated form in man and the lower animals. As soon as it was demonstrated ex- perimentally that simple uncomplicated erysipelas is a disease attended by but little danger to life, the suggestion was made that, if the disease could be arti- ficially produced in man by inoculation with pure cultures, the local and general conditions thus pro- duced might prove useful in the cure or amelioration of inoperable malignant tumors. Of seven persons the subjects of malignant tumors, inoculated by 2 Fehleisen with pure cultures, six developed typical erysipelas; in the seventh case the patient had passed through an attack of erysipelas only a few weeks previously and wras, in all probability, still pro- tected against a new attack. This patient was inoc- ulated a second time with a negative result. Fehleisen has seen, by this treatment, a cancer of the breast become smaller, while a case of fibre-sarcoma and another of sarcoma were not materially affected by this method of treatment. Janicke and Neisser have recorded a death from the erysipelas thus intentionally produced, in a case of cancer of the breast beyond the reach of an operation. At the post-mortem it was shown that the tumor had almost completely disappeared, and the microscopic examination of portions that had remained appeared to prove that the tumor cells had been destroyed through the direct action of the microbes. Biedert saw in a child suffering from a sarcoma, in- volving the posterior part of the cavity of the mouth and pharynx of the left half of the tongue, the naso- pharyngeal space and the right orbit, the tumor disappear almost completely during an attack of erysipelas. Kleeblatt reports the case of a lympho-sarcoma fol- lowed by infection of the cervical glands, in which the tumors diminished markedly in size under the influ- ence of an inter-current attack of erysipelas, but re- sumed its former malignant tendencies as soon as the disease had subsided. The patient was afterward in- tentionally inoculated with a pure culture of the streptococcus of erysipelas, but the beneficial effect was, as before, only a temporary one, as the tumors steadily increased in size, the patient dying of exhaus- tion. In another somewhat similar case, the inocula- tion caused a typical attack of erysipelas, under the influence of which the tumor rapidly disappeared. Cases, on the other hand, have been reported in 'which, after an accidental or intentional attack of ery- sipelas, the malignant tumor began to grow more 3 rapidly. Neelsen describes a case of carcinoma of the breast in which, after two severe attacks of erysipelas, the tumor not only began to grow faster, but at the same time regional infection progressed more rapidly. Bruns gives an account of the effect of erysipelas on tumors in twenty-two patients. Among these, three cases of sarcoma were permanently cured. Two cases of multiple keloid after burns were also per- manently benefited. In four cases of lymphoma of the neck, some of the glandular swellings disap- peared completely and some were reduced in size. In three cases of carcinoma of the breast, one was not influenced by the treatment, in one the tumor was diminished one-half in size, and in the third it contracted to the size of a pea, in which condition it remained at the time the report was made. A mul- tiple fibro-sarcoma was greatly benefited, while an orbital sarcoma was not improved. Spraenth concludes as the result of his observa- tions that the products of the erysipelatous inflam- mation in certain cases can act in a curative manner upon malignant growths. He injected subcutane- ously at a point distant from the tumor the sterilized toxic products of the microbes of erysipelas. Im- provement and even complete disappearance of the tumors followed, although recurrence usually took place. The effect was much more marked in sarcoma than in carcinoma. Burch observed that as a result of accidental or intentional infections with the microbe of erysip- elas, tumors such as sarcoma disappeared by fatty degeneration. Janicke and Neisser demonstrated by microscopic examination that cancer cells were actually destroyed by erysipelas streptococci. In view of the uncer- tainty of the result and the not inconsiderable danger to life which attends the inoculation of live cultures of the streptococcus of erysipelas, in pa- tients debilitated by antecedent disease, it is safe to 4 predict that this therapeutic resource will be aban- doned in the future treatment of malignant tumors. Coley, of New York, has made the treatment of malignant tumors with live and sterilized cultures of the streptococcus of erysipelas a special study since 1891, In 1893 he reported ten new cases of malig- nant tumors treated by repeated inoculations with erysipelas. From a study of the literature of this sub- ject at that time it was found that there were recorded thirty-eight cases of malignant tumors in which an attack of erysipelas had occurred, either by accident or intent. In thirty-three cases the erysipelas was accidental and in fifteen it was the result of inocula- tion. Of seventeen cases of carcinoma, three were permanently cured. Of the seventeen cases of sar- coma, seven were free from recurrence from one to seven years after the attack of erysipelas. Ten cases showed quite marked improvement; one patient died as the result of an accidental attack of erysipelas. In the summary of the analysis of recorded cases, Coley excluded eight cases of his own, treated by re- peated inoculations with erysipelas cultures ; in none of these cases did an actual attack of erysipelas re- sult, and yet the inoculations appear to have been followed by marked improvement, and this would indicate that there exists in the cultures some sub- stance which is antagonistic to the tumor growth. In view of the fact that the artificial production of erysipelas by inoculations with active cultures of the erysipelas microbe is not devoid of risk to life, and that improvement in certain cases followed, by inoculations with live cultures, which did not produce erysipelas ; these facts led Coley and others to employ sterilized cultures, which appear to have produced the same therapeutic effects as the active cultures. It was also ascertained by experiments that the efficiency of the dead cultures is increased by the addition of the bacillus prodigiosus, a comparatively harmless microbe. In a recent article on the treat- ment of malignant tumors with the toxins of these 5 two microbes, Coley maintains the efficiency of the mixed dead cultures of these two microbes in the treatment of some cases of malignant tumors, es- pecially sarcoma. In the same publication he reports nine cases of inoperable sarcoma permanently cured by repeated inoculations with the mixed toxins of these two microbes, that came under his own obser- vation, and refers to a few successful cases in the practice of other physicians. The toxins which he uses now are prepared in the following manner; “Method of Preparation of the Toxins.—To make the toxins of erysipelas and prodigiosus, ordinary peptonized bouillon is put into small flasks, contain- ing 50 to 100 cc., which, after proper sterilization, are inoculated with the streptococci of erysipelas and allowed to grow for three weeks at a temperature of 50 to 35 degrees C. The flasks are then inoculated with bacillus prodigiosus, and the cultures allowed to grow for another ten or twelve days at room tem- perature. At the end of that time, after being well shaken up, the cultures are poured into sterilized glass-stoppered one-half ounce bottles, and heated to a temperature of 50 to 60 degrees C. for an hour; sufficient to render them perfectly sterile. After cool- ing, a little powdered thymol is added as a preserva- tive, and the toxins are ready for use. The toxins when prepared in this way are very much stronger than when filtered through a Pasteur, Chamberland or Kitasato filter, the active principles contained in the germs themselves being preserved. If, as is some- times the case, the preparation is found to be too strong to use with safety, it can be diluted with gly- cerin or sterilized water. “ The best method of making the bouillon is to soak a pound of chopped lean meat over . night in water. In the morning strain it through a cloth, make up to 1,000 cc., and boil for one hour. Then filter through a cloth, add peptone and salt, neutralize and boil again for an hour. The bouillon will then pass through filter-paper perfectly clear, and be ready 6 to put into the flasks. It is not, however, necessary to neutralize the bouillon, as the streptococci will grow even more readily in acid bouillon, and the re- sulting preparation is, if anything, stronger than when neutralized bouillon is used. “ In order to keep up the virulence of the cultures they are put through rabbits in the following way: the hair of the ear is clipped close with a pair of scissors, and the skin washed with weak carbolic acid, and then sterilized water. A minute quantity of a bouillon culture, forty-eight hours old, is then injected subcutaneously in four or five different places in the ear. Forty-eight hours later, after again wash- ing the ear with carbolic acid and sterilized water, a flat needle sterilized in the flame is inserted under the skin at or near the point of inoculation, and the layer of the skin cut off with a sharp sterilized scal- pel. The piece of skin is then rubbed well over the surface of an agar tube with a thick platinum-wire needle. After twenty-four hours in the incubator the colonies of streptococci will show as minute white specks, and from them a pure culture can be obtained. If the agar is made with 75 per cent, of bouillon and 25 per cent, of urine, the streptococci will grow more freely than if bouillon alone is used. The dose of this preparation varies from 1 to 8 min- ims; I have had a temperature of 105 degrees F. fol- low the injection of 2 minims. I usually begin with the minimum dose and gradually increase until the desired reaction, e,g., temperature 103 to 104 degrees F. is reached.” Coley does not say that this treatment is success- ful in all cases, and reports his failures with his suc- cessful cases, but his satisfactory results are out of proportion to those of any other practitioner, in the employment of the same remedy in similar cases. It is generally known that carcinoma has proved more refractory to the toxins of the streptococcus of erysipelas and the mixed toxins than sarcoma. A distinction should be made between the thera- 7 peutic action of non-malignant tumors of erysipelas and the subcutaneous injections of sterilized cultures of the microbe of this disease. In erysipelas involv- ing a malignant tumor, the superficial lymphatic channels are the seat of an active inflammation, the product of which always temporarily obstructs the pathways through which local, regional and general infections occur and, in exceptional cases, permanent interruption of the lymph current may limit or arrest the growth of the tumor. No such anatomic changes ure produced by the injection of the toxins. The treatment of inoperable sarcoma and carcinoma with the mixed toxins, as advised and practiced by Coley, has been given a fair trial in the surgical clinic of Rush Medical College, and so far it has resulted uniformly in failure. The accompanying table is a brief summary of the cases subjected to this treatment. The injections were made daily, gradually increas- ing the dose until the desired reaction was produced. In most of the cases the reaction was initiated by a chill, or at least a sense of chilliness. The tempera- ture reached the maximum height in the course of a few hours, and continued from six to twenty-four hours. The toxins used were obtained from three different sources, the last supply directly through the courtesy of Dr. Lambert, of the laboratory of the Cancer Hospital, New York. A temporary swelling and diffuse reddening of the skin at the point of puncture was a common occurrence; abscess forma tion was seldom observed. Loss of appetite, restless- ness and insomnia were some of the general symptoms most constantly produced by the injections, when used in doses large enough to provoke febrile reac- tion. In all of the cases, the injections failed to effect even temporary improvement, and in some of them the local and general conditions appeared to be aggravated by the treatment. The results of this treatment have been most discouraging in my hands, and although I shall continue to resort to it in other- 8 wise hopeless cases in the future, I have become sat- isfied that it will be abandoned in the near future and assigned to a place'in the long list of obsolete remedies employed at different times in the treatment of malignant tumors, beyond the reach of a radical operation. o g Dose in minims. - Name. Tumor. S.O fi I Mini- Maxi- s