34. I. Holmgren, Stockholm.

Employment of B. C. G., especially in Intravenous Injection.

For somewhat more than two years I have been experimenting with intravenous injection of B C G vaccine. In my experiments I have been aided by several of my assistants, in particular by Dr. GOSTA LJUNGBERG. Inasmuch as, so far as I know, B C G is hardly employed intravenously anywhere else, a brief account of my ex- periences may perhaps be of some interest.

I have considered i t to be justifiable to test the intravenous injec- tion of B C G, since a now very great experience has shown definitely that B C G is perfectly avirulent for man, and since, moreover, I have myself a fairly extensive experience of the intravenous injec- tion of tuberculin in man. I t is a considerable time since I made these experiments-on cancer patients-and I should now like to show a lantern slide illustrating how cancer patients react to intrav- enous injections of tuberculin (Fig. 1 and 1 a).’

From this figure we see that the patient reacts with a sudden and brief rise in temperature after each injection. Subjective symptoms are shivering or cold fits, besides general, fairly rapidly passing, feelings of malaise, something like those experienced at the onset of any infection, e.g. influenza. In these experiments a large number of intravenous injections were given, and, as is seen, in considerable doses, even up to 200 mg. of alttuberculin in one intravenous in- jection. After these experiences with tuberculin, I also choosed cancer patients for my B C G experiments. I have as yet given intravenous injections to a total of 28 cancer patients, the majority of whom were suffering from cancer of the stomach. Further, I have also tried intravenous B C G injections in 5 cases of other kinds of disease, so that a t present a total of 33 patients have been given intravenous B C G injections. The aggregate number of in- travenous injections given to these patients is 180.

Most of these patients were given merely one or some few in-

35 1

jections, but some of them were given numerous injections, dis- tributed over shorter or longer periods. The greatest number of injections given t o any individual patient was 37, totalling 2.68 mg. B C G, and distributed over a period of more than one year. The preparation I employed, and a m still employing, is tha t prepared by ANDERS WASSEN, Gothenburg. I t contains 0.5 mg. of bacilli per cm3. Using this preparation we have given intravenous in- jections in doses varying between 0.025 mg. and 0.4 mg. Thus a

Fig. 1.

maximum in the neighbourhood of 1 cm3 of the bacterial emulsion. The injections have always been given a t or about 10 a. m. in a cubital vein. The immediate reaction to the injection is a rise in temperature, shivering and general symptoms of infection, which the patients themselves compare to the symptoms of influenza. These phenomena are more or less pronounced, depending upon the size of the dose. They are also greatly subject to individual variation, and the degree of the reaction may also vary in the same person independently of the dosage, owing t o causes which I am unable to indicate.

Apart from the immediate discomfort, which passes within a day or less, the B C G injections have had no deleterious effect upon

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the general health of the patients, and more especially nothing has ever been observed to arouse suspicions that tuberculosis might be caused or aggravated by the injections. The injections have a certain analgesic and stimulating influence upon the patients, just as tuberculin injection has in the case of cancer patients.

I t is worthy of note that, even when intravenous injections of B C G are given in long series, no considerable degree of habituation results, i.e., no such form of immunity to the injections that the reactions are considerably enfeebled or fail altogether. Figs. 2 4

illustrate the conditions in this respect. We see that in some cases a certain degree of habituation is to be observed, so tha t at a later stage the patient may react with the same, (Fig. 2) or perhaps even a lower (Fig. 3) temperature to the injection of a larger dose than he did a t first to the injection of a small dose. But there are also instances of even stronger reactions to the same dose after a series of injections over a fairly long period (Fig. 4). This condition affords a sharp contrast to the reactions to tuberculin of cancer patients, who very quickly become practically completely habitu- ated, even in the case of intravenous injections of tuberculin, as is to be seen from Fig. 1. The habituation is hardly so complete however, that the injections fail to caIl forth any reaction whatever. Such however is the case with subcutaneous injection of tuberculin as is convincingly illustrated in Fig. 5 and 5a. This was the case of a

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patient with an inoperable maxillary cancer, t o whom I gave subcut- aneous injections of tuberculin for a period of two years. We see how, from the beginning (fig. 5), the patient showed a considerable insen- sitivity to the tuberculin, and how this insensitivity rapidly became almost complete, so that his tuberculin tolerance was finally so great (fig. 5a) that I could give him subcutaneously even up to 2000 mg.

Fig. 2. Mr. N., aged 70, cancer of stomach. Had previously b e e ~ ~ given 9 intravenous injections of B C G. On 4. Jan., 1935, intravenous injection of 0.40 mg of B C G (curve -). Then 2 more injections of the same dose. On

7. March intravenous injection of 0.04 (curve ---).

alttuberculin in a single dose, repeated a t intervals of only a couple of days, without the patient's reacting with fever or suffering in general health. On the contrary the analgesic and stimulating effect of the tuberculin was very pronounced. In the light of this cancer patient's rapid and complete habituation to the injection of tuber- culin, the slight degree of habituation to B C G is rather interesting.

During the course of serial B C G injections the cancer patients appear to acquire a certain degree of tuberculin allergy. With cancer patients the fact is that all of them, with few exceptions, are very

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insensitive to tuberculin, so that the ordinary tuberculin tests in such cases are negative. Thus, they do not react a t all, or extremely slightly to mg. alttuberculin intracutaneously and generally only with a rise in temperature of some tenths of a degree with subcutane.ous injections of such large doses as 5 to 20 mg. Thus they are nearly all tuberculin-negative according to the usual

Fig. 3. Miss S., aged 55, cancer of stomach. The patient had already been given 5 intravenous injections of B C G. On 31 Oct., 1933, intravenous injection of 0.05 rng of B C G. (curve -). Then 25 intravenous injections of B C G. On

6. July 1934 intravenous injection of 0.10 (curve -- -).

terminology. I have had considerable experience in this respect, inasmuch as ever since 1913 I have regularly been examining all my cancer patients in respect to their sensitivity to tuberculin, having now examined over 1000 cancer patients, including more than 600 patients with cancer of the stomach. It iow seems rather noteworthy that these cancer patients who are anergic t o tuber- culin nevertheless exhibit an allergic tuberculin reaction after the injection of B C G. This reaction does not generally appear to be very pronounced, but rather moderate; yet some cases show a

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considerable change in the patient's reaction to tuberculin, as is seen from Fig. 6.

Before the B C G injections this patient did not react with any rise of temperature worth mentioning to the injection of 10 mg. tuberculin, but after 20 intravenous injections of B C G he reacted 6l/, months later with a temperature of 40 C. to 5 mg. of

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Fig. 4. Mrs. L., aged 68, cancer of stomach. After having been given 17 intraven- ous injections of B C G, she was given on 5 June, 1934, a n intravenous injection of 0.20 mg of B C G (curve -). Then two more injections of the same dose,

and on 12 Ju ly another injection of 0.20 mg of B C G (curve ---).

tuberculin subcutaneously. This is interesting, I think, because i t shows that i t cannot be owing to a cachectic condition that the cancer patients do not react to tuberculin. This may also be observed directly from the fact that cancer patients whose general condition and strength are very good also show a similar negative reaction to tuberculin. This is so regularly the case that in my clinic I have for many years used i t in support of or against the diagnosis cancer in cases where the differential diagnosis was not clear. There must therefore be something else owing to which tuberculin allergy does

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not appear in cancer patients, as in other people, although they are similarly exposed to infection from virulent tubercle bacilli, or owing to which-if they have been tuberculin-allergic previously- they lose this allergy during the period prior to the manifestation of the cancer tumour and the establishment of the diagnosis.

Owing to lack of observations in the matter, I am unable to speak as to the response of future cancer patients to tuberculin before the appearance of the cancer.

Fig. 5.

In some cases I have injected B C G direct into the cancer tumour. In particular I have a t present in my clinic a patient suffering from inoperable cancer of the rectum. She was first given 14 intravenous injections, and after this 14 injections direct into the tumour, the dosage varying between 0.05 and 0.25 mg. Over a total period of 7 months she has been given an aggregate amount of 3.53 mg. B C G. The patient greatly appreciates these injections, and she feels they have a favourable effect upon her condition, lessening her pain and stimulating her. Now and then there is a slight rise of temperature, attended by a general feeling of malaise, associated with the injections. Since, as is wellknown, such symp- toms generally do not result from subcutaneous injections, in this case they probably are connected with richness of blood-vessels of the tumour which causes that often part of the injected B C G in

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variable quantities enters the veins-sometimes nothing a t all, and sometimes a part or the whole of the dose.

I have also injected R C G intrapleurally into the pleural exudate in cancer of the pleura, and intraperitoneally into the ascites fluid in cancer of the peritoneum. These injections have not been asso- ciated with any discomfort whatever. Here I would particularly mention-something which I should have pointed out already in my mention of the intravenous injections-that the intravenous

Fig. 5a.

injections never give rise to local reaction a t the site of the puncture, either immediately or subsequently, in the form of infiltrations of the skin, abscesses, etc., such as are met with rather frequently, at least after subcutaneous injections performed with the present technique. These after-effects of subcutaneous injections may be avoided, however, by giving the injections in the manner we have adopted. I always give subcutaneous B C G injections on the anterior surface of the thigh, applying the point of the needle perpendicularly to the skin and giving a deep injection in the subcutis, or intramuscularly. When the injection is given in this manner, the above-mentioned undesirable phenomena are absent'). On the other hand, such an injection may occasionally give rise to some swelling and tenderness of the muscle, but I have never

l) Added a t the reading of the proofs: not always absent.

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as yet observed any inconvenience of this kind which did not gradu- ally or rapidly disappear.

Returning to the intravenous injections, as I mentioned before, I have also made a few of these in cases other than cancer. They all reacted in the same way as I have already described, and the injection was not followed by any complications. I haye also em-

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Fig. 6 .

ployed subcutaneous injection og B C G for desensitization pur- poses in several kinds of allergic morbid conditions. I t is well known, that tuberculin has been used for the same purpose, especially in cases of bronchial asthma. I shall refrain from presenting any of my results here, since time does not permit.

Finally, I have also tried subcutaneous injections of B C G in three cases of pulmonary tuberculosis. One patient was given only one injection; in the other two cases I gave serial subcutaneous in- jections of B C G. Both the latter patients were in poor condition, with high fever and pronounced changes in the lungs. In these cases there seemed to be no possibility of collapse therapy or any other form of therapy that might give a reasonable promise of a favour-

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able effect upon the course of the disease. One patient was given 6 injections of 0.05 mg. l3 C G during a period of 6 weeks (Fig. 7). The other patient was given 11 injections within the period from April 1 l t h to June 4th, the doses being 0.05 mg. and 0.1 mg. (Fig. 8). This patient was given altogether 0.70 mg. B C G. These injections were not accompanied by any discomfort whatever, and they brought about no local reaction, nor any general reaction. During

Fig. 7.

the period of treatment, on the contrary, the patients felt a con- siderable improvement, and their previously high temperatures fell rapidly. Thus there resulted a quite surprising improvement in the patients, manifesting itself objectively by the fall in tempera- ture, and subjectively by the fact that the patients themselves felt better while receiving the B C G injections.

I did not know when I commenced these experiments that similar experiments had been made previously. I t is possible tha t such experiments may have been made in many quarters, but I know nothing about them, except what Calmette himself reported in 1933, when he mentioned tha t 4 patients were given 0.01 mg. subcutaneously, the result being a local abscess, which healed with- out adenitis of the regional lymph nodes; and that 5 other patients

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who were given 0.025 mg. B C G only exhibited a small local papule, which was reabsorbed in 5 to 6 months. These are the only results of such experiments that he presents. Thus both of my patients were given B C G doses infinitely greater than those men- tioned by Calmette-no less than 70 times greater than the doses given to those patients who received 0.01 mg. R C G, and 280

Fig. 8.

times greater than the dose given to the patients who received 0,025 mg. B C G.

I t is interesting to see, thus, that repeated doses of I3 C G in cases of progressive pulmonary tuberculosis, even when they are given a t short intervals and in considerable amounts, have not had the unfavourable influence upon the course of the disease that general experience has shown to result from injections of tuberculin. On the contrary, the injections of B. C G have been attended by an improvement of the general condition and by a fall in the temper- ature, which may surely be looked upon as the very strongest in- dication of the absence of any injurious effect. In view of these experiences, my opinion is that B C G, given in the form of sub-

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cutaneous injection, ought to be tried as a therapeutic measure in tuberculosis, and for my part I intend to do so.

Discussion. 0. SCHEEL. The drawback associated with the usual vaccination

with B C G in the form of cutaneous or subcutaneous injection is abscess formation. For this reason I thought a t one time to go over to intravenous injection of B C G in order to obtain allergy with- out abscess formation. However, I was advised very strongly by the Pasteur Institute not to adopt this method-in fear of the possibility of abscess formation in the internal organs.

I wish, therefore, to ask Professor HOLMGREN if he on autopsy of his cancer patients has found any such internal abscesses after injection of the B C G vaccine.

I. HOLMGREN. I t is correct that a great many of my cancer patients have been examined post mortem. Such autopsy has in no instance revealed anything that might suggest-or even raise suspi- cions-that injury had been brought about by the B C G injections.

I have not said anything about the purpose of the injections, because this topic does not properly belong to the question under discussion-and i t would require too long to deal with it. Since the question has been raised however, I may state, that these experi- ments with B C G must naturally be regarded in connection with the tuberculin experiments I briefly mentioned, and which were performed a longer time ago. To begin with i t was therapeutic interest that led me to the tuberculin experiments, and the experi- ments with B C G constitute a direct continuation of my tuberculin experiments. I t is not possible here for me to give the considerations that led me to the idea of trying if possibly tuberculin might have therapeutic effect upon cancer. The idea is not unreasonable. I merely wish to recall for example, Calmettes recent experiments in the treatment of cancer by means of Cobra venom. I wish to point out however, that I have seen no remarkable, effect, as far as the growth of the cancer is concerned, from the administration of tuberculin or B C G. Nevertheless they are not altogether without any effect, but I do not wish here to go into more details than I have already mentioned in my lecture.