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different sporadic tumours in the animals primarily affected are not equally efficacious in ensuring a continuance of proliferation under the similar experimental conditions of artificial propagation. We must therefore conclude that the causative factors have operated with varying intensity, or that additional factors are superadded in some cases.

The behaviour of some strains of Jensen's tumour present a parallel to the other tumours now under consideration. We have already alluded to the negative results sometimes obtained on transplanting Jensen's tumour. In the graphic record (fig. 12) the steps are shown

FIG. 12.-Graphic record of propagation of a strain of Jensen's tumour which gradually gave a lower and lower percentage of success till a negative result terminated growth. Cf. fig. 10 and fig. 11.

by which a strain of Jensen's tumour, at first giving a high percentage of success, progressively exhibits weaker and weaker powers of proliferation, till finally the tumours obtained gave negative results on transplantation. Such strains are not uncommon; they have frequently been followed to a finish during our experiments. Thus one chapter, as it were, in the life history of Jensen's tumour reproduces the entire life history of other tumours under artificial propagation. These results are difficult to harmonise with the assumption that the apparently continuous proliferation of Jensen's tumour is purely vegetative. Together with the facts of spontaneous absorption they strengthen the conclusion derived from a study of the details of that proliferation, that a cyclical process is involved.

The importance of the preceding analysis of the growth of propagated cancer is obvious in appraising the results of attempts to modify growth experimentally. The experimental conditions whose variations cause irregularities in the success of artificial propagation must be taken account of. In particular, the age of the animals would seem to call for especial attention, because the short duration of the life of a mouse magnifies the effect of the lapse of time involved in procedures for inducing immunity. Specially adapted control experiments must be performed in order to obviate the fallacy which the ageing of the animals introduces. Those fluctuations which cannot be referred to the experimental conditions but are natural features of the proliferation of the tumour cells are an even more urgent reason for caution in interpreting the results of therapeutical experiments. The difficulty or even impossibility of predicting the time at which spontaneous absorption will affect the propagated tumours indicates the necessity for accurate records of their previous history.

In another paper with Dr. Cramer we shall discuss the results we have obtained on re-inoculating mice in which the absorption of well-established tumours had occurred spontaneously and under the action of radium.

[Reprinted by permission of the Council from the PROCEEDINGS OF THE

ROYAL SOCIETY, B. Vol. 79, 1907.]

THE NATURAL AND INDUCED RESISTANCE OF
MICE TO THE GROWTH OF CANCER.

By E. BASHFORD, M.D., J. A. MURRAY, M.B., AND
W. CRAMER, PH.D., D.Sc.

[Communicated by Dr. J. ROSE BRADFORD, F.R.S. Received December 10, 1906; Read January 17, 1907.]

may

IN the present paper we propose to give an account of experiments conducted during the past three years on the means whereby mice be completely protected against the inoculation of transplantable carcinomata, which grow readily in normal mice. At the same time we shall show that these experiments throw fresh light on the nature of cancer. The Executive Committee and the Pathological Sub-Committee of the Imperial Cancer Research Fund have been informed of the progress of these investigations, and some provisional results have also been laid before the General Committee at the Annual Meetings. The experiments are being continued, but some of the results which have accumulated make it advisable to give an account of the stage at which they have now arrived. They are based mainly on a study of 23 transplantable carcinomata of the mamma of the mouse, and of other malignant new growths which could not be propagated artificially.

In these experiments we have used, for the most part, the growth of Jensen's tumour in normal animals to bring out the changes induced in protected animals and the refractoriness of insusceptible animals; but we shall also employ another tumour (XXVII) of different histology, which grows equally well under artificial propagation. We have employed Jensen's tumour as a standard for the following reasons:— (1) It was the only tumour used to control some of our earlier observations; (2) With proper precautions it gives regularly 85 to 100 per cent. of successful inoculations in a large number of animals; (3) Within ten days the inoculation of 0·01 to 0:02 gramme of tumour tissue gives large easily recognisable tumours, often 15 grammes in weight; (4) We have fully demonstrated that it may produce large metastases, that it may extend by the blood or lymphatic streams, and behave

under experimental conditions typically as a malignant new growth; (5) Its rate of growth is not exceeded by any mouse tumour now being propagated; (6) It is in the hands of most investigators throughout the world, who will be able to repeat our observations. It therefore fulfils better than any other tumour the requirements of such a standard.

Historical.

Jensen stated in papers appearing in 1901, 1902, and 1903* that he had observed the complete disappearance of tumours from mice that had been inoculated successfully. He added, however, that the "results of attempts to cure mice of tumours have hitherto been uncertain; at times they have been positive to an unexpected extent, at other times they have been entirely negative." For this reason he postponed the detailed discussion of his experiments till he had come to a clearer understanding of their significance, and to more reliable results. Referring to the fact that 40 to 50 per cent. of the total inoculations of his tumour had been unsuccessful, Jensen interpreted this to mean that the mice were protected by some natural means. It seemed to him impossible to explain the fact that a tumour which was growing well at the time of its removal from one mouse should be unable to grow in other mice, except on the assumption that the tumour had been transferred to a more refractory group of mice; but he stated, "it appears that the nature of the inoculated tissue is of no little importance for the success attained. So far as it is possible to form an estimate, the results appear less certain when small young tumours are used which are actively growing, and the percentage of successful inoculations is higher if the healthy portions be selected from older and larger tumours." Jensen especially pointed out that mice which had been unsuccessfully inoculated at the first essay were also refractory to subsequent inoculations; but he was careful to point out that it would be a mistake to assert that the second negative result was solely the consequence of natural refractoriness, since it would be wrong to assume that the material inoculated and absorbed in the first instance had not contributed to the exemption subsequently exhibited.

"Nogle Forsøg med Kraeftsvulster," Lecture, December, 1901; "Forsøg med Musecancer," Lecture, April, 1902, Biolog. Selskabs Forhandlinger, Köbenhavn,' 1901-02; "Experimentelie Untersuchungen über Krebs bei Mäusen," Centr. f. Bakt.,' vol. 34, 1903.

Borrel drew attention to the difficulties attending primary transplantation and recorded suggestive experiments directed to obtaining a polyvalent immune serum against human cancer, on the assumption that distinct sera might be necessary for tumours of different histological types.

In November, 1903, we were able to add the study of Jensen's tumour to that of tumours discovered by ourselves, and we at once began investigations along the lines indicated by Jensen. In our earlier experiments, the successful inoculation of Jensen's tumour fluctuated between 20 and 90 per cent. of the number of animals inoculated.

In a series of papers † we have drawn attention to the greater susceptibility of young than old mice, to the important influence on the success of transplantation, of the character and phase of the tumours inoculated, the dosage, and site of inoculation. In the course of a careful study of the process of the absorption of tumours after exposure to radium, we showed its identity with localised changes in the majority of propagated tumours, changes which were found to have become general in the only case we had then noted, where a tumour of three weeks' growth and of 1 cm. in diameter had actually diminished in size. While recognising the importance of hæmorrhage as an integral part of the process of absorption both when spontaneous and following exposure to radium, we pointed out that the phase of growth of the tumour was also of great and probably decisive importance. These observations harmonised well with Jensen's experience, and tended to explain the irregularities in the disappearance of tumours under his observation. Our position was summarised as follows:-No conclusion has yet been arrived at as to what are the essential and what the subsidiary features in this prolonged proliferation. The variations make it difficult to correlate different observations, and to be sure of their proper interpretation. Efforts to influence growth by immune

6

"Epithélioses infectieuses et Epithéliomas," Annales de l'Inst. Pasteur,' vol. 11, 1903; Roy. Soc. Proc. vol. 73, 1904.

First and Second Scientific Reports of Imperial Cancer Research Fund, 1904, 1905; Roy. Soc. Proc. B, vol. 78, 1906.

We recorded the precautions we had taken in searching for tumours undergoing spontaneous absorption. Clowes has taken this criticism of our own procedure as implying that in our opinion his "spontaneous recoveries were ulcerations" (‘Brit. Med. Journ.' December 1, 1906). Regression of inflammatory swellings may take place without ulceration, and our remarks apply to our own doubtful "tumours" of less than 14 days' growth, within which time Clowes made no mention of tumours having appeared.