between the relations of the organism as a whole to the malignant new growth it supports, under natural and experimental conditions respectively. Dr. Haaland and Dr. Cramer carry this line of investigation further in contributions on glycogen, fat, and respiratory metabolism.

Dr. Cramer's paper shows how precise bio-chemical methods can now be applied to the study of the growth of cancer, and brings new and exact information on the nature of the relations existing between a tumour and the animal bearing it. The effect which a growing tumour produces on a normal organism is a problem of nutrition similar to the growth of a foetus in a pregnant animal; it cannot be explained by assuming the formation of pathogenic "cancer-ferments" or "cancertoxins."

The parallel between the growth of tumours under natural and experimental conditions, drawn in the Second Scientific Report, can now be extended to constitutional conditions in animals, as accompaniments of the disease whether naturally or artificially produced, e. g., constitutional conditions favourable to growth, and therefore to dissemination, where a primary tumour is present; the response of the digestive system to a growing tumour both in natural and experimental cancer, as well as the relation of the metabolism of a tumour to the metabolism of its host. Thus it comes about that the experimental investigation of cancer is being conducted under what we might almost call ideal conditions, and it is perhaps an advantage rather than otherwise, that these experiments cannot be conducted "in vitro " but only "in vivo,” for, as I pointed out some years ago in reference to the study of the phenomena of immunity, convenient as the test-tube experiment is, grave fallacies may be involved in directly transferring the results to the living animal'. The living mouse has to take the place of the test-tube, even for maintaining an adequate supply of cancer-cells. This complicates the nature of the mere routine of experimentation

1 On toxic and antitoxic action in vitro and in corpore. Journal of Pathology,' March 1902, and earlier and later papers.

and increases enormously the number of inoculations which, as distinct from experiments proper, require to be made in the conduct of the work.

If the Report be reviewed as a whole, it will be obvious that the experimental study of cancer has already enabled us to approach many -practically all-clinical and pathological aspects of the disease in man, and to throw new light upon each of the aspects of the disease to which it has been applied.

Cancer is ubiquitous in man and vertebrate animals. It has been shown that cancerous tissue of a species of animal retains the characters of that species, whereas in infective tumours (e. g. tubercle) occurring naturally in separate species, the biological characters of the newly formed tissue are determined by the common infective agent and not by the tissues of the affected animal. Within a species the individual tissues after they have become cancerous retain characters corresponding to those which distinguish the several normal tissues from one another. There are fluctuations in the rate of proliferation of cancer cells the discovery of which appears of be of theoretical and practical importance. The demands of cancerous tissue for food upon which it may grow, is responded to by the digestive apparatus of normal animals. The growth of experimental tumours can be prevented in its inception by treatment with normal tissues, e. g., by skin in the case of skin cancer. It is a remarkable fact, that whereas the inoculation of skin will protect practically every mouse against a primary inoculation of squamouscelled carcinoma, there is the greatest difficulty once transplantation has been successful, in immunising such a mouse by the inoculation of skin against a second inoculation of the same tumour. It is probable that the presence of an inoculated tumour modifies the animal constitutionally in a direction which favours dissemination. The future definition of the circumstances which determine the relations obtaining here, may be expected to yield a promise that dissemination and the formation of secondary growths in distant organs may be prevented.

These facts, elicited by using the living cancer cell as an indicator of changes in the living animal, and per contra the living animal as an indicator of changes in cancer cells, can therefore only be studied by experiments on the living animal. A practical outcome is not yet in sight, and an emphatic caveat must be entered against their premature application to treatment of the disease in man. There are no indications that an antitoxic or other serum will be obtainable with curative powers, or that a prophylactic vaccine may be produced; but further investigation is indicated in the direction of preventing dissemination of a malignant new growth by enhancing the resistance of the organism, and by endeavouring to take advantage of the negative phase in the proliferation of cancer-cells, i. e., the time at which experiment has already proved they are most vulnerable.

Meantime the rationale of the early surgical removal of primary tumours is amply justified by experiments, and no substitute for it has been found either by their means, or in alleged empirical remedies.

Apart from the subject matter, each of the papers dealing with experiments contains a detailed account of how the results were obtained and recorded. This has been done of set purpose in order that other investigators may be able to repeat our observations or to compare their results with our own. In the hope of securing some uniformity in experimental methods, there are given in the following pages details of those employed in the Laboratory.

It is essential if comparisons are to be made, that in all experiments uniformity should be aimed at both as regards the manner in which they have been carried out, and in the way in which the results are recorded. There is no reason why other investigators should not repeat the investigations of the Imperial Cancer Research Fund in these respects. Particular attention is directed to a method of studying and recording the course of spontaneous cancer in mice as regards the tumour, the animal itself, and the results of surgical

or other interference.

All experiments are recorded with detailed reference to age of animals used, race, dosage, intervals of time, size or weight of tumours, and percentages of successful inoculations. Graphic methods are used to show the sizes of tumours by reproducing them to scale from protocols where they have been drawn as silhouettes of natural size. Percentage curves of the successful inoculations during prolonged propagation will be used to compare and illustrate the biological behaviour of different tumours. Where necessary, complete genealogical trees of the descent of all propagated tumours are also given.

Our experiments during the past six years can all be compared, and repeated if necessary, owing to the early adoption of certain elementary rules for making experiments and recording the results. Our papers have been purposely burdened with statements of doses, weights of tumours and of animals, statements of age, of time, number of animals inoculated as well as of mere percentages of positive results. We have therefore given every facility to others who may desire to repeat our observations. We have also given away our material freely to all serious workers who have asked for it, in the belief that free independent investigation and discussion should be encouraged.

Some sources of confusion in the results recorded by various investigators are avoidable for they are due to disregard of the necessity for employing standards which are especially important in "in vivo" experiments before comparisons can be drawn. It is strange how discrepancies which depend upon different dosage give rise to confusion again and again, whenever a new line of biological investigation is instituted. So far as my knowledge goes the minimal lethal dose of a drug was determined for the first time by Fraser between 1863 and 1868 for Physostigma venenosum and its active principle, and made the basis of important experiments on drug antagonism'. Its importance has been

On the characters, actions, and therapeutic uses of the ordeal bean of Old Calabar. Edinburgh Medical Journal, vol. ix. 1863; cf. also Proceedings Roy. Soc. Edin., 1868-9, pp. 587-590; Trans. Roy. Soc. Edin., xxvi. 1872, pp. 529–713.

consistently insisted on by him since, e. g., in his later work on the antidotes of venoms and toxins, and in other investigations on the action of various medicinal substances. Nevertheless for nearly another forty years controversy continued to rage as to whether or not atropine could abolish the lethal action of morphine: not one of the disputants on either side made the minimal lethal dose of morphine the basis of his arguments. At Fraser's instigation I was able to prove, after determining the minimal lethal doses of the two drugs, that atropine did abolish the lethal action of morphine, and to show that the most contradictory statements could all be harmonised as incidents in a scale of events determined by differences in the physiological effects, according to the quantitative relations between the doses of the two alkaloids1. Similar inaccuracies confused many of the earlier results of investigations in bacteriology, and into the relations between toxin and anti-toxin, all of which Ehrlich did so much to remove. They have also been potent already in causing discrepancies in the results of the experimental investigation of cancer, especially in estimations of the rate of growth. of tumours, the extent to which protection can be induced against inoculation, and the specific or universal application of the results.

The papers of many authors do not contain the details necessary for the accurate repetition of their experiments. It is therefore impossible to appraise independently the value of their results, or to harmonise them with our own when divergent. Knowledge would be more certainly advanced if authors, instead of merely reaffirming their conclusions, gave the requisite details which would permit of independent estimations as to the comparative rapidity of growth of the tumours in their possession. An objective statement can be substituted so easily for the loose description of a tumour as "virulent" or "avirulent." The progressive growth of a tumour can be charted in silhouette at regular intervals, or, it can be stated, that from the inoculation of a

1 Untersuchungen über das Bestehen eines gegenseitigen Antagonismus zwischen Atropin und Morphin. Archives internationales de Pharmacodynamie, vol. viii 1901, pp. 311-351.

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