As a corollary to the foregoing, the possible influence of trauma may be considered. It is generally conceded that many malignant growths are primarily of traumatic origin, trauma being considered in its broadest sense as any agent tending toward irritation. With injury a stimulation of cellular production ensues with a consequent increase in the formation of waste products. Should these wastes influence the control of such production the increase might become excessive, causing pressure and thus an extension of the trauma. This would again result in more waste formation, and thus cellular production be subject to a constantly decreasing control. Thus directly through the impaired elimination of normal, or indirectly by the formulation through exogenous causes of abnormal wastes, groups of cells might become the seat of a pernicious activity. The effects of this latter not improbably would show progressive characteristics, as the influence would propagate its own cause.

The ultimate causative principle, then, would lie in the substance or substances resulting from the cell katabolism, and the tissues undergoing these pernicious changes should contain the toxic. substances responsible for their continued growth and propagation. While the poisons might be present in such small quantities as to escape isolation and detection by chemical means, an investigation of the chemical theory thus outlined must find its starting point in an attempt to demonstrate the presence of such compounds in the substance of malignant growths. Repeated experiment led to the following method of procedure. (') Freshly extirpated growths of proven malignant character were freed from fat and extraneous tissue, minced and exhaustively extracted with boiling water. The watery extract was concentrated, freed from protein and fat, and the residue acidified and extracted with ether. The ethereal extracts were collected, freed from the solvent, the residue dissolved in water, neutralized and allowed to crystallize on spontaneous evaporation. The long, white, needle-shaped crystals were purified by repeated recrystallization, and a sterile saturated aqueous solution (of about 4 per cent strength) made up for the subsequent determinations.

Rabbits were selected for the initial experiments as these animals are not normally subject to tumor growths. Four healthy adults were injected under aseptic conditions, each with 10 milligrams of the toxic substance in sterile solution, while 4 controls received the same amount of normal saline. One of the animals developed a septic condition, due probably to faulty technique-and died on the third day. The others, after several days of apparent good health, gradually lost weight and suffered a progressive dimi

The detailed statement of the chemical procedure will be given in a subsequent Communication.

nution in activity and bodily strength. A general cachexia developed, terminating fatally inside of three months. In all cases the site of injection showed induration with continuous increase in area. In one case there was marked breaking down, attended by complete destruction of tissue. In each case the rabbit presented the clinical picture of malignant disease. The post-mortem showed extensive glandular involvement outside of the primary focus, and all the growths presented the characteristic histological features of carcinoma. In a subsequent experiment the effects were still more strikingly illustrated. Five rabbits were injected with sublethal doses at 10-day intervals. Although the abdomen was the site of the injections, the primary lesions developed severally as follows:-one in the thyroid, one on the right cheek, involving nose and orbit, one on the left foot and the remaining two in the head: one on the left side of the lower jaw, the other involving the left eye. All of these showed the characteristic progress of a general cachexia, in every instance terminating fatally. The post-mortem disclosed numerous metastatic foci, the picture being that of a general miliary carcinomatosis. The histological findings were equally definitive.

Beside the studies on the specific action of the tumor extract, its general toxicity was investigated. Doses of 20 milligrams injected into guinea pigs caused intoxications of a tetanic character, fatal in less than two hours, while with rabbits a similar dose produced an analogous condition with death in from 12 to 15 hours. Further, from the peritoneal cavity of the poisoned guinea pigs could be secured an exudate, 0.2 c. c. of which would kill a guinea pig in 20 minutes and 0.5 c. c. a rabbit in two hours, the symptoms being those of the original intoxication. This marked increase in toxicity would seem to bear upon the possible stimulation of cell groups to a pernicious activity.

To prove that the results observed were referable to the specific effect of the tumor substance, control determinations were carried out (a) with the lactic acid salt of the base used in the separation, (b) with the substance prepared from benign tumors by the same procedure as that used for the chemical treatment of the carcinonata. Neither with amount ten times that of the lethal dose of the malignant extract nor with the repeated injections over a long period of time, has it been possible to produce local or constitutional symptoms. The conclusion is thus warranted: that carcinomata contain some substance or substances which are susceptible of isolation and which when injected into healthy tissue produce results which are dependent upon the inherent chemical nature of the material itself.

A series of immunization experiments were now undertaken,

and 53 healthy adult rabbits were injected under carefully maintained conditions at 10-day intervals according to the following scheme. The site of the injections was, in every instance, the abdomen.

Five of these animals developed carcinoma (already described in an earlier section) while 10 more have shown signs of a general constitutional disturbance. The remaining 38 are in excellent health and have increased somewhat in size and weight, and only these have been used in the later experiments. At the end of the immunizing period, blood was drawn from these rabbits by plunging the needle of a sterile syringe directly into the heart. No fatalities have resulted from this operation. From the blood thus drawn the serum was prepared and stored, following the familiar technique for the preparation of immune sera.

Two sets of experiments have been carried out on guinea pigs with this serum. In the first a pig was injected with 1. c. c. of the serum and two days later with 1. c. c. of the tumor extract. The control animal, similarly injected with the poison, died in 30 minutes, while the experimental guinea pig did not show the slightest. effect at the time or in the weeks that have since elapsed. The second set can be presented to the best advantage in the following table.

1.00

0.00

I.*

Serum (in c.c.)

1.00

0.00

2.*

3.

.99

ΟΙ

4.

.99

ΟΙ

5.

.98

.02

6.

•98

.02

Note:

TABLE II.

Result :

Death in 22 minutes.

Death in 24 minutes.

Slight temporary constitutional disturbance; no other effect.

No initial effect. Later both animals died. Post-mortem showed that injection puncture had pierced liver, causing general peritonitis.

It will be noticed that in non-immunized rabbits this dose would kill in 12 hours. In the present instance some of the animals showed transitory evidence of intoxication, and the subsequent doses were reduced to that of the second injection which had been shown to be readily tolerated.

*Controls.

·98

.02

12.

·98

.02

Same as 3 and 4.

Repetition of 5 and 6. Same as 3 and 4. The minimum constitutional effect shown with this proportion.

With the exceptions noted above, the animals are all in excellent health.

Parallel experiments upon rabbits have been even more successful, no deaths having occurred with the immunized animals.

SUMMARY.

I. A highly toxic substance has been isolated from carcinomata by a method precluding the presence of organic life.

2. This substance has been shown to be characteristic of carcinomata.

3. The tumor substance will produce well-defined carcinomata on injection into healthy rabbits.

The appearance of the primary lesion is followed by the development of numerous metastatic foci while the characteristic cachexia manifests itself.

5. The substance possesses marked general toxicity.

6. The peritoneal exudate produced during a fatal intoxication is far more toxic than the original substance.

7. Rabbits have been immunized by the repeated injection of sub-lethal doses.

8. The serum of the immunized animals antagonizes the toxic action of the tumor substance both when injected previously to or simultaneously with the latter.

INTERNAL SECRETIONS FROM THE SEX GLANDS AND THEIR RELATION TO PHYSICAL AND PSYCHICAL

DEVELOPMENT.

By WINFIELD SCOTT HALL, Ph.D., M.D., Professor of Physiology, Northwestern University Medical School, Chicago.

Secretions are classified into two groups, the external secretions being those that are poured out upon the cutaneous or mucous surface. Examples of external secretions are the saliva, poured into the mouth; perspiration, poured out upon the surface of the skin; gastric juice, poured into the stomach; bile from the liver, poured out into the intestines, etc. Examples of internal secretions are the secretion from the thyroid gland, the secretion from the

suprarenal bodies, which are two little glands just above the kidneys. Some glands make only external secretions, as the salivary glands and the sweat glands. Other glands make only internal secretions, as the thyroid gland and the suprarenal glands. But some glands make both external and internal secretions. For example, the pancreas prepares the well-known pancreatic juice, which is an external secretion poured into the intestines, there to exert an important influence on digestion. The pancreas also prepares an internal secretion, which is absorbed back into the blood, there to exert an important influence on the use of sugars and starches in the body. The liver prepares an external secretion, the bile, which is poured out into the intestine, to exert an important influence on digestion. It also prepares several substances that are absorbed back into the blood. These substances are internal secretions.

The sex glands belong to this third group of glands, namely, to those glands that prepare both external and internal secretions. With the external secretions of the sex glands, men have been acquainted for thousands of years. The oldest writings make occasional reference to the "seed of the man." While this term "seed of the man" applies frequently to the progeny of man, in other cases it is evident from the context that it refers to the semen of the man. In fact the word semen means seed. In a similar way, men have for a long time known about the products from the ovaries, the external secretion, the eggs;-but it is comparatively recently that we have come to know about the internal secretion; in fact the whole subject of internal secretions is a distinctly modern subject. There was no thought of any such thing existing before the epoch-making work of Brown-Sequard, (1) whose principal publication on this subject appeared in the Archives of Physiology in 1889. Two years later Poehl, (2) of Germany, writing in the Berlin Medical Weekly, refers to this internal secretion from the testicles as "spermin," a term which has frequently been applied to it since, though not universally used to designate it. In 1896 Zoth (3) made some important contributions on this subject, which were published in Pflueger's Archives of Physiology. Zoth showed that this substance immensely increased the working power of muscles when injected into them before experiment. Since that time more than a score of important communications have been published regarding researches in the laboratories of Europe. Most of these have been within the last ten years; and, practically, without exception, they have confirmed the earlier findings; so that the proof is now positive and final that the testicles, as well as the ovaries, prepare this internal secretion from the beginning of adolescence throughout adolescence and middle life and until the beginning of the senile period. The best summary of these recent in