TUMOUR GROWTH IN HYPOPHYSEAL DWARFISM

689 and is

usually

sparse, there

being only

a

single

row

of

cells, often incomplete, but in the basal ganglia, midbrain, pons and medulla there are occasionally as many as

four

Fat

rows.

phagocytes

tion, especially where there is

around the affected vessel, and

demyelinated

areas.

There

are

also a

occur

zone

of

in the infiltra-

demyelination

few are present in other also a few small hbomor-

a

The "cuffed" vessels are few and are situated more often in the white matter than in the grey, but there appears to be no constant relation between the, demyelination and " cuffing " : any one vessel may show both changes together or either

rhages associated with the " cuffing."

separately. A demyelinating encephalitis is present in which the demyelination is less conspicuous and perivascular infiltration more conspicuous than usually described. CASE 4.-A mild case, the prominent features of which were involuntary movements of the head and grimacing. .

A female aged 1 yr. 4 mths. History.-June 11th, 1936: cough, coryza, discharging eyes. June 12th : rash, which first appeared on face. On admission (June 12th).-Temperature 99° F., pulserate 104, respirations 24. Typical attack of measles of

moderate

severity. Progress.-June

17th: symptoms of measles largely Child irritable. June 30th : temperature 105° F.; attack of enteritis. July 2nd : involuntary movements of face and head; grimacing; smiling at apparently nothing in particular, as she appeared unaware of her environment; twitching of left side of face ; head nodding and other " purposeless " movements. No evidence of tetany; no meningeal signs. Examination of central nervous system negative except that right knee-jerk was not elicited and left knee-jerk was feeble. Still irritable. July 4th : parents visited the patient and thought she had a blank look and did not recognise them. Movements continued rather intermittently. Abdominal reflexes and tendon-jerks not elicited. Plantar responses doubtful. July 5th : little more irritable. Doubtful rigidity of neck. July 10th : improving ; still grimacing but not so frequently. Tendon reflexes still absent but abdominals now brisk and equal. No meningeal signs. Indefinite weakness of left leg. Thereafter improvement continued slowly, and after July 31st no movements were seen. August 14th : apparently mentally normal; says " mummie" and "daddy." Stands by herself and walks around cot. All tendon reflexes present but anklejerks feeble ; abdominal reflexes present and equal. General condition good. August 20th : discharged. subsided.

CASE 5.-A severe case successfully treated with convalescent measles-encephalitis serum. The striking feature was the resemblance of the disease to epidemic

encephalitis. A female

aged

4 yrs. 6 mths.

History.-July 5th, 1936 : cough. Julv 6th : rhinorrhoea ; rash, which first appeared on the face. July 9th : vomiting. On admission (July 10th).—Temperature 101’8° F., pulse-rate 152, respirations 56. Quite ill; feverish and restless; breathing distressed; marked coryza; rales scattered over lungs ; general morbilliform rash ; Koplik spots in profusion. Proqre88.-July 11th: vacant look ; slight internal squint; incontinence of urine ; obstinate constipation ; temperature subsiding. of

July

12th :

indefinite

rigidity

retraction ; Kernig sign not elicited ; deep jerks, eye reflexes, and superficial reflexes present. Screaming attacks, particularly when disturbed ; does not talk ; refuses food ; nasal feeding begun. July 15th : definite signs in the nervous system : neck rigidity ; positive Kernig; left knee-jerk and both ankle-jerks absent ; abdominal reflexes absent; plantar reflexes doubtfully extensor; pupils equal, react to light and accommodation ; vacant expression; doubtful weakness of the right side of face; doubly incontinent; temperature neck ;

no

rising.

Lumbar puncture showed clear fluid under moderate pressure. Report (Dr. W. Mair) :

July 17th : much more lethargic ; almost unconscious. deep jerks and abdominal reflexes absent. Temperature 100° F. ; general condition much worse ; prognosis considered almost hopeless. Serum treatment.-At this stage Dr. W. Gunn suggested the administration of serum from a patient convalescent from measles encephalitis ; 20 c.cm. were given intravenously and produced immediate benefit. The downAll

ward progress was arrested and within 24 hours there was evidence of definite improvement. Consciousness returned sufficiently to allow the patient to answer simple questions ; the temperature began to subside ; she started taking fluids by mouth ; and the neurological signs improved. July 19th : neck rigidity less pronounced ; Kernig sign almost disappeared; abdominal reflexes present; left knee-jerk present ; drowsiness largely gone. Thereafter her condition steadily improved and on July 22nd no abnormality could be detected in the central nervous system. She was talking and feeding herself. July 23rd : a considerable change appeared in her demeanour. She was " naughty," screaming at the top of her voice, constantly trying to get out of bed, and tending to be vicious and destructive. After one meal she threw her plate across the ward. A fine tremor of the parkinsonian type appeared. This changed manner persisted for a week during which time she slept badly and required hypnotics. She then improved fairly rapidly and by August 2nd was apparently normal, tremor having disappeared. She was discharged on August 22nd mentally normal, well behaved, with normal speech, regular action of the bowels, and no abnormality of the central nervous system. DISCUSSION

Of the cases in this series all showed involvement of the sphincter of the bladder. Definite meningeal signs were present in all except Cases 1 and 4. In Cases 3, 4, and 5 mental symptoms or interference with consciousness occurred, associated with involuntary muscular movements. Case 5 was striking in its resemblance to epidemic encephalitis ; and its rapid response to convalescent measles-encephalitis serum was most encouraging. REFERENCES

Dufourt, A., and Reure, J. (1932) Lyon méd. 149, 235. Ford, F. R. (1928) Bull. Johns Hopk. Hosp. 43, 140. Guibert, L. E. M. (1936) Rev. Serv. San. mil. 104, 477. Lowenburg, H., and Schaller, A. L. (1926) Arch. Pediat. 43, 73. Peterman, M. G., and Fox, M. J. (1933) Amer. J. Dis. Child. 46, 512.

TUMOUR GROWTH IN HYPOPHYSEAL DWARFISM BY Prof. BERNHARD ZONDEK, M.D.

(From

the Gynæcological and Obstetrical Department Rothschild-Hadassah Hospital, Jerusalem)

of

the

As reported in previous papers (Zondek 1936) it is possible to produce dwarfism experimentally in rats by the prolonged administration of follicular hormone, which prevents the growth hormone elaborated in the anterior pituitary from entering the blood stream. The absence of the growth hormone is shown by the fact that the rats will grow more slowly and cease growth earlier than normally. While the control animals are 16 - 5 cm. long and weigh 170 g. on an average, the dwarfs reach a length of only 14-4 cm. and a weight of 90-100 g. The slackening of growth is proportionate, affecting equally all parts of the body-the head, the bones, the tail, and the internal organs. That the dwarfing is hypophyseal in origin may be deduced from the finding that Evans’s pituitary growth hormone will stimulate the dwarf animals to grow again.

690 TUMOURS IN DWARF RATS

It seemed interesting to investigate the development of malignant tumours in dwarf animals, since it has been suggested that this is influenced by the anterior pituitary. Ball and Samuels (1932) observed a less pronounced growth of transplanted mammary carcinoma in hypophysectomised albino rats. Reiss, Druckrey, and Hochwald (1933) have stated that if a rat weighing 60-120 g. is inoculated with Jensen sarcoma two or three weeks after hypophysectomy, the tumour will grow to the size of a pea, or at most to that of a cherry, and will then undergo complete involution. The greater the time since hypophysectomy, the shorter will be the duration of life for the tumour. This effect is missed even if the slightest

Eunuchoid dwarf rat (b) in which dwarfing was produced by 300,000 M.U. of dimenformon given from the age of one month, and control rat (a). Both were males, aged 6 months, and are shown five weeks after the implantation of a

benzpyrene

sarcoma.

remnant of anterior pituitary tissue is left during the extirpation, which shows that it is the anterior lobe that inhibits the growth of the tumour. This is also proved by the fact that the growth-inhibition is counteracted by giving Evans’s growth hormone. If, therefore, the growth of malignant tumours depends upon the growth hormone of the anterior pituitary, one would expect that malignant tumours would not grow-or at least would grow much more slowly-in our hypophyseal dwarf rats than in the controls. For the experimental tumour I used the benzpyrene sarcoma described by Kennaway and Cook et al. (1935). I did not use, however, the primary tumours obtained by prolonged subcutaneous injection of benzpyrene, but those that had already gone through several passages on transplantation ; all these tumours " took."1 For the first experiments a tumour material was used that had gone through six passages. Pieces of the tumour, the size of a small pea, were implanted into the left axilla of the rat. As experimental animals we chose male rats that had each received twice a week 5000 M.U. (mouse units) of Dimenformondiluted in 0 2 c.cm. of oil, for at least five months. They were typical dwarf males, 14’4 cm. long and weighing 100 g. The control animals were each injected over the same period twice a week with 0’2 c.cm. of olive oil. They were 16’5 cm. long and weighed 170 g. After the tumour implantation the dwarf rats were further treated with dimenformon, the control animals still receiving olive oil. 1 For the supply of the tumour material I am indebted to Prof. L. Halberstaedter of the cancer research institute in the Hebrew University, Jerusalem. 2 I am indebted to Dr. Marion Tausk of Messrs. Organon (Oss, Holland) for supplying dimenformon.

A tumour the size of a bean was palpable ten days after the implantation in both the control and the experimental animals. The tumours grew rapidly, and three weeks after implantation they had already reached the size of a pigeon’s egg. At five weeks the tumours were enormous compared with the size of the rat, being about as big as a hen’s egg. The important fact is that the growth of the tumour was just as rapid in the dwarf animals as in the controls (see Figure). ,Eight months later I carried out the same experiments in female animals, this time using a tumour material that had gone through twenty passages. Here again the tumour " took " in every animal. The result was the same as in the first series. The tumours grew extraordinarily rapidly and there was no difference between the controls and the dwarfs.

These experiments prove that the growth of the tumour in hypophyseal dwarf animals is the same as in normal animals. Although in the dwarf rats the growth hormone is out of action, and the growth of the body and of internal organs is accordingly inhibited, its absence does not seem to affect the development of implanted malignant tumours. There is, however, a characteristic difference between a hypophysectomised animal and our experi. mental animal. In the former, besides the growth hormone, all the hormones elaborated in the anterior lobe are absent. In my experimental animals the growth hormone is probably being produced in the anterior lobe, but its secretion into the blood stream is being prevented. In my animals I block certain hormones, and among them the growth hormone. Perhaps the hypophysectomised animal differs in its behaviour towards the tumour growth from one in which the pituitary is merely blocked by follicular hormone; and possibly my results, so contrary to those hitherto reported, may be explained by this difference. This, however, does not seem to me to be very probable. If, indeed, the growth hormone is one, or the only, stimulating factor in the growth of malignant tumours, one would expect that in our dwarf animals the malignant tumours would not grow at all, or would at least grow much more slowly than in the controls. Since, however, the development of the tumours in our dwarf animals has not been inhibited at all, I do not believe that the anterior pituitary regulates the growth of malignant tumours. SUMMARY

treatment with follicular hormone the function of the growth hormone of the anterior pituitary, and hence results in hypophyseal dwarfism. The release of the growth hormone into the blood stream is inhibited by follicular hormone, and this reduces the growth of the whole body, including the internal organs. 2. When malignant tumours are implanted into hypophyseal dwarf rats-I used a sarcoma caused by benzpyrene which had gone through several passages-the tumours grow as fast in the dwarfs as in the control animals. The absence of growth hormone in the dwarf rats consequently does not impede the growth of malignant tumours. 3. From this it follows that the growth hormone of the anterior pituitary has no important effect upon the growth of malignant tumours. 1.

Prolonged

impairs

REFERENCES

Ball,

H.

A.,

and

Samuels, L.

T.

(1932) Amer. J. Cancer, 16, 351.

Kennaway, E. L., and Cook, J. W., et al. (1935) Proc. Roy Soc. B.

117, 318. Reiss, M., Druckrey, H., and Hochwald, A. (1933) Z. Med. 90, 408. Zondek, B. (1936) Lancet, 1, 10, 776 ; 2, 842.

ges. exp.