NECHELES

AND APPEIr---GASTRIC

SECRETION IN EXTRAGASTRIC MALIGNANCY

261

of regional enteritis. The occurrence of this disease in three members of one f a m i l y is uncommon. The g r e a t difficulties t h a t may arise in the m a n a g e m e n t of this disease are illustrated by the cases of the sisters. In the light of present knowledge, resection of the diseased portion is the t h e r a p e u t i c procedure of choice but a b e t t e r u n d e r s t a n d i n g of this unusual disease may, in the future, offer a less radical t r e a t m e n t . We feel t h a t enterocolitis is a late stage in the p r o g r e s s of regional enteritis.

meats. Improvement was slow and when this paper was w r i t t e n there was no immediate prospect t h a t operation would be performed. Hence, it was hoped t h a t a period at home might hasten h e r improvement. In this case, as f a r as could be determined from the roentgenogram, the disease extended f r o m the t e r m i nal portion of the ileum to the splenic flexure of the colon. I f this is correct, there is reason to hope t h a t a remission may ensue. If such occurs, the surgeon may be able to effect a shunt, so to speak, around the diseased portions, as well as to resect the segment affected by enterocolitis.

REFERENCES 1.

SUMMARY Three siblings, two sisters and a brother, have been found to exhibit various m a n i f e s t a t i o n s c h a r a c t e r i s t i c

2. 3.

Crohn, B. B., Ginzburg, Leon and Oppenheimer, G. D.: Regional Ileitis; a Pathologic and Clinical Entity. J. A. M. A., 99:13231329, Oct. 15, 1932. Crohn, B. B. : The Broadening Conception of Regional Ileitis. Am. J. Digest. Dis. and Nutrit., 1:97-99, April, 1934. Pemberton, J. deJ. and Brown, P. W.: Regional Ileitis. A n n . Surg., 105:855-870, May, 1937.

Gastric Secretion in Extragastric Malignancy By H. NECHELES, M.D., Ph.D. and

MAX APPEL, M.D., B.Sc. (Tor.) With the assistance of DONALD WALD and WM. OLSON CHICAGO, I L L I N O I S

diminution in g a s t r i c secretion which occurs T inHEcases of g a s t r i c malignancy has long been recognized. Evidence has also been produced on several occasions which suggests t h a t a s i m i l a r reduction in stomach secretion is found in p a t i e n t s with extrag a s t r i c malignancy. Fenwick (1) in 1880 made careful histologic studies of the g a s t r i c mucosa in a series of cases of carcinoma of the b r e a s t and uterus, and in many of these found marked a t r o p h y of the g a s t r i c mucosa. Ewald (2) reported g a s t r i c anacidity and mucosal a t r o p h y in a p a t i e n t with a carcinoma ef the duodenum situated 2 cms. below the pylorus. The a n a c i d i t y and mucosal a t r o p h y in this case were probably due to pyloric occlusion or pyloric spasm and g a s t r i t i s . Moore, Alexander, Kelly and Roaf (3) ~n 1905 investigated 17 patients with " m a l i g n a n t disease of organs other t h a n the stomach." They concluded t h a t "the absence of free hydrochloric acid in cancer of the stomach is not due to local action in t h a t organ, for hydrochloric acid is absent or reduced g r e a t l y in amount w h a t e v e r may be the situation in the body of the growth." Riegel (4) observed lowered g a s t r i c acidity in c a s e s of carcinoma of the esophagus. F r i e d e n w a l d and his collaborators (5 and 6) carefully investigated g a s t r i c secretion in patients with extrag a s t r i c malignancies. In a large proportion of these cases they found lowered g a s t r i c acidity which persisted "even a f t e r removal of the cancerous mass." If t h i s lowered g a s t r i c acidity in association with e x t r a g a s t r i c malignancy actually does occur, it would ~Aided by t h e Max Folk Memorial Fund and the H e n r y Levy Fund. From the Departments of Gastro-Intestinal Research and of Pathology, Michael Reese Hospital, Chicago. Submitted February 21, 1939.

be of considerable significance for two main reasons. F i r s t the reduction in acid content of the stomach secretion would serve as a useful diagnostic aid in questionable cases of malignancy, and secondly, it might reveal a hitherto unknown relationship between g a s t r i c secretion and m a l i g n a n t growths. It was f o r the purpose of d e t e r m i n i n g experimentally if e x t r a g a s t r i c carcinomas are accompanied by impaired g a s t r i c secretion t h a t this investigation was undertaken. M A T E R I A L AND M E T H O D S The determinations were carried out on r a b b i t s which had been inoculated with the Brown-Pearce r a b b i t carcinoma.+ The l a t t e r is a highly m a l i g n a n t carcinoma of the testis which metastasizes extensively and rapidly produces a diffuse carcinomatosis. Tumors were also t r a n s p l a n t e d into the a n t e r i o r chambers of r a b b i t ' s eyes and suspensions of t u m o r cells were inoculated intravenously. In all, 16 tumor r a b b i t s were used, 14 of which had bilateral p r i m a r y t e s t i c u l a r t u m o r s with extensive metastases to all the thoracic and abdominal viscera, one had a large t u m o r of the eye, and one had been inoculated intravenously w i t h a suspension of t u m o r cells producing an overwhelming carcinomatosis. In order to ensure a more fulmin a t i n g carcinomatosis the animals were also t r e a t e d with l : 2 : 5 : 6 - d i b e n z a n t h r a c e n e as d e s c r i b e d i n a previous communication (7). In order to d e t e r m i n e the normal values f o r g a s t r i c ~This t u m o r was supplied through the courtesy of Dr. J. B. Murphy of the Rockefeller Institute for Medical Research.

262

AMERICAN JOURNAL OF DIGESTIVE DISEASES

acidity and pepsin in our rabbits gastric analyses were done on 5 normal rabbits. Gastric analyses were also done on two rabbits receiving injections with l:2:5:6-dibenzanthracene lo determine whether or not this substance might affect gastric secretion. The determinations were done twice weekly. The animals were starved for 24 hours before aspiration

and for pepsin 8.30. Only in an occasional tumor animal did the gastric acidity values fall below this level, the average values for all the tumor animals being higher than this level (Table I I ) , the average free acid being" 80, the total acid 153 and the pepsin 5.42. In tumor rabbit No. 13 the free acid dropped to 24 and the total acid to 85. However, as was proven at autopsy one day after the first aspiration, this I

TABLE

Average values for gastric secretion in each animal CONTROLS R a b b i t No. No. of g a s t r i c aspirations Free acid

1

2

3

TUMOR RABBITS 4

5

8

9

10

11

12

13

14

15

5

2

6

3

3

4

2

4

6

1

1

1

104

13

86

89

76

67

96

87

66

55

24

148

103

16

%

17

18

19

2O

21

22

23

5

2

2

4

1

5

3

1

96

145

66

59

127

71

88

76

T o t a l acid

125

40

i 129

163

146

126

J57

134

96

73

85

198

158

156

189

135

121

167

112

133

111

Pepsin

11.21

6.78

3.96

6.27

13.28

8.58

.93

2.60

7.10

3.06

26.83

2.82

10

4.39

3.89

2.21

9.88

3.72

3.87

2.16

4.65

in order to obtain partial evacuation of the stomach without which gastric juice could not be aspirated. The technique of aspiration was as follows: A No. 16 urethral catheter was slowly passed over the rabbit's tongue, the forefinger of the operator's hand being kept in the animal's mouth between the jaws, thus compelling the animal to perform chewing movements. In this manner the tube was directed down the esophagus and prevented from entering the trachea. Five to ten ccms. of gastric juice could usually be aspirated without great difficulty. The gastric juice was titrated for free and total acidity using TSpfer's reagent, phenolphthalein and N/10 s o d i u m hydroxide. The values for acidity are expressed in clinical units, i.e. ccms. of N/10 HC1 in 100 ccms. of gastric juice. Pepsin determinations were done by the modified Mett method (8), Pepsin values are expressed in Mett units, i.e. in squares of the average digestion of the Mett tubes. Careful histologic studies of the gastric mucosa were also done in several of the tumor animals to determine if any mucosal atrophy occurred as described by Fenwick (1). RESULTS A few of the animals did not tolerate the aspiration procedures well and died, usually of a bronchopneumonia following the first or second aspiration. In most of the rabbits, however, it was possible to obtain at least four or five samples of gastric juice before the animals succumbed to the effects of the carcinomatosis, cachexia and usually a terminal bronchopneumonia. At autopsy an extensive spread of the carcinoma to lungs, liver, spleen, kidneys, lymph nodes and other organs was found in all the tumor animals. The average duration of life following the first appearance of the tumor was usually three to five weeks. An analysis of Table I shows essentially that there is very little variation in gastric secretion between normal animals and cancer animals. In only an occasional rabbit was there any reduction in gastric acidity. Even in those animals which died with marked cachexia and extensive carcinomatosis normal values for free and total acid and for pepsin were obtained in nearly all cases. In the normal animals the average value for free acid was 74, for total acid 121,

rabbit had a bilateral bronchopneumonia and was extremely cachectic in addition to having a diffuse carcinomatosis at the time the gastric juice was obtained. It is an established fact that a severe infection with high fever such as a bronchopneumonia will cause a reduction in gastric acidity. This is f u r t h e r substantiated by the fact that control rabbit No. 2, without tumor growth had low levels for gastric acidity (free acid 13, total acid 40) and at autopsy following the second aspiration was also found to have a bilateral confluent bronchopneumonia. Even t u m o r rabbit No. 23, which had been inoculated intravenously with a suspension of tumor cells and which at autopsy was TABLE I I

Average values for gastric secretion in the series of normal rabbits and in the series of rabbits with extragastric carcinoma Controls N u m b e r of r a b b i t s

5

Tumor Rabbits 16

T o t a l n u m b e r of g a s t r i c aspirations

19

47

F r e e acid

74

80

T o t a l acid

121

153

Pepsin

8.30

5.42

found to have hundreds of tumor nodules scattered throughout the various organs, had a free acidity elf 76 and a total acidity of 111. Confirming various authors we noted that in those. animals with low gastric acidity the pepsin values were elevated, and that in animals with high acidity values for pepsin were diminished. In the two nbrmal rabbits treated with l : 2 : 5 : 6 dibenzanthracene to determine whether this substance might affect gastric acidity no essential changes in gastric secretion were observed. Histologic studies of the gastric mucosa of rabbits with diffuse carcinomatosis failed to reveal any evi-

GAUSS--THE GASTRO-INTESTINALONSET OF PULMONARY TUBERCULOSIS

263

by Vanzant, Alvarez, Eusterman, Dunn and Berkson (10), the percentage of true and apparent achlorhydria in males between 50-54 is 19.5% and 18.5% respectively and in women it is 22.8% and 15.8% respectively. These authors also showed that in man the free and total acid diminish considerably with advancing age. It is apparent therefore that in the relatively small series of cases reported by Friedenwald and Rosenthal the authors 'are not justified in ascribing the reduced gastric acidity to the malignant growths since most of their patients fall into the age group in which achlorhydria is fairly common in normal individuals. SUMMARY AND CONCLUSIONS Gastric secretion was investigated in a series of 16 rabbits with Brown-Pearce tumors in an attempt to substantiate the c l i n i c a l observation that human beings with extragastric malignancies have diminished gastric acidity. No alteration in gastric acidity or pepsin was observed even in animals with extensive carcinomatosis. These findings together with the observation that diminished gastric acidity may be present long before the appearance of a malignant tumor, and the fact that a higher incidence of achlorhydria and diminished gastric acidity occur normally with advancing age lead to the conclusion that reduced acid secretion in the stomach in cases of extragastric malignancy has not been established beyond doubt.

dence of mucosal atrophy as reported by Fenwick (1). All of the tumor rabbits developed a moderate secondary anemia, the hemoglobin levels ranging from 60%-75%, and the red blood cell count from 4,000,0005,000,000. DISCUSSION The above described experiments provide fairly conclusive evidence that in rabbits the secretion of the stomach is not affected by extragastric malignant tumors. In only one of the tumor rabbits (No. 11) was a progressive drop in the free and total acid content of the gastric juice noted, but as mentioned above this animal had a bilateral bronchopneumonia at the time the gastric secretion was obtained. The reduction in gastric acidity in this case was probably due to the overwhelming infection and fever. In a few of the other tumor rabbits occasional low acid values were observed, but they invariably returned to normal levels even though the tumors continued to grow progressively and the animals became more and more cachectic. I f we are to apply these results to man the conclusions described by the authors mentioned above must be doubted; this is supported by observations of other authors: Comfort, Butsch and Eusterman (9) studied gastric acidity in 89 patients before and after the development of carcinoma of the stomach. The gastric acidity was low in 79 of these subjects before gastric carcinoma developed; a number of these cases were investigated many years before the malignancy appeared. Another important fact which must be considered in evaluating the results obtained by the earlier investigators is the well known observation that in the age group in which malignant growths usually appear a high incidence of hypoacidity or anacidity is found in a normal population. In the series of cases described by Friedenwald and Rosenthal (6) of the 29 patients, 13 were males ranging in age between 42-69 with an average age of 54, and 16 were females whose ages ranged between 38-62 years with an average age of 52 years. According to a statistical study made on a vast number of subjects

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Fenwick, S . : On Atrophy of the Stomach and on Nervous A f fections of the Digestive Organs. Churchill, London, 1880. Ewald, C. A . : Berlin klin. Wochenschr., 23:527, 1886. Moore, B., Alexander, W., Kelly, R. E. and Roaf, I-I. E . : Lancet, 1:1120, 1905. R i e g e l : Zeitschr. f. klin. Med., Berlin, 11:1, 1886. Friedenwald, J . and Brown, L. T . : Med. J. and Record, 126:491, 1927. Friedenwald, J . and Rosenthal, L. J . : N e w Fork Med. J., 24:344, 1907. A1opel, M., Strauss, A. A., Kolischer, G. and Necheles, H. : Amer. J. of Cancer, 28:239, No, 2, 1938. H a w k , P. B. and Bergeim, O. : Practical Physiological Chemistry. 10th edition, !o. 299, 1931. P. Balkiston's Son & Co., Inc., Philadelphia. Comfort, M. W., Butsch, W. L. and E u s t e r m a n , G. B . : Amer. J. Dig. Dis. and Nutrit., 4:673, 1937. Vanzant, F. R., Alvarez, W. C., E u s t e r m a n , G. B,, Dunn, tI. L. and Berkson, J . : Arch. Int. Med., 49:345, 1932.

The Gastro-lntestinal Onset oF Pulmonary Tuberculosis By HARRY GAUSS, M.D. D E N V E R , COLORADO

HE onset of pulmonary tuberculosis is extremely T variable. At times it fails to be recognized by both patient and physician. Tuberculosis is a disease of many manifestations. Like syphilis, it may masquerade as other ailments. Seldom does it affect two persons in exactly the same manner. Even when two individuals of the same age, sex, and approximate station in life develop pulmonary tuberculosis of the same lung area, nevertheless their respective clinical courses may be entirely different. One of them may have a normal temperature, the other has a fever; one ~ F r o m the D e p a r t m e n t of Medicine, U n i v e r s i t y of Colorado. Read before the Colorado Tuberculosis Society, F e b r u a r y 15, 1939. Submitted February 24, 1939.

carries on his work, the other is bed-fast; one lives, the other dies. W. G. Brown (1)~ a lay victim of tuberculosis, was writing his "Confessions of a T. B." in 1914, when he was interrupted by the Grim Reaper before he could complete his task. His unfinished manuscript appeared posthumously in the Atlantic Monthly in which he describes his "initiation into the brotherhood of the T. B.s." "A word about the way we enter it," he wrote, "of the initiation into our brotherhood. Unfortunately it is not always the same. On the contrary, the entrances are innumerable, however sole the exit. Indeed the