Ana Surgical Clinics On the Cause of Death in Cancer: Systemic Effects of Nonendocrine Tumors**Aided by U.S. Public...
Sorun bildirThis book has a different problem? Report it to us
Check Yes if Check Yes if Check Yes if Check Yes if
you were able to open the file
the file contains a book (comics are also acceptable)
the content of the book is acceptable
Title, Author and Language of the file match the book description. Ignore other fields as they are secondary!
Check No if Check No if Check No if Check No if
- the file is damaged
- the file is DRM protected
- the file is not a book (e.g. executable, xls, html, xml)
- the file is an article
- the file is a book excerpt
- the file is a magazine
- the file is a test blank
- the file is a spam
you believe the content of the book is unacceptable and should be blocked
Title, Author or Language of the file do not match the book description. Ignore other fields.
Change your answer
On the Cause of Death in Cancer Systemic Effects of Nonendocrine Tumors*t From the Department of Surgery and the University Hospital, University of Mississippi Medical Center, jackson JAMES D. HARDY, M.D., F.A.C.S. Professor and Chairman, Department of Surgery; Surgeon-in-Chief, University Hospital; Chief Surgical Consultant, Jackson Veterans Hospital and Mississippi Tuberculosis Sanatorium THE PATHOPHYSIOLOGIC MECHANISMS by which malignant tumors cause death of the patient were for many years obscure. Although in some instances hemorrhage or major interference with the normal activity of some vital organ or tissue had clearly occurred, in perhaps the majority of patients no such gross organ dysfunction was apparent. That is, the immediate cause of the "malignant cachexia" could not be discerned. In recent years, however, a considerable body of information has been accumulated which documents the fact that nonendocrine tumors do in fact produce subtle and at times less subtle changes in the metabolism of the host. It is reasonable to assume that these biochemical changes contribute to the death of the patient/· 2 and it is the purpose of this report to present the evidence for this assumption. The systemic effects of the common endocrine tumors will not be discussed, since most physicians are familiar with the changes brought about by excessive production of one or the other of the common thyroid, parathyroid, pancreatic and adrenal hormones. Nevertheless, several tumors will be considered which probably do represent endocrine tumors but which are not usually classified as such. Due to space limitations, only selected references to the rapidly expanding pertinent literature will be cited. The initial portion of the discussion deals with the systemic effects of tumors arising from various organs, followed by certain systemic effects common to tumors of different organs. For example, bronchogenic *Aided by U.S. Public Health Service Grant Number A-5122. t Based on the Hodgen Lecture delivered befo; re the St. Louis Surgical Society, March 6, 1962. 305 306 JAMES D. HARDY SOME SYSTEMIC EFFECTS OF ~NONENDOCRINE- TUMORS CEREBELLAR HEMANGIOMA POLYCYTHEMIA LUNG CARCINOMA THYMIC AND MEDIASTINAL TUMORS BONE AND JOINT CHANGES NEUROMUSCULAR CHANGES CEREBELLAR ATROPHY HYPERCALCEMIA CUSHING'S SYNDROME GYNECOMASTIA MYASTHENIA GRAVIS ANEMIA (APLASTIC) .HYPOGAMMAGLOBULINEMIA CUSHING'S SYNDROME RETROPERITONEAL FIBROMA HYPOGLYCEMIA ULCEROGENIC ISLET CELL TUMOR OF PANCREAS POLYCYTHEMIA HYPOGLYCEMIA GASTRIC HYPERSECRETION FLUSHING AND DIARRHEA HYPERNEPHROMA MALIGNANT CARCINOID WITH HEPATIC METASTASES CARCINOMA RIGHT COLON POLYCYTHEMIA MYOPATHY HYPERCALCEMIA ·· VILLOUS PAPILLOMA OF RECTUM ANEMIA FLUID AND ELECTROLYTE LOSSES TUMORS OF BLOOD-FORMING TISSUES AND RELATED ELEMENTS PROSTATE ACID PHOSPHATASE ANEMIA BONE PAIN HYPERCALCEMIA DEFECTIVE IMMUNITY ABNORMAL PROTEINS FEVER Fig. 1. Many of the various nonendocrine tumors have been shown to produce distant effects not due to metastases. carcinoma may produce hypercalcemia or neuromuscular dysfunction, but so may epithelial cell tumors of other organs. TUMORS OF SPECIFIC ORGANS Many neoplasms have relatively nonspecific or, at best, poorly documented systemic effects. The emphasis here will be directed toward those tumors certain of whose general effects have already been more positively identified (Fig. 1). The nonpituitary brain tumors cause few known specific systemic biochemical effects, but certain hemangioblastomas of the cerebellum produce polycythemia. 3 Tumors of the Thymus Gland MYASTHENIA GRAVIS. The association between thymic tumors and myasthenia gravis has long been recognized.H There is increasing evi- On the Cause of Death in Cancer 307 dence that a chemical substance may be secreted by the thymic tissue in many cases of myasthenia gravis. Thus in a sense the thymus might be considered an endocrine organ. Wilson and Wilson10 have apparently produced a potent extract of thymus from patients with myasthenia gravis which has a nerve-blocking effect similar to that of curare. Such an effect was not produced by extracts of the thymus glands of normal adults but was produced by factors present in infantile or fetal thymic tissue as well as in the fetal thymus of the whale. Nevertheless, the thymic extracts which they evaluated did not result in the characteristic features of myasthenia gravis nor was the effect reversed by neostigmine. Additional evidence that a chemical substance may be liberated by the thymus of the patient with myasthenia gravis was the report that perhaps one-third of the infants born to mothers with this disease may exhibit myasthenia for a day or so following birth. Such infants recover quickly and require only temporary support. 11 AGAMMAGLOBULINEMIA. Congenital agammaglobulinemia is the result of a recessive sex-linked gene, which affects males only and becomes clinically manifest in early childhood.l 2 However, idiopathic acquired agammaglobulinemia has been reported in association with thymoma. Six such cases have been reported to date 12- 16 and others will doubtless be encountered. MacLean and associates14 found that removal of the thymic tumor had no effect upon the enhanced susceptibility to infection exhibited by their patient with acquired agammaglobulinemia. Experimental thymectomy in animals had no effect upon the gamma globulin concentration of plasma. 14 APLASTIC ANEMIA. A refractory type of anemia has been noted in association with thymomas,t 7- 20 and occasionally splenomegaly has also been present. The primary defect would appear to be a suppression of erythrogenesis, and the anemia has been found to improve following excision of the tumor, at least in some cases. 21 Tumors of the Lungs and Pleura Tumors of the lungs and pleura may be associated with a variety of clinical changes. In fact, bronchogenic carcinoma represents perhaps the best example of a nonendocrine neoplasm whose systemic effects may be multiple and profound. An analysis of such effects strongly suggests that many other and probably most malignant nonendocrine tumors will be found to have deleterious systemic effects. BoNE AND JOINT CHANGES. Clubbing of the fingers and periosteal proliferation involving the long bones and particularly the tibiae are commonly present in patients with bronchogenic carcinoma. Of course, these changes are not peculiar to pulmonary and pleural neoplasms, but such tumors should at least be considered in the presence of the clinical and roentgenological findings. Wierman, Clagett and McDonald22 reviewed the clinical records of 481 patients who had had 308 JAMES D. HARDY malignant lung tumors resected. They found marked joint changes had been present in 5.2 per cent of the cases. Clagett and his associates 6 also reported a series of 24 cases in which a localized fibrous mesothelioma had been removed surgically. There were 14 men and 10 women, with an average age of 49.3 years. Among the clinical findings were chills or a chilly sensation, fever, and at times painful and perhaps migratory involvement of the joints, with or without clubbing of the fingers. Surgical removal of the tumor produced prompt relief of these symptoms. GYNECOMASTIA. Whereas most thoracic surgeons have ,.encountered patients with bronchogenic carcinoma who had bone and joint changes, gynecomastia is not so frequently present in such cases. Nevertheless, we 23 reported three cases of gynecomastia associated with lung cancer and have since observed a fourth. This combination wasfound to have been reported previously' by others. 24 · 25 Two of our patients also had clubbing of the fingers, and in one of these the joint manifestations were so severe that arthritis had been given as the admission diagnosis. In one patient gynecomastia had been the presenting complaint and had been treated elsewhere with hormones for several weeks before chest pain had led to a search for intrathoracic disease which disclosed the lung lesion. While the endocrine factors responsible for the bilateral gynecomastia were not definitely established, varying degrees of testicular atrophy wefe present in all three patients, and a subnormal level of androgen production was indicated by the 24-hour 17-ketosteroid excretion of 5.3 mg. exhibited by one of the two patients so studied, In another patient the urinary estrogen content was reported as "elevated." It will be seen that adrenocortical activity is frequently abnormal in the presence of bronchogenic carcinoma, and a combination of reduced androgen production and increased adrenal estrogen secretion may play a role in the gynecomastia occasionally present in male patients with these tumors. ADRENOCORTICAL HYPERFUNCTION. There has long existed a special interest in possible relationships between steroid metabolism and tumors. As early as 1944 Dobriner and his associates26 · 27 reported the presence of the particular steroid 11-hydroxyaetio_cholanolone in the urine of a high proportion of patients with malignant tumors, as well as in patients with Cushing's syndrome. 28 In the intervening years varying degrees of adrenocortical hyperactivity have been recorded in association with different malignant tumors, among these being pancreatic and mediastinal tumors but especially lung cancers. 2s-32 Segaloff and his associates33 have found consistently elevated resting plasma cortisol levels, as well as a hyper-responsiveness to ACTH, in patients with bronchogenic carcinoma. Vogel, Keating and Bahn32 collected 23 cases of Cushing's syndrome associated with lung cancer. In reviewing in 1952 the incidence of Cushing's syndrome associated with bronchial carcinoma, Thorne 28 pointed out that in such patients the tumor was usually of the small cell ("oat-cell") type. The adrenal On the Cause of Death in Cancer 309 cortices were usually found at autopsy to be hyperplastic, and the possible mechanisms by which the hyperplasia was produced were considered. It was suggested that both the tumor and the Cushing's syndrome might be due to a basic endocrine dysfunction; or that the tumor produced an ACTH-like substance which caused adrenocortical hypertrophy; or that the tumor stimulated the anterior pituitary to release increased amounts of ACTH. More recently, Marks, Anderson and Liberman31 have reviewed this problem in the course of reporting a case of epidermoid carcinoma of the lung associated with extreme bilateral adrenocortical hyperplasia. Although their patient exhibited a markedly exaggerated free and conjugated plasma 17-hydroxycorticosteroid response to the conventional ACTH test, no objective clinical evidence of either hyper- or hypoadrenocorticism was present. They postulated that the adrenocortical enlargement had been produced by the action of an as yet unidentified adrenal growth factor which did not affect adrenal secretion per se. As indicated previously, such a factor might be produced by the tumor itself, or the tumor might stimulate the pituitary to release such a substance. SERUM ELECTROLYTE CHANGES. Hypercalcemia. Various abnormalities of the serum electrolytes have been described in connection with pulmonary neoplasms, but the most prominent one of these has been hypercalcemia, which at times has been so severe as to be misdiagnosed as hyperparathyroid crisis. Inasmuch as such elevations in the serum calcium level have been described in connection with a variety of tumors, particularly epithelial cell tumors, further discussion concerning such changes will be presented subsequently in connection with blood changes produced by malignant tumors in general. Nevertheless, it is important to emphasize here that hypercalcemia is commonly found in patients with bronchogenic carcinoma. It has been estimated that an elevation of the serum calcium level is present in perhaps 10 per cent of all cases of bronchogenic carcinoma at some point in the natural history of the disease. Demonstrable bone involvement need not be present for the hypercalcemia to develop. 34 Hyponatremia. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone in two patients with bronchogenic carcinoma was reported by Schwartz and his associates. 36 Although renal and adrenal functions were apparently within normal limits, the urine was persistently hypertonic with respect to the plasma, and the contraction of body fluid volume did not occur as sodium depletion and hypotonicity of the plasma progressed. The authors believed that the underlying disease process had in smr.e manner induced a sustained, inappropriate secretion of antidiuretic hormone, and that the syndrome was the consequence of the resulting expansion of the body fluid volume. All the essential features of the syndrome were produced in normal subjects by continuous administra- 310 JAMES D. HARDY tion of pitressin and water, resulting in a type of water intoxication. As with the normal subjects, restriction of fluids in the two patients with bronchogenic carcinoma prevented sodium loss and hyponatremia. Such syndromes of sodium loss and hyponatremia have been described in other conditions, such as central nervous system lesions. 36 It will be pointed out subsequently that various types of malignancies, and especially bronchogenic carcinoma, may result in nervous system dysfunction. We ourselves have observed marked hyponatremia in a patient with bronchogenic carcinoma, though the mechanisms involved were not clear. NEUROMUSCULAR DYSFUNCTION. A peculiar type of myasthenia has been reported by various workers in association with pulmonary and other types of tumors, and this will be discussed more extensively in the section dealing with central nervous system effects of various nonendocrine tumors. Nevertheless, this peculiar type of myasthenia should be mentioned here also in connection with the effects of lung tumors. Rooke and his associates 37 have recently studied this problem. The myasthenia associated with nonthymic malignant neoplasms exhibited significant and consistent differences from the typical myasthenia gravis, and they outlined the clinical and electrophysiologic distinctions of the myasthenia due to nonthymic neoplasms as contrasted with the usual myasthenia gravis. The most common tumor producing "nonthymic" myasthenia was the small cell bronchogenic carcinoma. A number of their patients had been studied for myasthenia prior to the development, or at least the detection, of the malignant pulmonary neoplasm. Indeed, the development of a malignant lung tumor in 14 of 19 patients differentiated from those having typical myasthenia gravis was a striking finding. These workers also reviewed other publications relating to the association between bronchial neoplasms and myasthenia. 38- 44 In numerous reported instances of nonthymic malignant tumor associated with myopathy and myasthenia, the neuromuscular defect has been abolished by total resection of the malignant neoplasm. Tumors of the Liver (Primary) The most prominent among the systemic effects of hepatic neoplasms are hypoglycemia, polycythemia and fever, with or without leukocytosis. In view of the remarkably extensive and complex metabolism that occurs in the liver, it is likely that additional syndromes will be delineated in the future. HYPOGLYCEMIA. Hypoglycemia associated with hepatic carcinoma was reported in 1929 by Nadler and Wolfer, 45 and others have since recorded similar findings. In reporting a case of hepatic carcinoma and hypoglyecmia that was incidentally associated with polycythemia, Schonfeld and his associates 46 offered the opinion that the abnormal metabolic process which results in the hypoglycemia is inherent in the On the Cause of Death in Cancer 311 hepatoma itself. In their patient there was a normal insulin-like activity in the serum, but an elevated insulin-like activity in extracts of the tumor, as demonstrated by two different methods. It was believed that the patient's tumor itself might have metabolized glucose in amounts greater than normal. 47- 60 These tumors are frequently very large, and they may also interfere grossly with liver function. The precise incidence of hypoglycemia associated with hepatoma varies in reports by different authors, but it may be far more common than has previously been recognized, perhaps as high as 30 per cent. 48 PoLYCYTHEMIA. In 1958, McFadzean, Todd and Tsang51 reported polycythemia in 10 per cent of their series of hepatomas studied in Hong Kong. The cause of this polycythemia is not clear, but it appears to add the liver to the growing list of organs whose tumors may be associated with polycythemia. As will be seen later, the kidney, lung, uterus, and cerebellum have all been found to be the site of neoplasms which may result in polycythemia. Experimental studies of the erythropoietic principle by Osnes52 would appear to place the liver among those organs which are able to produce an erythropoietic substance. FEVER. One of the most striking findings in hepatoma is the fact that the febrile course may closely simulate a liver abscess. In fact, it is at times extremely difficult to determine whether or not the enlarged and tender liver harbors a tumor or an abscess. Leukocytosis may further complicate the picture. Retroperitoneal Tumors with Special Reference to Fibrous Tumors A very interesting group of tumors are the neoplasms of mesodermal origin that occur generally in the retroperitoneal and subdiaphragmatic areas and are often associated with hypoglycemia. 58-5 7 These tumors have been classified as fibrogenic, 58 mesodermal, 59 mesothelial cell sarcoma 80 and fibrosarcoma. 81 • 82 In reporting two cases of nonpancreatic mesodermal tumors associated with hypoglycemia, Miller and his associates59 in 1959 also reviewed the literature and found that only 15 such patients had previously been reported, 10 of these having appeared in the previous four years. Typical attacks of demonstrated hypoglycemia during fasting, relieved by ingestion of glucose, were experienced by most of these patients. In the two cases reported by Miller and his associates, previous distal pancreatectomy had not abolished hypoglycemia, but subsequent removal of a large diaphragmatic fibrous mesothelioma in one patient had been followed by complete recovery. The other patient died following complications of the large sarcomatous mesodermal tumor involving the prostatic area. In only one of the two patients was an increased insulin-like activity in the tumor tissue demonstrated. Sellman and his associates 60 could not demonstrate insulin-like activity from the tissue in the mesothelial cell sarcoma removed from their patient. Whitney and Heller 82 were able to demonstrate increased 312 JAMES D. HARDY insulin-like activity in the serum of a patient with spontaneous hypoglycemia associated with a retroperitoneal fibrosarcoma, and the serum insulin-like activity returned to normal levels following surgical removal of the tumor. It was suggested that the tumor was the source of the insulin-like material responsible for the spontaneous hypoglycemia. Thus, despite the fact that the mechanism of the hypoglycemia associated with retroperitoneal tumors of mesodermal origin is not agreed upon by all investigators, there is evidence that a number of such lesions may produce hypoglycemia by various means, and perhaps in some by the actual elaboration of increased amounts of an insulin-like substance. Pancreatic Islet Cell Tumors and Peptic Ulceration In 1952 Strom 63 of Norway reported a case of peptic ulcer associated with an "insuloma" of the pancreas. He discussed in some detail the possible relationship between islet cell tumors and a particularly malignant type of peptic ulceration. However, he concluded that as yet the evidence was inadequate to establish definitely that the islet cell tumor caused the severe ulcer diathesis. In the United States the association of certain islet cell tumors with a severe type of peptic ulceration was carefully studied by Zollinger and Ellison 64 and many cases have since been reported. These neoplasms, which usually do not secrete insulin, have been termed ulcerogenic tumors. This entity has been characterized as consisting of a fulminating and frequently fatal peptic ulceration associated with excessive gastric secretion. The excessive secretion of acid often results in atypical and multiple ulcers of the alimentary tract, at times involving even the jejunum and occasionally the ileum, and it has been found that in some of these patients the contents of the jejunum are acid in character. The removal of a pancreatic tumor has apparently resulted in the return of gastric secretion to normal levels in some patients. This has suggested that a hormonal or chemical factor arising in the pancreatic tumor was capable of stimulating the gastric glands to secrete, and thus might be the causative agent of the ulcer disease, as reported by Ellison. 66 Such a gastrin-like hormone has now been extracted from a pancreatic tumor by Gregory and co-workers. 66 As tested in a denervated fundic pouch in dogs, the subcutaneous injection of the extract was followed by a sharp increase in both the volume and the acidity of gastric juice. Most commonly, the ulcerogenic tumor has appeared to be derived from the alpha cells of the pancreas as contrasted with the beta cells which produce insulin. Nevertheless, the cell type of the tumor has varied in reports by different workers. There has also been a difference of opinion regarding the true significance of the association between the tumor of the pancreas and peptic ulceration. For example, Moore and his associates 67 have suggested that pituitary adenomas and other dysfunctions cause not only the increased gastric secretion but also the On the Cause of Death in Cancer 313 islet cell tumor of the pancreas, as well as adenomas in other organs such as the parathyroids and adrenals. Schmid, Labhart and Rossier, 68 in discussing the relationship of multiple endocrine adenomas to the syndrome of ulcerogenic islet cell adenomas, reported a familial factor. A family of seven siblings was described, of which three sisters had multiple endocrine adenomas involving pituitary, pancreas and/or parathyroids; one brother had hyperparathyroidism; and two brothers died of atypical peptic ulcers. The findings were considered to offer further evidence that the ulcerogenic tumor syndrome may occur as part of the more inclusive, genetically transmitted entity of multiple endocrine adenomatosis. Nevertheless, the work of Gregory and associates, cited above, would appear to represent strong support of the basic hypotheses advanced by Zollinger and Ellison. 64 If the primary defect is produced by the tumor, simple removal of the tumor should suffice for management of the ulcer diathesis, without resort to vagotomy or partial gastric resection. Such a case was reported by Rawson and associates. 69 IsLET CELL TuMoRs AssociATED WITH FLusHING AND/OR DIARRHEA. Although the typical islet cell tumor associated with peptic ulceration may also be associated with diarrhea in some instances, 70 other workersn have described patients with islet cell adenomas and chronic diarrhea in whom no peptic ulceration occurred. Chears and associates 72 reported a patient who had a pancreatic islet cell tumor associated with severe diarrhea and potassium depletion, both relieved by resection of the tumor. The diarrhea improved strikingly on two occasions during adrenocortical steroid therapy, as had been noted in a patient reported by Priest and Alexander. 70 The patient reported by Chears and his group 72 exhibited at laparotomy extreme thinning of the wall of the ileum and cecum, with a large amount of watery fluid within the lumen of the ileum and large bowel. Profuse serous fluid had been repeatedly observed in the rectum. It appeared likely that the absorptive function of the ileum and the cecum had been defective in this patient, leading to the loss of large quantities of fluid. It was not determined whether this failure of fluid absorption was secondary to an excessive influx of pancreatic or gastrointestinal secretion, exceeding the absorptive capacity of the ileum and cecum, or to actual inhibition of absorption, possibly by a humoral substance elaborated by the tumor. Defective absorption appeared to be somewhat more likely in view of the atrophic appearance of the bowel as observed at laparotomy. A noninsulin-producing islet cell adenoma of the pancreas associated with profuse diarrhea and hypokalemia with hypokalemic nephropathy was reported by Murray and associates. 73 In addition, their patient had pronounced flushing and headache, which were striking features of his 16-year illness. This combination of flushing and diarrhea suggested to them a hyperserotonemia, though laboratory findings did not document an elevation of the serum serotonin level. The attacks of flushing dis- 314 JAMES D. HARDY appeared when the tumor was removed, suggesting that the tumor was releasing some substance causing the vascular reaction. The potassium depletion secondary to diarrhea was not surprising, in view of similar cases previously reported. With the exception of fever, we are not aware of systemic effects of tumors of the exocrine cells of the pancreas. This does not, of course, exclude the sprue and other findings which may result in the absence of adequate pancreatic exocrine function, or obstruction of the duodenum or common bile duct by the tumor. Tumors of the Kidney Whereas tumors of the kidney have long been known to be a cause of otherwise unexplained fever in some instances, it has been found more recently that the hypernephroma may be associated with polycythemia, 74-7 8 with reversible hypercalcemia, 79 and with a reversible type of myopathy with or without hypercalcemia. 80 PoLYCYTHEMIA. For many years it has been realized that polycythemia is occasionally present in association with renal carcinoma, early reports having been those of Bliss 81 in 1929 and Medvei 82 in 1934. However, this phenomenon was accorded little attention until recently. Damon and his associates 83 have reported 10 new cases, two with long hematologic remissions following nephrectomy. Unquestionably the recent investigation of erythropoietin 84 has resulted in an increased interest in the relationship between renal carcinoma and simple polycythemia without the splenomegaly and other findings characteristic of polycythemia vera. Damon and his co-workers 83 found that the syndrome had occurred in approximately 4.4 per cent of 205 patients with polycythemia and 2.6 per cent of 350 patients with renal carcinoma studied in the Presbyterian Hospital of New York. The polycythemia was, for the most part, a simple erythrocytosis without marked splenomegaly, leukocytosis or thrombocytosis. In this respect it thus resembled secondary rather than primary polycythemia, with the important exception that it apparently was not dependent upon the degree of arterial oxygen saturation. Two of their patients had complete hematologic remission following nephrectomy, one for two years and the other for 11 years. Similar remissions have been described by others. The mechanisms of the erythrocytosis were not discerned, but it was believed that the tumor or the neighboring renal tissue elaborated an erythropoietic substance. They emphasized that the presence of unexplained polycythemia, and particularly the presence of hematuria with polycythemia, renders urologic investigation for tumor essential. In studying a case of hypernephroma associated with erythrocythemia, Hewlett and his associates 78 were able to demonstrate an increased erythropoietic-stimulating activity. Using a bio-assay of the extract of the tumor, the erythropoietic-stimulating activity· was significantly On the Cau/Se of Death in Cancer 315 greater than that obtained with extracts of normal renal tissue or of a hypernephroma unassociated with erythrocythemia. They believed that this substance was responsible for the erythrocythemia. It should not be concluded, of course, that an increased erythrocyte production by the tissue of renal origin is associated only with hypernephroma. Polycythemia or erythrocythemia has been reported in association with hydronephrosis 85 • 86 and polycystic renal disease. 87- 89 Friend and his associates 87 point out that most renal lesions which have been found to be associated with polycythemia have been space-occupying lesions. For this reason the combination of uremia and a normal or high hematocrit level should lead one to suspect the diagnosis of polycystic kidney disease, especially in the absence of renal neoplasm or hydronephrosis. Whereas erythrocythemia with renal disease may be the result of an increased production of erythropoietin, 90 the anemia seen in renal insufficiency may reflect the opposite mechanism, namely, a decrease in the production of erythropoietin. 78 Both Joske and his as:sociates 91 and Loge and his co-workers 92 have utilized radioactive iron to investigate the red cell production in chronic renal disease and have found an impairment of erythropoiesis as the primary cause of anemia in this condition. HYPERCALCEMIA IN RENAL TuMoRs. Tumors of the kidney, particularly carcinomas, are not infrequently associated with a type of hypercalcemia that may be reversed by removal of the tumor. 79 Epithelial tumors of the lung and the ovary, as well as of the perineal region, 93 have also been associated with reversible hypercalcemia. Alanis and Flanagan 80 reported a case in which marked weakness and other symptoms reflecting myopathy were apparently largely due to the hypercalcemia that was present. MYOPATHY. A severe myopathy with weakness and atrophy of the muscles may be associated with hypernephroma, 80 as with certain other tumors which will be discussed under tumors affecting the nervous system. Tumors of the Alimentary Tract Systemic effects of tumors of the alimentary tract are not so well documented as are tumors affecting, for example, the lung or kidney. Nevertheless, it is increasingly apparent that systemic effects of alimentary tumors will be demonstrated in the future. Meanwhile, definite effects have been demonstrated for certain neoplasms which affect the intestine and these will be touched upon briefly. CARCINOID TUMORS AND THE MALIGNANT CARCINOID SYNDROME. While carcinoid tumors may be found in other locations as, for example, the bronchus, 94 the vast majority of these lesions are found in the alimentary tract. In a certain number of instances these carcinoid tumors 316 JAMES D~ HARDY elaborate large amounts of a chemical substance 95 which Rapport and his co-workers 96 identified in 1948 as 5-hydroxytryptamine and gave the name serotonin. Serotonin is widely present throughout the body, but perhaps the highest concentrations are to be found in the argentaffin cells of the gastrointestinal tract. It is also present in platelets and in those parts of the central nervous system which are associated with autcnomic nervous activity. 97 In reviewing 44 cases of carcinoid tumors of i he gastrointestinal tract treated at the Hines Veterans Administration Hospital between 1936 and 1958, Kantor and associates 97 found that 10 occurred in the ileum and 12 in the rectum. The remainder were scattered throughout the alimentary tract. The relatively low incidence of appendiceal involvement in this group may have been due to the age population of the hospital. The malignant carcinoid syndrome has been clearly delineated only within the last decade, 9 8-100 though a case reported by Cassidy101 in 1931 probably was an example of this syndrome. Since both the lung and the liver are efficient in deactivating serotonin, liver metastases must usually be present to release unaltered serotonin into the hepatic veins to produce the malignant carcinoid ,effects upon the right heart and lungs. Of course, the monoamine oxidase in the lungs may not inactivate all the serotonin reaching them, and certain systemic effects may be noted. However, when serotonin bypasses the lungs in sufficient quantity to affect the valves of the left side of the heart, an intracardiac shunt is present in most instances. The carcinoid syndrome consists of recurrent or intermittent cyanotic flushing accompanied by fluctuations in blood pressure. Thus the patient may exhibit tachycardia, diarrhea, asthmatic-like attacks and signs of pulmonic stenosis with right heart failure. At autopsy endocardial fibrosis with valvulitis may be found, often resulting in pulmonic stenosis and tricuspid valve insufficiency.l 02 The malignant carcinoid syndrome may be cured by complete resection of the functioning tumor tissue, but as a rule hepatic metastases are so extensive that only palliative partial hepatectomy can be achieved. 103 Palliative control of the syndrome with drug therapy leaves much to be desired. 104 CARCINOMA OF THE CECUM AND RIGHT CoLON. For a great many years it has been appreciated that one of the main presenting findings in patients with carcinoma of the right colon and especially the cecum is a profound anemia. Marw of these' anemic patients have never noted blood in the stool, and occult blood studies are not positive in some individuals. It would appear likely that these tumors elaborate some substance that interferes with either the production of erythrocytes or the life span of the erythrocyte or both, though long-continued minor red cell destruction within the tumor tissue itself is not excluded. This last might be reflected by the excretion of increased amounts of blood pigment in the urine. Tumors of the alimentary tract may likewise produce On the Cause of Death in Cancer 317 marked anorexia, which is frequently improved following removal of the major portion of the tumor, even if there were local infiltrates which could not be removed at operation. VILLous TuMoRs oF THE REcTUM AND CoLoN CHARACTERIZED BY SEVERE FLUID AND ELECTROLYTE Loss.l 05- 109 The villous tumor of the large intestine is now recognized as a distinct clinical and pathological entity. This tumor usually occurs in the rectum or sigmoid colon of elderly individuals as a large sessile polyp with a broad, flat attachment to the bowel wall. 110 These large tumors may offer a vast secreting surface which produces large quantities of mucus and causes a "pseudodiarrhea." McKittrick and Wheelockm reported the case of an 82 year old woman who experienced fainting, oliguria and weakness associated with electrolyte loss from such a large villous papilloma of the rectum. Numerous reports of this lesion have thus established that dehydration, hyponatremia, hypokalemia, hypochloremia, circulatory collapse and prerenal azotemia with metabolic acidosis may develop as a result of the copious secretion of watery mucus from such villous tumors of the distal colon. The patient is cured if the tumor can be successfully removed, as is usually the case . Cancer of the Prostate and Phosphatase Enzyme 112 The elevation in the serum acid phosphatase level in association with prostatic cancer is so generally used in diagnosis and in following the effectiveness of therapy that no further elaboration is needed here. Huggins113 established the hormonal-enzymatic relationships of this tumor as a classic prototype of the hormone-dependent tumor. Tumors of Blood-Forming Tissues and Related Elements The systemic effects of tumors of the blood-forming tissues and related elements are widely appreciated, and only brief comment is indicated here. Fever is a common finding in many of these conditions, including Ewing's sarcoma. Patients with lymphosarcoma may exhibit increased · rates of red cell destruction, 114 and those with Hodgkin's disease a defective immune response. 115 In multiple myeloma116 bone pain and hypercalcemia are often experienced, though these findings frequently represent actual bone involvement per se. However, there are other changes which include the production of the Bence-Jones protein, rouleau formation, and a rapid sedimentation rate. There may be a diminished red cell life span due to sequestration and destruction of these cells in the spleen. Occasionally, a cryoglobulin may be associated with the precipitation of protein in peripheral blood vessels, and uremia may develop due to the deposition of Bence-Jones protein in the renal tubules. Bleeding in the absence of thrombocytopenia may result from adsorption of proteins necessary for blood coagulation on the myeloma protein. 318 JAMES D. HARDY EFFECTS OF TUMORS UPON BODY SYSTEMS: FURTHER DISCUSSION It has been seen that specific tumors arising from various organs do, in fact, have systemic effects. The net result of their metabolic encroachment will now be further emphasized by examining the effects upon specific body systems which a variety of tumors may produce. The Neuromuscular System It has become increasingly clear that a localized tumor may produce brain changes consisting of cortical and cerebellar atrophy/ 17 • 118 in addition to peripheral neuropathy and myopathy, quite in the absence of metastases.U 9 • 120 At times the evidence of nervous system disease has appeared prior to the diagnosis of the tumor and, in fact, the investigation of the neuromuscular symptoms has commonly resulted in diagnosis of the malignant tumor. 121 Furthermore, the neuromuscular dysfunction has frequently been abolished by complete removal of the tumor. Although Oppenheim122 is credited with first suggesting that disorders of the nervous system in patients with cancer might be due to a toxic process, the first modern statement regarding this problem was that of DennyBrown123 in 1948. He described primary sensory neuropathy with muscular changes associated with carcinoma. Since that time many reports of nervous system changes associated with malignant tumors in the absence of nervous system metastases have been reported. Brain and his group124 · 125 have particularly emphasized the neurologic syndromes associated with carcinoma-the carcinomatous neuropathies. Findings include cerebellar disorders with vertigo, sensory disturbances with paresthesias, and the neuromuscular manifestations of wasting and weakness. Croft126 noted an abnormal response of the patient with malignant tumor and carcinomatous neuropathy to muscle relaxants. He reported three patients with myasthenia-like syndromes who had carcinomatous neuropathy but without overt myasthenia. These patients showed an abnormal response to muscle relaxants. It is of course apparent that abnormal sensitivity to the relaxant drugs in such a patient undergoing surgery could result in seriously prolonged delay of the return of spontaneous respiration. The malignant tumors associated with "idiopathic" neuropathy have included squamous cell neoplasms, lymphoma, reticulosis and myeloma.127 The most frequent types of malignancies have been those of the lung, breast, gastrointestinal tract, ovary, uterus, rectum, prostate, lymph nodes and bone marrow. However, first in incidence among the neoplasms causing neuropathy has been bronchogenic carcinoma. 41 · 128 The existence of multiple types and sites of malignancy associated with idiopathic neuropathy suggests denominators common among these tumors in their relationship to neuropathy. The neuropathy may affect On the Cause of Death in Cancer 319 multiple neural tracts, sensory or motor, as noted above. Alanis and Flanagan 80 reported a 63 year old man whose complaint during the first three months of illness was muscular weakness, affecting especially the legs and progressing to complete disability. Eventually a carcinoma of the right kidney was diagnosed and removed. This was followed by marked improvement in the neuromuscular status almost to normal. When the deep reflexes in the leg did not return, biopsy of the quadriceps femoris muscle revealed extensive atrophy. Again, inasmuch as the brain changes and peripheral neural dysfunction may precede the development of the overt neoplasm by months or years, patients with so-called idiopathic nervous system dysfunction should be examined periodically for cancer in the course of repeated neurologic re-evaluations. The Skin The incidence of dermatomyositis in association with malignant tumors would seem to be somewhat greater than that which could be ascribed to chance alone. It appears that Bezecny129 first suggested such a relationship, but since then various authors have reported pertinent cases. 131H 38 Thus a patient presenting evidence of dermatomyositis should also be investigated for a malignant tumor. The Skeletal System The occurrence of arthralgia139 and hypertrophic pulmonary osteoarthropathy in association with tumors affecting the lung and pleura was quoted in the discussion of lung neoplasms. 6 • 22 It is mentioned here only to re-emphasize the importance of careful examination for tumors, and in particular intrathoracic tumors, when the patient exhibits bone and joint changes. Blood and Blood Vessels CoAGULATION MECHANISMS H ypercoagulability Resulting in Thrombi. For many years clinicians have speculated regarding the possible etiologic relationship between so-called idiopathic venous thrombosis and hidden cancer, 140 · 141 particularly in the abdomen and perhaps involving the pancreas. Trousseau142 is given credit for having first pointed out in 1877 the possible relationship between venous thrombosis and neoplasia. Hubay and Holden 143 reported eight patients who were admitted with peripheral venous thrombosis and/or pulmonary embolism. Seven of these proved to have occult neoplastic lesions and one had tuberculosis. These authors called attention to the fact that, in the presence of necrotic tissue in tumors and inflammations, the physiologic response of the host to necrosis may alter blood coagulation in some as yet undetermined man- 320 JAMES D. HARDY ner. It was noted that spontaneous peripheral venous thrombosis should alert the physician to the possibility of an obscure visceral neoplasm. Williams 144 also reported that malignant tumors might be associated with vascular manifestations such as thrombophlebitis migrans and Raynaud's phenomenon. In disagreement with the above reports was the review by Anlyan, Shingleton and DeLaughter. 145 In contesting the popular belief that the incidence of hidden cancer in patients with idiopathic venous thrombosis is significant, these workers reviewed the data offered by SprouP 46 They concluded that the data presented in her paper did not warrant the assumption of a statistically significant etiologic relationship between cancer of the pancreas and idiopathic venous thrombosis. In their group of 301 cases of acute or subacute venous thrombosis seen during a fiveyear period, 44 occurred in patients with cancer but in only five did clinical evidence of thrombosis develop prior to operation. In no instance was the malignancy silent, although in two patients the thromboembolism altered the clinical findings regarding the malignancy. Thus, contrary to the impression suggested in the literature, they concluded that there is no significant association between idiopathic venous thrombosis and hidden cancer. Lieberman, Borrero, Urdaneta and Wright 147 recently reviewed the experience at the New York Hospital. They believed that there was evidence of a definite relationship between cancer and thrombophlebitis, possibly on the basis of an increased blood coagulability. The thrombophlebitis often presented months before clinical evidence of the tumor was apparent. Moreover, the thrombophlebitis tended to be recurrent or migratory and to appear in multiple extremities. It was often markedly resistant to anticoagulation and was attended by an increased risk of pulmonary embolism. Many different types of malignant tumors were represented in their series. Tumors of the lung, female reproductive tract and pancreas were most frequent in their series but not in all reported series. Those who do not accept a specific relationship between malignant tumors and thrombophlebitis point to the frequency with which venous disease occurs in association with tissue necrosis due to infection or trauma. The present author has not reviewed statistically the experience in his own hospital, but some very striking cases of thrombophlebitis associated with malignant tumor have been observed. A possible relationship between various malignant tumors and increased arterial thrombosis was noted by Nyhus. 148 That blood coagulability may be increased in patients with malignant neoplasms was emphasized by Fumarola. 149 He found this to be present particularly in patients with neoplasms of the digestive and respiratory tracts. Coagulation Defects in the Presence of Malignant Tumors. Various neoplasms have been reported to produce a defective clotting mechanism. On the Cause of Death in Cancer 321 Seale and her associates160 reported a case of metastatic carcinoma of the prostate in which there was a marked bleeding tendency, apparently secondary to a reduction in circulating plasma fibrinogen. Hypocoagulability in the presence of certain tumors of the female genital apparatus has been reported. ANEMIA AND PoLYCYTHEMIA Anemia. One of the most conspicuous findings in many different types of malignancy is anemia, and this anemia has been the subject of a large amount of study. 114 · 15 1-163 The anemia may result from actual blood loss at the surface of or within the tumor, from diminished red cell production or from diminished life span of the erythrocyte. In studying the anemia of disseminated malignant neoplastic disease, Hyman, Gellhorn and Harvey154 noted a diminished life span of the erythrocyte. Ultmann165 offered evidence of increased splenic activity in the hemolytic anemia which certain types of patients exhibit. Both infection and malignant tumors unquestionably have a deleterious effect upon red cell formation in some instances. In discussing mechanisms of anemia in cancer, Ley114 specifically noted the iron deficiency anemias, the uncommon myelophthisic anemias, and the hemolytic anemias of lymphomas and certain ovarian teratomas. It was suggested that, since in profound cancer anemia the bone marrow activity is often normal or subnormal when it should have increased to counteract the anemia tendency, the factors (erythropoietin?) regulating erythropoiesis may be at fault. Green and his associates162 suggested that the anemia in cancer patients represents a type of auto-immune reaction, as revealed by a positive Coombs test. Price and Greenfield163 called attention to the fact that when a patient has lost much lean body mass, a relatively smaller red cell mass is required, and that not all "anemic" cancer patients are truly anemic. They found that patients with colon cancer were more often truly anemic than were those with lung or pancreatic cancer, for example. These authors believed important mechanisms causing anemia to be lysis, phagocytosis, hemorrhage (often hidden within the confines of the tumor or surrounding tissues) and thrombosis in blood vessels. Sheets and his associates166 reported instructive cases and analyzed mechanisms of red cell destruction in patients with carcinoma of the cervix uteri. Polycythemia. The presence of polycythemia in association with renal carcinoma was discussed previously and need not be touched upon further here. Polycythemia has also been reported in association with hepatoma. However, it is less well known that an erythropoietic effect has been described associated with uterine tumors and cerebellar hemangioblastoma.3 Although polycythemia associated with a myxoma of the right atrium has been reported/ 57 it appeared likely that emboli to the lungs might have produced the changes which resulted in the poly- 322 JAMES D. HARDY cythemia. In other words, some defect in pulmonary blood flow or oxygenation may be postulated to have affected red cell production. HYPERCALCEMIA Much interest has centered recently upon hypercalcemia associated with malignant tumors in the absence of metastases. 34 • 16 s-16° Following the report by Plimpton and Gellhorn34 in 1956, various workers have reported increasingly penetrating studies of this problem. Schatten and his associates 93 studied a patient in whom hypercalcemia and hypophosphatemia were associated with squamous cell carcinoma involving the vulva. There was a direct correlation between the presence of tumor and the serum abnormalities; a fall of serum calcium and a rise of serum phosphorus followed excision of the tumor, and a second rise in serum calcium with a fall in serum phosphorus followed its regrowth. The parathyroid glands were normal at exploration and at autopsy, and there were no osseous metastases. These workers suggested that the tumor may have produced a substance related to parathyroid hormone. Abouav and his associates 79 reported a case in which the syndrome of hypercalcemia and hypophosphatemia was associated with a localized masculinizing tumor of the ovary. The diagnosis was considered preoperatively, making metabolic studies possible. The characteristic features were hypercalcemia with hypercalciuria and hypophosphatemia, plus hypophosphaturia. The hypophosphaturia and normal tubular reabsorption of phosphorus made possible the differentiation of this ovarian tumor from a primary parathyroid tumor and prevented unnecessary exploration of the neck. The syndrome was demonstrated to be reversible when it disappeared following removal of the tumor. The problem of hypercalcemia in neoplastic disease was reviewed by Myers.l 61 • 162 It was found that the hypercalcemia which may develop without demonstrable bone metastases occurs most commonly in patients with cancer of the breast, lung or kidney and in those with lymphomas and myeloma. The signs and symptoms of the hypercalcemia are similar to those occurring with hypercalcemia due to other causes. TUMORS AND THE IMMUNE RESPONSE: HYPOGAMMAGLOBULINEMIA For many years the probable immunologic relationships between the tumor and the host have been debated. Certain biologic phenomena in the natural history of tumors and their metastases have indicated a dynamic state between host resistance and the capacity of the tumor to overwhelm the host. For example, the tumor may grow at different rates at different times, metastases may become larger and then regress, or something may affect the host to permit the tumor to grow rapidly where previously it grew very slowly. Many experiments have been performed in which a portion of the tumor was used to attempt to increase the resistance of the host to this antigen. ' On the Cause of Death in Cancer 323 It is the purpose here to indicate the effects of certain tumors which diminish the usual immune activities of the host. Many other examples could doubtless be cited, but these will suffice. It is generally accepted that one of the important materials in the formation of an effective immune response, particularly against bacterial organisms, is gamma globulin. Thus the report of O'Brien and Walsh163 is of interest, in that they described hypogammaglobulinemia and hypersplenism associated with lymphosarcoma of the spleen. They noted that the secondary variety of hypogammaglobulinemia has been encountered in chronic lymphatic leukemia, lymphosarcoma, thymoma (see above), multiple myeloma, and undifferentiated lymphomas. They advised that in any patient with hypogammaglobulinemia and splenomegaly, with or without lymphadenopathy, the secondary hypogammaglobulinemias should be considered. The incidence of infection and defective immunity in chronic lymphocytic leukemia has also been emphasized. 164 • 165 It has also been noted that the patient with Hodgkin's disease has a defective immune response and will tolerate homografts somewhat longer than will the normal patient without Hodgkin's disease.U 5 Finally, Grace and Dao 166 have expressed the opinion that the erythematous reaction in inflammatory carcinoma of the breast is due to the patient's sensitivity either to his own tumor or to its products. It is true that lymph nodes draining the area of a tumor frequently show increased histiocytosis and other changes which reflect an influence of the tumor upon regional lymph nodes in the absence of actual tumor emboli.l 67 An analytical review of "tumor immunity" was offered by Barrett. 168 Effects upon the Liver Inasmuch as the liver is the center of a large segment of the metabolic activity of the body, it is perhaps surprising that a larger number of specific effects of various distant tumors upon this organ have not been recorded. One of the first specific and consistent biochemical lesions demonstrated in the presence of actively growing neoplasms was that of Greenstein, Jenrette and White 169 with respect to liver catalase activity, in 1941. They showed that this activity in rats carrying the Jensen sarcoma at three weeks, and in rats carrying transplanted hepatic tumor, was approximately one-tenth that of the normal rat liver. Extirpation of the hepatic tumor caused a rapid restoration of the liver catalase activity which reached the normal level within 24 to 48 hours. The effect produced by the presence of the transplanted tumor was tentatively interpreted as due to the elaboration by the tumor of a toxic material which traveled by way of the circulatory system to the liver. In this connection, Lucke and his associates170 showed that this capacity of a tumor to produce a reduction in liver catalase activity crossed a parabiotic union to reduce the liver catalase activity in the animal bearing no tumor. 324 .JAMES D. HARDY LIVER HYPERTROPHY. In 1942 Abels and his co-workers171 reported hypertrophy of the liver in 42 per cent of patients with cancer of the gastrointestinal tract. Zamecnik and associates172 demonstrated in 1948 that liver slices of induced rat hepatomata incorporated more radioactivity froip. labeled alanine and glycine than did slices of normal rat liver. Rutman and his group 173 found a similar capacity in preneoplastic livers and those with mice hepatoma in 1954, in that the mitochondria exhibited an enhanced ability to incorporate labeled alanine into peptide linkages. Fever, Anorexia and Weight Loss: Cachexia Last, but perhaps most significant of all the systemic manifestations of advanced neoplasia, is the classic "malignant cachexia." This is often the net result of mechanisms producing fever, anorexia and weight loss. FEVER Many patients with malignant tumors run fever. This has been well known for many years. The hypernephroma is a tumor which is associated with fever in many instances. Clarke and Goade174 surveyed 36 cases of renal cancer to determine the incidence of fever as a diagnostic sign of this disease. Two of the 36 patients had presented with otherwise unexplained fever as a chief complaint, while eight others had had fever as a symptom or sign. The daily maximum temperatures varied in these cases from 100° to 102° F. In nine of the ten patients fever disappeared following nephrectomy, and in the one patient in whom fever did not disappear, hepatic metastases had been proved at operation. The inflammatory reaction associated with neurogenic tumors may simulate an infectious process, 175 and the febrile response associated with Ewing's sarcoma is well known. Thus the possibility of underlying malignancy in the patient with fever of obscure origin should be considered. Geraci and his associates176 examined the diagnostic value of laparotomy in 70 patients with febrile states that had lasted longer than two weeks and had not been explained by repeated thorough physical and laboratory examinations. In 21 of these patients exploration of the abdominal cavity revealed malignant disease, and in ten of these the lesion was a lymphoblastoma. We have been particularly impressed with silent retroperitoneal tumors which caused fever, such as tumors of the body of the pancreas. The hepatoma may present a markedly febrile course. The cause of fever associated with malignant tumors is obscure. The febrile response may be occasioned by something released by the tumor itself, or may be no more complex than a reaction to the necrosis within the tumor. It is of course not uncommon to find collections of liquefaction necrosis within a large tumor. We are reminded of a patient with a huge goiter who had multiple collections of what appeared to be creamy pus i On the Cause of Death in Cancer 325 within the goiter. This patient had been unsuccessfully treated for fever for some weeks, but the fever was abruptly abolished by thyroidectomy. The collections of "purulent" material were all sterile on culture. ANoREXIA AND WEIGHT Loss One of the hallmarks of advanced cancer is the cachexia which has usually been occasioned by anorexia and weight loss. Although the weight loss may be due to defective utilization of some food products, it has been established that in many instances the weight loss is due primarily to a diminished nutritional intakeP 7 Craig and Waterhouse178 examined the body compositional changes in patients with advanced cancer and found that they could in fact utilize ingested nutrients, as have we in our laboratory. Thus it could be assumed that one of the prime defects in the malnutrition leading to weight loss is a failure to ingest food, and the mechanism by which the anorexia is produced is of considerable interest. In studying comparative protein repletion in cancer and noncancer cachexia, Peden and co-workers179 found that while hyperalimentation would produce weight gain in certain patients with advanced malignancy, there was a striking failure in the regeneration of plasma albumin and hemoglobin. In contrast, in noncancer cachexia the hyperalimentation increased not only body weight but the plasma albumin and hemoglobin levels as well. The anorexia may be due to both local and general factors. In the case of carcinoma of the stomach, for example, removal of the tumor frequently is followed by an improvement in appetite and weight gain. In this instance one might surmise that the actual local removal of the neoplasm had improved the appetite. Nevertheless, this might not be the case, since with the gastric neoplasm as with, for example, the pulmonary neoplasm, the anorexia may have been occasioned by distant effects of products elaborated by the tumor. It has been seen that neoplasms can cause degenerative brain changes in the absence of metastases. In this connection, therefore, it would perhaps not be too surprising if the tumor might have an adverse physiologic effect upon hypothalamic nuclei which have to do with appetite. This possibility has been expressed on various occasions, particularly in the foreign literature, but the supporting data have not as yet been convincing. Extensive biochemical studies have dealt with the nutritional problems and deficiencies in the presence of experimental neoplasia, but only a few will be cited. Posner, 180 in investigating the decrease in body lipids which occurs, demonstrated in tumor-bearing rats a decreased gut absorption of triglyceride labeled with radioiodine-as reflected in the amount of fat recovered from the thoracic duct lymph of the tumorbearing rats as compared with normal and pair-fed control rats. In pursuing the hypothesis that the rapidly growing tumor competes successfully with normal tissues for essential nutrients, Millar and associ- 326 .JAMES D. HARDY ates181 found that the use of tumor tissue as a dietary constituent increased appetite and growth in Walker carcinosarcoma 256-bearing rats. A biochemical concept of tumor growth infiltration and cachexia was offered by Wiseman and Ghadially. 182 They pointed out that a perplexing property of a growing tumor is its ability to build up protein and increase its weight in a host who is fast losing general body weight. They suggested that the degree of malignancy exhibited by a tumor is directly related to its metabolic aggressiveness, especially in its capacity to capture and incorporate amino acids. Three stages of tumor-host relationship were suggested: the first, in which both tumor and host gain weight; the second, in which the tumor gains weight and the host loses weight; and the third, in which the tumor and host both lose weight, though the tumor rarely loses weight as rapidly as does the host. Thus this metabolic superiority of the cancer cell is considered the vital feature permitting infiltration, with cell-by-cell destruction of normal cells at the interface between the tumor and normal tissue. Benign tumors are viewed as merely compressing surrounding tissues, whereas malignant tumors destroy. Green183 suggested that normal tissue destruction may be due to the antigenic aggression of metastatic cells which have lost their own marker antigens but which maintain their capacity to form antigens against other tissues. SUMMARY AND CONCLUSIONS Many localized nonendocrine tumors have now been shown to produce distant effects. Among the organs whose nonendocrine tumors have been shown to cause systemic changes are brain, thymus, lung, pleura, diaphragm, pancreas, liver, kidney, intestine, blood-forming tissues, bone and prostate. The distant and nonmetastatic manifestations of different nonendocrine tumors include myopathy and myasthenia, dermatomyositis, agammaglobulinemia and abnormal immune response, anemia of several types, polycythemia, bone and joint changes with arthralgia, gynecomastia, Cushing's syndrome, peptic ulceration, liver hypertrophy, flushing and diarrhea, heart valve deformities, hypoglycemia, hypercalcemia, abnormal plasma proteins, changes in blood coagulation and enzyme concentrations, hyponatremia, abnormal food assimilation, fever, anorexia and weight loss. The metabolic aggressiveness of the malignant cell at the local and systemic level appears to be a major factor in producing fatal malignant cachexia. REFERENCES 1. Hardy, J. D.: Importance of Enzymes in Surgery; Mechanisms of Survival (Editorial). Surgery 31: 765, 1952. On the Cause of Death in Cancer 327 2. Hardy, J. D.: Why Do Cancer Patients Die? (Editorial). Surg. Gynec. & Obst. 108: 368, 1959. 3. Waldman, T. A., Levin, E. H. and Baldwin, M.: Association of Polycythemia with a Cerebellar Hemangioblastoma. Production of an Erythropoiesis Stimulating Factor by the Tumor. Am. J. Med. 31: 318, 1961. 4. Blalock, A.: Thymectomy in Treatment of Myasthenia Gravis; Report of 20 Cases. J. Thor. Burg. 13: 316, 1944. 5. Blalock, A., Mason, M. F., Morgan, H. J. and Riven, S. 8.: Myasthenia Gravis and Tumors of Thymic Region; Report of Case in Which Tumor Was Removed. Ann. Burg. 110:· 544, 1939. 6. Clagett, 0. T., McDonald, J. R. and Schmidt, H. W.: Localized Fibrous Mesothelioma of Pleura. J. Thor. Burg. 24: 213, 1952. 7. Eaton, L. M. and Clagett, 0. T.: Present Status of Thymectomy in Treatment of Myasthenia Gravis. Am. J. Med. 19: 703, 1955. 8. Keynes, G.: Surgery of Thymus Gland; Second (and Third) Thoughts. Lancet 1: 1197, 1954. 9. Sellors, T. H.: Tumours of Mediastinum. Tr. M. Soc. Lond. 73: 164, 1957. 10. Wilson, A. and Wilson, H.: The Thymus and Myasthenia Gravis. Am. J. Med. 19: 697, 1955. 11. Longmire, W. P.: In discussion of paper by Olson, Briggs, and Spikard. Am. J. Burg. 98: 196, 1959. 12. Gafni, J., Michaeli, D. and Heller, H.: Idiopathic Acquired Agammaglobulinemia Associated with Thymoma: Report of Two Cases and Review of the Literature. New England J. Med. 263: 536, 1960. 13. Lambie, A. T., Burrows, B. A. and Sommers, S. C.: Clinicopathologic Conference: Refractory Anemia, Agammaglobulinemia and Mediastinal Tumor. Am. J. Clin. Path. 27: 444, 1957. 14. MacLean, L. D., Zak, S. J., Varco, R. L. and Good, R. A.: Thymic Tumor and Acquired Agammaglobulinemia: A Clinical and Experimental Study of the Immune Response. Surgery 40: 1010, 1956. 15. Martin, C. M., Gordon, R. S. and McCullough, N. B.: Acquired Hypogammaglobulinemia in Adult: Report of a Case with Clinical and Experimental Studies. New England J. Med. 254: 449, 1956. 16. Ramos, A. J.: Presentation of Case. J.A.M.A. 160: 1317, 1956. 17. Clarkson, B. and Prockop, D. J.: Aregenerative Anemia Associated with Benign Thymoma. New England J. Med. 259: 253, 1958. 18. Jamplis, R. W. and Cressman, R. D.: Current Concepts of Thymomas. Am. J. Surg. 98: 202, 1959. 19. Ross, J. F., Finch, S. C., Street, R. B. Jr. and Strieder, J. W.: Simultaneous Occurrence of Benign Thymoma and Refractory Anemia. Blood 9: 935, 1954. 20. Weinbaum, J. G. and Thompson, R. F.: Erythroblastic Hypoplasia Associated with Thymic Tumor and Myasthenia Gravis. Report of Case. Am. J. Clin. Path. 25: 761, 1955. 21. Bayrd, E. D. and Bernatz, P. E.: Benign Thymoma and Agenesis of Erythrocytes. J.A.M.A. 163: 723, 1957. 22. Wierman, W. H., Clagett, 0. T. and McDonald, J. R.: Articular Manifestations in Pulmonary Diseases. Analysis of Their Occurrence in 1,024 cases in Which Pulmonary Resection was Performed. J.A.M.A. 155: 1459, 1954. 23. Hardy, J. D.: Gynecomastia Associated with Lung Cancer. J.A.M.A. 173: 1462, 1960. 24. Del Castillo, E. B., De La Baize, F. A. and Reforzo Membrives, J.: Ginecomastia y cancer del pulm6n. Semana med. 1: 1419, 1941. 25. Vantrappen, G.: Osteoarthropathie, gynecomastie en longcarcinoom. Belg. tijdschr. geneesk. 13: 1335, 1957. 26. Dobriner, K. and Rhoads, C. P.: Abnormal Alpha Ketosteroid Excretion in Patients with Neoplastic Disease. Science 99: 494, 1944. 27. Dobriner, K., Lieberman, 8., Wilson, H., Eckman, B. and Rhoads, C. P.: Pituitary-Adrenal Function. Am. A. for Advancement of Sc., edited by R. C. Christman, 1951, p. 518. 328 JAMES D. HARDY 28. Thorne, M. G.: Cushing's Syndrome Associated with Bronchial Carcinoma: An Enquiry into the Relationship of This Syndrome to Neoplastic Disease. Guy's Hosp. Rep. 101: 251, 1952. 29. Bornstein, P., Nolan, J. P. and Bernanke, D.: Adrenocortical Hyperfunction in Association with Anaplastic Carcinoma of Respiratory Tract. New England J. Med. 264: 363, 1961. 30. Harrison, M. T., Montgomery, D. A. D., Ramsey, A. S., Robertson, J. H. and Welbourn, R. B.: Cushing's Syndrome with Carcinoma of Bronchus and with Features Suggesting Carcinoid Tumor. Lancet 1: 23, 1957. 31. Marks, L. J., Anderson, A. E. and Liberman, H.: Carcinoma of Lung Associated with Marked Adrenocortical Hyperplasia and Adrenal Hyper-responsiveness to ACTH in the Absence of Cushing's Syndrome. Ann. Intern. Med. 54: 1243, 1961. 32. Vogel, M. D., Keating, F. R. Jr. and Bahn, R. C.: Acute Cushing's Syndrome Associated with Bronchogenic Carcinoma. Proc. Staff Meet. Mayo Olin. 36: 387, 1961. 33. Segaloff, A., Hatch, H. and Rongone, E. L.: Elevated Plasma Corticoids Associated with Lung Cancer. Cancer Chemother. Rep., in press. 34. Plimpton, C. H. and Gellhorn, A.: Hypercalcemia in Malignant Disease Without Evidence of Bone Destruction. Am. J. Med. 21: 750, 1956. 35. Schwartz, W. B., Bennett, W., Carelop, S. and Bartter, F. C.: A Syndrome of Renal Sodium Loss and Hyponatremia Probably Resulting from Inappropriate Secretion of Antidiuretic Hormone. Am. J. Med. 23: 529, 1957. 36. Goldberg, M. and Handler, J. S.: Hyponatremia and Renal Wasting of Sodium in Patients with Malfunction of the Central Nervous System. New England J. Med. 263: 1037, 1960. 37. Rooke, E. D., Eaton, L. M., Lambert, E. H. and Hodgson, C. H.: Myasthenia and Malignant Intrathoracic Tumor. M. Olin. North America 44: 977, 1960. 38. Anderson, H. J., Churchill-Davidson, H. C. and Richardson, A. T.: Bronchial Neoplasm with Myasthenia: Prolonged Apnaea After Administration of Succinylcholine. Lancet 2: 1291, 1953. 39. Eaton, L. M. and Lambert, E. H.: Electromyography and Electric Stimulation of Nerves in Diseases of Motor Unit: Observations on Myasthenic Syndrome Associated with Malignant Tumors. J.A.M.A. 163: 1117, 1957. 40. Heathfield, K. W. G.: Peripheral Neuritis and Carcinoma of Bronchus. Proc. Roy. Soc. Med. 1,.5: 229, 1952. 41. Heathfield, K. W. G. and Williams, J. R. B.: Peripheral Neuropathy and Myopathy Associated with Bronchogenic Carcinoma. Brain 77: 122, 1954. 42. MacKenzie, I.: Bronchial Neoplasm with Myasthenia. Lancet 1: 108, 1954. 43. Rooke, E. D., Lambert, E. H., Hodgson, C. H. and Eaton, L. M.: Myasthenia and Malignant Intrathoracic Tumors. Tr. Am. Neurol. A., 1958, pp. 24-28. 44. Wyburn-Mason, R.: Bronchial Carcinoma Presenting as Polyneuritis. Lancet 1: 203, 1948. 45. Nadler, W. H. and Wolfer, J. A.: Hepatogenic Hypoglycemia Associated with Primary Liver Cell Carcinoma. A.M.A. Arch. Intern. Med. 44: 700, 1929. 46. Schonfeld, A, Babbott, D. and Gundersen, K.: Hyopglycemia and Polycythemia Associated with Primary Hepatoma. New England J. Med. 265: 231, 1961. 47. Klein, H. and Klein, S. P.: Spontaneous Hypoglycemia Associated with Massive Hepatoma: Review of Current Concepts and Report of Case. A.M.A. Arch. Intern. Med. 103: 273, 1959. 48. McFadzean, A. J. S. and Yeung, T. T.: Hypoglycemia in Primary Carcinoma of Liver. A.M.A. Arch. Intern. Med. 98: 720, 1956. 49. Silvis, R. S. and Simon, D. S.: Marked Hypoglycemia Associated with Non. pancreatic Tumors. New England J. Med. 254: 14, 1956. 50. Thompson, C. M. and Hilferty, D. J.: Primary Carcinoma of Liver (Cholangioma) with Hyperglycemic Convulsions. Gastroenterology 20: 158, 1952. 51. McFadzean, A. J. S., Todd, D. and Tsang, K. C.: Polycythemia in Primary Carcinoma of Liver. Blood 13: 427, 1958. On the Cause of Death in Cancer 329 52. Osnes, S.: Experimental Study of Erythropoietic Principle Produced in Kidney. Brit. M. J. 2: 650, 1959. 53. Arkless, H. A.: Coincidence of Rhabdomyofibroma of Diaphragm, Idiopathic Hypoglycemia and Retroperitoneal Sarcoma. M. Bull. V.A. 19: 225, 1942. 54. Doege, K. W.: Fibro-sarcoma of Mediastinum. Ann. Surg. 92: 955, 1930. 55. Hines, R. E.: Hypoglycemia Apparently Due to Retroperitoneal Sarcoma. M. Bull. V.A. 20: 102, 1943. 56. Holten, C.: Hypoglycaemia-Inducing Tumour Resembling Spindle-Cell Sarcoma. Acta med. scandinav. 157: 97, 1957. Fasc. II. 57. Porter, M. R. and Frantz, V. K.: Tumors Associated with HypoglycemiaPancreatic and Extrapancreatic. Am. J. Med. 21: 944, 1956. 58. Scholz, D. A., Woolner, L. B. and Priestley, J. T.: Spontaneous Hypoglycemia Associated with Fibrogenic Tumor. Report of Two Cases. Ann. Intern. Med. 1,.6: 796, 1957. 59. Miller, D. R., Bolinger, R. E., Janigan, D., Crockett, J. E. and Friesen, S. R.: Hypoglycemia Due to Nonpancreatic Mesodermal Tumors. Report of Two Cases. Ann. Surg. 150: 684, 1959. 60. Sellman, J. C., Perkoff, G. T., Null, F. C., Kimmel, J. R. and Tyler, F. H.: Hypoglycemia Associated with Massive Intra-abdominal Mesothelial-Cell Sarcoma. New England J. Med. 260: 847, 1959. 61. August, J. T. and Hiatt, H. H.: Severe Hypoglycemia Secondary to a Nonpancreatic Fibrosarcoma with Insulin Activity. New England J. Med. 258: 17, 1958. 62. Whitney, J. E. and Heller, B. I.: Increased Insulin-like Activity of Serum in Patient with Spontaneous Hypoglycemia Associated with Retroperitoneal Fibrosarcoma. Am. J. Med. 30: 633, 1961. 63. Strj'lm, R.: A Case of Peptic fficer and Insuloma. Acta chir. scandinav. 10.1,.: 252, 1952. 64. Zollinger, R. M. and Ellison, E. H.: Primary Peptic fficerations of Jejunum Associated with Islet Cell Tumors of Pancreas. Ann. Surg. 1.1,.2: 709, 1955. 65. Ellison, E. H.: fficerogenic Tumor of Pancreas. Surgery 1,.0: 147, 1956. 66. Gregory, R. A., Tracy, H. J., French, J. M. and Sircus, W.: Extraction of Gastrin-like Substance from Pancreatic Tumour in Case of ZollingerEllison syndrome. Lancet 1: 1045, 1960. 67. Rudolf, L. E., Dammin, G. F. and Moore, F. D.: Intractable Peptic Ulcer and Endocrine Adenomas with Pituitary Amphophilic Hyperplasia. A Reinterpretation of the Ellison-Zollinger Syndrome. Surgery 1,.8: 170, 1960. 68. Schmid, J. R., Labhart, A. and Rossier, P. H.: Relationship of Multiple Endocrine Adenomas to Syndrome of Ulcerogenic Islet Cell Adenomas (ZollingerEllison). Occurrence of Both Syndromes in One Family. Am. J. Med. 31: 343, 1961. 69. Rawson, A. B., England, M. T., Gillam, G. G., French, J. M. and Stammers, 70. 71. 72. 73. F. A. R.: Zollinger-Ellison Syndrome with Diarrhea and Malabsorption: Observations on Patient Before and After Pancreatic Islet-Tumour Removal Without Resort to Gastric Surgery. Lancet 2: 131, 1960. Priest, W. M. and Alexander, M. K.: Islet-Cell Tumour of Pancreas with Peptic fficeration, Diarrhoea, and Hypokalaemia. Lancet 2: 1145, 1957. Verner, J. V. and Morrison, A. B.: Islet Cell Tumor and a Syndrome of Refractory Watery Diarrhea and Hypokalemia. Am. J. Med. 25: 374, 1958. Chears, W. C. Jr., Thompson, J. E., Hutcheson, J. B. and PattPrson, C. 0.: Pancreatic Islet Tumor with Severe Diarrhea. Am. J. Med. 29: 529, 1960. Murray, J. S., Paton, R. R. and Pope, C. E. II: Pancreatic Tumor Associated with Flushing and Diarrhea. Report of Case. New England J. Med. 26.1,.: 436, 1961. 74. Conley, C. L., Kowal, J. and D'Antonio, J.: Polcythemia Associated with Renal Tumors. Bull. Johns Hopkins Hosp. 101: 63, 1957. 75. Drivsholm, A.: Hypernephroma and Polycythemia. Brit. Med. J. 2: 1063, 1960. 76. Forssell, J.: Polycythemia and Hypernephroma. Acta med. scandinav. 150: 155, 1954. 77. Frey, W. G. III: Polycythemia and Hypernephroma: Review and Report of Case with Apparent Surgical Cure. New England J. Med. 258: 842, 1958. 330 JAMES D. HARDY 78. Hewlett, J. S., Hoffman, G. C., Senhauser, D. A. and Battle, J. D. Jr.: Hypernephroma with Erythrocythemia. Report of Case and Assay of Tumor for Erythropoietic-Stimulating Substance. New England J. Med. 262: 1058, 1960. 79. Abouav, J., Berkowitz, S. B. and Kolb, F. 0.: Reversible Hypercalcemia in Masculinizing Hypernephroid Tumor of Ovary; Report of Case. New England J. Med. 260: 1057, 1959. 80. Alanis, B. F. and Flanagan, J. F.: Myopathy and Hypercalcemia Occurring with Carcinoma of Kidney. J.A.M.A. 111: 2076, 1959. 81. Bliss, T. L.: Basal Metabolism in Polycythemia Vera. Ann. Intern. Med. 2: 1155, 1929. 82. Medvei, C. V.: Uber ein bemerkenswertes Zusammentreffen von Arthritis urica, Erythriimie Typ Vaquez und Hypernephroma malignum. Wein. Arch. f. inn. Med. 24: 417, 1934. 83. Damon, A., Holub, D. A., Melicow, M. M. and Uson, A. C.: Polycythemia and Renal Carcinoma. Report of Ten New Cases, Two with Long Hematologic Remission Following Nephrectomy. Am. J. Med. 25: 182, 1958. 84. Jacobson, L. 0., Goldwasser, E., Gurney, C. W., Fried, W. and Plzak, L.: Studies of Erythropoietin: The Hormone Regulating Red Cell Production. Ann. New York Acad. Sc. 77: 551, 1959. 85. Cooper, W. M. and Tuttle, W. B.: Polycythemia Associated with Benign Kidney Lesion: Report of Case of Erythrocytosis with Hydronephrosis, with Remission of Polycythemia Following Nephrectomy. Ann. Intern. Med. 47: 1008, 1957. 86. Gardner, F. H. and Freymann, J. G.: Erythrocythemia (Polycythemia) and Hydronephrosis: Report of Case with Radio-Iron Studies, with Recovery After Nephrectomy. New England J. Med. 259: 323, 1958. 87. Friend, D. G., Hoskins, R. G. and Kirkin, M. W.: Relative Erythrocythemia (Polycythemia) and Polycystic Kidney Disease, with Uremia. New England J. Med. 264: 17, 1961. 88. Forssell, J.: Nephrogenous Polycythaemia. Acta med. scandinav.161: 169,1958. 89. Kurrle, G. R.: Case of Gaisbiick's Disease (Polycythaemia Hypertonica). M. J. Australia 1: 777, 1954. 90. Gurney, C. W.: Erythropoietin, Erythropoiesis and the Kidney. J.A.M.A. 173: 1828, 1960. 91. Joske, R. A., McAlister, J. M. and Prankerd, T. A. J.: Isotope Investigations of Red Cell Production and Destruction in Chronic Renal Disease. Clin. Sc. 15: 511, 1956. 92. Loge, J. P., Lange, R. D. and Moore, C. V.: Characterization of Anemia Associated with Chronic Renal Insufficiency. Am. J. Med. 24: 4, 1958. 93. Schatten, W. E., Ship, A. G., Pieper, W. J. and Bartter, F. C.: Syndrome Resembling Hyperparathyroidism Associated with Squamous Cell Carcinoma. Ann. Surg. 148: 890, 1958. 94. Schneckloth, R. E., Mcisaac, W. M. and Page, I. H.: Serotonin Metabolism in Carcinoid Syndrome with Metastatic Bronchial Adenoma. J.A.M.A. 170: 1143, 1959. 95. Lembeck, F.: 5-Hydroxytryptamine in a Carcinoid Tumour. Nature 172: 910, 1953. 96. Rapport, M. M., Green, A. A. and Page, I. H.: Partial Purification of the Vasoconstrictor in Beef Serum. J. Biol. Chern. 174: 735, 1948. 97. Kantor, S., Crane, R. D. and Gillesby, W. J.: Carcinoid Tumors of Gastrointestinal Tract. Am. Surg. 27: 448, 1961. 98. McKusick, V. A.: Carcinoid Cardiovascular Disease. Bull. Johns Hopkins Hosp. 98: 13, 1956. 99. Sjoerdsma, A., Weissbach, H. and Udenfriend, S.: A Clinical, Physiologic and Biochemical Study of Patients with Malignant Carcinoid (Argentaffinoma). Am. J. Med. 20: 520, 1956. 100. Thorson, A. H.: Studies on Carcinoid Disease. Acta med. scandinav. supp. 334, pp. 1-132, 1958. On the Cause of Death in Cancer 331 101. Cassidy, M. A.: Abdominal Carcinomatosis with Probable Adrenal Involvement. Proc. Roy. Soc. Med. 24-: 139, 1930. (Cited by McKusick, V. A.: Bull. Johns Hopkins Hosp. 98: 13, 1956.) 102. Thorson, A., Bjorck, G., Bjorkman, G. and Waldenstrom, J.: Malignant Carcinoid of Small Intestine with Metastases to Liver, Valvular Disease of Right Side of Heart (Pulmonary Stenosis and Tricuspid Regurgitation Without Septal Defects), Peripheral Vasomotor Symptoms, Bronchoconstriction, and Unusual Type of Cyanosis: A Clinical and Pathologic Syndrome. Am. Heart J. 4-7: 795, 1954. 103. Wilson, H. and Butterick, 0. D. Jr.: Massive Liver Resection for Control of Severe Vasomotor Reactions Secondary to Malignant Carcinoid. Ann. Surg. 14-9: 641, 1959. 104. Gailitis, R. J. and Scheiber, W.: Malignant Carcinoid Syndrome and Latest Concepts in Serotonin Metabolism; Use of Cortisone, Prednisone and Antiserotonin Compound 45-50. Am. J. Surg. 99: 84, 1960. 105. Findlay, C. W. Jr. and O'Connor, J. F.: Villous Adenomas of Large Intestine with Fluid and Electrolyte Depletion. J.A.M.A. 176: 404, 1961. 106. FitzGerald, M.G.: Extreme Fluid and Electrolyte Loss Due to Villous Papilloma of Rectum. Case Report. Brit. M. J. 1: 831, 1955. 107. Gutierrez Blanco, H.: Hiperazohemia extrarrenal por tumor velloso rectal hipersecretante; comunicaci6n de dos observaciones. Arch. Urug. med. 50: 184, 1957. 108. Jordan, G. L. Jr. and Erickson, E.: Villous Papilloma of Rectum with Severe Fluid and Electrolyte Depletion. A.M.A. Arch. Surg. 77: 248, 1958. 109. Mayfield, L. H. and Milnor, J.P. Jr.: Villous Tumor of Rectum and Portion of Sigmoid Flexure Causing Severe Electrolyte Imbalance. Dis. Colon & Rectum 2: 311, 1959. 110. Shnitka, T. K., Friedman, M. H. W., Kidd, E. G. and MacKenzie, W. C.: Villous Tumors of Rectum and Colon Characterized by Severe Fluid and Electrolyte Loss. Surg. Gynec. & Obst. 112: 609, 1961. 111. McKittrick, L. S. and Wheelock, F. C. Jr.: Carcinoma of the Colon. In American Lectures in Abdominal Viscera (L. R. Dragstedt, Ed.). Springfield, Illinois, Charles C Thomas, 1954, pp. 61-63. 112. Bonner, C. D., Homburger, F., Smithy, G. B. and Borges, P.R. F.: "Prostatic" Serum Acid Phosphatase Level in Cancer of Prostate. Diagnostic and Clinical Significance as Illustrated by Thirteen Case Histories. J.A.M.A. 164-: 1070, 1957. 113. Huggins, C.: The Prostatic Secretion. Harvey Lect. 4-2: 148, 1947. 114. Ley, A. B.: Mechanisms of Anemia in Cancer. M. Clin. North America 4-0: 857, 1956. 115. Kelly, W. D., Lamb, D. L., Varco, R. L. and Good, R. A.: An Investigation of Hodgkin's Disease with Respect to Problems of Homotransplantation. Ann. New York Acad. Sc. 87: 187, 1960. 116. Gellhorn, A.: Recent Studies on Pathophysiologic Mechanisms in Human Neoplastic Disease. J. Chron. Dis. 8: 158, 1958. 117. Auth, T. L. and Chodoff, P.: Transient Cerebellar Syndrome from Extracerebral Carcinoma. Neurology 7: 370, 1957. 118. Furtado, D.: Sindromes neurol6gicos das neoplasias malignas. I. Neuropatias associadas ao cancro. Arch. pat. (Lisboa) 29: 173, 1957. 119. Parker, H. L. and Kernohan, J. W.: Parenchymatous Cortical Cerebellar Atrophy (Chronic Atrophy of Purkinje's Cells). Brain 56: 191, 1933. 120. Meerloo, A. M.: The Initial Neurologic and Psychiatric Syndrome of Pulmonary Growth. J.A.M.A. 126:558, 1944. 121. Holt, G. W.: Idiopathic Neuropathy in Cancer. A First Sign in Multiple System Syndromes Associated with Malignancy. Am. J. M. Sc. 24-2: 93, 1961. 122. Oppenheim, H.: tl'ber Hirnsymptome bei Carcinomatose ohne nachweisbare Veriinderungen im Gehirn. Charite-Ann. 1886, Berl. 1888, 13, 335-344. (Cited by Brain, R., and Henson, R. A.: Lancet 2: 971, 1958.) 123. Denny-Brown, D.: Primary Sensory Neuropathy with Muscular Changes Associated with Carcinoma. J. Neurol. Neurosurg. & Psychiat. 11: 73,1948. 332 JAMES D. HARDY 124. Brain, R. and Henson, R. A.: Neurological Syndromes Associated with Carcinoma: The Carcinomatous Neuromyopathies. Lancet 2: 971, 1958. 125. Brain, W. R., Daniel, P.M. and Greenfield, J. G.: Subacute Cortical Cerebellar Degeneration and Its Relation to Carcinoma. J. Neurol. Neurosurg. & Psychiat. 14: 59, 1951. 126. Croft, P. B.: Abnormal Responses to Muscle Relaxants in Carcinomatous Neuropathy. Brit. M. J. 1: 181, 1958. 127. Victor, M., Banker, B. Q. and Adams, R. D.: The Neuropathy of Multiple Myeloma. J. Neurol. Neurosurg. & Psychiat. 21: 73, 1958. 128. Henson, R. A., Russell, D. S. and Wilkinson, M.: Carcinomatous Neuropathy and Myopathy: A Clinical and Pathological Study. Brain 77: 82, 1954. 129. Bezecny, R.: Dermatomyositis. Arch. f. Dermat. u. Syph 171:242, 1935. (Cited by Jordal, R.: Danish M. Bull. 4: 196, 1957.) 130. Caldwell, W.: A Dermatomyositic Symptom-Complex Associated with Malignant Disease. Brit. J. Cancer 9: 575, 1955. 131. Curtis, A. C., Blaylock, H. C. and Harrell, E. R. Jr.: Malignant Lesions Associated with Dermatomyositis. J.A.M.A. 150: 844, 1952. 132. Firmat, F. and Lipsett, M. B.: Cancer and Dermatomyositis. Cancer 11: 63, 1958. 133. Jordal, R.: Dermatomyositis and tumor. Danish M. Bull. 4: 196, 1957. 134. Lansbury, J.: Collagen Disease Complicating Malignancy. Ann. Rheum. Dis. 12: 301, 1953. 135. Schuermann, H.: Maligne Tumoren bei Dermatomyositis und progressiver Sklerodermie. Arch. f. Dermat. u. Syph. 192: 575, 1951. 136. Scott, 0. L.: Dermatomyositis with Malignant Disease. Proc. Roy. Soc. Med. 4-9: 423, 1956. 137. Sheard, C. Jr. and Knoepfier, P. T.: Dermatomyositis and Incidence of Associated Malignancy. Connecticut M. J. 20: 626, 1956. 138. Talbott, J. H. and Ferrandis, R. M.: Collagen Diseases. New York, Grune & Stratton, 1956, p. 119. 139. Parra, L. J. and Ramirez, E.: Comentarios sobre un s!ndrome de excepcional interes en el diagn6stico clinico de tumores malignos. La artralgia, con el caracter de reumatismo pluriartioular, como sintoma precoz en el cancer. Rev. elm. esp. to: 138, 1953. 140. Smith, J. P. and Yates, P. 0.: Thrombotic Syndrome Associated with Carcinoma. J. Path. Bact. 70: 111, 1955. 141. A Warning Sign of Cancer (Editorial). J.A.M.A. 177: 568, 1961. 142. Trousseau, A.: Clinique medicale de l'Hotel-Dieu de Paris. 5th ed., Paris iii, 1877, pp. 105 and 700. (Cited by Smith, J. P. and Yates, P. 0.: J. Path. Bact. 70: 111, 1955.) 143. Hubay, C. A. and Holden, W. D.: Venous Thrombosis, Necrosis, and Neoplasia. Surg. Gynec. & Obst. 98: 309, 1954. 144. Williams, A. A.: Malignant Disease Associated with Vascular Phenomena Brit. M. J. 2: 82, 1954. 145. Anlyan, W. G., Shingleton, W. W. and DeLaughter, G. D. Jr.: Significance of Idiopathic Venous Thrombosis and Hidden Cancer. J.A.M.A. 161: 964, 1956. 146. Sproul, E. E.: Carcinoma and Venous Thrombosis: Frequency of Association of Carcinoma in Body or Tail of Pancreas with Multiple Venous Thrombosis. Am. J. Cancer 34: 566, 1938. 147. Lieberman, J. S., Borrero, J., Urdaneta, E. and Wright, I. S.: Thrombophlebitis and Cancer. J.A.M.A. 177: 542, 1961. 148. Nyhus, L. M.: Carcinoma and Arterial Disease. Surg. Gynec. & Obst. 105: 635,1957. 149. Fumarola, D. and Del Buono, G.: Il quadro emocoagulativo nei portatori di neoplasie maligne. Progr. med. (Napoli), 14: 11, 1958. 150. Seale, R. A., Jampolis, R. W. and Bargen, J. A.: Clotting Defect in Presence of Metastatic Carcinoma of Prostate. S. CLIN. NoRTH AMERICA 31: 1111, 1951. 151. Crosby, W. H. and Benjamin, N. R.: An Abnormal Hemolytic System Associ- r: On the Cause of Death in Cancer 333 a ted with Leukemia and Other Disseminated Malignant Diseases. Blood 12: 701, 1957. 152. Green, H. N., Wakefield, J. and Littlewood, G.: Nature of Cancer Anaemia and Its Bearing on the Immunological Theory of Cancer. Brit. M. J. 2: 779, 1957. 153. Price, V. E. and Greenfield, R. E.: Anemia in Cancer. Advances Cancer Res. 5: 199, 1958. 154. Hyman, G. A., Gellhorn, A. and Harvey, J. L.: Studies on Anemia of Disseminated Malignant Neoplastic Disease. II. Study of Life Span of Erythrocyte. Blood 11: 618, 1956. 155. IDtmann, J. E.: Role of Spleen in Hemolytic Anemia of Cancer Patients. Cancer Res. 18: 959, 1958. 156. Sheets, R. F., Hamilton, H. E., DeGowin, E. L. and Janney, C. D.: Studies with Inagglutinable Erythrocyte Counts. V. Spontaneous and X-ray-Induced Hemolysis in Malignancy. J. Olin. Invest. 33: 179, 1954. 157. Levinson, J.P. and Kincaid, 0. W.: Myxoma of the Right Atrium Associated with Polycythemia. Report of Successful Excision. New England J. Med. 264: 1187, 1961. 158. Connor, T. B., Thomas, W. C. Jr. and Howard, J. E.: Etiology of Hypercalcemia Associated with Lung Carcinoma. J. Olin. Invest. 35: 697, 1956. 159. Gutman, A. B., Tyson, T. L. and Gutman, E. B.: Serum Calcium, Inorganic Phosphorus and Phosphatase Activity in Hyperparathyroidism, Paget's Disease, Multiple Myeloma and Neoplastic Disease of Bones. A.M.A. Arch. Intern. Med. 57: 379, 1936. 160. McGeown, M. G. and Montgomery, D. A. D.: Multiple Myelomatosis Simulating Hyperparathyroidism. Brit. M. J. 1: 86, 1956. 161. Myers, W. P. L.: Hypercalcemia in Neoplastic Disease. Cancer 9: 1135, 1956. 162. Myers, W. P. L.: Metabolic Disturbances in Disseminated Neoplastic Disease. Bull. New York Acad. Med. 33: 704, 1957. 163. O'Brien, J. S. and Walsh, J. R.: Hypogammaglobulinemia and Hypersplenism Associated with Lymphosarcoma of Spleen. Normal Serum Gamma Globulins Postsplenectomy. Am. J. Med. 30: 813, 1961. 164. Infection and Immunity in Chronic Lymphocytic Leukemia (Editorial). J.A.M.A. 174: 985, 1960. 165. Shaw, R. K. and others: Infection and Immunity in Chronic Lymphocytic Leukemia. A.M.A. Arch. Intern. Med. 106: 467, 1960. 166. Grace, J. T. Jr. and Dao, T. L.: Etiology of Inflammatory Relations in Breast Carcinoma. Burg. Forum 9: 611, 1959. 167. Black, M. M. and Speer, F. D.: Lymph Node Reactivity in Cancer Patients. Burg. Gynec. & Obst. 110: 477, 1960. 168. Barrett, M. K.: Critical Analysis of "Tun10r Immunity." J. Chron. Dis. 8: 136,1958. 169. Greenstein, J. P., Jenrette, W. V. and White, J.: Liver Catalase Activity of Tumor-Bearing Rats and Effect of Extirpation of the Tumors. J. Nat. Cancer Inst. 2: 283, 1941. 170. Lucke, B., Berwick, M. and Zeckwer, I.: Liver Catalase Activity in Parabiotic Rats with One Partner Tumor-Bearing. J. Nat. Cancer Inst. 13: 681, 1953. 171. Abels, J. C., Rekers, P. E., Binkley, G. E., Pack, G. T. and Rhoads, C. P.: Metabolic Studies in Patients with Cancer of Gastrointestinal Tract. II. Hepatic Dysfunction. Ann. Intern. Med. 16: 221, 1942. 172. Zamecnik, P. C., Frantz, I. D. Jr., Loftfield, R. B. and Stephenson, M. L.: Incorporation in vitro of Radioactive Carbon from Carboxyl-Labeled dZAlanine and Glycine into Proteins of Normal and Malignant Rat Livers. J. Bioi. Chern. 175: 299, 1948. 173. Rutman, R. J., Cantarow, A. and Paschkis, K. E.: Studies in 2-Acetylaminofluorene Carcinogenesis. II. The in vitro uptake of Alanine-1-014 by Preneoplastic Liver and Hepatoma Mitochondrial Protein. Cancer Res. 14: 115, 1954. 174. Clarke, B. G. and Goade, W. J. Jr.: Fever and Anemia in Renal Cancer. New England J. Med. 254: 107, 1956. 334 JAMES D. HARDY 175. Botton, J. E.: Neurogenic Tumors Simulating Infectious Process. Report of Two Cases of Diagnostic Interest. J.A.M.A. 177: 65, 1961. 176. Geraci, J. E., Weed, L.A. and Nichols, D. R.: Fever of Obscure Origin-the Value of Abdominal Exploration in Diagnosis. Report of Seventy Cases. J.A.M.A. 169: 1306, 1959. 177. Pareira, M.D., Conrad, E. J., Hicks, W. and Elman, R.: Clinical Response and Changes in Nitrogen Balance, Body Weight, Plasma Proteins, and Hemoglobin Following Tube Feeding in Cancer Cachexia. Cancer 8: 803, 1955. 178. Craig, A. B. Jr. and Waterhouse, C.: Body-Composition Changes in Patients with Advanced Cancer. Cancer 10: 1106, 1957. 179. Peden, J. C. Jr., Bond, L. F. and Maxwell, M.: Comparative Protein Repletion in Cancer and Non-cancer Cachexia with Special Reference to Changes in Blood Volume and Total Circulating Plasma Protein and Hemoglobin. Am. J. Clin. Nutr. 5: 305, 1957. 180. Posner, I.: Abnormal Fat Absorption in Tumor-Bearing Rats. Proc. Soc. Exper. Bioi. & Med. 98: 477, 1958. 181. Millar, F: K., White, J., Brooks, R. H. and Mider, G. B.: Walker Carcinosarcoma 256 Tissue as a Dietary Constituent. I. Stimulation of Appetite and Growth in the Tumor-Bearing Rat. J. Nat. Cancer Inst. 19: 957, 1957. 182. Wiseman, G. and Ghadially, F. N.: A Biochemical Concept of Tumour Growth, Infiltration and Cachexia. Brit. M. J. 2: 18, 1958. 183. Green, H. N.: An Immunological Concept of Cancer: Preliminary Report. Brit. M. J. 2: 1374, 1954. 2500 North State Street Jackson 6, Mississippi