[CANCER RESEARCH 37, 2366-2372, July 1977]

Summary

Cancer involving the alimentary tract may produce significant effects on the nutritional status of the patient. Theorgans in the gastrointestinal system are among the mostmetabolically active in the body. Consequently, food depniVation may adversely affect absorptive capacity and contribute to malabsorption by its effect on intestinal mucosalenzymes. Mucosal changes associated with malnutritionmay occur in the presence of cancers outside the alimentarytract (“cancerenteropathy' ‘),but such changes appear tobe the result of and not the cause of cachexia. Long-termpreexisting celiac disease is associated with the development of intestinal lymphoma and carcinoma. Intestinal lymphoma itself can present as a celiac syndrome. The mostcommon direct effect of alimentary tract neoplasms on nutnitional status relates to partial or complete obstruction at 1or more sites. In addition to impaired food intake, fluid andelectrolyte and acid base problems may result from persistent vomiting and/or diarrhea. Maldigestion and malabsorption may occur as a result of gastric hypersecretion, pancreatic exocnine insufficiency, or bile insufficiency. Themalabsorption occurring from these various conditions canlead to deficiencies of a variety of nutrients. Hepatoma maybe associatedwith severe hypoglycemia, and liverfailureleads to progressive malnutrition. Ovarian tumors exert anadverse effect with the development of ascites or intestinalobstruction. Cervical and bladder carcinoma may obstructthe ureters causing renal dysfunction.

Neoplasiaof the DigestiveTract

Because of the fundamental roles of the gastrointestinaltract related to ingestion , digestion , and absorption of food,the occurrence of cancer anywhere in that system mayproduce significant effects on the nutritional status of thepatient (Table 1). Included in this system are the entirealimentary tract from the lips to the anus, the liver, gallbladden, pancreas, and the ducts connecting them to the aumentary tract proper.

There is a close interrelationship between the function ofthe components of the gastrointestinal tract and the behavior of the patient in relation to food and nutrition. In addition, there is an important “reverse―relationship betweenthe ability of the patient to consume food in adequateamounts and the subsequent behavior of the gastrointes

, Presented at the Conference on Nutrition and Cancer Therapy, Novem

ber 29 to December 1, 1976, Key Biscayne, Fla.

tinaltract.Itisa dictum inmedicine thatwhen a patienthasan unexplained loss in appetite and body weight one shouldlook for an occult neoplasm. Often such neoplasms are inthe gastrointestinal tract. Table 2 summarizes some data onthe incidence of weight loss and anorexia on presentationof patients with primary alimentary tract cancers.

Malnutrition and Intestinal Function

Any tumor, although related to the gastrointestinal tract,or treatment of that tumor which leads to profound anorexiaor in other ways interferes seriously with the ingestion offood can adversely affect the absorption of food . The ongans in the gastrointestinal system are among the mostmetabolically active in the body. It is therefore not surpnising to learn that marked intestinal changes occur with starvation or protein deficiency (Table 3).

In the fasting adult rat, for example, nitrogen losses after24 hr were 15% of the original content in small intestine andliver and were approximately double this after 4 days atwhich time pancreas loss was also 30% and stomach loss11%. When calories were supplied as a protein-free diet,nitrogen losses were very high at 24 hr for pancreas andliver (25 and 20%, respectively, of the control values). Smallbowel losses were appreciably less than with fasting (18).

In recent years attention has been directed to specificchanges in structure, composition, and absorption. There isa diminution in mitotic figures in crypt regenerative areas, areduction of cells in the crypts and villi, and cytologicalalterations after 4 to 5 days of starvation (7, 26).

McManus and Isselbacher (37) noted decreases afterovernight fasts in weight of the bowel and DNA content(apparently related to the smaller cell mass of the mucosalfraction of the small bowel) and in amino acid and hexosetransport in the fasted animals as compared to the fedanimals together with decreased activity of the enzyme palmitoyl thiokinase (an enzyme used as an index of microsomal activity). While there was no difference in the measured length of intestine between fasted and fed youngadult rats after 3 days, the wet weight of the mucosa in the1st 30 cm of intestine dropped to one-third the control valuein the fasted rat, and the total mucosal protein fell to approximately one-half of control values (42). However, mucosal protein expressed per g of wet weight of mucosaactually increased slightly. There were similar changes observed throughout the small intestine. There were alsomarked decreases in total sucrase, maltase, and monoacylglycerol acyltransferase activities. However, specific activi

CANCERRESEARCHVOL. 372366

Nutritional Problems Associated with Gastrointestinaland Genitourinary Cancer1

Maurice E. Shils

Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, New York 10021

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Weight loss, anorexia, and dysphagiain patients presentcarcinomasof the alimentary tracting

with%

ofPatientsNo.

of pa- Ano- DysSitetients Wt loss rexiaphagiaRef.Esophagus60

2 25332Stomach111284° 302031Pancreas255

67 36449 73b2024Liver

(primary)53 34 1965 79c

52d21313

Nutrition, Gastrointestinal and Genitourinary Cancer

Table 1Nutritional problems associatedwith gastrointestinal neoplasms

1. Anorexia and weight loss2. Malnutrition causing intestinal changes3. Malabsorptionwith preexisting celiac diseaseand subsequentintestinal cancers4. Impaired food intake and malnutrition secondary to obstruction at any level5. Malabsorptionassociatedwith:

A. Deficiency or inactivation of pancreatic enzymesB. Deficiencyof bile saltsC. Fistulous bypass of small bowelD. Infiltration of small bowel wall and mesentery by malignant cellsE. Blind loop with partial upper small bowel obstruction

6. Protein-losingenteropathy7. Electrolyte and fluid problems with:

A. Persistentvomiting in obstructionB. Vomiting with increased intracranial tumorsC. Intestinal fluid lossesthrough fistulasD. Intestinal secretoryabnormalitieswith hormone-secretingtumorsE. Ectopic antidiuretic hormone secretionF. Hyperadrenalismsecondaryto excessivecorticotropin or corticosteroid production

bytumors

Table 2 Table 3Changesin the gastrointestinal tract during starvation

1. Decreasedweight thickness and protein content2. DecreasedDNA, RNA,and protein synthesis in gastric parietal

cells, pancreas,and small intestine3. Decreasedtotal enzymeactivity with a few exceptions4. Little or no change of specific enzymeactivity5. Function deterioratesbefore morphological changesappear6. Increasedgluconeogenic and lysosomalenzymeactivities7 Hormonaleffects related to route of feeding and starvation

3rd day (30). Four obese fasting subjects on prolonged fastswere found to have abnormal villi on biopsy; however, theperiods of starvation prior to biopsies are not stated (48).

Observations have been made on protein- and caloriemalnourished children and adults. Intestinal malabsorptionand jejunal histological abnormalities have been amply documented (8, 46, 53). Viteri et al. (53) studied absorption of anumber of nutrients in 32 protein-calorie malnourished children on admission to hospital and throughout recovery.Severe malabsorption of all substances was present mitially. As nutritional recovery progressed, absorption of nitrogen, D-xylOse, and vitamin A palmitate recovered soonafter initiation of therapeutic diets while absorption of fatand vitamin B52recovered more slowly.

Changesin Small IntestineMucosa Related to Extragastrointestinal Tract Cancers

Creamer (12) studied the small bowel mucosa in 9 patients with cancer. In 3 of 6 subjects in whom the neoplasmarose outside the intestinal tract there was a flat mucosa,and in the 4th there was a hypoplastic mucosa. The other 3patients had cancer in the stomach, small intestine, andcecum; the 1st 2 had abnormal mucosa. Of the 6 patientswith abnormal mucosa, 5 had lost weight and 4 had steatorrhea. He suggested that “someof the ill-health and loss ofweight in malignancy is caused by an abnormal small intestinal mucosa.―A number of papers then followed supporting this suggestion of a “cancerenteropathy―(14, 15, 21,35, 55); however, other investigators have been unable toconfirm these findings (4, 18, 29).

In the paper of Gilat et a!. (21), 82 patients with cancers (in

a Of those with resectable lesions, 74% had weight loss and 18%

had anorexia.a Of those with resectable lesions, 76% had weight loss and 27%

had anorexia.C With cirrhosis.

d Without cirrhosis.

ties of sucrase and maltase were unchanged by fasting andthat of lactase was increased while that of the acyltransferase expressed per mg of microsomal protein decreased.These results appear most consistent with the hypothesis ofdecreased cell proliferation in starvation, probably with achange in the proportion of the usual cell type, possibly anincreased proportion of younger differentiated cells in thelower villus.

Partial or total food deprivation for 7 days in obese subjects significantly decreased the activities of certain jejunalglycolytic enzymes in man; jejunal fructose diphosphataseactivity (a gluconeogenic enzyme) adaptably increased withfasting (43). Either starvation or protein deprivation over a2-week period in normal and obese human volunteers resuIted in reduction of amino acid absorption in 12 of 14patients in addition to a decrease in the absorption rates ofamino acids. Despite the reduced amino acid absorptionrates, the jejunal mucosal histology and cell organellesappeared intact (1). In overweight individuals there apparently is little gross histological change in jejunal mucosaeven after 28 days of fasting, although protein concentration and disaccharidase activities decrease as early as the

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M. E. Shils

57 of this group, the alimentary tract was involved) werecompared with 73 patients without neoplasia, malabsorption, orotherdisease involving the small bowel. No mentionis made of weight in comparison with normal weight orpreillness weight. Ten patients with cancer had partial vilbus atrophy and 1 had subtotal villous atrophy. None of thebenign group had any villous atrophy. Of interest is thefinding that 8 of the 10 patients having partial Villous atrophy had a tumor involving the gastrointestinal tract and the1 patient with subtotal villous atrophy had carcinoma of theovary with a single metastasis in the small bowel.

In a more definitive study Barry in essence asked thequestion: if mucosal changes occur in malignant diseases(as they appear to do), how much of these changes isassociated with weight loss and how much with cancer (4)?Three groups of patients were studied ; 1 group consisted of32 patients, with minimum weight loss of 21 pounds withbiopsy-proved malignant disease occurring anywhere in thebody but not involving the gastrointestinal tract either primanly or secondarily. This group was compared with a 2ndgroup of 20 patients matched for age who were hospitalizedfor investigation of vague abdominal symptoms but whohad no evidence of organic disease or weight loss. A 3rdgroup was a population of 15 wasted patients who were illand had lost more than 28 pounds for reasons other thancancer or gastrointestinal disease. Lactose utilization, epithelial cell loss rate, and the appearance of fresh peroralbiopsies were examined. They found abnormal changes inthese parameters in patients with cancer. However, thesesame abnormalities were present in the wasted patientswithout cancer; in fact, the wasting illnesses appeared tohave a more marked effect on intestinal appearance thandid cancer. In addition, mucosal morphologywasstudied in3 groups at necropsy. One group consisted of 23 individualsdying of extensive malignant disease not affecting the gastrointestinal tract. The 2nd group consisted of 36 patientsdying suddenly and without cancer. A 3rd postmortemgroup consisted of 52 patients dying after illnesses otherthan cancers or gastrointestinal disease with a weight lossof 28 pounds or greater. There was a highly significantdifference between the mucosal architecture in “normalcontrols―and those with wasting diseases; a very similartrend was shown in malignant disease but did not reach alevel of statistical significance with the numbers available.The author concludes “althoughmucosal changes undoubtedly occurred in malignant disease, the changes arenot specific for malignancy and the concept of “cancerenteropathy―is not tenable. It is suggested that mucosalchanges are the effect of and not the cause of cachexia.―

Association of Carcinoma and Intestinal Mucosal Abnormalit'ies

The literature on the association among villous atrophy,steatorrhea, and primary small bowel tumors was reviewedup to 1966 by Brzechwa-Ajdukiewicz et a!. (10); a tablemodified fromtheir paper is presented asTable 4. Bossaketa!. (6) reviewed 94 patients with celiac disease (gluten enteropathy, nontropical sprue), 5 of whom had intestinal carcinomas. Harris et al. (25) reported 202 patients with adult

celiac disease or sprue of whom 14 had carcinomas of thealimentary tract, 6 of which were in the esophagus. Eighteen of 26 patients with such cancers were males. Varioushypotheses have been suggested for the carcinomatousinvolvement in these patients including possibilities that theabnormal small bowel epithelium permits increased absorption of carcinogens, that the chronic inflammation of thelamina propria or lymphoid hyperactivity somehow plays arole, or that environmental factors such as prolonged nutritional deficiency secondary to malabsorption or intestinalorganisms may account for the malignant changes.

Celiac Syndrome and Intestinal Lymphomas

Prior to 1962 steatorrhea in lymphomatous patients wasconsidered to be the consequence of mesenteric lymphomacausing obstruction of lymphatic flow or of diffuse lymphomatous infiltration of the small bowel. In 1962 Gough etal. (23) advanced the hypothesis that small bowel reticulosismay develop as a complication in patients with celiac syndrome. Austed eta!. (3) found a 10% incidence of lymphomain their celiac patients. Benson et a!. (5) reported an mcidence of 6.2%, and Harris et al. (25) reported an incidenceof 6.9% (with a similar incidence of carcinoma in their seriesof 202 patients). Nine of the 14 patients of Harris et a!. (25)had lymphoma involving the stomach, jejunum, or ileum; 12ofthe 14 had celiac disease diagnosed for more than 5 years(the average being 21 years for the group of 14). Of the 14,4had Hodgkin's disease in none of whom the intestine wasinvolved. The others had reticulum cell sarcoma with theintestine involved in 8 patients. Many of the older studieshad no histological proof of villous atrophy by biopsy andthe diagnosis of celiac syndrome was made by history orabnormal fat absorption and/or in response to gluten-freediets.

Lymphoma involving the small bowel mesentery lymphnodes may present as malabsorption (9, 17, 39). Patientswith abdominal lymphomas and malabsorption often present with abdominal pain, weight loss, anorexia, and bulkystool suggestive of steatorrhea. They may have clubbing,glossitis, angular stomatitis, and peripheral edema. Laboratory findings may include abnormal D-xylOseabsorption, flatglucose tolerance curves, hypoalbuminemia, and fat andB12malabsorption;megaloblastosismaybe present(9, 17,39). There may be deficits in fat-soluble vitamins. Folic aciddeficiency may occur on occasion (41).

Because of this relationship lymphoma should be suspected with the onset of the celiac syndrome in middle ageespecially, but also in young people particularly in certainareas and in certain racial backgrounds (17, 27). Malesabove 40 years of age with long-standing celiac syndromewho are not on a gluten-free diet are a major risk group.

Primary lymphomas originate in the intestinal tract inapproximately 10 to 20% of reported cases (38). A majorityof these tumorsare lymphocytic lymphomas, with approximately twice (38) or 2.5 times as many (34) occurring in thestomach as in the small intestine. Disseminated lymphomaoften secondarily involves 1 or more sites along the gastrointestinal tract; tumor, ulcerations, erosions, and infection may occur with deleterious effects to the patient (16).

The mechanisms for the development of malabsorption

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Duration of idiopathic steator

rhea before diagnosis of carci

SiteReportAgeSexnoma(yr)TongueHarris

et al.(1966)FTonsilGreenand Wollaeger(1960)TracheaCase2 (presentreport)70M14PharynxCase3 (presentreport)46F26EsophagusBossak

et al. (1957)Harris et al. (1966)

Case4 (present report)Case5 (present report)45 54F

5M1F

M109StomachBossak

et al. (1957)

Huizengaet al. (1961)Harris et al. (1966)56F F

2M'9

1317

22Small

intestineOgilvie and Shaw (1955)Case Records, Massachusetts

GeneralHospital (1958)Girdwood et al. (1961)Moerteland Hargraves(1961)Fric et al. (1963)Case6 (present report)Case7 (present report)40

60

5068446572M

M

MMFMFFor

years11

261124Since childhood

42ColonBossak

et al. (1957)Kelleyetal. (1961)Harris et al. (1966)55MM3RectumHarris

et al.(1966)MAnusHarriset al. (1966)M

Nutrition , Gastrointestinal, and Genitourinary Cancer

Table 4Carcinomaand idiopathic steatorrhea

This table was taken from Brzechwa-Adjukiewicz et al. (10).

I Refers to the number of male patients reported by these authors.

are several. The intestinal epithelium may be disrupted bythe generalized villous atrophy found in association withlymphomatous involvement. Infiltration of the lamina propria and draining lymph nodes can lead to obstruction ofmesenteric lymph channels and dilation of the lymphaticswithin the intestinal villi which in turn can lead to development of a protein-losing enteropathy with hypoalbuminemia, hypoglobulinemia, and lymphocytopenia (54). Proteinlosing enteropathy has also been described with cases ofgastric carcinoma (54).

The blind loop syndrome in the upper small bowel secondary to partial obstruction with bacterial overgrowth mayalso result in steatorrhea and vitamin B12deficiency. Recentevidence indicates that the blind loop syndrome involvesnot only direct interaction of bacteria with certain nutrientsbut also the development of abnormalities of the intestinalepithelium to account for associated malabsorption (50).

Nutritional replacement and support in such malabsorption syndromes are useful while direct antineoplastic treatment with radiation and chemotherapy are undertaken.

Obstructionalongthe AlimentaryTract

The most common direct effect of alimentary tract neo

plasms on nutritional status relates to partial or completeobstruction at 1 or more sites.

It is estimated that about 20% of surgical admissions foracute abdominal conditions are associated with intestinalobstruction and that the 3rd most common cause of obstruction is neoplasm of the bowel (45). When obstructionoccurs acutely, medical attention is very likely to be soughtimmediately. However, most neoplasms obstruct slowly andprogressively. It is a common observation that a significantnumber of patients will defer seeking medical care untiltheir dysphagia, anorexia, pain , nausea, vomiting , diarrhea,or anemia from chronic blood loss have persisted to thepoint where weight loss and weakness are prominent (Table2). In addition to weight loss secondary to poor intake offood there are fluid, electrolyte, and acid-base problemsthat result from persistent vomiting or diarrhea or as aconsequence of malnutrition per se.

Endocrineand ParacrineProductionby Tumors

A number of biologically active agents are formed byneoplasms of the gastrointestinal tract in amounts whichmay create serious problems in fluid and electrolyte balance(44). These endocrine and paracrine substances have beendescribed by Lipsett (33) at this conference.

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M. E. ShilS

Pancreatic Exocrine Insufficiency

A marked decrease in the secretion or activities of pancreatic enzymes results in maldigestion and consequentmalabsorption of fats, proteins, and long-chain carbohydrates.

Carcinoma of the pancreas may cause enzyme deficiency,especially when there is extensive involvement of this organ, particularly in the head region. Although the number ofsuch patients that has been reported is small (56), it is myexperience that malabsorption in this condition is not uncommon. The resulting malabsorption combined with anorexia frequently apparent in such patients contributes toprogressive weight loss. Treatment with pancreatic replacement is indicated if there is any suspicion of enzyme deficiency. Despite a priori supposition that vitamin B12absorption would be normal in pancreatic insufficiency, there havebeen reports indicating that there may be reduction in vitamin B12absorption in approximately 40 to 50% of patientswith this condition (51, 52) and in partially pancreatectomized rats (49). Where pancreatic insufficiency exists withpancreatic carcinoma, there may be a role for pancreaticenzymes in improving the absorption of vitamin B12as wellas protein, fat, and carbohydrate.

Irreversible denaturation and dilution of pancreatic enzymes in proximal small intestine in the Zollinger-Ellisonsyndrome as a result of excess gastric acid production maybe a contributing factor in the malabsorption noted in thiscondition (22).

Conjugated bile salts play an important role in the absorption of fat; hence, any condition that reduces the concentration of such bile salts below the critical level for adequatemicellar formation will lead to steatorrhea. This may occurwith obstruction or diversion of biliary flow. Concentrationsof conjugated bile salts may decrease as the result of bacterial action in the blind loop syndrome or following precipitation of glycmne-conjugated bile salts into a microcrystallinephase as a result of a low pH in the Zollinger-Ellison syndrome (22). Bile insufficiency reduces intestinal absorptionof vitamin K and leads to reduction in plasma levels of thevitamin K-dependent coagulation factors. This can be overcome by parenteral administration of relatively smallamounts of vitamin K1oxide. There is recent evidence thatlack of bile in the small intestine depresses the lipid-reesterifying capacity of the small bowel (47).

Bypass of significant portions of small bowel as a result ofgastrocolic, enteroentero-, enterocolic, or enterocutaneousfistulas secondary to tumor can induce malabsorption, theseverity of which depends upon the extent of small bowelbypass. The rather abrupt occurrence of diarrhea or ofsteatorrheic stools in the patient with suspected or knownabdominal tumors, particularly where there has been previous surgery or radiation, should include this possibility inthe differential diagnosis and work-up.

Liver Carcinoma

Weight loss, weakness, and ascites occur in approximately 79% and jaundice occurs in 41% of patients withprimary carcinoma in whom there is preexisting cirrhosis;

the incidences are lower in those with noncirrhotic livers(13). In poorly differentiated hepatoma, which is the common type, weight loss is early and severe; hypoglycemiaoccurs late and in about 17% of these cases. InweIl-differentiated tumors weight loss is late but hypoglycemia is verycommon, manifests itself early, and is difficult to control.The hypoglycemia does not result from ectopic insulin production but appears to be related to the deletion in thetumor cells of normal enzyme systems for glycogenolysisand gluconeogenesis and to rapid tumor growth (36).

The liver is second only to regional lymph nodes as a siteof metastases for various tumors. Fifty % of patients withgastrointestinal tumors have hepatic metastases at autopsy.Clinical manifestations when such metastases are widelydisseminated in the liver are similar to those occurring withprimary carcinoma. Hypoalbuminemia and hypoprothrombinemia occur progressively as the result of progressivemalnutrition with jaundice. Renal failure without apparentcause may develop in the course of liver decompensation.The development of azotemia under these circumstancesbears with it a very poor prognosis (40). Serum vitamin B12levels are often excessively high (>1000 mg/mI) in patientswith liver disease (29). Mild folate deficiency appears to becommon in patients with disseminated cancer, either as aresult of decreased intake, increased need , or both (29).

Tumorsof the ReproductiveSystem

Tumors arising from the organs of this system in malesand females do not have a direct effect on nutrition per seother than through endocrine changes. They may have secondary effects through local spread or distant metastases.Ovarian tumors have a propensity for seeding the peritoneum and peritoneal cavity with the development of ascitesand its resultant problems in terms of hypoalbuminemia andfluid retention or of obstruction of the intestine. Cervicalcarcinoma in its spread laterally may obstruct the ureterswith resultant impairment of renal function. The effect ofmetastatic spread to liver has been described earlier.

TumorsAffectingthe UrinaryTract

Nutritional consequences of involvement of this tract relate primarily to the effects of interference with normal renalfunction. Primary tumors of the kidney such as Wilms',neuroblastoma, and clear cell carcinoma will progressivelydamage the involved kidney or kidneys. Metastases to thekidney do occur although they are not common. More cornmon is the development of ureteral obstruction secondaryto encroaching pelvic tumors or to primary bladder cancerIn his review of the causes of death in 150 cases of bladdercancer, Cooling (11) noted that 25% were directly attributable to renal damage and electrolyte disturbances.

With destruction of renal tissue there is progressive deterioration with its usual consequences of azotemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, and thehematological and neurological problems attendant on progressive renal failure. Partial obstruction of urine outflowfrom both kidneys may lead to back pressure and impairment of both glomerular and tubular function resulting in

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Nutrition , Gastrointestinal, and Genitourinary Cancer

azotemia and associated changes, polyuria, and electrolyteproblems. Total obstruction causes anuria and the dangerof nephron destruction if not relieved. The sudden relief ofsevere urinary tract obstruction can lead to very large fluidand electrolyte output (postobstructive diuresis) which, although self-limiting, may be life-threatening during itscourse and requires careful fluid and electrolyte management of the patient until kidney function is restored. Diettherapy can play an important role in the care of patientswith significant renal failure. Restriction of the intakes ofprotein, potassium, phosphate, and sulfate and carefulmanagement of fluid and electrolytes are often of majorconcern. When renal tubular dysfunction occurs recognition must be given to the possibilities of increased losses ofsodium, magnesium, and phosphorus. With advanced renaldisease there is an increased need for histidine (19).

Renal tubular disorders may occur secondarily as a resultof tumor activities elsewhere. For example, chronic potassium depletion may result from excessive potassium lossesin diarrhea as a result of the excessive production of certainintestinal hormones. The hypokalemia may be severeenough to damage renal tubules with resultant impairedability to reabsorb other ions and water. Similarly, hypercalcemia secondary to either ectopic production by tumors ofparathyroid hormone-like substance or parathyroid hormone itself, or from lytic lesions of bone, can impair tubularfunction with inability to concentrate urine.

References

1. Adibi, S. A., and Alien, E. R. Impaired Jejunal Absorption Rates ofEssential Amino Acids Induced by Either Dietary, Caloric, or ProteinDeprivation in Man. Gastroenterology, 59: 404-413, 1970.

2. Ai-Sarraf, M., Go, T. S., Kithier, K., and Vaitkevicius, V. K. Primary LiverCancer. A Review of the Clinical Features, Blood Groups, Serum Enzymes, Therapy, and Survival of 65 Cases. Cancer, 33: 574-582, 1974.

3. Austed, W. I., Comes, J. S., Gough, K. A., McCarthy, C. F., and Read, A.E. Steatorrhea and Malignant Lymphoma. Am. J. Digest. Diseases 12:475—490,1967.

4. Barry, A. E. Malignancy, Weight Loss, and the Small Intestinal Mucosa.Gut, 15: 562-570, 1974.

5. Benson, G. D., Kowlessar, 0. D., and Sleisenger, M. H. Adult CoeliacDisease with Emphasis upon Response to Gluten Free Diet. Medicine 43:1-40, 1964.

6. Bossak, E. T., Wang, C. L., and Aldersberg, D. Clinical Aspects of theMaiabsorption Syndrome (idiopathic Sprue). J. Mt. Sinai Hosp. N.Y., 24:286-303, 1957.

7. Brown, H. 0., Levine, M. L., and Lipkin, M. Inhibition of Intestinal CellRenewal and Migration Induced by Starvation. Am. J. Physioi., 205: 868—872, 1963.

8. Brunser, 0., Reid, A., Monckeberg, F., Maccioni, A., and Contreras, J.Jejunal Mucosa in infant Malnutrition. Am. J. Clin. Nutr., 21: 976-983,1968.

9, Brunt, T. W., Sircus, W., and MacLean, N. Neopiasia and Coeliac Syndrome in Adults. Lancet 1: 180—184,1969.

10. Brzechwa-Ajdukiewicz, A., McCarthy, C. F., Austad, W., Comes, J.,Harrison, W. J., and Read, A. E. A. Carcinoma, Villous Atrophy, andSteatorrhea. Gut 7: 572-577, 1966.

11. Cooling, C. I. The Mode of Death in Carcinoma of the Urinary Bladder. InD. M. Wallis (ed), Tumors of the Bladder, pp. 187-193. Edinburgh, E. &S. Livingstone, 1959.

12. Creamer, B. Malignancy and the Small Intestinal Mucosa. Brit. Med. J.,2: 1435-1436, 1964.

13. Curutchet, H. P., Terz, J. J., Kay, S., and Lawrence, W., Jr. Primary LiverCancer. Surgery, 70: 467-479, 1971.

14. Deller, D. J., Murrell, T. G. C., and Blowes, A. Jejunal Biopsy in Malignant Disease. Australasian Ann. Med., 16: 236-241, 1967.

15. Dymock, I. W., Mackey, N., Miller, V., etal. Small Intestinal Function inNeoplastic Disease. Brit. J. Cancer, 21: 505—511,1967.

16. Ehrlich, A. N., Stalder, G., Geller, W., and Sherlock, P. GastrointestinalManifestations of Malignant Lymphoma. Gastroenterology, 54: 1115-1121,1968.

17. Eidelman, S., Parkins, R. A., and Rubin, C. E. Abdominal LymphomaPresenting as Malabsorption. Medicine, 45: 111-137, 1966.

18. Fischer, A. A., Rosoff, B. M., Altshuler, J. H., et al. Disacchariduria inMalignant Disease. Cancer, 18: 1278-1284, 1965.

19. FUrst, P. ‘5NStudies in Severe Renal Failure. ii. Evidence for the Essentiality of Histidine. Scand. J. Clin. Lab. invest., 30: 307-312, 1972.

20. Gambili, E. E. Pancreatic and Ampullary Carcinoma Diagnosis and Prognosis in Relationship to Symptoms, Physical Findings, and Elapse ofTime as Observed in 255 Patients. Southern Med. J., 63: 1119—1122,1970.

21. Gilat, T., FischeI, B., Dannon, J., and Loewenthal, M. Morphology ofSmall Bowel Mucosa in Malignancy. Digestion, 7: 147-155, 1972.

22. Go, V. L. W., Poley, J. A., Hofman, A. F., and Summerskill, W. H. G.Disturbances in Fat Digestion induced by Acidic Jejunal pH Due toGastric Hypersecretion in Man. Gastroenterology, 58: 638-646, 1970.

23. Gough, K. A., Read, A. E., and Naish, J. M. Intestinal Reticulosis as aComplication of Idiopathic Steatorrhea. Gut, 3: 232-239, 1962.

24. Gray, L. W., Jr., Crook, J. N., and Cohn, I., Jr. Carcinoma of thePancreas. In: Seventh National Cancer Conference, pp. 503-510. Philadeiphia: J. B. Lippincott Co., 1973.

25. Harris, 0. D., Cooke, W. T., Thompson, H., and Waterhouse, J. A. H.Malignancy in Adult Coeliac Disease and idiopathic Steatorrhea. Am. J.Med.,42:899-912,1967.

26. Hooper, C. S., and Blair, M. The Effect of Starvation on EpithelialRenewal in the Rat Duodenum. Exptl. Cell Res. 14: 175-181 , 1958.

27. Huntington, A. W., Jr., Larkwood, T. E., Armstrong, F., et al, ChronicMalabsorption (Steatorrhea, Non-tropical Sprue) in an Adolescent withDeath from Malignant Lymphoma, Histocytic Type (Reticulum Cell Sarcoma). Cancer, 25: 206-211, 1970.

28. Ju, J. S., and Nasset, E. S. Changes in Total Nitrogen Content of SomeAbdominal Viscera in Fasting and Reaiimentation. J. Nutr. 68: 633-645,1959.

29. Klipstein, F. A. , and Smarth, G. Intestinal Structure and Function inNeoplastic Disease. Am. J. Digest Diseases, 14: 887-899, 1969.

30. Knudsen, K. B., Bradley, E. M., Lecoq, F. A., Bellamy, H. M., and Welsh,J. 0. Effect of Fasting and Refeeding on the Histology and Disaccharidase Activity of the Human Intestine. Gastroenterology, 55: 46-51 , 1968.

31. LaDue, J. S., Munson, P. J., McNeer, G., and Pack, G. T. Symptomatology and Diagnosis of Gastric Cancer. Arch. Surg., 60: 305—335,1950.

32. Lindsay, J. A. The Early Diagnosis of Carcinoma of the Esophagus. Ann.Otoi. Rhinol. Laryngol. 50: 675-680, 1941.

33. Lipsett, M. B. Effects of Cancers of the Endocrine and Central NervousSystems on Nutritional Status. Cancer Res., 37: 2373-2376, 1977.

34. Loehr,W.J.,Mujahed,Z.,Zahn,F.D.,Gray,G.F.,andThorbjarnarson,B. Primary Lymphoma of the Gastrointestinal Tract: A Review of 100Cases. Ann. Surg. 170: 232-238, 1969.

35. Loehry, C. A., and Creamer, B. Post-Mortem Studies of Small-IntestinalMucosa. Brit. Med. J., 1: 827-829, 1966.

@ 36. Margolis, S. , and Homcy, C. Systemic Manifestations of Hepatoma.Medicine,51: 381-391, 1972.

37. McManus, J. P. A., and lsselbacher, K. J. Effects of Fasting versusFeeding on the Rat Small Intestine. Gastroenterology, 59: 214-221 , 1970.

38. Naqvi, M. S., Burrows, L., and Kark, A. E. Lymphoma of the Gastrointestinal Tract: Prognostic Guides Based on 162 Cases. Ann. Surg. 170: 221-231,1969.

39. Novis, B. H., Banks, S., Marks, I. N., Seizer, G., Kahn, L., and Sealy, A.Abdominal Lymphoma Presenting as Malabsorption. Quart. J. Med., 40:521-540, 1971.

40. Papper, S., and Vaamonde, C. A. The Kidney in Liver Disease. In: M. B.Strauss and L. G. Welt (eds.), Diseases of the Kidney, Ed. 2. Boston:Little, Brown & Co., 1971.

41. Pitney, W. A., Joske, A. A., and Mackinnon, N. L. Folic Acid and OtherAbsorption Tests in Lymphosarcoma, Chronic Lymphocytic Leukemia,and Some Related Condition. J. Clin. Pathol., 13: 440, 1960.

42. Powell, G. K., and McElveen, M. A. Effect of Prolonged Fasting on FattyAcid Re-esterification in Rat intestinal Mucosa. Biochim Biophys. Acta,369: 8—15,1974.

43. Aosensweig, N. S., Herman, A. H., and Stifel, F. B. Dietary Regulationsof Giycolytic Enzymes. VI. Effects of Dietary Sugars and Oral Foiic Acidon Human Jejunal Pyruvate Kinase, Phosphofructokinase, and Fructosediphosphatase Activities. Biochim. Biophys. Acta, 208: 373-380, 1970.

44, Schmitt, M. G., Soergel, K. H., Hensley, G. T., and Chey, W. V. WateryDiarrhea Associated with Pancreatic Islet Cell Carcinoma. Gastroenterology, 69: 206-@16,1975.

45. Schwartz, J. S., and Storer, E. H. Manifestations of Gastrointestinaldisease. In: J. S. Schwartz et al. (eds.), Principles of Surgery, Ed. 2, p.980. New York: McGraw-Hill Book Co., Inc.

46. Tandon, B. N., Magotra, M. L., Saraya, A. K., and Aamaiingaswami, V.Small Intestine in Protein Malnutrition. Am. J. Clin. Nutr. 21: 813—819,1968.

47. Tandon, A., Edmonds, A. H., and Rodgers, J. B. Effects of Bile Diversionon the Lipid-reesterifying Capacity of the Rat Small Bowel. Gastroenterology, 63: 990-1003, 1972.

JULY 1977 2371

on June 2, 2018. © 1977 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

48. Thompson, T. J., Auncie, J., and Miller, V. Treatment of Obesity by TotalFasting for up to 249 days. Lancet, 2: 992-996, 1966.

49. Toskes, P. P., and Deren, J. J. The Role of the Pancreas in Vitamin B12Absorption: Studies of Vitamin B12Absorption in Partially Pancreatectomized Rats. J. Clin. Invest., 51: 216-223, 1972.

50. Toskes, P. P., Gianneiii, A. A., Jervis, H. A., Rout, W. A., and Takeuchi,A. Small intestinal Mucosal injury in the Experimental Blind Loop Syndrome. Gastroenterology, 68: 1193-1203, 1975.

51. Toskes, P. P., Hansell, J., Cerda, J., and Deren, J. J. Vitamin B12Malabsorption in Chronic Pancreatic Insufficiency. New Engi. J. Med., 284:627-632, 1971.

52. Veeger, W., Abels, J., Heilemans, N., and Nieweg, H. 0. Effect of Sodium

Bicarbonate and Pancreatin on the Absorption of Vitamin B12and Fat inPancreatic Insufficiency. New EngI. J. Med., 267: 1341-1344, 1962.

53. Viteri, S. E., Flores, J. M., Alvarado, J., and Behar, M. intestinal Malabsorption in Malnourished Children Before and During Recovery: RelationBetween Seventy of Protein Deficiency in the Malabsorption Process.Am. J. Digest. Diseases 18: 201-211, 1973.

54. Waldman, T. A., Broder, S., and Strober, W. Protein-losing Enteropathies in Malignancy. Ann. N. Y. Acad. Sci. 230: 306-317, 1974.

55. Wangei, A. G., and Deiler, D. J. Malabsorption Syndrome Associatedwith Carcinoma of the Bronchus. Gut, 6: 73-76, 1965.

56. Wilson, F. A., and Dietschy, J. N. Differential Diagnostic Approach toProblems of Maiabsorption. Gastroenterology, 61: 911-931 , 1971.

2372 CANCER RESEARCH VOL. 37

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1977;37:2366-2372. Cancer Res   Maurice E. Shils  Genitourinary CancerNutritional Problems Associated with Gastrointestinal and

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