Effects of luminal gastrin on the growth of rat intestinal mucosa.
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Biomedical subjects
Publications and source records attributed to S J Dudrick.
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Over 1,500 patients at our institution have received intravenous hyperalimentation (IVH) as nutritional support for nutritional rehabilitation prior to and/or during oncologic therapy. Stimulation of tumor growth has not been identified, and septic and metabolic complications of this technique have been minimal. Nutritional repletion resulted in return of immunocompetence and was associated with a reduction in sepsis, proper wound healing, and an apparent increase in tumor response to chemotherapy. If these observations were related as cause and effect, then a method of restoring and maintaining adequate nutrition should be added to the armamentarium of the oncologist. The use of IVh allowed specific oncologic therapy to be administered to a group of malnourished patients who otherwise might not have been acceptable candidates for intensive antineoplastic therapy.
Depending on the severity of malnutrition, protein depletion is associated with general debilitation, inanition, slow healing of wounds, delayed convalescence, increased susceptibility to infection, and other pathophysiologic conditions. In an effort to decrease the incidence and severity of these complications, Hermann Hospital and the University of Texas Medical School at Houston have implemented a comprehensive nutritional assessment program to identify clinical and subclinical malnutrition and to implement aggressive, effective therapy. A multidisciplinary team approach to nutritional assessment, therapy, and research can lead to an increased awareness of the importance of nutritional support and optimal nutritional care for the hospitalized patient under all conditions at all times.
This study confirms recent reports from other disciplines that show a high incidence of nutritional depletion among hospitalized patients. Preoperative assessments revealed a 50% incidence of subclinical nutritional depletion. Nutritional assessment is of value in the diagnosis, treatment, and continuing evaluation of the orthopaedic patient. Clearly the incidence and consequences of malnutrition in orthopaedic patients deserve further evaluation. Appropriate nutritional support needs to be more widely disseminated to and evaluated in this population. Whereas it is doubtful that sterile technique and operative procedures will be greatly improved in the foreseeable future, supportive nutrition therapy may offer the best prospect for immediate and substantial improvement in patient care.
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Host and tumor response to methotrexate (MTX) was studied in 122 tumor-bearing, malnourished rats during nutritional repletion. Sprague-Dawley rats with transplanted Walker-256 carcinosarcoma were fed a regular diet (RD) for five days followed by a protein-free diet (PFD) for ten days. On day 15, one group was orally repleted with a regular diet, while the other group continued on PFD. Methotrexate (20 mg/kg) therapy was begun in RD groups either on day 17 or day 21. Similarly, MTX (20 mg/kg) was begun in PFD groups either on day 17 or day 21. Untreated (no MTX) rats served as control animals and gained more body weight than MTX-treated rats. Tumor weight (TW) to carcass weight (CW) ratios were significantly less in both PFD and RD groups when MTX was given two days after dietary manipulation compared with results when MTX was given six days after dietary manipulation. Maximum tumor inhibition by MTX (least change in tumor diameter compared with control rats) was significantly greater when MTX was given to nutritionally repleted animals compared with results when MTX was given to animals continued on the protein-free diet. Dietary protein depletion inhibited tumor growth and tumor response to methotrexate. Nutritional repletion stimulated host and tumor growth. A short period of nutritional repletion (two days) prior to MTX chemotherapy resulted in improved host nutritional status and maximum tumor inhibition.
Maintenance of rats on total parenteral nutrition for 10 days increased the susceptibility of these animals to gastric ulceration and death due to cold-temperature restraint stress. Animals fed the identical diet orally were much less susceptible. Serum gastrin concentrations were increased by stress in both groups of animals despite initially low serum levels. Glucosamine synthetase specific activity was not altered by the method of feeding but tended to be decreased by restraint. These results suggest that orally administered food protects the animal from stress-induced damage by a mechanism(s) involving neither dietary composition nor gastrin.
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The effects of nutritional manipulation on host body weight dynamics, tumor growth patterns and host-tumor responses to chemotherapy were studied in Sprague-Dawley rats with Walker-256 carcinosarcomas. Group I maintained throughout on a regular diet (RD) gained carcass weight steadily. Group II lost carcass weight while fed a protein-free diet (PFD) but rapidly gained weight after switching to RD on day 15. Mean tumor volume increased 105% in Group I from day 15 to 21, 218% in Group II and 77% in Group III (continued on PFD p less than 0.05). From day 21 to day 33 tumor growth patterns were similar in Groups I and II, while mean tumor volume eventually plateaued in Group III. In Study B, Group II animals were given Methotrexate (MTX-20 mg/kg) two days and six days after switching from PFD to RD. The mean change in tumor volume in the MTX-treated rats was 1.31 +/- 0.1 cm3 compared with 8.14 +/- 0.1 cm3 (p less than 0.001) in the saline-treated control rats. MTX did not significantly affect tumor growth patterns in Group III (PFD) rats. In Study A, protein-calorie malnutrition resulted in host carcass weight loss and tumor growth retardation while nutritional repletion restored host carcass weight and stimulated tumor growth. In Study B, MTX was maximally effective in tumor-bearing rats that were switched from PFD to RD demonstrating that nutritional manipulation can improve host nutritional status and increase tumor response to chemotherapy.
Effects of nutritional repletion with intravenous hyperalimentation (IVH) on sequential skin test reactivity were evaluated in 160 malnourished cancer patients undergoing chemotherapy (76 patients), surgery (49 patients), radiation therapy (20 patients) and supportive care (15 patients). In the chemotherapy group, 45 patients had negative reactions initially, and 25 patients (55%) had at least one skin test convert to positive in an average period of 19 days of IVH. In the surgery group, 23 patients (46%) were initially positive and remained positive, 13 patients (24%) converted from negative to positive, and 13 patients (30%) remained negative or converted to negative. Postoperative complications occurred in 25% of positive reactors, compared with 69% (p < 0.01) of negative reactors. In the radiation therapy group, the skin tests of six patients (30%) remained positive, three patients (15%) converted from negative to positive and the skin tests of nine patients (45%) remained negative. In the supportive care group, the skin tests of 73% of the patients either remained positive or converted to positive with IVH within an average period of 11 days of treatment. Nutritional therapy with IVH was associated with restored skin test reactivity in 51% of malnourished cancer patients undergoing oncologic therapy. Radiation therapy was generally immunosuppressive despite adequate nutritional repletion. In surgical patients, positive skin test reactivity correlated directly with a favorable response to operative therapy.
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Exogenous secretin and cholecystokinin (CCK) have been shown to stimulate the growth of the exocrine pancreas. To conclude that a hormone produces an effect under normal physiological conditions, one must demonstrate that the endogenous hormone also produces the action in question. To release endogenous secretin 0.01 N HCl was continuously infused into the duodenums of eight rats for 5 days. Sixteen animals were prepared with catheters inserted 1 cm below the pylorus. The other eight animals were infused with PO4 buffer, pH 7.5. The infusion rate for both groups was 2 ml/h. Animals were killed at the end of 5 days, and the oxyntic gland mucosa and pancreas were examined. Pancreatic weights, DNA synthesis, DNa, RNA, and protein content were significantly increased in rats receiving acid. An identical experiment was set up to release endogenous CCK. In this experiment eight rats received a solution containing 50 mM phenylalanine and 50 mM tryptophan. The controls received the caloric equivalent in glucose. At the end of 1 wk the pancreases of the rats infused with amino acids averaged 405 (P < 0.001) heavier than the controls. Similar increases occurred in DNA, RNA, and protein content. These studies suggest that endogenous secretin and CCK can be released in amounts sufficient to stimulate growth.
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