Michael M. Meguid

Cancer of the breast after prophylactic subcutaneous mastectomy

We have reported a case of carcinoma of the breast in a patient that occurred after bilateral prophylactic subcutaneous mastectomy. We recommend that the patient and physician be aware of the limitations of prophylactic mastectomy in terms of cancer prevention and that patients who undergo prophylactic mastectomy continue to be carefully followed.

Oxidative stress and wasting in cancer.

Purpose of reviewCancer anorexia–cachexia syndrome is becoming a critical component in the comprehensive approach to cancer patients because it influences morbidity, mortality and quality of life. Consequently, pathogenic mechanisms have been elucidated to facilitate development of better therapies. Reported findings indicate that increased production of reactive oxygen species and reduced activity of antioxidant enzymes contribute to development of anorexia and cachexia in cancer. Recent findingsSystemic inflammation impairs tryptophan handling, promoting oxidative stress, which appears to mimic hypothalamic negative feedback signalling. Thus, tryptophan contributes to cancer anorexia by stimulating hypothalamic serotonergic activity and promoting oxidative stress, because neuroinflammation facilitates tryptophan degradation into free radical generators via the kynurenine pathway. Upregulation of protein degradation by increased oxidative stress has been documented in cancer. Also, hypothalamic, cytokine-mediated suppression of fatty acid oxidation reduces food intake, and triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle, thus potentially increasing oxidative stress. SummaryIncreased oxidative stress contributes to cancer anorexia and cachexia. Preliminary clinical data on the efficacy of antioxidant therapy in cancer patients are encouraging, but uncertainty persists regarding the optimal dose and timing of administration. Also, better biological/genetic characterization of those cancer patients who are more likely to obtain significant clinical benefits appears necessary.

Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats.

Study of neurotransmitter role in food intake regulation in a leptin signaling deficient model, such as the Zucker rat, would benefit in the understanding of mechanisms of human obesity, in which leptin resistance is a common syndrome. We studied dopamine (DA) and serotonin (5-HT) concentrations in vivo in the ventromedial nucleus (VMN) of the hypothalamus, as they relate to eating after food deprivation in obese and lean 9-week-old male Zucker rats. DA and 5-HT concentrations were measured by HPLC via microdialysis before and during refeeding in 24-h food-deprived rats. Before food was provided, mean baseline DA and 5-HT levels were lower in obese than in lean rats (9.2 ± 0.9 vs 15.1 ± 1.9 pg/10 μl, p < 0.01, and 0.68 ± 0.05 vs 1.17 ± 0.02 pg/10 μl, p < 0.001, respectively). Food intake was accompanied by a decrease in DA levels in both obese and lean rats to 64% (p < 0.01) and 65% (p < 0.02) of their baseline levels respectively. 5-HT levels were significantly increased during eating by 41% in obese and 35% in lean rats (p < 0.01) from the baseline levels. Thus in obese rats with altered leptin signaling we found an unaltered pattern of DA and 5-HT release associated with food deprivation and refeeding, but with presence of their low levels. This points to an impaired postsynaptic monoaminergic action to produce an adequate metabolic response in obese Zucker rats in response to feeding state.

The early cancer anorexia paradigm: changes in plasma free tryptophan and feeding indexes.

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.

Sustained Weight Loss After Roux-en-Y Gastric Bypass Is Characterized by Down Regulation of Endocannabinoids and Mitochondrial Function

Objective:To determine the physiologic importance of endocannabinoids and mitochondrial function in the long-term outcome using a rat model of Roux-en-Y gastric bypass (RYGB) surgery. Background:Sixteen million people are morbidly obese and RYGB surgery is the most effective treatment. Endocannabinoids are implicated in appetite stimulation and regulation of peripheral energy metabolism. We hypothesize that down-regulation of endocannabinoids and alterations in mitochondrial function and hormones favoring catabolism contribute to sustained RYGB-induced weight loss. Methods:Diet-induced obese Sprague-Dawley rats were randomized to sham-operated obese controls, RYGB, and sham-operated obese pair-fed rats. Body weight and food intake were recorded, and food efficiency was calculated. Endocannabinoid levels in skeletal muscle and liver, muscle mitochondrial respiratory complex I–V content, and hormones concentrations were determined 14 and 28 days postsurgery, reflecting rapid and sustained weight loss periods after RYGB, respectively. Results:Compared with pair-fed controls, RYGB rats had significant reduction in body weight and food efficiency (P < 0.001). Increased cholecystokinin, reduced insulin, leptin, adiponectin, T3, and down-regulation of mitochondrial complex I were evident on day 14 postsurgery. On day 28, leptin, insulin, and T3 remained low, whereas adiponectin and cholecystokinin were normal. Along with complex I, the endocannabinoids anandamide in muscle (P = 0.003) and 2-arachidonoylglycerol in liver were significantly down-regulated (P < 0.001). Conclusions:The attenuated caloric intake, reduced food efficiency, and normalization of hormonal levels on day 28 post-RYGB were associated with significant down-regulation of endocannabinoids anandamide and 2-arachidonoylglycerol in muscle and liver, respectively. These results suggest a role for endocannabinoids in the mechanism of sustained weight loss and RYGB success, and may have implications for treatment of morbid obesity.

Standardized Enteral Orders Attain Caloric Goals Sooner: A Prospective Study

Standardized enteral nutrition order forms were introduced listing the enteral formulary, the advancement schedule of formulae, and whether feedings should be given continuously or intermittently. The efficiency of these forms was evaluated prospectively by counting the number of days needed to reach the patients estimated caloric needs in a total of 113 patients studied 3 months before (pre-group) and 3 months after (post-group) the introduction of the form. When the standardized enteral order forms were used, patients in the post-group reached their caloric goals 3.1 days sooner than did those in the pre-group. Use of standardized enteral nutrition order forms decreases the time needed to reach a patients estimated caloric needs, thereby achieving effective nutritional therapy sooner.

Adenomyomatosis of the gallbladder

Adenomyomatosis of the gallbladder is characterized by hyperplasia of the mucosa and hypertrophy of the muscularis which may result from a functional obstruction to the outflow of bile. The resulting increased intracystic pressure results in invagination of the mucosa through the muscularis as intramural diverticula which may be diffuse, segmental or localized. From a series of 1,500 patients who had cholecystectomies performed during a 10 year period, 9 patients presented with symptoms indistinguishable from calculous cholecystitis and were found to have a pathologic diagnosis of adenomyomatosis without other pathologic findings. The striking feature in this group of patients was the chronicity of the symptoms before surgery (mean 7.7 years). During this time, eight of the nine patients underwent repeated radiologic investigation of the upper gastrointestinal tract for frequent symptoms. Surgical treatment led to the disappearance of symptoms in eight of the nine patients and marked improvement in the remaining patient. The presence of adenomyomatosis in a patient presenting with a symptom complex similar to that of calculous cholecystitis is an indication for cholecystectomy.

Circadian variation in response to potassium infusion.

The response of 5 normal men to an intravenous infusion of potassium chloride was compared at midday and midnight. Each subject was maintained on strict supine bedrest with oral intake limited to 100 ml distilled waterlhr for the 9 hr before and after each infusion. Potassium chloride, 37 mEq, (with an added label of 200 µCi 42KCl) in iso‐osmolar solution was administered via a central venous catheter over 1 hr starting either at midday or midnight. Plasma potassium concentration was elevated by 40% more at midnight than at midday, and plasma 42K activity also rose to a higher level at midnight. These differences were reflected by greater T wave elevations of the electrocardiogram at midnight than at midday, although urinary potassium excretion (total and 42K labeled) was higher at midday than at midnight, indicating that there was reduced renal excretory responsiveness to elevations in plasma potassium concentration at midnight compared with midday. Plasma aldosterone concentration rose during the potassium infusions at both midday and midnight by a similar amount, which suggests that the induced increments in aldosterone secretion were not a major determinant of the differing renal response. These findings indicate that circadian modulations in the physiologic mechanisms which regulate potassium homeostasis profoundly influence the response to exogenous potassium loads. Special caution must therefore be taken in administering potassium infusions at night.

Glucagon infusion in normal man: Effects on 3-mthylhistidine excretion and plasma amino acids

In order to assess the role of glucagon in human protein metabolism and to examine its action as a catabolic hormone, studies were conducted in two normal male subjects over an 8-day period. After minimum and stable urinary nitrogen excretion had been produced by the continuous nasogastric administration of carbohydrate (720 g/day) for 8 consecutive days, a continuous intravenous infusion of glucagon (1.0 mg/24 hr) was superimposed on days 7 and 8. Excretion of total nitrogen (N) and urea-N increased significantly (p less than 0.05). Excretion of 3-methylhistidine was unaltered, suggesting that the source of the N losses produced by glucagon did not derive from increased muscle proteolysis. Although striking hypoaminoacidemia was produced, the reductions of extracellular amino acids alone could not account for all of the extra urea excreted. These data suggest that hyperglucagonemia in normal man induces mild nitrogen losses by stimulation of hepatic ureogenesis from free intracellular amino acid pools and not by increased rates of muscle protein breakdown.

Hepatic vagus does not mediate IL-1α induced anorexia

Peripherally infused interleukin-alpha (IL-1 alpha) reduces food intake. Since the innervated liver modulates eating activity via the vagus, we investigated the role of the hepatic vagus in the etiology of IL-1 alpha induced anorexia. Ten male Fischer 344 rats were randomly assigned to hepatic vagotomy (HX-IL-1 group) or sham operation (Sham-IL-1 group), and an internal jugular catheter was inserted in all rats. Another six sham operated rats receiving normal saline i.v. throughout the study period served as general controls. After a 10-day recovery period, HX-IL-1 and Sham-ILI-1 rats were infused with 3 micrograms day-1 of IL-1 alpha for 3 days, followed by a 4 day infusion of saline. During the IL-1 alpha infusion, food intake was reduced at a similar rate and by a similar amount in both vagotomized and sham-operated rats. When IL-1 alpha infusion was stopped, food intake normalized at a similar rate in both HX-ILI-1 and Sham-IL-1 groups. These data indicate that the hepatic vagus is not involved in the etiology of IL-1 alpha induced anorexia.