Kirby I. Bland

The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection

In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a healthy gut. Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.

Prophylactic glutamine protects the intestinal mucosa from radiation injury.

Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine‐enriched elemental diet, administered before whole‐abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine‐enriched or glutamine‐free for 4 days. The animals were then subjected to a single dose of 1000 cGy x‐radiation to the abdomen. After irradiation, all animals received the glutamine‐free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine‐fed rats. Rats receiving the glutamine‐enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine‐free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine‐free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation which may accelerate healing of the acutely radiated bowel.

Oral glutamine reduces bacterial translocation following abdominal radiation

The effect of dietary glutamine on bacterial translocation was studied in rats following administration of a single dose of abdominal radiation (1000 rad) that causes a reproducible mucosal injury and results in a high incidence of culture-positive mesenteric lymph nodes after radiation (XRT). Following XRT, rats received only the amino acid glutamine (3%, +GLN) in their drinking water or a control nonessential amino acid (glycine, -GLN). Diets were isonitrogenous and isovolumetric. Four days after XRT, rats were anesthetized and a laparotomy was performed. Mesenteric lymph nodes were sterilely excised and cultured. Arterial blood was also obtained for whole blood glutamine determination. Control rats received no XRT but received identical diets. In XRT rats who received the GLN-free diet, the incidence of culture-positive mesenteric lymph nodes was 89% (eight of nine rats) while in the radiated rats receiving the GLN-enriched diet, the incidence fell to 20% (P less than 0.05). In non-radiated control rats receiving GLN-enriched and GLN-depleted diets for 4 days, bacterial translocation occurred in zero of eight and one of eight rats, respectively (NS). Provision of glutamine to XRT rats resulted in higher blood levels of glutamine (408 +/- 25 microM in XRT +GLN vs 311 +/- 19 microM in XRT -GLN, P less than 0.05). In addition, provision of GLN maintained mucosal mass and reduced weight loss (P less than 0.05). The data lend further support to the hypothesis that glutamine helps maintain the gut mucosal barrier and thereby decreases the incidence of bacterial translocation following bowel injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: The final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial

BACKGROUNDnA phase III, randomized, double-blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia melanoma oncolysate (VMO) was performed in patients with stage III (American Joint Commission on Cancer) melanoma to determine the efficacy of VMO to increase the disease-free interval (DFI) or overall survival (OS) in these patients. Two interim analyses of data from this trial were performed in May 1994 and June 1995. Although the results from these analyses showed no statistically significant improvement in DFI or OS in all patients using VMO, two subsets-men aged 44-57 years with one to five positive nodes and all patients with clinical stage I and pathologic stage II disease-showed an overall survival advantage with VMO therapy. A final analysis of data from this trial was performed in May 1996 and is reported here. The design of future melanoma vaccine trials is discussed based on information learned from this first randomized, multicenter trial of ASI therapy.nnnSTUDY DESIGNnA polyvalent VMO was prepared using melanoma cells derived from four melanoma cell lines and vaccinia vaccine virus (V). Patients were accrued from 11 United States institutions and were randomized by the Statistical Center at the University of Alabama, Birmingham. Two hundred fifty patients were randomized to treatment with either VMO (1 U containing 2 mg of total protein derived from 5 x 10(6) melanoma cells and 10(5.6) 50% tissue culture infectious dose of vaccinia virus) or control V (1 U containing 10(5.4) 50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks and then once every 2 weeks for a total of 12 months, or until recurrence. Patient data were collected by the Statistical Center and analyzed as of May 1996 for DFI and OS using Wilcoxon test and log-rank analysis.nnnRESULTSnTwo hundred seventeen patients were found to be eligible according to the inclusion criteria. Data from these patients were analyzed for DFI and OS after a median followup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final analysis showed no statistically significant increase in either DFI (p = 0.61) or OS (p = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113). At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of patients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of patients treated with V. In a retrospective subset analysis, male patients aged 44-57 years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3% improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treatment with VMO when compared with V (n = 18) (p = 0.046).nnnCONCLUSIONSnThis study was a randomized, multicenter, placebo-controlled evaluation of an active specific immunotherapeutic agent to increase the DFI or OS of patients with stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO when compared with V showed no difference in either DFI or OS. In a retrospective subset analysis, however, a subset of men with one to five positive nodes, between the ages of 44 and 57 years, showed a survival advantage with VMO. This result suggests that one must include a detailed subset analysis in the design of future trials of ASI for patients with American Joint Commission on Cancer stage III melanoma. An appropriate control arm also must be included in ASI trials.

Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth

Glutamine is a principal fuel utilized by rapidly growing tumors. Advanced malignant disease results in muscle glutamine depletion and weight loss. Concern exists about providing dietary glutamine to the host with cancer since it may stimulate tumor growth. This study examined the effects of oral glutamine on muscle glutamine metabolism and tumor growth. Twenty-four rats with large sarcomas were pair fed a glutamine-enriched or glutamine-free elemental diet. Diets were isonitrogenous and isocaloric. After 6 days of feeding, the animals were anesthetized and arterial glutamine, hindquarter glutamine flux, muscle glutamine content, tumor weight, tumor DNA content, tumor glutaminase activity, and number of metaphase mitoses/high power field (HPF) in the tumor were determined. There was no difference in arterial glutamine between the two groups, but provision of a glutamine-enriched diet increased muscle glutamine content by 60% (2.31 +/- 0.21 mumole/g tissue vs 1.44 +/- 0.22 mumol/g tissue, P less than 0.05), which supported muscle glutamine release. There were no differences among tumor DNA content, tumor glutaminase activity, or tumor weight and there was no difference histologically in the number of metaphase mitoses/HPF. Glutamine-enriched oral diets may replete host glutamine stores and support muscle glutamine metabolism without stimulating tumor growth.

Combined chemotherapy, radiation, and surgery for epithelial cancer of the anal canal

Combined chemotherapy and radiation therapy have been reported to produce a high incidence of complete regression of epithelial cancer of the anal canal, resulting in prolonged disease‐free survival. This modality has been advocated as an alternative to abdominoperineal resection as a primary treatment for this disease. Our group treated 19 patients between 1979 and 1985. Treatment included two infusions of 5‐fluorouracil (1000 mg/m2/24 hours), one dose of mitomycin C (15 mg/m2), and simultaneous whole‐pelvis radiation (3000 rad). The complete response rate was 88%. Three patients had anal cancer incompletely controlled by that therapy. They underwent abdominoperineal resections and are alive without disease at 10, 39, and 43 months, respectively. Actuarial disease‐free survival at 40 months was 87.5 ± 8.8 (% ± standard error of the mean [SEM]). Complications included gastrointestinal, hematologic, and cutaneous toxicity. These results confirmed a high complete response rate to this therapy. Local treatment failures may occur, but these may be salvaged with abdominoperineal resection.

Growth factors and determinants of wound repair

The application of contemporary biochemical, analytical, and production technology have, in part, clarified the physiologic processes and identified many new factors active in wound repair. A restructuring of the sequence of the reparative events for the wound environment followed the identification of an array of hormonal polypeptides and growth factors. Deterrents of the early phases of repair include neoplasms and therapeutic doses of steroidal and cytotoxic agents. The physiological effects of these agents are rapidly reversed following their removal with a resultant enhancement of wound tear strength and wound energy. The use of synthetic growth hormone and recombinant DNA-produced polypeptide may reverse the deleterious wound healing events initiated in the injured and tumor-bearing host.

Clinically resectable adenocarcinoma of the rectum treated with preoperative irradiation and surgery.

Seventy-four patients with clinically resectable adenocarcinoma of the rectum were treated with preoperative irradiation and surgery at the University of Florida between August 1975 and February 1982. All patients have been folloved for at least five years. Between 1975 and 1978, 29 patients received 3500 cGy; thereafter the dose was increased to 4000 to 5000 cGy for the remaining 45 patients. All patients were treated at 180 cGy per fraction. Following preoperative irradiation, 65 of 74 patients (88 percent) underwent complete resection of their lesions. Compared with a series of historical controls treated with surgery alone, the local recurrence rate at five years was 5 of 65 (7.7 percent)vs. 39 of 135 (29 percent) (P=.001), and the five-year absolute survival was 43 of 65 (66 percent)vs. 51 or 135 (38 percent) (P<.001). The local recurrence rate was 13 percent for patients receiving 3500 cGy and 5 percent for doses of 4000 to 5000 cGy. There was no apparent increased incidence in postoperative complications in the preoperatively irradiated patients.

Extracorporeal shock-wave lithotripsy of bile duct calculi: an interim report of the Dornier U.S. bile duct lithotripsy prospective study

A multi-institutional study to evaluate the efficacy, clinical application, and safety of extracorporeal shock-wave lithotripsy (ESWL) with the Dornier HM-3 or HM-4 lithotripter for bile duct calculi (BDC) was initiated in September, 1987. Symptomatic patients who entered into this prospective trial had BDC in the common bile duct and/or the intrahepatic, cystic or lobar ducts of the liver that were inaccessible or untreatable by papillotomy or percutaneous stone extraction. The study excluded gallbladder stones. Nasobiliary (54.4%) or transhepatic catheters (10.5%) and T-tube or cholecystostomy tubes (17.5%) or combinations (14.0%) permitted access for radiographic contrast to allow fluoroscopic monitoring of stone position and fragmentation. Exclusion criteria included pregnancy, failure to localize the stone, disturbances of coagulation, pacemakers, or vascular aneurysms or large bones that lie in the focal axis of the shock waves. Eleven institutions treated 42 patients (23 male, 19 female) with BDC; age range was 25 to 95 years (mean +/- SD, 73.5 +/- 13.8) and ASA risk category was 1 to 4 (mean, 2.3 +/- 0.8). Fourteen patients (33.3%) had a single BDC; 28 had 2 to 8 stones (mean, 2.7 +/- 1.8) ranging in size from 6 mm to 30 mm (mean, 18.5 +/- 6.4). The majority (66.7%) of patients were postcholecystectomy. The 42 patients received 57 ESWL treatments consisting of 600 to 2400 shocks per treatment (mean, 1924 +/- 289) at 12 to 22 kV (mean, 18.5 +/- 1.9) administered over 20 to 125 minutes (mean, 52.9 +/- 20.8). General anesthesia was used in 32% of the treatments; the majority were treated with epidural or regional block (42.1%), local infiltration (28.1%), or intravenous sedation (38.6%). Fifteen patients (35.7%) required two ESWL treatments. Stone fragmentation occurred in 94.6% of evaluable patients and in 90.4% of ESWL treatments, respectively; however, BDC fragments remained in 59.5% of patients 24 hours after treatment (diameter less than or to 3 mm, 12%; 4 to 9 mm, 16%; greater than or equal to 10 mm, 68%). Some patients (50%) required adjunctive procedures to achieve stone removal that included endoscopic extraction (n = 10; 47.6%), biliary lavage (n = 8; 38.1%), endoscopic bile duct prosthesis (n = 1; 4.8%), and operation (n = 2; 9.5%). ESWL treatment complications during hospitalization were observed in 15 patients (35.7%) and were present in four (9.5%) at discharge. Complications included macrohematuria (5%), biliary pain (15%), biliary sepsis (5%), hemobilia (10%), ileus (2.5%), and adverse pulmonary changes (7.5%). One patient developed pancreatitis before ESWL at ERCP that resolved prior to discharge.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased survival of patients treated with a vaccinia melanoma oncolysate vaccine: second interim analysis of data from a phase III, multi-institutional trial.

OBJECTIVEnThe efficacy of vaccinia melanoma oncolysate (VMO) vaccine to increase overall survival and disease-free survival of patients with surgically resected International Union Against Cancer (UICC) stage II melanoma was studied in a phase III, randomized, multi-institutional trial.nnnSUMMARY BACKGROUND DATAnPhase I and II trials with VMO showed minimal toxicity and clinical efficacy in patients with melanoma. In a recently completed phase III VMO trial, the first interim analysis performed in April 1994 showed an increasing trend in the survival of patients treated with VMO. The second interim analysis was performed in April 1995.nnnMETHODSnPatients with surgically resected stage II (UICC) melanoma were treated with VMO (N = 104) or placebo vaccinia vaccine virus (V) (N = 113) once a week for 13 weeks and then once every 2 weeks for a total of 12 months. Patients clinical data were collected as of May 1995 and analyzed for survival.nnnRESULTSnIn this second interim analysis, the mean follow-up time is 42.28 months. No survival difference was observed between VMO and V treatments. However, in a retrospective subset analysis, a subset of males between the ages of 44 and 57 years and having one to five positive nodes (at 2-, 3-, and 5-year intervals, 13.6%, 15.9%, and 20.3% difference insurvival in favor of VMO [N = 20] when compared to V [N = 18] [p = 0.037]) and another subset of patients with clinical stage I (at 3- and 5-year intervals, 30% and 7% difference in survival in favor of VMO [N = 20] when compared to V [N = 23], [p = 0.05]) showed significant survival advantage with VMO.nnnCONCLUSIONSnAlthough VMO vaccine therapy in surgical adjuvant setting did not produce a significant survival benefit to all patients with melanoma, patients from the above two subsets had significant survival benefit.