The Impact of a Multimodal Sport Science-Based Prehabilitation Program on Clinical Outcomes in Abdominal Cancer Patients: A Cohort Study.

BACKGROUND: The potential for prehabilitation programs to impact clinical outcomes is uncertain in abdominal cancer patients due to the short window of time to intervene and the weakened state of the patients. To improve the effectiveness of prehabilitation intervention, a multimodal sports science approach was implemented. METHODS: Prior to cancer-related surgery, 21 patients participated in a 4-week exercise and nutrition prehabilitation program comprised of blood flow restriction exercise (BFR) and a sports nutrition supplement. Retrospective data of 71 abdominal cancer patients who underwent usual preoperative care was used as a comparator control group (CON). At 90 days post-surgery, clinical outcomes were quantified. RESULTS: Prehabilitation was associated with a shorter length of hospital stay (P = .02) with 5.5 fewer days (4.7 ± 2.1 vs 10.2 ± 1.2 days in CON) and decreased incidence of any complications (P = .03). Prehabilitation was not related to incidence of serious complications (P = .17) or readmission rate (P = .59). The prehabilitation group recorded 58% more steps on day 5 after surgery (P = .043). DISCUSSION: A 4-week home-based prehabilitation program composed of BFR training and sports nutrition supplementation was effective in reducing postoperative complications and length of hospital stay in older patients with abdominal cancer.ClinicalTrials.gov Identifier: NCT04073381.

A Mobile App With Multimodality Prehabilitation Programs for Patients Awaiting Elective Surgery: Development and Usability Study.

BACKGROUND: Complying with a prehabilitation program is difficult for patients who will undergo surgery, owing to transportation challenges and a limited intervention time window. Mobile health (mHealth) using smartphone apps has the potential to remove barriers and improve the effectiveness of prehabilitation. OBJECTIVE: This study aimed to develop a mobile app as a tool for facilitating a multidisciplinary prehabilitation protocol involving blood flow restriction training and sport nutrition supplementation. METHODS: The app was developed using "Appy Pie," a noncoding app development platform. The development process included three stages: (1) determination of principles and requirements of the app through prehabilitation research team meetings; (2) app prototype design using the Appy Pie platform; and (3) app evaluation by clinicians and exercise and fitness specialists, technical professionals from Appy Pie, and non-team-member users. RESULTS: We developed a prototype of the app with the core focus on a multidisciplinary prehabilitation program with accessory features to improve engagement and adherence to the mHealth intervention as well as research-focused features to evaluate the effects of the program on frailty status, health-related quality of life, and anxiety level among patients awaiting elective surgery. Evaluations by research members and random users (n=8) were consistently positive. CONCLUSIONS: This mobile app has great potential for improving and evaluating the effectiveness of the multidisciplinary prehabilitation intervention in the format of mHealth in future.

Prehabilitation program composed of blood flow restriction training and sports nutrition improves physical functions in abdominal cancer patients awaiting surgery.

INTRODUCTION: The impact of prehabilitation remains controversial due to a short presurgical waiting period and the diminished capacity of the patient population. A strategy to augment and optimize the effectiveness of prehabilitations for abdominal cancer patients may be found in the unlikely field of sport science. We investigated the use of blood flow restriction training and sport nutrition supplementation to augment functional capacity and increase muscle strength in twenty-four abdominal cancer patients awaiting surgery. MATERIALS AND METHODS: The sport science-based program was comprised of blood flow restriction exercise 5 to 6 times per week and a daily sports nutrition supplement containing l-citrulline, creatine monohydrate, and whey protein. RESULTS: After 4 weeks of prehabilitation, 6-min walk test, timed up and go, short physical performance battery, 5-chair stand test and physical component score of quality of life were significantly improved (all p < 0.05). Total body and appendicular lean mass as assessed by dual energy X-ray absorptiometry increased by 0.73 ± 1.04 kg (p = 0.004) and 0.42 ± 0.64 kg (p = 0.006), respectively. Total body fat mass and trunk fat mass decreased (p = 0.004 and p = 0.021). There were no significant changes in hand grip strength, fear of falling, the mental component summary of quality of life, or fasting serum concentrations of myostatin, follistatin, and growth hormone. CONCLUSION: A multimodal prehabilitation program, which encompasses blood flow restriction training and sports nutrition supplements, is both feasible and effective in improving lean mass and physical function in abdominal cancer patients prior to surgery.

The Enhanced Recovery After Surgery (ERAS) Elements that Most Greatly Impact Length of Stay and Readmission.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been shown to decrease length of stay (LOS) and improve patient outcomes in a wide variety of surgical fields; however, barriers exist preventing the implementation of all elements. We hypothesize that a subset of ERAS elements are most influential on LOS and readmission following colorectal surgery. STUDY DESIGN: A retrospective review of 840 patients was performed and their compliance with 24 ERAS components evaluated. Two independent machine-learning statistical algorithms were employed to determine which subset of ERAS elements was most impactful on LOS <3 days and hospital readmission. RESULTS: Increasing compliance with ERAS elements had an inverse linear relationship with LOS. Open (vs minimally invasive) surgery was associated with increased LOS. Early mobilization and multimodal pain management are the elements most protective against increased LOS. Readmissions increase with the number of morphine milligram equivalents (MME)/day. The subset of patients who underwent minimally invasive procedures, had multimodal pain control, and less than 16 MME per day were least likely (23%) to have >3-day LOS. Those patients who underwent an open procedure with less than 15 ERAS elements completed were most likely (84%) to have >3-day LOS. CONCLUSION: While increasing compliance with ERAS protocols and minimally invasive procedures decrease LOS and readmission overall, a subset of components-multimodal pain control, limited opioid use, and early mobilization-was most associated with decreased LOS and readmission. This study provides guidance on which ERAS elements should be emphasized.

Spatiotemporal Gradient and Instability of Wnt Induce Heterogeneous Growth and Differentiation of Human Intestinal Organoids.

In a conventional culture of three-dimensional human intestinal organoids, extracellular matrix hydrogel has been used to provide a physical space for the growth and morphogenesis of organoids in the presence of exogenous morphogens such as Wnt3a. We found that organoids embedded in a dome-shaped hydrogel show significant size heterogeneity in different locations inside the hydrogel. Computational simulations revealed that the instability and diffusion limitation of Wnt3a constitutively generate a concentration gradient inside the hydrogel. The location-dependent heterogeneity of organoids in a hydrogel dome substantially perturbed the transcriptome profile associated with epithelial functions, cytodifferentiation including mucin 2 expression, and morphological characteristics. This heterogeneous phenotype was significantly mitigated when the Wnt3a was frequently replenished in the culture medium. Our finding suggests that the morphological, transcriptional, translational, and functional heterogeneity in conventional organoid cultures may lead to a false interpretation of the experimental results in organoid-based studies.

Three-Dimensional Regeneration of Patient-Derived Intestinal Organoid Epithelium in a Physiodynamic Mucosal Interface-on-a-Chip.

The regeneration of the mucosal interface of the human intestine is critical in the host-gut microbiome crosstalk associated with gastrointestinal diseases. The biopsy-derived intestinal organoids provide genetic information of patients with physiological cytodifferentiation. However, the enclosed lumen and static culture condition substantially limit the utility of patient-derived organoids for microbiome-associated disease modeling. Here, we report a patient-specific three-dimensional (3D) physiodynamic mucosal interface-on-a-chip (PMI Chip) that provides a microphysiological intestinal milieu under defined biomechanics. The real-time imaging and computational simulation of the PMI Chip verified the recapitulation of non-linear luminal and microvascular flow that simulates the hydrodynamics in a living human gut. The multiaxial deformations in a convoluted microchannel not only induced dynamic cell strains but also enhanced particle mixing in the lumen microchannel. Under this physiodynamic condition, an organoid-derived epithelium obtained from the patients diagnosed with Crohn's disease, ulcerative colitis, or colorectal cancer independently formed 3D epithelial layers with disease-specific differentiations. Moreover, co-culture with the human fecal microbiome in an anoxic-oxic interface resulted in the formation of stochastic microcolonies without a loss of epithelial barrier function. We envision that the patient-specific PMI Chip that conveys genetic, epigenetic, and environmental factors of individual patients will potentially demonstrate the pathophysiological dynamics and complex host-microbiome crosstalk to target a patient-specific disease modeling.

Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth.

Although ectopic expression of the cholecystokinin B/gastrin receptor (CCK-BR) is widely reported in human colorectal cancers, its role in mediating the proliferative effects of gastrin1-17 (G-17) on these cancers is unknown. Here we report the isolation of a novel splice variant of CCK-BR that exhibits constitutive (ligand-independent) activation of pathways regulating intracellular free Ca(2+) ([Ca(2+)](i)) and cell growth. The splice variant (designated CCK-BRi4sv for intron 4-containing splice variant) is expressed in colorectal cancers but not in normal colonic mucosa adjacent to the cancer. Balb3T3 cells expressing CCK-BRi4sv exhibited spontaneous, ligand-independent, oscillatory increases in [Ca(2+)](i), whereas cells expressing wild-type CCK-BR did not. Primary cultures of cells isolated from resected colorectal cancers also exhibited a similar pattern of spontaneous [Ca(2+)](i) oscillations. For both Balb3T3 and primary tumor cells, application of G-17 (10 and 200 nm, respectively) caused an increase in [Ca(2+)](i). Selective CCK-BR antagonists blocked the G-17-stimulated Ca(2+) responses but not the spontaneous [Ca(2+)](i) oscillations. Cells expressing CCK-BRi4sv exhibited an increased growth rate ( approximately 2.5-fold), in the absence of G-17, compared with cells expressing wild-type CCK-BR. The selective pattern of expression, constitutive activity, and trophic action associated with CCK-BRi4sv suggest that this variant may regulate colorectal cancer cell proliferation though a gastrin-independent mechanism.

Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies.

BACKGROUND: The majority of patients with primary or metastatic malignancies confined to the liver are not candidates for resection because of tumor size, location, multifocality, or inadequate functional hepatic reserve. Cryoablation has become a common treatment in select groups of these patients with unresectable liver tumors. However, hepatic cryoablation is associated with significant morbidity. Radiofrequency ablation (RFA) is a technique that destroys liver tumors in situ by localized application of heat to produce coagulative necrosis. In this study, we compared the complication and early local recurrence rates in patients with unresectable malignant liver tumors treated with either cryoablation or RFA. PATIENTS AND METHODS: Patients with hepatic malignancies were entered into two consecutive prospective, nonrandomized trials. The liver tumors were treated intraoperatively with cryoablation or RFA; intraoperative ultrasonography was used to guide placement of cryoprobes or RFA needles. All patients were followed up postoperatively to assess complications, treatment response, and local recurrence of malignant disease. RESULTS: Cryoablation was performed on 88 tumors in 54 patients, and RFA was used to treat 138 tumors in 92 patients. Treatment-related complications, including 1 postoperative death, occurred in 22 of the 54 patients treated with cryoablation (40.7% complication rate). In contrast, there were no treatment-related deaths and only 3 complications after RFA (3.3% complication rate, P<0.001). With a median follow-up of 15 months in both patient groups, tumor has recurred in 3 of 138 lesions treated with RFA (2.2%), versus 12 of 88 tumors treated with cryoablation (13.6%, P<0.01). CONCLUSIONS: RFA is a safe, well-tolerated treatment for patients with unresectable hepatic malignancies. This study indicates that (1) complications occur much less frequently following RFA of liver tumors compared with cryoablation of liver tumors, and (2) early local tumor recurrence is infrequent following RFA.

Down-regulation of vascular endothelial growth factor in a human colon carcinoma cell line transfected with an antisense expression vector specific for c-src.

Vascular endothelial growth factor (VEGF) is implicated in the angiogenesis of human colon cancer. Recent evidence suggests that factors that regulate VEGF expression may partially depend on c-src-mediated signal transduction pathways. The tyrosine kinase activity of Src is activated in most colon tumors and cell lines. We established stable subclones of the human colon adenocarcinoma cell line HT29 in which Src expression and activity are decreased specifically as a result of a transfected antisense expression vector. This study determined whether VEGF expression is decreased in these cell lines and whether the smaller size and reduced growth rate of antisense vector-transfected cell lines in vivo might result, in part, from reduced vascularization of tumors. Northern blot analysis of these cell lines revealed that VEGF mRNA expression was decreased in proportion to the decrease in Src kinase activity. Under hypoxic conditions, cells with decreased Src activity had a <2-fold increase in VEGF expression, whereas parental cells had a >50-fold increase. VEGF protein in the supernatants of cells was also reduced in antisense transfectants compared with that from parental cells. In nude mice, subcutaneous tumors from antisense transfectants showed a significant reduction in vascularity. These results suggest that Src activity regulates the expression of VEGF in colon tumor cells.

Colorectal cancer screening and follow-up.

Cancer of the colon and rectum is a significant health problem in the United States. Nearly 50% of the 186,000 patients diagnosed annually with colorectal cancer will eventually die of their disease. Because development of a colorectal carcinoma is most frequently preceded by the development of a well-recognized pre-malignant lesion, screening modalities can significantly impact the incidence and mortality rate of this disease. Population screening employing digital rectal examination, fecal occult blood testing and endoscopic examination of the rectum and colon has been demonstrated to reduce the risk of death from colorectal cancer. Screening regimens should be instituted at an earlier age and with increased frequency for patients in the highest risk categories. Patients who have been treated for a cancer of the colon or rectum should undergo surveillance at regular intervals in an attempt to identify recurrences of disease both in the residual colon and rectum and at distant sites. Most physicians and patients believe that intensive follow-up strategies will afford improved survival and quality of life, however few randomized studies examining the utility of intensive follow-up programs have been performed and the quality of cancer-related follow-up literature is generally poor. Good-quality clinical trials are needed to sort out which tests make a difference in the patient's long-term outcome. The algorithm for surveillance for recurrence in the future may be altered as newer testing modalities are developed.

Effectiveness of mastectomy by response to induction chemotherapy for control in inflammatory breast carcinoma.

BACKGROUND: Controversy exists as to the treatment regimen necessary to best provide optimal local control for inflammatory breast carcinoma (IBC). This study was conducted to determine if mastectomy combined with radiotherapy offered any advantages over radiotherapy alone in patients with IBC who had been treated with doxorubicin-based combination chemotherapy. METHODS: A retrospective review of 178 women treated for IBC on doxorubicin-based multimodality therapy protocols between January 1974 and September 1993 was performed. Clinical and histologic response to treatment, time to local recurrence, survival, and ultimate control of local disease were analyzed. Kaplan-Meier analysis was used to examine survival and relapse times, and Fisher's exact test was used to test differences in treatment outcomes. Significance was determined at p < or = 0.05. RESULTS: Median follow-up was 89 months (range 22 to 223 months). Locoregional disease persisted in seven patients and recurred in 44 patients who had been rendered disease free at a median time of 10 months. The mortality rate after a local recurrence (LR) was 98%, and all patients but one with LR developed systemic metastases. Response to induction chemotherapy influenced the incidence of LR, and the amount of residual disease found on histologic examination of mastectomy specimens was highly prognostic for local failure. Patients who underwent mastectomy in addition to radiotherapy had a lower incidence of LR than did patients who received radiotherapy alone (16.3% vs. 35.7%, p = 0.015). CONCLUSIONS: The addition of mastectomy to combination chemotherapy plus radiotherapy improved local control in patients with IBC. The addition of mastectomy to chemotherapy plus radiotherapy improved distant disease-free and overall survival in patients with a clinical complete or partial response to induction chemotherapy. Patients who had no significant response to induction chemotherapy received no survival or local disease-control benefit from the addition of mastectomy to their treatment regimen. These patients should be considered for entry into clinical trials of new treatment regimens.

Regulation of vascular endothelial growth factor expression in human colon carcinoma cells by activity of src kinase.

BACKGROUND: The c-src protooncogene encodes a protein tyrosine kinase, pp60c-src, that is a mediator in many signal transduction pathways. One pathway in which pp60c-src protein tyrosine kinase activity is implicated involves regulation of vascular endothelial growth factor (VEGF), an angiogenic factor important to neovascularization of growing tumors. Recently we demonstrated that decreased activity of pp60c-src in colon tumor cells contributes to decreased expression of VEGF. This study examined the relationship between pp60c-src activation, cell density, and VEGF production in a colon tumor cell line. METHODS: Parental HT-29 colon adenocarcinoma cells and stable subclones created by transfection with c-src antisense and sense (control) expression vectors were plated under sparse (2 x 10(4) cells/cm2) and confluent (20 x 10(4) cells/cm2) conditions and grown for 36 hours. Protein and RNA were extracted from cells to determine pp60c-src levels, c-Src tyrosine kinase activity, and VEGF mRNA expression. RESULTS: The pp60c-src kinase activity of HT-29 cells and control sense-transfected clones grown under confluent conditions was increased threefold to fivefold compared with cells grown under sparse conditions. In contrast, the ability of confluent culture conditions to increase pp60c-src activity was blunted in antisense transfectants. By regression analysis, VEGF expression was found to vary directly with pp60c-src levels (r2 = 0.886). CONCLUSIONS: Cell density contributes to the regulation of c-src kinase activity and VEGF expression in HT-29 cells. When the steady-state level of pp60c-src is reduced in antisense transfectants, not only is the steady-state level of VEGF reduced, but the ability of confluence to stimulate pp60c-src activity and VEGF production is too. These data suggest that c-src may be an intermediary of both constitutive and inducible pathways for VEGF production in colon tumor cells.

Laparoscopically guided bipolar radiofrequency ablation of areas of porcine liver.

BACKGROUND: Bipolar radiofrequency ablation (BRFA) is a promising technique with which to treat unresectable primary and metastatic liver tumors. Its effects on normal liver tissue and postoperative liver function, however, are unknown. We performed this study to determine (1) the feasibility of using laparoscopic ultrasound to guide placement of BRFA needle electrodes in the liver and (2) the histopathologic, hepatic biochemical, and systemic hemodynamic responses to BRFA. METHODS: Two BRFA lesions were created in the liver of adult domestic pigs to ablate 8-10% of the normal liver volume. Laparoscopic ultrasound was used to guide creation of one peripheral liver lesion and one central liver lesion (with a major hepatic or portal venous vein branch in the center of the BRFA lesions) in each animal. BRFA of liver tissue was performed by passing 12 W of RF power for 16 min across two 16-gauge active-needle electrodes placed 3 cm apart. RESULTS: All animals survived the procedure without significant hemodynamic alterations during or after BRFA. All animals had a transient elevation in serum transaminase levels that returned to normal within 1 week of the BRFA of liver tissue. Gross and microscopic histopathology of the BRFA lesions revealed 2.0-2.5-cm zones of complete coagulative necrosis around and between the BRFA needle tracks without destruction of major blood vessel walls. CONCLUSIONS: This study demonstrates (1) that laparoscopic ultrasound can be used to guide placement of BRFA needles in the liver and (2) that BRFA produces focal destruction of liver without significant systemic hemodynamic responses or alterations in liver function. Further studies of this technique to ablate malignant liver tumors are ongoing.

Overexpression of focal adhesion kinase (p125FAK) in human colorectal carcinoma liver metastases: independence from c-src or c-yes activation.

BACKGROUND: p125FAK, pp60C-src, and pp62c-yes are protein tyrosine kinases that function in signaling pathways regulating cell adhesion, migration, and growth. The expression and tyrosine kinase activities of pp60c-src and pp62c-yes, and the expression of p125FAK are increased in colorectal tumor metastases relative to normal mucosa. This study investigates whether differences in the activation of pp60c-src and pp62c-yes in colorectal liver metastases correlated with differences in p125FAK expression and whether prognostic significance could be demonstrated from the extent of expression of p125FAK in metastases. METHODS: Activities of pp60c-src and pp62c-yes were measured in the immune complex kinase assay. Relative levels of p125FAK, pp60c-src, and pp62c-yes were determined by immunoblotting. RESULTS: p125FAK was overexpressed in 29 of 30 colorectal cancer liver metastases (range of two-to 195-fold increase compared with normal mucosa). The degree of overexpression of p125FAK was not a significant prognostic factor in survival. A differential activation of pp60c-src and pp62c-yes in colorectal carcinoma liver metastases was observed. However, overexpression of p125FAK was observed in metastases with either pp60c-src or pp62c-yes activated in colorectal carcinoma liver metastases. CONCLUSIONS: p125FAK overexpression appears to be a marker present in colorectal cancer cells with a metastatic phenotype. Furthermore, p125FAK overexpression is independent of pp60c-src or pp62c-yes activation in human colorectal carcinoma liver metastases.

The safety of helium for abdominal insufflation.

BACKGROUND: A search for alternative methods of abdominal insufflation has been prompted by the fact that CO2 insufflation may cause acidosis, decreased cardiac output, increased systemic vascular resistance, and increased cardiac filling pressures. This study evaluates the safety and the cardiopulmonary effects of helium abdominal insufflation (HAI). METHODS: Thirteen ASA class III and IV patients undergoing laparoscopic procedures were studied in a prospective, nonrandomized protocol using HAI. Cardiopulmonary parameters were measured before and after anesthetic induction and every 30 min during HAI. Abdominal insufflation pressure was initially 10 mmHg and was increased to 15 mmHg after 30 min. All measurements were repeated 15 min after deflation of the abdomen. Changes were evaluated by ANOVA. RESULTS: No significant cardiopulmonary complications were observed. No patient developed hypercarbia or acidosis. Peak inspiratory pressure increased with HAI from 20 +/- 1 to 34 +/- 2 cm H2O (p < 0.0001). Cardiac index decreased (3.35 +/- 0.19 vs 2.37 +/- 0.19 l/min/m2; p = 0.0303) and systemic vascular resistance increased (1,123 +/- 66 vs 1,406 +/- 126 dyne . s/cm5; p = 0.0512) while cardiac filling pressures increased with insufflation to 15 mmHg. CONCLUSIONS: Minimal cardiac and pulmonary aberrations were observed. Helium was safe for abdominal insufflation and may be the insufflating agent of choice in patients with significant cardiopulmonary disease.

Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle.

We have used stable isotopic tracers of amino acids to measure in vivo transmembrane transport of phenylalanine, leucine, lysine, alanine, and glutamine as well as the rates of intracellular amino acid appearance from proteolysis, de novo synthesis, and disappearance to protein synthesis in human skeletal muscle. Calculations were based on data obtained by the arteriovenous catheterization of the femoral vessels and muscle biopsy. We found that the fractional contribution of transport from the bloodstream to the total intracellular amino acid appearance depends on the individual amino acid, varying between 0.63 +/- 0.02 for phenylalanine and 0.22 +/- 0.02 for alanine. Rates of alanine and glutamine de novo synthesis were approximately eight and five times their rate of appearance from protein breakdown, respectively. The model-derived rate of protein synthesis was highly correlated with the same value calculated by means of the tracer incorporation technique. Furthermore, amino acid transport rates were in the range expected from literature values. Consequently, we conclude that our new model provides a valid means of quantifying the important aspects of protein synthesis, breakdown, and amino acid transport in human subjects.

Effect of ibuprofen on the inflammatory response to surgical wounds.

Patients suffering severe trauma frequently become immunosuppressed following injury. This can predispose patients to infectious sequelae. Biochemically, these patients synthesize excessive quantities of cyclooxygenase products (prostaglandins). It has been hypothesized that the prostaglandins cause the immunosuppression and that inhibition of the cyclooxygenase enzyme could thus prevent the immunosuppression. We investigated the effect of the cyclooxygenase inhibitor ibuprofen on the inflammatory response. Rats were subjected to a 30% total body surface area burn and were administered either ibuprofen for a period of 7 days or 14 days, or were administered the carrier for 14 days. The rats were then killed and multiple immunologic variables were measured. Ibuprofen was found to decrease neutrophil chemiluminescence, lymphocyte blastogenesis, and helper/inducer T-lymphocyte infiltration of a sponge matrix model. The same ibuprofen protocol decreased survival in a cecal ligation and puncture model. In conclusion, the cyclooxygenase enzyme system appears to produce metabolites essential for optimal survival following traumatic injury.

Effect of insulin-like growth factor 1 on host response to tumor.

Oncology patients suffer multiple detrimental metabolic alterations. Among these are catabolism of tumor free body mass to supply nutrients to feed the tumor. This results not only in enhanced tumor growth but also poor wound healing and immunosuppression of the tumor host. Efforts are therefore being directed at finding methods for improving the nutritional status of the tumor host without enhancing tumor growth. We investigated the ability of two hormones, insulin-like growth factor-1 (IGF-1) and insulin, to improve physiologic function in tumor-bearing animals. Tumor-bearing animals received a continuous infusion of IGF-1 (2.20 mg/kg/day), insulin (820 microns/kg/day) or placebo via an osmotic minipump for 7 days. All animals were pair fed to eliminate nutritional intake as a variable. The placebo group lost 31.37 +/- 4.3 g of tumor free body mass during the study period. The insulin treated group lost 26.34 +/- 7.42 g and the IGF-1 group lost 5.07 +/- 3.25 g (P < 0.001, ANOVA). IGF-1 treatment failed to alter plasma glucose, lactate, or total amino acid concentration and failed to alter hepatic ketone body concentrations, but did improve hepatic mitochondria redox potential. Finally, IGF-1 improved splenic weight by 110% and splenic lymphocyte count by 300%. In conclusion IGF-1 appears to offer potential in supporting tumor free host body mass without stimulating tumor growth.