Shogo Yoshida

Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer.

OBJECTIVE The objective of this study was to determine whether oral glutamine supplements can protect lymphocyte and gut barrier function in patients with advanced esophageal cancer undergoing radiochemotherapy. SUMMARY BACKGROUND DATA Glutamine supplements improved protein metabolism in tumor bearing rats who underwent chemotherapy and reduced the toxicity of chemotherapy through an enhancement of glutathione production in rats. METHODS Thirteen patients with esophageal cancer were randomly placed in either a control or a glutamine group. Glutamine was administered orally (30 g/day) at the start of radiochemotherapy and for the subsequent 28 days. All patients underwent mediastinal irradiation and chemotherapy consisting of 5-fluorouracil and cisplatin. The lymphocyte count was determined, and blast formation was assessed after stimulation with phytohemagglutinin and concanavalin A. Gut barrier function was assessed by measuring the total amount of phenolsulfonphthalein excreted in the urine after the oral administration of phenolsulfonphthalein. RESULTS Glutamine supplements prevented a reduction in the lymphocyte count (control: 567 +/- 96/mm3 vs. glutamine: 1007 +/- 151, p < 0.05), and blast formation of lymphocyte (phytohemagglutinin, control: 19478 +/- 2121 dpm vs. glutamine: 33860 +/- 1433, p < 0.01, concanavalin A, control: 19177 +/- 1897 dpm vs. glutamine: 29473 +/- 2302, p < 0.01), and amount of phenolsulfonphthalein excretion in the urine was greater with control than with glutamine group (control: 15.4 +/- 2.4% vs. glutamine: 7.4 +/- 1.2, p < 0.05) 7 days after the initiation of radiochemotherapy. CONCLUSIONS Oral glutamine supplementation protects lymphocytes and attenuates gut permeability in patients with esophageal cancer during radiochemotherapy.

Effect of surgical stress on endogenous morphine and cytokine levels in the plasma after laparoscopoic or open cholecystectomy

AbstractBackground: Endogenous morphine in the brain leads to various biological responses after surgery. The aim of this study was to determine whether morphine levels in the plasma would be enhanced by open laparotomy rather than by laparoscopic procedures. Methods: We compared 19 patients who underwent laparoscopic cholecystectomy with five patients who underwent resection of the gallbladder by open laparotomy. Morphine levels in the plasma were measured by an electrochemical detection system. Results: Postoperative endogenous morphine levels were higher with open laparotomy than with the laparoscopic technique (three h after surgery: open, 200 ± 52.6 fmol/ml vs laparoscopy, 17.6 ± 3.7, p < 0.01). This morphine elevation accounted for higher levels of cytokine, greater pain scores, and longer duration of fasting in open laparotomized patients than in laparoscopic cholecystectomy patients. Stress hormone levels in the plasma were also higher with open laparotomy than with laparoscopy. Conclusion: Morphine synthesis was enhanced by open laparotomy, resulting in greater biological response postoperatively than that seen with laparoscopic cholecystectomy.

Glutamine supplementation in cancer patients.

OBJECTIVES Three series of studies investigated whether 1) glutamine deficiency occurs in tumor-bearing rats, 2) glutamine supplementation improves protein metabolism during chemotherapy in tumor-bearing rats, and 3) oral glutamine supplement improves systemic immune and gut-barrier function in patients with esophageal cancer receiving radiochemotherapy. METHODS In the animal studies, AH109A hepatoma cells or Yoshida sarcoma cells were inoculated into male Donryu rats to induce tumors. Glutamine production was measured by U-14C-glutamine infusion and the conversion of arginine to glutamine was measured by infusion of U-14C-arginine. The effect of glutamine on protein metabolism was investigated by 1-14C-leucine infusion. In the clinical study, 13 patients with esophageal cancer were randomized into two groups, control and glutamine supplemented (30 g/d), for 4 wk. RESULTS Glutamine levels in plasma and skeletal muscle were decreased in tumor-bearing rats, although glutamine production and the conversion of arginine to glutamine were increased. Glutamine-supplemented total parenteral nutrition reduced whole-body protein breakdown rate during chemotherapy in tumor-bearing rats. Oral supplementation of glutamine to the patients with esophageal cancer enhanced lymphocyte mitogenic function and reduced permeability of the gut during radiochemotherapy. CONCLUSIONS Glutamine depletion in host tissues occurs in tumor-bearing rats. Glutamine supplementation can attenuate loss of protein in the muscle in tumor-bearing animals and protect immune and gut-barrier function during radiochemotherapy in patients with advanced cancer.

Effect of glutamine supplementation on protein metabolism and glutathione in tumor-bearing rats

BACKGROUND Since tumor-bearing rats are deficient in glutamine, we investigated whether (1) glutamine and glutathione deficiency occur in tumor-bearing rats, (2) glutamine supplementation caused an increase of glutathione levels in host tissues and tumor, (3) glutamine enhances protein synthesis in host tissues, and (4) glutamine stimulated the tumor to synthesize protein and DNA. METHODS Male Donryu rats were randomized into four groups: (1) non-tumor-bearing rat (NTB) + standard total parenteral nutrition (STPN); (2) NTB + glutamine-supplemented TPN (GTPN); (3) tumor-bearing rat (TB) + STPN; (4) TB + GTPN. On day 0 AH109A rat hepatoma cells were subcutaneously injected into the backs of rats to induce tumor. The animals were maintained on TPN for 6 days from day 10 through day 15. On day 15, 1-14C-leucine was given by a 5-hour continuous infusion (2.0 microCi/h per rat) to determine the fractional synthesis rate and endogenous leucine production. The levels of glutamine and glutathione were measured by HPLC. the tumor DNA synthesis was estimated by bromodeoxyuridine labeling index. RESULTS Tumor development led to a significant weight loss, but this weight loss was significantly lessened by glutamine supplementation because of an increase in muscle protein synthesis. Glutamine did not enhance tumor weight, protein, and DNA synthesis in the tumor. Tumor development caused a significant reduction of glutathione in the muscle, jejunum, and liver, but supplemented glutamine increased the levels of glutathione in the jejunum. CONCLUSION Glutamine supplementation is beneficial in preventing deficiencies of glutamine and glutathione and in improving protein metabolism in tumor-bearing rats.

Intraoperative intercostal nerve blockade for postthoracotomy pain.

BACKGROUND Epidural analgesia is widely employed as a means to control postthoracotomy pain, but is sometimes inadequate. The purpose of this study is to evaluate the effectiveness of intraoperative, temporary, intercostal nerve blockade in addition to epidural analgesia for control of postthoracotomy pain. METHODS Forty patients undergoing elective lobectomy through antero-axillary thoracotomy were randomized to receive epidural analgesia only (group A, n = 20) or epidural analgesia plus temporary, intraoperative intercostal nerve blockade using 0.25% bupivacaine (group B, n = 20). Postoperative pain was assessed using a subjective analogue visual scale, and with the Prince Henry pain scale. Food intake and nonsteroidal analgesic consumption were also investigated. Serum ACTH and cortisol in each group were measured before and after the operation. RESULTS The analogue visual scale scores were significantly higher in group A than group B (p < 0.001), and were significantly higher on the day of operation and postoperative days 1, 2, and 3 (p < 0.001, p < 0.005, p < 0.005, p < 0.05, respectively). Prince Henry pain scale scores were significantly higher on the day of operation and postoperative day 1 (p < 0.05, p < 0.005, respectively). Food intake was significantly lower in group A than in group B (p < 0.05), and nonsteroidal analgesic consumption was not significantly different between groups. There was no significant difference between group A and group B in serum ACTH or in cortisol levels. CONCLUSIONS Additional intraoperative intercostal nerve blockade provides an additive benefit for postthoracotomy pain relief, especially early after operation.

A New Parameter for Assessing Postoperative Recovery of Physical Activity Using an Accelerometer

AbstractPurpose. While many retrospective and prospective observational studies have shown laparoscopic surgery to be less invasive than conventional open surgery, this issue has not been evaluated by objective parameters. Currently available clinical parameters, such as the day of first ambulation, the day food intake is commenced, and the length of postoperative hospital stay, are subjective. The purpose of this study was to investigate whether measuring postoperative physical activity with an accelerometer is a useful parameter for evaluating postoperative recovery after surgical stress. Methods. The subjects included 20 patients who underwent laparoscopic partial gastrectomy (LPG group), 35 patients who underwent open distal gastrectomy (ODG group), and 20 patients who underwent open total gastrectomy (OTG group). The cumulative acceleration of voluntary movement, measured by an Active tracer AC-301 (ACT) accelerometer for 7 days postoperatively, was compared among these three groups. Results. The cumulative acceleration of physical activity for 24 h was significantly better in the LPG group than in the ODG and OTG groups on each postoperative day. The recovery time, defined as the day that cumulative acceleration had recovered to more than 90% of the preoperative level, was significantly shorter in the LPG group (2.8 ± 0.9 days) than in the ODG (6.6 ± 2.1 days) and OTG (7.8 ± 1.2 days) groups. Conclusion. These results showed that convalescence differed with the degree of surgical stress, and that measurement of the cumulative acceleration of voluntary movement by using an accelerometer could be a useful objective and quantitative parameter for evaluating postoperative recovery.

Carbon dioxide pneumoperitoneum reduces levels of TNF-a mRNA in the brain, liver, and peritoneum in mice

Background: Cytokines are important regulators of the biological response to surgical stress. The aim of this study was to determine whether the CO2 pneumoperitoneum would change the expression of TNF-a mRNA in the visceral organs, including the brain, in mice. Methods: Mice were randomly assigned to one of six groups: control, anesthesia alone, insufflation with carbon dioxide, insufflation with air, laparotomy by short incision, or laparotomy by long incision. The brain, liver, jejunum, and peritoneum were harvested either 3 or 24 h after surgery. Levels of TNF-a mRNA in each tissue was measured by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Results: The air insufflation group showed higher TNF-a mRNA levels in the brain and liver than the short-incision group. Levels of TNF-a mRNA in the brain, liver, and peritoneum were lower in the CO2 pneumoperitoneum group than in the air insufflation group. Plasma IL-6 and catecholamine in the urine were lower in the CO2 pneumoperitoneum group than the air insufflation group. Conclusion: Reduced synthesis of TNF-a in the visceral organs, including the brain, is correlated with a less marked biologic response to laparoscopic surgery.

Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition

Arginine supplementation increases glutamine levels in muscle and plasma. Since glutamine production is increased in catabolic states, these observations prompted us to investigate whether the flux of arginine to glutamine was increased in tumor-bearing (TB) rats, and we measured the synthesis rate of glutamine from arginine in control versus TB rats receiving standard total parenteral nutrition (TPN) solution. Male Donryu rats (N = 36; body weight, 200 to 225 g) were divided into two groups, control and TB rats. Yoshida sarcoma cells (1 x 10(6)) were inoculated into the back of the rats (n = 18) subcutaneously on day 0. The rats were given free access to water and rat chow. On day 5, all animals, including non-TB rats (n = 18), were catheterized at the jugular vein and TPN was begun. On day 10, TPN solution containing either U-14C-glutamine (2.0 microCi/h) or U-14C-arginine (2.0 microCi/h) was infused as a 6-hour constant infusion. At the end of the isotope infusion, plasma was collected to determine the glutamine production rate in rats receiving U-14C-glutamine, and the ratio of specific activity of glutamine to specific activity of arginine was measured in rats receiving U-14C-arginine. Only 2 g tumor caused a decrease in glutamine levels and an increase in glutamine and arginine production. The low flux rate of arginine to glutamine was observed in control rats (Arg to Gln, 41.0 +/- 11.9 mumol/kg/h). On the other hand, TB caused a significant increase in Arg to Gln compared with the control (213.3 +/- 66.1 mumol/kg/h, P < .01 v control). An increase in the flux rate of Arg to Gln was associated with an enhancement in the ratio of specific activity of ornithine to specific activity of arginine in TB rats (control 51.5% +/- 10.9% v 77.4% +/- 8.9%, P < .05). We conclude that (1) glutamine and arginine metabolism is altered with very small tumors, (2) although the flux of Arg to Gln was increased in TB and rats, the small increase in Arg to Gln cannot explain the observed large increase in Gln production.

Effect of methionine-deprived total parenteral nutrition on tumor protein turnover in rats

Background. Previous studies have shown that a methionine‐lacking diet inhibited tumor growth in rats. The aim of this study was to determine how methionine free total parenteral nutrition (MTPN) can result in the inhibition of tumor growth on tumor protein metabolism in rats.

Effect of fentanyl on morphine levels in the brain in rats receiving intracerebroventricular injection of TNF-α

Fentanyl citrate analgesia attenuates the excess nitrogen excretion in the urine and glucose production induced by trauma. On the other hand, intracerebroventricular injection of morphine stimulates excretion of stress hormones, such as catecholamines and corticosterone. Furthermore, morphine levels in the brain are increased during fasting and sepsis. The aims of this study were to determine whether intracerebroventricular injection of tumor necrosis factor-alpha (TNF-alpha) elevates morphine levels in the rat brain and whether prophylactic administration of fentanyl blocks metabolic responses induced by intracerebroventricular injection of TNF-alpha because of a reduction of morphine levels in the brain. Morphine levels in the brain were increased from 648 to 1,134 fmol/g at 30 min after intracerebroventricular injection of TNF-alpha (P < 0.05 vs. control). This increase was associated with an increase in stress hormones (corticosterone: 416.1 +/- 69.1 ng/ml, P < 0.05 vs. control; epinephrine: 3,778.3 +/- 681.3 pg/ml, P < 0.01 vs. control) and an enhancement of proteolysis (254.2 +/- 45.7 micromol Leu . kg-1 . h-1, P < 0.01 vs. control) and glucose production (7.5 +/- 0. 7 mg . kg-1 . min-1, P < 0.05 vs. control). Fentanyl reduced morphine levels in the brain to 624 fmol/g (not significant vs. control), resulting in a reduction of stress hormone levels in the plasma and blunted metabolic responses. In conclusion, prophylactic administration of fentanyl prevented an increase in morphine levels in the brain induced by intracerebroventricular injection of TNF-alpha, leading to a reduction in stress hormone levels and subsequent metabolic responses.Fentanyl citrate analgesia attenuates the excess nitrogen excretion in the urine and glucose production induced by trauma. On the other hand, intracerebroventricular injection of morphine stimulates excretion of stress hormones, such as catecholamines and corticosterone. Furthermore, morphine levels in the brain are increased during fasting and sepsis. The aims of this study were to determine whether intracerebroventricular injection of tumor necrosis factor-α (TNF-α) elevates morphine levels in the rat brain and whether prophylactic administration of fentanyl blocks metabolic responses induced by intracerebroventricular injection of TNF-α because of a reduction of morphine levels in the brain. Morphine levels in the brain were increased from 648 to 1,134 fmol/g at 30 min after intracerebroventricular injection of TNF-α ( P < 0.05 vs. control). This increase was associated with an increase in stress hormones (corticosterone: 416.1 ± 69.1 ng/ml, P < 0.05 vs. control; epinephrine: 3,778.3 ± 681.3 pg/ml, P < 0.01 vs. control) and an enhancement of proteolysis (254.2 ± 45.7 μmol Leu ⋅ kg-1 ⋅ h-1, P < 0.01 vs. control) and glucose production (7.5 ± 0.7 mg ⋅ kg-1 ⋅ min-1, P < 0.05 vs. control). Fentanyl reduced morphine levels in the brain to 624 fmol/g (not significant vs. control), resulting in a reduction of stress hormone levels in the plasma and blunted metabolic responses. In conclusion, prophylactic administration of fentanyl prevented an increase in morphine levels in the brain induced by intracerebroventricular injection of TNF-α, leading to a reduction in stress hormone levels and subsequent metabolic responses.