Nobuya Ishibashi

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.

Repeat pulmonary resection for isolated recurrent lung metastases yields results comparable to those after first pulmonary resection in colorectal cancer.

Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5-year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3-year, and 5-year-survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.

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.

Elevated preoperative serum carcinoembrionic antigen level may be an effective indicator for needing adjuvant chemotherapy after potentially curative resection of stage II colon cancer.

To determine the prognostic factors and to rationalize adjuvant therapy, the clinicopathologic data of patients with a stage II colon cancer were analyzed retrospectively.

Modulation of inflammatory response in sepsis by proteasome inhibition

The Ubiquitin‐proteasome system has recently been shown to be involved in the regulation of cytokine expression. We tested the hypothesis of whether the in vivo administration of proteasome inhibitor MG‐132 can modulate cytokine response and mortality in sepsis. Sepsis was induced in mice by caecal ligation and puncture (CLP). Animals were divided into four groups: control, CLP, CLP and 1 μg MG‐132/g of b.w. intraperitoneally, and CLP and 10 μg MG‐132/g of b.w. Plasma levels of interleukin (IL)‐1, tumour necrosis factor‐α (TNF‐α, IL‐6 and IL‐10 were determined by ELISA 6 h after the induction of sepsis. CLP induced significant increase in plasma levels of all measured cytokines. MG‐132 treatment resulted in lower increase in IL‐1, TNF‐α and IL‐10 levels. IL‐6 was not significantly affected. A mortality study revealed prolonged survival in MG‐132 treated mice. We conclude that MG‐132 treatment decreases inflammatory response and prolongs survival in the CLP model of sepsis.

The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer

Background: The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression in primary colorectal cancer tissues. Patients and Methods: The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5′-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors. Results: Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors. Conclusions: The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5′-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Effectiveness of the portable ultrasound bladder scanner in the measurement of residual urine volume after total mesorectal extirpation

The measurement of residual urine volume by bladder catheterization causes quite some suffering to the patient and sometimes causes urinary tract infections. To evaluate the postoperative measurement of residual urine volume with a portable ultrasound bladder scanner (Bladder Scan BVI 3000) and the cost-benefit analysis as compared with postoperative catheterization we carried out a study on 30 patients with primary rectal cancer. The data were then compared with actual urine volumes. This was a prospective study dealing with the economical benefit of ultrasound scanning over catheterization during the hospital stay. The ultrasound bladder scanner was found to be a reliable method of estimating residual urine volume since its data correlated with actual volumes with a coefficient of 0.9. The results satisfied both physicians and patients. Ultrasound scanning of the bladder to measure residual urine volume reduced the frequency of catheterization by 38% as compared with the patients on intermittent catheterization, with 17.4 catheters saved for each patient. In conclusion, the ultrasound bladder scanner could protect patients from the discomfort and urethral injury which might have been caused by bladder catheters, thus decreasing medical expenses. This technique will play an important role in determining whether to conduct invasive urethral catheterization for postoperative urinary disturbance in rectal cancer.

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.

Ultrasound-guided rectus sheath block for single-incision laparoscopic cholecystectomy

Single‐incision laparoscopic cholecystectomy (SILC) is increasingly applied for cholecystectomy and has been reported as safe and feasible, with short‐term operative outcomes equivalent to four‐port cholecystectomy. Although many investigators in randomized studies have noted the cosmetic advantages of SILC, the benefit of decreased pain in SILC remains controversial. Therefore, this study aimed to assess the efficacy of the rectus sheath block in SILC with respect to subjective pain.