Hiroshi Terasawa

Early Removal of Prophylactic Drains Reduces the Risk of Intra-abdominal Infections in Patients With Pancreatic Head Resection: Prospective Study for 104 Consecutive Patients

Objective:The aim of this study was designed to determine whether the period of drain insertion influences the incidence of postoperative complications. Background Data:The significance of prophylactic drains after pancreatic head resection is still controversial. No report discusses the association of the period of drain insertion and postoperative complications. Methods:A total of 104 consecutive patients who underwent pancreatic head resection were enrolled in this study. To assess the value of prophylactic drains, we prospectively assigned the patients into 2 groups: group I underwent resection from January 2000 to January 2002 (n = 52, drain to be removed on postoperative day 8); group II underwent resection from February 2002 to December 2004 (n = 52, drain to be removed on postoperative day 4). Postoperative complications in the 2 groups were compared. Results:The rate of pancreatic fistula was significantly lower in group II (3.6%) than in group I (23%) (P = 0.0038). The rate of intra-abdominal infections, including intra-abdominal abscess and infected intra-abdominal collections, was significantly reduced in group II (7.7%) compared with group I (38%) (P = 0.0003). Eighteen of 52 (34.6%) patients in group I had an inserted drain beyond 8 days, whereas only 2 of 52 (3.7%) patients in group II had an inserted drain beyond 4 days (P = 0.0002). Cultures of drainage fluid were positive in 16 of 52 (30.8%) patients in group I, and in 2 of 52 (3.7%) patients in group II (P = 0.0002). Intraoperative bleeding (>1500 mL), operative time (>420 minutes, and the period of drain insertion were significant risk factors for intra-abdominal infections (P = 0.043, 0.025, 0.0003, respectively). The period of drain insertion was the only independent risk factor for intra-abdominal infections by multivariate analysis (odds ratio, 6.7). Conclusion:Drain removal on postoperative day 4 was shown to be an independent factor in reducing the incidence of complications with pancreatic head resection, including intra-abdominal infections.

Improvement of Delayed Gastric Emptying in Pylorus-Preserving Pancreaticoduodenectomy: Results of a Prospective, Randomized, Controlled Trial

Objective:To determine if an antecolic or a retrocolic duodenojejunostomy during pylorus-preserving pancreaticoduodenectomy (PpPD) was associated with the least incidence of delayed gastric emptying (DGE), in a prospective, randomized, controlled trial. Summary Background Data:The pathogenesis of DGE after PpPD has been speculated to be related to factors such as inflammation, ischemia, gastric atony, motilin levels, and type of surgical procedure. Previous retrospective studies have shown a lower incidence of DGE after antecolic duodenojejunostomy. A prospective trial is needed. Methods:Forty patients were enrolled in this trial between May 2002 and April 2004. Just before duodenojejunostomy during PpPD, the patients were randomly assigned to undergo either an antecolic or a retrocolic duodenojejunostomy. Results:DGE occurred in 5% of patients with the antecolic route for duodenojejunostomy versus 50% with the retrocolic route (P = 0.0014). Those with the antecolic route had a significantly shorter duration of postoperative nasogastric tube drainage than did those with the retrocolic route (4.2 days versus 18.9 days, respectively, P = 0.047). By postoperative day 14, all patients with the antecolic route could take solid foods, while only 55% (11 of 20) of the patients with the retrocolic route could take solid foods (P = 0.0007). The length of stay in the hospital was 28 days for the antecolic group versus 48 days for the retrocolic group (P = 0.018). Conclusions:Antecolic reconstruction for duodenojejunostomy during PpPD decreases postoperative morbidity and length of hospital stay by decreasing DGE. Our data suggest that PpPD with antecolic duodenojejunostomy is a safer operation.

Complications with reconstruction procedures in pylorus-preserving pancreaticoduodenectomy

This study was conducted retrospectively to examine the efficacy of Traverso reconstruction compared with Billroth I reconstruction after pylorus-preserving pancreaticoduodenectomy, in the prevention of several complications. Pylorus-preserving pancreaticoduodenectomy is an aggressive surgery, and insufficiency of the pancreaticoenterostomy plays an important role in the postoperative progression. However, reports examining the correlation between pancreatic fistula and the type of reconstruction after pylorus-preserving pancreaticoduodenectomy have been limited. Sixty-four patients who underwent pylorus-preserving pancreaticoduodenectomy (33 reconstructed by the Traverso technique and 31 reconstructed by the Billroth I technique) were entered into this study to investigate whether the complications were related to the type of reconstruction procedure employed. Insufficiency of the pancreaticojejunostomy, including major leakage and pancreatic fistula, occurred in 18.2% of the reconstructions by Billroth I and 0% of the reconstructions by Traverso (p < 0.05). In addition, jejunal obstruction by recurrent tumor in the remnant pancreas was observed in 3 patients reconstructed by Billroth I, and required palliative bypass surgery. Reconstruction by the Traverso procedure after pylorus-preserving pancreaticoduodenectomy is a safe surgical method and has an advantage for advanced pancreatic cancer, which has high risk of jejunal obstruction by recurrent tumor in the remnant pancreas.

Impact of lymph node metastasis on survival in patients with pathological T1 carcinoma of the ampulla of vater

To determine the prognostic factors for patients with pathological T1 (pT1) carcinoma of the ampulla of Vater, 36 consecutive patients with carcinoma of the ampulla of Vater who underwent surgery were retrospectively analyzed in terms of clinicopathological features. The overall 5-year Kaplan-Meier survival in all patients was 50.2%, and the median survival of all patients was 64.0 months. Factors favorably influencing a long-term outcome were the absence of lymph node metastasis (P<0.0001), the absence of ulcer formation of the tumor (P=0.0062), and the absence of tumor invasion into the duodenum (P = 0.0025) and the pancreas (P=0.0098). In a multivariate analysis, lymph node metastasis was the only predictor of survival (P=0.0023). In the pT1 stage patients, 20% of the patients had lymph node metastasis, and their survival was statistically poor compared to the pT1 patients without lymph node metastasis (P=0.017). As for survival after the operation, there was no significant difference between pancreatoduodenectomy and pylorus-preserving pancreatoduodenectomy.

P-glycoprotein-expressing tumor cells are resistance to anticancer drugs in human gastrointestinal cancer

The resistance to doxorubicin (DOX) by some tumor cells is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance-1 (mdr1) gene. We tried to prove the correlations between P-glycoprotein expression and the sensitivity for anticancer drugs including DOX and other cytotoxic drugs that are currently used for gastrointestinal cancer patients. We quantified the P-glycoprotein expression by flow cytometry techniques, and the sensitivity for anticancer drugs using a tetrazolium salt, 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), assay in highly purified fresh human tumor cells obtained from 25 cancer patients. The inhibition rates were the lowest in DOX and mitomycin C (MMC), compared with other drugs. The most significant correlation between DOX and MMC was seen in the inhibition rates. A significant correlation was also seen between the inhibition rates for DOX and P-glycoprotein expression, whereas only a slight correlation between the sensitivity for MMC and P-glycoprotein expression was observed. We should therefore pay close attention to the effect of P-glycoprotein when treating cancer patients, especially if both the inhibition rates of DOX and MMC are low based on the findings of an MTT assay.

Antitumor Effects of Interleukin-2 Gene-modified Fibroblasts in an Orthotopic Colon Cancer Model

We transduced the interleukin‐2 (IL‐2) gene into murine fibroblasts BALBCL7 or murine colon cancer CT26 using a retroviral vector. BALBCL7 transduced with IL‐2 gene secreted 748 pg/ml of IL‐2, whereas IL‐2 gene‐modified CT26 secreted 1,167 pg/ml of IL‐2 (48 h incubation, 1×106/ml). Then, we inoculated gene‐modified BALBCL7 and/or CT26 cells into BALB/c female mice, and observed the tumor growth. The tumor growth was inhibited in mice inoculated with parental CT26 plus IL‐2 gene‐modified BALBCL7, compared with that in mice given parental CT26 alone (P < 0.01). Moreover, we investigated the cytotoxic activity of spleen cells derived from mice treated with gene‐modified cells, and performed phenotypic analysis of the effector cells. The killer cells derived from mice inoculated with IL‐2 gene‐modified BALBCL7 plus parental CT26 showed higher cytotoxic activity than those from mice inoculated with CT26 alone. The cytotoxic activity was almost completely blocked by anti‐CD8 antibody (Ab), and partially blocked by anti‐asialo GM1 Ab. Next, we inoculated CT26 tumor tissue into murine cecum orthotopically, and treated the animals with gene‐modified BALBCL7 plus parental CT26. The tumor size in the cecum was significantly decreased, compared with parental CT26 alone (P < 0.01).

Modulation of multidrug resistance by cepharanthine in fresh human gastrointestinal tumor cells

Resistance to doxorubicin (DOX) is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance (MDR) gene. Cepharanthine (CEP) has been shown to circumvent multidrug resistance in P-glycoprotein-expressing cell lines. In the present study, we investigated the augmentation of DOX sensitivity by CEP using an MTT assay, and assessed the correlation between DOX sensitivity and P-glycoprotein expression by flow cytometry, in highly purified fresh human tumor cells obtained from 73 cancer patients. DOX sensitivity was decreased in proportion to P-glycoprotein expression. The cytotoxicity of DOX was increased by CEP in tumor cells possessing low DOX sensitivity. Moreover, there was a significant correlation between the effect of CEP on cytotoxicity and P-glycoprotein expression. Thus, CEP might be able to circumvent DOX resistance in cancer patients.

Clinical significance of quantitative analysis of carcinoembryonic antigen assessed by flow cytometry in fresh human gastric cancer cells

The expression of carcinoembryonic antigen(CEA) on tumor cells freshly excised from 51 patients with gastric cancer was studied using flow cytometry. The expression of CEA by flow cytometry was more quantitative than that by immunohistochemical staining. There was no relationship between the fluorescence intensity assessed by flow cytometry and serum CEA levels, except for patients with a high titer of serum CEA. The patients with high grade CEA expression on tumor cells by flow cytometry had poor prognoses, compared to patients with low CEA expression in undifferentiated gastric cancer. Thus, it is suggested that the quantitative CEA expression on tumor cells by flow cytometry could be a useful prognostic marker in postoperative gastric cancer patients.

Synergistic effects of tamoxifen and cepharanthine for circumventing the multidrug resistance

We examined the synergistic effects of tamoxifen (TAM) and cepharanthine (CEP) for doxorubicin (DOX) sensitivity using MTT assay. The augmentation of DOX sensitivity by TAM and CEP was significantly correlated with the P-glycoprotein expression. The cytotoxic effect of DOX with TAM and CEP was significantly higher than that of DOX alone, or DOX with TAM, and this synergistic effect was dominant in cell lines with high expression of P-glycoprotein. It was also examined that the intracellular concentration of DOX was increased in combined exposure of TAM and CEP, compared with the exposure of TAM, because TAM and CEP promoted the influx and inhibited the efflux of DOX. Thus, TAM and CEP might be able to circumvent DOX-resistance for treatment in cancer patients.

Dose of Adenoviral Vectors Expressing Interleukin-2 Plays an Important Role in Combined Gene Therapy with Cytosine Deaminase/5-Fluorocytosine : Preclinical Consideration

Using a syngeneic murine model, we investigated the therapeutic efficacy of combined gene therapy using adenoviral vectors expressing murine interleukin‐2 (AdmIL‐2) and Escherichia coli cytosine deaminase (AdCD). In a subcutaneous tumor model, tumor‐bearing mice were treated with an intratumoral injection of adenoviral vectors and received an intraperitoneal administration of 5–fluorocytosine (5–FC). Only the mice treated with AdCD (2×108 pfu) and an intermediate dose of AdmIL‐2 (1×106 pfu) survived significantly longer than mice treated with AdCD alone (P<0.01). Moreover, 40% of these treated mice obtained complete remission from tumor‐bearing status. The cytotoxicity of splenocytes obtained from the treated mice was related to the survival period. Tumor‐specific cytotoxic T lymphocyte assay showed that the cell‐mediated cytotoxic response was specific for parental tumor cells. In a hepatic metastasis model, mice treated with an intravenous administration of both AdCD (2×l08 pfu) and an intermediate dose of AdmIL‐2 (1×106 pfu) demonstrated the most significant reduction of metastatic foci and the longest survival following a 5–FC administration. These results suggest that gene therapy combined with AdmIL‐2 and AdCD may be a promising strategy for clinical application and, in addition, that translation of combined gene therapy from murine models into the clinical setting will require careful attention to the variables of cytokine expression levels in the design of clinical trials and in the evaluation of treatment efficacy.