Mikito Inokuchi

A Comparison of Roux-en-Y and Billroth-I Reconstruction After Laparoscopy-assisted Distal Gastrectomy

Objective:The present study evaluated the efficacy of Roux-en-Y (R-Y) reconstruction and Billroth-I (B-I) reconstruction after laparoscopy-assisted distal gastrectomy (LADG). Patients and Methods:Between October 2000 and February 2006, a total of 133 consecutive patients who underwent LADG for gastric carcinoma were classified into 2 groups according to reconstruction (B-I, n = 65; R-Y, n = 68). Parameters analyzed included patients and tumor characteristics, operative details, postoperative outcomes, and nourishment state. Endoscopic findings of the gastric remnant and lower esophagus were evaluated at 12 months postoperatively. Results:Regarding postoperative complications, no significant differences were found between groups. In the B-I group, 3 patients developed anastomotic leakage and 4 patients suffered anastomotic stricture requiring endoscopic balloon dilation. So-called functional stasis after R-Y reconstruction was not found in this study. Incidence of heartburn at 12 months postoperatively was 37% in the B-I group and 8% in the R-Y group (P = 0.0002). Amount of meal consumed compared with preoperative value at 12 months postoperatively was significantly higher for the R-Y group than for the B-I group (83.6% ± 15.3% vs. 77.8% ± 16.0%; P = 0.047). Endoscopic findings showed that incidence of remnant gastritis was significantly lower in the R-Y group than in the B-I group (12% vs. 34%; P = 0.002). Bile reflux into the remnant stomach was not observed in the R-Y group. Conclusion:R-Y reconstruction seems superior to B-I reconstruction for preventing both bile reflux into the gastric remnant and postoperative complications. We consider R-Y reconstruction as a feasible and safe method for LADG.

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer.

Gastric cancer is the second most common cause of cancer deaths worldwide. The identification of molecular genetic parameters that are associated with response to chemotherapy and prognosis is of utmost interest. We examined methylation of the apoptosis‐related genes, TMS1 and DAPK, in 81 primary gastric cancers using methylation‐specific PCR and compared their methylation status with clinicopathological findings. Aberrant methylation of TMS1 and DAPK genes was detected in 26 (32.1%) tumors and in 18 (22.2%) tumors, respectively. The overall survival of patients with both methylated genes was significantly shorter compared with those with only one methylated gene or no methylated genes (p = 0.0003). Neither gene methylation had any relation to other clinicopathological findings. Next, we examined 43 patients treated by 5‐fluorouracil–based chemotherapy, who had distant metastasis or recurrence after radical resection, to determine the relation between chemosensitivity and methylation. The response rate was lower in patients with either methylation than without (TMS1: 22.2% vs. 48.0%; DAPK: 21.4% vs. 44.8%). Overall survival tended to be shorter in the patients with both methylations compared with either or no methylations (p = 0.0806). The time to progression of patients with methylation of TMS1 or DAPK was significantly shorter than patients without methylation (TMS1: p = 0.0123; DAPK: p = 0.0464). Furthermore, the time to progression of patients with both methylated genes was significantly shorter than patients with one methylation or no methylation (p = 0.0082). In conclusion, TMS1 and DAPK methylation might predict the prognosis and response to chemotherapy in gastric cancer.

Phase I/II study of S-1 combined with irinotecan for metastatic advanced gastric cancer

A dose-escalation study of irinotecan (CPT-11) combined with S-1, an oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was administered orally at 80 mg m−2 day−1 from day 1 to 14 of a 28-day cycle and CPT-11 was given intravenously on day 1 and 8 at an initial dose of 70 mg m−2 day−1, stepping up to 100 mg m−2. The treatment was repeated every 4 weeks, unless disease progression was observed. In the phase I portion, the MTD of CPT-11 was presumed to be 100 mg m−2, because 66.6% of patients (two of three) developed DLTs. All three patients at the initial RD of CPT-11 (90 mg m−2) experienced grade 4 haematological or grade 3 nonhaematological toxicities at second course, followed by the dose reduction of CPT-11 from the third course. Considering safety and the ability to continue treatment, the final RD was determined to be 80 mg m−2. In the phase II portion, 42 patients including seven patients in the final RD phase I portion were evaluated. The median treatment course was five (range: 1–13). The incidences of severe (grade 3–4) haematological and nonhaematological toxicities were 19 and 10%, respectively, but all were manageable. The RR was 62% (26 of 42, 95% confidence interval: 47.2–76.6%), and the median survival time was 444 days. Our phase I/II trial showed S-1 combined with CPT-11 is effective for AGC and is well tolerated, with acceptable toxicity.

Relation between outcomes and localisation of p-mTOR expression in gastric cancer

The mammalian target of rapamycin (mTOR), a Ser/Thr protein kinase that mediates intracellular signalling related to cell growth, proliferation, and differentiation, has received considerable interest as a possible target for cancer treatment. We evaluated the correlation of mTOR expression with clinicopathological features, outcomes, and the expression of Akt, an upstream regulator of mTOR, in gastric cancer. Tumour samples were obtained from 109 patients with gastric adenocarcinomas who underwent a radical gastrectomy. The expressions of phosphorylated mTOR (p-mTOR) and phosphorylated Akt (p-Akt) in the cytoplasm and in the nucleus were analysed by immunohistochemical staining. Cytoplasmic p-mTOR expression positively correlated with the depth of tumour invasion (T1 vs T2–4, P=0.003), involved lymph nodes (P=0.010), and tumour stage (I vs II–IV, P=0.002). In contrast, nuclear p-mTOR expression negatively correlated with these variables (P<0.001,=0.035, and <0.001). Cytoplasmic p-mTOR expression was associated with significantly poorer relapse-free survival (RFS, P=0.037) and overall survival (OS, P=0.024), whereas nuclear p-mTOR expression was associated with better RFS and OS (P=0.029, 0.059). Neither cytoplasmic nor nuclear p-Akt expression was associated with any clinicopathological factor or with survival. Localisation of p-mTOR may play an important role in tumour progression and outcomes in patients with gastric cancer.

Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer

Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.

Vimentin expression is associated with decreased survival in gastric cancer.

Gastric cancer rich in stromal tissue, such as diffuse-type disease, carries a poor prognosis. In some cancers, expression of vimentin, a mesenchymal maker, is associated with poor survival. The expression of mesenchymal markers such as vimentin is observed after epithelial-mesenchymal transition (EMT), an important initial behavioral change related to the adhesion and migration properties of tumor cells that is required for local tumor invasion. A hallmark of EMT is the loss of E-cadherin. EMT-inducing regulators, including SIP1, Slug, and Twist, repress E-cadherin transcription by interacting with E-cadherin promoter. We investigated the expression of vimentin and EMT-related genes, including SIP1, Slug, and Twist, in frozen cancer tissues and normal tissues by real-time quantitative reverse-transcriptase polymerase chain reaction. Tumor samples were obtained from 106 patients with gastric adenocarcinomas who underwent a gastrectomy. The relation of the expression of these genes to clinicopathological factors and outcomes was studied. Vimentin mRNA was significantly higher in diffuse type compared to intestinal type according to Laurens classification (p=0.048) and was significantly elevated in patients with recurrent or distant metastatic disease (p=0.049). Immunohistochemically, however, vimentin was detected only in cancer stroma. Twist mRNA expression significantly correlated with tumor depth (p=0.042) and advanced tumor stage (I-II vs. III-IV, p=0.030). E-cadherin immunohistochemical expression was significantly associated with Laurens histopathological type (p<0.001). Univariate analysis of relapse-free survival showed that tumor depth, lymph node metastasis, Laurens histopathological type, and vimentin mRNA expression were significant prognostic factors (p<0.001, p=0.013, p=0.011, and p=0.019). On multivariate analysis, vimentin mRNA expression was an independent prognostic factor [hazard ratio (HR)=2.1; 95% confidence interval (CI), 1.0-4.4; p=0.036], coming after tumor depth (HR=9.7; 95%CI, 3.7-24; p<0.001). Vimentin mRNA expression is associated with recurrence or distant metastasis and decreased survival in gastric cancer.

Gene expression of 5-fluorouracil metabolic enzymes in primary colorectal cancer and corresponding liver metastasis

PurposeExpression of thymidylate synthase (TS) and the 5-fluorouracil (5-FU) metabolic enzymes, including dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), and uridine phosphorylase (UP), has been reported to be associated with the sensitivity to 5-FU-based chemotherapy in colorectal cancer. We evaluated the correlation of the expression of these genes between primary tumors and corresponding liver metastases.MethodThe mRNA levels of TS, DPD, OPRT, TP, and UP were measured by real-time quantitative RT-PCR in samples from 23 consecutive patients with both primary colorectal adenocarcinoma and liver metastasis.ResultsThe DPD, OPRT, TP, and UP mRNA levels were significantly higher in liver metastases than in primary tumor (expression in relation to that of β-actin mRNA: 0.42 vs 0.16, P=0.00053; 1.4 vs 0.92, P=0.016; 23 vs 11, P=0.00014; 0.36 vs 0.25, P=0.0026; respectively). However, the TS mRNA level did not differ significantly between liver metastases than primary tumor (0.20 vs 0.16, P=0.28). No correlation was observed for any gene between primary tumor and liver metastases. In both primary tumor and liver metastasis, the TS mRNA levels correlated significantly with the OPRT mRNA level (primary rS=0.83, P=0.00000081; liver metastasis rS=0.49, P=0.017), while the DPD mRNA level correlated significantly with the TP mRNA level rS=0.81, P=0.0000024; rS=0.63, P=0.0014; respectively).ConclusionsThe differential gene expression of 5-FU metabolic enzymes between primary colorectal cancer and corresponding liver metastases should be taken into consideration when estimating the sensitivity to 5-FU-based chemotherapy in colorectal cancer. The gene expression of TS and OPRT, which are involved in de novo pyrimidine synthesis, and that of DPD and TP, may be coregulated.

Prognostic value of RKIP and p-ERK in gastric cancer

BackgroundThe mitogen-activated protein kinase (MAPK) signaling pathway participates in several steps of tumour development and is considered a prominent therapeutic target for the design of chemotherapeutic agents. We evaluated the expressions of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MEK), an upstream regulator of ERK, and Raf kinase inhibitor protein (RKIP), and investigated correlations of these expressions with clinicopathological features and outcomes in gastric cancer.MethodsTumour samples were obtained from 105 patients with gastric adenocarcinomas who underwent radical gastrectomy. The expressions of phosphorylated ERK (p-ERK), phosphorylated MEK (p-MEK), and RKIP were analysed by immunohistochemical staining.ResultsExpression of RKIP, p-MEK, and p-ERK was found in 69 (66%), 54 (51%), and 64 (61%) of all tumours, respectively. RKIP expression negatively correlated with the depth of invasion (p < 0.001), lymph node involvement (p = 0.028), and Union for International Cancer Control (UICC) stage (p = 0.007). RKIP expression was associated with significantly longer relapse-free survival (RFS) (p = 0.0033), whereas p-MEK was not (p = 0.79). Patients with p-ERK expression had slightly, but not significantly shorter RFS than those without such expression (p = 0.054). Patients with positive p-ERK and negative RKIP expression had significantly shorter RFS than the other patients (p < 0.001). The combination of RKIP and p-ERK expression was an independent prognostic factor (hazard ratio, 2.4; 95% confidence interval, 1.3 - 4.6; p = 0.008).ConclusionsOur results demonstrated that loss of RKIP was associated with tumour progression and poor survival. Negative RKIP expression combined with positive p-ERK expression was an independent predictor of poor outcomes in patients with gastric cancer.

Laparoscopy-Assisted Gastrectomy in Patients Older Than 80

BACKGROUND With the changing age distribution, the number of elderly patients with gastric cancer is anticipated to increase. This study evaluated the morbidity and mortality of laparoscopy-assisted gastrectomy (LAG) in patients older than 80. METHODS AND METHODS A total of 74 patients who underwent LAG for gastric cancer were assigned to two groups: an elderly group (70-79 y; n=56) and a very elderly group (older than 80; n=18). Preoperative comorbidity, operative results, and postoperative outcome were retrospectively analyzed. RESULTS In terms of concurrent illness, cardiovascular disease was significantly more frequent in the very elderly group than in the elderly group (P=0.042). Percent vital capacity (%VC) and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio were lower in the very elderly group than in the elderly group (%VC; 97.9% +/- 18.8% versus 109.0% +/- 18.0%, P=0.035, FEV(1)/FVC ratio; 68.0% +/- 7.8% versus 73.5% +/- 8.7%, P=0.026). Preoperative hemoglobin was significantly lower in the very elderly group than in the elderly group (11.8+/-2.0 versus 13.1+/-2.0, P=0.026). Incidence of postoperative complications and postoperative hospital stay were similar in both groups. No significant differences in time to first flatus or time to fever resolution (<37 degrees C) were noted between the two groups. CONCLUSION Our analysis revealed that LAG can be safely performed in patients older than 80, with complication rates and operation outcomes similar to those for patients aged 70-79.