Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo.

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

[Complete Response to Neoadjuvant Chemotherapy with Imatinib of a Large Gastric GIST-A Case Report].

A 54-year-old woman was presented with the intraabdominal mass to our hospital. Abdominal CT showed 22 cm tumor of the stomach with invasion to the pancreas and the spleen. Upper GI endoscopy showed submucosal tumor at the stomach body, and endoscopic US showed low echoic tumor. The tumor was diagnosed as gastric GIST by biopsy with c-kit positive cells. After 4 months of neoadjuvant therapy with imatinib, she underwent total gastrectomy, distal pancreatectomy and splenectomy. Histopathologically, there were no viable tumor cells in the resected specimen. The patient has no evidence of recurrence at 8 months post operation.

Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells.

Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction prevents cancer cells, but not normal cells from proliferation under methionine restriction (MR). Previous studies reported that MR altered the histone methylation levels in methionine-addicted cancer cells. However, no study has yet compared the status of histone methylation status, under MR, between cancer cells and normal cells. In the present study, we compared the histone methylation status between cancer cells and normal fibroblasts of H3K4me3 and H3K9me3, using recombinant methioninase (rMETase) to effect MR. Human lung and colon cancer cell lines and human normal foreskin fibroblasts were cultured in control medium or medium with rMETase. The viability of foreskin fibroblasts was approximately 10 times more resistant to rMETase than the cancer cells in vitro. Proliferation only of the cancer cells ceased under MR. The histone methylation status of H3K4me3 and H3K9me3 under MR was evaluated by immunoblotting. The levels of the H3K4me3 and H3K9me3 were strongly decreased by MR in the cancer cells. In contrast, the levels of H3K4me3 and H3K9me3 were not altered by MR in normal fibroblasts. The present results suggest that histone methylation status of H3K4me3 and H3K9me3 under MR was unstable in cancer cells but stable in normal cells and the instability of histone methylation status under MR may determine the high methionine dependency of cancer cells to survive and proliferate.

Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model.

Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise.

Efficacy of oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil on primary colon cancer in a patient-derived orthotopic xenograft mouse model.

The aim of this study was to determine the efficacy of oral recombinant methioninase (o-rMETase) on a colon cancer primary tumor using a patient-derived orthotopic xenograft (PDOX) nude mouse model. Forty colon cancer primary tumor PDOX mouse models were divided into 4 groups of 10 mice each (total 40 mice) by measuring the tumor size. The groups were as follows: untreated control; 5-fluorouracil (5-FU) (50 mg/kg, once a week for two weeks, N = 10 mice) and oxaliplatinum (OXA) (6 mg/kg, once a week for two weeks, N = 10 mice); o-rMETase (100 units/day, oral 14 consecutive days, N = 10 mice); combination of 5-FU + OXA and o-rMETase (N = 10 mice). All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA and o-rMETase was significantly more efficacious than other treatments. The present study demonstrates the efficacy of o-rMETase combination therapy on a PDOX colon cancer primary tumor, suggesting potential clinical development of o-rMETase in recalcitrant cancer.

Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model.

Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma.

A combination of irinotecan/cisplatinum and irinotecan/temozolomide or tumor-targeting Salmonella typhimurium A1-R arrest doxorubicin- and temozolomide-resistant myxofibrosarcoma in a PDOX mouse model.

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.

Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma.

Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma.

Novel Potent ABCB1 Modulator, Phenethylisoquinoline Alkaloid, Reverses Multidrug Resistance in Cancer Cell.

ATP-binding cassette (ABC) transporters, which are concerned with the efflux of anticancer drugs from cancer cells, have a pivotal role in multidrug resistance (MDR). In particular, ABCB1 is a well-known ABC transporter that develops MDR in many cancer cells. Some ABCB1 modulators can reverse ABCB1-mediated MDR; however, no modulators with clinical efficacy have been approved. The aim of this study was to identify novel ABCB1 modulators by using high-throughput screening. Of the 5861 compounds stored at Tohoku University, 13 compounds were selected after the primary screening via a fluorescent plate reader-based calcein acetoxymethylester (AM) efflux assay. These 13 compounds were validated in a flow cytometry-based calcein AM efflux assay. Two isoquinoline derivatives were identified as novel ABCB1 inhibitors, one of which was a phenethylisoquinoline alkaloid, (±)-7-benzyloxy-1-(3-benzyloxy-4-methoxyphenethyl)-1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinoline oxalate. The compound, a phenethylisoquinoline alkaloid, was subsequently evaluated in the cytotoxicity assay and shown to significantly enhance the reversal of ABCB1-mediated MDR. In addition, the compound activated the ABCB1-mediated ATP hydrolysis and inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin. Furthermore, the compound also reversed the resistance to paclitaxel without increasing the toxicity in the ABCB1-overexpressing KB-V1 cell xenograft model. Overall, we concluded that the newly identified phenethylisoquinoline alkaloid reversed ABCB1-mediated MDR through direct interaction with the substrate-binding site of ABCB1. These findings may contribute to the development of more potent and less toxic ABCB1 modulators, which could overcome ABCB1-mediated MDR.

Lymph nodes around the posterior gastric artery: their existence, frequency, and clinical implications.

PURPOSE: The lymphatic flow along the posterior gastric artery (PGA) is considered of possible clinical importance in terms of lymphatic metastasis; however, little is known about the lymph nodes (LNs) around this artery. The purpose of this study was to establish if LNs exist around the PGA and to evaluate their clinical implications. METHODS: We examined the tissues surrounding the PGA from 21 cadavers to search for LNs. We also investigated the patterns of lymphatic metastases in patients who underwent surgery for gastric neoplasms at our institute to detect their presence along the PGA. RESULTS: The PGA was identified in 11 cadavers, and LNs around the PGA were detected microscopically in 2 of these. Lymphatic metastasis directly to the LNs at the splenic artery without any metastases was regarded as skip metastasis along the PGA. Skip metastasis was found in two of ten patients who underwent surgery for remnant gastric cancer. CONCLUSIONS: The existence of LNs around the PGA was confirmed, and based on our findings, lymphatic metastasis through the PGA is possible in patients with remnant gastric cancer.

Synthetic Analogs of Curcumin Modulate the Function of Multidrug Resistance-Linked ATP-Binding Cassette Transporter ABCG2.

Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells.

A phase II study of an enhanced recovery after surgery protocol in gastric cancer surgery.

BACKGROUND: The enhanced recovery after surgery (ERAS) protocol integrates a number of perioperative interventions and techniques, aiming at decreasing the morbidity rate and the length of postoperative hospital stay after surgery. Although it has become a standard perioperative management for colorectal surgery, the feasibility of the ERAS protocol for gastric surgery remains unclear. METHODS: This single-center, prospective phase II study included patients with gastric cancer undergoing curative gastrectomy. The primary end point was the incidence of Clavien-Dindo grade II or higher postoperative complications. The secondary end points were the incidence of anastomotic leakage, the incidence of pneumonia, the proportion of patients starting oral feeding at postoperative day 2, the completion rate of the ERAS protocol, the length of postoperative hospital stay, the readmission rate within 30 days after discharge, and the mortality rate. RESULTS: From September 2013 to September 2014, 121 eligible patients were enrolled in this study. The incidence of postoperative complications was 10.7 % (90 % confidence interval, 6.47-16.54 %). Anastomotic leakage and pneumonia was observed in one and zero patients, respectively. The median length of postoperative hospital stay was 8 days, and the completion rate of the ERAS protocol was 85.1 %. The readmission rate and the mortality rate were 0 %. CONCLUSIONS: The ERAS protocol can be safely used in patients undergoing gastric cancer surgery. The superiority of the ERAS protocol over non-ERAS perioperative management should be clarified.

Risk Classification using the Ki-67 Labeling Index for Surgically-Treated Gastric Gastrointestinal Stromal Tumors.

BACKGROUND/AIMS: Adjuvant treatment with imatinib mesylate (IM) improves survival of patients with a high risk of recurrence of gastrointestinal stromal tumors (GISTs). However, the optimal adjuvant treatment strategy remains unknown. Thus, this study aimed to identify patients who do not require adjuvant IM treatment using the Ki-67 labeling index (LI). METHODOLOGY: The Ki-67 LI was calculated in 59 patients with gastric GISTs. A new risk classification using the Ki-67LI and tumor size was established using cut-off values determined by receiver operating characteristic analysis. This Ki-67 classification was compared with the modified Fletcher classification (MF). RESULTS: The best cut-off values for the Ki-67LI and tumor size were 8.6% and 80 mm, respectively. According to the MF, 42, 10, and 7 patients were categorized as low, intermediate, and high risk, respectively, while the Ki-67 classification rated 38, 17, and 4 patients as low, intermediate, and high risk, respectively. The 7 patients classified as high risk by MF were graded high risk (4 patients) and intermediate risk (3 patients) by the Ki-67 classification. Recurrence was not observed in patients classed intermediate risk by the Ki-67 classification. CONCLUSIONS: The Ki-67 classification is helpful for identifying patients for whom adjuvant IM treatment is not necessary.

Early phase II study of robot-assisted distal gastrectomy with nodal dissection for clinical stage IA gastric cancer.

BACKGROUND: Robot-assisted distal gastrectomy (RADG) is increasingly performed in Japan and Korea and is thought to have many advantages over laparoscopic gastrectomy. However, a prospective study investigating the safety of RADG has never been reported. The present study evaluated the safety of RADG with nodal dissection for clinical stage IA gastric cancer. METHODS: This single-center, prospective phase II study included patients with clinical stage IA gastric cancer located within the lower two-thirds of the stomach. The primary endpoint was the incidence of postoperative intraabdominal infectious complications including anastomotic leakage, pancreas-related infection, and intraabdominal abscess. The secondary endpoints included all in-hospital adverse events, RADG completion rate, and survival outcome. RESULTS: From May 2012 to November 2012, 18 eligible patients were enrolled for this study. The incidence of intraabdominal infectious complication was 0 % (90 % CI, 0-12.0 %). The overall incidence of in-hospital adverse events was 22.2 % (90 % CI, 8.0-43.9 %). No patient required conversion to laparoscopic or open gastrectomy; thus, the RADG completion rate was 100 %. CONCLUSIONS: This early phase II study suggested that RADG might be a safe and feasible procedure for stage IA gastric cancer, providing experienced surgeons perform the surgery. This conclusion should be clarified in subsequent late phase II studies with a larger sample size.

The optimal extent of lymph node dissection for adenocarcinoma of the esophagogastric junction differs between Siewert type II and Siewert type III patients.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing worldwide. We investigated the clinicopathological characteristics of patients with Siewert type II and III AEGs and clarified the optimal intra-abdominal lymph node dissection in these patients. METHODS: This study included 132 patients with AEG who underwent curative resection at Shizuoka Cancer Center from September 2002 to December 2012. We used the index of estimated benefit from lymph node dissection (IEBLD) to assess the efficacy of lymph node dissection of each station. The clinicopathological characteristics and IEBLDs of each station were compared between patients with Siewert type II and III AEGs. RESULTS: We analyzed 92 patients with Siewert type II AEG and 40 patients with Siewert type III AEG. The incidence of lymph node metastasis was high in both groups (64.1 % in type II AEG and 75.0 % in type III AEG). The 5-year survival rates were similar for the patients with Siewert type II and III AEGs, at 54.0 and 53.4 %, respectively. The IEBLDs of stations located near the esophagogastric junction were generally high in both groups, while the IEBLDs of lower perigastric lymph nodes were higher in Siewert type III than in Siewert type II AEG cases. CONCLUSIONS: The IEBLDs were similar between Siewert type II and III AEGs at all stations except for lower perigastric lymph nodes. Total gastrectomy should be selected as a standard treatment for Siewert type III AEG, whereas in Siewert type II AEG, preservation of the distal part of the stomach may be an acceptable procedure.

The impact of preoperative lymph node size on long-term outcome following curative gastrectomy for gastric cancer.

BACKGROUND: Multidetector-row computed tomography (MDCT) is widely used to predict pathological nodal status. However, an appropriate nodal size cutoff value to predict pathological nodal status has not been determined, and the impact of preoperative lymph node size on long-term outcomes is unclear. METHODS: This study included 137 gastric cancer patients with nodal involvement who underwent R0 gastrectomy between September 2002 and December 2006. Lymph nodes with a short-axis diameter of 10 mm or more as measured by MDCT were regarded as metastasized. An appropriate cutoff value with a high positive predictive value (PPV) and high specificity also was identified, and the subsequent clinicopathological characteristics and long-term outcomes were investigated. RESULTS: A cutoff value of 15 mm was found to be appropriate for grouping patients into large (≥15 mm) and small (<15 mm) lymph node metastasis (LLNM and SLNM) groups, with a high PPV (98.6 %) and specificity (99.8 %). There were no differences in clinicopathological characteristics between the groups except for pathological nodal status. In the LLNM group, the 5-year survival rate was 55 %, which was significantly lower than in the SLNM group (73.2 %; P = 0.008). After stratification by tumor depth, the same trend was observed in patients with pT3 disease (46.8 % vs. 72.7 %; P = 0.015) and those with pT4 disease (14.3 % vs. 64.8 %; P = 0.035). CONCLUSIONS: Gastric cancer patients with lymph nodes measuring 15 mm or more preoperatively have worse long-term outcomes. These patients would therefore be suitable candidates for future clinical trials investigating the efficacy of neoadjuvant chemotherapies.

Value of splenectomy in patients with Siewert type II adenocarcinoma of the esophagogastric junction.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been increasing recently in both Western and Eastern countries. However, an optimal treatment strategy for Siewert type II AEG is still unclear. The aim of this study was to clarify the value of splenectomy in patients with Siewert type II AEG. METHODS: From September 2002 to November 2011, 42 patients underwent total gastrectomy with D2 lymph node dissection for Siewert type II AEG and were included in this study. We used the index of estimated benefit from lymph node dissection (IEBLD) to assess the efficacy of lymph node dissection of each station. Surgical complications were graded by the Clavien-Dindo classification. RESULTS: The overall 5-year survival rate of the 42 patients was 57.5 %. The incidence of splenic hilar lymph node metastasis was 4.8 % and the 5-year survival rate of patients with splenic hilar lymph node involvement was zero. Consequently, the IEBLD of splenic hilar lymph nodes was zero. Postoperative morbidities occurred in 25 patients (59.5 %). Pancreas-related complications were the most frequently observed (28.5 %), followed by intraabdominal abscess (14.3 %) and anastomotic leakage (9.5 %). CONCLUSIONS: Splenic hilar lymph node dissection may be omitted without decreasing curability in patients with Siewert type II AEG, although a prospective study is necessary for more conclusive results.

[A case experienced long-term survival after repeat hepatectomy for liver metastases from gastric cancer].

Although the standard treatment for liver metastasis from gastric cancer is chemotherapy, there are several reports demonstrating better survival after hepatectomy. However, repeat hepatectomy for liver metastasis is still rare. We present a case of long-term survival after repeat hepatectomy for liver metastasis from gastric cancer. A 68-year-old male underwent distal gastrectomy with D2 lymphadenectomy for a gastric cancer. The histopathological finding revealed that the tumor was a moderately-differentiated tubular adenocarcinoma 43mm in diameter, with invasion to subserosa(T3; SS). There was one metastasis to the regional lymph node(#11p). The tumor was classified as T3N1M0(stage II B)according to the 14th edition of the Japanese Classification of Gastric Carcinoma. Fourteen months after the operation, computed tomography revealed two metastases in the lateral segment of the liver. He underwent left lateral segmentectomy followed by adjuvant chemotherapy with S-1(100mg)for one year. Sixteen months after the hepatectomy, a solitary hepatic metastasis 30mm in size at segment 8 was found by follow-up CT scan. He underwent repeat hepatectomy. He is free of recurrence now without adjuvant chemotherapy four years after repeat hepatectomy.

Intra-abdominal infectious complications following gastrectomy in patients with excessive visceral fat.

BACKGROUND: Excessive visceral fat may be a better predictor of the development of postoperative morbidity after gastrectomy than body mass index (BMI). The aim of the present study was to clarify the most appropriate fat parameter to predict pancreas-related infection and anastomotic leakage following gastrectomy. METHODS: The study was performed in 206 patients who underwent curative gastrectomy at the Shizuoka Cancer Center between April 2008 and March 2009. Relationships between fat parameters, including visceral fat area (VFA), and early surgical outcomes were investigated. The risk factors for pancreas-related infection and anastomotic leakage were identified using univariate and multivariate analyses. RESULTS: There was no strong association between any of the fat parameters and operating time, intraoperative blood loss, the number of lymph nodes retrieved, or the duration of the postoperative hospital stay. Pancreas-related infection occurred in 18 patients (8.7%), whereas anastomotic leakage was observed in 10 patients (4.9%). Of all the fat parameters, only VFA was found to be an independent risk factor for both pancreas-related infection and anastomotic leakage, with odds ratios (95% confidence intervals) of 1.015 (1.005-1.025) and 1.010 (1.000-1.021), respectively. CONCLUSIONS: Excessive visceral fat, represented by the VFA, was found to be an independent risk factor for both pancreas-related infection and anastomotic leakage following gastrectomy.