Meta-analysis of Robot-assisted Versus Laparoscopic Surgery for Rectal Cancer.

BACKGROUND/AIM: A meta-analysis was conducted to evaluate and compare the short- and long-term outcomes of robot-assisted (RAS) and conventional laparoscopic surgery (LAS) for rectal cancer. MATERIALS AND METHODS: We searched MEDLINE for relevant papers published between 2010 and December 2017 by using specific search terms. We analyzed outcomes over short- and long-term periods. RESULTS: We identified 23 papers reporting results that compared RAS for rectal cancer with LAS. Our meta-analysis included 4,348 patients with rectal cancer; 2,068 had undergone RAS, and 2,280 had undergone LAS. In the short- and long-term period, 27 and 7 outcome variables were examined, respectively. RAS for rectal cancer was significantly associated with a greater operative time and a lower conversion rate to open surgery in the short-term, and results in almost similar outcomes in the long-term, compared to LAS. CONCLUSION: RAS may be an acceptable surgical treatment option compared to LAS for rectal cancer.

[Two cases of esophageal variceal rupture associated with chemotherapy for liver metastasis of breast cancer].

A morphological change resembling liver cirrhosis called pseudocirrhosis may be observed following chemotherapy for liver metastasis of breast cancer. Pseudocirrhosis is hypothesized to be caused by retraction of the hepatic capsule along with tumor shrinkage and subsequent scar formation around the metastatic lesion, as a response to the infiltrating tumor or chemotherapy-induced hepatic injury. The progression of cirrhotic changes may result in portal hypertension and esophageal varices. We managed two cases of esophageal variceal rupture during chemotherapy for breast cancer with liver metastasis. Hemostasis was successfully achieved by the endoscopic variceal ligation technique in both cases. We conclude that clinicians should be aware of the risk of pseudocirrhosis during chemotherapy for liver metastasis, and a periodic endoscopic follow-up is recommended along with appropriate management of esophageal varices.

Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGFß signaling.

Epithelial mesenchymal transition (EMT) is considered to be correlated with malignancy of cancer cells and responsible for cancer invasion and metastasis. We previously reported that distant metastasis was associated with hypoxia in gastric cancer. We therefore investigated the effect of hypoxic condition on EMT of gastric cancer cells. Gastric cancer cells were cultured in normoxia (21% O2) or hypoxia (1% O2) for 24 h. EMT was evaluated as the percentage of spindle-shaped cells in total cells. Effect of transforming growth factor ß1 (TGFß1) or tyrosine kinase inhibitors on the EMT was evaluated. The expression level of TGFß1 and TGFßR was evaluated by real time RT-PCR. The TGFß1 production from cancer cells was measured by ELISA. Hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, but not that of OCUM-2M cells. The expression level of TGFß1 mRNA under hypoxia was significantly higher than that under normoxia in all of three cell lines. The expression level of TGFßR mRNA was significantly increased by hypoxia in OCUM-2MD3 cells, but not in OCUM-2M cells. TGFßR inhibitor, SB431542 or Ki26894, significantly suppressed EMT of OCUM-2MD3 and OCUM-12. TGFß1 production from OCUM-2MD3 and OCUM-12 cells was significantly increased under hypoxia in comparison with that under normoxia. These findings might suggest that hypoxia stimulates the EMT of gastric cancer cells via autocrine TGFß/TGFßR signaling.

[Successful treatment of locally advanced squamous cell carcinoma of the esophagus by combination chemotherapy with 5-fluorouracil plus nedaplatin following tracheal stent tube placement-a case report].

The patient was a 68-year-old man who complained of hoarseness and dyspnea. Upper gastrointestinal endoscopy revealed a type 3 tumor located in the middle thoracic esophagus at 30 cm from the incisor tooth that involved one-fourth of the circumference of the esophagus. Histopathological examination revealed moderately differentiated squamous cell carcinoma. Chest computed tomography( CT) revealed severe tracheal stenosis due to compression by a metastatic lymph node along the left recurrent laryngeal nerve. The patient was diagnosed as having cT4( 106recL-trachea), N2( 101L, 106recL, 106recR), M0, Stage IVa unresectable esophageal carcinoma. After insertion of a tracheal stent tube( spiral Z stent: diameter, 18 mm; length, 80 mm) to improve dyspnea, combination chemotherapy with 5-fluorouracil( 5-FU) plus nedaplatin was administered. Subsequent CT and endoscopy showed that the main tumor and the metastatic lymph node had significantly reduced in size and that complete response (CR) had been achieved. Thirty months after the initial treatment, the patient showed no sign of disease recurrence, after completion of 19 cycles of chemotherapy. The patient did not experience any severe adverse events. We report a case of a patient with locally advanced squamous cell carcinoma of the esophagus successfully treated with 5-FU/nedaplatin combination chemotherapy following tracheal stent tube placement.

[A case of solitary adrenal metastasis from breast cancer successfully resected by laparoscopy].

A 47-year-old woman had undergone breast-conserving treatment for right breast cancer (T3, N1, M0, Stage IIIA, human epidermal growth factor receptor[ HER]-2 enriched subtype) after primary systemic chemotherapy with trastuzumab. Pathological examination revealed a quasi-pathological complete response( CR) in the breast tumor and no axillary nodal involvement. The patient then received conventional breast irradiation and adjuvant trastuzumab therapy. However, adjuvant anti- HER2 therapy was discontinued in the 19th week because of a decreased left ventricular ejection fraction( approximately 50%). A left adrenal tumor was detected by abdominal computed tomography (CT) 2 years after surgery. Positron emission tomography( PET) scans showed strong accumulation in the left adrenal gland and in the lymph node near the adrenal tumor. No other obvious lesion was detected on meticulous examination. Laparoscopic adrenalectomy was performed for diagnosis and treatment. Pathological examination of the resected specimen revealed that the tumor was a metastatic adenocarcinoma with overexpression of the HER2 protein but without expression of hormonal receptors. The patient received 12 cycles of chemotherapy with paclitaxel and trastuzumab, which was followed by trastuzumab monotherapy. However, trastuzumab monotherapy could not be continued because the left ventricular ejection fraction decreased to 50% at 24 weeks after initiation of chemotherapy. The patient has been observed since the cessation of trastuzumab, without the administration of anticancer therapy, and she continues to have a good performance status without relapse. Herein, we report a case of solitary adrenal metastasis from breast cancer, an extremely rare condition, and review the relevant literature.

[Mechanisms responsible for the progression of scirrhous gastric cancer].

Scirrhous gastric carcinoma is characterized by rapid cancer cell infiltration and proliferation accompanied by extensive stromal fibrosis. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors, FGF7 and TGFbeta produced by organ-specific fibroblasts. Peritoneal fibroblasts morphologically change mesothelial cells, and stimulate the migratory capability of cancer cells. A FGFR2 phosphorylation inhibitor prolongs the survival of mice with peritoneal metastasis of scirrhous gastric cancer. A TGFbetaR inhibitor decreases the growth of fibroblast, and invasion-stimulating activity of fibroblasts on cancer cells. A FGFR2 phosphorylation inhibitor or TGFbetaR inhibitor appears therapeutically promising in scirrhous gastric carcinoma.

RhoA/ROCK signaling mediates plasticity of scirrhous gastric carcinoma motility.

The small guanosine triphosphatase (GTPase) Rho and its downstream effector Rho-associated kinase (ROCK) is one of a key mediator involved in controlling focal adhesions and the dynamics of actin stress fibers. The molecular mechanisms for the function of Rho/ROCK pathway leading to the progression in scirrhous gastric carcinoma cells have not been defined. The activation of RhoA in several gastric carcinoma cells was examined. The role of RhoA/ROCK pathway in the metastatic processes of gastric carcinoma cells, using a human scirrhous gastric cancer cell line, OCUM-2MD3 was investigated by in vitro adhesion and invasion assay. The effect of ROCK inhibitor, Y-27632 on the mRNA expression of the integrin family and MMP in gastric carcinoma cells was subsequently examined by Reverse transcriptional (RT)-PCR analysis. Finally, Random OCUM-2MD3 cell motility was evaluated using Time-lapse microscopy. ROCK inhibitor significantly increased the adhesion of OCUM-2MD3 cells to the extracellular matrix (ECM) protein matrigel. Further examination using ECM components showed enhanced binding ability was obtained only in laminin and Integrin subunits α3-integrin was clearly up-regulated by treatment with Y-27632 in OCUM-2MD3 cells. ROCK inhibitor also enhanced the invasion of OCUM-2MD3 cells through matrigel and the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP). Time-lapse microscopy showed conversion of OCUM-2MD3 cells from round to more elongated morphology in the presence of Y-27632, suggesting that inhibition of RhoA/ROCK pathway undergo a so-called 'amoeboid to mesenchymal' transition. The fact that Rac1 inhibitor decreased the facilitated invasion by ROCK inhibitor suggested the possibility that increased invasion ability of OCUM-2MD3 cells was related to Rac activity. These data may suggest that RhoA/ROCK regulate plasticity of metastatic gastric carcinoma via mesenchymal-amoeboid transition, leading to provide new insights for designing a new and effective treatment for this type of refractory carcinoma.

Borrmann's macroscopic criteria and p-Smad2 expression are useful predictive prognostic markers for cytology-positive gastric cancer patients without overt peritoneal metastasis.

BACKGROUND: All patients with peritoneal-free cancer cells (CY1) do not always develop a peritoneal recurrence (P1). The goal of this study was to identify characteristic features of peritoneal-free cancer cells that could develop into peritoneal recurrence. METHODS: Of 1,474 patients, 91 were identified with CY1P0, and the remaining 1,383 with CY0P0. Immunohistochemical staining with anti-phosphorylated Smad 2 (p-Smad2) was performed on paraffin-embedded specimens from the 91 CY1P0 patients. RESULTS: CY1 was significantly correlated with Borrmann's type-4 cancer, clinical T stage, and lymph node metastasis. CY1P0 patients with Borrmann's type-4 cancer more frequently develop peritoneal recurrence than do those with other types of tumors. The 5-year survival rate of patients with Borrmann's type-4 tumors was significantly (p = 0.023) low (6.3%) compared with that of patients with other types of tumors (27.7%). The prognosis for p-Smad2-positive patients was significantly poorer than that of p-Smad2-negative patients. In CY1 and/or P1 patients with Borrmann's type-4 tumors, no significant difference in prognosis was identified between those who had surgery and those who did not. CONCLUSIONS: Activated Smad signaling might be associated with a high potential for peritoneal recurrence in CY1P0 patients. Borrmann's macroscopic criteria and p-Smad2 expression are useful markers for surgeons selecting advanced gastric cancer patients with CY1P0 for gastrectomy.

Phosphorylated smad2 in advanced stage gastric carcinoma.

BACKGROUND: Transforming growth factor ß (TGFß) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFß receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages. METHODS: Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas. RESULTS: The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor. CONCLUSION: The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.

Transforming growth factor ß signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity.

The transforming growth factor ß (TGFß) stimulates tumor progression and metastasis. Secretion of TGFß by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFß signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFß receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFß activity.

Combination effect of a TGF-beta receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice.

Transforming growth factor-beta (TGF-beta) signals are closely associated with the distant metastases of gastric cancer. The aim of this study was to clarify the effect of a TGF-beta receptor I (TbetaR-I) phosphorylation inhibitor, Ki26894, in combination with anticancer drugs, on the lymph node (LN) metastasis of scirrhous gastric cancer. A novel TbetaR-I kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at the ATP binding site of TbetaR-I. S1 is a 5-fluorouracil analog. The human scirrhous gastric cancer cell line OCUM-2MLN and the human gastric fibroblasts NF-33 were used. OCUM-2MLM cells in the upper well and NF-33 cells in the lower well were co-incubated with or without Ki26894. The proliferation of OCUM-2MLN cells was significantly stimulated by co-culture with NF-33 cells. Ki26894 significantly suppressed the growth interactions between OCUM-2MLN cells and NF-33 cells. Gastric cancer models established by orthotopic inoculation of OCUM-2MLN cells showed diffusely infiltrating gastric adenocarcinoma accompanied by LN metastases. We divided these mice into four groups, (control vehicle, Ki26894, S1, Ki26894 plus S1), and examined the effect of Ki26894 and/or S1 on phosphorylation of Smad2, tumor size, LN metastases, and lymphatic involvements. Ki26894 inhibited the Smad2 phosphorylation of cancer cells and decreased the extent of lymphatic involvement, compared with the control or S1 only group. The Ki26894 plus S1 administration group significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the TbetaR-I kinase inhibitor with S1 is useful for the treatment of scirrhous gastric carcinoma with LN metastasis. (Cancer Sci 2010).

Plasma pharmacokinetics after combined therapy of gemcitabine and oral S-1 for unresectable pancreatic cancer.

BACKGROUND: The combination of gemcitabine (GEM) and S-1, an oral 5-fluorouracil (5-FU) derivative, has been shown to be a promising regimen for patients with unresectable pancreatic cancer. METHODS: Six patients with advanced pancreatic cancer were enrolled in this pharmacokinetics (PK) study. These patients were treated by oral administration of S-1 30 mg/m2 twice daily for 28 consecutive days, followed by a 14-day rest period and intravenous administration of GEM 800 mg/m2 on days 1, 15 and 29 of each course. The PK parameters of GEM and/or 5-FU after GEM single-administration, S-1 single-administration, and co-administration of GEM with pre-administration of S-1 at 2-h intervals were analyzed. RESULTS: The maximum concentration (Cmax), the area under the curve from the drug administration to the infinite time (AUCinf), and the elimination half-life (T1/2) of GEM were not significantly different between GEM administration with and without S-1. The Cmax, AUCinf, T1/2, and the time required to reach Cmax (Tmax) were not significantly different between S-1 administration with and without GEM. CONCLUSION: There were no interactions between GEM and S-1 regarding plasma PK of GEM and 5-FU.

[A long-term survival case of unresectable intrahepatic cholangiocarcinoma treated with chemotherapy].

An 83-year-old man commuting to our hospital with postoperative ascending colon cancer was pointed out an increase of CA19-9. CT scan revealed an intrahepatic cholangiocarcinoma in the left lobe. In May 2007, an operation was performed. We recognized a lymph node swelling in the hepatoduodenal ligament. Pathologically, it was moderately differentiated adenocarcinoma. Therefore, the operation did only the cholecystectomy. Gemcitabine was administered once a week for 3 weeks followed by a week rest. It was administered for about 20 months and the evaluation during the period was PR or SD. Afterwards, the tumor had increased gradually. Gemcitabine was changed to S-1. Then, S-1 was changed to gemcitabine again because the enlargement of the tumor and the rise of tumor markers were observed. Consequently, tumor markers decreased. Now, the patient is under an outpatient care maintaining ADL.

In vitro and in vivo evidence that a combination of lapatinib plus S-1 is a promising treatment for pancreatic cancer.

Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S-1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca-2, PANC-1, Capan-1 and Capan-2 was measured by flow cytometry. The anti-tumor effects of lapatinib (30 mg/kg) and/or S-1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S-1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti-human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti-tumor effect of lapatinib in vivo. Lapatinib synergized with S-1 to inhibit the tumor growth of MiaPaca-2 and PANC-1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti-tumor activity of the S-1 components 5-fluorouracil and 5-chloro-2,4-dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S-1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules.

Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma.

Scirrhous gastric carcinoma (SGC) carries the highest mortality because of a frequent metastasis to lymph node (LN). S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at an advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of SGC. The objective of this study is to clarify the benefit of a combination of S1 and kinase inhibitors including FGFR2 inhibitor Ki23057 in gastric cancer. OCUM-2MLN and KATO-III were derived from SGC. MKN-7 and MKN-74 were derived from non-SGC. MTT assay was used to examine the growth-inhibitory activity of 5 small-synthetic molecules including Ki23057, Sunitinib, Glivec, Lapatinib or SU11274, in cells cultured with 5-FU. Combination effects of 5-FU with Ki23057 on proliferation, apoptosis and mRNA expression were examined. S1 and/or Ki23057 were administered to murine models of SGC created by the orthotopic inoculation of OCUM-2MLN cells. Ki23057 at 100 nM significantly (p < 0.01) inhibited the proliferation and decreased the phosphorylation of FGFR2 in SGC cells, but not in non-SGC. Ki23057 showed synergistic antitumor effects for SGC cells in combination with 5-FU using CalcuSyn analysis, but Sunitinib, Glivec, Lapatinib and SU11274 did not. The combination of Ki23057 and 5-FU decreased DPD expression and increased apoptosis rates and p21 expression level of SGC cells. The combined administration of S1 and Ki23057 significantly (p < 0.05) decreased orthotopic tumors as well as LN metastasis more effectively than S1 alone. These findings suggested that the combined treatment with 5-FU and Ki23057 produced synergistic antitumor effects and is therapeutically promising for SGC treatment.

Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma.

Cancer stem cells (CSCs) are considered to be responsible for cancer metastasis, but the evidence to conclusively prove this hypothesis remains uncertain. The side population (SP), as evaluated by a flow cytometric analysis using Hoechst 33342, has been known as CSC-rich population. The aim of this study was to clarify the characterization of the SP cells in peritoneal metastasis of gastric carcinoma. Gastric cancer cell lines OCUM-2M, OCUM-2D, and OCUM-2MD3 (a daughter cell line with high potential for peritoneal metastasis) were used. We isolated SP cells from OCUM-2M and OCUM-2D using flow cytometry. Serial sorting was performed three times to enrich SP cells, and they were designated as OCUM-2M/SP and OCUM-2D/SP cells. Flow cytometric analysis showed 0.46%, 0.29%, 5.24%, 6.49%, and 11.3% of the SP cells to be found in OCUM-2M, OCUM-2D, OCUM-2MD3, OCUM-2M/SP, and OCUM-2D/SP cells, respectively. The intraperitoneal inoculation of SP cells and OCUM-2MD3 cells produced peritoneal metastasis, but parent cells did not. The adhesion ability of SP and OCUM-2MD3 cells was significantly high in comparison to that of parent cells. The expression level of adhesion molecules alpha2-, alpha5-, beta3-, and beta5-integrin, and CD44, was high in SP cells compared to parent cells. The expression of stemness markers, Oct3/4 and Sox2, increased in the SP-cell-injected tumors. These findings suggested that CSC-like SP cells expressing alpha2-, alpha5-, beta3-, and beta5-integrin, and CD44, may play an important role for peritoneal metastasis in gastric carcinoma. Oct3/4 and Sox2 may be associated with CSC in gastric cancer.

Expression of ERas oncogene in gastric carcinoma.

BACKGROUND: Embryonic stem cell expressed Ras (ERas) oncogene is associated with the tumorigenicity of embryonic stem cells. The aim of this study was to clarify the significance of ERas expression in clinical samples of gastric carcinomas. MATERIALS AND METHODS: Three hundred and few tissues from gastric cancer patients were analyzed by immunohistochemical techniques using an anti-ERas antibody. ERas mRNA expression in 77 gastric carcinomas was examined by reverse-transcription polymerase chain reaction. RESULTS: ERas expression was positive in 135 (44%) of 304 gastric carcinomas. ERas-positive expression had a significant relationship with invasion depth (p<0.01), histological type (p<0.01), clinical stage (p=0.013) and curability (p=0.001). Prognosis of ERas-negative patients was significantly (p=0.029) poorer than that of ERas-positive patients, while ERas was not an independent prognostic factor. Expression of ERas mRNA was found in 35 (45%) out of 77 gastric cancer tissues. CONCLUSION: ERas oncogene is associated with the tumorigenic process of human gastric carcinomas.

DNA methyltransferase inhibitor 5-aza-CdR enhances the radiosensitivity of gastric cancer cells.

The National Comprehensive Cancer Network guidelines recommend radiotherapy as a standard treatment for patients with a high risk of recurrence in gastric cancer. Because radiation is harmful to the surrounding organs, a radiation sensitizer might therefore be useful to decrease the side effects of patients with advanced gastric carcinoma. The aim of the current study was to clarify the effect of a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (CdR), on radiation sensitivity in gastric cancer cells. Five gastric cancer cell lines, OCUM-2M, OCUM-12, KATO-III, MKN-45, and MKN-74, were used. The effects of 5-aza-CdR with irradiation on the growth activity, cell-cycle distribution, apoptosis, and apoptosis-associated gene expression were examined. 5-aza-CdR sensitized three of five gastric cancer cell lines to radiation. A combination of irradiation and 5-aza-CdR significantly (P<0.05) decreased the growth activity compared with irradiation alone in OCUM-2M, OCUM-12, and MKN-45 cells, but not in KATO-III and MKN-74 cells. The percentage of cells in G2-M phase and the apoptotic rate with irradiation in combination with 5-aza-CdR were increased in OCUM-2M, OCUM-12, and MKN-45 cells compared with irradiation alone, but not in KATO-III and MKN-74 cells. 5-aza-CdR increased the expression of p53, RASSF1, and death-associated protein kinases (DAPK) genes compared with the control or irradiation alone. These findings suggest that 5-aza-CdR might therefore be useful as a radiation sensitizer to treat some types of gastric carcinoma. The arrest at G2-M phase and increased apoptotic rate might be partly mediated by enhanced expression of the p53, RASSF1, or DAPK gene families by 5-aza-CdR.

A novel transforming growth factor beta receptor kinase inhibitor, A-77, prevents the peritoneal dissemination of scirrhous gastric carcinoma.

PURPOSE: Transforming growth factor beta receptor (TGFbeta-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFbeta-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer. EXPERIMENTAL DESIGN: Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro. RESULTS: The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of alpha(2), alpha(3), and alpha(5) integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells. CONCLUSION: The TGFbeta-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma.

[Efficacy of m-FOLFOX6 therapy for colorectal cancer in elderly patients].

Combination chemotherapy of oxaliplatin, fluorouracil/leucovorin (FOLFOX) has reportedly become a standard regimen for colorectal cancer. In this study, we investigated the efficacies and adverse effects of modified FOLFOX6 (m-FOLFOX6) regimen in elderly patients. Thirty-nine patients with colorectal cancer, who received m-FOLFOX6 in our institution, were studied. Ten of the 39 patients, were older than 70 (elderly patients). Efficacies and adverse effects of m-FOLFOX6 were compared between patients over 70 years of age and those younger than 69 (younger patients). In terms of the response rate, there were no differences between the older and younger elderly patients. Moreover, the grade and frequency of adverse events were similar between them. We concluded that m-FOLFOX6 may bring about the same response rate in older and younger elderly patients. Moreover, m-FOLFOX6 may be given safely regardless of patient age.