北山 丈二

Background: Intraperitoneal administration of paclitaxel (PTX) can elicit a marked clinical response in peritoneal metastases of gastric cancer. Methods: In this study, we retrospectively analyzed the clinical outcome of 17 patients who underwent R0 resection with D2 dissection for advanced gastric cancer with macroscopic serosal exposure and received intraperitoneal PTX as adjuvant therapy. Results: A pathological study revealed that the depth of invasion of the primary tumor was pT4a or pT4b in 10 cases, and that the pN stage was more than pN2 in 8 cases. Genetic analysis of peritoneal lavage fluid was performed in 14 cases, all of which were positive for carcinoembryonic antigen mRNA. In these patients, PTX was intraperitoneally administered at 20-60 mg/m2 with oral S-1 for 3-36 months after surgery. In a median follow-up period of 66 months, recurrence occurred in the liver and peritoneum in 2 (11.7%) and 1 (5.9%) patients, respectively, and no nodal recurrence was observed. Five-year overall survival and disease-free survival were 88.2 and 82.3%, respectively. Conclusion: Since these patients are considered to be a high-risk group for peritoneal recurrence, this result strongly suggests that adjuvant chemotherapy including intraperitoneal PTX is a promising protocol to improve the outcome of patients with advanced gastric cancer with serosal exposure. © 2014 S. Karger AG, Basel.

Background: Right-sided colon cancer is considered to be biologically different from left-sided colon cancer; however, conflicting results have been reported regarding differences in prognosis. We aimed to clarify the prognostic impact of tumor location in stage IV colon cancer. Methods: Stage IV colon cancer treated from January 1997 to December 2007 (n = 2208) were retrospectively studied. Clinical and pathological features were compared between right-sided colon cancer (cecum, ascending, and transverse colon) and left-sided colon cancer (descending, sigmoid, and rectosigmoid colon). The impact of tumor location on cancer-specific survival (CSS) was analyzed in a multivariate analysis and propensity score analysis to mitigate the differences in background features. Results: Right-sided colon cancer was associated with older age, female sex, larger tumor size, poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma, a more advanced state within stage IV disease, and a worse CSS. In the cohort matched by propensity scores for background clinicopathological features, tumor location in the right-sided colon was associated with a significantly worse CSS (hazard ratio 1.2, 95% confidence interval 1.1-1.4, p = 0.008) in patients treated with palliative primary tumor resection, but not in those treated with R0 resection or no resection. Conclusion: Right-sided colon cancer were diagnosed at a more advanced state within stage IV disease and showed a significantly worse prognosis than left-sided colon cancer, suggesting that stage IV right-sided colon cancer is oncologically more aggressive than left-sided colon cancer. (C) 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Background: The identification of responders is an important issue in chemotherapy for metastatic colorectal cancer (mCRC). 'Deepness of response' (DpR), defined as the maximum rate of reduction from the initial tumor burden, was recently proposed as a novel hypothetical parameter associated with overall survival (OS) in first-line chemotherapy plus cetuximab for mCRC. We determined whether this concept was universally applicable to diverse standard chemotherapeutic regimens for mCRC. Methods: We reviewed mCRC patients who received the first-line systemic chemotherapy regimens FOLFOX, CapeOX or FOLFIRI (with biologics) at our department between June 2005 and March 2015. Data such as clinicopathological parameters, metastasized organs, chemotherapeutic regimens, the best response by RECIST v1.1, progression-free survival (PFS) and OS were retrospectively retrieved for patients who exhibited tumor shrinkage. DpR was calculated as the uni-dimensional maximum reduction rate of measurable tumors. We addressed the association between DpR and survival. Results: Of the 156 patients receiving first-line chemotherapy regimens, tumor shrinkage was observed in 63 (41 of whom were men; median age 62 years). Complete remission was achieved in 6 patients, partial remission in 42 and stable disease in 15. The median DpR was 44.2% and was employed as the cutoff, in line with previous reports. DpR >= 45% (31 patients) was correlated with longer PFS (median 16.4 vs. 8.1 months for DpR <45%, p = 0.006) and OS (median 58.6 vs. 30.9 months for DpR <45%, p = 0.041). There was basically no difference in the subsequent chemotherapy between the DpR >= 45% and DpR <45% groups. Conclusion: DpR correlated with OS in various first-line systemic upfront chemotherapy regimens for mCRC. (C) 2015 S. Karger AG, Basel

The tumor suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumors. APC stimulates the activity of the Cdc42- and Rac1-specific guanine nucleotide exchange factor Asef and promotes the migration and invasion of colorectal tumor cells. Furthermore, Asef is overexpressed in colorectal tumors and is required for colorectal tumorigenesis. It is also known that NOTCH signaling plays critical roles in colorectal tumorigenesis and fate determination of intestinal progenitor cells. Here we show that NOTCH3 up-regulates Asef expression by activating the Asef promoter in colorectal tumor cells. Moreover, we demonstrate that microRNA-1 (miR-1) is down-regulated in colorectal tumors and that miR-1 has the potential to suppress NOTCH3 expression through direct binding to its 3'-UTR region. These results suggest that the miR-1-NOTCH3-Asef pathway is important for colorectal tumor cell migration and may be a promising molecular target for the treatment of colorectal tumors.

As no treatment method has a sufficient level of evidence of success in the treatment of gastric cancer with peritoneal metastasis, there is an urgent need to develop a new treatment that takes into account the pathophysiology of the disease. A novel multidisciplinary treatment approach combining intraperitoneal (IP) paditaxel (PTX), systemic chemotherapy, and gastrectomy is one of the promising treatment options. We designed a combination chemotherapy regimen of S-1, weekly intravenous and IP PTX and determined the recommended dose in a phase I study. In the phase II study, the median survival time (MST) was 23.6 months. Out of 100 patients treated with this regimen, we performed gastrectomy on 62 patients after disappearance or obvious shrinkage of the peritoneal metastasis, and the MST was 34.5 months. Currently, we are carrying out a phase III trial (PHOENIX-GC trial) comparing our IP regimen to S-1 plus CDDP.

BACKGROUND The prognosis of patients with gastric cancer with peritoneal metastasis is extremely poor. This phase 2 study evaluated the benefits and tolerability of weekly intravenous and intraperitoneal paclitaxel (PTX) treatment combined with oral S-1 in patients with gastric cancer who had macroscopic peritoneal metastasis. METHODS Patients with gastric cancer who had primary tumors with macroscopic peritoneal metastasis were enrolled. PTX was administered intravenously at 50 mg/m(2) and intraperitoneally at 20 mg/m(2) on days 1 and 8, respectively. S-1 was administered at 80 mg/m(2) per day for 14 consecutive days, followed by 7 days of rest. The primary endpoint was the 1-year overall survival (OS) rate. The secondary endpoints were the response rate, efficacy against malignant ascites, and safety. RESULTS Thirty-five patients were enrolled. The median number of treatment courses was 11 (range, 2-35). The 1-year OS rate was 77.1% (95% confidence interval, 60.5-88.1). The overall response rate was 71% in 7 patients with target lesions. Malignant ascites disappeared or decreased in 15 of 22 (68%) patients. The frequent grade 3/4 toxic effects were neutropenia (34%), leukopenia (23%), and anemia (9%). CONCLUSIONS Combination chemotherapy consisting of intravenous and intraperitoneal PTX with S-1 is well-tolerated and effective in patients with gastric cancer who have macroscopic peritoneal metastasis. Cancer 2013;119:3354-8. (c) 2013 American Cancer Society.

Both hepatic steatosis (HS) and colorectal cancer (CRC) are conditions associated with metabolic syndrome. The liver is the most frequent site of distant metastasis of CRC; however, the impact of HS on the incidence of liver metastasis of CRC is not clearly defined. Then, the correlation with the presence or absence of HS was analyzed. A total of 604 CRC patients receiving curative surgical resection who had a preoperative non-enhanced computed tomography (CT) were enrolled. The mean attenuation values (in Hounsfield units) of the liver and spleen were obtained on a plain CT slice, and the patients with liver-spleen attenuation ratio lower than 1.1 were objectively defined as HS. The clinicopathological features of these patients were analyzed, and the association between HS and the clinical features of CRC was examined. Sixty-three (10.4 %) among the 604 patients were diagnosed as HS. Recurrence-free survival (RFS) and hepatic RFS, but not extrahepatic RFS, were significantly higher in the group with HS (p = 0.04 and p = 0.006). However, this effect was not evident in the group of patients with obesity, defined as body mass index > 25.0. Among the stage I similar to III cases, HS was significantly associated with lower hepatic, but not extrahepatic, RFS. Moreover, absence of HS was an independent risk factor for hepatic RFS (p = 0.003). Metastases of CRC are less frequent in fatty liver. Steatosis may be an unfavorable microenvironment for metastatic formation in the liver.

Background: A hypoxic environment exists in most solid tumors because in rapidly growing tumors, the development of angiogenic vasculature is heterogenous, usually not enough to overcome the necessary oxygen supply. In an ischemic condition, cancer cells develop escape mechanisms to survive and leave the unfavorable environment. That result in the acquisition of increased potential for local invasion and evasion to distant organs. However, the escapemechanisms of cancer cells from hypoxic stress have not been fully characterized. Materials and methods: The human colon cancer cell line LoVo was cultured in hypoxia, and the adhesive and migratory properties were analyzed. The expression of cell surface and cytoplasmic molecules was also investigated. Results: Under hypoxic conditions, cells developed epithelial-mesenchymal transition. The expression levels of alpha 2, alpha 5, and beta 1 integrins were significantly upregulated and, as a consequence, the ability to adhere to and migrate on collagen and fibronectin was increased. On the other hand, the expression of 67-kDa laminin receptor and the abilities to adhere to and migrate on laminin were decreased. Additionally, the expression of CXCR4 was significantly increased on cells cultured in hypoxia, and the chemotactic activity to stromal cell-derived factor 1 alpha was remarkably increased. Conclusions: Hypoxic stress induced active epithelial-mesenchymal transition in colon cancer cells, with the typical morphologic and functional changes. These morphologic and functional changes of b1 integrins, the 67-kDa laminin receptor, and CXCR4 may be essential for the acquisition of the invasive and metastatic features in colorectal cancer. (C) 2013 Elsevier Inc. All rights reserved.

Background/Aims: Perianal adenocarcinoma associated with anal fistula is a rare disease with a poor prognosis. The relatively small number of patients with this disease has led to a lack of any consensus regarding diagnosis and appropriate treatment. The purpose of this study was to present our experience of 11 cases of this disease, and to highlight its clinical features, treatments and outcomes. Methodology: The patients were divided into three groups according to the modality of treatment. Four patients received surgical resection without preoperative therapy (operation group), 3 patients were treated with radiotherapy prior to surgery (RT group), and 4 were treated with combined chemoradiation therapy prior to surgery (CRT group). Results: The resection stump was pathologically negative for cancer in 6 (85.7%) patients in RT or CRT group, and 3 of 6 are alive with no evidence of disease recurrence. However, the resection stump was negative in only 1 (25%) patient in the operation group. Moreover, among the patients who underwent neoadjuvant RT/CRT and abdominoperineal resection with a cancer-free resection stump, 2 patients with postoperative adjuvant therapy had no recurrence of disease. Conclusions: Multimodality therapy including neoadjuvant RT or CRT and adjuvant chemotherapy is considered to be effective for treatment of this disease.

Although thrombocytosis has been reported in patients with various cancers including the colorectal one, the impact of elevated platelet counts on the response to chemoradiotherapy (CRT) for rectal cancer has not been fully investigated. We investigated the clinical significance of pre- and post-CRT platelet counts in patients with rectal cancer. The medical records of 101 patients with rectal cancer, who had received CRT followed by surgical resection, were retrospectively reviewed. The correlations between the clinicopathological variables and the pre- or post-CRT platelet counts were analyzed. The correlations between tumor regression rate induced by CRT, as evaluated by barium enema and pathological examination, and the pre- or post-CRT platelet counts were also evaluated. Finally, the impact of pre-CRT thrombocytosis on the prognosis of these patients was assessed. The pre-CRT platelet count correlated with venous invasion and tumor size, and it strongly correlated with the response rate evaluated by barium enema and the grade of pathological tumor regression. Furthermore, patients with pre-CRT thrombocytosis had significantly shorter local recurrence-free survival. Platelet count before CRT should be a promising biomarker for predicting the efficacy of CRT and the risk of local recurrence in rectal cancer patients after CRT.

Among the secretory phospholipase A2s (sPLA2), sPLA2 group X (PLA2GX) has the most potent hydrolyzing activity toward phosphatidylcholine, and has recently been shown to be implicated in chronic inflammatory diseases. The aim of the present study was-to investigate PLA2GX expression in colorectal cancer (CRC) and its correlation with patient clinicopathological features. The present study comprises a series of 158 patients who underwent surgical resection for primary CRC. PLA2GX expression in CRC tissues was examined by immunohistochemistry and compared with patient clinicopathological findings and survival. A total of 64% of the tumors expressed PLA2GX at high levels. Statistical analysis revealed that PLA2GX expression was inversely correlated with hematogenous metastasis (P=0.005). In the subgroup analysis, left-sided tumors with high PLA2GX expression showed an inverse correlation with lymph node metastasis (P=0.018) and hematogenous metastasis (P=0.017). Patients with high PLA2GX expression tended to have a longer disease-specific survival compared with those with low PLA2GX expression in left-sided, but not right-sided, CRC (P=0.08). In light of the present results, we suggest that PLA2GX has an inhibitory effect on the progression of CRC.

A 63-year-old man underwent a colectomy for sigmoid colon cancer in 1997. The upper lobe of his left lung and his left adrenal gland were resected because of metachronous metastases, 7 and 10 years after the initial surgery, respectively. Recurrence of metastases to the middle lobe of the right lung and left adrenal gland were sequentially detected in 2007, and a multimodal therapy, consisting of the combination of radiotherapy and chemotherapy, was conducted since 2007. The chemotherapy included drugs such as FOLFOX, FOLFIRI, bevacizumab, capecitabine, and cetuximab. In 2011, the complete response of all metastatic lesions could be achieved, and no recurrence was detected for more than 1 year. In spite of repeated recurrences, by the combination of surgical resection, chemotherapy, and radiotherapy, the complete response could be achieved 14 years after the initial surgical resection, which can be attributed to the development of new treatment modalities and new agents for colorectal cancer.

CD133 has been identified as a putative cancer stem cell (CSC) marker in various cancers including colorectal cancer. The relation between CD133 expression and biological characteristics of colorectal cancer remains to be clarified. Protein expression of CD133 was immunohistochemically evaluated in surgical specimens of 225 patients with colorectal cancer who were treated by surgery, as well as those of 78 patients with rectal cancer who received preoperative chemoradiotherapy (CRT) followed by curative resection. The correlation between CD133 expression and clinicopathological features, tumor recurrence and overall survival was analyzed in both populations. Among 225 colorectal cancers without CRT, 93 (41.3%) were positive for CD133 expression, which was enhanced in cases with advanced T stage and venous invasion. Moreover, CD133 was positive in 47 (60.3%) of 78 cases with CRT, which was significantly higher than the CD133-positive rate in non-CRT specimens (P = 0.05). Expression of CD133 was independently correlated with the histological tumor regression grade (P < 0.01). These results suggest that CD133 is not a distinctive colorectal CSC marker; expression of CD133 is suggested to be one of the key factors associated with resistance to CRT in colorectal cancer.

Background and Aim: Gastrointestinal (GI) luminal obstruction or malignant biliary obstruction (MBO) is not a rare condition in gastric cancer patients with peritoneal metastasis. The role of endoscopic or percutaneous interventions is not fully elucidated in this setting. Methods: A total of 123 patients with unresectable or recurrent gastric adenocarcinoma with peritoneal metastasis receiving intravenous and intraperitoneal paclitaxel combined with S-1 were retrospectively studied. Safety and efficacy of interventions for GI luminal obstruction and MBO were evaluated. Results: A total of 27 patients (22%) underwent GI luminal and/or biliary interventions; GI luminal alone in 10, biliary alone in 10 and both in seven, with a technical success rate of 100%. Clinical success rate was 65% in self-expandable metallic stents (SEMS) placement for GI luminal obstruction. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was prognostic of clinical success in GI luminal stenting (100% in PS of 1 vs 14% in PS of 23, P?<?0.001). Biliary drainage (endoscopic SEMS placement in four and percutaneous transhepatic biliary drainage in 12) relieved obstructive jaundice in 94%. Six complications were observed: four after GI luminal stenting (two occlusion and one aspiration pneumonia) and two after biliary stenting (one cholangitis and one cholecystitis). Median survival after the initial intervention was 5.7?months. PS at interventions was prognostic of survival after interventions (12.3?months in PS of 1 vs 2.2?months in PS of 2 or 3, P?<?0.001). Conclusion: Endoscopic or percutaneous interventions for GI luminal obstruction or MBO were feasible and effective in gastric cancer patients with peritoneal dissemination receiving combination chemotherapy.

The efficacy of intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis has been verified by clinical trials. To perform intraperitoneal chemotherapy safely and effectively, the appropriate management of intraperitoneal access ports is essential. The aim of this study was to investigate the occurrence of port complications during cyclically repeated intraperitoneal chemotherapy. The medical records of 131 gastric cancer patients with peritoneal metastases who received intraperitoneal paclitaxel between 2005 and 2011 were retrospectively analyzed. The median period of intraperitoneal chemotherapy using a port system was 12.9 months (range: 0.861.5 months), and a total of 27 (20.6) patients experienced port complications. Inflow obstruction (7.6) and infection (6.9) were the main complications, followed by reflux (3.1), subcutaneous masses (1.5) and fistulae (1.5). The median interval between port implantation and port complication was 5.4 months (range: 0.340.9 months). Complications were controllable and chemotherapy was not terminated by complications. Survival was not affected by the presence or absence of port complications (median survival time: 22.5 vs. 17.2 months, respectively; P 0.65). Intraperitoneal chemotherapy for gastric cancer using a port is safe and feasible under appropriate management.

Malignant tumors are often associated with denervation, suggesting the functional implication of axonal guidance molecules in tumor growth. Here, we assessed the role of semaphorin 3C (sema3C) in the progression of gastric cancer. Immunohistochemistry of human samples revealed that sema3C was strongly expressed in neoplastic cells, especially at the invasion front. Stable transfection of target sequences of sema3C miRNA did not affect the in vitro proliferative activity of human gastric cancer AZ-521 cells. However, when the tumor growth was examined in vivo using an orthotopic model in nude mice, primary stomach tumors as well as metastatic liver tumors were significantly suppressed by sema3C silencing with the reduction of microvessel density. Immunostaining of primary tumor indicated the rate of Ki-67 positive carcinoma cells was decreased, whereas that of apoptotic cells was significantly increased in sema3C-silenced tumor. In addition, capillary-like tubular formation was reduced by the addition of culture media of sema3C miRNA cells compared with the media of control miRNA cells. Semaphorin 3C is positively expressed in gastric cancer cells and may be involved in tumor progression, presumably through the stimulation of angiogenesis. (Cancer Sci 2012; 103: 1961-1966)

BACKGROUND: Chronic kidney disease, a disease entity increasing in number, may be an obstacle in various aspects of treatment for malignant neoplasm, such as perisurgical management and implementation of chemotherapy. OBJECTIVE: The aim of this study was to evaluate both short- and long-term outcomes of patients with colorectal cancer who have chronic kidney disease. DESIGN: This study is a retrospective cohort study of patients. SETTINGS: This study as conducted at an academic tertiary hospital in Japan. PATIENTS AND INTERVENTIONS: We investigated 1127 consecutive patients with stages 0 to III primary colorectal cancer who underwent curative resection in our department from January 2001 to December 2010. Based on estimated glomerular filtration rate, patients were classified into stages 0 to 2 (including normal renal function, 882 patients, 78.2%), stages 3 to 4 (226 patients, 20.1%), or stage 5 chronic kidney disease (19 patients, 1.7%). MAIN OUTCOME MEASURES: Clinicopathological data, perioperative course, frequencies of postoperative complications, adjuvant chemotherapy, and recurrence-free and overall survivals after surgery for colorectal cancer were compared among the 3 different chronic kidney disease stage groups. RESULTS: Patients with chronic kidney disease stage 5 frequently experienced diabetes mellitus and cardiovascular comorbidities. They were also hypoalbuminemic and anemic and more likely to receive blood transfusions, although estimated blood loss was smaller during surgery than in the other patients. Perioperative cardiovascular complications were more frequent in the chronic kidney disease stages 3 to 4 and 5 groups (5.3%) than those in the stages 0 to 2 group (0.8%, p < 0.0001). However, the frequencies of other complications were similar. There were no differences in the frequency of adjuvant chemotherapy and recurrence-free survival among different chronic kidney disease stages; in contrast, the chronic kidney disease stage 5 group showed a poorer overall survival. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: From these data, we conclude that surgical resection for colorectal cancer in patients with chronic kidney disease can be performed with acceptable outcomes.

Although it is known that those patients who have developed colorectal cancer (CRC) are at a higher risk to develop metachronous adenoma or CRC, no study has been performed to analyze the relationship between the risk factors and the time course for the formation of postoperative adenoma using survival analysis. One hundred seventy-six patients with CRC, who had received surgical resection, were endoscopically followed-up to detect the development of metachronous adenoma or adenocarcinoama. The association between the risk factors such as age, synchronous adenomas with index CRC or other clinicopathological variables and the formation of postoperative adenoma was assessed using the logrank test and the Cox proportional hazard model. Age over 60, synchronous lesions at the time of surgery for primary CRCs and presence of diabetes mellitus (DM) as the associated disease were positively related to the formation of postoperative adenoma. Among those patients with the three risk factors, only 27.8% remained adenoma-free during 5 years after operation, whereas in the group without any risk factor, it was 90.4%. From our data, age over 60, synchronous adenomas or CRCs and DM were the potential risk factors for the postoperative formation of adenoma or CRC, and they should be taken into consideration when defining the appropriate interval of postoperative colonoscopy.

Autophagy is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemotherapy. Recently, chloroquine diphosphate (CQ), a widely used antimalarial drug, has been studied as a potential inhibitor of autophagy. Here, we aimed to investigate the role of CQ in potentiating the effect of 5-fluorouracil (5-FU), the chemotherapeutic agent of first choice for the treatment of colorectal cancer, in an animal model of colon cancer. The mouse colon cancer cell line colon26 was used. For the in-vivo study, colon26 cells were injected subcutaneously into BALB/c mice, which were treated with saline as a control, CQ (50 mg/kg/day), 5-FU (30 mg/kg/day), or the combination therapy (CQ plus 5-FU). The tumor volume ratio and body weight were monitored. After the sacrifice, tumor tissue protein extracts and tumor sections were prepared and subjected to immunoblotting for the analysis of autophagy-related and apoptosis-related proteins, and the terminal transferase uridyl end labeling assay. The combination of CQ resulted in the inhibition of 5-FU-induced autophagy and a significant enhancement in the 5-FU-induced inhibition of tumor growth. Furthermore, the combination treatment of CQ and 5-FU resulted in a significant increase in the ratio of apoptotic cells compared with other treatments. The expression levels of the proapoptotic proteins, namely Bad and Bax, were increased by the CQ treatment in the protein extracts from tumors. Our findings suggest that the combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of colorectal cancer. Anti-Cancer Drugs 23:675-682 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The intraperitoneal administration of paclitaxel has been shown to be a promising treatment strategy for peritoneal malignancy. The present study evaluated the effects of intraperitoneal administration of NK105, a paclitaxel-incorporating micellar nanoparticle, which has been shown to have a remarkable effect in a mouse model of gastric cancer. Intraperitoneal NK105 significantly reduced peritoneal tumors in vivo compared with the conventional paclitaxel formulation of paclitaxel solubilized in Cremophor EL and ethanol (PTX-Cre). Moreover, intraperitoneal NK105 significantly reduced the size of subcutaneously inoculated tumors, whereas no such effect was seen with PTX-Cre. Similar systemic toxic effects were observed following the intraperitoneal administration of both NK105 and PTX-Cre. Although NK105 disappeared rapidly almost within a day from the peritoneal cavity, the paclitaxel concentration in peritoneal nodules 4h after intraperitoneal administration was significantly higher in the NK105 group than in the PTX-Cre group (P<0.05), whereas there were no significant differences in liver paclitaxel concentrations between the two groups. We also evaluated the pharmacokinetics following intraperitoneal administration of NK105 and PTX-Cre. Serum paclitaxel concentrations 6, 12, 24, and 48h after the intraperitoneal administration of the drugs were significantly higher in the NK105 than the PTX-Cre group. Furthermore, the peak serum concentration was higher in the NK105 than PTX-Cre group (24100 +/- 3560 vs 108 +/- 25 similar to ng/mL, respectively; P<0.001), as was the area under the concentrationtime curve from 0 to 48h (191000 +/- 32100 vs 1500 +/- 108ng center dot h/mL, respectively; P<0.001). Therefore, intraperitoneal chemotherapy with nanoparticulate paclitaxel NK105 may offer a novel treatment strategy for improving drug delivery in gastric cancer with peritoneal dissemination because of enhanced drug penetration into peritoneal nodules and its prolonged presence in the systemic circulation. (Cancer Sci 2012; 103: 13041310)

Liver-transplant patients have an increased risk of developing primary malignancies, possibly due to prolonged immunosuppression. However, no information on the incidence and biological characteristics of colorectal cancer after living-donor liver transplantation is available. The medical records of 392 consecutive adult patients who had undergone living-donor liver transplantation were retrospectively analyzed. Colorectal cancer developed in 6 (1.5) patients; 3 of 204 (1.5) presented with hepatic cirrhosis, 2 of 77 (2.5) with primary biliary cirrhosis and 1 (2.6) of 39 with subacute fulminant hepatitis, but none of 13 patients with primary sclerosing cholangitis. Four patients were successfully treated with curative surgery and one with endoscopic resection, while another patient died 3 months after palliative surgery because of the progression of peritoneal metastasis. A pathological study revealed vessel invasion in all the five cases of surgically removed colorectal cancer and nodal metastasis in four (80) cases. Colorectal cancer develops at a relatively high frequency after living-donor liver transplantation, even in non-primary sclerosing cholangitis cases, and might have high malignant potential. The screening program for colorectal cancer should be more intensified after living-donor liver transplantation compared with that in the general population.

Introduction: Although neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer (RC), markers predicting response have not been adequately defined. Patients and Methods: In 73 cases with advanced RC, we evaluated the tumor response with the reduction rate of the longitudinal size of RC using barium enema image taken before and after CRT. Then, we retrospectively examined the association with various blood values taken before CRT. The tumor size reduction rate was significantly greater in ten CR cases than in 63 non-CR cases (p&lt 0.001). Results: Interestingly, the size reduction ratio was positively associated with hemoglobin, albumin level and lymphocyte percentage in leukocytes, while being negatively associated with platelet counts, C-reactive protein and fibrinogen levels as well as neutropliles percentage. Moreover, high lymphocyte counts (&gt 1,800/mm3) had an independent association with disease-free survival. Conclusions: Blood data have a major impact on the tumor response to CRT. Control of host condition may improve the effectiveness of CRT in advanced RC. © Springer Science+Business Media, LLC 2011.

Background/Aims: Although preservation of the vaguas nerve is recommended in surgery for early-stage gastric cancer, the physiological effect of vagotomy on the postoperative course has not been well documented. We assessed the effect of vagotomy on the change in fat volume after gastrectomy. Methodology: Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in computed tomographic images taken before and more than 6 months after surgery, using Fat Scan software. The ratios of postoperative/preoperative values of these two fat areas as well as body weight were calculated in 45 patients who underwent DG with (n=24) or without (n=21) vagotomy. Results: Vagotomy did not affect the change in body weight (91.3 +/- 1.7% vs. 92.1 +/- 1.7%). In patients with vagotomy, VFA was reduced to 59.0 +/- 5.1%, which was significantly greater than the reduction in SFA (74.3 +/- 8.7%, p=0.042). In contrast, the reduction ratios of VFA and SFA were equal in vagus nerve-preserved patients (78.4 +/- 6.7% vs. 78.2 +/- 6.9%, p=0.97). Conclusions: The vagus nerve may have a function to locally regulate the intra-abdominal fat volume and preservation of the vagus nerve results in the maintenance of visceral fat after DG.

Serum tumor markers have been shown to correlate with the clinical status of patients with advanced gastric cancer. However, the clinical significance of each tumor marker in patients with peritoneal dissemination has not been fully verified. Four serum markers, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA125, and CA72-4, were periodically measured in 102 patients with peritoneal dissemination who received combination intravenous and intraperitoneal chemotherapy. The initial values at diagnosis and after treatment were analyzed in association with clinicopathological factors, response to chemotherapy, and overall survival. The sensitivities of CEA, CA19-9, CA125, and CA72-4 for peritoneal metastasis at the initial diagnosis were 19, 36, 46, and 45%, respectively. The CA125 level was significantly correlated with the degree of peritoneal dissemination and the existence of malignant ascites. Patients with ovarian metastasis showed significantly higher levels of CA72-4. The median survival time of patients with an elevated CA125 level was significantly shorter than that of patients with a normal CA125 level (36.7 vs. 16.6 months, p < 0.001). Multivariate analysis showed that the degree of peritoneal metastasis and an elevated CA125 level were independent prognostic factors. Normalization of the CA125 level after 3 courses of chemotherapy was correlated with reduced ascites and improved survival. Serum CA125 and CA72-4 are clinically useful markers in diagnosis, evaluating the efficacy of chemotherapy, and predicting the prognosis of patients with peritoneal dissemination. From an academic point of view, periodic measurements of these markers are warranted in gastric cancer patients with possible peritoneal dissemination.

Adiponectin is a hormone secreted by adipose tissue and has a variety of functions including the inhibition of tumor growth. The expression and function of the two major adiponectin receptors, AdipoR1 and AdipoR2, in malignant tissue have not been well characterized. In the present study, we evaluated the mRNA levels of AdipoR1 and AdipoR2 expression in 48 surgically resected colorectal cancer specimens, as well as normal colonic mucosa, by quantitative RT-PCR. The values obtained were standardized by beta-actin m RNA, and the correlation between their relative expression levels and the clinicopathological characteristics of the patients was examined. The relative expression levels of AdipoR1 and AdipoR2 were significantly reduced in cancer tissue compared with normal tissue (AdipoR1: 0.97 +/- 0.39 vs. 1.37 +/- 0.41, P<0.0001; AdipoR2: 0.92+/-0.31 vs. 1.60+/-0.46, P<0.0001). AdipoR1 and AdipoR2 levels were further reduced in tumors with nodal metastases and the difference was statistically significant in the case of AdipoR2 (0.79+/-0.27 vs. 1.02+/-0.30, P=0.012). The results of this study demonstrated that the expression levels of adiponectin receptors are reduced in cancer specimens compared to normal tissue, indicating a downregulation in the course of the development and progression of colorectal cancer. Since adiponectin is abundantly present in the whole body and has inhibitory effects on cancer cells, this downregulation of the receptors may be an escape mechanism of malignant cells from the suppressive effects of adiponectin.

Background. Body weight loss is a well-known complication after gastrectomy, and is mainly due to reduced fat volume. The effect of vagotomy on the postoperative fat volume was investigated in patients with early stage gastric cancer who underwent gastrectomy. Methods. Subcutaneous fat area (SFA) and visceral fat area (VFA) were separately measured in a computed tomographic (CT) image at the level of the umbilicus using Fat Scan software. The changes in these two fat areas were determined by comparing CT images taken before and more than 6 mo after gastrectomy, and the ratio of postoperative to preoperative fat area was calculated in 77 patients. Results. VFA was reduced significantly greater after total gastrectomy (TG) than distal gastrectomy (DG) (P = 0.0003). In 63 patients who underwent DG, the reduction in VFA, but not in SFA, was significantly less in vagus nerve-preserved than in vagus nerve-nonpreserved cases (59.0% +/- 24.2% versus 74.9% +/- 28.2%, P = 0.027). If compared in each case, VFA showed a significantly greater decrease than did SFA in vagus-nonpreserving, but not in vagus-preserving, gastrectomy (68.2% +/- 37.0% versus 52.7% +/- 25.2%, P < 0.0001; 76.3% +/- 30.0% versus 74.9% +/- 28.2%, P = 0.79). Conclusions. The vagus nerve has a function to locally regulate the amount of intra-abdominal fat tissue, and selective vagotomy in gastrectomy results in a preferential reduction of visceral fat in gastrectomy. Surgical denervation of vagus may be reconsidered as a reasonable treatment for excessive obesity. (C) 2012 Published by Elsevier Inc.

Background: Cancer cells can acquire resistance to therapy under hypoxic condition. We aimed to investigate the mechanisms regulating chemoresistance induced by hypoxia. Materials and Methods: Human colorectal cancer cells, HT-29 and SW480, were cultured under hypoxic conditions and the sensitivity to 5-fluorouracil (FU), oxaliplatin, and SN-38 (active metabolite of irinotecan) was tested. The cell cycle was evaluated by flow cytometry after staining of cells with propidium iodide (PI). hypoxia-inducible factor 1 alpha (HIP-1 alpha) expression was evaluated by western blot analysis. Results: Hypoxia induced strong G(0)/G(1) cell cycle arrest of cancer cells and abrogated the cytotoxic effects of 5-FU and oxaliplatin, but not that of SN-38. This effect was dependent on the significant inhibition of the accumulation of HIF-1 alpha in cancer cells cultured under hypoxia by SN-38. Neither 5-FU nor oxaliplatin affected HIP-I a expression. Conclusion: SN-38, through inhibition of HIF-1 alpha can overcome chemoresistance under hypoxic conditions of colon cancer cells.

There is little information regarding the recent trend of synchronous and metachronous pulmonary metastases in patients with primary colorectal cancer. We investigated patients with sporadic colorectal cancer who underwent surgery in our department between 1990 and 2009. Clinicopathological parameters of primary cancer and lung metastases and survival time were retrospectively reviewed. Of the 2,286 patients included in this study, 64 (2.8%) had synchronous lung metastases at the time of colorectal surgery. A total of 18 patients (28%) received pulmonary metastasectomy for these lesions with curative intent. Out of 2,082 curatively operated cases, 212 (10.2%) developed metachronous lung metastases. The frequency of synchronous and/or metachronous lung metastases detected in curative cases increased from 8.9% in the 1990s to 11.9% in the 2000s (p=0.03). Among predictive factors for metachronous lung metastases, the presence of distant organ metastases, i.e. initial stage IV, significantly increased over time. Notably, patients with unresectable metachronous lung metastases in the 2000s. characterized by smaller size, exhibited more favorable prognosis than in the 1990s (p=0.003). Recent improvement of imaging modalities is considered to have facilitated the prompt diagnosis of lung metastases. Moreover, marked progress in multidisciplinary treatment has presumably achieved more favorable prognosis in an increasing number of patients with advanced colorectal cancer.

Prediction of peritoneal recurrence in gastric cancer patients is important for application of adjuvant chemotherapy. After surgery, occasional patients have peritoneal recurrence despite negative cytology of the peritoneal washings. Thus, molecular detection of a subliminal number of cancer cells in peritoneal washings may overcome the sensitivity limitation of conventional cytology. In this study, expressions of five specific marker genes, namely, TFF1, TFF2, CK20, FABP1 and MUC2, were evaluated for their usefulness as markers of micro-dissemination. It was found that reverse transcriptase-polymerase chain reaction for these five genes yielded results highly specific for the depth of invasion and disease stage. Furthermore, the expression of CK20, FABP1 and MUC2 was a reliable prognostic indicator of peritoneal metastasis. Our results suggest that evaluation of the expression of CK20, FABP1 and MUC2 in peritoneal washings is a useful tool for identifying patients at high risk of peritoneal recurrence who may need adjuvant chemotherapy.