北山 丈二

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.

Although thrombocytosis has been reported in patients with various types of cancer, the association between thrombocytosis and the clinicopathological features of patients with colorectal cancer (CRC) has not been fully investigated. We evaluated the clinical features associated with thrombocytosis in CRC. The medical records of 636 consecutive CRC patients undergoing surgery in our department between January 2002 and July 2008 were retrospectively reviewed. The correlation between the clinicopathological variables and the preoperative platelet count was analyzed by univariate and multivariate analyses. The impact of thrombocytosis on the prognosis of these patients was assessed, in comparison with the other clinicopathological variables. Platelet count showed significant correlation with gender, age, venous involvement, tumor size, depth of invasion, regional lymph node metastasis, distant metastasis in univariate analysis, and tumor size and depth of invasion were independent factors in multivariate analysis. The cancer-specific survival (CSS) of CRC patients with thrombocytosis was significantly shorter than that for those without thrombocytosis (P < 0.001), specifically in patients with stage III CRC (P < 0.001). Multivariate analysis indicated that thrombocytosis was an independent prognostic factor of CSS (hazard ratio = 2.96, 95% confidence interval [CI] = 1.72-5.00). Moreover, within stage II CRC, the univariate analysis revealed that disease-free survival (DFS) was associated with preoperative thrombocytosis, but not the other clinicopathological variables. Preoperative thrombocytosis is not only an independent indicator of poor CSS in CRC patients but also an independent predictor of poor DFS in patients with stage II CRC.

BACKGROUND: Intraoperative colonic irrigation and intraoperative on-table colonoscopy may be useful for a more accurate diagnosis of colorectal cancer before colectomy in patients with obstructive left-sided colorectal cancer, but the clinical benefit of this technique has not been investigated in large-scale studies. OBJECTIVE: The aim of this study was to evaluate the usefulness of intraoperative colonic irrigation with a Y-shaped irrigation device and intraoperative colonoscopy in the management of obstructive colorectal cancer in patients undergoing elective surgery. DESIGN AND SETTING: This was a retrospective cohort study of patients undergoing surgical treatment at a single tertiary care institution in Japan. PATIENTS AND INTERVENTION: Among 715 consecutive patients with left-sided colorectal cancer, 101 patients (14.1%) with obstructing tumor received intraoperative colonic irrigation and intraoperative colonoscopy before colectomy and primary anastomosis, and 614 patients with nonobstructive colorectal cancer underwent preoperative colonoscopy with mechanical bowel preparation. MAIN OUTCOME MEASURES: Detection rates of proximal synchronous lesions, occurrence of postoperative complications, and changes in the surgical procedure prompted by the results of the intraoperative colonoscopy were evaluated. RESULTS: Intraoperative colonoscopy detected synchronous adenomatous polyps in 27 patients (26.8%), carcinoma in 4 patients (4%), and obstructive colitis in 2 patients (2%). Findings of the intraoperative colonoscopy prompted changes in surgical procedure in 9 patients (8.9%). The overall morbidity in the intraoperative group was 17%, with anastomotic leakages in 3 patients, wound infection in 5, and postoperative ileus in 3 patients. The risk of these complications was not increased in patients with intraoperative colonoscopy with intraoperative colonic irrigation compared with those receiving preoperative colonoscopy with mechanical bowel preparation. The operation time was 28 minutes longer in the intraoperative than in the preoperative group, but neither the time to start of oral intake nor the length of postoperative hospital stay was significantly different between the 2 groups. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: In patients with obstructive colorectal cancer, intraoperative colonic irrigation with intraoperative colonoscopy is a useful strategy for detecting synchronous lesions located proximally to the obstructing tumor, without increasing patient morbidity.

Background: The aim of this study was to assess whether the neutrophil to lymphocyte ratio (NLR) and other laboratory markers may predict the prognosis of advanced colorectal cancer (CRC) patients receiving palliative chemotherapy. Methods: The study population included 50 patients with far advanced or recurrent unresectable CRC who received oxaliplatin-based combination chemotherapy as first-line treatment in our hospital between June 2005 and November 2010. Seven clinical variables and 7 laboratory indices before chemotherapy were evaluated retrospectively as the possible prognostic factors of overall and progression-free survival. Results: During the study period, 27 patients (54%) died of CRC. Elevated NLR (>= 4.0) was observed in 15 patients (30%). By univariate analysis, elevated NLR, performance status and hypoalbuminemia were significantly associated with both poor overall and progression-free survivals. Multivariate analysis showed that elevated NLR (hazard ratio 4.39, 95% confidence interval 1.82-10.7; p = 0.0013) and thrombo-cytosis (hazard ratio 5.02, 95% confidence interval 1.69-13.4; p = 0.0066) were independently associated with overall survival. Conclusion: Elevated NLR is a powerful predictor of poor response to oxaliplatin-based chemotherapy in patients with unresectable CRC. The ratio is a simply accessible and inexpensive but useful biomarker in CRC patients receiving chemotherapy. Copyright (C) 2012 S. Karger AG, Basel

The standard of care for gastric cancer with peritoneal metastasis is systemic chemotherapy. However, there is no chemotherapy regimen with a sufficient level of evidence supporting its effectiveness, and thus S-1 plus cisplatin (CDDP), which is regarded as the standard regimen for advanced metastatic gastric cancer, is widely applied. Meanwhile, the efficacy of intraperitoneal (IP) administration of taxanes has been verified, and the novel multidisciplinary treatment combining chemotherapy and surgery is now being tested. We developed a combination chemotherapy regimen of S-1, weekly intravenous and IP paclitaxel (PTX), and determined the recommended dose of IP PTX to be 20 mg/m2 in our phase I study. In our phase II study, the median survival time (MST) of 40 patients enrolled was 23.6 months, and peritoneal cytology turned negative for 86% of 28 patients. Moreover, we performed gastrectomy on 60 patients after the disappearance or obvious shrinkage of peritoneal metastasis, and the MST was 34.5 months. Multidisciplinary treatment combining IP-containing chemotherapy and surgery is safe and effective for gastric cancer patients with peritoneal metastasis. We have started a phase III trial (PHOENIX-GC trial) comparing our IP regimen to S-1 plus CDDP.

Purpose: Autotaxin (ATX) is molecularly identical to lysophospholipase D (lysoPLD) and is a main enzyme producing lysophosphatidic acid (LPA), which mediates a broad range of cellular responses including stimulation of cell motility. Patients and Methods: Using immunohistochemical staining, we examined the expression of ATX/lysoPLD in 98 cases of early colorectal cancer with submucosal invasion. ATX/lysoPLD was highly expressed in infiltrating cells in tumor tissue in the submucosal layer, which were characterized as mast cells. Results: The number of ATX/lysoPLD-positive cells was significantly greater in tumors with a macroscopically depressed lesion than in tumors without depression. The density of ATX/lysoPLD-positive cells tended to have a positive correlation with microvessel vascular density (MVD), while it was not correlated with vessel invasion and nodal metastases as well as lymphovascular vessel density (LVD). Conclusion: Our results suggest that local production of LPA through ATX/lysoPLD may weakly correlate with formation of a depressive lesion and tumor angiogenesis in the early stage of colorectal cancer. © 2010 Springer Science+Business Media, LLC.

We detected 7 cases of leptomeningeal carcinomatosis in 126 patients with peritoneal dissemination of gastric cancer who received combined systemic and intraperitoneal chemotherapy. Leptomeningeal carcinomatosis was diagnosed 79-1540 days after the diagnosis of the primary gastric cancer. Patients presenting with various neurological symptoms were diagnosed by cerebrospinal fluid (CSF) cytology and radiological imaging. Irradiation to the whole brain and spine was performed in 4 patients, and provided palliation and increased survival for 1 patient. Intrathecal chemotherapy and drainage of CSF was performed in 1 patient each, but produced no significant clinical benefit in either of them. Survival after the diagnosis of leptomeningeal carcinomatosis was between 3 and 155 days. As patients with peritoneal dissemination of gastric cancer are living longer because of improved chemotherapy, clinicians must recognize the possibility of leptomeningeal carcinomatosis when patients complain of neurological symptoms.

We investigated the effectiveness of prophylactic FOLFOX after curative resection of synchronous metastases in patients with colorectal cancer (CRC). Clinicopathological information including postoperative chemotherapy, such as a therapeutic regimen, relapse-free survival (RFS), site of recurrence, etc., was retrospectively analyzed in 116 CRC patients with synchronous distant metastases, and 63 patients with metachronous metastases who had received surgery in our hospital between 2000 and 2009. Fifty-three patients (84%) out of 63 without adjuvant chemotherapy, and 38 (83%) out of 46 patients that received oral or intravenous 5-fluorouracil (5-FU) (alone or with leucovorin (LV) orisovorin) developed recurrent tumor (s) afterwards. The median RFSs were 119 and 281 days, respectively. By contrast, a single patient among 6 who underwent FOLFOX (up to 12 therapeutic courses) showed recurrence 476 days after surgery. The RFS of the FOLFOX was significantly higher than that of the 5-FU (+LV) or surgery alone (p=0. 03, p=0. 007, respectively). In conclusion, the FOLFOX regimen is more beneficial for CRC patients with synchronous metastasis as adjuvant chemotherapy than 5-FU (+LV) or other follow-up strategies.

The role and clinical significance of the alteration of sympathetic nerve fibers (SNF) was assessed in gastric cancer. Loss of nerve fibers in malignant tumors has previously been described; however, how dysfunction of the nervous system is involved in cancer progression has not been clarified in clinical studies. The distribution of SNF was examined in 82 surgically resected gastric cancer specimens with immunohistochemical staining of tyrosine hydroxylase (TH), and the association with clinicopathological findings as well as the clinical outcome of the patients was retrospectively evaluated. Arterioles in the normal gastric wall were totally covered with SNF, while the immunoreactivity to TH was markedly reduced around arterioles in cancer tissue. The degree of loss of SNF was significantly correlated with the depth of invasion (P < .0001) and lymph node metastasis (P < .0001) as well as microvessel density (MVD) (P = .0043). Moreover, patients who had tumors with marked loss of SNF showed a markedly worse clinical outcome, with an independent association by multivariate analysis. Loss of periarteriolar SNF is associated with aggressive phenotype of gastric cancer possibly through enhanced angiogenesis and thus could be a useful marker to predict the clinical outcome.

Recent studies have suggested that tumor shrinkage in response to radiotherapy (RT) is greatly dependent on the host immune response. A Balb/c mouse model of simultaneous subcutaneous tumor and liver metastasis of Colon26 was prepared and, after irradiation of the subcutaneous tumor (2 Gy x 5 day x 2 cycles), interleukin-2 (IL-2) (2 x 10(4) U) was injected intra-tumorally, and the fate of both the subcutaneous tumor and liver metastatic lesions was evaluated. Intratumoral injection of IL-2 greatly enhanced the anti-tumor effects of RT and completely eradicated the established subcutaneous tumor. Interestingly, although RT was given locally to the subcutaneous tumor, liver metastasis formation was also inhibited in mice receiving only local RT. More impressively, the combination of RT + IL-2 completely inhibited liver metastasis formation. Splenocytes in mice receiving RT + IL-2 contained a higher percentage of CD4(+) T cells, but lower percentages of CD4(+)CD25(+) regulatory T cells and CD11b(+) Gr-1(+) myeloid-derived suppressor cells. Immunohistochemical investigation of human rectal cancer revealed that the density of CD8(+) cells infiltrating into irradiated rectal tumor was positively associated with a lower frequency of distant metastasis as well as histological response grade. Local administration of IL-2 not only enhances shrinkage of the irradiated tumor itself, but can also suppress the development of distant metastasis located outside the RT field, possibly though the induction of a systemic T cell response. Augmentation of T-cell-mediated antitumor immunity during RT might be critical for improvement of the clinical efficacy of neoadjuvant RT for the treatment of advanced rectal cancer. (Cancer Sci 2011; 102: 1257-1263)

Gastropericardial fistulae are rare and may cause fatal complications such as acute purulent carditis and cardiac tamponade. The present report describes a case of a gastropericardial fistula caused by a peptic ulcer perforating a retrosternal reconstructed gastric tube 2 years after subtotal esophagectomy for esophageal cancer. Surgical intervention involved left thoracotomy, pericardium fenestration, and drainage of the pericardium and left thoracic cavity. The patient suffered postoperative complications including septic shock, acute respiratory distress syndrome, and cardiac insufficiency; however, he recovered after successful surgical intervention. In this case, the withdrawal of proton pump inhibitors and the patient's sustained drinking habit after esophageal replacement surgery may have caused peptic ulcers in the gastric tube. Early diagnosis and surgical treatment of gastropericardial fistulae are essential to avoid fatal complications.

Context: Previously, we demonstrated that CD11b is expressed on peripheral blood memory B cells, and it plays an important role in the migration of B cells. And epigallocatechin gallate (EGCG), a bioactive component of green tea, by binding to CD11b, expressed on CD8(+) cytotoxic T cells, inhibited their migratory ability, one possible mechanism of the antiallergic activity of EGCG. Objective: Here, we investigated whether EGCG also affected CD11b expressed on B cells, similar to cytotoxic T cells. Materials and methods: Isolated peripheral blood CD19(+) B cells were treated with EGCG and the change in the expression of CD11b was analyzed using flow cytometry. The effects of EGCG on the ability of B cells to adhere to and to transmigrate through the endothelial cell layer were evaluated using the transwell assay. Results: EGCG significantly suppressed the apparent expression of CD11b on B cells, in the flow-cytometric analysis, and this apparent suppression was speculated to be dependent on the competitive binding of EGCG to CD11b. EGCG also significantly suppressed CD11b-mediated migration and adhesion of B cells to endothelial cells. Discussion and conclusion: EGCG has a strong suppressive activity on the adhesive and migratory abilities of peripheral blood B cells. This suppressive activity was mediated by the binding of EGCG to CD11b on B cells, and the consequent suppression of B-cell extravasation to the extravascular space. Because B cell plays an important role in the humoral immunity, EGCG could be a promising drug for the prevention and/or treatment of allergic and/or autoimmune diseases.

Adiponectin is known to have suppressive effects on tumor growth and is thought to be a key molecule in the positive correlation between obesity and cancer. However, the detailed mechanisms regulating tumor cell activity have not been elucidated. In this study, we found that both full-length (f-Ad) and globular adiponectin (g-Ad) inhibited cell growth in colon cancer cell lines in glucose-containing medium, whereas it supported cell survival in glucose-deprived medium, with an increase in AdipoR1 and AdipoR2 expression. The latter effect of adiponectin in glucose deprivation was significantly inhibited by adding autophagy inhibitors, chloroquine, 3-methyl adenine or a combination of pepstatin A and E-64d, suggesting that the effect of supporting cell growth was dependent, at least in part, on the induction of autophagy. The enhancement of autophagy was confirmed morphologically using green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) fusion proteins under a fluorescence microscope using stably transfected DLD-1 cells expressing GFP-LC3. Western blot analysis revealed that adiponectin increased the expression of LC3-1, LC3-2, phosphorylated AMPK alpha and PPAR alpha but decreased that of phosphorylated mTOR, insulin like growth factor (IGF)-1, phosphorylated serine/threonine kinase (Akt) and phosphorylated phosphatidylinositol 3-kinase (PI3K) in glucose-deprived medium. We conclude that adiponectin supports cell survival in glucose deprivation through enhancement of the autophagic machinery by AMPK alpha and PPAR alpha activation and IGF-1/PI3k/Akt/mTOR pathway inhibition. The bimodal effects of adiponectin are thought to be clinically important in the pathophysiology of tumor development and progression. (Cancer Sci 2011; 102: 999-1006).

Ultraviolet light B (UVB) phototherapy is widely used to treat dermatological diseases and therefore may be a potential optional strategy in the treatment of a skin lesion infiltrated by a malignant tumor. Currently, little is known regarding the effect of UVB phototherapy on human breast cancer cells. The present study aimed to investigate the effect of UVB phototherapy, as well as the potential effect of 5-fluorouracil (5-FU), the first-line anticancer drug for breast cancer, on radiosensitizing MCF-7 human breast cancer cells, in an attempt to develop new therapeutic strategies for the treatment of locoregional recurrence of breast cancer. MCF-7 cells were incubated in the presence of 5-FU for 48 h, and UVB irradiation at 750 mJ/cm(2) was administered in the midterm of 5-FU treatment. The viability of MCF-7 cells was analyzed by the trypan blue staining method. Apoptosis was quantified by flow cytometry and Hoechst 33258 staining. The cell cycle was evaluated by flow cytometry after the staining of cells with propidium iodide. The combination treatment of 5-FU and UVB resulted in a strong potentiation of the inhibitory effect of MCF-7 cell growth, dependent on the intra-S phase cell cycle arrest and induction of apoptosis, when compared to treatment with 5-FU or UVB alone. In conclusion, 5-FU sensitized human breast cancer cells to UVB phototherapy, and this combination therapy is an effective and promising strategy for the treatment of breast cancer, particularly for locoregional recurrence.

Background: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. Radiosensitivity has recently been shown to be greatly affected by immune function of the host. Methods: In 48 cases of advanced RC, we retrospectively examined the density of tumor infiltrating CD4(+) and CD8(+) T cells using immunohistochemical staining of biopsy samples before CRT, and examined the correlation with tumor response. Results: The numbers of both CD4(+) and CD8(+) tumor-infiltrating lymphocytes (TIL) in pre-CRT biopsy samples were strongly correlated with tumor reduction ratio evaluated by barium enema. Moreover, the densities of CD4(+) and CD8(+) TIL were significantly associated with histological grade after CRT. The density of CD8(+) TIL was an independent prognostic factor for achieving complete response after CRT. Conclusions: In RC patients, T lymphocyte-mediated immune reactions play an important role in tumor response to CRT, and the quantitative measurement of TIL in biopsy samples before CRT can be used as a predictor of the clinical effectiveness of CRT for advanced RC.

Background: Although preoperative radiotherapy (RT) is widely used as the initial treatment for locally advanced rectal cancer (RC) in the neoadjuvant setting, factors determining clinical response have not been adequately defined. In order to find other factors possibly related with radiosensitivity, we evaluated the relationships between circulating blood cell counts and RT effects. Methods: In 179 cases with advanced RC, we retrospectively examined hemoglobin (Hb) levels and counts of white blood cells (WBC), platelets and WBC subsets before and after RT and investigated their associations with the complete response (CR) rate together with other clinicopathological factors. Results: The ratio of lymphocytes in WBC taken before RT was significantly greater in 15 CR cases as compared with those in non-CR cases. Patients with high lymphocyte percentages (25.7%) showed better outcome than the counterparts. Conversely, the ratio of neutrophiles was reduced in CR cases. The lymphocyte ratio showed an independent association with CR with multivariate analysis, and tended to be maintained at relatively high levels in CR cases. Conclusions: In RC patients, peripheral blood lymphocytes have a significant impact on the CR rate in response to RT. Lymphocyte-mediated immune reactions are supposed to have positive roles on clinical response in radiotherapy for RC.

Although hyperfibrinogenemia has been reported in patients with colorectal cancer, neither its clinical implications nor the effect of chemoradiotherapy (CRT) on the fibrinogen levels have been fully investigated. We investigated the clinical significance of pre- and post-CRT fibrinogen levels in patients with rectal cancer. The medical records of 82 patients with rectal cancer, who had received CRT followed by surgical resection, were retrospectively reviewed. The correlation between the clinicopathological variables and the pre- and post-CRT plasma fibrinogen levels, and that between the changes of fibrinogen, C-reactive protein (CRP), or carcinoembryonic antigen (CEA) levels after CRT and the pathological tumor regression grading was analyzed. Furthermore, the impact of post-CRT fibrinogen levels on the prognosis of these patients was assessed. Plasma fibrinogen markedly decreased after CRT. The post-CRT fibrinogen level significantly correlated with lymphatic invasion, venous invasion, tumor size, depth of invasion, and the pathological tumor regression grading. The CRT-induced pathological tumor regression grading well correlated with the decrease of fibrinogen level, but not with that of CRP or CEA. Furthermore, patients with high post-CRT fibrinogen had significantly shorter disease-free survival. Reduction of plasma fibrinogen induced by CRT should be a promising biomarker for evaluating the efficacy of CRT in rectal cancer patients.

Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX-30W) prepared by solubulization with the amphiphilic copolymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX-30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green-conjugated PTX-30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX-30W, and thus, PTX-30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination. (Cancer Sci 2011; 102: 200-205).

Objectives: The prophylactic effect of FOLFOX regimen, a standard regimen for unresectable colorectal cancer (CRC), was investigated in the adjuvant setting of CRC cases with distant metastases. Methods: The study population included 116 CRC patients with synchronous metastases and 91 patients with metachronous metastases who had undergone curative operation in our hospital between 2000 and 2009. Clinicopathological parameters of CRC, postoperative chemotherapeutic regimen, recurrence rate, and relapse-free survival (RFS) were analyzed retrospectively. Results: After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received 5-fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only 1 (17%) among 6 patients who underwent FOLFOX treatment showed recurrence. The FOLFOX group exhibited significantly improved RFS as compared to the 5-FU (+ LV) or surgery-alone group (p = 0.03, p = 0.007, respectively). On the other hand, in patients with metachronous metastases, tumor-relapse rate and RFS were not significantly influenced by post-metastasectomy therapies. Conclusions: In this retrospective analysis, the adjuvant administration of FOLFOX appeared to reduce the risk of relapse in a small group of CRC patients with synchronous metastases. Prospective randomized trials will be required to confirm the benefits of this management strategy. Copyright (C) 2011 S. Karger AG, Basel