北山 丈二

Background: Lysophosphatidylserine (lysoPS) is a type of lysophospholipid mediator, which is involved in allergic conditions and tumor progression. We investigated the physiological function of lysoPS on colorectal cancer (CRC) cell lines, as well as the involved receptor and signaling pathways. Materials and Methods: Expression of lysoPS receptors on six cell lines was examined by reverse transcription-polymerase chain reaction (RT-PCR). The physiological functions of lysoPS were investigated, and experiments using small interfering RNA (siRNA) or inhibitors of the signaling pathways were conducted. Results: Among the three lysoPS receptors, GPR34 was highly expressed on all cell lines. LysoPS stimulated the chemotactic migratory ability. Wortmannin inhibited the migratory ability, as well as the GPR34 knock-down, strongly suggestive of the involvement of this receptor in the PI3K/Akt pathway. Conclusion: The involved receptor and pathways in the migratory ability in response to lysoPS was demonstrated, which opens premises for targeting as a new strategy for prevention and treatment of colorectal cancer.

Background. Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. Methods. A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. Results. In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). Conclusions. It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

The importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics. The protein expression of Notch1 and Notch3 was examined using immunohistochemistry in 305 CRC specimens. Nuclear expression of Notch1 and Notch3 and their associations with clinicopathological characteristics and distant relapse-free survival (dRFS) were evaluated. Nuclear Notch1 was overexpressed in 37 % of specimen, and nuclear Notch3 in 38 %. Nuclear Notch3 expression correlated with tumor differentiation status (P = 0.0099). Nuclear expression of Notch1 and Notch3 was associated with tumor recurrence (P = 0.0311 and P = 0.0053, respectively). In multivariate analysis, nuclear Notch3 expression [hazard ratio (HR) = 1.71; 95 % confidence interval (CI), 1.06-2.78; P = 0.0271), lymph node metastasis, and venous involvement were independently correlated with dRFS. In subgroup analysis, nuclear Notch3 expression was strongly associated with dRFS in Stage II CRC (HR = 3.47; 95 % CI 1.44-9.22; P = 0.0055). Both nuclear Notch1 and Notch3 were positive in 67 specimens (22 %) and both were negative in 144 specimens (47 %). Coexpression of nuclear Notch1 and Notch3 had an additive effect toward poorer dRFS compared with a negative subtype (HR = 2.48; 95 % CI, 1.41-4.40; P = 0.0019). Nuclear Notch3 expression might be a novel predictive marker for recurrence in Stage II and III CRC.

Surgery is the mainstay of treatment for gastrointestinal stromal tumors (GISTs). However, complete resection of rectal GISTs is sometimes difficult because of bulkiness and/or anatomical reasons. Neoadjuvant imatinib therapy has gained attention as an alternative treatment to increase the chance of en bloc resection of rectal GISTs, although it usually takes several months. In this case report, we first demonstrated that neoadjuvant imatinib therapy can be performed safely not only to downsize tumors, but also to allow adequate time for the effective treatment of major comorbid illnesses. A 74-year-old man was diagnosed with a 45 mm GIST of the lower rectum. He also had severe stenosis in the proximal segment of the left anterior descending coronary artery. Following the implantation of a drug-eluting stent, the patient received imatinib together with dual anti-platelet therapy for 12 months without obvious side effects. Follow-up image studies revealed tumor shrinkage as well as stent patency. En bloc resection of the GIST was performed laparoscopically, which preserved the anus. The patient is currently alive without any evidence of relapse for 12 months after surgery.

Peritoneal carcinomatosis (PC), caused by advanced abdominal malignancies, such as those of the ovarian and gastrointestinal tracts, has an extremely poor prognosis. Intraperitoneal (IP) chemotherapy has been clinically applied for several decades, but its clinical efficacy has not been fully determined. An accumulating body of evidence suggests that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the optimal treatment for selected patients with ovarian and colorectal cancers with PC. Recent studies suggest that IP administration of taxane with systemic chemotherapy in a neoadjuvant setting improves patient survival in gastric cancer with PC. The pharmacokinetics of IP-administered drugs should be primarily considered in order to optimize IP chemotherapy. Therefore, the development of specific IP drugs using newly emerging molecular targeted reagents or new drug delivery systems, such as nanomedicine or controlled absorption/release methods, is essential to improve the efficacy of IP chemotherapy. (c) 2014 Elsevier Ltd. All rights reserved.

BACKGROUND: Preoperative chemoradiotherapy has been widely used for the prevention of local recurrence of locally advanced rectal cancer, and the effect of chemoradiotherapy is known to be associated with overall survival. OBJECTIVE: We aimed to evaluate the association of the pathologic response grade with tumor recurrence rate after chemoradiotherapy, using radiographic analysis and the Response Evaluation Criteria in Solid Tumors as the parameters. DESIGN: This study was conducted at a single tertiary care institution in Japan. SETTING: This was a retrospective cohort study of patients undergoing preoperative chemoradiotherapy. PATIENTS: A total of 101 low rectal cancer patients receiving preoperative chemoradiotherapy from July 2004 to August 2012 were enrolled. MAIN OUTCOME MEASURES: The tumor reduction rate was measured with the use of traditional Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry, and the correlation between the reduction rate and the pathologic response grade was examined. RESULTS: The tumor reduction rate assessed according to Response Evaluation Criteria in Solid Tumors showed no association with the pathologic response grade (p =0.61). In contrast, the radiographic response rate by both barium enema and CT volumetry strongly correlated with the pathologic response grade (p < 0.0001 and p = 0.001). In terms of local tumor recurrence, those diagnosed as high responders by the pathologic response grade, Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry had a lower recurrence rate (p =0.03, p =0.03, p =0.0002, and p =0.001). The difference between high responders and low responders was especially prominent by barium enema and CT volumetry. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: Double-contrast barium enema and CT volumetry were superior to Response Evaluation Criteria in Solid Tumors in evaluating the effect of chemoradiotherapy and predicting the likelihood of tumor recurrence.

To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively. CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer. The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group. In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.

Temsirolimus (TEM) is a novel, water-soluble mammalian target of rapamycin (mTOR) inhibitor that has shown activity against a wide range of cancers in preclinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored. We evaluated the antitumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in vitro and in vivo. In vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Antitumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in vitro and in vivo. In vitro, TEM was effective in inhibiting the growth of two CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1 alpha and VEGF in all three cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. We also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the antitumor activity of TEM in vitro and in vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio. Based on these data, we propose TEM with or without chloroquine as a new treatment option for CRC.

Background: Urethral metastatic adenocarcinoma is extremely rare. Moreover, only 9 previous cases with metastases from colorectal cancer have been reported to date, and not much information on urethral metastases from colorectum is available so far. Case presentation: We report our experience in the diagnosis and the management of the case with urethral metastasis from a sigmoid colon cancer. A 68-year-old man, who underwent laparoscopic sigmoidectomy for sigmoid colon carcinoma four years ago, presented gross hematuria with pain. Urethroscopy identified a papillo-nodular tumor 7 mm in diameter in the bulbar urethra. CT-scan imaging revealed the small mass of bulbous portion of urethra and solitary lung metastasis. Histological examination of the tumor obtained by transurethral resection showed moderately differentiated adenocarcinoma, which was diagnosed as a metastasis of a sigmoid colon carcinoma pathologically by morphological examination. Immunohistochemical analysis of the urethral tumor revealed the positive for cytokertin 20 and CDX2, whereas negative for cytokertin 7. These features were consistent with metastatic adenocarcinoma of the sigmoid colon cancer. As the management of this case with urethral and lung metastasis, 6-cycle of chemotherapy with fluorouracil with leucovorin plus oxaliplatin was administered to the patient, and these metastases were disappeared with no recurrence of disease for 34 months. Conclusion: Urethral metastasis from colorectal cancer is a very rare occurrence. However, in the presence of urinary symptoms, the possibility of the urethral metastasis should be considered.

Published reports concerning internal hernias after extraperitoneal stoma construction are scarce. In our present report, we describe the case of a 56-year-old man who was referred to our hospital for the treatment of rectal cancer. He underwent abdominoperineal resection of the rectum with sigmoidostomy using an extraperitoneal route. On the ninth postoperative day, the patient experienced sudden and intense abdominal pain and was diagnosed with strangulation of the small intestine due to a stoma-associated internal hernia. Therefore, an emergency laparotomy was performed. The surgical findings showed that the small intestine protruded through the space between the sigmoid colon loop and the abdominal wall in a cranial-to-caudal direction. The strangulated portion of the small intestine was recovered, and the orifice of herniation was closed. No recurrence of internal herniation was observed during the follow-up period.

Intraperitoneal (IP) administration of paclitaxel (PTX) can enable direct infiltrate of high amount of PTX into peritoneal nodules and elicit remarkable clinical responses against peritoneal metastases. In this study, we examined the mechanisms leading to tumor shrinkage after IP PTX. We compared the microscopic features of peritoneal metastases before and after IP PTX in surgically removed human samples, as well as in a murine xenograft model using immunohistochemistry. We found that many microvessels exist in the peripheral areas of metastatic nodules in human samples before treatment. However, peripheral vessels were greatly reduced in number, and luminal obstructions were observed in lesions showing complete response after chemotherapy including IP PTX. Similar changes were observed in peripheral vessels of peritoneal tumors in MKN45-inoculated nude mice treated with IP-PTX. Moreover, pimonidazole staining revealed that highly hypoxic regions were produced by IP PTX at the tumor periphery. These findings strongly suggest that the remarkable efficacy of IP PTX in the treatment of peritoneal metastases is, at least in part, dependent on the destruction of peripheral microvessels by exposure to infiltrated PTX.

In this study, we analyzed intraperitoneal cells recovered from human samples and found that CD90(+)CD45(-) cells exist as a minor population but vigorously grow in culture, showing the morphological features of mesothelial cells (MC). Interestingly, the MC highly expressed arginase I and markedly suppressed T cell proliferation with the reduction of CD3 chain expression in T cells stimulated by coated anti-CD3 mAb. The addition of nor-NOHA (500 mu M), or L-arginine (1 mM) mostly restored the inhibitory effect of MC on T cell proliferation as well as the reduced expression of CD3 zeta chain. The expression level of CD3 zeta chain in T cells in the peritoneal cavity was significantly down-regulated from circulating T cells. These results suggest that intraperitoneal free MC have immunomodulatory functions through the control of L-arginine level, and thus may play significant roles in the pathogenesis of various diseases in the peritoneal cavity. (c) 2014 Elsevier Inc. All rights reserved.

Background. Peritoneal metastasis of gastric cancer has extremely poor clinical outcomes. Recently, we developed a combination chemotherapy that used intraperitoneal (IP) paclitaxel (PTX) and produced excellent antitumor effects against peritoneal lesions. However, no information is available about the benefit of gastrectomy in cases with malignant ascites. Methods. A total of 64 patients with severe peritoneal metastasis and ascites received IP PTX at 20 mg/m(2) via implanted subcutaneous peritoneal access ports as well as intravenous (IV) PTX at 50 mg/m(2) on days 1 and 8. S-1 was administered at 80 mg/m(2) day for 14 consecutive days, followed by 7 days of rest. In all patients, investigative laparoscopy was performed around the combination chemotherapy, and gastrectomy was performed on patients who showed apparent shrinkage of their peritoneal nodules as well as negative peritoneal cytology at the second laparoscopy. Results. Gastrectomy was performed in 34 patients. The median course of chemotherapy before surgery was 5 courses (range 2-16). R0 operation was achieved in 22 patients (65 %), and grade 2 and 3 histological responses were obtained in 7 (21 %) and 1 (3 %) patient(s), respectively. The median survival time and 1-year overall survival of the gastrectomized patients were 26.4 months and 82 %, and those of the 30 patients who did not receive gastrectomy were 12.1 months and 26 %, respectively. Morbidity was minimal, and there was no mortality. Conclusions. Salvage gastrectomy after chemotherapy of S-1 with IV and IP PTX is promising, even for patients with highly advanced gastric cancer and severe peritoneal metastasis and malignant ascites.

BackgroundPeritoneal metastasis (PM) is the most life-threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis. MethodsCells were recovered from ascites or peritoneal lavages from 106 patients who underwent abdominal surgery and additional 89 samples which were obtained from peritoneal catheter or access port in patients with PM (+) gastric cancer. The cells were immunostained with monoclonal antibodies to CD45 and to CD326 (EpCAM). Using flow cytometry, CD326 (+) and CD45 (+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated. ResultsIn 106 samples obtained by laparotomy, Median (M) of the TLR of PM (+) patients was 1.39% (0-807.87%) which was significantly higher than PM (-) patients (M=0%, 0-2.14%, P<0.001). In PM (+) patients, 86 CY (+) samples showed higher TLR than 61 CY (-) samples (M=2.81%, 0.02-1868.44% vs. M=0%, 0-3.45%, p<0.0001). In all of the 24 patients who were monitored for TLR before and after intraperitoneal (IP) chemotherapy, the TLR was reduced which was more dramatic than the results of the change in cytology. ConclusionsTLR measured with FACS is an excellent reflection of the tumor spread in the peritoneal cavity and could be a reliable diagnostic biomarker to determine the severity of PM as well as effectiveness of IP chemotherapy. (c) 2013 International Clinical Cytometry Society

In the present study, we aimed to characterize the predictive value of cytokines/chemokines in rectal cancer (RC) patients receiving chemoradiation therapy (CRT). Blood samples were obtained pre- and post-CRT from 35 patients with advanced RC, who received neoadjuvant CRT followed by surgery, and the correlation between plasma levels of cytokines/chemokines and the response to CRT was analyzed. The pre-CRT levels of soluble CD40-ligand (sCD40L) and the post-CRT levels of chemokine ligand-5 (CCL-5) were significantly associated with the depth of tumor invasion and with venous invasion. In addition, a significant decrease in sCD40L and CCL-5, as well as in platelet counts, was associated with a favorable response to CRT. A significant correlation between pre-CRT platelet counts and sCD40L was observed in patients with a favorable response. By contrast, higher post-CRT interleukin (IL)-6 was associated with a poor response. Platelets, immune system and cancer cells, cross-linked through various cytokines/chemokines, appear to play an important role in the response to CRT, and by understanding their roles, new approaches for the improvement of the therapy might be proposed.

Aberrant activation of Wnt signalling results in colorectal tumours. Lgr5 is specifically expressed in stem cells of the intestine and has an essential role in maintaining tissue homeostasis. Lgr5-positive stem cells are responsible for the intestinal adenoma initiated by mutations in adenomatous polyposis coli. Furthermore, Lgr5 interacts with R-spondins and thereby activates Wnt signalling. However, the function of Lgr5 in colorectal tumourigenesis is unclear. Here we show that LGR5 is required for the tumourigenicity of colorectal cancer cells. We show that the transcription factor GATA6 directly enhances the expression of LGR5. We further demonstrate that GATA6 is upregulated in colorectal cancer cells due to the downregulation of miR-363, which directly targets GATA6. Moreover, we show that overexpression of miR-363 suppresses the tumourigenicity of colorectal cancer cells. These results suggest that the miR-363-GATA6-LGR5 pathway is critical for colorectal tumourigenesis and would be a promising target for the treatment of colorectal cancer.

The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(2) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, alpha-smooth muscle actin and fibroblast activated protein-a by the stimulation with TGF-beta, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.

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.