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Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.

Most patients with Crohn’s disease (CD) experience surgical recurrence. In this era of novel therapies, we conducted this study to clarify which treatments effectively decrease the risk of surgical recurrence in patients with CD. The subjects of this retrospective study were 37 patients with CD. We created cumulative surgery rate curves and performed univariate and multivariate analyses. Univariate analysis revealed that patients who consumed an elemental diet (ED; ≥ 900 kcal/day), anti-tumor necrosis factor-alpha, and thiopurines had a significantly better prognosis than those who did not (p = 0.011, p = 0.025, and p = 0.0080, respectively). Multivariate analysis revealed that ED therapy and thiopurines were independent significant factors for controlling surgical recurrence (p = 0.046 and p = 0.032, respectively). Additional analyses showed that the most promising ED therapeutic dose was ≥ 1200 kcal/day, while an ED therapeutic dose of ≥ 900 kcal/day was acceptable. Although univariate analyses revealed that all three treatment strategies had significant effects on surgical recurrence in patients with CD, multivariate analysis revealed that only ED therapy was significantly associated with surgical recurrence rates. Thus, ED therapy plays an important role in the management of CD, even in the era of biological therapies.

Pancytopenia associated with vitamin B12 and folic acid deficiency has been reported in patients who have undergone total gastrectomy. Therefore, myelosuppression due to chemotherapy following total gastrectomy is considered to be more serious. We encountered three cases of severe thrombocytopenia in patients who received chemotherapy after total gastrectomy. The lowest platelet levels in these patients were 1.7 × 104/mm3, 2.3 × 104/mm3, and 0.9 × 104/mm3, respectively. None of the patients presented with vitamin B12 deficiency, and one patient presented with folic acid deficiency. The association between serum vitamin levels and chemotherapy-related adverse events is controversial. Since folic acid has a shorter half-life (6 hours) and cannot accumulate in the body, unlike vitamin B12 that is stored for a long time in the liver, folic acid deficiency is suspected to be associated with thrombocytopenia induced by post-total gastrectomy chemotherapy. However, serum folic acid levels fluctuate depending on the timing of evaluation and require a few days to evaluate. In conclusion, patients who undergo chemotherapy after total gastrectomy should be monitored for severe thrombocytopenia but serum vitamin B12 levels are not necessarily clinically important. By measuring serum folic acid levels at appropriate times, folic acid deficiency may prove to be a reference for predicting severe thrombocytopenia.

Objectives FOLFOX is a standard chemotherapy regimen used to treat colorectal cancer. Adverse events associated with FOLFOX treatment include peripheral neuropathy and myelosuppression. This report discusses the case of a 64-year-old man with rectal cancer who developed hyperammonemia and impaired consciousness following initiation of mFOLFOX6 as a postoperative adjuvant therapy. Methods This case study reports on the clinical disease progression of the aforementioned patient. Results Following preoperative chemoradiotherapy, the patient underwent low anterior resection for rectal cancer. mFOLFOX6 was then initiated as postoperative adjuvant therapy. During the 5th cycle of mFOLFOX6 treatment, the patient presented with impaired consciousness and upper extremity convulsions. Blood testing revealed marked hyperammonemia (349 µg/dL (normal range: 12 - 66 µg/dL)). Imaging did not reveal any intracranial lesions that could cause impaired consciousness. The patient recovered within a day after rehydration and BCAA substitution. Conclusion Although impaired consciousness is a rare adverse reaction of FOLFOX, it has a major psychological impact on the patient and his/her family. Hyperammonemia should therefore be considered a potential cause of impaired consciousness during FOLFOX therapy and should be appropriately diagnosed and treated.

Highlights • Systemic therapy can achieve good treatment outcomes in advanced CRC. • Suitable chemotherapeutics can markedly improve the prognosis of unresectable CRC. • Unresectable CRC can now be treated with systemic chemotherapy instead of BSC., Introduction Chemotherapy is difficult to administer in patients with poor performance status (PS), advanced metastatic lesion, and unresectable colon cancer. We report herein our experience of a patient who showed complete response to chemotherapy and marked PS improvement. The patient presented with the following adverse factors poor PS, advanced progression of metastatic lesions, advanced unresectable colorectal cancer with severe stricture, and old age. Presentation of case The patient was an 80-year-old male diagnosed with occlusive cancer of the descending colon with multiple metastases in the liver, Stage Ⅳb (National Comprehensive Cancer Network guidelines version 2. 2018). A 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) + panitumumab (Pmab) regimen was successfully administered and led to decreased tumor marker levels; oral intake also became possible. Additional examinations showed that the primary lesion and distant metastatic lesions had almost disappeared; the patient had achieved a near complete response (CR). Currently, 35 cycles of mFOLFOX6＋Pmab have been administered, and his near CR has been maintained for 32 months. Discussion Best supportive care (BSC) is the recommended option for elderly patients with advanced unresectable colon cancer. This is the first case in which an elderly patient with poor PS and advanced unresectable colorectal cancer was treated with combination chemotherapy of mFOLFOX6 + Pmab. Conclusion Although the use of chemotherapy for elderly with advanced unresectable colorectal cancer or those with poor PS is limited, this case shows that systemic chemotherapy is now an option for such cases previously managed with BSC.

Background: Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine decline and neuropsychiatric symptoms, including initial symptoms, and the effect of chemotherapy on serum thiamine levels in gastrointestinal and hematological cancer patients receiving chemotherapy. Method: We retrospectively identified 87 patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms, including initial symptoms (neuropsychiatric symptoms), the relationship between the presence of neuropsychiatric symptoms and serum thiamine levels, and changes in serum thiamine levels after chemotherapy. Results: Logistic regression analysis identified thiamine decline as a significant factor associated with neuropsychiatric symptoms (p

Objectives The aim of this retrospective study was to search for risk factors for neurological adverse events in gastrointestinal cancer patients receiving chemotherapy and analyze the relationship between thiamine serum levels and neurological adverse events. Materials and methods This is a single-center retrospective observational study. We enrolled patients who were diagnosed with gastrointestinal cancer at our hospital, for whom we measured the thiamine serum levels. We then performed a multivariate analysis (logistic regression) to identify risk factors for the neurological symptoms in our cohort. We then divided the patients into two groups, with and without neurological symptoms, based on their electronic medical records. By using the Mann-Whitney U-test, we performed a comparative analysis of the thiamine serum levels between the two groups. We also used descriptive statistics to examine the presence/absence of neurological symptoms or other potentially related clinical features in patients with decreased thiamine serum levels. Results The logistic regression analysis detected the decrease in thiamine serum levels as a statistically significant risk factor for neurological symptoms. The analysis of the relationship between the presence/absence of neurological symptoms and thiamine serum levels showed that the thiamine serum levels were significantly lower in the group presenting neurological symptoms. Descriptive statistics showed that all the patients with decreased thiamine serum levels had either cognitive decline, attention decline, or depression symptoms, and most of them were receiving the 5-fluorouracil anticancer drug and showing decreased serum albumin levels. We also observed a slight decrease in serum sodium, vitamin B12, and folate levels. Conclusion When neurological symptoms occur in patients receiving chemotherapy for gastrointestinal cancer, the measurement of thiamine serum levels may become a standard reference for treatment indication.

We describe a case of a patient treated for cognitive dysfunction (CD) with suspected thiamine deficiency (TD). A 74-year-old man with gastric cancer presented with grade 3 diarrhea and grade 1 anorexia. He had been receiving trastuzumab plus tegafur (a chemotherapeutic fluorouracil prodrug), gimeracil, and oteracil (S-1) and oxaliplatin. On admission, cognitive function was assessed with the Hasegawa's Dementia Scale (HDS-R) because he had impaired short-term memory. His thiamine levels increased from 22 to 109 ng/mL after administration of 75 mg of thiamine. Furthermore, the patient's HDS-R score improved from 9 to 22, and cognitive and memory functions improved. TD should be considered in older CD patients receiving oral chemotherapy agents including fluorouracil.

Introduction Primary benign adenomas of the appendix occur rarely. According to appendectomy and autopsy reports, benign adenomas of the appendix are sporadically reported, accounting for ~0.02–0.08% cases. Presentation of case We report the case of a 58-year-old woman with a segmental polyp protruding into the appendiceal orifice. The polyp was spotted during lower gastrointestinal endoscopy; however, treatment was postponed at the patient's request. During a confirmatory lower gastrointestinal endoscopy for treatment, the polyp was no longer found protruding from the appendiceal orifice and had disappeared. An appendicectomy was performed for diagnostic and therapeutic purposes. Pathological examination showed a low-degree atypical tubular adenoma with no malignant findings. Discussion Despite the risk of perforation, surgical resection remains the gold standard for treating appendiceal adenoma. Resection can be performed endoscopically if the stem and base of the adenoma can be identified. In the present case, laparoscopy was a good indication from the safety standpoint, and it was radically curative. Furthermore, upon performing an appendectomy, the patient was informed of the risks of cancer-related complications or the need for additional resection. Conclusion This suggestive case proves that appendiceal tumors can disappear endoscopically depending on the timing of examination and treatment., Highlights • Primary benign adenomas of the appendix are sporadic. • Surgical resection is the preferred treatment for appendiceal adenoma. • Appendiceal tumors can disappear endoscopically between examination and treatment. • A thorough postoperative histopathological examination should always be performed.

Highlights • Secondary perineal hernia can develop after abdominoperineal resection of the rectum. • An incarcerated secondary perineal hernia caused strangulated bowel obstruction. • Wound-healing-delaying factors are the risk factors for perineal hernia development. • The pelvic floor and peritoneum should be repaired via laparoscopic rectum surgery., Introduciton We report a recent case of strangulated bowel obstruction due to an incarcerated secondary perineal hernia that developed after laparoscopic rectal resection. Presentation of case A 75-year-old man undergoing treatment for alcoholic cirrhosis underwent laparoscopic abdominoperineal resection of the rectum (APR) for lower rectal cancer after preoperative chemoradiotherapy. Lung metastases were diagnosed 2 months postoperatively. Ten days after chemotherapy initiation, the patient was hospitalized on an emergency basis due to hepatic encephalopathy. Ten days thereafter, we observed perineal skin protrusion. Moreover, the skin disintegrated spontaneously, resulting in ascetic fluid outflow. Pain and fever developed, with inflammatory reactions. Contrast-enhanced computed tomography showed strangulated small bowel obstruction due to perineal hernia. We performed an emergency surgery, during which we found small intestine wall incarcerated in the pelvic dead space, with thickening and edema; no necrosis or perforation was observed. We performed internal fixation by introducing an ileus tube into the ileocecum and fixing its balloon at the cecal terminus. Discussion Secondary perineal hernia is rare and can develop after APR. Its prevalence is likely to increase in future because of the increasing ubiquity of laparoscopic APR, in which no repair of peritoneal stretching to the pelvic floor is performed. However, only two case of secondary perineal hernia causing strangulated bowel obstruction has been reported in the literature. The follow-up evaluation of our procedures and future accumulation of cases will be important in raising awareness of this clinical entity. Conclusion We suggest that the pelvic floor and the peritoneum should be repaired.

Highlights • A mobile cecum is not an uncommon congenital anomaly. • Acute appendicitis in the presence of mobile caecum may present with atypical abdominal findings. • The presence of mobile cecum should be considered in the differential diagnosis of acute abdomen. • CT examination may be helpful in establishing the diagnosis in atypical presentation of acute appendicitis. • Abdominal computed tomography (CT) should be done in diagnosing acute abdomen., Introduction A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. Presentation of case A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350 cells/mL) and C-reactive protein level (4.56 mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. Discussion In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. Conclusion Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.

Introduction: Inflammatory fibroid polyps (IFPs) are rare, benign lesions of the gastrointestinal tract. Their occurrence in the colon is rare. They are often surgically resected for various reasons. Case presentation: A 60-year-old woman presented to our institution. She had a history of gynecologic surgery for cervical cancer at 37 years of age. Colonoscopy was performed by a local doctor and a type I tumor on Bauhin’s valve was suspected. Colonoscopy performed by us revealed a pedunculated polypoid tumor with a 20-mm head that was found to have a long stalk in the cecum. It was inferred that the stalk was entering and exiting through the valve since submucosal bleeding was observed. Polypectomy was performed. The histopathological diagnosis was IFP. Colonoscopy performed after 6 months showed no polyp recurrence. Discussion: According to previous reports, the treatment of colonic IFP was surgical in 58% of cases and endoscopic resection was performed in only 23% of cases. The decision to perform surgery was based on various factors, such as polyp size and position, difficulty in diagnosis by biopsy, and patient symptoms. In the present case, we could successfully perform polypectomy before the appearance of symptoms. Endoscopic resection seems to be an appropriate treatment approach due to the benign nature of IFP. The etiology of IFP remains unknown. Conclusion: The decision to perform surgery or endoscopic resection should be done on a case-by-case basis, but we think that a favorable increase in the number of endoscopic resections will occur in the future.

Analysis of specific properties of tumor endothelium should be useful for development of novel antiangiogenic strategies. However, the isolation of pure endothelial cells from tumor tissues is still a fundamental problem. In this study, we have attempted to develop a reliable method for the isolation of endothelial cells from murine tumors. We found that the labeling with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-acetylated-low density lipoprotein (Dil-Ac-LDL), commonly used for this purpose, can result in the contamination of isolated endothelium by macrophages due to the overlapping staining patterns of these two distinct cell types. Therefore, we chose the CD16, which is expressed on macrophages but not endothelial cells, to better distinguish them when labeled with Dil-Ac-LDL. By using this method, we obtained pure populations of endothelial cells and macrophages from murine colorectal cancer tissues, showing characteristic morphological and functional properties of the either cell type. The endothelial cells were long spindle-shaped, spread on gelatin, formed tube-like structures on Matrigel and expressed MECA-32 but not CD68. In contrast, the macrophages were round-shaped, partially spread on gelatin, formed unorganized aggregates on Matrigel and expressed CD68 but not MECA-32. The additional analysis of normal and tumor tissues revealed a positive correlation between the relative numbers of tumor endothelial cells and macrophages, calculated as % total cells, as well as the respective relative number and tumor weight. The present method is hoped to be useful for the evaluation of tumor angiogenesis and antitumor immunity.

Background Although green tea polyphenol catechin has been reported to have antiallergic and anti-inflammatory activities, the precise mechanisms of its effect on the immune system have been poorly investigated. Objective In this study, we aimed to elucidate the mechanisms of the anti-inflammatory effect of catechin. For this purpose, we studied the effect of 2 kinds of catechin, epigallocatechin gallate (EGCG) and epicatechin gallate, on peripheral blood CD8+ T cells, which play the key role in immune responses. Methods Isolated peripheral blood mononuclear cells or CD8+ T cells were incubated without or with catechin, and the changes in the surface expression of integrin molecules were investigated by flow cytometry and the direct binding of catechin to CD11b molecule by competitive ELISA. Also, the effect of catechin on the ability of CD8+ T cells to bind intracellular adhesion molecule 1 and to migrate in response to chemokines was evaluated by using the adhesion and migration assays. Results The 2 catechins directly bound to CD11b expressed on CD8+ T cells, which caused a consequent decrease of flow-cytometric CD11b expression. The effect was more prominent with EGCG than epicatechin gallate, and the impaired expression of CD11b induced by EGCG resulted in decreased ability of CD8+ T cells to adhere intercellular adhesion molecule 1, and consequently decreased migration in response to chemokines. Conclusion We concluded that catechin, especially EGCG, by downregulating CD11b expression on CD8+ T cells and, in consequence, inhibiting infiltration of these cells into the sites of inflammation, is a promising new potent anti-inflammatory agent.

243 Background: We commenced a physician-led clinical trial to examine the efficacy of a combined treatment of peptide vaccine therapy for advanced pancreatic cancer that has no effective treatment. During this trial, there were inquiries from 367 cases, of which 145 cases (40%) were examined at our outpatient clinic. The purpose of this study was to examine these cases in detail and to consider the points to be noted in executing clinical trials for poor prognosis cases. Methods: We examined the timing of inquiry, medical condition, the person(s) they inquired, and other relevant information regarding the 367 subjects who made inquiries. For the 145 cases visited the outpatient clinic of our hospital, we examined their medical condition, treatment and whether or not they have participated in a clinical trial. Results: 140 of the 367 cases (38%) of inquiry were concentrated within the first two months after the start. During these two months, there was a concentration of patients who had completed standard treatments and were a few months into BSC, but were unable to participate in the clinical trial due to deterioration of their general condition. Many of the inquiries were made by family members (spouse or child) of the patients, around twice the number of inquiries made by patients themselves. Even among the 145 subjects that were examined in the outpatient clinic of our hospital, severe cases, in particular, were seen several months after the start of the study. There were many cases that required urgent hospitalization during outpatient visits or patients whose general condition rapidly deteriorated during the screening tests. 23 cases (16%) underwent the clinical trial. Conclusions: In clinical trials such as this one, which handles cases with poor prognosis, many of the subjects are in poor general condition at the inquiry stage, and most of these inquiries are concentrated immediately after the start of the study. Therefore, it is very important to deal with inquiries and make judgments during the outpatient examination on whether or not clinical trial participation is possible.

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)or isovorin) 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 followup strategies.

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.

Inhibitor of DNA binding (Id) proteins are essential for cell differentiation, proliferation, migration, invasion and angiogenesis. Recently, they have been shown to correlate with less differentiated phenotypes, high malignant potential and poor clinical outcome in various kinds of tumors. In an attempt to develop new strategies for the treatment of peritoneal metastasis of gastric cancer, we prepared an Id1, 3 double-knockdown gastric cancer cell line, MKN45, by RNA interference and investigated its effects on the development of metastatic nodules in the peritoneal cavity. Both cell proliferation and migration capabilities were decreased in Id1, 3 double-knockdown cells, as was their ability to bind to laminin, which could be explained by the decreased expression of integrin α6. These are important steps in the metastatic process. In a mouse model, the number of peritoneal metastatic nodules formed by Id1, 3 double-knockdown cells was reduced compared to mock-transfected control cells, as was the size of individual tumors. In this study, we clearly demonstrated that Id1, 3 double-knockdown significantly impaired the ability of gastric cancer cells to form peritoneal metastasis. Id should be considered an ideal target for the treatment and prevention of gastric cancer, and RNA interference is an attractive and promising strategy to achieve it. (Cancer Sci 2005; 96: 784–790)

Id genes (inhibitor of DNA binding/differentiation) play important roles in tumour growth. We have previously described crucial roles of Id gene over-expression in endothelial cells for tumour angiogenesis. Here, we have evaluated direct effects of Id gene down-regulation on tumour cells, namely on cell proliferation, motility, and adhesion to lung microvasculature during haematogenous metastasis. For this purpose, Id genes were stably down-regulated by RNA interference in human colorectal cancer cells. These cells showed delayed proliferation, inhibited motility and decreased expression of integrin alpha6 and consequently reduced adhesion to lung microvasculature in mice. Static adhesion assays and laminar flow assays revealed decreased laminin binding capacity of these cells, and blocking experiments confirmed that it could be attributed to decreased expression of integrin alpha6. The present results indicate important roles of Id genes in tumour cells during early steps of haematogenous metastasis and suggest dual effects from their therapeutic inhibition.

We have investigated a potential anti-angiogenic effect of plaunotol, an extract from the leaves of Plau-noi, in an angiogenesis model consisting of human umbilical vein endothelial cells (HUVECs). Plaunotol inhibited the proliferative activity of HUVECs in a dose-dependent manner. In addition, it caused a remarkable decrease of the ability of HUVECs to adhere and spread on gelatin and vitronectin, but not fibronectin. Tube-like formation in Matrigel was also inhibited in a dose-dependent way. These results strongly suggest the specific inhibition of integrin alphavbeta3 to be the main event of plaunotol-induced suppression of angiogenesis. The alphavbeta3 antagonists are known to be potent inhibitors of tumor angiogenesis and plaunotol, by causing the functional inhibition of alphavbeta3, should be considered a promising new anti-angiogenic drug.

High level expression of cyclooxygenase (COX)-2 is reported in 80–90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX-2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell-surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high-COX-2 (high level COX-2 expression) colon cancer cell line, HT-29, and a low-COX-2 (low level COX-2 expression), DLD-1, were used to investigate the anticolon cancer effect of the selective COX-2 inhibitor, JTE-522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE-522 caused a dose-dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down-regulation of β1-integrin expression, which was evident in HT-29, the high-COX-2 colon cancer cells, but not the low-COX-2, DLD-1. In addition, prostaglandin E2 almost completely reversed the effect of JTE-522, strongly suggesting the involvement of a COX-2-dependent pathway. In conclusion, for the first time, we could demonstrate the down-regulation of β1 integrin caused by COX-2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop. (Cancer Sci 2005; 96: 93–99)

Background Monocytes are the main effector cells of the immune system, and the regulation of their survival and apoptosis is essential for monocyte-involved immune responses. Green tea polyphenol catechin has been reported to have antiallergic and anti-inflammatory activities, but its effect on monocytes has not yet been explored. Objective To elucidate the mechanisms of the anti-inflammatory effect of catechin, we studied the effect of catechin, especially epigallocatechin gallate (EGCG), on the apoptosis of monocytes. Methods Isolated peripheral blood monocytes were incubated without or with catechin, and apoptosis was evaluated by annexin V and propidium iodide double-staining or terminal deoxynucleotidyl assay. The activation of caspases 3, 8, and 9 was also evaluated by flow cytometry. The influence of GM-CSF or LPS, the known monocyte survival factors, on the EGCG-induced apoptosis of monocytes was investigated. Results Among the 4 catechin derivatives tested, EGCG and epicatechin gallate induced apoptosis of monocytes. Caspases 3, 8, and 9, which play a central role in the apoptotic cascade, were dose-dependently activated by EGCG treatment. The EGCG-induced apoptosis of monocytes was not affected by GM-CSF or LPS. Conclusion Catechin, especially EGCG, by promoting monocytic apoptosis, may be a new promising anti-inflammatory agent, and should be tested in clinical trials.

High-level expression of cyclooxygenase (COX)-2 is reported in 80-90% of colorectal adenocarcinomas. Selective inhibition of COX-2 was shown to reduce colorectal tumorigenesis in different models of carcinogenesis and to prevent metastasis in xenograft tumor models, as well as to suppress in vitro induced angiogenesis. Recently, COX-2 was reported to be expressed not only in malignant epithelial cells, but also in the neovasculature that feeds the tumor in a variety of solid human cancers. Thus, one of the possible mechanisms by which selective COX-2 inhibitor reduces tumor growth and metastasis is through inhibition of tumor angiogenesis. Although a report suggested a possible role of endothelial COX-1 in the process of angiogenesis, in a recent study, the selective inhibition of COX-2 was shown to strongly inhibit angiogenesis by inducing endothelial cell (EC) apoptosis. In the present study, using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the potential antiangiogenic effect of the selective COX-2 inhibitor and its mechanism of action, and clearly demonstrated that selective inhibition of COX-2 caused a dose-dependent decrease in the proliferative activity of ECs, as well as an inhibition of capillary-like tube formation. The inhibitory effect on EC proliferation was dependent on the cell cycle arrest to the G1 phase and not on cell apoptosis.

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have been developed as lipid-lowering drugs, and are well recognized to reduce morbidity and mortality from coronary artery disease. Several recent experimental studies have focused on the inhibitory effects of HMG-CoA reductase inhibitor on tumor cell growth in vitro and in vivo, dependent on a direct effect on cancer cells. In the present study, we aimed to investigate the potential anti-angiogenic effect of pravastatin and its mechanism of action. Using human umbilical vein endothelial cells (HUVECs) as a model of angiogenesis, we investigated the effect of pravastatin on the various steps of angiogenesis, including endothelial cell proliferation and adhesion to extracellular matrix proteins. Pravastatin induced a dose-dependent decrease in the proliferative activity of endothelial cells, which was dependent on the cell cycle arrest to the G 1 phase and not on cell apoptosis. G 1 arrest was due to the decrease of cyclin D, cyclin E and cyclin-dependent kinase 2 levels. In addition, pravastatin inhibited tube formation on Matrigel and adhesion to extracellular matrix, but did not affect matrix metalloproteinase production. The present results demonstrate the anti-angiogenic activity of pravastatin and its potential use as an anticancer drug is suggested.

Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon-26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti-tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow-cytometry and chromium-release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio-dependent manner. Neither antibodies nor CTLs reacted with Colon26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HU-VECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self-angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer. (Cancer Sci 2004; 95: 85–90)

Background: Epigallocatechin gallate (EGCG), the major component of tea polyphenol, has been reported to have various physiologic modulatory activities. Several reports also have shown that catechin has a protective effect against HIV infection, part of which is mediated by inhibiting virions to bind to the target cell surface. Objective: We investigated the effect of EGCG on the expression of CD4 molecules and on its ability to bind gp120, an envelope protein of HIV-1. Methods: Peripheral blood CD4+ T cells were incubated in the presence of EGCG, and the expression of CD4 was evaluated by means of flow cytometry. The effect of EGCG on the antibody binding to CD4 was investigated by using a sandwich ELISA, and the effect on the gp120 binding to CD4 was analyzed by means of flow cytometry. Results: EGCG efficiently inhibited binding of anti-CD4 antibody to its corresponding antigen. This effect was mediated by the direct binding of EGCG to the CD4 molecule, with consequent inhibition of antibody binding, as well as gp120 binding. Conclusion: The present results suggest a potential preventive effect of EGCG on HIV-1 infection by modulating binding to CD4. (J Allergy Clin Immunol 2003;112:951-7.)