Successful treatment of rectovaginal fistula complicating ulcerative colitis with infliximab: a case report and review of the literature.

Rectovaginal fistula is a rare complication of ulcerative colitis (UC) regardless of surgical history of rectum. Various surgical treatment modalities for the closure of rectovaginal fistula have been developed, but a radically curative therapy remains to be developed. Recently, infliximab, the chimeric anti-human tumor necrosis factor alpha (TNF-α) antibody, has been largely applied for the treatment of inflammatory bowel disease (IBD), and a few reports have shown its partial effectiveness in the management of rectovaginal fistulas associated with UC. In the present report, we describe the successful management of a rectovaginal fistula, following the stapled ileo-anal canal anastomosis in a UC patient, by administration of infliximab. The patient was a 40-year-old female, initially diagnosed as UC (total colitis type) at the age of 15. She received a restorative proctocolectomy at the age of 22, and developed a rectovaginal fistula at the eighth postoperative day. The surgical treatment of the fistula was repeated four times during the 10-year period, but it recurred in intervals ranging between 2 months and 5 years after the operation. The last recurrence occurred at the age of 32, but the surgical repair was considered difficult and a conservative management was indicated. At the age of 40, infusions of infliximab were started. Four weeks after the first infusion, drainage from the fistula was evidently reduced, and 2 weeks later, the fistula was completely closed. Thereafter, no recurrence of the fistula is observed, as confirmed by the abdominal magnetic resonance imaging (MRI) and the barium-enema study. From the present case, we concluded that infliximab may be an effective strategy for the management of fistulas associated with UC.

Barium enema and CT volumetry for predicting pathologic response to preoperative chemoradiotherapy in rectal cancer patients.

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.

Drug development for intraperitoneal chemotherapy against peritoneal carcinomatosis from gastrointestinal cancer.

Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.

Colorectal cancer with multiple metachronous metastasis achieving complete remission 14 years after surgical resection: report of a case.

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.

Thrombocytosis before pre-operative chemoradiotherapy predicts poor response and shorter local recurrence-free survival in rectal cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Laboratory blood data have a significant impact on tumor response and outcome in preoperative chemoradiotherapy for advanced rectal cancer.

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 < 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 (>1,800/mm(3)) 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.

[FOLFOX as adjuvant chemotherapy after curative resection of distant metastatic lesions in patients with colorectal cancer].

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.

FOLFOX as adjuvant chemotherapy after curative resection of distant metastases in patients with colorectal cancer.

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.

Density of CD4(+) and CD8(+) T lymphocytes in biopsy samples can be a predictor of pathological response to chemoradiotherapy (CRT) for rectal cancer.

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.

Catechin inhibits adhesion and migration of peripheral blood B cells by blocking CD11b.

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.

Radiosensitization of human breast cancer cells to ultraviolet light by 5-fluorouracil.

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.

Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer.

Although neoadjuvant chemoradiotherapy (CRT) is the standard treatment for advanced rectal cancer (RC), markers to predict the treatment response have not been fully established. In 73 patients with advanced RC who underwent CRT in a neoadjuvant setting, we retrospectively examined the associations between the clinical effects of CRT and blood cell counts before and after CRT. Clinical or pathological complete response (CR) was observed in 10 (14%) cases. The CR rate correlated significantly with the size and the circumferential extent of the tumor. Hemoglobin level, white blood cell (WBC) count and platelet count before CRT did not show a significant difference between CR and non-CR cases. Interestingly, however, lymphocyte ratio in WBC was significantly higher (p = 0.020), while neutrophil ratio tended to be lower (p = 0.099), in CR cases, which was shown to be an independent association by multivariate analysis. When all the blood data obtained in the entire treatment period were evaluated, circulating lymphocyte count was most markedly decreased in the CRT period and gradually recovered by the time of surgery, while the numbers of neutrophils and monocytes were comparatively stable. Moreover, the lymphocyte percentage in samples obtained from CR patients was maintained at a relatively higher level than that from non-CR patients. Since tumor shrinkage is known to be dependent not only on the characteristics of tumor cells but also on various host conditions, our data raise the possibility that a lymphocyte-mediated immune reaction may have a positive role in achieving complete eradication of tumor cells. Maintenance of circulating lymphocyte number may improve the response to CRT in rectal cancer.

Pilot study of anti-angiogenic vaccine using fixed whole endothelium in patients with progressive malignancy after failure of conventional therapy.

Vaccines targeting tumour angiogenesis were recently shown to inhibit tumour growth in animal models. However, there is still a lack of information about the clinical utility of anti-angiogenic vaccination. Therefore, here, we aimed to test the clinical effects of a vaccine using glutaraldehyde-fixed human umbilical vein endothelial cells (HUVECs). Six patients with recurrent malignant brain tumours and three patients with metastatic colorectal cancer received intradermal injections of 5x10(7) HUVECs/dose (in total 230 vaccinations). ELISA and flow cytometry revealed immunoglobulin response against HUVECs' membrane antigens. ELISPOT and chromium-release cytotoxicity assay revealed a specific cellular immune response against HUVECs, which were lysed in an effectors:targets ratio-dependent manner. Gadolinium-contrasted MRI showed partial or complete tumour responses in three malignant brain tumour patients. Except for a DTH-like skin reaction at the injection site, no adverse effect of vaccination could be observed. Our results suggest that the endothelial vaccine can overcome peripheral tolerance of self-angiogenic antigens in clinical settings, and therefore should be useful for adjuvant immunotherapy of cancer.

Plaunotol induces apoptosis of gastric cancer cells.

Although some isoprenoids, such as taxans and geranylgeraniol (GGOH), have been reported to have strong anticancer activities, the effect of plaunotol, the isoprenoid extracted from the leaves of Plau-noi, on cancer has not yet been evaluated. Here, we aimed to investigate the effect of plaunotol on gastric cancer cell lines. Three gastric cancer cell lines, namely MKN-45, MKN-74 and AZ-521 were used. Plaunotol was tested at 10, 20, 30 and 40 micromol/L. Plaunotol dose-dependently inhibited the growth of all gastric cancer cells, dependent on the induction of apoptosis. Caspases-8, -9 and -3, were found to be activated in the apoptotic cells. The expression of Bax protein was increased, but Bcl-2 and Bcl-xL protein expressions were not significantly affected. Plaunotol should be a promising new antitumor agent, and since it is already available for clinical use in Japan, its anticancer properties should be confirmed in clinical trials.

Epigallocatechin gallate induces apoptosis of monocytes.

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.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (pravastatin) inhibits endothelial cell proliferation dependent on G1 cell cycle arrest.

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 G1 phase and not on cell apoptosis. G1 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.

Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer through autoimmunity.

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 Colon-26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HUVECs), 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.

Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding.

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.