Synchrotron radiation microtomography of brain hemisphere and spinal cord of a mouse model of multiple sclerosis revealed a correlation between capillary dilation and clinical score.

Multiple sclerosis is a neurological disorder in which the myelin sheaths of axons are damaged by the immune response. We report here a three-dimensional structural analysis of brain and spinal cord tissues of a mouse model of multiple sclerosis, known as experimental autoimmune encephalomyelitis (EAE). EAE-induced mice were raised with or without administration of fingolimod, which is used in the treatment of multiple sclerosis. Brains and spinal cords dissected from the EAE mice were lyophilized so as to reconstitute the intrinsic contrast of tissue elements, such as axons, in X-ray images. Three-dimensional structures of the brain hemispheres and spinal cords of the EAE mice were visualized with synchrotron radiation microtomography. Microtomographic cross sections reconstructed from the X-ray images revealed dilation of capillary vessels and vacuolation in the spinal cord of the EAE mice. Vacuolation was also observed in the cerebellum, suggesting that the neuroinflammatory response progressed in the brain. The vessel networks and vacuolation lesions in the spinal cords were modelled by automatically tracing the three-dimensional image in order to analyze the tissue structures quantitatively. The results of the analysis indicated that the distribution of vacuolations was not uniform but three-dimensionally localized. The mean vessel diameter showed a linear correlation with the clinical score, indicating that vasodilation is relevant to paralysis severity in the disease model. We suggest that vasodilation and vacuolation are related with neurological symptoms of multiple sclerosis.

Monitoring Mitochondrial Complex-I Activity Using Novel PET Probe 18F-BCPP-EF Allows Early Detection of Radiotherapy Effect in Murine Squamous Cell Carcinoma.

OBJECTIVES: Aerobic glycolysis, the main pathway of energy production in tumors (Warburg effect) allows detection of tumors by positron emission tomography (PET) using 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Since ionizing radiation (IR) is reported to switch aerobic glycolysis to mitochondrial oxidative phosphorylation, radiotherapeutic efficacy was monitored by the activity of mitochondrial complex I (MC-I), using a new PET probe 18F-BCPP-EF, 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy] -pyridine-3-ylmethoxy}-2H-pyridazin-3-one, compared with 18F-FDG uptake and the apoptosis index. METHODS: Tumor uptake of 18F-BCPP-EF or 18F-FDG was examined in C3H/HeN mice inoculated with murine squamous cell carcinoma SCCVII at various time points after a single dose of x-ray irradiation at 0, 6, 15, or 30 Gy. Apoptosis incidence was determined by TUNEL staining in excised tumor tissue. RESULTS: Tumor growth suppression was dose-dependent; tumor grew 10-fold (0 Gy), 5-fold (6 Gy), 2-fold (15 Gy), and reduced to half in its volume (30 Gy) 14 days after treatment. 18F-BCPP-EF uptake was significantly increased as early as 3 days after 15 Gy or 30 Gy, when tumor size and apoptosis index showed no difference among radiation doses. In contrast, 18F-FDG uptake was initially increased dose-dependently, remained elevated up to 7 days, and eventually decreased 10 days after 30 Gy and also 14 days after 15 Gy when tumor size was already reduced. Apoptosis index was increased after irradiation but failed to correlate with tumor response. CONCLUSION: Tumor uptake of 18F-BCPP-EF was increased dose-dependently early after effective doses of IR when 18F-FDG uptake as well as apoptosis incidence were not indicative of tumor response. The results suggest that 18F-BCPP-EF is a promising "positive" MC-I imaging PET probe for early detection of efficacy of tumor radiotherapy.

Liposome-Encapsulated Hemoglobin Improves Tumor Oxygenation as Detected by Near-Infrared Spectroscopy in Colon Carcinoma in Mice.

Liposome-encapsulated hemoglobin (LEH) with high (h-LEH, P50 O2  = 10 mm Hg) or low O2 affinity (l-LEH, P50 O2  = 40 mm Hg) may improve O2 delivery to sensitize tumor tissues for radiotherapy. A total of 10 mL/kg of h-LEH, l-LEH, red blood cells (RBCs), or saline was infused in mice transplanted with murine colon carcinoma with near-infrared spectroscopy (NIRS) detectors set at the tumor (right leg) and intact muscle (left leg). NIRS recorded changes in the amount of oxyhemoglobin (oxyHb), deoxyhemoglobin (deoxyHb), and their sum (tHb) with the animals spontaneously breathing room air (10 min), pure O2 (5 min), and then back to room air. The tumor was finally excised for histological examination. In mice treated with h-LEH, tHb significantly increased compared to mice receiving other solutions. The magnitude was significantly attenuated in the tumor compared to the intact muscle under room air. Reciprocal changes in oxyHb and deoxyHb between intact muscle and tumor in response to infused solutions allowed assumption of average tissue PO2 between 30 and 40 mm Hg in muscle and at around 10 mm Hg in tumor. While O2 respiration increased oxyHb and decreased deoxyHb both in muscle and tumor, their sum or tHb consistently decreased in muscle and increased in tumor regardless of preceding infusion. Such responses were totally reversed when mice were placed under hypoxia (10% O2 ), suggesting that a lack of physiological circulatory regulation in tumor may account for heavier immunohistochemical staining for human hemoglobin in tumors of mice treated with h-LEH than with l-LEH. The results suggest that h-LEH may cause significant tumor oxygenation compared to RBC, l-LEH, or saline probably due to its nanometer size (vs. RBC) and high O2 affinity (vs. l-LEH) without increasing O2 content in the intact tissue (vs. O2 respiration) probably due to a lack of physiological circulatory regulation.

Relation between Carcinoembryonic Antigen Levels in Colon Cancer Tissue and Serum Carcinoembryonic Antigen Levels at Initial Surgery and Recurrence.

OBJECTIVES: Carcinoembryonic antigen (CEA) is widely used for postoperative surveillance of colon cancer. Even if serum CEA is negative at initial surgery, it may turn positive at recurrence. We investigated the relation between serum CEA levels and the immunohistochemical staining status of CEA in the primary and resected metastatic tissues. METHODS: Out of 224 patients with recurrent colon cancer between 1998 and 2012, we studied 46 patients in whom serum CEA levels were measured and immunohistochemical staining for CEA was possible in the primary and metastatic tissues. RESULTS: The positive rate of serum CEA did not differ between initial surgery and recurrence, regardless of whether the cutoff value was set at 5 or 10 ng/ml (p = 0.829, p = 0.671). There was no relation between the CEA staining status and serum CEA level at initial surgery. However, the CEA staining status of metastatic tissue was significantly related to the serum CEA level at recurrence (p = 0.0046 and p = 0.0026). CONCLUSIONS: The immunohistochemical staining status of CEA in metastatic tissue is closely related to the serum CEA level. This finding suggests that serum CEA levels are influenced not only by the CEA production capacity of cancer cells but also by the ability of the surrounding tissue to release CEA into the blood.

Increase in Gene Expression of TYMP, DPYD and HIF1A Are Associated with Response to Preoperative Chemoradiotherapy Including S-1 or UFT for Rectal Cancer.

AIM: The aim of the study was to identify biomarkers capable of predicting response to preoperative chemoradiotherapy (CRT) including S-1 or UFT for rectal cancer using biopsy specimens obtained before CRT (Pre-samples) and 7 days after the start of CRT (Day-7 samples). MATERIALS AND METHODS: Preoperative CRT including S-1 or UFT was performed in 82 patients with locally advanced rectal cancer. The expression levels of 18 genes related to 5-fluorouracil, folate, and radiation in the Pre-samples and the Day-7 samples were evaluated using reverse transcription polymerase chain reaction (RT-PCR) assay. RESULTS: The gene expression levels of hypoxia inducible factor 1 alpha subunit (HIF1A), dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) were found significantly increased in Day-7 samples compared to Pre-samples in responders, but not in non-responders. CONCLUSION: Increases in gene expression levels of TYMP, DPYD, and HIF1A in tumor tissues at 7 days after the start of CRT may be useful for predicting the efficacy of CRT including S-1 or UFT.

Predictive markers of chemoradiotherapy for rectal cancer: comparison of biopsy specimens taken before and about 1 week after the start of chemoradiotherapy.

BACKGROUND: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in patients with rectal cancer. Although various biomarkers in biopsy specimens obtained before starting CRT have been examined, reliable prognostic factors have yet to be established. We tested the hypothesis that biopsy specimens obtained soon after the start of CRT can be used as prognostic factors. METHODS: Preoperative CRT was given to 70 consecutive patients with rectal cancer. Biopsies were taken before and about 7 days after starting CRT. The specimens were stained with hematoxylin and eosin (HE), and the expressions of Ki67, p53, and p21 and apoptosis were evaluated immunohistochemically. RESULTS: The expressions of Ki67, p53, and p21 and apoptosis before treatment were not significantly related to histologic response or tumor shrinkage. In specimens obtained about 7 days after CRT began, marked histologic regression was significantly higher in p21-positive, apoptosis-positive cases, and in cases with moderate changes on HE specimens (p = 0.017, p = 0.010, and p = 0.004, respectively). The tumor shrinkage was significantly higher in apoptosis-positive cases and cases with moderate changes on HE specimens (p = 0.002 and p < 0.001, respectively). Disease-free survival (DFS) was significantly higher in patients who had marked regression than in those who did not (p = 0.019). DFS was also significantly higher in patients with moderate changes on HE specimens than in those with mild changes (p = 0.016). CONCLUSIONS: Changes on HE-stained biopsy specimens obtained about 1 week after starting CRT are a reliable prognostic factor, similar to histologic marked regression in resected specimens; a major advantage is that the former results are available at an early phase.

A Phase II Trial of Combined Chemotherapy with Oral S-1 and 24-Hour Infusions of Irinotecan plus Bevacizumab in Patients with Metastatic Colorectal Cancer.

OBJECTIVES: Protracted low-dose infusion of irinotecan has been suggested to enhance antitumor activity. A phase II study was conducted to evaluate the safety and efficacy of oral S-1 combined with 24-hour infusion of irinotecan and intravenous bevacizumab for metastatic colorectal cancer (MCRC). METHODS: The subjects were 79 patients with MCRC; 57 were chemotherapy naïve. Irinotecan (125 mg/m(2)) was administered as a 24-hour infusion on days 1 and 15, S-1 (80 mg/m(2)) was administered orally on days 1-14, and bevacizumab (5.0 mg/kg) was given on days 1 and 15. The treatment was repeated every 4 weeks. RESULTS: Median follow-up was 20.0 months, and the mean number of cycles was 7. The overall response rate was 79.7% (95% CI, 69.2-88.0), 86.0% (95% CI, 74.2-93.7) for first-line and 63.6% (95% CI, 40.7-82.8) for second-line treatment. The median progression-free survival was 16.4 months (95% CI, 13.9-21.0) for first-line and 9.4 months (95% CI, 4.9-16.5) for second-line treatment. The median overall survival was not reached. Grade 3-4 toxicities were neutropenia (43%), leukopenia (20.3%), anorexia (19.0%), and diarrhea (10.1%). Toxicity was tolerable. CONCLUSIONS: Combination chemotherapy with oral S-1 and biweekly 24-hour infusions of irinotecan plus bevacizumab appears to be highly active and well tolerated both as first-line and second-line chemotherapy for MCRC.

Phase II study of preoperative concurrent chemoradiotherapy with S-1 plus bevacizumab for locally advanced resectable rectal adenocarcinoma.

OBJECTIVE: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of preoperative chemoradiotherapy (CRT) with concurrent S-1, bevacizumab, and radiation in patients with locally advanced rectal cancer (LARC). METHODS: Fifty-two patients with LARC were enrolled. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, S-1 was administered orally twice a day on days 1-14 and 22-35, and bevacizumab was administered on days 1, 15, and 29. Surgical resection was scheduled 8 weeks (6-10 weeks) after completing the CRT. RESULTS: All 52 patients underwent R0 radical surgery. Sphincter preservation was possible in 38 (73.1%) patients. A pathologic complete response was obtained in 10 (19.2%) patients, a pathologic downstaging was achieved in 37 (71.2%) patients, and the tumor shrinkage rate was 77.1%. The only grade 3 adverse events were leukopenia and rash in 1 (1.9%) patient. The rate of postoperative complications was 28.8%. Anastomotic leakage occurred in 9 (23.7%) of the 38 patients who underwent sphincter-preserving surgery. Perineal wound dehiscence developed in 2 (14.3%) of the 14 patients who received an abdominoperineal resection. CONCLUSIONS: Adding bevacizumab to S-1 clearly increased the incidence of wound-related complications, with no distinct enhancement of tumor response.

Liposome-encapsulated hemoglobin enhances chemotherapy to suppress metastasis in mice.

Liposome-encapsulated hemoglobin with high O2 -affinity (P50 O2 = 10 mm Hg, h-LEH) was reported to enhance tumor radiosensitivity. We hypothesize that targeted O2 delivery to tumor hypoxia by h-LEH may also enhance chemotherapy to suppress tumor growth and metastasis in mice. Doxorubicin (DXR; 0.5 or 2 mg/kg i.p.) or S-1 (4 or 8 mg/kg orally) alone or in combination with h-LEH (5 mL/kg i.v.) was administered for 2 weeks to C57BL/6N mice inoculated with Lewis Lung Carcinoma (LLC) in the leg. After the 2-week therapy in six treatment groups, mice were sacrificed for quantitative assessment of tumor growth and lung metastasis. The tumor was then evaluated for its expression of hypoxia-inducible factor-1α (HIF-1α) and matrix metallopoteinase-2 (MMP-2) activity. Combined use of h-LEH and chemotherapeutic agents (DXR or S-1) showed no additional enhancement on suppression of the tumor growth over the chemotherapeutic agent alone. However, the combination use of h-LEH significantly suppressed the number and total area of metastatic colonies in the lung compared with each chemotherapeutic agent alone. Although HIF-1α expression and MMP-2 activity in the original tumor was significantly suppressed in the groups of mice treated with either DXR or S-1 alone, the addition of h-LEH to either agent showed further enhancement of oxygen-mediated degradation of HIF-1α and suppression of MMP-2 activity. Although the addition of h-LEH to DXR or S-1 had little effect on original LLC tumor growth, it significantly enhanced suppression of lung metastasis in mice.

Effects of chemoradiotherapy on lymph nodes in patients with rectal adenocarcinoma: evaluation of numbers and sizes of retrieved lymph nodes inside and outside the radiation field.

BACKGROUND: Preoperative chemoradiotherapy (CRT) decreases the number of retrieved lymph nodes (LNs) in rectal cancer. LNs inside the irradiation field are affected by CRT, whereas those outside the irradiation field are affected only by concurrent chemotherapy. PATIENTS AND METHODS: The study cohort comprised of 210 patients with clinical stage II/III rectal adenocarcinoma. One hundred and eight received surgery alone (S group), and 102 received preoperative CRT (40 or 45 Gy) with concurrent oral UFT or S-1 uracil/tegafur or S-1 (CRT group). RESULTS: The number of LNs inside the irradiation field was significantly smaller in the CRT group (4 ± 4) than in the S group (6 ± 6, p<0.01), but the number of LNs outside the irradiation field did not differ (5 ± 4 in both groups). The longest diameters of LNs in the S group were significantly smaller than those of the CRT group both inside and outside the irradiation fields (p<0.01). CONCLUSION: The effects of CRT on LNs in patients with rectal adenocarcinoma differed inside and outside the radiation field.

Relationship between histologic response and the degree of tumor shrinkage after chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in advanced rectal cancer. We studied whether the degree of tumor shrinkage can be used as a predictor of histologic response. METHODS: The subjects were 114 patients with locally advanced rectal cancer who underwent total mesorectal excision after receiving radiotherapy combined with uracil/tegafur (UFT) or S-1. The degree of tumor shrinkage based on barium enema examination and magnetic resonance imaging (MRI) were assessed before CRT and immediately before surgery. RESULTS: A histologic complete response (ypCR), histologic marked regression, T and N downstaging were associated with significantly higher tumor-shrinkage rates on barium enema (P < 0.01, P < 0.01, P < 0.01, and P < 0.01, respectively) as well as on MRI (P < 0.01, P < 0.01, P < 0.01, and P = 0.01, respectively). On multivariate analysis, ypCR and histologic marked regression were significantly related only to tumor-shrinkage rates on barium enema (P < 0.01 and P < 0.01, respectively), and were not related to tumor-shrinkage rates on MRI. CONCLUSIONS: The degree of tumor shrinkage is closely related to the final histologic response. Two-dimensionally evaluated tumor-shrinkage rates based on barium enema are adequate for the prediction of histologic response.

Fermentation of non-sterilized fish biomass with a mixed culture of film-forming yeasts and lactobacilli and its effect on innate and adaptive immunity in mice.

Non-sterilized fish waste containing fish bones was fermented using combined starter cultures of film-forming yeast (Candida ethanolica) and lactic acid bacteria (LAB; Lactobacillus casei and Lactobacillus rhamnosus) in order to obtain a liquefied fermented broth without spoiling. During the entire fermentation, the number of LAB cells was maintained at a high level (6 × 10(8)-5 × 10(7) cells/ml). Although the number of general bacteria was 10(6)cell/ml after adding non-sterilized fish biomass, its growth was suppressed to be 1-3 × 10(4) cells/ml. The entire biomass had completely liquefied and the fermented broth contained all 20 α-amino acids composed of protein and also various kinds of minerals in abundance. The weight of mice group fed the fermented broth content feed (sample feed) for 31 days significantly increased compared with that fed no broth feed (control feed) (21.37 g vs 20.76 g (p < 0.05). No abnormal behavior and appearance were observed. All internal organs (the heart, the liver, the lung, the intestines, and the spleen) of both groups were confirmed to be normal by visual observation. In peripheral blood, the percentages of NK cells and CD8+ T cells of the mice in the sample feed group increased significantly relative to those in the control feed group (NK cells: 19% vs 11%, CD8+ T cells: 9% vs 5%, p < 0.05). In the spleen, the percentage of NK cells in the sample feed group also increased significantly compared to that in the control feed group (p < 0.05). The fermented fish biomass is expected to be effective for innate and adaptive immunity and thus fit for animal feed.

Reduction in γ-glutamyl hydrolase expression is associated with response to uracil and tegafur/leucovorin chemotherapy in patients with colorectal cancer.

To identify the genes and clinical parameters associated with efficacy of uracil and tegafur/leucovorin (UFT/LV) chemotherapy in colorectal cancer (CRC), we compared the levels of reduced folate in tumors between patients receiving LV and those not receiving LV (study I), and explored the changes in the expression levels of 14 genes after two weeks of UFT/LV chemotherapy in 73 patients with CRC (study II). In study I, the reduced folate levels after LV administration were approximately 3-fold higher than those without LV administration in patients with right-sided tumors or aged >75 years old (p=0.019). In study II, the reduction in γ-glutamyl hydrolase (GGH) expression in responders and in patients with right-sided tumors or aged >75 years old was significantly greater than that in non-responders (p<0.001) and in other patients, respectively (p=0.003). Increase of reduced folate and reduction in GGH expression were associated with response to UFT/LV chemotherapy in patients with right-sided tumors or aged >75 years old.

Optimal sutures for use in the abdomen: an evaluation based on the formation of adhesions and abscesses.

PURPOSE: This study explored the optimal suture materials for use in the peritoneal cavity based on the formation of adhesions and abscesses under clean and contaminated conditions. METHODS: The parietal peritoneum and muscle layer of rats were incised. The incision was followed by interrupted suturing in the clean group. A suspension of E. coli (1.0 × 10(6)) plus Bacteroides fragilis (1.0 × 10(5)) was sprayed onto the incision in the contaminated group, followed by interrupted suturing. Four types of sutures were used: nonabsorbable multifilament silk, absorbable multifilament Polyglactin 910 (Vicryl(®)), absorbable monofilament Polydioxanone (PDS(®)), and Poliglecaprone 25 (Monocryl(®)). The rats were killed at 2, 4 or 8 weeks after the surgery. RESULTS: The incidence of adhesions in the clean group was low with Polyglactin 910. The incidence of adhesions was 96 % or higher regardless of the suture type in the contaminated group. The incidence of severe adhesions was low with Polyglactin 910 and Poliglecaprone 25 and significantly higher with Polydioxanone in the contaminated group. The incidence of abscess formation around the silk was significantly higher than the other three types of sutures in the contaminated group. CONCLUSION: Polyglactin 910 was less likely to form adhesions than the other three types of sutures under both conditions, suggesting that Polyglactin 910 may be the optimal type of suture to use in the peritoneal cavity.

Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer.

PURPOSE: Preoperative chemoradiation therapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Various biomarkers in biopsy specimens obtained before CRT have been proposed as predictors of response. However, reliable biomarkers remain to be established. METHODS AND MATERIALS: The study group comprised 101 consecutive patients with locally advanced rectal cancer who received preoperative CRT with oral uracil/tegafur (UFT) or S-1. We evaluated histologic findings on hematoxylin and eosin (H&E) staining and immunohistochemical expressions of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7 days after starting CRT. These findings were contrasted with the histologic response and the degree of tumor shrinkage. RESULTS: In biopsy specimens obtained before CRT, histologic marked regression according to the Japanese Classification of Colorectal Carcinoma (JCCC) criteria and the degree of tumor shrinkage on barium enema examination (BE) were significantly greater in patients with p21-positive tumors than in those with p21-negative tumors (P=.04 and P<.01, respectively). In biopsy specimens obtained 7 days after starting CRT, pathologic complete response, histologic marked regression according to both the tumor regression criteria and JCCC criteria, and T downstaging were significantly greater in patients with apoptosis-positive and p21-positive tumors than in those with apoptosis-negative (P<.01, P=.02, P=.01, and P<.01, respectively) or p21-negative tumors (P=.03, P<.01, P<.01, and P=.02, respectively). The degree of tumor shrinkage on both BE as well as MRI was significantly greater in patients with apoptosis-positive and with p21-positive tumors than in those with apoptosis-negative or p21-negative tumors, respectively. Histologic changes in H&E-stained biopsy specimens 7 days after starting CRT significantly correlated with pathologic complete response and marked regression on both JCCC and tumor regression criteria, as well as with tumor shrinkage on BE and MRI (P<.01, P<.01, P<.01, P<.01, and P=.03, respectively). CONCLUSIONS: Immunohistochemical expressions of p21 and apoptosis together with histologic changes on H&E-stained biopsy specimens obtained 7 days after starting CRT are strong predictors of the response to CRT.

Liposome-encapsulated hemoglobin ameliorates tumor hypoxia and enhances radiation therapy to suppress tumor growth in mice.

We hypothesize that liposome-encapsulated hemoglobin with high O2 affinity (P5002 = 12 mm Hg, h-LEH) may increase O2 delivery to hypoxic tumors and enhance radiation therapy synergistically to suppress tumor growth. First, h-LEH (5, 10, and 20 mL/kg) was intravenously infused 30 min before radiation (20 Gy) of SCCVII tumor grown in C3H/HeN mice. Second, 10 mL/kg of h-LEH was administered 30, 60, 90, and 120 min prior to radiation to determine optimal timing. Tumor size was monitored thereafter to titrate tumor growth suppression. Third, additional mice with SCCVII tumor were infused with h-LEH or empty liposome (EL), and tumors were excised at various time points for immunohistochemical examination of h-LEH and hypoxia-inducible factor-1α (HIF-1α). h-LEH was most effective at 10 mL/kg in comparison to 5 or 20 mL/kg of h-LEH or EL. Tumor growth was most suppressed when the interval between h-LEH infusion and radiation was shortest, 30 min. As a result, 10 mL/kg of h-LEH infusion 30 min prior to radiation prolonged 5-fold tumor-growth time from 20.0 days (radiation and EL) to 26.5 days, P<0.01, synergy ratio 1.42. While human hemoglobin (h-LEH) was detected in tumors 0.5 to 24 h after administration, HIF-1α accumulation was sparse and became significantly reduced compared to controls 48 and 72 h after h-LEH infusion. h-LEH (10 mL/kg) was highly effective in enhancing radiation therapy synergistically under ambient respiration against tumor growth in mice. Decreased accumulation of HIF-1α in h-LEH-treated tumor may suggest targeted tumor oxygenation as a potential mechanism.

Optimal suture materials for contaminated gastrointestinal surgery: does infection influence the decrease of the tensile strength of sutures?

PURPOSE: Suture materials are selected based on the following factors: absorbable/non-absorbable, monofilament/multifilament, duration with sufficiently high tensile strength, and the tissue to be sutured. Absorbable sutures are hydrolyzed in tissues. However, little is known about the influence of infection on the hydrolysis and decrease in the tensile strength. METHODS: Four kinds of sutures, i.e., non-absorbable multifilament silk, non-absorbable monofilament polypropylene (Prolene(®)), absorbable multifilament polyglactin 910 (Vicryl(®)), and absorbable monofilament polydioxanone (PDS(®)) were implanted in the back of rats. A suspension of Escherichia coli + Bacteroides fragilis or saline was injected subcutaneously into the contaminated and clean condition groups, respectively. The sutures were removed 1, 2, 4 or 8 weeks after the implantation. RESULTS: There was significantly more severe inflammation macroscopically for the silk sutures under the contaminated conditions (p = 0.03), however, no significant differences were observed among the other three sutures. All 4 kinds of sutures showed a reduction of the tensile strength over time. There were no significant differences in the magnitude of reduction between both the clean and contaminated conditions for any of the sutures. CONCLUSIONS: The reduction of the tensile strength with time did not differ significantly between sutures exposed to contaminated and clean conditions, even for the absorbable sutures.

Phase I/II study of preoperative concurrent chemoradiotherapy with S-1 for locally advanced, resectable rectal adenocarcinoma.

PURPOSE: To assess the maximum tolerability of a combination of S-1 and preoperative radiotherapy and to evaluate the feasibility and activity in patients with locally advanced rectal cancer. METHODS: Patients (n = 30) with adenocarcinoma of the middle or lower rectum were enrolled in a phase I (n = 9) and/or phase II (n = 21) trial. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, and S-1 was orally administered twice a day on days 1-14 and 22-35. Surgical resection was scheduled 4-8 weeks after the completion of chemoradiation. RESULTS: In phase I, the recommended dose (RD) of S-1 was 80 mg/m(2)/day, and the maximum-tolerated dose was never reached. A total of 27 cases, including the 6 RD cases in phase I, were enrolled in phase II. In phase II, a pathological complete response (pCR) was observed in 6/27 patients (22%), pathological downstaging was observed in 21/27 patients (78%), and a tumor volume reduction of 69 ± 22% was obtained. These results were similar to the previously reported pCR rates of 16-18%, pathological downstaging rates of 49-59%, and tumor volume reduction of 68% after chemoradiotherapy with capecitabine. Grade 3 adverse events consisted of one case of leukopenia (4%), 2 cases of anemia (7%) and 3 cases of diarrhea (11%). Overall, the adverse events were very mild. Hand-foot syndrome was not observed. CONCLUSION: The efficacy of chemoradiotherapy with S-1 seems to be equivalent to the efficacy reported for chemoradiotherapy with capecitabine, but the adverse events were much milder, although further study is warranted.

Optimal duration of prophylactic antibiotic administration for elective colon cancer surgery: A randomized, clinical trial.

BACKGROUND: Procedures for perioperative infection prophylaxis in elective colon cancer surgery consist of preoperative mechanical preparation, chemical preparation with oral antibiotic administration, perioperative intravenous antibiotic administration, and others. However, the optimal combination of these procedures and drugs and their durations of administration have not yet been established. A randomized study was conducted to determine the optimal duration of perioperative antibiotic administration with use of mechanical and chemical preparation. METHODS: A total of 370 patients who were to undergo elective colon cancer surgery were randomized into 2 groups. After mechanical and chemical preparations, a single, 1-g dose of flomoxef was administered immediately before surgery to patients in group A. Flomoxef 1 g was administered twice daily for a total of 4 days from the day of surgery to postoperative day 3 to patients in group B. RESULTS: Comparison was performed between 179 patients in group A and 181 patients in group B with analyzable data. The incidences of incisional surgical site infections (SSIs), organ/space SSIs, and remote infections (RIs) were 15 patients (8.4%), 1 patient (0.6%), and 8 patients (4.5%), respectively, in group A, and 13 patients (7.2%), 2 patients (1.1%), and 6 patients (3.3%), respectively, in group B. There were no differences in the incidence of incisional SSIs, organ/space SSIs, or RIs between groups A and B. CONCLUSION: It was shown that a single dose of intravenous antibiotic immediately before surgery is sufficient as perioperative infection prophylaxis in elective colon cancer surgery when mechanical and chemical preparation is performed.

[Pharmacokinetic study of S-1 for the treatment of peritoneal metastasis from colon cancer--using a mouse peritoneal metastasis model].

OBJECTIVE: To investigate the usefulness of S-1 for the treatment of peritoneal metastasis from colon cancer using a colon cancer peritoneal metastasis model. METHODS: Colon 26 PMF-15 cells were transplanted intraperitoneally into mice. The concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) in the plasma and peritoneal tissue of the mice were determined at 6 sampling time points, i. e., pre-dosing and at 30min, 1, 2, 4 and 8 hrs after oral administration of S-1 (10mg/kg equivalent of FT) on day 20 post-transplantation. RESULTS: The AUC0-8h values of both 5-FU and CDHP were greater in the peritoneal tumor tissue than in the normal peritoneal tissue. The AUC of 5-FU in the peritoneal tumor tissue was 2. 90 times higher than that in plasma. CONCLUSION: The results suggest that S-1 may exert an antitumor effect on peritoneal metastasis arising from colon cancer and be potentially useful as a therapeutic agent in cases of colon cancer with peritoneal metastasis, which is generally recognized as carrying an unfavorable prognosis.