Evaluation of vascular anatomy for colon cancer located in the splenic flexure using the preoperative three-dimensional computed tomography angiography with colonography.

PURPOSE: The aim of this study is to reveal the vascular branching variation in SFC (splenic flexure cancer) patients using the preoperative three-dimensional computed tomography angiography with colonography (3D-CTAC). METHODS: We retrospectively analyzed patients with SFC who underwent preoperative 3D-CTAC between January 2014 and December 2019. RESULTS: Among 1256 colorectal cancer (CRC) patients, 96 (7.6%) manifested SFC. The arterial branching from the superior mesenteric artery (SMA) was classified into five patterns, as follows: (type 1A) the left branch of middle colic artery (LMCA) diverged from middle colic artery (MCA) (N = 47, 49.0%); (2A) the LMCA diverged from the MCA and the accessory middle colic artery (AMCA) (N = 26, 27.1%); (3A) the LMCA independently diverged from the SMA (N = 16, 16.7%); (4A) the LMCA independently diverged from the SMA and AMCA (N = 3, 3.1%); (5A) only the AMCA and the LMCA was absent (N = 4, 4.1%). Venous drainage was classified into four patterns, as follows: (type 1V) the SFV flows into the inferior mesenteric vein (IMV) then back to the splenic vein (N = 50, 52.1%); (2V) the SFV flows into the IMV then back to the superior mesenteric vein (SMV) (N = 19, 19.8%); (type 3V) the SFV independently flows into the splenic vein (N = 3, 3.1%); (type 4V) the SFV is absent (N = 24, 25.0%). CONCLUSION: 3D-CTAC could reveal accurate preoperative tumor localization and vascular branching. These classifications should be helpful in performing accurate complete mesocolic excision and central vessel ligation for SFC.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Global histone modification of H3K27 correlates with the outcomes in patients with metachronous liver metastasis of colorectal cancer.

BACKGROUND: We evaluated the methylation patterns of histone H3 lysine 27 (H3K27), H3 lysine 36 (H3K36) and the expression of H3K27 methylase EZH2 in patients with colorectal carcinomas with metachronous liver metastasis to search for biomarkers identifying these patients. METHODS: Double 2-mm core tissue microarrays were made from 54 paraffin-embedded samples of primary colorectal adenocarcinomas and corresponding liver metastases and examined using an immunohistochemical analysis of dimethylation and trimethylation in H3K27, H3K36 and EZH2. Positive tumor cell staining for each histone modification (H-score) was used to classify patients into low- and high-staining groups, which were then examined to identify any correlations between the clinicopathological parameters and the clinical outcomes. RESULTS: The H-scores of H3K27me2 were lower in the liver metastases than in the corresponding primary tumors, while the H-scores of H3K36me2 were higher in the liver metastases than in the corresponding primary tumors (P < 0.001). H3K27me2 in the primary tumors correlated with tumor size (P = 0.016), H3K36me2 in the primary tumors correlated with histological type (P = 0.038), and H3K36me3 in the primary tumors correlated with lymph node metastasis (P = 0.017). In addition, lower levels of H3K27me2 in the primary tumors correlated with poorer survival rates (P = 0.039). The multivariate survival analysis showed that the H3K27me2 status is an independent prognostic factor for colorectal cancer patients (P = 0.047). CONCLUSIONS: Our findings suggest that the methylation level of H3K27me2 detected with immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.

The cellular level of histone H3 lysine 4 dimethylation correlates with response to adjuvant gemcitabine in Japanese pancreatic cancer patients treated with surgery.

BACKGROUND: To search for biomarkers identifying pancreatic cancer patients likely to benefit from adjuvant gemcitabine chemotherapy, we investigated the status of several histone modifications in pancreatic tumors and their relationship to clinicopathological features and outcomes. METHODS: Sixty one pancreatic cancer patients, primarily treated by surgical removal of tumors, were involved in the study. Thirty patients completed postoperative adjuvant gemcitabine, and in 31 it was discontinued. Tumor specimens were examined using immunohistochemistry for di- and tri-methylation of histone H3 lysine 4 (H3K4me2 and H3K4me3), dimethylation and acetylation of histone H3 lysine 9 (H3K9me2 and H3K9ac), and acetylation of histone H3 lysine 18 (H3K18ac). Positive tumor staining for each histone modification was used to classify patients into low- and high-staining groups, which were examined for relationships to clinicopathological features and clinical outcomes. RESULTS: High expression of H3K4me3 was related to the well and moderately differentiated tumor histological type (p = 0.012) and low expression of H3K4me2 was related to the presence of perineural invasion (p = 0.007). No cellular histone modifications were associated with overall or disease-free survival of patients as a whole. In the subgroup analyses, a low level of H3K4me2 was significantly associated with worse disease free survival in patients that completed adjuvant gemcitabine (p = 0.0239). Univariate and multivariate hazard models also indicated that a low level of H3K4me2 was a significant independent predictor of disease-free survival (p = 0.007). CONCLUSION: H3K4me2 was found to be a predictor of response to adjuvant gemcitabine in Asian patients with pancreatic cancer.

Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis.

A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10-/-) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10-/- mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10-/- mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4+ T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10-/- mice ameliorated the colitis, probably as a result of decreasing the number of CD4+ T cells in the colonic mucosa and an associated reduction in IFN-gamma production.

The first grid for the oral and maxillofacial region and its application for speech analysis.

OBJECTIVES: Introduction of a new grid-based method for analyzing speech functions which takes into account the related information of patients' data and the oral air flow with pronouncing analyzed by computational fluid dynamics. METHODS: An on-line speech analyzer was developed for clinical use utilizing GridPort2.3.1 based on globus2.4.2, comprising several computational tools such as unified data storage, semantic data analysis, computational fluid dynamics analysis and three-dimensional visualization of calculated results from different hardware sources with various types of operation systems. RESULTS: The power transportation layer between dental clinics and computational and storage resources could be provided by using a WWW-based portal. The backend data management system could be constructed using a storage resource broker (SRB) and extensible mark up language (XML). CONCLUSIONS: The new method allows the construction of a data warehouse through this grid-based speech function analysis in order to extract the principal factors related to speech disorders.

Sandwich technique via right ventricle incision to repair postinfarction ventricular septal defect.

We describe two cases where postinfarction ventricular septal defect (VSD) was treated with a new technique. Application of direct ultrasonography to the right ventricular (RV) wall enables the surgeon to visualize the region and perform appropriate incision into the right ventricle and trabecula resection. The VSD is sealed with gelatin-resorcin-formal (GRF) glue between two patches, one placed on the left ventricular side and the other on the right ventricular side. RV incision provides easy bleeding control and the "sandwich technique" using two patches and GRF sealing provides geometric preservation of the left ventricular shape and prevents residual shunt.

Advantages of laparoscope-assisted surgery for recurrent Crohn's disease.

BACKGROUND: Laparoscopic surgery has been applied to patients with primary Crohn's disease, and its beneficial outcomes have been already investigated. However, there is no systematic study of laparoscopic surgery for patients with recurrent diseases. METHODS: We performed reoperation for 43 patients with recurrent Crohn's disease, including 23 patients who underwent laparoscope-assisted surgery. RESULTS: For all the patients, laparoscope-assisted surgery could be performed safely, even if the patients had been treated previously by open surgery or had undergone multiple abdominal procedures. Conversion to open or hand-assisted laparoscopic surgery was necessary for 16 patients (69.6%) because of dense adhesions (11 cases) or bulky tumor (5 cases). Importantly, even if the procedure was converted, the skin incision was significantly shorter than with open surgery, and postoperative recovery was faster, especially for the patients who underwent conversion to hand-assisted laparoscopic surgery. CONCLUSIONS: Laparoscope-assisted surgery is feasible and advantageous in reoperation for patients with recurrent Crohn's disease.

Alteration of V beta usage and cytokine production of CD4+ TCR beta beta homodimer T cells by elimination of Bacteroides vulgatus prevents colitis in TCR alpha-chain-deficient mice.

A major pathogenic factor for the development of inflammatory bowel disease (IBD) is the breakdown of the intestinal homeostasis between the host immune system and the luminal microenvironment. To assess the potential influence of luminal Ags on the development of IBD, we fed TCR alpha(-/-) mice an elemental diet (ED). ED-fed TCR alpha(-/-) mice showed no pathologic features of IBD, and their aberrant mucosal B cell responses were suppressed. Similar numbers of CD4(+), TCR betabeta homodimer T cells (betabeta T cells) were developed in the colonic mucosa of ED-fed mice; however, Th2-type cytokine productions were lower than those seen in diseased regular diet (RD)-fed mice. The higher cytokine production in diseased RD-fed mice could be attributed to the high incidence of Bacteroides vulgatus (recovered in 80% of these mice), which can induce Th2-type responses of colonic CD4(+), betabeta T cells. In contrast, ED-fed TCR alpha(-/-) mice exhibited a diversification of Vbeta usage of betabetaT cell populations from the dominant Vbeta8 one associated with B. vulgatus in cecal flora to Vbeta6, Vbeta11, and Vbeta14. Rectal administration of disease-free ED-fed mice with B. vulgatus resulted in the development of Th2-type CD4(+), betabeta T cell-induced colitis. These findings suggest that the ED-induced alteration of intestinal microenvironments such as the enteric flora prevented the development of IBD in TCR alpha(-/-) mice via the immunologic quiescence of CD4(+), betabeta T cells.

Relation of motility of subgingival microflora as a clinical parameter to periodontal disease status in human subjects.

BACKGROUND/AIMS: The purpose of this study was to evaluate the possible relationship between the motility of subgingival microflora and 5 clinical parameters commonly used in dental clinics. METHOD: The clinical parameters were pocket depth, gingival inflammation, plaque accumulation, bleeding on probing and pus discharge. The motility of human subgingival microflora was estimated as the number of pixels remaining after subtraction of serial video frames using a high speed shutter camera and image analysis system, and was defined as the sum of pixels of 10 successive subtractions per sample over a 10-s time period. RESULTS: The bacterial motility showed significant positive, moderate or low associations with the five clinical parameters. The highest correlation was observed between the bacterial motility and pocket depth (r=0.36, p=0.0001). Furthermore, clinically defined periodontal healthy and diseased sites were significantly different with respect to the bacterial motility (p<0.0001). To determine whether the bacterial motility was dependent or independent of the other clinical variables, the data were analyzed based on common factor analysis. Three factors were extracted and explained about 75% of the variance of the original 6 clinical parameters. Only the bacterial motility had a positive coefficient for all these three factors. The plot of bacterial motility was placed separately from those of other variables in the scatterplot of the loadings of factor 2 versus factor 1 and factor 2 versus factor 3. CONCLUSIONS: This suggests that bacterial motility may be an independent variable among the clinical parameters. Taken together, these data indicate that bacterial motility provides unique information about the clinical periodontal condition and may be a useful tool for the monitoring of subgingival plaque in relation to periodontal disease.

Lifestyle and periodontal health status of Japanese factory workers.

The present study investigated the association of lifestyles to periodontal health status of workers in a manufacturing company in Japan. In a annual health checkup, periodontal health status was assessed by using the Community Periodontal Index (CPI) criteria and analysed by modified Miller's CPI score. Lifestyle information was also obtained by a self-administered questionnaire. Bivariate and multivariate analyses were used to examine the relationship between lifestyle and oral health care variables and 2 indicators of periodontal health status. These were the modified Miller's CPI score and the probability of subjects in the upper 25th percentile of CPI distribution as an indicator of poor periodontal health. The modified Miller's CPI score was found to increase with age, but to vary according to the workers' lifestyles. In bivariate analyses, significant variables were age, smoking, alcohol consumption, toothbrushing frequency, toothbrushing method, and use of interdental cleaners. In multivariate analyses, age, smoking, and use of interdental cleaners had significantly independent effects. Amount of smoking or alcohol consumption was associated with periodontal health status. Excessive use of alcohol may contribute to the development of periodontal disease, although further investigations are required to confirm this finding. The data from this study indicate that lifestyles which include smoking and insufficient oral health care have an independent association with periodontal disease.

Semi-automated measurement of motility of human subgingival microflora by image analysis.

The purpose of this investigation was to quantitatively estimate bacterial motility by image analysis, and to apply this method for the measurement of motility of human subgingival microflora. We developed a semi-automated method for the quantification of bacterial motility using video microscopy, digitization and image processing. Moving images of both authentic bacterial samples and clinical samples were recorded using a phase contrast microscope with a high speed (1/100 s) shutter camera. The motility was evaluated by measuring the total number of pixels remaining after the subtraction of 2 serial video images. The total number of pixels was significantly correlated with both the sum of the velocity of each bacterial cell and the number of motile bacteria on the same original images. Motility of subgingival microflora from 140 clinical samples tested was measured at 0 pixels to 3600 pixels, whereas the effect of Brownian movement was less than 150 pixels. The motility of subgingival microflora estimated with this image analysis system did not differ much from objective judgments by the naked eyes of experts. These results suggest that a semi-automated image analysis system may be useful in the evaluation of the motility of human subgingival microflora.

Dental interview system with a native-language interpreting engine.

We developed a Dental Interview System with a Native-language Interpreting Engine (DISNIE) on the Internet. DISNIE uses simple natural sentences without dental terminology and interprets these sentences in five languages such as Japanese, English, Korean, Chinese and French, respectively. DISNIE is a good tool not only for patients who are able to read, write and speak only their mother languages but also for the staff at a dental hospital because of its accessibility via the Internet.

Binding of hemoglobin by Porphyromonas gingivalis.

In this study, we investigated whether Porphyromonas gingivalis can bind hemoglobin as an initial step in the acquisition of heme from hemoglobin. The binding of human hemoglobin by P. gingivalis cells was determined using [3H]hemoglobin. Hemoglobin binding occurred rapidly, reversibly and specifically. A Scatchard analysis of the binding data generated a linear plot, indicating a single population of binding proteins. The apparent Kd was 1.0 +/- 0.19 x 10(-6) M and there were 3.2 +/- 0.76 x 10(4) binding sites per cell. Hemoglobin binding was inhibited by unlabeled human hemoglobin but not by hemin and protoporphyrin IX. The binding was only partially inhibited by human serum albumin, transferrin, lactoferrin, catalase and cytochrome c. These results suggest that the ligand recognized by the binding protein may not be the heme moiety. The binding of hemoglobin considerably increased when the organisms were grown under hemin-limited conditions. Hemoglobin bound to outer membrane proteins extracted from P. gingivalis cells on a dot blot binding assay and binding ability was lost after heating bacterial proteins. These results suggest that P. gingivalis cells interact with human hemoglobin through specific binding sites on their surfaces as a preliminary step in iron acquisition.

Interaction of Porphyromonas gingivalis with transferrin.

In this study, we characterized the binding of transferrin to Porphyromonas gingivalis using a classical receptor-binding assay, and examined the relationship between the binding and availability of transferrin for the growth of P. gingivalis. The binding of 125I-labeled human transferrin to P. gingivalis occurred rapidly, reversibly and specifically. Scatchard analysis yielded a Kd of 1.37 +/- 0.16 microM and an apparent number of 1.13 +/- 0.26 x 10(5) receptors per cell. The binding of transferrin was much increased when organisms were grown in iron-limited conditions. Among the species of black-pigmented anaerobic.rods, those strains of P. gingivalis which had high transferrin-binding activity exhibited unrestricted growth following the addition of transferrin to the hemin-free culture medium. On the other hand, the presence of transferrin in the culture medium did not support unrestricted growth of organisms that had low transferrin-binding activity. These results suggest that the binding of transferrin to P. gingivalis cells may be a preliminary step in iron acquisition, which allows them to survive in the healthy periodontal environment.

Estimation of motility of subgingival microflora using high speed shutter camera and image analysis system.

This paper reports on the development of a motility measuring system for human subgingival microflora using a high speed shutter camera and an image analysis system. The paper first presents the method for estimating the motility of subgingival microflora by the total number of pixels and then describes the evaluation of the total number of pixels as an indicator of bacterial motility. Our results with this system demonstrate that the motility of subgingival microflora can be expressed as the total number of pixels.

Evaluation of implementing a multi-user integrated case management system for undergraduate students during a clinical training period.

In this paper, we evaluate the efficiency of our multi-user system, which enables undergraduate students to now determine their progress in clinical requirements through their clinical training period. After implementing the system, instructors in each clinic can understand the progress or laziness of every student better than before.

Characterization of coaggregation and fibrinogen-binding by Porphyromonas gingivalis.

We have examined whether the adhesin of Porphyromonas gingivalis which aggregates Streptococcus oralis contributes to its fibrinogen-binding. Various properties of coaggregation between P. gingivalis and S. oralis were compared with those of fibrinogen-binding to P. gingivalis cells. The coaggregation activity was measured by a turbidimetric method and the fibrinogen-binding activity was determined by using 125I-fibrinogen. Both the activities showed maximum values in the pH range from 5.0 to 6.0 and they were inhibited by arginine and lysine. Heating treatment of P. gingivalis 381 cells at 75 degrees C abrogated the activities. However, treatment of P. gingivalis 381 cells with proteinase K considerably reduced the fibrinogen-binding activity but not the coaggregation activity. Metal ions such as Zn2+ and Cu2+ inhibited the coaggregation activity but enhanced the fibrinogen-binding activity. The results also indicated that P. gingivalis strains 381, ATCC 33277 and SU-3 showed relatively higher activities both in coaggregation and fibrinogen-binding, whereas P. gingivalis strains W83, 51 and 165 showing lower fibrinogen-binding activity than P. gingivalis 381 did not coaggregate with S. oralis ATCC 9811. These findings suggest that coadhesin of P. gingivalis with S. oralis is not be associated with its fibrinogen-binding.