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In the real world, there are numerous and various events that occur on and alongside networks, including the occurrence of traffic accidents on highways, the location of stores alongside roads, the incidence of crime on streets and the contamination along rivers. In order to carry out analyses of those events, the researcher needs to be familiar with a range of specific techniques. Spatial Analysis Along Networks provides a practical guide to the necessary statistical techniques and their computational implementation. Each chapter illustrates a specific technique, from Stochastic Point Processes on a Network and Network Voronoi Diagrams, to Network K-function and Point Density Estimation Methods, and the Network Huff Model. The authors also discuss and illustrate the undertaking of the statistical tests described in a Geographical Information System (GIS) environment as well as demonstrating the user-friendly free software package SANET. Spatial Analysis Along Networks: * Presents a much-needed practical guide to statistical spatial analysis of events on and alongside a network, in a logical, user-friendly order. * Introduces the preliminary methods involved, before detailing the advanced, computational methods, enabling the readers a complete understanding of the advanced topics. * Dedicates a separate chapter to each of the major techniques involved. * Demonstrates the practicalities of undertaking the tests described in the book, using a GIS. * Is supported by a supplementary website, providing readers with a link to the free software package SANET, so they can execute the statistical methods described in the book. Students and researchers studying spatial statistics, spatial analysis, geography, GIS, OR, traffic accident analysis, criminology, retail marketing, facility management and ecology will benefit from this book.

Background It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors. Method There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354–365, 2009; West et al., J Clin Oncol 28:272–278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction. Result The oncological rationale for CME and various technical aspects of the surgical management will be explored. Conclusion The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.

Background It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors. Method There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354-365, 2009; West et al., J Clin Oncol 28:272-278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction. Result The oncological rationale for CME and various technical aspects of the surgical management will be explored. Conclusion The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.

Epithelial–mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial- and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1 -induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200 -family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo . Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200 -family expression and activation of ZEB1 in CRC.

Background:Rituximab (RTX), an anti-CD20 antibody, has recently become an effective treatment for systemic sclerosis, which causes progressive fibrotic lesions in multiple organs. The efficacy and safety of rituximab therapy must be investigated in real-world clinical use, as there is only evidence from a small number of clinical trials.Objectives:To evaluate the short-term efficacy and safety of RTX for cutaneous sclerosis and interstitial lung disease (ILD) in systemic sclerosis patients in at our institution.Methods:Systemic sclerosis patients diagnosed using ACR/EULAR Systemic Sclerosis Classification Criteria 2013 and treated with RTX from June 2021 to October 2023 and available for evaluation after six months of treatment were included. Efficacy after 6 months of RTX treatment was analyzed for changes in modified Rodnan’s total skin thickness score (mRSS) for skin effect, %FVC, %DLCO, and serum KL-6 for ILD. The safety of rituximab therapy was examined by the occurrence of adverse events at 6 months.Results:Of the 29 patients treated with RTX for systemic sclerosis at our institution, 11 completed the 24-week evaluation; mean age at RTX induction was 59.5 ± 10.4 years and disease duration was 10.2 ± 9.8 years. Four patients received concomitant immunosuppressive drugs (azathioprine, mycophenolate mofetil, and tacrolimus), three of whom also received nintedanib. ILD complication was observed in 9 of 11 SSc patients. The mRSS, which was 14.8 ± 12.6 before RTX introduction, significantly decreased to 4.3 ± 6.2 after 24 weeks. The %FVC and %DLCO at the start of rituximab treatment were 76.6 ± 22.9% and 57.0 ± 19.4%, respectively, and were 78.1 ± 24.4% and 50.0 ± 15.3% at 24 weeks after, respectively. KL-6 was 720.7±434.1U/mL before induction and decreased by 48.6±183.1U/mL after induction. In the analysis of adverse events, two patients had complications of infection, bacterial pneumonia and COVID-19, respectively. Other serious adverse events included one patient treated with rituximab monotherapy who had grade 4 severe thrombocytopenia, which improved within a few days.Conclusion:In our clinical practice,RTX therapy showed to improve scleroderma and inhibit ILD progression in patients with systemic sclerosis. However, additional caution is needed because of adverse events, such as severe thrombocytopenia, that have not been observed in clinical trials.REFERENCES:[1] Satoshi Ebata, Ayumi Yoshizaki, Koji Oba, Kosuke Kashiwabara, Keiko Ueda, Yukari Uemura,et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial. The Lancet Rheumatology Vol 3, ISSUE 7, E489-E497, 2021.[2] Rubio-Rivas M, Royo C, Simeón CP, Corbella X, Fonollosa V. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum, 44: 208-219, 2014.[3] Distler O Highland KB Gahlemann M et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J; 380: 2518-2528, Med. 2019.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Fecal calprotectin is a well-established predictive marker for inflammatory bowel disease activity, but this marker has been reported to be elevated in spondyloarthritis (SpA) patients even in the absence of inflammatory bowel disease or any other chronic intestinal disease [1]. Fecal calprotectin may be useful as an indicator of treatment choice as well as for assessing disease activity in SpA; however, reference values of fecal calprotectin may vary by race and type of SpA. Most of these data were reported from Western countries, and data on Japanese patients with SpA are limited.Objectives:To determine the differences in fecal calprotectin levels among Japanese SpA types and non-SpA rheumatic and musculoskeletal disease (RMD).Methods:Twenty-three patients with SpA and 23 patients with other RMDs at Kagawa University Hospital from October 2020 to December 2023 were included in the study. All subjects in this study were over the age of 18. Fecal calprotectin was measured by fluorescence enzyme immunoassay (cutoff value 50μg/g). Subjects complicated with inflammatory bowel disease were excluded. We firstly compared fecal calprotectin levels in patients with SpA and patients with other RMDs. Additionally, the association between clinical characteristics and fecal calprotectin levels in patients with SpA was analyzed. We used the Mann–Whitney U test to compare fecal calprotectin levels. All P values were 2-sided, and a P value of <0.05 was considered significant.Results:Of the 23 patients with SpA included in the study, 8 had ankylosing spondylitis and 9 had psoriatic arthritis. The other RMDs without SpA included 17 cases of Behcet’s disease and 2 cases of systemic lupus erythematosus. In the analysis of clinical characteristics, SpA and other RMDs groups showed differences in C-reactive protein levels and age, but not between ankylosing spondylitis and other SpAs.Fecal calprotectin level in patients with SpA was significantly higher than in other RMDs patients (168 μg/g; IQR 38-444 μg/g vs. 36 μg/g; IQR 13-96 μg/g, p=0.0044). Patients with ankylosing spondylitis tended to have higher fecal calprotectin level than patients with other SpAs (435 μg/g; IQR 142-985 μg/g vs. 101 μg/g; IQR 36-269 μg/g, p=0.0707).Conclusion:Among Japanese patients, fecal calprotectin level in patients with SpA was significantly higher than that in other RMDs patients. Because fecal calprotectin levels in patients with SpA are higher than reference values in healthy individuals and in other rheumatic diseases, caution must be exercised in the interpretation of this biomarker used to screen for inflammatory bowel disease complications at determining therapeutic agents. Further study is needed to evaluate the significance of fecal calprotectin measurement in SpA.REFERENCES:[1] Simioni J, Skare TL, Campos APB, et al. Fecal Calprotectin, Gut Inflammation and Spondyloarthritis. Arch Med Res. 2019;50(1):41-46.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Japanese patients with connective tissue diseases (CTD) are frequently complicated by interstitial lung disease (CTD-ILD) and many patients with CTD-ILD were treated with various immunosuppressive agents (IS). Recently, nintedanib (NTB), a multitargeted tyrosine kinase inhibitor, has been approved for the treatment of progressive fibrosing ILD (PF-ILD) including CTD-ILD. However, the efficacy of combination therapy with NTB and IS for CTD-associated PF-ILD (CTD-PF-ILD) is unclear.Objectives:We aimed to clarify the efficacy and safety of the NTB treatment combined with IS for CTD-PF-ILD in real clinical practice.Methods:CTD-PF-ILD patients who received NTB at our institution between May 1, 2020 and September 30, 2023, and who underwent pulmonary function tests (PFT) before and after NTB treatment were included in this retrospective study. The patients were required to meet the criteria for PF-ILD [1]. To clarify the efficacy and safety of NTB treatment combined with IS for CTD-PF-ILD, patients were divided into two groups: one in which NTB alone was added (NTB group) and the other in which NTB and IS were added (NTB+IS group). Changes before and after NTB treatment in pulmonary function (FVC (%), FVC (mL), DLCO (%)) and serum Krebs von den Lungen-6 (KL-6), reported as a biomarker of disease activity in CTD-ILD, and the incidence of adverse events (AEs) during NTB treatment were investigated and compared between the two groups using the Wilcoxon rank-sum test and Fisher’s exact test. All p values were 2-sided, and a p value <0.05 was considered significant.Results:Twenty-six patients with CTD-PF-ILD were included in this study. Patient characteristics are shown in Table 1. After the diagnosis of CTD-PF-ILD, NTB alone was added in 15 of the 26 patients (NTB group), and NTB plus IS were added in 11 patients (NTB+IS group). Among the 11 participants in the NTB+IS group, the most common additional IS was rituximab (RTX) in 6 participants (54.6%), followed by GC in 4 participants (36.4%). After NTB treatment, FVC (%) and FVC (mL) increased slightly (not statistically significant) and FVC (%/M) improved significantly (Figure 1). In comparison between the NTB group and the NTB+IS group, ⊿FVC (%), ⊿FVC (mL), ⊿FVC (%/M) were all significantly greater in the NTB+IS group than NTB group (Figure 1). Mean KL-6 (U/mL) in all patients decreased from 1240.1 U/mL to 964.4 U/mL, and ⊿KL-6 (U/mL) was significantly greater in the NTB+IS group than NTB group (-490.1 U/mL vs. -118.5 U/mL, p=0.0059). A significant negative correlation was observed between ⊿KL-6 (U/mL) and ⊿FVC (%) (ρ=-0.6620, p=0.0002). As for AEs, fourteen patients (53.9%) had diarrhea, two (7.7%) had elevated liver enzymes, one (3.9%) had nausea, and one (3.9%) had headache. The dose of NTB was reduced in 11 patients (42.3%), mainly due to diarrhea. There was no difference in the incidence of AEs between the two groups.Conclusion:This study suggested the NTB treatment combined with IS may be more effective for CTD-PF-ILD in preventing the reduction of FVC than NTB monotherapy. Furthermore, NTB combined with IS may be a potential to increase FVC in patients with CTD-PF-ILD.REFERENCES:[1] Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381:1718-1727.Figure 1.Changes in pulmonary function before and after treatment and the differences in changes in pulmonary function between the NTB group and the NTB+IS group. FVC, forced vital capacity; DLCO, diffusing capacity for carbon monoxide; NTB, nintedanib; IS, immunosuppressive agents. For statistical analyses * p<0.05, **p<0.01. p value: Wilcoxon signed rank test, Wilcoxon rank sum testAcknowledgements:NIL.Disclosure of Interests:None declared.

Background:Arthritis is positioned as one of the main symptoms in Behcet’s disease (BD), and it is a frequent symptom that is observed in about 57% of patients in Japan. Arthritis associated with BD is considered important domain affecting the patient QOL same as oral ulcers. However, few reports have compared the clinical symptoms and QOL of BD patients with and without arthritis [1,2].Objectives:This study aims to clarify the correlation between arthritis and other clinical manifestations of BD and how arthritis affects the patient QOL in Japanese patients with BD.Methods:This was a retrospective study. Fifty-three BD patients treated at Kagawa University Hospital for more than 6 months and who visited the hospital from January 2022 to February 2023 were included in this retrospective study. All patients were 18 years of age or older and met the International Criteria for Behcet’s disease. We divided these patients into with (Arthritis group) or without arthritis (Non-arthritis group), and evaluated clinical symptoms, disease activity, and patient QOL. Patient’s global assessment (PGA), Evaluator’s global assessment (EGA) and Behcet‘s disease current activity form (BDCAF) were used as indices of disease activity. To evaluate disease activity related to lesions other than arthritis, BDCAF excluding arthritis items was also calculated. Behcet’s disease quality of life scale (BDQOL) was used to assess patient QOL. We used the Mann–Whitney U test to compare these data between two groups. All P values were two-sided, and a P value of <0.05 was considered significant.Results:Arthritis was present in 49.1% of BD patients enrolled in this study. No significant difference in patient background was observed between two groups. In Arthritis group, arthritis activity evaluated by SDAI, CDAI, and DAS-28CRP was low to moderate (9.7; IQR 5.9-12.7, 9.4; IQR 5.9-12.0 and 2.8; IQR2.3-3.4, respectively). The frequency of oral ulcers and skin lesions was significantly higher in Arthritis group than in Non-arthritis group (p=0.0092 and p=0.0483, respectively). Among the skin domain, papulopustular lesion tended to be observed more frequently in Arthritis group. EGA and BDCAF were significantly higher in Arthritis group (p=0.0198 and <0.0001, respectively). BDCAF was also significantly higher in Arthritis group even when comparing items excluding arthritis (p=0.0004). PGA and BDQOL tended to be higher in Arthritis group, but were not statistically significantly different than in Non-arthritis group.Conclusion:Japanese BD patients with arthritis were complicated with oral ulcer and skin lesions more frequently. In addition, Japanese BD patients with arthritis tended to have high disease activity and low QOL, even if the activity arthritis was low to moderate. Because this study was a small, single-center and observational study, further research is needed to clarify the relationship between clinical characteristics and QOL in BD patients.REFERENCES:[1] Tunc R, et al. Target organ associations in Turkish patients with Behçet’s disease: a cross sectional study by exploratory factor analysis. J Rheumatol. 2002 Nov;29(11):2393-6.[2] Soejima Y, et al. Changes in the proportion of clinical clusters contribute to the phenotypic evolution of Behçet’s disease in Japan. Arthritis Res Ther. 2021 Feb 1;23(1):49.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:S100 proteins has been reported to be a biomarker associated with disease activity in SLE, but it is not clear which pathophysiology of SLE S100 protein reflects [1, 2].Objectives:This study aims to determine the utility of S100 protein measurement as a therapeutic indicator for SLE.Methods:SLE patients who received additional treatment at our hospital from January 2016 to December 2023 were included. SLEDAI-2K, SLE-DAS, and CLASI score were used to assess disease activity, and serum S100A8 and S100A9 were measured using ELISA (CircuLex ELISA KitⓇ,MBL); the association between S100 protein and disease activity indices, organ lesions, and treatment content were analyzed before and after treatment.Patients were divided into five groups according to the type of immunosuppressant added: HCQ alone (HCQ group), low-dose glucocorticoid (GC) or combined with immunosuppressant (IS group), medium or higher GC (GC group), belimumab (BEL group), and anifrolumab (ANI group), and the relationship between each treatment and changes in S100 protein was investigated. Statistical analysis was performed using JMP® 17.0.0 software (SAS Institute, Cary, NC, USA).Results:This study comprised 109 SLE patients, 101 females, with a mean age of 42.3 years old. The median disease activity score was SLEDAI 4 points and SLE-DAS 4.3 points. The median values of S100A8 and S100A9 were 271.5 ng/ml and 27.8 ng/ml, respectively, with no clear association with overall disease activity index. However, it was higher in patients with lupus nephritis (S100A8 p=0.037, S100A9 p=0.035,) and in skin involvement, serum S100 protein was higher in patients with higher CLASI activity scores and positively correlated with S100A9 (r=0.19, p=0.044). After 3 months of treatment, all disease activity scores and S100 protein levels decreased significantly (p<0.0001).In the examination by treatment type, compared to the HCQ group (SLEDAI: p=0.001, SLE-DAS: p=0.0124), and titers of the dsDNA antibody was significantly lower in the ANI group than in the other four groups (p<0.0001).Before treatment, S100A8 and S100A9 levels were not significantly different among all the groups, but S100A8 was lowest in the ANI group and S100A9 was lowest in the BEL and ANI groups (Table 1). Regardless of treatment type, S100 protein decreased after 3 months of treatment (Figure 1). S100A8 and S100A9 levels decreased 3 and 6 months after treatment in the ANI group, which had lower S100 protein level before treatment, and the rate of decrease in S100A8 and S100A9 levels after 3 months was not significantly different in all the groups.Conclusion:S100 protein decreases with declining SLE activity and may be an indicator of disease activity that reflects treatment efficacy.REFERENCES:[1] Kim JW, et al. Front Immunol. 2022;13:886209.[2] Ruacho G, et al. Lupus Sci Med. 2022;9:e000607.Table 1. Characteristics of patients with SLE enrolled in this study#Nonparametric distributions are represented as median (interquartile range [IQR]). low disease activity state scale: LLDAS.Figure 1.Serum S100A8 and S100A9 levels at baseline were compared with levels after 3 and 6 months of additional treatment with Bonferroni correction.For statistical analyses, ***p<0.0001, **p<0.015, p values were determined using the Wilcoxon signed-rank test.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:C5a production through activation of the complement pathway is a component of the pathogenesis of ANCA-associated vasculitis (AAV). In the ADVOCATE trial [1], avacopan, an oral C5a receptor inhibitor, was demonstrated to be an alternative to glucocorticoids (GC) in the treatment of microscopic polyangiitis (MPA)/granulomatosis with polyangiitis (GPA) and was approved in several countries including Japan. However, there are still few reports as for the efficacy and safety of avacopan in real clinical practice. Additionally, the impact of avacopan treatment on AAV biomarkers is also unclear.Objectives:We aimed to clarify the efficacy and safety of avacopan in remission induction therapy for MPA/GPA in real clinical practice, as well as changes in serum C5a and S100 A9 levels, which is biomarkers of vasculitis before and after treatment with avacopan.Methods:Patients with MPA/GPA who received remission induction therapy with GC plus rituximab or cyclophosphamide at our institution from January 2017 to June 2023 were included in this retrospective study. To evaluate the efficacy and safety of avacopan, patients were divided into two groups: one group received avacopan in combination with remission induction therapy (avacopan group) and the other group did not (non-avacopan group). The achievement rate of BVAS=0, daily GC dose (prednisolone-equivalent), and the incidence of adverse events (AEs) until 6 months after treatment were investigated and compared between the two groups using the Wilcoxon rank-sum test and Fisher’s exact test. Serum C5a and S100A9 were measured in the avacopan group before and 3 months after treatment. The association of serum C5a or S100A9 with disease activity was analyzed. We also analyzed the effect of treatment on serum C5a or S100A9 using Wilcoxon’s signed-rank test.Results:A total of 73 patients with MPA/GPA were included, 15 in the avacopan group and 58 in the non-avacopan group. There were no differences between the two groups in age, ANCA status, proportion of MPA/GPA, or type of remission induction therapy, except for gender proportion (Table 1). The achievement rate of BVAS=0 at 1, 3, and 6 months was not significantly different between the avacopan and non-avacopan groups (60.0% vs. 50.0%, 93.3% vs. 80%, 100% vs. 95.7%, respectively) (Figure 1). On the other hand, the mean daily GC dose at 1, 3, and 6 months was significantly lower in the avacopan group than in the non-avacopan group (14.5 ± 9.2 mg/day vs. 24.8 ± 9.4 mg/day, 6.1 ± 4.4 mg/day vs. 11.9 ± 4.0 mg/day, 3.0 ± 2.4 mg/day vs. 7.8 ± 2.8 mg/day, respectively) (Figure 1). The incidence of GC-related AEs (defined as hypertension, diabetes, osteoporosis, cataract and glaucoma, and severe infection) within 6 months was significantly lower in the avacopan group than in the non-avacopan group (6.7% vs. 50.0%, p<0.01). Serum C5a and S100A9 were measured in 11 patients in the avacopan group. A significant positive correlation was observed between serum C5a levels and BVAS before treatment (ρ=0. 8111, p<0.01). The median value of serum C5a increased from 75.3 ng/mL to 89.7 ng/mL while the median value of serum S100A9 decreased from 50.8 ng/mL to 30.8 ng/mL. In patients with higher serum C5a levels at the start of treatment, serum S100A9 tended to decrease after treatment with avacopan (Figure 1).Conclusion:In real clinical practice, avacopan was confirmed to be useful in achieving high remission rates and reducing GC doses and GC-related AEs. In addition, serum S100A9 may be a biomarker reflecting the therapeutic effect of avacopan.REFERENCES:[1] Jayne DRW, et al. N Engl J Med. 2021;384:599-609.Table 1. Clinical characteristics of the patients.RTX: rituximab; CY: cyclophosphamide; IQR: interquartile range. For statistical analyses * p<0.05. p value: Wilcoxon rank sum test, Fischer’s exact testFigure 1.(A) The comparison of the achievement rate of BVAS=0 at 1, 3 and 6 months between the two groups. (B) The comparison of the daily GC dose at 1, 3 and 6 months between the two groups. (C) The association between serum C5a levels before treatment and BVAS and changes in serum S100A9 levels. For statistical analyses **p<0.01, ***p<0.0001.Acknowledgements:NIL.Disclosure of Interests:None declared.