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Background: A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients., Methods: We analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD., Results: Thirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684-27.79; p = 0.007)., Conclusions: Patients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fujita, Fukui, Umeda, Tsuji, Iwamoto, Nakashima, Horai, Suzuki, Okada, Aramaki, Ueki, Mizokami, Origuchi, Watanabe, Migita and Kawakami.)

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p&#95;{Σ}) ranging from 470 to 650  MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst)  mb for 470

Background: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs)., Methods: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared., Results: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008)., Conclusions: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients., (© 2021. Japanese Society of Gastroenterology.)

Background: Microsatellite instability (MSI) is a key marker for predicting the response of immune checkpoint inhibitors (ICIs) and for screening Lynch syndrome (LS)., Aim: This study aimed to see the characteristics of cancers with high level of MSI (MSI-H) in genetic medicine and precision medicine., Methods: This study analyzed the incidence of MSI-H in 1000 cancers and compared according to several clinical and demographic factors., Results: The incidence of MSI-H was highest in endometrial cancers (26.7%, 20/75), followed by small intestine (20%, 3/15) and colorectal cancers (CRCs)(13.7%, 64/466); the sum of these three cancers (15.6%) was significantly higher than that of other types (2.5%)(P < 0.0001). MSI-H was associated with LS-related cancers (P < 0.0001), younger age (P = 0.009), and family history, but not with smoking, drinking, or serum hepatitis virus markers. In CRC cases, MSI-H was significantly associated with a family history of LS-related cancer (P < 0.0001), Amsterdam II criteria [odds ratio (OR): 5.96], right side CRCs (OR: 4.89), and multiplicity (OR: 3.31). However, MSI-H was very rare in pancreatic (0.6%, 1/162) and biliary cancers (1.6%, 1/64) and was null in 25 familial pancreatic cancers. MSI-H was more recognized in cancers analyzed for genetic counseling (33.3%) than in those for ICI companion diagnostics (3.1%)(P < 0.0001). Even in CRCs, MSI-H was limited to 3.3% when analyzed for drug use., Conclusions: MSI-H was predominantly recognized in LS-related cancer cases with specific family histories and younger age. MSI-H was limited to a small proportion in precision medicine especially for non-LS-related cancer cases., (© 2022. The Author(s).)

Spear-like collagen complexes, known as actinotrichia, underlie the epidermal cell layer in the tip of teleost fins and are known to contribute toward fin formation; however, their specific role remains largely unclear. In this study, we investigated of actinotrichia in the role of caudal fin formation by generating collagen9a1c (col9a1c)-knockout zebrafish. Although actinotrichia were initially produced normally and aligned correctly in the knockout fish, the number of actinotrichia decreased as the fish grew and their alignment became disordered. Simultaneously, the fin tip gradually shortened in the dorsal-ventral direction and the entire fin became oval-shaped, while the fin-rays rarely bifurcated and instead underwent fusion, suggesting that actinotrichia are essential for spreading fins dorsoventrally. Furthermore, the epithelial cells that are usually thinly spread in normal fish became spherical in the knockout fish, reducing the area covered by each cell and thus the area of the fin tip. Together, these findings suggest that the tight alignment of actinotrichia provides physical support in the dorsal-ventral direction that allows caudal fins to expand in a triangular-shape., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to compare computed tomography (CT) angiography (CTA) imaging of deep inferior epigastric artery perforator (DIEP) using the ultrahigh-resolution CT (UHRCT) and conventional multidetector CT (MDCT)., Methods: This retrospective study enrolled 20 patients who underwent CTA of DIEP flap with UHRCT and MDCT. Computed tomography values were measured at 4 large vessels (thoracic aorta, abdominal aorta, common iliac artery, and external iliac artery) and 5 peripheral vessels (proximal and distal internal thoracic artery, proximal and distal deep inferior epigastric artery, and DIEP)., Results: There were no significant differences in mean CT values of the major vessel between UHRCT and MDCT. Ultrahigh-resolution CT shows higher CT values of the peripheral vessels than MDCT (P < 0.05 for all). The median CT values of the DIEP in UHRCT were approximately 3 times higher than those in MDCT (P < 0.001)., Conclusions: Ultrahigh-resolution CT provides higher-quality CTA of DIEP compared with MDCT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet., Approach and Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC., Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients., Competing Interests: Sadahisa Ogasawara received honoraria from Bayer, Leverkusen, Germany; Eisai, Tokyo, Japan; Eli Lilly, Indianapolis, IN, USA; Chugai Pharma, Tokyo, Japan; AstraZeneca, Cambridge, UK; and Merck & Co., Inc., Kenilworth, NJ, USA, consulting or advisory fees from Bayer, Eisai, Merck & Co., Inc., Chugai Pharma, Eli Lilly, and AstraZeneca, and research grants from Bayer, AstraZeneca, and Eisai. Michihisa Moriguchi received honoraria from Eisai, Bayer, Eli Lilly, and Chugai Pharma, and consulting or advisory fees from Eisai, Bayer, Eli Lilly, and Chugai Pharma. Naoki Morimoto received research grants from Eisai and Abbvie, Lake Bluff, IL, USA. Yoshihiko Ooka received honoraria from Eisai. Tatsuo Kanda received research grants from Towa Pharmaceutical, Osaka, Japan; Abbvie, Chugai Pharma, Daiichi Sankyo, Tokyo, Japan; and Shionogi, Osaka, Japan. Kengo Nagashima received a lecture fee from Pfizer, New York, NY, USA. Norio Isoda received research grants from Eisai and Abbvie. Takeshi Aramaki received speaker's bureau from Eli Lilly, Chugai Pharma, Termo, Milano, Italy; Eisai, and Taiho Pharma, Tokyo, Japan. Yoshito Itoh received speaker's bureau from MSD, Kenilworth, NJ, USA, Eisai, and Chugai Pharma; and research grants from MSD, Eisai, Bayer, and Chugai Pharma. Naoya Kato received honoraria from Bayer, Eisai, Sumitomo Dainippon Pharma, Tokyo, Japan, and Merck & Co., Inc.; consulting or advisory fees from Bayer and Eisai; and research grants from Bayer and Eisai. The other authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: The aim of this study was to evaluate anatomical resection (AR) versus non-AR for primary solitary hepatocellular carcinoma (HCC) with predicted microscopic vessel invasion (MVI) and/or microscopic intrahepatic metastasis (MIM)., Methods: This retrospective study included 358 patients who underwent hepatectomy and had no evidence of MVI and/or MIM on preoperative imaging. The predictors of MVI and/or MIM were identified. The AR group (n = 222) and the non-AR group (n = 136) were classified by number of risk factor, and the survival rates were compared., Results: Microscopic vessel invasion and/or MIM were identified in 81 (22.6%) patients. A multivariate analysis showed that high des-gamma-carboxy prothrombin concentration [odds ratio (OR) 3.35], large tumor size (OR 3.16), and high aspartate aminotransferase concentration (OR 2.13) were significant predictors. The 5-year overall survival (OS) in the patients with zero, one, two, and three risk factors were 97.4%, 73.5%, 71.5%, and 65.5%, respectively. The OS of AR is superior to that of non-AR only in patients with one or two risk factors., Conclusion: The present findings suggest that AR should be performed for patients with one or two risk factors, and that AR may prevent recurrence, as these patients are at risk of having MVI and/or MIM., (© 2021. Springer Nature Singapore Pte Ltd.)

Objectives: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA., Methods: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method., Results: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks., Conclusion: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

Purpose: The purpose of this study was to evaluate changes in the body composition and nutritional status after total pancreatectomy (TP)., Methods: Consecutive 45 patients underwent TP between February 2003 and July 2018. Among them, 32 had computed tomography images available before TP and at 6 and 12 months after TP. The skeletal muscle index (SMI), visceral fat tissue index (VFI), and subcutaneous fat tissue index (SFI) were measured using images at each time. Body mass index (BMI), serum albumin levels (Alb), hemoglobin A1c levels (HbA1c), and daily insulin use were also recorded., Results: There were significant reductions in SMI (median, 38.7 vs. 36.6 cm 2 /m 2 , P = 0.030), VFI (12.4 vs. 5.1 cm 2 /m 2 , P < 0.001), SFI (26.5 vs. 9.2 cm 2 /m 2 , P < 0.001), BMI (20.3 vs. 18.7 kg/m 2 , P < 0.001), and Alb (4.2 vs. 3.7 g/dL, P = 0.031) at 6 months after TP compared with preoperative period. HbA1c significantly increased at 6 months after TP compared with postoperative discharge (6.7 vs. 7.3%, P < 0.001). The daily insulin use significantly increased at 12 months after TP compared with 6 months after TP (22 vs. 26 units/day, P < 0.001), whereas there were no significant changes in other parameters., Conclusions: Significant losses in fat and skeletal muscle mass as well as the BMI and Alb occurred within the first 6 months after TP. A subsequent increase in the daily insulin use occurred during the next six months, which helped preserve the body composition., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Cryogenic Dark Matter Search low ionization threshold experiment (CDMSlite) achieved efficient detection of very small recoil energies in its germanium target, resulting in sensitivity to lightly ionizing particles (LIPs) in a previously unexplored region of charge, mass, and velocity parameter space. We report first direct-detection limits calculated using the optimum interval method on the vertical intensity of cosmogenically produced LIPs with an electric charge smaller than e/(3×10^{5}), as well as the strongest limits for charge ≤e/160, with a minimum vertical intensity of 1.36×10^{-7}  cm^{-2} s^{-1} sr^{-1} at charge e/160. These results apply over a wide range of LIP masses (5  MeV/c^{2} to 100  TeV/c^{2}) and cover a wide range of βγ values (0.1-10^{6}), thus excluding nonrelativistic LIPs with βγ as small as 0.1 for the first time.

We present limits on spin-independent dark matter-nucleon interactions using a 10.6 g Si athermal phonon detector with a baseline energy resolution of σ&#95;{E}=3.86±0.04(stat)&#95;{-0.00}^{+0.19}(syst)  eV. This exclusion analysis sets the most stringent dark matter-nucleon scattering cross-section limits achieved by a cryogenic detector for dark matter particle masses from 93 to 140  MeV/c^{2}, with a raw exposure of 9.9 g d acquired at an above-ground facility. This work illustrates the scientific potential of detectors with athermal phonon sensors with eV-scale energy resolution for future dark matter searches.

Objective: To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting., Methods: A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks., Results: The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, -0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated., Conclusions: Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings., (© 2021. The Author(s).)

Abstract: We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Hepatectomy with vascular resection (VR) for perihilar cholangiocarcinoma (PHCC) is a challenging procedure. However, only a few reports on this procedure have been published and its clinical significance has not been fully evaluated., Methods: Patients undergoing surgical resection for PHCC from 2002-2017 were studied. The surgical outcomes of VR and non-VR groups were compared., Results: Some 238 patients were included. VR was performed in 85 patients. The resected vessels were hepatic artery alone (31 patients), portal vein alone (37 patients) or both (17 patients). The morbidity rates were almost the same in the VR (49.4 per cent) and non-VR (43.8 per cent) groups (P = 0.404). The mortality rates of VR (3.5 per cent) and non-VR (3.3 per cent) were also comparable (P > 0.999). The median survival time (MST) was 45 months in the non-VR group and 36 months in VR group (P = 0.124). Among patients in whom tumour involvement was suspected on preoperative imaging and whose carbohydrate antigen 19-9 (CA19-9) value was 37 U/ml or less, MST in the VR group was significantly longer than that in the non-VR group (50 versus 34 months, P = 0.017). In contrast, when the CA19-9 value was greater than 37 U/ml, MST of the VR and non-VR groups was comparable (28 versus 29 months, P = 0.520)., Conclusion: Hepatectomy with VR for PHCC can be performed in a highly specialized hepatobiliary centre with equivalent short- and long-term outcomes to hepatectomy without VR., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept., Methods: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change., Results: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status., Conclusion: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept., Trial Registration: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000014657.

Background: Lymph node metastasis is one of the strongest prognostic factors of pancreatic cancer. However, the clinical implication of pathologically node-negative pancreatic cancer (pN0-PC) has not been fully investigated., Methods: Patients who underwent surgical resection for radiologically resectable pancreatic cancer between 2002 and 2018 were included in this study. A clinicopathological examination focusing on pN0-PC was performed., Results: Of all 533 patients, 155 (29.1%) were diagnosed with pN0-PC and 378 (70.9%) were diagnosed with node-positive pancreatic cancer (pN1/2-PC). The 5-year survival rates of patients with pN0-PC and pN1/2-PC were 57.1% and 25.0%, respectively (p < 0.001). A multivariate analysis revealed six prognostic factors in pN0-PC: age ≥ 70 years, nonadministration of adjuvant chemotherapy, anterior serosal invasion, nerve plexus invasion, and microscopic lymphatic and venous invasions. The 5-year survival rates of patients who had pN0-PC with 0-1 risk factor, with 2-3 risk factors, and with 4-6 risk factors were 87.6%, 47.9%, and 16.4%, respectively. Survival of patients who had pN0-PC with 4-6 risk factors was comparable to that of pN1/2 patients. The diagnostic capability of metastasis-negative lymph node was unsatisfactory, with a predictive value of < 43%., Conclusions: Although the prognosis of patients with pN0-PC was better than that of patients with pN1/2-PC, it is not satisfactory. Survival of patients who had pN0-PC with 0-1 risk factors was extremely favorable; however, survival of patients who had pN0-PC with 4-6 risk factors was similar to those with pN1/2-PC.

Background: The absence of the portal bifurcation (APB) is a rare anatomic variation, in which the horizontal part of the left portal vein (PV) is missing. The aim of this study was to identify the vascular architecture in livers with APB., Methods: Computed tomography data for 17,651 patients were reviewed; five patients (0.03%) were found to present with APB. The liver volume and anatomy of APB patients were compared with those of 30 patients with normal livers., Results: All the APB patients exhibited an independent posterior branch of the PV. The intrahepatic left PV (LPV) ran through either the ventral (n = 2, 40%) or dorsal side (n = 3, 60%) of the middle hepatic vein. The frequency of medial branches diverging from the LPV was higher in patients with APB than in normal patients (p < 0.001). The left hepatic duct (LHD) ran through the inside of the left lobe along the left PV in 40% of the patients with APB, whereas in the remaining 60% of the patients with APB, the LHD ran on the outside of the liver separately from the left PV and joined the right hepatic duct. The liver volume of the left lateral section was significantly smaller (p = 0.014), and the posterior section was significantly larger (p = 0.014) in patients with APB than in patients with normal livers., Conclusion: The unique anatomical characteristics and the positional relation of the vessels should be considered preoperatively in patients with APB.

Aim: Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) in Japan. However, the cause and prognosis of HCC may be dramatically changed by direct acting antiviral agents (DAAs). Although the 2015 nationwide survey used a large cohort, its findings may be outdated. The present study therefore aimed to show the latest outcomes by patients' hepatitis virus infection status., Methods: We included 552 patients who underwent hepatectomy for primary HCC between 2002 and 2018 and compared clinical factors between those treated before 2014 (n = 380) and after 2014 (n = 172), when DAAs became available., Results: Distribution of hepatitis virus infection status between the two groups differed significantly ( P  < 0.001). In the earlier group, 46% of the patients had HCC with HCV infection (C-HCC), whereas the rate of C-HCC decreased (31%) and 54% of the patients had HCC with no hepatitis virus infection (NBNC-HCC) in the latter group. The proportion of HCC with hepatitis B virus infection (B-HCC) and the prognosis of B-HCC did not significantly change between the two groups. Among patients with C-HCC, the latter patients had significantly longer relapse-free survival (RFS) than the earlier patients ( P  = 0.033). However, RFS did not significantly differ between the earlier and latter patients with NBNC-HCC., Conclusion: Postoperative prognosis has changed according to patients' hepatitis virus infection status. The proportion of patients with NBNC-HCC has increased, but their prognosis has not been improved. Treatment strategies for NBNC-HCC should be established., Competing Interests: Conflict of Interest: All authors have no conflict of interest regarding the current study. Funding: No funding was received for this study., (© 2021 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Background: The true anatomy of right-sided ligamentum teres (RSLT) has not been fully explained for a century. This study aimed to clarify the exact anatomy of RSLT., Methods: The computed tomography data of 17 651 surgical patients were observed and 76 patients with RSLT, were classified into the bilateral ligamentum teres (LT) group (type A) and three RSLT groups, (B) bifurcation type, (C) trifurcation type, and (D) independent posterior branch type., Results: Type A had double LT that connected to both the right and left sides of the umbilical portion (UP). Types B-D had a P3 + 4 rather than a left UP. Type D was anatomically different from types A-C. Upon comparing types A-C and type D, type D had a significantly smaller volume of segments 3 + 4 (P < .001), and the UP was more often on the left side. The position of the gallbladder fundus in type D was more commonly observed on the right side of the LT compared with that observed in the other types (P = .007)., Conclusions: The change in the volume of segments 3 + 4 and the extent of the RSLT shift create a false perception that the gallbladder changes the position., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

IVR-CT was developed at Aichi Cancer Center (Japan) in 1992 and is now in use worldwide. It was developed initially for the purpose of performing CT more easily during arteriography, but also during non-vascular IR procedures such as biopsy and drainage. Four-detector-row IVR-MDCT was introduced to Shizuoka Cancer center in 2002, which was upgraded to 320-Row IVR-ADCT (320-IVR-CT) by 2013. Although we performed an initial investigation into the efficacy of 320 IVR-CT for vascular intervention, the direct MPR method using volume scanning is predominant in the field of non-vascular intervention. In this review, we describe the history of IVR-CT, report the efficacy of 320-IVR-CT for vascular and non-vascular intervention, and report our experiences.

Objectives: The objective of this study was to compare the clinical effectiveness of uncovered stent and covered stent as percutaneous endoprosthesis for malignant biliary obstruction of the extrahepatic bile duct., Materials and Methods: After completion of percutaneous internal and external tube placement for unresectable malignant biliary obstruction, 60 patients were registered and randomly assigned in a 1:1 ratio to an uncovered or covered stent group. Metallic stent placement was performed within 1 week after registration, and an external biliary drainage tube was removed >3 days after stent placement. The primary endpoint was the obstructive jaundice-free survival rate at 24 weeks after registration, and the secondary endpoints were the success rate of percutaneous tube removal and adverse events., Results: The obstructive jaundice-free survival rate at 24 weeks after registration was 13/29 (44.8%, 95% confidence interval [CI]: 28.4%-62.5%) and 15/30 (50.0%, 95% CI: 33.2%-66.8%) in the uncovered and covered stent groups, respectively. The success rate of percutaneous tube removal was 28/29 (96.6%, 95% CI: 82.8%-99.4%) and 30/30 (100%, 95% CI: 90.5%-100%) in the uncovered and covered stent groups, respectively. There were no procedure-related deaths. Twenty-eight adverse events were observed in 21 patients (7 in the uncovered stent group and 14 in the covered stent group)., Conclusions: There was no significant difference in the obstructive jaundice-free survival rate at 24 weeks between the 2 groups. Considering the technical difficulty and invasiveness of covered stent placement, the placement of covered stents may not be needed in patients with a short prognosis of <24 weeks.

Objectives: To determine prognostic factors for the Health Assessment Questionnaire-Disability Index (HAQ-DI) progression in patients with rheumatoid arthritis (RA) in clinical practice., Methods: We evaluated 388 biological disease-modifying anti-rheumatic drug (bDMARD)-naïve Japanese patients with RA with moderate to high disease activity at study entry after being treated with conventional synthetic DMARDs. These patients were treated according to a treat-to-target (T2T) strategy for one year. The Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) and the HAQ-DI were assessed every three months. We also evaluated joint destruction using a modified total Sharp score at baseline and at one year. HAQ-DI progression was defined as the yearly progression of HAQ-DI >0.1. We performed a multiple logistic regression analysis to explore the factors predicting HAQ-DI progression at one year., Results: HAQ-DI progression was observed in 18% of the patients. The multiple logistic regression analysis revealed the independent variables associated with HAQ-DI progression were: DAS28-ESR >5.1 at baseline (odds ratio [OR] 0.31, 95% con dence interval [CI] 0.13-0.74, p=0.0083); HAQ-DI score at baseline <0.5 (OR 2.27, 95% CI 1.22-4.26, p=0.0102); and achievement of low disease activity at 12 weeks (OR 0.42, 95% CI 0.21-0.82, p=0.0112)., Conclusions: Our data suggest that maintaining clinical improvement according to T2T and initiating the treatment at an early stage are important for functional improvement after one year and that patients with low baseline HAQ scores have a higher risk of HAQ disability progression.

Postoperative chylothorax is a potentially lethal complication after esophagectomy. A 53-year-old woman underwent subtotal esophagectomy. The thoracic duct was resected due to swollen lymph nodes. Postoperative chylothorax was diagnosed but conservative treatment was ineffective. Lipiodol lymphangiography revealed leakage from a duplicated left-sided thoracic duct. Left-sided video-assisted thoracoscopic ligation of the left-sided thoracic duct was performed. Because anatomical variations in the thoracic duct contribute to refractory chylothorax, lymphangiography is useful in detecting the position of thoracic duct injury as well as any duct anomalies. Based on lymphangiography, left-sided video-assisted thoracoscopic surgery could be considered in case of left-sided thoracic duct injury.

Purpose: The clinical impact of abutment to an artery and its branch on resectability and prognosis in patients with borderline resectable pancreatic cancer is unclear., Methods: Patients diagnosed with borderline resectable pancreatic cancer due to artery abutment between April 2012 and December 2018 were enrolled. Contact between arteries and the tumour was assessed by computed tomography (CT)., Results: A primary lesion was resected in 63 patients (R group) and unresected in 19 patients (UR group). Overall survival (OS) was worse in the UR group than in the R group (P < 0.001). Multivariate analysis showed that abutment to the superior mesenteric artery (SMA) branches (P = 0.001) was an independent predictor of poor OS after surgery. Regarding the initial recurrence pattern, abutment to the SMA branches was significantly associated with high incidence of distant metastasis (P < 0.001). According to the most distal SMA branch attached on CT, significant differences in RFS were found between absent-J1A (P = 0.017), J2A-J3A (P = 0.0313) and J3A-middle colic artery (MCA, P = 0.0476) but not between J1A-J2A (P = 0.8207). Significant prognostic differences in OS after initiation of the treatment were found between absent-J1A/J2A (P = 0.006) and J1A/J2A-J3A/MCA (P = 0.033) but not between J3A/MCA-UR (P = 0.494)., Conclusion: Abutment to the SMA branches was associated with high incidence of distant metastasis after resection and a poor survival. Especially, abutment to the J3A or MCA was associated with poor prognosis comparable with that of the UR group.

Fibrous collagen imparts physical strength and flexibility to tissues by forming huge complexes. The density and orientation of collagen fibers must be correctly specified for the optimal physical property of the collagen complex. However, little is known about its underlying cellular mechanisms. Actinotrichia are collagen fibers aligned at the fin-tip of bony fish and are easily visible under the microscope due to their thick, linear structure. We used the actinotrichia as a model system to investigate how cells manipulate collagen fibers. The 3D image obtained by focused ion beam scanning electron microscopy (FIB-SEM) showed that the pseudopodia of mesenchymal cells encircle the multiple actinotrichia. We then co-incubated the mesenchymal cells and actinotrichia in vitro , and time-lapse analysis revealed how cells use pseudopods to align collagen fiber orientation. This in vitro behavior is dependent on actin polymerization in mesenchymal cells. Inhibition of actin polymerization in mesenchymal cells results in mis-orientation of actinotrichia in the fin. These results reveal how mesenchymal cells are involved in fin formation and have important implications for the physical interaction between cells and collagen fibers., (Copyright © 2020 Kuroda, Itabashi, Iwane, Aramaki and Kondo.)

The precise measurement of cosmic-ray antinuclei serves as an important means for identifying the nature of dark matter and other new astrophysical phenomena, and could be used with other cosmic-ray species to understand cosmic-ray production and propagation in the Galaxy. For instance, low-energy antideuterons would provide a "smoking gun" signature of dark matter annihilation or decay, essentially free of astrophysical background. Studies in recent years have emphasized that models for cosmic-ray antideuterons must be considered together with the abundant cosmic antiprotons and any potential observation of antihelium. Therefore, a second dedicated Antideuteron Workshop was organized at UCLA in March 2019, bringing together a community of theorists and experimentalists to review the status of current observations of cosmic-ray antinuclei, the theoretical work towards understanding these signatures, and the potential of upcoming measurements to illuminate ongoing controversies. This review aims to synthesize this recent work and present implications for the upcoming decade of antinuclei observations and searches. This includes discussion of a possible dark matter signature in the AMS-02 antiproton spectrum, the most recent limits from BESS Polar-II on the cosmic antideuteron flux, and reports of candidate antihelium events by AMS-02; recent collider and cosmic-ray measurements relevant for antinuclei production models; the state of cosmic-ray transport models in light of AMS-02 and Voyager data; and the prospects for upcoming experiments, such as GAPS. This provides a roadmap for progress on cosmic antinuclei signatures of dark matter in the coming years.

Background/aim: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC)., Patients and Methods: We retrospectively studied 154 patients with HCC who received sorafenib therapy., Results: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation., Conclusion: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: The present study aimed to evaluate the scan technique of computed tomography (CT)-guided puncture procedures using partial exposure mode (PEM) on the radiation dose of the operator's hand and image quality., Methods: Radiation dose was evaluated using three types of scanning methods: one-shot scan (OS), OS with a bismuth shield added (OSBismuth), and a half-scan (i.e., PEM) capable of an adjustable exposure angle. Dose evaluation was performed using a torso phantom, while a circular phantom simulating the liver parenchyma and lesions was used for image quality evaluation. For each scanning method, four measurements were made to determine the radiation dose to the operator's hand and the dose distribution on the surface of the patient's torso; the output-dose profile was determined from five measurements. Image quality was evaluated in terms of contrast and contrast-to-noise ratio (CNR). Analysis of variance (ANOVA) or Friedman test were used for comparison between groups as appropriate. The post hoc tests were Tukey's honestly difference (HSD) test for parametric data or Wilcoxon signed rank test with Bonferroni correction for nonparametric data., Results: The PEM yielded a radiation dose to the operator's hand that was 84% (0.35 vs. 2.33 mGy) lower than that of the OS. The dose to the patient's torso was reduced by 35% and 68% for the OSBismuth and PEM, respectively, relative to that of the OS. Compared with the CNR of the other two scanning methods (OS, 2.9±0.1; OSBismuth, 2.9±0.1), the PEM increased the standard deviation and decreased the CNR (2.1±0.04, Tukey's HSD, P < 0.001 for all). Images acquired with PEM showed visibility equivalent to that of other scanning methods when window conditions were adjusted., Conclusion: This study demonstrated that CT-guided puncture procedure using PEM effectively reduces the operator's exposure to radiation while minimizing image quality deterioration.

Microbial involvement in the pathogenesis have been suggested in both antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and sarcoidosis, both of which have lung involvement. However, exhaustive research to assess the bacteria in the lung in AAV and in sarcoidosis have not been performed. We sought to elucidate the distinct dysbiotic lung microbiota between AAV and sarcoidosis. We used 16S rRNA gene high-throughput sequencing to obtain the bacterial community composition of bronchoalveolar lavage fluid (BALF) in patients with AAV (n = 16) compared to patients with sarcoidosis (n = 21). The patients had not undergone therapy with immunosuppressive medication when their BALF was acquired. No difference was observed in α-diversity between patients with AAV and patients with sarcoidosis when using all the detected taxa. We defined the taxa of the oral cavity by using the data of oral microbiota of healthy individuals from the Human Microbiome Project (HMP). The analysis using only oral taxa made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. Besides, the analysis using detected taxa except for oral taxa also made the difference in α-diversity between AAV and sarcoidosis clearer compared with those using all the detected taxa. A linear negative relationship between the α-diversity and Birmingham vasculitis activity score (BVAS) was detected in the AAV group. The observed p-value for the effect of the disease groups on the ß-diversity was small while the effect of other factors including sex and smoking status did not have small p-values. By excluding oral taxa from all the detected taxa, we found a cluster mainly consisted of sarcoidosis patients which was characterized with microbial community monopolized by Erythrobacteraceae family. Our results suggested the importance of considering the influence of oral microbiota in evaluating lung microbiota.

Background: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study., Methods: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL., Results: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%)., Conclusions: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.

Background: A randomized, controlled trial to evaluate the superiority of percutaneous transesophageal gastro-tubing over nasogastric tubing as palliative care for bowel obstruction in patients with terminal malignancy was conducted., Subjects and Methods: The subjects were patients with malignant bowel obstruction with no prospect of improvement, for whom surgery was not indicated and with a Palliative Prognostic Index of < 6. They were randomly allocated in a 1:1 ratio to receive either percutaneous transesophageal gastro-tubing (PTEG group) or nasogastric tubing (NGT group). Their symptom scores (the worst 0 to no symptoms 10) were measured for a 2-week period after enrollment, and the areas under the curves for the two groups were compared. The EQ-5D and SF-8 were also used to assess overall quality of life., Results: Forty patients were enrolled between October 2009 and January 2015, with 21 allocated to the PTEG group and 19 to the NGT group. The mean areas under the curves (95% confidence intervals) for the PTEG group and the NGT groups were 149.6 (120.3-178.8) and 44.9 (16.4-73.5), respectively, significantly higher for the NGT group (p < 0.0001). The secondary endpoints of quality of life as assessed by the EQ-5D and SF-8 scores were also significantly higher for patients in the PTEG group (p = 0.0036, p = 0.0020). There was no difference in survival between the groups. No serious adverse events were observed., Conclusions: In terms of quality of life, percutaneous transesophageal gastro-tubing was superior to nasogastric tubing as palliative care for patients with bowel obstruction due to terminal malignancy.

Objective: Recently, Human T-cell leukemia virus type-1 proviral load (HTLV-1 PVL) has been evaluated as an important predictor of adult T-cell leukemia/lymphoma (ATL) in HTLV-1 carriers. We aimed to evaluate whether HTLV-1 PVL is also important for the development of ATL among HTLV-1-positive patients with rheumatoid arthritis (RA). Methods: We established a cohort of 82 HTLV-1-positive RA patients between 2017 and 2018. Of those, 27 (32.9%) were treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with/without methotrexate. We measured HTLV-1 PVL in peripheral blood mononuclear cells (PBMCs) at study entry and compared the value by clinical status and treatment options. Results: The median PVL for all was 9.6 copies per 1000 PBMCs without sex difference (male 17.2 and female 8.6; p  = .24). The median PVL was significantly higher for patient's comorbid bronchiectasis, malignancies, and opportunistic infectious diseases, compared with patients without comorbidity. There were no significant differences in PVL levels among types of bDMARDs, although the level was tended to be higher for patients treated with JAK inhibitor. Conclusions: HTLV-1 seropositive RA patients comorbid for any diseases having higher HTLV-1 PVLs will be a higher risk for developing ATL. Careful follow-up of these patients is necessary to detect ATL development.

Summary: KofamKOALA is a web server to assign KEGG Orthologs (KOs) to protein sequences by homology search against a database of profile hidden Markov models (KOfam) with pre-computed adaptive score thresholds. KofamKOALA is faster than existing KO assignment tools with its accuracy being comparable to the best performing tools. Function annotation by KofamKOALA helps linking genes to KEGG resources such as the KEGG pathway maps and facilitates molecular network reconstruction., Availability and Implementation: KofamKOALA, KofamScan and KOfam are freely available from GenomeNet (https://www.genome.jp/tools/kofamkoala/)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)

To investigate the spatiotemporal dynamics of skin pattern formation, we developed a simple method for artificially disarranging the placement of all three pigment cell types in the body trunk of zebrafish (Danio rerio). We generated transgenic fish with melanophores that ectopically expressed a variant of channelrhodopsin-2 (ChR2). Blue light (BL) irradiation induced melanophore depolarization and random migration; the latter resulted in the disarrangement of the two other pigment cell types (xanthophores and iridophores). This BL disarrangement (BLD) method was effective in both young and adult fish, but it did not affect the initial placement of pigment cells in juvenile fish (approximately 5 weeks post-fertilization). Irradiation with BL was not harmful to cells, and the patterning process immediately resumed when BL was switched off. Using the BLD method, we demonstrated that interactions between pigment cells determined stripe width in the absence of any pre-set positional cues, while the initial horizontal alignment of iridophores determined their directionality. The BLD method can be adapted to any zebrafish skin-pattern mutant, providing a novel tool for analyzing pattern formation mechanisms under a variety of conditions and facilitating further study in this field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aim: Intrahepatic metastasis (IM) of hepatocellular carcinoma (HCC) occurs via vascular invasion; the tumor diameter that affects the risk of micro intra-hepatic metastasis (MIM) should be larger than that which affects the risk of micro vessel invasion (MVI). The aim of the present study was to determine the optimum tumor diameter cut-off value for predicting the presence of MIM in HCC patients without treatment history and HCC patients with a treatment history and to compare these diameters between cases of MVI and MIM., Methods: This retrospective study included 621 patients without macroscopic vessel invasion or intrahepatic metastasis on preoperative imaging who underwent hepatectomy. The cut-off tumor diameter for predicting the presence of MIM was determined by a receiver operating characteristic curves analysis., Results: The optimum cut-off value for predicting the presence of MIM in HCC patients without treatment history was 43 mm. In contrast, the optimum cut-off value for predicting the presence of MIM in HCC patients with a treatment history was 20 mm. Among 46 HCC patients with MIM without treatment history, there were 20 patients with MIM without MVI who were considered to have potential multi-centric (MC) tumors rather than IM. The cumulative overall survival rates in patients with MIM without MVI (potential MC) was significantly better than that in patients with both MIM and MVI (P = 0.022)., Conclusions: The tumor diameter cut-off value for predicting MIM differed between HCC patients without treatment history and with a treatment history and slightly smaller than those for predicting MVI beyond our expectation.

Objectives : To investigate predictors of inadequate response to first conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis (RA) patients in daily clinical practice. Methods : Inadequate response to MTX or other csDMARDs was defined as being not low disease activity at 12 months in more than 3 of 4 composite measures, and discontinuation or start of biologic DMARDs. The association between baseline factors and csDMARDs-IR was assessed by univariate and multivariate logistic regression analyses. Results : Four hundred and eleven and 146 patients were started on MTX and other csDMARDs, respectively; 218 patients were responsive to MTX, with a response rate of 47.0%. Tender joint count (TJC, ≥6 in 28joints, odds ratio [OR] = 1.67, 95% confidence interval [CI] 1.06-2.64) and CRP (≥1.0 mg/dL, OR = 1.72, 95%CI: 1.10-2.70) at baseline were identified as predictors on multivariate logistic regression analysis. TJC (OR = 3.60, 95%CI: 1.29-10.00) was the factor identified as a predictor of the development of other csDMARDs-IR. Conclusion : In this observational study, patients with untreated RA at risk of inadequate response to MTX included those with a higher TJC and higher CRP, while a higher TJC was the only independent predictor of an inadequate response to csDMARDs other than MTX.

Introduction: Hepatic arterial infusion chemotherapy (HAIC) is a feasible treatment for patients with colorectal cancer (CRC) with unresectable liver metastases., Objective: The aim of this retrospective study was to assess HAIC of 5-fluorouracil (5FU) in patients with unresectable liver metastases from CRC refractory to standard systemic chemotherapy., Methods: A total of 137 patients (85 men, 52 women; median age, 62 years; with KRAS mutation, n = 57) were recruited from seven institutions from September 2008 to December 2015. These patients were refractory to systemic chemotherapy including three cytotoxic agents (fluoropyrimidine, oxaliplatin, and irinotecan) with two molecular-targeted agents (bevacizumab and epidermal growth factor receptor antibody [cetuximab or panitumumab]). All patients underwent HAIC of continuous 5FU for unresectable liver metastases. Overall survival time, time to treatment failure, objective response rate, disease control rate, and incidence of adverse events to HAIC were assessed retrospectively., Results: The median overall survival time was 4.8 months (95% confidence interval [CI], 4.0-5.7 months), whereas time to treatment failure was 2.4 months (95% CI, 2.0-2.8 months). The objective overall response rate and disease control rate were 12.4 and 64%, respectively. Grade 3 or 4 adverse events were observed in 2.9% of the patients (hyperbilirubinemia in 2, liver abscess in 1, and myelosuppression in 1)., Conclusions: There were few incidences of severe adverse events to HAIC of 5FU for liver metastases from CRC refractory to standard systemic chemotherapy. Therefore, it might present as a treatment option as last-line chemotherapy., (© 2020 S. Karger AG, Basel.)

Background: Some parameters using preoperative computed tomography (CT) have been evaluated to predict the development of pancreatic fistula (PF) after pancreaticoduodenectomy (PD). The present retrospective study evaluated the predictive value of pancreatic attenuation for PF after PD., Methods: A retrospective review was conducted of the patients who underwent PD between January 2010 and December 2014. The pancreatic attenuation was measured in unenhanced preoperative CT images. Pre- and intraoperative variables were analyzed for the risk of PF after PD., Results: Of the 346 consecutive patients, PF occurred in 116 (34%). The pancreatic attenuation was significantly greater in patients with PF than in those without PF (median, 40.0 vs. 33.3 Hounsfield units [HU], P < 0.001). A multivariate analysis showed that a pancreatic attenuation ≥30.0 HU (odds ratio [OR], 3.72; P < 0.001), a body mass index ≥25.0 kg/m 2 (OR, 3.67; P < 0.001) and a diameter of the main pancreatic duct <3.0 mm (OR, 1.84; P = 0.034) were independent risk factors for PF after PD., Conclusion: The degree of pancreatic attenuation on preoperative CT images was significantly associated with PF, and a pancreatic attenuation ≥30.0 HU was an independent risk factor of PF after PD., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Hepatic arterial infusion chemotherapy (HAIC) is a treatment option for metastatic breast cancer (MBC) patients with extensive liver metastasis (LM); however, the appropriate regimen and the treatment effects have not been discussed. The aim of this study is to evaluate the efficacy and safety of HAIC with the 5-FU, epirubicin, and mitomycin-C (FEM) regimen., Patients and Methods: We reviewed MBC patients with critical LM who were resistant to standard systemic chemotherapies and had received HAIC with an FEM regimen., Results: We identified 57 patients who received HAIC between 2003 and 2017. The patient characteristics were as follows: i) median age=56 (30-80), and ii) Eastern Cooperative Oncology Group Performance Status, 0/1/2=43/11/3. The median number of LMs was 8 (range 1 to ≥20), the median diameter of LM was 5.2 cm (range=1.6 to 20.1). The median overall survival from the initiation of HAIC was 11.3 months (95% confidence interval=8.5-15.6). The objective response rate of LM was 63%., Conclusion: HAIC with an FEM regimen is an effective salvage treatment for MBC patients with advanced LM., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: When a postoperative hepatic artery pseudoaneurysm develops after massive hepatectomy, both an intervention for the pseudoaneurysm and patency of hepatic artery should be considered because occlusion of the residual hepatic artery results in critical liver failure. However, the treatment strategy for a pseudoaneurysm of the hepatic artery after hepatobiliary resection is not well established., Case Presentation: A 65-year-old woman underwent right hepatectomy, extrahepatic duct resection, and portal vein resection, for gallbladder cancer. Although the patient had an uneventful postoperative course, computed tomography on postoperative day 6 showed a 6-mm pseudoaneurysm of the hepatic artery. Angiography revealed the pseudoaneurysm located on the bifurcation of the left hepatic artery to the segment 2 artery plus the segment 3 artery and 4 artery. Stent placement in the left hepatic artery was not feasible because the artery was too narrow, and coiling of the pseudoaneurysm was associated with a risk of occluding the left hepatic artery and inducing critical liver failure. Therefore, portal vein arterialization constructed by anastomosing the ileocecal artery and vein was performed prior to embolization of the pseudoaneurysm to maintain the oxygen level of the remnant liver, even if the left hepatic artery was accidentally occluded. The pseudoaneurysm was selectively embolized without occlusion of the left hepatic artery, and the postoperative laboratory data were within normal limits. Although uncontrollable ascites due to portal hypertension occurred, embolization of the ileocolic shunt rapidly resolved it. The patient was discharged on postoperative day 45., Conclusion: Portal vein arterialization prior to embolization of the aneurysm may be a feasible therapeutic strategy for a pseudoaneurysm that develops after hepatectomy for hepatobiliary malignancy to guarantee arterial inflow to the remnant liver. Early embolization of arterioportal shunting after confirmation of arterial inflow to the liver should be performed to prevent morbidity induced by portal hypertension.

Connexin 39.4 (Cx39.4) and connexin 41.8 (Cx41.8), two gap-junction proteins expressed in both melanophores and xanthophores, are crucial for the intercellular communication among pigment cells that is necessary for generating the stripe pigment pattern of zebrafish. We have previously characterized the gap-junction properties of Cx39.4 and Cx41.8, but how these proteins contribute to stripe formation remains unclear; this is because distinct types of connexins potentially form heteromeric gap junctions, which precludes accurate elucidation of individual connexin functions in vivo Here, by arranging Cx39.4 and Cx41.8 expression in pigment cells, we have identified the simplest gap-junction network required for stripe generation: Cx39.4 expression in melanophores is required but expression in xanthophores is not necessary for stripe patterning, whereas Cx41.8 expression in xanthophores is sufficient for the patterning, and Cx41.8 expression in melanophores might stabilize the stripes. Moreover, patch-clamp recordings revealed that Cx39.4 gap junctions exhibit spermidine-dependent rectification property. Our results suggest that Cx39.4 facilitates the crucial cell-cell interactions between melanophores and xanthophores that mediate a unidirectional activation-signal transfer from xanthophores to melanophores, which is essential for melanophore survival., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Background: The length of tumour-vein contact between the portal-superior mesenteric vein (PV/SMV) and pancreatic head cancer, and its relationship to prognosis in patients undergoing pancreatic surgery, remains controversial., Methods: Patients diagnosed with pancreatic head cancer who were eligible for pancreatoduodenectomy between October 2002 and December 2016 were analysed. The PV/SMV contact was assessed retrospectively on CT. Using the minimum P value approach based on overall survival after surgery, the optimal cut-off value for tumour-vein contact length was identified., Results: Among 491 patients included, 462 underwent pancreatoduodenectomy for pancreatic head cancer. PV/SMV contact with the tumour was detected on preoperative CT in 248 patients (53·7 per cent). Overall survival of patients with PV/SMV contact exceeding 20 mm was significantly worse than that of patients with a contact length of 20 mm or less (median survival time (MST) 23·3 versus 39·3 months; P = 0·012). Multivariable analysis identified PV/SMV contact longer than 20 mm as an independent predictor of poor survival, whereas PV/SMV contact greater than 180° was not a predictive factor. Among patients with a PV/SMV contact length exceeding 20 mm on pretreatment CT, those receiving neoadjuvant therapy had significantly better overall survival than patients who had upfront surgery (MST not reached versus 21·6 months; P = 0·002)., Conclusion: The length of PV/SMV contact predicts survival, and may be used to suggest a role for neoadjuvant therapy to improve prognosis., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: The long-term patency of the portal vein (PV) in patients who survive after pancreaticoduodenectomy (PD) remains unclear. The aim of the present study was to investigate the clinical features and risk factors for benign PV stenosis after PD., Methods: We retrospectively analyzed the patients who underwent PD from September 2002 and December 2015 at our institution without intraoperative radiation therapy or concomitant PV resection. The postoperative computed tomography of each patient was evaluated, and PV stenosis was defined as the shortest diameter of the PV being <3 mm. The patients with PV stenosis due to local recurrence were excluded., Results: Of the 458 patients, PV stenosis occurred in 57 (12.4%), including benign PV stenosis in 28 (6.1%) and PV stenosis due to local recurrence in 29 (6.3%). Of the 28 patients with benign PV stenosis, 7 (25%) developed symptoms related to portal hypertension, namely recurrent gastrointestinal bleeding in 5 and refractory ascites in 2. Six patients were treated with percutaneous transhepatic PV stent placement, and all of their symptoms improved. A multivariate analysis found that a postoperative pancreatic fistula was an independent risk factor for benign PV stenosis after PD (odds ratio, 4.36; p = 0.005)., Conclusions: Postoperative pancreatic fistula was a significant risk factor for benign PV stenosis after PD. Stent placement for benign PV stenosis was effective for the patients with symptoms due to portal hypertension.

Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ≥20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escalation; ontuxizumab 2-12 mg/kg weekly) and part 2 (cohort-expansion; 4 or 8 mg/kg weekly, or 12 mg/kg biweekly). Results Fifteen patients were treated in part 1, and 31 in part 2 (16 patients with GC and 15 with HCC). In part 1, the most common treatment-related, treatment-emergent adverse event (TEAE) was fatigue (20%); no patients had grade ≥ 3 treatment-related TEAEs. In part 2, the most common treatment-related TEAEs were constipation, malaise, hiccups, and increased bilirubin; treatment-related grade 3 TEAEs occurred in two patients with HCC. In part 1, no patients achieved a partial response, and 6/15 (40%) had stable disease (SD). In part 2, 2/15 patients (13.3%) with GC and 8/15 (53.3%) with HCC had SD. Tumor shrinkage was observed in 5/15 HCC patients (33.3%). Conclusions Ontuxizumab, up to a dosage of 12 mg/kg weekly, was generally safe and well tolerated in this population, with no dose-limiting toxicities. The maximum tolerated dose was not reached; 8 mg/kg weekly or 12 mg/kg biweekly were the recommended dosages. We observed long-term disease stabilization in GC and extraskeletal chondrosarcoma, and tumor shrinkage in gastrointestinal stromal tumor and HCC. Trial registration: NCT01773434 ( ClinicalTrials.gov ).

Background: Portal vein thrombosis (PVT) is a life-threatening complication after hepatectomy. However, the relationship between postoperative PVT and morphometric features of the PV has not been fully elucidated yet., Patients and Methods: A total of 81 patients who underwent hepatectomy for perihilar cholangio-carcinoma (PHCC) were studied. We investigated the diameters and angles of PV using pre- and postoperative computed tomography (CT) reconstructed by SYNAPSE VINCENT®., Results: The incidence of PVT after hepatectomy was 11.1%. There were significant differences with respect to the remnant liver PV diameter (p=0.015), the diameter ratio (p=0.001), and the postoperative PV angle (p=0.001) between patients with and without PVT. Multivariate analysis revealed that a postoperative PV angle of less than 90° (p=0.008) and a diameter ratio of less than 45% (p=0.041) were independent risk factors for PVT., Conclusion: A postoperative PV angle of less than 90° and diameter ratio of less than 45% eventually lead to PVT after hepatectomy for PHCC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To provide lessons learned for colleges of pharmacy and large health systems that are contemplating or in the process of undergoing integration. Method: This report describes the merger of an academic medical center and large health system with a focus on the implications of the merger for pharmacy from the perspectives of both a college of pharmacy and a health system's pharmacy services. Results: Overarching pharmacy issues to consider include having an administrator from the college of pharmacy directly involved in the merger negotiation discussions, having at least one high-level administrator from the college of pharmacy and one high-level pharmacy administrator from the health system involved in ongoing discussions about implications of the merger and changes that are likely to affect teaching, research, and clinical service activities, having focused discussions between college and health system pharmacy administrators on the implications of the merger on experiential and research-related activities, and anticipating concerns by clinical faculty members affected by the merger. Conclusion: The integration of a college of pharmacy and a large health system during the acquisition of an academic medical center can be challenging for both organizations, but appropriate pre- and post-merger discussions between college and health system pharmacy administrators that include a strategic planning component can assuage concerns and problems that are likely to arise, increasing the likelihood of a mutually beneficial collaboration., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.

We examined the efficacy and safety of denosumab as treatment for glucocorticoid-induced osteoporosis (GIOP) patients complicated with rheumatic diseases, by measuring patients' lumber bone mineral density (BMD) and bone turnover markers. A total of 66 consecutive patients for whom denosumab was initiated between July 2013 and August 2016 were enrolled and evaluated for 12 months. All of the patients were treated with glucocorticoids for underlying rheumatic diseases. The clinical assessment included measurements of the BMD of the lumbar spine (L2-L4) by a dual-energy X-ray absorptiometry technique and the bone turnover markers N-terminal telopeptide of type 1 collagen (NTX) in urine, serum intact procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatase (BAP) at baseline, 6 months and 12 months after the start of denosumab treatment. Adverse events (AEs) until 12 months were also analyzed. The mean percentage changes in BMD from baseline to 6 and 12 months were significant (2.85% increase, p < 0.0001 and 4.40% increase, p < 0.0001, respectively) regardless of the prior anti-osteoporotic drugs treatment (16 no transition from anti-osteoporotic drugs, 27 transition from bisphosphonate, 23 transition from teriparatide). The decreases in NTX, P1NP and BAP at 6 and 12 months were also significant. No serious AEs were noted. A multivariable logistic analysis showed that the prednisolone dose at baseline was associated with the clinical response to denosumab. In a real-world setting, denosumab was effective and safe for treating GIOP patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drug treatment.

Purpose: To evaluate the embolic effect and the safety of transarterial embolization (TAE) using n-butyl-2-cyanoacrylate (NBCA) in a prospective multicenter trial., Materials and Methods: This study was an open-label, multicenter, phase II trial. The inclusion criteria were (1) active bleeding or pseudoaneurysm, (2) true aneurysm, (3) arteriovenous malformation (except cerebral lesion), (4) arteriovenous fistula, or (5) need for arterial distribution before transarterial treatment. Selective TAE with NBCA diluted 2-10 times was performed. The primary endpoint was the success rate of embolization with a per-patient analysis based on the angiographic findings. Secondary endpoints were safety, evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) version 4, and the success rate of embolization with a per-vessel calculation., Results: Sixty-five patients were initially enrolled, but due to protocol violation in two patients, efficacy was ultimately analyzed in 63 patients (103 vessels) and safety was analyzed in 64 patients. The success rate per patient was 98.4% (62/63; 95% confidence interval (CI), 91.5-100.00), and the success rate per vessel was 99.0% (102/103; 95% CI, 94.7-100.0). Adverse events of grade 3 or above based on CTCAE version 4 occurred in 22/64 patients (34.4%). Twelve intraoperative or postoperative adverse events grade 3 or above, which may have been related to embolization using NBCA, occurred in 11/64 patients (17.2%). Three patients died after embolization using NBCA, but their deaths were unrelated to TAE., Conclusion: In this prospective multicenter clinical trial, the efficacy of TAE using NBCA was 98.4% and adverse events were clinically acceptable., Level of Evidence: Level 3b.