Search

Solid pseudopapillary neoplasms (SPNs) of the pancreas have low malignant potential. However, malignant SPNs are not fully understood.To evaluate risk factors affecting malignant potential, the clinicopathologic features of 375 surgically resected SPNs were compared.Fifty (13.3%) had malignant histologic features. Twenty-seven and 22 had perineural and lymphovascular invasions, respectively. Adjacent organ invasion was noted in 9 cases. Recurrence occurred in 8 cases. The median recurrence time after surgical resection was 67 months and was associated with a higher pT category (P = 0.001), lymphovascular invasion (P 0.001), and synchronous metastasis (P 0.001). SPN patients with malignant histologic features had worse recurrence-free survival (RFS; 10-year survival rate, 73.2%) than those without malignant histologic features (96.3%; P = 0.01). Patients with a higher pT category (P = 0.04), synchronous metastasis (P 0.01), and lymphovascular invasion (P 0.01) had worse RFS. Lymphovascular invasion (P = 0.042) and a higher T category (P = 0.002) were poor prognostic factors for recurrence.Lymphovascular invasion and a higher T category were worse prognostic factors for recurrence in SPN patients with malignant histologic features. For SPN patients with malignant histologic features, a longer follow-up may be required.

Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs.Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (HE)-stained slides.Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps .05).Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.

Background Non-HLA antibodies, anti-angiotensin II type 1 receptor antibodies (anti-AT1R) and anti-endothelial cell antibodies (AECA), are known to play a role in allograft rejection. We evaluated the role of both antibodies in predicting post-transplant outcomes in low-risk living donor kidney transplantation (LDKT) recipients. Methods In 94 consecutive LDKT recipients who were ABO compatible and negative for pre-transplant HLA donor-specific antibodies, we determined the levels of anti-AT1Rs using an enzyme-linked immunosorbent assay and the presence of AECAs using a flow cytometric endothelial cell crossmatch (ECXM) assay with pre-transplant sera. Hazard ratio (HR) was calculated to predict post-transplant outcomes. Results Pre-transplant anti-AT1Rs (≥11.5 U/mL) and AECAs were observed in 36 (38.3%) and 22 recipients (23.4%), respectively; 11 recipients had both. Pre-transplant anti-AT1Rs were a significant risk factor for the development of acute rejection (AR) (HR 2.09; P=0.018), while a positive AECA status was associated with AR or microvascular inflammation only (HR 2.47; P=0.004) throughout the follow-up period. In particular, AECA (+) recipients with ≥11.5 U/mL anti-AT1Rs exhibited a significant effect on creatinine and estimated glomerular filtration rate (P

Background BK virus (BKV)–associated nephropathy is a significant complication of kidney transplantation that progresses to graft dysfunction and graft loss. The aim of this study was to know the infection rate and progression of BKV according to our strategy. Materials and Methods This study included 302 patients who received kidney transplantation between August 2010 and October 2012. Patients were divided into 4 groups: no BK infection, BK viruria only, low BK viremia, and high BK viremia. Results In this study, 57 patients had BK viremia (18.9%), and 18 patients had BK nephropathy (5.9%) during a 2-year follow-up period. Age, sex, cytomegalovirus (CMV) viremia, existence of donor-specific antibodies, type of transplantation, and delayed graft function were not significantly different. Disappearance of BKV infection was better in the viruria and low viremia groups than in the high viremia group (P = .001), and duration of BK infection was longer in the high viremia group than the low viremia group (P = .002). Conclusion All diagnosed cases of BKV nephropathy were in the high BK viremia group. For BK viruria and viremia, early detection of BK infection together with early intervention by reduced immunosuppressant is a useful strategy to maintain allograft function. Long-term follow up is required to identify the risk factors for BK infection and graft survival after kidney transplantation.

Summary: Background: Many immunosuppressive drugs are prescribed as twice-daily dosing. A simplified once-daily dosing of immunosuppressive drug regimen may improve medication adherence. We investigated medication adherence of simplified once-daily immunosuppressive regimen consisting of extended-release tacrolimus, sirolimus, and corticosteroids along with the efficacy and safety of this regimen. Methods: This study was a prospective, multicenter, controlled and cohort trial. Stable kidney transplant recipients who had received transplantation at least 3 months before the study enrollment were eligible for the study. Participants were required to fill-out the self-reported immunosuppressant therapy barrier scale (ITBS) questionnaire before and after the conversion. Other clinical laboratory parameters and adverse events were evaluated until 6 months post-conversion. Results: A total of 160 kidney recipients comprised the intention-to-treat population. The mean total ITBS score was 19.5 ± 4.0 at pre-conversion and 6 months after converting, the mean total ITBS score was 16.6 ± 3.6 (p

The New Zealand public sector reform process of the late 1980s and early 1990s was notable for its attempt to clarify public accountability through the specification of outputs, contractual agreements and the disaggregation of government departments into smaller, more sharply focused agencies. While the reforms achieved managerial improvements, the accountability regime was less successful because of the difficulties of specification and the continuing robustness of ministerial responsibility in the face of attempts to limit the political control and accountability. INTRODUCTION: REASSESSING THE NEW ZEALAND MODEL New Zealand holds a special place in the recent history of public sector reform. In three major pieces of legislation in the 1980s (the State-Owned Enterprises Act 1986, the State Sector Act 1988 and the Public Finance Act 1989) it implemented a particularly radical version of what became known as the 'new public management' (NPM) and indeed provided an archetype of that movement (Hood 1991). The fact that reform was premised on a coherent theoretical blueprint (Treasury, 1987), which was then followed through with remarkable thoroughness and consistency marked New Zealand out as especially interesting to academic analysts as well as to practitioners with a taste for rational principle rather than incremental pragmatism. The degree of principled consistency was always somewhat overstated (Boston et al., 1996:84-85), and the system was subject to constant adjustment after its initial enactment. None the less, it stands out as a heroic, and ultimately (and predictably) unsuccessful, attempt to ground public management on clear assumptions and unambiguous principles. Clarity was the watchword of the reforms. The root causes of government inefficiency and ineffectiveness were perceived to be the failure to specify the objectives of government agencies and confusion over roles (between politicians and public servants and within public agencies) (Treasury, 1987; Scott, 1996). Once each agency and each key actor had their role clarified and their objectives specified, they could be freed from debilitating controls over inputs and processes. They could also be more readily held accountable for their performance in terms of clearly specified roles and objectives. From these assumptions followed most of the key elements of the new system (Boston et al., 1996; Treasury, 1996), including the separation of the roles of ministers and departmental chief executives (CEs), with ministers responsible for choosing 'outcomes' and CEs responsible for delivering 'outputs'; the emphasis on clear specification and costing of departmental outputs; the separation between the government's interest as 'purchaser' of public services and its interest as 'owner' of government agencies (and the consequent distinction between 'vote' ministers and 'responsible' ministers); the decoupling of non-departmental agencies ('crown entities' and 'state owned-enterprises') from ministerial direction; the disaggregation of large multi-function departments into more narrowly focused policy ministries, service delivery agencies and independent monitoring agencies; the reliance on explicit contract-like agreements to spell out the government's expectations from individual CEs and agencies. The New Zealand system has been subject to extensive examination (Scott 2001:42-62), including two major government-sponsored reviews (Logan 1991; Schick 1996) as well as several thorough academic assessments (Boston et al., 1996). In terms of improved efficiency and effectiveness, considerable benefits have been found to flow from the relaxation of central agency controls over inputs, the reorientation of agencies towards results and the adoption of strategic planning. Savings have been achieved through the decoupling of public service provision from core government departments, for instance through outsourcing, corporatization and privatization. …

Background: This study aimed to develop and validate the Kidney Transplantation and Quality of Life (KTQoL) questionnaire to evaluate the quality of life (QoL) in Korean kidney transplantation (KT) patients. During the validation, the KTQoL was used to compare the QoL of KT patients before and after conversion from twice-daily to a once-daily regimen of tacrolimus. Methods: Construct and content validity of the 24-item KTQoL was evaluated using factor analysis and a panel of experts, respectively. The questionnaire was validated in 50 KT patients, conducted before and after conversion from twice-daily to once-daily tacrolimus. Internal consistency was evaluated based on Cronbach’s alpha coefficient. Results: The KTQoL showed high internal consistency (Cronbach’s alpha 0.71 to 0.88). Besides the Concerns category, both the general and specific QoL of KT patients were relatively good (≥70% of positive responses) and did not change markedly after conversion to the once-daily regimen (42.9±8.8 vs. 43.6±8.6, P=0.740). After conversion, men scored better than women in total KTQoL, Specific QoL, and Symptoms, while employed patients had better Daily Life scores and showed greater improvement in Daily Life scores compared with unemployed patients. Conclusions: The KTQoL seems to be a reliable instrument to evaluate general and specific QoL in Korean KT patients. Most patients evaluated their QoL positively. Conversion to once-daily tacrolimus had no significant effect on QoL in the total sample of KT patients. The QoL of men and/or employed persons might improve more after conversion to once-daily tacrolimus.

BackgroundGallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.Materials and MethodsTo determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.ResultsThree of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.ConclusionMMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

The innovative pure laparoscopic living donor right hepatectomy (LLDRH) procedure for liver transplantation has never been fully compared to open living donor right hepatectomy (OLDRH). We aimed to compare the donor safety and graft results of pure LLDRH to those of OLDRH.From May 2013 to July 2017, 288 consecutive donors underwent either OLDRH (n = 197) or pure LLDRH (n = 91). After propensity score matching, 72 donors were included in each group. The primary outcome was postoperative complications during a 90-day follow-up period. Comprehensive complication index, duration of hospital stay, need for additional pain control, readmission, and donor outcomes were also compared.The incidence of major complication during the 90-day follow-up was higher in the LLDRH group than the OLDRH group (6.6% vs 15.4%, P = 0.017) but was not statistically significant in propensity-matched analysis (11.1% vs 13.9%, odds ratio [OR], 1.29; 95% confidence interval [CI], 0.47-3.51; P = 0.62). A right hepatic duct1 cm was independently associated with complication in the pure LLDRH group (odds ratio, 4.01; 95% confidence interval, 1.08-14.99; P = 0.04).In the initial 91 pure LLDRH cases, incidence of major complication was higher than in the OLDRH group, but the difference was not significant in propensity-matched analysis. A right hepatic duct verified as1 cm may be related to increased frequency of complications in pure LLDRH donors. Further analysis is needed.

The influence of lymph node (LN) response to preoperative chemoradiotherapy (PCRT) has not been well evaluated for prognosis and additional use of adjuvant treatment after PCRT in rectal cancer patients. The aim of this study was to evaluate the prognostic effect of LN regression grade (LRG) in rectal cancer after PCRT and radical resection.From 2008 to 2011, 389 patients with rectal cancer treated with PCRT followed by radical resection were identified. The pathologic LRG (pLRG) score was determined on the basis of the proportion of tumor cells and fibrosis. The sum of the pLRG of each evaluated LN was used as the final LRG score, LRG-sum. Cox regression analysis was used to evaluate the association of LRG-sum and recurrence-free survival (RFS).The distribution of LRG-sum was significantly associated with tumor regression grade of the primary tumor (P .001). LRG-sum showed different values even in patients with the same number of metastatic LNs. LRG-sum was confirmed as the most relevant associated factor among LN-related variables with RFS along with ypT stage in multivariate analysis. Patients were categorized according to the cutoff points of LRG-sum distribution: LRG1 (LRG-sum 0 to ≤3), LRG2 (LRG-sum 3 to ≤21), and LRG3 (LRG-sum21). RFS showed a significant difference according to LRG group (P .001) and showed more effective difference in RFS in the same ypN stage subgroup on the basis of the number of metastatic LNs.LRG was a prognostic factor of oncologic outcomes of rectal cancer. LN response to PCRT might help in prognostication and determination of treatments after PCRT.

Objective The objective of this study was to analyze the impact of induction immunosuppression on the incidence of recurrent IgA nephropathy (IgAN). Methods We conducted recurrence-free survival analysis of recipients of a first kidney transplant for IgAN who received a graft between 1995 and 2015. Kaplan-Meier and Cox regression analyses were used to sort the significant risk factors for recurrence. A total of 226 recipients with biopsy-proven IgAN received a kidney transplant, and 218 recipients were enrolled. Results Among the recipients, 29 cases of IgAN recurrence were observed. The recipients were categorized into 3 groups according to induction immunosuppression: no induction (group 1, n = 72), anti-CD25 (group 2, n = 86), and antithymocyte globulin (ATG, group 3, n = 60). The 5- and 10-year cumulative IgAN recurrence rates were 9.7% and 21.0%, respectively. Recipients receiving ATG (group 3) exhibited significantly higher 4- and 5-year recurrence-free graft survival rates (both 96.4%) than recipients who received anti-CD25 (group 2, both 85.1%, P = .03). However, the induction therapy used (ATG or basiliximab) was not the risk factor for IgAN recurrence. Conclusions Therefore, we concluded that ATG induction seems to postpone IgAN recurrence. These findings should be evaluated with well-designed prospective studies.

In rheumatoid arthritis research, NHP models of collagen-induced arthritis are important because these species share many immunologic and pathologic features with humans. In addition, serum levels of various cytokines in patients with rheumatoid arthritis have been studied as immune markers for disease prediction, early diagnosis, and effective therapeutic management. The purpose of this study was to identify changes in cytokine levels that occur during the development of collagen-induced arthritis in female cynomolgus macaques (n = 8) and to assess the relationships between these changes and various disease parameters. Blood samples were collected weekly before (week 0) and after (weeks 1 through 7) immunization with type II collagen; clinicopathologic and cytokine data from those samples and other clinical parameters were used in correlation analysis. Serum levels of IFN γ, chemokine (C-C motif) ligand 2 (CCL2), and IL6 showed significant changes after generation of collagen-induced arthritis. IFNγ levels showed a strong negative correlation with body weight (an indicator of general body condition), and CCL2 and IL6 showed moderate negative correlation with body weight. Serum IL6 levels showed moderate positive correlation with the soft tissue swelling score and strong positive correlation with serum C-reactive protein levels in our NHP model of collagen-induced arthritis. In addition, serum levels of matrix metalloproteinase 3 increased significantly after inoculation with type II collagen and showed a moderate positive correlation with serum levels of C-reactive protein, IL6, and IL15. These results suggest close correlations between various cytokines and disease parameters in NHP models of rheumatoid arthritis. These cytokines therefore potentially could be used as markers for monitoring the efficacy of novel treatments in NHP models of rheumatoid arthritis.

While 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been investigated in extremity sarcomas, there is no evidence on its usefulness in retroperitoneal sarcoma. This study was designed to evaluate the usefulness of 18F-FDG PET/CT in predicting aggressiveness of retroperitoneal liposarcoma. Patients experienced surgery for retroperitoneal liposarcoma from November 2007 to February 2018 and underwent preoperative 18F-FDG PET/CT were included. Preoperative maximum standardized uptake value (SUVmax) was calculated. To evaluate the predictability of SUVmax for Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 3, receiver operating characteristics (ROC) curve analysis was performed. To analyze whether SUVmax can be a risk factor for prognosis, multivariable Cox regression was performed including potential risk factors regarding operation and histopathology. A total of 133 patients were included. ROC curve showed area under the curve of 0.877 (P max showing 85.7% sensitivity and 78.3% specificity. Cox analyses showed that SUVmax > 4.5 was a significant factor for recurrence-free survival (HR = 2.148, CI 1.301–3.546, P = 0.003) and overall survival (HR = 5.052, CI 1.854–13.766, P = 0.002). SUVmax is highly predictive of FNCLCC grade 3 and SUVmax > 4.5 can be used as a prognostic factor before obtaining the histopathology.

Tacrolimus is one of the most commonly used immunosuppressive agents in animal models of transplantation. However, in these models, oral administration is often problematic due to the lowered compliance associated with highly invasive surgery and due to malabsorption in the intestinal tract. Therefore, we carried out a study to determine the pharmacokinetics of tacrolimus after intramuscular (IM) injection and to determine the optimal IM dosing regimens in primate models. Six male cynomolgus monkeys (Macaca fascicularis) were used in the study. Doses of 0.1 mg/kg and 5 mg were administered via IM injection and oral administration, respectively, once to determine single-dose pharmacokinetics and once daily for 5 days to determine multiple-dose pharmacokinetics. According to pharmacokinetic model estimates, the inter- and intra-individual variabilities in bioavailability following IM injection were remarkably reduced compared with those following oral administration. Monte Carlo simulations revealed that Cpeak, Ctrough and AUC would also have less variability following IM injection compared with oral administration. In this study, we found that the pharmacokinetic characteristics of tacrolimus were more constant following IM injection compared with oral administration. These results suggest that IM injection can be an alternative route of administration fin non-human primate model studies. Keywords: Tacrolimus, Cynomolgus monkey, Intramuscular injection, Intra-individual variability

Background: Endoscopic ultrasound-guided ablation (EUS-A) therapy is a minimally invasive procedure for pancreatic-cystic tumors in patients with preoperative comorbidities or in patients who are not indicated for surgical resection. However, histopathologic characteristics of pancreatic cysts after ablation have not been well-elucidated. Methods: Here, we analyzed pathological findings of 12 surgically resected pancreatic cysts after EUS-A with ethanol and/or paclitaxel injection. Results: Mean patient age was 49.8 ± 13.6 years with a 0.3 male/female ratio. Clinical impression before EUS-A was predominantly mucinous cystic neoplasms. Mean cyst size before and after ablation therapy was similar (3.7 ± 1.0 cm vs. 3.4 ± 1.6 cm; p = 0.139). Median duration from EUS-A to surgical resection was 18 (range, 1–59) months. Mean percentage of the residual neoplastic lining epithelial cells were 23.1 ± 37.0%. Of the resected cysts, 8 cases (67%) showed no/minimal (Conclusion: Above all, diffuse egg shell-like calcification along the pancreatic cystic walls with residual lining epithelia and/or ovarian-type stroma were characteristics of pancreatic cysts after EUS-A. Therefore, understanding these histologic features will be helpful for precise pathological diagnosis of pancreatic cystic tumor after EUS-A, even without knowing the patient’s history of EUS-A.

Many groups are working to improve the results of clinical allogeneic islet transplantation in a primate model. However, few studies have focused on the optimal islet dose for achieving normal glycemia without exogenous insulin after transplantation in primate models or on the relationship between rejection and islet amyloid polypeptide (IAPP) expression. We evaluated the dose (10,000, 20,000, and > 25,000 islet equivalents (IEQ)/kg) needed to achieve normal glycemia without exogenous insulin after transplantation using eleven cynomolgus monkeys, and we analyzed the characteristics exhibited in the islets after transplantation. 10,000 IEQ/kg (N = 2) failed to control blood glucose level, despite injection with the highest dose of exogenous insulin, and 20,000 IEQ/kg group (N = 5) achieved unstable control, with a high insulin requirement. However, 25,000 IEQ/kg (N = 4) achieved normal glycemia without exogenous insulin and maintained it for more than 60 days. Immunohistochemistry results from staining islets found in liver biopsies indicated that as the number of transplanted islets decreased, the amount of IAPP accumulation within the islets increased, which accelerated CD3+ T cell infiltration. In conclusion, the optimal transplantation dose for achieving a normal glycemia without exogenous insulin in our cynomolgus monkey model was > 25,000 IEQ/kg, and the accumulation of IAPP early after transplantation, which depends on the transplanted islet dose, can be considered one factor in rejection.

Many groups are working to improve the results of clinical allogeneic islet transplantation in a primate model. However, few studies have focused on the optimal islet dose for achieving normal glycemia without exogenous insulin after transplantation in primate models or on the relationship between rejection and islet amyloid polypeptide (IAPP) expression. We evaluated the dose (group 1/10,000, group 2/20,000, and group 3/>25,000 islet equivalents (IEQ)/kg) needed to achieve normal glycemia without exogenous insulin after transplantation using eleven cynomolgus monkeys, and we analyzed the characteristics exhibited in the islets after transplantation. Group 1 (n2) failed to control blood glucose level, despite injection with the highest dose of exogenous insulin, and group 2 (n5) achieved unstable control, with a high insulin requirement. However, group 3 (n4) achieved normal glycemia without exogenous insulin and maintained it for more than 60 days. Immunohistochemistry results from staining islets found in liver biopsies indicated that as the number of transplanted islets decreased, the amount of IAPP accumulation within the islets increased, which accelerated immune cell infiltration. In conclusion, the marginal transplantation dose for achieving a normal glycemia without exogenous insulin in our cynomolgus monkey model was >25,000 IEQ/kg, and the accumulation of IAPP early after transplantation, which depends on the transplanted islet dose, can be considered one factor in rejection.

Objectives Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). Methods Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. Results Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non‐tolerant group). The CD45RA−FOXP3++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non‐tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA−FOXP3++ Treg cells to CD45RA−FOXP3+ cells indicated good discrimination between the tolerant and non‐tolerant groups. Conclusion Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT.

Background/aim Emerging evidence suggests that Insulin-like growth factor II mRNA-binding protein 3 (IMP3) promotes tumor progression in several human malignancies. We investigated whether IMP3 expression has clinicopathological and prognostic significance in gallbladder adenocarcinoma (GBAC). Patients and methods We examined immunohistochemical IMP3 expression in 204 GBACs and its associations with clinicopathological parameters and patient outcomes. Results The majority (87.7%) of GBACs exhibited at least focal cytoplasmic and membranous IMP3 immunoreactivity. Tumor-specific IMP3 expression highlighted proper muscle invasion, which was not detected in the corresponding hematoxylin and eosin-stained slides. This finding upgraded pathological tumor stage (pT) from pT1a to pT1b in four well-differentiated GBACs. High IMP3 expression was associated with high histological grade, advanced stage, and lymphatic invasion, as well as worse overall survival. Conclusion Tumor-specific IMP3 expression in GBAC is helpful in determining the tumor extent, especially in well-differentiated tumors. High IMP3 expression reflects aggressive oncogenic behavior of GBAC. IMP3 expression may be used as a diagnostic and prognostic marker in GBAC.

PurposeDual kidney transplantation (DKT) offers a way to extend the use of kidneys from expanded criteria donors (ECDs). Here, we compared the outcomes of DKT with those of single kidney transplantation from standard criteria donors (SCDs) and ECDs.MethodsIn 2014, we began performing DKT using both kidneys from deceased donors greater than 70 years of age with one of two risk factors: serum creatinine (sCr) level over 3.0 mg/dl or eGFR under 30 ml/min. By 2017, we had performed 15 DKTs. We compared the outcomes of the 15 DKT recipients with those of 124 patients who received a kidney from an SCD and 80 patients who received a kidney from an ECD.ResultsCompared with ECDs and SCDs, DKT donors were older, had a higher diabetes burden, and a higher sCr level (p p p ConclusionsThe survival rates of DKT grafts were compatible with those of single KT grafts. Therefore, DKT may be considered a suitable an option to expand the donor pool.

OBJECTIVES There is an increasing need for grading with small endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) specimens for the proper diagnosis and therapy selection of patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, our understanding of EUS-FNAB specimen grading is limited compared with surgically resected specimens. METHODS We retrospectively determined Ki-67 labeling index (LI) of 33 matched EUS-FNAB and surgically resected PanNETs with digital image analyzer. Pairwise grades between the matched biopsy and surgically resected PanNET specimens were compared. RESULTS The mean Ki-67 LI was higher in surgically resected PanNET specimens (5.5%) than in biopsy specimens (3.2%; P = 0.022). There was moderate agreement between the Ki-67 LI grades when individually evaluated matched biopsy and resected specimen pairs were compared (κ value = 0.62; P < 0.0001). However, discordance was noted in 6 cases (18%), and all of them were either grade 2 or 3 in resected PanNETs. CONCLUSIONS Although Ki-67 LI grading of EUS-FNAB specimens may be concordant with that of matched surgically resected specimens in a large proportion of the PanNET cases, Ki-67 LI grading of EUS-FNAB specimens should be carefully applied in clinical practice because of the possibility of grading underestimation with grade 2 to 3 PanNET cases.

The diagnosis of latent tuberculosis infection (LTBI) in solid organ transplantation (SOT) patients under lifelong immunosuppression has profound effects on preoperative and postoperative management. Interferon-gamma release assay (IGRA) is widely used to screen LTBI before or after transplantation.We evaluated the effect of posttransplantation immunosuppression on IGRA and influencing factors by measuring interval change of QuantiFERON-TB Gold Plus (QFT-Plus) between pretransplantation (pre-QFT-Plus) and posttransplantation (post-QFT-Plus) state in 20 patients who previously had reactive IGRA but not taken LTBI treatment.Eleven (55%) out of 20 pre-QFT-Plus reactive patients became nonreactive state in repeated QFT-Plus (post-QFT-Plus) at 194-413 days (median, 257 days) after transplantation (discordant group). Even in persistently reactive group (concordant group), interferon-gamma (IFN-γ) levels after transplantation were decreased about 34% and 36% of their pretransplantation levels for TB1 and TB2, respectively. The only significant factors that affect interval change of QFT-Plus between pre- and post-SOT status were the concentrations of IFN-γ in pre-QFT-Plus (6.93 vs. 0.44 IU/mL in TB1 and 7.33 vs. 0.71 IU/mL in TB2).The reactivity of QFT-Plus is significantly compromised by immunosuppressive therapy, which increase the risk of false negative, particularly in patients with low level of IGRA reactivity. Therefore, interpretation of IGRA under immunosuppressive treatment require a caution and eventually, more sensitive tuberculosis-specific cytokine markers might be needed.

Well-differentiated pancreatic neuroendocrine neoplasms/tumors (PanNETs) are rare neoplasms with diverse clinical behavior. Biomarker discovery is important for predicting clinical course and prognosis of PanNET patients. Carbonic anhydrase 9 (CA9) and vimentin are hypoxia and epithelial-mesenchymal transition-related proteins of which expression in many carcinomas has been associated with poor prognosis, but their significance in PanNET has yet to be determined. We assessed CA9 and vimentin expression in 164 PanNETs and compared this with clinicopathologic characteristics. CA9 expression was observed in normal islets, while neuroendocrine microadenomas and small (

While minimal invasive surgery is becoming popular in liver resection, right posterior sectionectomy (RPS) is still considered as a difficult procedure. We summarize the clinical data and investigate the feasibility of laparoscopic right posterior sectionectomy (LRPS) in hepatocellular carcinoma (HCC) by comparing its outcomes with those of open right posterior sectionectomy (ORPS). We retrospectively reviewed 191 patients who underwent RPS for HCC during January 2009 to August 2016 at Samsung Medical Center. After 1:2 propensity score matching, 53 patients in LRPS group were matched to 97 patients in ORPS group. There was no statistical difference in preoperative data. While operation time was significantly longer in LRPS group (381.1 ± 118.7 vs. 234.4 ± 63.7 min, P

This study was designed to analyze differences between retroperitoneal liposarcoma (RLPS) extending into the inguinal canal and inguinoscrotal liposarcoma.We retrospectively reviewed the records for patients who were managed for inguinal liposarcoma at Samsung Medical Center, a tertiary hospital, between January 1998 and December 2016. Patient data on demographics, tumour location, surgery, adjuvant therapy, histology, recurrence and death were collected. We used Mann-Whitney, Fisher exact and Kaplan-Meier log-rank tests to analyze differences between groups.Seven of 179 (3.9%) patients with abdominal liposarcoma had inguinoscrotal liposarcoma, and 6 of 168 (3.6%) patients with RLPS had extension to the inguinal canal. No differences were observed between groups in sex (Although initial signs and symptoms can be similar, RLPS extending into the inguinal canal was associated with significantly higher morbidity and mortality than inguinoscrotal liposarcoma.Cette étude visait à examiner les différences entre le liposarcome rétropéritonéal s'étendant au canal inguinal et le liposarcome inguino-scrotal.Nous avons procédé à une analyse rétrospective des dossiers de patients traités pour un liposarcome inguinal au Samsung Medical Center, un hôpital de soins tertiaires, entre janvier 1998 et décembre 2016. Nous avons recueilli les données des patients en ce qui a trait aux caractéristiques démographiques, au siège de la tumeur, à la chirurgie, au traitement adjuvant, à l'histologie, à la récidive et au décès. Nous avons utilisé le test de Mann-Whitney, la méthode exacte de Fisher et les tests logarithmiques par rangs de Kaplan-Meier pour analyser les différences entre les 2 groupes.Sept des 179 (3,9 %) patients atteints de liposarcome abdominal avaient un liposarcome inguino-scrotal, et 6 des 168 (3,6 %) patients atteints de liposarcome rétropéritonéal présentaient une extension au canal inguinal. Aucune différence n'a été observée entre les groupes pour le sexe (Malgré la similarité des premiers signes et symptômes, le liposarcome rétropéritonéal s'étendant au canal inguinal était associé à des taux de morbidité et de mortalité significativement plus élevés que le liposarcome inguino-scrotal.

Introduction This prospective observational study compared the postoperative analgesic effectiveness of intrathecal morphine (ITM) and surgical-site infusion (SSI) of ropivacaine as adjuncts to intravenous (IV) patient-controlled analgesia (PCA) (fentanyl) in living-donor kidney transplant recipients. Methods Patients undergoing living-donor kidney transplantation who received ITM or SSI in addition to IV PCA were included. Rescue analgesia was achieved with IV meperidine as required. The primary outcome, measured using the Numeric Pain Rating Scale (NRS), was pain at rest and when coughing. Patients were assessed for 48 hours after surgery. Results A total of 53 patients (32 ITM, 21 SSI) were included in the study. The ITM group showed significantly lower NRS scores, at rest and when coughing, for up to 12 and eight hours. NRS scores were comparable between the groups at other times. The ITM group had significantly less postoperative systemic opioid requirement in the first 24 hours, but there was no significant difference between the systemic opioid consumption of the groups on postoperative Day 2. In the ITM group, 3 (9.4%) patients presented with bradypnoea and 1 (3.1%) with excessive sedation in the first 12 postoperative hours. More patients in the ITM group developed pruritus requiring treatment during the first 24 hours. There were no differences between the groups in other outcomes (e.g. nausea/vomiting, change in pulmonary or kidney functions). Conclusion Compared with SSI, ITM reduced immediate postoperative pain and IV opioid consumption on postoperative Day 1 after living-donor kidney transplantation, but at the cost of increased pruritus and respiratory depression.

BACKGROUND This study was designed to analyze the clinical implications of mycophenolic acid trough concentration monitoring. MATERIAL AND METHODS We collected data of patients with mycophenolic acid trough concentration monitoring after their first kidney transplant between November 2006 and March 2015 who were prescribed tacrolimus, mycophenolate, and methylprednisolone. Analyses were performed on 3 periods: 1 month, 1 month to 1 year, and after 1 year post-transplantation. To analyze factors related to acute cellular rejection, logistic regression was used for 1 month, while Cox analysis was used during 1 month to 1 year and after 1 year post-transplantation. RESULTS In the 145 patients receiving mycophenolate mofetil, mean tacrolimus trough ≥7.0 ng/mL (OR=0.177, CI=0.060-0.524, p=0.002) and mean mycophenolic acid trough ≥1.7 mg/L (OR=0.190, CI=0.040-0.896, p=0.036) were protective for rejection during 1 month. Mean mycophenolic acid trough ≥1.7 mg/L (HR=0.179, CI=0.040-0.806, p=0.025) and ≥0.7 mg/L (HR=0.142, CI=0.028-0.729, p=0.019) were related to better rejection-free survival during 1 month to 1 year and after 1 year, respectively. In 399 patients receiving enteric-coated mycophenolate sodium, mean tacrolimus trough ≥7.0 ng/mL (OR=0.258, CI=0.131-0.507, p

AIM The purpose of this study was to evaluate the efficacy of en bloc nephrectomy for perirenal retroperitoneal sarcoma (RPS) with respect to postoperative kidney function and oncological benefits. METHODS We performed a comparative study of 114 patients undergoing surgery for primary RPS, classifying cases as nephrectomy (NPX, n = 65) versus no nephrectomy (no-NPX, n = 49). The Δ and % change between preoperative and postoperative estimated glomerulus filtration rate (eGFR) were analyzed to compare renal function changes after surgery. Kaplan-Meier analysis was performed to verify the incidence of local relapse between the two groups. RESULTS During a median follow-up of 29 months, median postoperative GFR of 65 patients in the NPX group decreased to 73.5% of preoperative eGFR. Although 38 patients (58%) in the NPX group experienced a progression in chronic kidney disease stage after nephrectomy, no patients progressed to end-stage renal disease (ESRD). In French Federation of Cancer Centers Sarcoma grade 2, the NPX group had statistically significant local control benefits, compared with the no-NPX group (P = 0.048). CONCLUSIONS Residual renal function after en bloc nephrectomy was stabilized without progression to ESRD. Moreover, en bloc nephrectomy for perirenal RPS might secure a complete resection margin for local tumor control.

Background aims Major challenges in de-differentiated liposarcoma (DDLPS) therapy are the high rate of sequential recurrence (>80%) and metastasis (20–30%) following surgical removal. However, well-defined therapeutic strategies for this rare malignancy are lacking and are critically needed. Methods We investigated a new approach to DDLPS therapy with mesenchymal stromal cells expressing herpes simplex virus–thymidine kinase (MSC-TK). In an effort to evaluate this efficacy, in vitro cytotoxicity of MSC-TK against DDLPS cells was analyzed using an apoptosis assay. For pre-clinical study, the MSC-TK–induced reduction in recurrence and metastasis was validated in a recurrent DDLPS model after the macroscopic complete resection and lung metastasis DDLPS model. Results MSC-TK induced apoptosis in DDLPS cells by bystander effects via gap junction intracellular communication (GJIC) of toxic ganciclovir (GCV). Recurrent DDLPS models following no residual tumor/microscopic tumor resection and lung metastasis DDLPS models were established, which suggested clinical relevance. MSC-TK markedly reduced locoregional recurrence rates and prolonged recurrence-free survival, thus increasing overall survival in the recurrent DDLPS model. MSC-TK followed by GCV treatment yielded a statistically significant reduction in early- and advanced-stage lung metastasis. Discussion This therapeutic strategy may serve as an alternative or additional strategy by applying MSC-TK to target residual tumors following surgical resection, thus reducing local relapse and metastasis in these patients.

Type 2 autoimmune pancreatitis (type 2 AIP) develops in isolation or sometimes in association with ulcerative colitis. Its diagnosis requires the histologic confirmation of granulocytic epithelial lesions (GELs) with no diagnostic biomarker currently available. This study aimed to elucidate the tissue expression of cytokines and their diagnostic value in this condition. In quantitative polymerase chain reaction for multiple cytokines using tissue-derived mRNA, the expression level of interleukin (IL)-8 was markedly higher in type 2 AIP than in type 1 AIP (P

BACKGROUND Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients. METHODS To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival. RESULTS PR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5-year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses. CONCLUSIONS Loss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients.

To compare preoperative incision design markings between both eyelids in upper blepharoplasty.This retrospective study examined 22 patients who underwent bilateral upper blepharoplasty surgery resulting from senile dermatochalasis and/or blepharoptosis. The initial preoperative incision design markings were drawn with the patient sitting upright. Then, with the patient in a supine position, preoperative design photographs were taken. The authors measured medial canthal excision angle, maximal lid excision height, maximal lid excision width, peak point angle, and peak point distance and compared measurements between both upper eyelids designs using Image J software.The mean medial canthal excision angle, maximal lid excision height, and maximal lid excision width for the right side (30.68° ± 10.16°, 1.17 ± 0.24 cm, and 0.72 ± 0.19 cm) were significantly different from those for the left side (35.39° ± 13.82°; Plt; 0.001, 1.24 ± 0.25 cm; P = 0.002, and 0.77 ± 0.21 cm; P = 0.011). The mean peak point angle and peak point distance for the right side (15.67° ± 5.09°, 2.41° ± 0.31°) were significantly different from those for the left side (18.11° ± 5.49°; P = 0.001, 2.22 ± 0.28 cm; P = 0.001).In upper blepharoplasty, the preoperative incision marking design measurements of the left side were significantly greater than those of the right side. The symmetry can therefore be maximized by including the asymmetries in the preoperative design.

Purpose To investigate the causes of lower eyelid retraction and evaluate the outcomes of various surgical procedures. Methods We conducted a retrospective medical record review of patients who underwent lower eyelid retraction surgery performed by a single surgeon at Kim's Eye Hospital between 2006 and 2013. We investigated the causes of lower eyelid retraction, clinical history, characteristics, treatment, and surgical outcomes. Preoperative and postoperative margin reflex distance 2 and inferior scleral show were measured for each eyelid. Success was defined as a positive eyelid elevation and a decrease in inferior scleral show. Results A total of 19 lower eyelids were treated in 14 patients with lower eyelid retraction. For cosmetic reasons, surgical correction for congenital lower eyelid retraction was performed on seven eyelids (36.8%). Ten eyelids (52.6%) exhibited secondary lower eyelid retraction after surgery. One eyelid (5.3%) was affected by facial palsy and one eyelid (5.3%) exhibited exophthalmos of an unknown origin. We adopted a selective approach based on lower eyelid retraction severity. Spacer grafting via a subconjunctival approach was the most commonly performed surgical technique (13 eyelids, 68.4%). The lateral tarsal strip procedure was used to horizontally tighten three eyelids (15.8%). At the time of the procedure, one of these eyelids (5.3%) also received an adjuvant suborbicularis oculi fat lift. Autogenous dermis fat grafting was performed on two lower eyelids (10.5%), whose retraction was caused by fat and soft tissue loss. Cosmetic outcomes were satisfactory in all cases. Conclusions To achieve satisfactory surgical outcomes, surgeons should adopt an approach based on the severity of lower eyelid retraction. Mild lower eyelid retraction can be corrected without grafts. When retraction is severe and exceeds 2 mm, spacer grafts that push the lower eyelid margin upwards and support it from below are required.

A 52-year-old man was admitted with an incidentally detected right renal artery aneurysm (RAA). Computed tomographic angiography with three-dimensional reconstruction revealed that the aneurysm was 2.2 cm in diameter and located at the renal hilum. We performed hand-assisted laparoscopic nephrectomy with ex vivo repair of the RAA and auto-transplantation with minimal elongation of Gibson incision. The operation and postoperative course were uneventful. At last follow-up, the patient was alive with a well-functioning auto-transplant. Hand-assisted laparoscopic nephrectomy and auto-transplantation is a useful treatment option for hilar RAA.

Objectives Endonasal dacryocystorhinostomy (DCR) is a well-established treatment method in patients with nasolacrimal duct obstruction. However, there are a few reports about the overall management of failed endonasal DCR. We investigated the causes and management strategies of failed endonasal DCR. Methods This retrospective review included 61 patients (61 eyes) who had undergone revision surgery by the same surgeon after failed endonasal DCR between January 2008 and December 2012. The appropriate revision method was determined after analysis of the etiology of failure by the fluorescein dye disappearance test, nasal endoscopy, lacrimal irrigation, and probing. The criteria for success of the revision surgery were defined by the passage of fluid without resistance upon lacrimal irrigation and normalization of the tear meniscus height. Results The mean duration between the primary endonasal DCR and revision surgery was 15.3 months. The average follow-up period after revision surgery was 12.2 months. The most common cause of endoscopic revision surgery was membranous obstruction. Endoscopic revision surgery was performed in 48 patients, while lacrimal silicone tube intubation under endoscopy was performed in 13 patients. The most common indication for lacrimal silicone tube intubation was functional epiphora. The overall success rate of the revision surgery was 89%. Conclusion The most common cause of failed endonasal DCR was membranous obstruction. When patients with failed endonasal DCR presented at the clinic, it is important to identify the cause of the failure. Revision surgery could increase the final success rate of endonasal DCR.

Purpose To compare the clinical effects of the single wide-diameter bicanalicular silicone tube and the double bicanalicular silicone tube in endonasal dacryocystorhinostomy (DCR) with canalicular trephinization for canalicular obstruction. Methods We retrospectively reviewed the records of 121 patients with monocanalicular or common canalicular obstruction who had undergone endonasal DCR with random bicanalicular insertion of either double silicone tubes (insertion of two tubes into each canaliculus) or a single wide-diameter (0.94 mm) silicone tube. The tubes were removed at around 3 months after surgery. Results This study included 79 eyes of 61 patients in the double-tube intubation group and 68 eyes of 60 patients in the single wide-diameter tube intubation group. Anatomical success, evaluated by syringing, was achieved in 72 of the 79 eyes (91.1%) in the double-tube intubation group and 60 of the 68 eyes (88.2%) in the single wide-diameter tube intubation group. Functional success was achieved in 65 of the 79 eyes (82.3%) in the double-tube intubation group and 61 of the 68 (89.7%) eyes in the single wide-diameter tube intubation group. There were no significant differences in the success rates of surgery between the two groups. One patient in the double-tube intubation group underwent conjunctivodacryocystorhinostomy (CDCR) and two in the wide-diameter tube intubation group underwent CDCR or reintubation to treat recurrence. Conclusions Intubation using a single wide-diameter tube during endonasal DCR is as effective as double-tube intubation for the treatment of canalicular obstruction, with a lower rate of complications such as inflammation or patient discomfort.

Seung Yeon Son,1 Hye Ryoun Jang,1 Jung Eun Lee,1 Heejin Yoo,2 Kyunga Kim,2,3 Jae Berm Park,4 Sung Joo Kim,4 Ha Young Oh,1 Wooseong Huh1 1Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 2Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, 3Department of Digital Health, SAIHST, 4Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Abstract: This study aimed to evaluate the long-term efficacy and safety of a generic tacrolimus (Tacrobell [TCB]) compared to the original tacrolimus (Prograf [PGF]) in kidney transplant recipients. In this retrospective observational study, we analyzed the data from 444 patients who took TCB as a first-line immunosuppressive drug and 245 patients who took PGF. The 5-year graft survival rate was 92% for patients in the PGF group and 97% for patients in the TCB group, respectively. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval [CI] limit of the hazard ratio [HR]

BACKGROUND Isoniazid (INH) prophylaxis (Px) has good efficacy for preventing tuberculosis (TB) in the general population. However, its use for the treatment of latent TB infections (LTBI) in liver transplant (LT) recipients is challenging because little is known about INH-induced hepatotoxicity in graft recipients. We evaluated the efficacy and safety of INH Px in LT recipients. MATERIAL AND METHODS From March 2008 to December 2012, we retrospectively reviewed data on 277 patients who received LT at a single center. We examined the results of tuberculin skin tests and interferon-γ release assays, use of INH, INH-induced hepatotoxicity, and post-LT TB occurrence. RESULTS Among 277 recipients, 7 cases of post-transplant TB were detected (2.52%). Seventeen patients received post-transplant INH Px. Among INH Px recipients, post-LT TB infection did not occur. Hepatotoxicity after INH Px was significantly lower in the patients who received INH Px at an aspartate aminotransferase (AST) level that was less than 50 U/L than in those who received INH Px at an AST level that was more than 50 U/L (P=0.046, 0.002). CONCLUSIONS INH is likely to be effective for preventing post-LT TB recurrence in LTBI. However, because of INH-induced hepatotoxicity, it is better to avoid using it in the early post-LT period and to wait to initiate INH Px until liver function is stable in LT recipients.

Background The lowering of calcineurin inhibitor exposure is possibly considered as the proper strategy to prevent calcineurin inhibitor–induced nephrotoxicity in kidney transplant. This clinical study was designed to compare the efficacy and tolerability of reduced-dose tacrolimus with standard-dose mycophenolate mofetil (MMF) vs standard-dose tacrolimus with reduced-dose MMF. Methods A prospective, multicenter, open-label, randomized, and parallel-group clinical trial was conducted at 4 transplant centers in Korea. A total sample size was 108, and eligible patients were randomly assigned in a 1:1 ratio to either reduced-dose tacrolimus with standard-dose MMF (the study group) or standard-dose tacrolimus with reduced-dose MMF (the control group) for 6 months in de novo kidney transplant recipients. Graft function, the incidence of efficacy failure, and adverse events were compared. Results The mean estimated glomerular filtration rate at 6 months post-transplantation was 69.83 ± 16.68 mL/min/1.73 m2 in the study group and 69.92 ± 17.55 mL/min/1.73 m2 in the control group (P > .05). The overall incidence of biopsy-proven acute rejection was 3.64% (n = 2) in the study group, compared to 3.77% (n = 2) in the control group (P > .05). There was no graft loss, death, or loss of follow-up in either group. Conclusion In conclusion, the results suggest that tacrolimus minimization with standard-dose MMF provides adequate immunosuppression with proper renal function and similar rate of incidence of acute rejection compared with the regimen including standard-dose tacrolimus with reduced-dose MMF.

Background Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex-mismatched combined kidney and bone marrow transplantation (CKBMT). Methods From December 2011 to May 2017, 8 major histocompatibility complex-mismatched patients received CKBMT. The initial conditioning regimen (protocol 1) consisted of cyclophosphamide (CP), rituximab, rabbit antithymocyte globulin, and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS). Results This regimen was complicated by transient acute kidney injury, which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of 2 subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (protocol 2). The final modification was reducing the fludarabine and rabbit antithymocyte globulin doses (protocol 3). Mixed chimerism, detected by the short tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the 3 subjects treated with protocol 2, IS was successfully discontinued for >35 months in one subject, but the other 2 subjects suffered from severe BK virus-associated nephritis. All 3 subjects treated with protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo donor-specific antibody was not detected in any subject during all the follow-up periods. Conclusions Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT.

Mutations affect gene functions related to cancer behavior, including cell growth, metastasis, and drug responses. Genome-wide profiling of cancer mutations and drug responses has identified actionable targets that can be utilized for the management of cancer patients. Here, the recapitulation of pharmacogenomic data revealed that the mutation of EPHB6 is associated with paclitaxel resistance in cancer cells. Experimental data confirmed that the EPHB6 mutation induces paclitaxel resistance in various cancer types, including lung, skin, and liver cancers. EPHB6 mutation-induced paclitaxel resistance was mediated by an interaction with EPHA2, which promotes c-Jun N-terminal kinase (JNK)-mediated cadherin 11 (CDH11) expression. We demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. The present results suggest that the EPHB6 mutation and its downstream EPHA2/JNK/CDH11/RhoA/FAK signaling axis are novel diagnostic and therapeutic targets for overcoming paclitaxel resistance in cancer patients., Cancer: Gene mutation spurs drug resistance Mutations in a gene linked to cancer growth also underpin resistance to a common chemotherapy drug. Hyun Goo Woo and colleagues from Ajou University in Suwon, South Korea, analyzed a large database of genetic information on more than 1,000 human cancer cell lines looking for mutated genes associated with resistance to certain drugs. The top association was between mutated forms of EPHB6, a gene previously linked to tumor invasiveness, and resistance to paclitaxel, a chemotherapy drug used to treat a range of different cancers. They experimentally validated the finding in lung, skin and liver cancer cell lines. The researchers also identified two proteins activated by mutant EPHB6 that promote the cell adhesion responsible for paclitaxel resistance. Inhibiting these two proteins reversed the drug resistance in cells, suggesting the therapeutic value of targeting this pathway.

Background Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor. Methods We analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS. Results Our results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation. Conclusion From these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials. Electronic supplementary material The online version of this article (10.1186/s12885-019-5713-2) contains supplementary material, which is available to authorized users.

Supplemental digital content is available in the text., Background A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs). Methods Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2–0.3 mg/kg; target trough level, 6–10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4–6 ng/mL, weeks 4–12; 3–5 ng/mL, weeks 12–52) or standard-exposure PR-T (target: 6–10 ng/mL, weeks 4–52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded. Results Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, –2.82; 95% confidence interval, −7.91 to 2.27; P = 0.272). At week 52, there was no significant difference in creatinine clearance (P = 0.375) or serum creatinine (P = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively. Conclusions Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.