Post Hoc Analysis of Predictors of Clinical Response to Repository Corticotropin Injection in Persistently Active Rheumatoid Arthritis.

INTRODUCTION: A phase IV clinical trial confirmed the safety and efficacy of repository corticotropin injection (RCI, Acthar® Gel) in patients with refractory rheumatoid arthritis (RA) that was nonresponsive to standard-of-care therapies. The objective of this post hoc analysis was to identify baseline demographics and clinical characteristics that may be predictors of response to RCI. METHODS: The phase IV trial was a two-part, randomized, placebo-controlled withdrawal study. Post hoc analysis was conducted with the open-label portion of the trial data, in which all 258 subjects received RCI (80 U) twice weekly for 12 weeks. Responders were subjects who achieved low disease activity (LDA) by a Disease Activity Score with 28-joint count and erythrocyte sedimentation rate (DAS28-ESR) of < 3.2 at week 12. Responders were compared with nonresponders by assessing the proportion of subjects in each group for demographics and clinical characteristics, including weight, disease duration, medical history including osteoarthritis and unrelated joint conditions, hemoglobin A1c, C-reactive protein, ESR, DAS28-ESR, Clinical Disease Activity Index (CDAI), depression, anxiety, tender joint count (TJC), and swollen joint count (SJC). Bivariate analysis followed by multiple logistic regression analysis were conducted to identify significant baseline predictors for the outcome of achieving LDA by week 12. RESULTS: Bivariate analysis showed that RCI responders had significantly lower baseline TJC (p = 0.0310), SJC (p = 0.0018), ESR (p = 0.0487), and CDAI (p = 0.0112) and shorter RA disease duration (p = 0.0446). Subjects were less likely to achieve LDA if they had osteoarthritis (p < 0.0001), other joint-related conditions unrelated to RA (p < 0.0001), anemia (p = 0.0132), depression (p = 0.0006), or prior or concomitant use of targeted-synthetic or biologic disease-modifying antirheumatic drugs (p < 0.0001). Multiple logistic regression analysis revealed that, of the above, only ongoing osteoarthritis (p = 0.0272) or other joint-related conditions (p = 0.0193) were significant negative predictors of RCI response. CONCLUSIONS: These results identify specific patient characteristics that may be considered predictors of positive or negative clinical response to RCI.

IL4Rα and IL13Rα1 Are Involved in the Development of Human Gallbladder Cancer.

BACKGROUND: Gallbladder cancer is commonly associated with inflammation, which indicates that inflammation-related cytokines and cytokine receptors are related to the progression of gallbladder cancers. Interleukin 4 (IL4) is a well-known cytokine that promotes the differentiation of naive helper T cells (Th0) to T helper type 2 cells (Th2). IL13 is a cytokine that is secreted by Th2 cells. IL4 and IL13 are closely related in immune responses. However, the role of IL4Rα and IL13Rα1 signaling pathway has not been fully understood in the development of gallbladder cancer. METHODS: In human gallbladder carcinomas, the expression of IL4Rα and IL13Rα1 were evaluated with immunohistochemical staining in tissue microarray tissue sections. After knockdown of IL4Rα or IL13Rα1, cell assays to measure the proliferation and apoptosis and Western blotting analysis were conducted in SNU308 human gallbladder cancer cells. Since Janus kinases2 (JAK2) was considered as one of the down-stream kinases under IL4Rα and IL13Rα1 complex, the same kinds of experiments were performed in SNU308 cells treated with AZD1480, Janus-associated kinases2 (JAK2) inhibitor, to demonstrate the cytotoxic effect of AZD1480 in SNU308 cells. RESULTS: Immunohistochemical expression of IL4Rα was significantly associated with the expression of IL13Rα1 in human carcinoma tissue. In univariate analysis, nuclear expression of IL4Rα, cytoplasmic expression of IL4Rα, nuclear expression of IL13Rα1, and cytoplasmic expression of IL13Rα1 were significantly associated with shorter overall survival and shorter relapse-free survival. Multivariate analysis revealed nuclear expression of IL4Rα as an independent poor prognostic indicator of overall survival and relapse-free survival. Then, we found that knockdown of IL4Rα or IL13Rα1 decreased viability and induced apoptosis in SNU308 cells via activation of FOXO3 and similarly, AZD1480 decreased viability and induced apoptosis in SNU308 cells with dose dependent manner. CONCLUSIONS: Taken together, our results suggest that IL4Rα and IL13Rα1 might be involved in the development of human gallbladder cancer cells and IL4Rα and IL13Rα1 complex/JAK2 signaling pathway could be efficient therapeutic targets for gallbladder cancer treatment.

Post Hoc Analysis of the Correlation Between Patient-Reported Outcomes and Clinical Response to Repository Corticotropin Injection for Persistently Active Rheumatoid Arthritis.

PURPOSE: Approximately 6% of patients with rheumatoid arthritis (RA) in the USA have refractory disease that is resistant to standard-of-care therapies. A recent phase IV clinical trial affirmed the safety and efficacy of repository corticotropin injection (RCI; Acthar® Gel) for refractory RA. This post hoc analysis of the clinical trial data assessed whether changes in clinical measures correlated with patient-reported outcome (PRO) improvements. METHODS: Data were assessed from the trial's open-label period when patients received RCI (80 U) twice weekly for 12 weeks. Clinical assessments included hemoglobin A1c, C-reactive protein, erythrocyte sedimentation rate (ESR), total joint count (TJC), swollen joint count (SJC), Disease Activity Score with 28 joint count and ESR (DAS28-ESR), and Clinical Disease Activity Index (CDAI). PROs included pain (Visual Analog Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]), disability (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and activity impairment (Work Productivity and Activity Impairment [WPAI] questionnaire). Patients grouped by minimal clinically important difference (MCID) improvement vs no improvement in PROs were compared with clinical measures at week 12. Correlations were determined by multivariable linear regression analysis and standardized coefficient estimates. RESULTS: RCI responders, defined as patients with DAS28-ESR < 3.2 at week 12, reported significantly greater PRO improvements for pain, disability, fatigue, activity impairment, current work impairment, and overall work impairment than nonresponders. Patients with MCID improvements in all PROs showed significantly greater decreases in mean values for TJC, DAS28-ESR, and CDAI, whereas those with pain, fatigue, and disability improvements had significantly greater SJC and ESR reductions. Multivariable linear regression analysis determined that improvement from baseline in all PROs correlated with significant decreases in TJC, DAS28-ESR, and CDAI. ESR reduction significantly correlated with improvements in pain and disability, but not fatigue or WPAI. CONCLUSIONS: These results confirm that clinical responses to RCI were directly correlated with patient perception of improvement.

Dextroplantation of Left Liver Graft in Infants.

The position of the left side liver graft is important, and it could lead to complications of the hepatic vein (HV) and portal vein (PV), especially in a small child using a variant left lateral section (vLLS) graft. The purpose of this study was to evaluate the outcome of a novel technique for the implantation of a vLLS graft to the right side (dextroplantation) in infants. For 3 years, 10 consecutive infants underwent dextroplantation using a vLLS graft (group D). The graft was implanted to the right side of the recipient after 90° counterclockwise rotation; the left HV graft was anastomosed to inferior vena cava using the extended right and middle HV stump, and PV was reconstructed using oblique anastomosis without angulation. Surgical outcomes were compared with the historical control group (n = 17, group C) who underwent conventional liver transplantation using a vLLS during infancy. Group D recipients were smaller than group C (body weight <6 kg: 50.0% versus 11.8%; P = 0.03). The rate of graft-to-recipient weight ratio >4% was higher in group D (60.0%) than C (11.8%; P = 0.01). Surgical drains were removed earlier in group D than in group C (15 versus 18 postoperative days [PODs]; P = 0.048). Each group had 1 PV complication (10.0% versus 5.9%); no HV complication occurred in group D, but 3 HV complications (17.6%) occurred in group C (P > 0.05). Hospital stay was shorter in group D than in group C (20 versus 31 PODs; P = 0.02). Dextroplantation of a vLLS graft, even a large-for-size one, was successful in small infants without compromising venous outcomes, compared with conventional vLLS transplantation. We could remove the surgical drains earlier and reduce hospital stays in cases of dextroplantation.

Defining phenotypes of long-term lithium and valproate response, including combination therapy: a modified application of the Alda scale in patients with bipolar disorders.

BACKGROUND: When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. METHODS: The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. RESULTS: There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of 'poor responder' with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive-compulsive disorder and mixed episode showed significant negative associations in valproate users. CONCLUSIONS: The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates.

Expression of FAM83H and ZNF16 are associated with shorter survival of patients with gallbladder carcinoma.

BACKGROUND: Recently, FAM83H was reported to have roles in cancer progression in conjunction with oncogenic molecules such as MYC and b-catenin. Moreover, the data from the public database indicates a molecular relationship between FAM83H and zinc finger proteins, especially between FAM83H and ZNF16. However, studies on FAM83H and ZNF16 in gallbladder cancer have been limited. METHODS: This study investigated the expression of FAM83H and ZNF16 in 105 gallbladder carcinomas. RESULTS: In human gallbladder carcinomas, immunohistochemical expression of FAM83H was significantly associated with ZNF16 expression. In univariate analysis, nuclear and cytoplasmic expression of FAM83H or ZNF16 were significantly associated with shorter survival of gallbladder carcinoma patients. Multivariate analysis revealed the nuclear expression of FAM83H as an independent indicator of poor prognosis of overall survival (p = 0.005) and relapse-free survival (p = 0.005) of gallbladder carcinoma patients. Moreover, co-expression patterns of nuclear FAM83H and ZNF16 were also independent indicators of shorter survival of gallbladder carcinoma patients (overall survival; p <  0.001, relapse-free survival; p <  0.001). CONCLUSIONS: This study suggests FAM83H and ZNF16 are associated with the progression of gallbladder carcinoma, and the expressions of FAM83H and ZNF16 might be novel prognostic indicators of gallbladder carcinoma patients.

The Degree of Hyperglycemia Excursion in Patients of Kidney Transplantation (KT) or Liver Transplantation (LT) Assessed by Continuous Glucose Monitoring (CGM): Pilot Study.

OBJECTIVE: This study used a continuous glucose monitoring system (CGMS) to investigate the glucose profiles and assess the degree of hyperglycemic excursion after kidney or liver transplantation during the early period after operation. METHODS: Patients to whom a CGMS was attached during a postoperative period of approximately one month after transplantation were included. The CGM data of 31 patients including 24 with kidney transplantation (KT) and seven with liver transplantation (LT) were analyzed. RESULTS: Hyperglycemia over 126 mg/dL (fasting) or 200 g/dL (postprandial) occurred in 42.1% (8/19) and 16.7% (1/6) of KT and LT patients, respectively, during this early period after transplantation, except for patients with preexisting diabetes (5 KT, 1 LT). The average mean amplitude of glycemic excursion (MAGE) and mean absolute glucose (MAG) levels were 91.18 ± 26.51 vs. 65.66 ± 22.55 (P < 0.05) and 24.62 ± 7.78 vs. 18.18 ± 7.07 (P < 0.05) in KT vs. LT patients, respectively, in patients without preexisting DM or PTDM patients who showed normal glucose levels. Average increase from the lowest level to the peak glucose value was higher in KT patients than LT patients (P < 0.05). Conclusions. The transplanted organ also needs to be considered as an important factor affecting glucose control and the occurrence of more severe glucose excursions in patients who receive transplantation although immunosuppression agents are well-known important factors; however, our study was limited to the early posttransplantation period. Further studies involving CGM follow-up at regular intervals based on the time since transplantation are needed.

Different prognostic factors and strategies for early and late recurrence after adult living donor liver transplantation for hepatocellular carcinoma.

BACKGROUND: Some patients with hepatocellular carcinoma (HCC) recurrence after LT show good long-term survival. We aimed to determine the prognostic factors affecting survival after recurrence and to suggest treatment strategies. METHODS: Between January 2000 and December 2015, 532 patients underwent adult living donor liver transplantation (LDLT) for HCC. Among these, 92 (17.3%) who experienced recurrence were retrospectively reviewed. RESULTS: The 1-, 3-, and 5-year survival rates after recurrence were 59.5%, 23.0%, and 11.9%, respectively. In multivariate analysis, time to recurrence >6 months and surgical resection after recurrence were related to longer survival after recurrence, while multi-organ involvement at the time of primary recurrence was related to poorer survival. We classified patients into early (≤6 months) and late (>6 months) recurrence groups. In the early recurrence group, tumor size >5 cm in the explant liver, liver as the first detected site of recurrence, and multiple organ involvement at primary recurrence were related to survival on multivariate analysis. In the late recurrence group, mammalian target of rapamycin inhibitor (mTORi) usage and multi-organ involvement were significantly associated with the prognosis on multivariate analysis. CONCLUSIONS: Various therapeutic approaches are needed depending on the period of recurrence after LT and multiplicity of involved organs.

Role of prophylactic antibiotics in elective laparoscopic cholecystectomy: A systematic review and meta-analysis.

BACKGROUNDS/AIMS: The role of prophylactic antibiotics for laparoscopic cholecystectomy in low-risk patients is still unclear. This study aimed to verify the conclusion of previous meta-analyses concerning the effectiveness of antibiotic prophylaxis for elective laparoscopic cholecystectomy in low-risk patients. METHODS: Comprehensive literature searches were performed on electric databases and manual searches. Randomized controlled trials (RCTs), prospective studies, and retrospective studies comparing antibiotic prophylaxis to placebo or no antibiotics in low-risk elective laparoscopic cholecystectomy were included. RESULTS: This study included 28 RCTs, three prospective studies, and three retrospective studies. In RCTs, prophylactic antibiotics did not prevent deep surgical site infections (SSI) (RR 1.10, 95% confidence interval [CI] [0.45-2.69], p=0.84) but reduced SSI (RR 0.70, 95% CI [0.53-0.94], p=0.02), and superficial SSI (RR 0.58, 95% CI [0.42-0.82], p=0.01). Prospective studies showed prophylactic antibiotics did not reduce superficial SSI (RR 0.35, 95% CI [0.01-8.40], p=0.52) but reduced SSI (RR 0.12, 95% CI [0.04-0.35], p=0.0001). In retrospective studies, antibiotic prophylaxis did not reduce SSI (RR 1.59, 95% CI [0.30-8.32], p=0.58). The pooled data (12121 patients) including RCTs and prospective and retrospective studies showed that prophylactic antibiotics were not effective in preventing deep SSI (RR 1.01 95% CI [0.46-2.21], p=0.98) but effective in reducing SSI (RR 0.67, 95% CI [0.51-0.88], p=0.003) and superficial SSI (RR 0.61, 95% CI [0.45-0.83], p=0.002). CONCLUSIONS: The use of prophylactic antibiotics is effective for reducing the incidence of SSI and superficial SSI but is not effective for preventing deep SSI in low-risk patients who underwent elective laparoscopic cholecystectomy.

The rate of hepatic artery complications is higher in pediatric liver transplant recipients with metabolic liver diseases than with biliary atresia.

BACKGROUND: Liver transplantation (LT) is an excellent treatment option for patients with biliary atresia (BA) who fail portoenterostomy surgery. LT is also increasingly performed in patients with metabolic liver diseases. This study compared the outcomes in pediatric patients who underwent LT for metabolic liver diseases and BA. BASIC PROCEDURES: Data from 237 pediatric patients who underwent primary LT at Seoul National University Hospital from 1988 to 2015, including 33 with metabolic liver diseases and 135 with BA, were retrospectively analyzed. MAIN FINDINGS: Compared with children with BA, children with metabolic liver diseases were significantly older at the time of LT (121.3 vs. 37.3 months; P < 0.001), and had lower Child-Pugh (7.1 vs. 8.4; P = 0.010) and Pediatric End-stage Liver Disease (6.5 vs. 12.8; P = 0.042) scores. Overall survival rates were similar (87.8% vs. 90.8%; P = 0.402), but hepatic artery (HA) complications were significantly more frequent in children with metabolic liver diseases (12.1% vs. 1.5%; P = 0.014). PRINCIPAL CONCLUSION: Despite similar overall survival, children with metabolic liver diseases had a higher rate of HA complications. TYPE OF SUBMISSION: Original article, Case control study, Retrospective. EVIDENCE LEVEL: III.

One Hundred Fifteen Cases of Pure Laparoscopic Living Donor Right Hepatectomy at a Single Center.

BACKGROUND: The pure laparoscopic approach to donor hepatectomy is being taken more often. However, few centers perform pure laparoscopic donor right hepatectomy (PLDRH) because it requires a high level of surgical skill. Studies reporting initial outcomes of PLDRH may prompt further implementation of the technique and help reduce initial learning curves at other transplant centers. This study reports performance of PLDRH at a single center with extensive experience of adult living donor liver transplantation. METHODS: Data from 115 donors (and recipients) who underwent PLDRH between November 2015 and June 2017 were analyzed retrospectively. Subgroup analysis was performed to compare outcomes between the initial (November 2015 to October 2016) and more recent (November 2016 to June 2017) periods. RESULTS: During the initial period, 3 (2.6%) donors experienced complications greater than grade III on the Clavien-Dindo scale. By contrast, no donors developed complications during the recent period. The operative time (293.6 minutes vs 344.4 minutes; P < 0.001) and hospital stay (7.3 days vs 8.3 days; P = 0.002) were significantly shorter during the more recent period. Also, Δhemoglobin (Hb)%, calculated as ΔHb% = [(preoperative Hb - postoperative Hb)/preoperative Hb] × 100 (14.9% vs 17.5%; P = 0.042), and Δaspartate aminotransferase (AST)%, calculated as ΔAST% = [(peak AST - preoperative AST)/preoperative AST] × 100 (1048.9% vs 1316.6%; P = 0.009), were significantly lower during the recent period. CONCLUSIONS: Pure laparoscopic donor right hepatectomy is both feasible and safe when performed at a center experienced in adult living donor liver transplantation. Performance of about 60 PLDRHs over 1 year is sufficient to standardize the procedure.

Pediatric Living Donor Liver Transplantation Using a Monosegment Procured by Pure 3D Laparoscopic Left Lateral Sectionectomy and In situ Reduction.

BACKGROUND: Improvements in laparoscopic imaging systems and instruments have increased the performance of pure laparoscopic living donor hepatectomy. This operation is no longer limited to left lateral sectionectomy but is used for left hepatectomy and right hepatectomy.1-5 This report describes a donor who underwent pure laparoscopic left lateral sectionectomy and in situ reduction using 3D laparoscopy and indocyanine green (ICG) near-infrared fluorescence cholangiography to obtain a monosegment. METHODS: A 43-year-old woman offered to donate part of her liver to her daughter, who required a transplant for acute liver failure after a Kasai operation for biliary cirrhosis caused by biliary atresia. Donor height was 150.4 cm, body weight was 56.8 kg, and body mass index was 25.1 kg/m2. Liver dynamic CT showed a left lateral liver volume of 223 cm3, and an estimated graft-to-recipient weight ratio (GRWR) of 4.4%. The entire procedure including in situ reduction was performed under 3D laparoscopic view. The optimal bile duct division point was determined by real time ICG fluorescence cholangiography. RESULTS: The total operation time was 320 min, with no transfusion required and no intraoperative complications. Intraoperative real time ICG fluorescence cholangiography revealed the donor's bile duct anatomy and identified the optimal division point. The final graft weighed 167 g, 48 g being reduced in situ, with a GRWR of 3.3%. The donor was discharged on postoperative day 8 with no complications. CONCLUSION: Pure 3D laparoscopic left lateral sectionectomy and in situ reduction are feasible for obtaining a donor monosegment for pediatric living donor liver transplantation.

Memory T cells are significantly increased in rejected liver allografts of rhesus monkeys.

The rhesus monkey (RM) is an excellent preclinical model in kidney, heart, and islet transplantation that has provided the basis for new immunosuppressive protocols for clinical studies. However, there remain relatively few liver transplantation (LT) models in nonhuman primates. In this study, we analyzed the immune cell populations of peripheral blood mononuclear cells (PBMCs) and secondary lymphoid organs along with livers of normal RMs and compared them with those of rejected LT recipients following withdrawal of immunosuppression. We undertook 5 allogeneic ABO compatible orthotopic LTs in monkeys using 5 normal donor monkey livers. We collected tissues including lymph nodes, spleens, blood, and recipient livers, and we performed flow cytometric analysis using isolated immune cells. We found that CD4 or CD8 naïve T cells were normally seen at low levels, and memory T cells were seen at high levels in the liver rather than lymphoid organs or PBMC. However, regulatory cells such as CD4+ forkhead box P3+ T cells and CD8+ CD28- cells remained in high numbers in the liver, but not in the lymph nodes or PBMC. The comparison of CD4/8 T subpopulations in normal and rejected livers and the various tissues showed that naïve cells were dramatically decreased in the spleen, lymph node, and PBMCs of rejected LT monkeys, but rather, the memory CD4/8 T cells were increased in all tissues and PBMC. The normal liver has large numbers of CD4 regulatory T cells, CD8+ CD28-, and myeloid-derived suppressor cells, which are known immunosuppressive cells occurring at much higher levels than those seen in lymph node or peripheral blood. Memory T cells are dramatically increased in rejected liver allografts of RMs compared with those seen in normal RM tissues. Liver Transplantation 24 256-268 2018 AASLD.

Exploration of comorbid obsessive-compulsive disorder in patients with bipolar disorder: The clinic-based prevalence rate, symptoms nature and clinical correlates.

BACKGROUND: Comorbidity of bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has received clinical attention. However, the detailed nature and nolosogic validity of the comorbidity have not been fully explored. This study investigated the comorbidity rate, clinical nature, and correlates of OCD in patients with BD. METHODS: Patients (n = 314) with BD were recruited and lifetime clinical characteristics were evaluated comprehensively. The comorbid OCD ('OCD-BD') group and the 'non-OC BD' group were compared in terms of the clinical variables of BD. RESULTS: OCD was found in 15.9% of patients. Earlier age at onset, more frequent pharmacological (hypo)manic switch and a higher rate of comorbid panic disorder were associated with comorbid OCD. In two-thirds (65.4%) of the OCD-BD subjects, obsessive-compulsive symptoms worsened or were confined to depressive episodes. Contamination obsession and checking compulsion were the most common types of obsessive-compulsive symptoms. Drug-induced (hypo)manic switch was observed in more than 60% of the OCD-BD subjects who were previously exposed to antidepressants. None of the OCD-BD subjects were taking antidepressants for OCD in the current specialty clinics. LIMITATIONS: Subject recruitment from specialty clinics, retrospective and cross-sectional evaluation, and difficulties in clarifying the causal relationships. CONCLUSIONS: The comorbidity rate of OCD in Korean BD patients was comparable to that of Caucasian patients. Even though OCD seems to be more often linked to depressive episodes, a heterogeneous nosologic relationship including a possibility of drug-mediated induction is suggested.

Effect of PNPLA3 I148M polymorphism on histologically proven non-alcoholic fatty liver disease in liver transplant recipients.

AIM: PNPLA3 I148M polymorphism (rs738409 C>G) is the most important and best-known polymorphism for non-alcoholic fatty liver disease (NAFLD). However, little is known about the effect of this polymorphism on NAFLD after liver transplantation (LT). We aimed to evaluate the association between this polymorphism and post-LT NAFLD. METHODS: We designed a prospective case-control study. Among adult recipients who underwent LT between April 2014 and October 2015, those whose whole blood was preoperatively collected for genotyping in both recipients and coupled donors and those who underwent protocol biopsy at 1 year post-LT were enrolled. RESULTS: A total of 32 recipients were enrolled. Histologically proven steatosis (≥5%) was present in 28.1% of patients at a mean time of 12.7 ± 2.0 months after LT. Moderate and more severe steatosis (≥33%) was present in 9.4%. One year after LT, steatosis was present in 50.0% of homozygous recipients with the rs738409-G allele. It was present in 27.3% of heterozygous recipients with the rs738409-G allele, and in 9.1% (P = 0.041) of recipients with rs738409-CC. The genotype of the donor was not significantly (P = 0.647) associated with post-LT NAFLD. When both recipient and coupled donor showed heterogeneous or homozygous genotype of the rs738409-G allele, there was significantly more post-LT NAFLD compared to that in others (47.1% vs. 6.7%; P = 0.018). In univariate and multivariate analyses, only the presence of the rs738409-G risk allele in both donor and recipient was a significant risk factor for post-LT NALFD (relative risk, 26.95; P = 0.048). CONCLUSIONS: PNPLA3 I148M polymorphism can significantly affect histologically proven NAFLD at 1 year post-LT.

Pretransplantation fetal-maternal microchimerism in pediatric liver transplantation from mother.

AIM: To investigate the rates of pretransplantation fetal-maternal microchimerism (MC) and its effect on rejection in children receiving maternal liver grafts. METHODS: DNA or blood samples before liver transplantation (LT) were available in 45 pediatric patients and their mothers. The presence of pretransplantation MC to non-inherited maternal antigens (NIMAs) (NIMA-MC) in the peripheral blood was tested using nested PCR-single-strand conformation polymorphism analysis for the human leukocyte antigen (HLA)-DRB1 alleles. NIMA-MC was successfully evaluated in 26 of the 45 children. Among these 45 pediatric LT recipients, 23 children (51.1%) received transplants from maternal donors and the other 22 from non-maternal donors. RESULTS: Among these 26 children, pretransplantation NIMA-MC was detected in 23.1% (n = 6), 6.1 (range, 0.8-14) years after birth. Among the children with a maternal donor, the rate of biopsy-proven cellular rejection (BPCR) was 0% in patients with NIMA-MC positivity (0/3) and those with HLA-DR identity with the mother (0/4), but it was 50% in those with NIMA-MC negativity (5/10). Patients with NIMA-MC positivity or HLA-DR identity with the mother showed significantly lower BPCR rate compared with NIMA-MC-negative patients (0% vs 50%, P = 0.04). NIMA-MC-positive patients tended to show lower BPCR rate compared with NIMA-MC-negative patients (P = 0.23). CONCLUSION: The presence of pretransplantation NIMA-MC or HLA-DR identity with the mother could be associated with BPCR-free survival in pediatric recipients of LT from maternal donors.

Sirolimus and Metformin Synergistically Inhibits Colon Cancer In Vitro and In Vivo.

We estimated the effect of various immunosuppressants (ISs) and metformin (M) to provide theoretical background of optimal therapeutic strategy for de novo colon cancer after liver transplantation (LT). Three colon cancer cell lines (HT29, SW620, and HCT116) were used in in vitro studies. HT29 was also used in BALB/c-nude mice animal models. Following groups were used in both in vitro and in vivo studies: sirolimus (S), tacrolimus (T), cyclosporin A (CsA), M, metformin/sirolimus (Met/S), metformin/tacrolimus (Met/T), and metformin/cyclosporin A (Met/CsA). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed and western blot analyses were performed for mTOR pathway proteins, apoptosis proteins, and epithelial-mesenchymal-transition (EMT) proteins. Tumor volume was measured for 4 weeks after inoculation. MTT-assay revealed significant cell viability inhibition in all 3 colon cancer cell lines in groups of S, M, and Met/S. Of note, group Met/S showed synergistic effect compare to M or S group. Western blot analysis showed significant low levels of all investigated proteins in groups of S and Met/S in both in vitro and in vivo experiment. Tumor growth was significantly inhibited only in the Met/S group. Combination of Met and S showed the most potent inhibition in all colon cancer cell lines. This finding might have application for de novo colon cancer.

Pure laparoscopic right hepatectomy in a patient with situs inversus totalis: A case report.

RATIONALE: Hepatectomy in a patient with situs inversus totalis (SIT) is technically challenging, and pure laparoscopic major hepatectomy has not been previously described. PATIENT CONCERNS: A 70-year-old male with SIT was referred to our hospital for investigation and treatment of a liver mass in segment 5/6. DIAGNOSIS: Computed tomography (CT) and magnetic resonance imaging (MRI) showed features of chronic liver disease and a 5-cm sized mass with a bulging contour at segment 5/6. INTERVENTIONS: Pure laparoscopic right hepatectomy was performed. OUTCOMES: There was no intraoperative complication and the procedure was completed without a transfusion. The patient recovered well and was discharged on postoperative day 8. LESSONS: Considering the position of the port sites and the assistant, and the operator's hand for the working port, a pure laparoscopic right hepatectomy can be a feasible procedure, even in a patient with SIT.

Split liver transplantation for retroperitoneal immature teratoma masquerading as hepatoblastoma.

Extragonadal teratoma originating from the retroperitoneum represents less than 5% of all teratomas and accounts for less than 10% of all pediatric retroperitoneal neoplasms. To date, there has been no report of teratoma managed with LT. This study reports an infant aged 3 months with retroperitoneal immature teratoma involving the hepatic hilum, refractory to chemotherapy and treated with LT. The patient was referred to our hospital for management of a growing abdominal mass. Histopathology of a fine needle biopsy of the lesion suggested the possibility of a hepatoblastoma with teratoid features. Cisplatin-based chemotherapy was initiated, but rapid growth of the tumor encasing the hepatic artery proper was detected, even after two cycles of chemotherapy. A split LT was carried out, and pathological examination of the explanted liver revealed the involvement of numerous neuroepithelial components, confirming the diagnosis of a Norris grade 3 immature teratoma. The patient recovered well and was discharged on day 19 post-LT. As on date, on postoperative day 240, he has completed seven cycles of a 12-cycle vinblastine and doxorubicin-based adjuvant chemotherapy.

Long-term response to mood stabilizer treatment and its clinical correlates in patients with bipolar disorders: a retrospective observational study.

BACKGROUND: The efficacy and utility of long-term prophylactic treatment in patients with bipolar disorders (BDs) have not been fully explored. This study aims to estimate the long-term clinical response of patients with BDs to mood stabilizer treatment and to identify the clinical factors associated with that response. METHODS: The study subjects consisted of 80 patients with bipolar I or bipolar II disorder who had been receiving treatment with lithium and/or valproate for more than 2 years at a single bipolar disorder clinic. The long-term response to the best treatment option based on treatment algorithms was evaluated using the Alda scale. Clinical characteristics were evaluated on a lifetime basis. Patients were classified into two response groups based on frequentist mixture analysis using the total Alda scale score. RESULTS: Thirty-four percent of the patients were good responders, with a total Alda score of 5 or higher. The treatment response rate did not differ between the lithium and valproate groups, but lithium and valproate combination therapy was associated with poorer response. The number of previous mixed episodes was associated with a worse response (p = 0.026). Of individual symptoms, delusions during manic episodes (p = 0.008) and increased appetite (p = 0.035) during depressive episodes were more common in moderate/poor responders than in good responders. Co-morbid anxiety disorders were more frequently observed in the moderate/poor response group (p = 0.008). CONCLUSIONS: Psychotic, mixed, and atypical features of BDs were found to be correlated with long-term treatment outcomes. Lithium and valproate showed similar efficacy but moderate/poor responders preferred to use polypharmacy.