Pediatric living donor liver transplantation (PLDLT) is a successful therapeutic option for children with chronic and acute liver disease. After early transplant results, many technical advancements ...were introduced in the field to reduce the rate of complications and improve survival. The aim of this study is to present the outcomes of 975 primary PLDLTs in 3 periods: initial practice (period 1, 29 patients, January 1995 to December 1999), second period (period 2, 331 patients, January 2000 to December 2009), and third period (period 3 P3, 615 patients, January 2010 to September 2019). Among the technical refinements introduced in P3 are the use of hyperreduced left lateral segment grafts, abdominal wall prosthetic mesh closure, double hepatic artery anastomosis, and increased use of vascular grafts for portal vein reconstruction. The outcomes included significant reductions of hepatic artery thrombosis (HAT), early portal vein thrombosis (EPVT), and retransplantation, with better patient and graft survival in P3. Additional analyses showed that the factors independently associated with worse 90‐day patient survival were HAT, EPVT, and increasing Pediatric End‐Stage Liver Disease score. In conclusion, the introduction of technical refinements in P3, in addition to improvements in patient care, determined a reduction in EPVT, HAT, and retransplantation. Consequently, patient and graft survival rates increased in all time points studied.
Departments of 1 Regenerative Medicine and Tissue Engineering, 3 Cardiac Physiology, and 6 Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565; Departments of 2 Internal ...Medicine and 7 Cardiovascular Surgery, National Cardiovascular Center, Osaka; 4 Tissue Engineering Research Center, National Institute of Advanced Industrial Science and Technology, Hyogo; and 5 Cardiovascular Division, Kansai Rosai Hospital, Hyogo 660-8511, Japan
Submitted 10 November 2003
; accepted in final form 13 July 2004
Mesenchymal stem cells (MSCs) are pluripotent cells that differentiate into a variety of cells, including cardiomyocytes and endothelial cells. However, little information is available regarding the therapeutic potency of systemically delivered MSCs for myocardial infarction. Accordingly, we investigated whether intravenously transplanted MSCs induce angiogenesis and myogenesis and improve cardiac function in rats with acute myocardial infarction. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. At 3 h after coronary ligation, 5 x 10 6 MSCs (MSC group, n = 12) or vehicle (control group, n = 12) was intravenously administered to Lewis rats. Transplanted MSCs were preferentially attracted to the infarcted, but not the noninfarcted, myocardium. The engrafted MSCs were positive for cardiac markers: desmin, cardiac troponin T, and connexin43. On the other hand, some of the transplanted MSCs were positive for von Willebrand factor and formed vascular structures. Capillary density was markedly increased after MSC transplantation. Cardiac infarct size was significantly smaller in the MSC than in the control group (24 ± 2 vs. 33 ± 2%, P < 0.05). MSC transplantation decreased left ventricular end-diastolic pressure and increased left ventricular maximum dP/d t (both P < 0.05 vs. control). These results suggest that intravenous administration of MSCs improves cardiac function after acute myocardial infarction through enhancement of angiogenesis and myogenesis in the ischemic myocardium.
left ventricular end-diastolic pressure; cell transplantation; differentiation; homing
Address for reprint requests and other correspondence: N. Nagaya, Dept. of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (E-mail: nnagaya{at}ri.ncvc.go.jp )
Background
Three costimulation blockade‐based regimens have been explored after transplantation of hearts from pigs of varying genetic backgrounds to determine whether CTLA4‐Ig (abatacept) or ...anti‐CD40mAb+CTLA4‐Ig (belatacept) can successfully replace anti‐CD154mAb.
Methods
All pigs were on an α1,3‐galactosyltransferase gene‐knockout/CD46 transgenic (GTKO.CD46) background. Hearts transplanted into Group A baboons (n = 4) expressed additional CD55, and those into Group B (n = 3) expressed human thrombomodulin (TBM). Immunosuppression included anti‐thymocyte globulin with anti‐CD154mAb (Regimen 1: n = 2) or abatacept (Regimen 2: n = 2) or anti‐CD40mAb+belatacept (Regimen 3: n = 2). Regimens 1 and 2 included induction anti‐CD20mAb and continuous heparin. One further baboon in Group B (B16311) received a modified Regimen 1. Baboons were followed by clinical/laboratory monitoring of immune/coagulation parameters. At biopsy, graft failure, or euthanasia, the graft was examined by microscopy.
Results
Group A baboons survived 15 to 33 days, whereas Group B survived 52, 99, and 130 days, respectively. Thrombocytopenia and reduction in fibrinogen occurred within 21 days in Group A, suggesting thrombotic microangiopathy (TM), confirmed by histopathology. In Group B, with follow‐up for >4 m, areas of myofiber degeneration and scarring were seen in two hearts at necropsy. A T‐cell response was documented only in baboons receiving Regimen 2.
Conclusions
The combination of anti‐CD40mAb+belatacept proved effective in preventing a T‐cell response. The expression of TBM prevented thrombocytopenia and may possibly delay the development of TM and/or consumptive coagulopathy.
The importance of shared decision-making (SDM) between physicians and patients is increasingly recognized. In Japan, patients have shown more willingness to participate in treatment if medical ...professionals provide sufficient information; however, relationships between physicians and patients have traditionally been asymmetric, with patients accepting information from physicians without discussion. To explore the benefits of SDM in cancer treatment, including confidence in treatment decisions, satisfaction with treatment, and trust in healthcare providers, this study developed Japanese versions of the Control Preference Scale (CPS) and Information Needs Questionnaire (INQ).
Reliability and validity of the CPS and INQ were tested with 49 breast cancer patients.
The CPS showed good test-retest reliability (kappa coefficient: 0.61, weighted kappa coefficient: 0.61, Kendall's tau coefficient: 0.61) and acceptable criterion validity. The INQ showed adequate consistency; the mean number of circular triads and coefficient of consistency were 3 (range 0-19) and 0.9 (range 0.37-1), respectively. Using the CPS and INQ to identify patients' roles in decision-making and information needs, results further suggested that breast cancer patients in Japan want to participate in SDM. Medical issues, including disease spread and cure, were found to be of high interest, while social and psychological issues, including sexual attractiveness, genetic risk, and family impact, tended to be low.
The Japanese CPS and INQ can be used to assess patients' needs to improve care. Further, as patients' information needs change along the care trajectory, these tools should be used throughout treatment.
In pig-to-baboon transplantation models, there is increasing evidence of systemic inflammation in xenograft recipients (SIXR) associated with pig xenograft failure. We evaluated the relationship ...between systemic inflammatory factors and pig kidney xenograft failure.
Baboons received kidney transplants from genetically engineered pigs (n=9), and received an anti-CD40mAb-based (n=4) or conventional (n=5) immunosuppressive regimen. The pig kidney grafts were monitored by measurements of serum creatinine, serum amyloid A (SAA), white blood cell (WBC) and platelet counts, plasma fibrinogen, and pro-inflammatory cytokines (baboon and pig IL-6, TNF-α, IL-1β).
Six baboons were euthanized or died from rejection, and 3 were euthanized for infection. Changes in serum creatinine correlated with those of SAA (r=0.56, p<0.01). Serum
IL-6 was increased significantly on day 1 after transplantation and at euthanasia (both p<0.05) and correlated with serum creatinine and SAA (r=0.59, p<0.001, r=0.58, p<0.01; respectively). but no difference was observed between rejection and infection. Levels of serum
IL-6, TNF-α, IL-1β were also significantly increased on day 1 and at euthanasia, and serum pig IL-6 and IL-1β correlated with serum creatinine and SAA. The level of serum baboon IL-6 correlated with the expression of IL-6 and amyloid A in the baboon liver (r=0.93, p<0.01, r=0.79, p<0.05; respectively).
Early upregulation of SAA and serum IL-6 may indicate the development of rejection or infection, and are associated with impaired kidney graft function. Detection and prevention of systemic inflammation may be required to prevent pig kidney xenograft failure after xenotransplantation.
BACKGROUNDHepatic artery thrombosis (HAT) increases morbidity and mortality after liver transplantation (LT). The identification of risk factors for HAT may aid transplant teams in the development of ...strategies aimed at reducing HAT. This article describes the risk factors for HAT and outcomes after LT.
METHODSThis report describes a retrospective study (1995 to 2015) of primary pediatric living donor LT (LDLT). Pretransplant and technical variables were included in the study. Binary logistic regression was used for data analysis.
RESULTSThis study included 656 primary LDLT. The median age, body weight, and pediatric end-stage liver disease score at the time of transplant were 13 months, 8.4 kg and 15, respectively. Twenty-one (3.2%) patients developed HAT. Intraoperative HAT (odds ratio, 62.63; 95% confidence interval, 12.64-310.19; P < 0.001) and the use of liver grafts with a graft-to-recipient weight ratio less than 1.1% (odds ratio, 24.46; 95% confidence interval, 4.55-131.56; P < 0.001) retained statistical significance in the multivariate model. Patient and graft survivals were significantly worse in cases with HAT. The overtime trend analysis revealed a decrease in the incidence of HAT (P = 0.008) and an increase in the use of 2-arterial anastomosis (P < 0.001).
CONCLUSIONSA graft-to-recipient weight ratio of 1.1% or less and intraoperative HAT were independently associated with HAT. Trend analysis further revealed a significant reduction in the incidence of HAT over time, as well as the increased use of 2 hepatic arteries for anastomosis during graft implantation. The double artery anastomosis may represent an extra protection to pediatric recipients undergoing LDLT.
During investigations of unnatural death, the time of death is generally estimated using anatomical examinations. However, it can be difficult to accurately determine the day of death, because ...postmortem changes in the body tissues can be greatly affected by the circumstances of the location of the corpse. We recently developed a method to estimate the day of drug ingestion, using micro-segmental hair analysis based on internal temporal markers (ITMs). In this method, ITMs are ingested at a specific time interval before hair collection to mark timescales within individual hair strands. A single hair strand is segmented at 0.4-mm intervals, corresponding to average daily hair growth. The day of drug ingestion is eventually estimated by calculating the distances between segments containing the drug and ITMs in a hair strand. In the present study, the method was applied to estimate the day of death. A corpse was discovered with a documented medical history of lidocaine administration for surgery 57 days before the discovery. Micro-segmental analysis of a hair plucked from the corpse was performed using lidocaine as an ITM. Lidocaine was detected at specific regions in the hair strands. The day of death was estimated using the known surgery day, the distance from the hair root to the lidocaine peak in the hair strand, and the average hair growth rate. The novel estimation method using a hair enabled us to narrow the estimated time range of death up to the day of death, unlike the conventional anatomical examination. The micro-segmental hair analysis based on drug use history can be extremely helpful in determining the time of an unnatural death.
The one-step nucleic acid amplification (OSNA) assay is a molecular-based lymph-node metastasis detection procedure that can assess a whole node and yields semi-quantitative results for the detection ...of clinically relevant nodal metastases. We aimed to determine the performance of the OSNA assay as an accurate nodal staging tool in comparison with routine histological examination.
Subjects comprised 183 consecutive patients with pT1-2 breast cancer who underwent axillary dissection after positive sentinel-node (SN) biopsy with the OSNA assay. Of these, for non-SN evaluation, 119 patients underwent OSNA assay evaluation, whereas 64 had single-section histology. We compared the detection rates of non-SN metastasis and upstaging rates from the SN stage according to the American Joint Committee on Cancer staging between the OSNA and histology cohorts.
OSNA detected more cases of non-SN metastases than histology (OSNA 66/119, 55.5% vs histology 13/64, 20.3%; P<0.001), particularly micrometastases (36/119, 30.3% vs 1/64, 1.6%; P<0.001). Total upstaging rates were similar in both cohorts (20/119, 16.8% vs 9/64, 14.1%, P=0.79).
OSNA detects a far greater proportion of non-SN micrometastases than routine histological examination. However, upstaging rates after axillary dissection were not significantly different between both cohorts. Follow-up of the OSNA cohort is required to determine its clinical relevance.
Summary Objectives Knee osteoarthritis (OA) pain is suggested to be associated with inflammation and detrimental mechanical loading across the joint. In this cross-sectional study, we simultaneously ...examined the inflammation and alignment of the lower limb and examined how the pain components varied depending on the disease progression. Design One-hundred sixty female medial type of early- n = 74 in Kellgren–Lawrence (K/L) 2 to advanced-stage ( n = 96 in K/L >2) knee OA subjects (70.5 years on average) were enrolled. Knee pain was evaluated using a pain visual analog scale (VAS) and the pain-related subcategory of the Japanese Knee Osteoarthritis Measure (JKOM-pain). The serum interleukin (sIL)-6 level reflecting synovitis, and the high sensitivity C-reactive protein (hs-CRP) level were measured to evaluate the severity of inflammation. The anatomical axis angle (AAA) was measured as an alignment index. The β -coefficient was estimated after adjusting for age and the body mass index (BMI) using a multiple linear regression analysis. Results Multiple linear regression analyses showed that the sIL-6 levels, but not AAA, associated with the pain VAS β = 10.77 (95% confidence interval (CI): 4.14–17.40), P < 0.01 and JKOM-pain scores β = 3.19 (95% CI: 1.93–4.44), P < 0.001 in the early stage. Conversely, AAA, but not the sIL-6 levels, was found to be associated with the pain VAS β = −1.29 (95% CI: −2.51 to −0.08), P < 0.05 and JKOM-pain scores β = −0.49 (95% CI: −0.82 to −0.16), P < 0.01 in the advanced stage. Conclusions The presence of a higher level of sIL-6 and the varus alignment of the joint is associated with pain in early- and advanced-stage knee OA patients, respectively.
BACKGROUND.The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the ...results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen.
METHODS.Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA US Food and Drug Administration-approved regimens, n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts.
RESULTS.The median survival in GroupB was 186 days (range 90–260), which was significantly longer than in GroupA; median 14 days (range 12–32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis.
CONCLUSIONS.Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.
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