Tetsuya Tajima

Transplantation is limited by how long organs survive outside the body. Current methods slow metabolism or sustain physiological support, but neither eliminates ischemia-reperfusion injury, which shortens storage and drives organ discard. Embryonic diapause and hibernation show that mammalian cells retain a latent capacity for reversible metabolic arrest. Screening the PI3K-mTOR axis, we identified a dual inhibitor that reversibly pauses embryonic stem cells at ambient oxygen and holds mouse embryos in arrest for 8.5 days. Combined with a mitochondria-targeted hydrogen sulfide donor, this yields TorPause, a two-component flush compatible with existing preservation protocols. In a rat liver transplantation model, TorPause reduced structural injury and improved recipient survival after 5 hours of static storage at room temperature, potentially expanding the usable donor pool.

Unlike deceased‐donor liver transplantation, living‐donor liver transplantation (LDLT) for Budd‐Chiari Syndrome (BCS) presents distinctive challenges in hepatic venous (HV)‐outflow reconstruction because diseased HV–inferior vena cava (IVC) cannot be entirely replaced with healthy donor vessels. In the Asia‐Pacific region, where LDLT predominates, BCS frequently involves the hepatic IVC, thus requiring innovative surgical strategies for HV–IVC reconstruction. Here we introduce a novel series of surgical technique—“intrapericardial approach (IPA)”—which reconstructs HV‐outflow tract in the pericardium using only healthy vascular tissues, thereby minimizing post‐transplant BCS recurrence. Detailed procedures are illustrated for four typical LDLT scenarios, classified by graft‐type (left‐ or right‐lobe) and by the need for IVC reconstruction (acute or chronic BCS). A representative surgical video is also provided. Of our 2089 consecutive liver transplants, 20 patients underwent LDLT for BCS: 10 with conventional IVC‐preserving techniques (cavoplasty and/or patch‐plasty) and 10 using IPA. Across all four clinical scenarios aforementioned, the key concept of IPA—creating new HV‐outflow with only healthy vessels—was consistently applicable. IPA was associated with significantly lower post‐transplant BCS recurrence ( p = 0.04) and improved both relapse‐free and overall recipient survival ( p = 0.02 and 0.03, respectively) compared to conventional techniques, yielding 100% graft and patient survival through 10 years. This report also highlights key considerations and pitfalls for pre‐, intra‐, and post‐transplant management in BCS‐LDLT. In conclusion, IPA appears to be associated with reduced post‐transplant BCS recurrence and favorable short‐ and long‐term outcomes, offering a novel practical solution for challenging HV–IVC reconstruction in BCS‐LDLT.

Background: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living‐donor liver transplantation (LDLT) remain unclear.Methods: We retrospectively reviewed 1781 primary LDLT recipients (1990–2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age‐adjusted Japanese general population.Results: After 21 845 person‐years follow‐up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person‐years. DNMs included 81 post‐transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5‐ and 10‐year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR_1993–1995: 8.12 (95% CI: 3.71–15.4, p < .001) and SIR_1996–1998: 3.11 (1.34–6.12, p = .01) were significantly high, but had decreased time‐dependently to SIR_2005–2007: 1.31 (0.68–2.29, p = .42) and SIR_2008–2010: 1.34 (0.75–2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR_2014–2016: 2.27 (1.54–3.22, p < .001) and SIR_2017–2019: 2.07 (1.40–2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non‐PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor‐recipient HLA‐mismatches, the less the post‐transplant DNMs development.Conclusion: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993‐1998), but once became equivalent (2005‐2013), then significantly increased again (2014‐2019) due to recent recipient aging and resultant increase in solid cancers.

Background: Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis.Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre‐transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis.Results: The uni−/multivariable competing risk analyses revealed the combination of EBV‐seropositive donor and EBV‐naïve recipient (D+R−) was a significant risk factor for PTLD development (sub‐hazard ratio: 2.79 [1.34–5.78], p = .006) and EBV DNAemia (2.65 [1.72–4.09], p < .001). Patients with D+R− were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non‐PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6‐month post‐transplant. Among non‐liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01).Conclusions: D+R− is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow‐up of EBV viral load within 6‐month post‐transplant, especially for patients with D+R− and/or non‐liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant.

Background: Outcomes of intestinal transplantation with colon allograft (ICTx) remain controversial. We aimed to assess the outcomes of ICTx in comparison to intestinal transplantation without colon (ITx) using the UNOS/OPTN registry database.Methods: We retrospectively reviewed 2612 patients who received primary intestinal transplants from 1998 to 2020. The rates of acute rejection (AR) within 6 months after transplant were compared between ICTx and ITx. Risk factors of 6‐month AR were examined using logistic regression model by era. Furthermore, conditional graft survival was analyzed to determine long‐term outcomes of ICTx.Results: Of 2612 recipients, 506 (19.4%) received ICTx. Graft and patient survival in ICTx recipients were comparable to those in ITx recipients. White ICTx recipients had a higher incidence of AR within 6 months compared to ITx during the entire study period (p = .002), colonic inclusion did not increase the risk of 6‐month AR in the past decade. ICTx recipients who experienced 6‐month AR had worse graft and patient survival compared to those who did not (p <.001 and p = .004, respectively). Among patients who did not develop 6‐month AR, Cox proportional hazard model analysis revealed that colonic inclusion was independently associated with improved conditional graft survival.Conclusions: In the recent transplant era, colonic inclusion is no longer associated with a heightened risk of 6‐month AR and may provide better long‐term survival compared to ITx when AR is absent. Risk adjustment for rejection and proper immunosuppressive therapy are crucial to maximize the benefits of colonic inclusion.

AimLiving-donor liver transplantation (LDLT) is a highly effective life-saving procedure; however, it requires substantial medical resources, and the cost-effectiveness of LDLT versus conservative management (CM) for adult patients with end-stage liver disease (ESLD) remains unclear in Japan.MethodsWe performed a cost-effectiveness analysis using the Diagnostic Procedure Combination (DPC) data from the nationwide database of the DPC research group. We selected adult patients (18 years or older) who were admitted or discharged between 2010 and 2021 with a diagnosis of ESLD with Child-Pugh class C or B. A decision tree and Markov model were constructed, and all event probabilities were computed in 3-month cycles over a 10-year period. The willingness-to-pay per quality-adjusted life-year (QALY) was set at 5 million Japanese yen (JPY) (49,801 US dollars [USD]) from the perspective of the public health-care payer.ResultsAfter propensity score matching, we identified 1297 and 111,849 patients in the LDLT and CM groups, respectively. The incremental cost-effectiveness ratio for LDLT versus CM for Child-Pugh classes C and B was 2.08 million JPY/QALY (20,708 USD/QALY) and 5.24 million JPY/QALY (52,153 USD/QALY), respectively. The cost-effectiveness acceptability curves showed the probabilities of being below the willingness-to-pay of 49,801 USD/QALY as 95.4% in class C and 48.5% in class B. Tornado diagrams revealed all variables in class C were below 49,801 USD/QALY while their ranges included or exceeded 49,801 USD/QALY in class B.ConclusionsLiving-donor liver transplantation for adult patients with Child-Pugh class C was cost-effective compared with CM, whereas LDLT versus CM for class B patients was not cost-effective in Japan. We performed a cost-effectiveness analysis of living-donor liver transplantation (LDLT) compared to conservative management (CM) for adult patients using the Japanese nationwide database of the Diagnostic Procedure Combination research group. LDLT compared with CM for patients with Child-Pugh class C was cost-effective, with an incremental cost-effectiveness ratio (ICER) of 2.08 million JPY/QALY (20,708 USD/QALY), whereas LDLT versus CM for patients with Child-Pugh class B was not cost-effective, with an ICER of 5.24 million JPY/QALY (52,153 USD/QALY).image

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Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004–2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without (p=0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63–16.3], p=0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05–10.0], p=0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not (p=0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009–2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development (p p=0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Donor–recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living‐donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990–2020). The primary and secondary endpoints were recipient survival and the incidence of T cell–mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA‐A, HLA‐B, HLA‐C, HLA‐DR, and HLA‐DQ. Subgroup analyses were also performed in between‐siblings that characteristically have widely distributed 0–10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult‐to‐adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA‐A, HLA‐B, HLA‐C, HLA‐DR, and HLA‐DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA‐B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21–5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11–5.35; p = 0.03) in between‐siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor–recipient relationships are parent‐to‐child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.