Impact of a Liver Immune Status Index among Living Liver Transplant Recipients with Hepatocellular Carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is a major global health challenge, being the fifth most prevalent neoplasm and the third leading cause of cancer-related deaths worldwide. Liver transplantation offers a potentially curative approach for HCC, yet the risk of recurrence posttransplantation remains a significant concern. This study investigates the influence of a liver immune status index (LISI) on the prognosis of patients undergoing living-donor liver transplantation for HCC. Methods: In a single-center study spanning from 2001 to 2020, 113 patients undergoing living-donor liver transplantation for HCC were analyzed. LISI was calculated for each donor liver using body mass index, serum albumin levels, and the fibrosis-4 index. This study assessed the impact of donor LISI on short-term recurrence rates and survival, with special attention to its correlation with the antitumor activity of natural killer (NK) cells in the liver. Results: The patients were divided into two grades (high donor LISI, >-1.23 [n = 43]; and low donor LISI, ≤-1.23 [n = 70]). After propensity matching to adjust the background of recipient factors, the survival rates at 1 and 3 years were 92.6% and 88.9% and 81.5% and 70.4% in the low and high donor LISI groups, respectively (p = 0.11). The 1- and 3-year recurrence-free survival were 88.9% and 85.2% and 74.1% and 55.1% in the low and high donor LISI groups, respectively (p = 0.02). Conclusions: This study underscores the potential of an LISI as a noninvasive biomarker for assessing liver NK cell antitumor capacity, with implications for living-donor liver transplantation for HCC. Donor LISI emerges as a significant predictor of early recurrence risk following living-donor liver transplantation for HCC, highlighting the role of the liver antitumor activity of liver NK cells in managing liver malignancies.

Immunotherapy Using Activated Natural Killer Cells Improves Postoperative Neutrophil-to-Lymphocyte Ratio and Long-Term Prognosis of Living Donor Liver Transplant Recipients With Hepatocellular Carcinoma.

OBJECTIVE: Preoperative neutrophil-to-lymphocyte ratio (NLR) is a well-known prognostic indicator in various malignancies; however, the impact of postoperative NLR on living donor liver transplant (LDLT) recipients is unknown. Immunotherapy with donor liver-derived activated natural killer (NK) cells may improve postoperative NLR by coactivating immune cells or suppressing activated neutrophils. This study aims to clarify the clinical significance of postoperative NLR in recipients after LDLT with HCC and assess whether immunotherapy improves postoperative NLR. METHODS: We conducted a retrospective study of LDLT recipients between 2001 and 2022 to evaluate the clinical significance of postoperative NLR. Furthermore, the correlation between postoperative NLR and the activation marker of infused NK cells was also evaluated. The postoperative NLR was examined 4 weeks after LDLT. RESULTS: The postoperative high NLR group (N = 78) had preoperative lower NLR and higher model for end-stage liver disease and a higher rate of postoperative infection within 30 days after LDLT than the postoperative low NLR group (N = 41). Postoperative high NLR (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.01-6.79; P = .047) and nontreatment of immunotherapy (HR, 3.10; 95% CI, 1.33-7.22; P < .01) were independent risk factors for poor overall survival in multivariate analysis. Furthermore, the activation marker of infused NK cells is inversely correlated with decreased postoperative NLR. CONCLUSIONS: The higher level of postoperative NLR was independently associated with poor prognosis in patients after LDLT with HCC. Immunotherapy using activated NK cells may improve postoperative NLR and long-term prognosis.

Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study.

Background: In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. Materials and methods: This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5 ml/body weight 1 kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. Conclusion: This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.

Association of Abdominal Aortic Calcification With the Postoperative Metabolic Syndrome Components After Liver Transplantation.

BACKGROUND: This study aimed to assess the risk factors for components of metabolic syndrome, such as diabetes mellitus, hypertension, and dyslipidemia, more than a year after liver transplantation. METHODS: This study included 164 patients with liver failure secondary to acute and chronic liver disease or hepatocellular carcinoma who underwent liver transplantation between 2000 and 2019. Univariate and multivariate analyses were performed to identify the risk factors associated with metabolic syndrome components after liver transplantation. RESULTS: The median follow-up period was 10.5 years. Of the 164 patients who underwent liver transplantation, 144 (87.8%) developed components of metabolic syndrome after liver transplantation. The most common cause of liver failure was hepatitis C virus infection (34.1%). The incidence of hepatocellular carcinoma was 36.0%. In univariate analysis, preoperative diabetes mellitus was a significantly more common component of metabolic syndrome than the others. In multivariate analysis, preoperative abdominal aortic calcification was a risk factor for the new onset of all components of metabolic syndrome after liver transplantation, despite the varying degree of calcification at risk of development (odds ratio for diabetes mellitus = 3.487, P = .0069; odds ratio for hypertension = 2.914, P = .0471; odds ratio for dyslipidemia = 3.553, P = .0030). CONCLUSIONS: Preoperative abdominal aortic calcification was significantly associated with the development of each metabolic syndrome component after liver transplantation.

Anti-Donor T-Cell Responses Are Not Necessarily Attenuated During Cytomegalovirus Infection in Kidney Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV), the most common opportunistic infection of kidney transplantation (KT), is preventable by prophylactic and preemptive antiviral drugs in CMV-immunoglobulin (Ig)G-positive donors. Our preemptive therapy optimized immunosuppressive doses based on mixed lymphocyte response (MLR) results, regardless of preoperative CMV-IgG serostatus pairing. This study used the MLR to compare the anti-donor T-cell responses between CMV antigenemia-positive and -negative cases. METHODS: One hundred patients underwent KT using a cyclosporine (CsA)-based immunosuppressive regimen at Hiroshima University Hospital. CMV antigenemia-positive cells were defined as 4/50,000 CMVpp65-positive cells. T-cell responses to allo-antigens were measured using MLR assays to evaluate patients' anti-donor immune reactivity. After analyzing the proliferation of CD4+ and CD8+ T-cell subsets, the stimulation indices of CD4+ or CD8+ T cells were quantified. The study used no prisoners, and the participants were neither coerced nor paid. The manuscript was created in compliance with the Helsinki Congress and the Declaration of Istanbul. RESULTS: Forty-three patients tested positive for CMV antigenemia within 3 months after KT. No significant differences were found between the CMV antigenemia-positive and -negative groups in the stimulation indices for CD4+ and CD8+ T-cell responses to anti-donor stimulation. However, T-cell responses to third-party stimuli during the postoperative month 1 were significantly less in the CMV antigenemia-positive than -negative group. CONCLUSION: Anti-donor T-cell responses are not necessarily attenuated during CMV infection in KT recipients. In CMV-infected KT recipients, caution should be exercised against inadvertent dose reduction of immunosuppressants.

Effect of Abdominal Aortic Calcification on Recurrence Following Initial Hepatectomy for Colorectal Liver Metastases.

BACKGROUND/AIM: The aim of the study was to analyze the association between abdominal aortic calcification (AAC) and patient prognosis following resection of colorectal liver metastases (CRLM). AAC potentially reflects intrahepatic immunity and is involved in tumor development and progression. However, the clinical effects of AAC on colorectal cancer (CRC) prognosis after curative-intent liver resection for CRLM remain unclear. PATIENTS AND METHODS: We evaluated the effect of AAC on the clinical prognosis and metastatic patterns in 99 patients who underwent hepatectomy for CRLM between 2010 and 2019. RESULTS: The high-AAC group had significantly worse overall survival (OS) and remnant liver recurrence rate (RR) after propensity score matching to adjust for differences in baseline characteristics of patients and tumors. In multivariate Cox regression analyses, high AAC volume was an independent risk factor for poor OS and liver RR, but not poor lung RR. The expression of tumor necrosis factor-related apoptosis-inducing ligand, known as an anti-tumor marker, in liver natural killer (NK) cells was lower in the high-AAC group than in the low-AAC group. CONCLUSION: High AAC volume showed a strong relationship with remnant liver RR after curative resection of CRLM. High AAC volume may be responsible for the suppression of anti-tumor activity of liver NK cells, which results in an increased risk of liver recurrence and poor prognosis.

Impact of KIR-HLA Genotype on Natural-Killer-Cell-Based Immunotherapy for Preventing Hepatocellular Carcinoma after Living-Donor Liver Transplantation.

Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma (HCC). We performed adaptive immunotherapy using donor-liver-derived natural killer (NK) cells after living-donor liver transplantation (LDLT) to prevent HCC recurrence. Dominant inhibitory signals tightly regulate NK cell activity via human leukocyte antigen (HLA)-specific inhibitory receptors, such as killer immunoglobulin-like receptors (KIRs). The functional recognition of HLA through KIR raises the NK cell capacity, which is a process termed "licensing." Here, we investigated the effect of polymorphic KIR-HLA genotypes on the efficacy of NK-cell-based immunotherapy after LDLT. Seventy-seven Japanese recipients with HCC who underwent LDLT and their corresponding donors between 1996 and 2016 were enrolled in this study. The median follow-up period was 8.3 years. The HCC recurrence risk was stratified using radiological and pathological assessments according to the Milan criteria. Of the 77 recipients, 38 received immunotherapy. Immunotherapy improves early post-transplantation survival and lowers the recurrence rate in the intermediate-risk recipients. We analyzed the genotypes of five inhibitory KIRs and HLA using sequence-specific polymorphism-based typing. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy.

Prognostic impact of pre- and postoperative tumor markers in patients with intrahepatic cholangiocarcinoma.

PURPOSE: The present study assessed the impact of pre- and postoperative tumor markers on the survival of patients with intrahepatic cholangiocarcinoma. METHODS: Medical records of 73 patients with intrahepatic cholangiocarcinoma were reviewed retrospectively. The pre- and postoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels were assessed. Patient characteristics, clinicopathological factors, and prognostic factors were analyzed. RESULTS: The median recurrence-free survival and overall survival were 30.0 and 90.9 months, respectively. A multivariate survival analysis revealed that elevated postoperative carbohydrate antigen 19-9 (p = 0.023) was the only independent poor prognostic factor. The median overall survival of patients with normal and elevated postoperative carbohydrate antigen 19-9 levels was 101.4 and 15.7 months (p < 0.001), respectively. Multivariate logistic regression identified elevated preoperative carbohydrate antigen 19-9 as an independent preoperative risk factor for elevated postoperative carbohydrate antigen 19-9. The optimal cutoff value of preoperative carbohydrate antigen 19-9 for predicting elevated postoperative carbohydrate antigen 19-9 was 40 U/mL, with a sensitivity and specificity of 92% and 87%, respectively (area under curve = 0.915). CONCLUSIONS: Elevated postoperative carbohydrate antigen 19-9 was an independent poor prognostic factor. Preoperative predictors, such as elevated preoperative carbohydrate antigen 19-9, may indicate the need for neoadjuvant therapies to improve the survival.

Moderate Splenic Injury Caused by Colonoscopy.

Little is known about iatrogenic splenic injury (SI) as an adverse event after colonoscopy. SI is sometimes fatal because of hemorrhaging. We herein report a man who developed SI after colonoscopy. He recovered conservatively. His history of left hydronephrosis and insertion with a maximally stiffened scope were suspected as possible risk factors. Endoscopists should consider the possibility of SI when they encounter patients suffering from left-sided abdominal pain after colonoscopy. Careful interview concerning the medical history and gentle maneuvering around the splenic flexure can help avoid SI.

Fulminant necrotizing fasciitis by Edwardsiella tarda in a patient with alcoholic liver cirrhosis: A case report.

We herein present a unique and extremely rare fulminant case of Edwardsiella tarda infection-related necrotizing fasciitis. The patient had alcoholic cirrhosis and preferred to consume raw fish. He experienced painful swelling of the right forearm one day after he got a minor injury when falling from the ladder, and visited our hospital. His accompanied symptoms were diarrhea and general fatigue. His consciousness got deteriorated after the admission. The lesion of the right forearm had spread and the color had deteriorated with epidermolysis in a few hours. Necrotizing soft-tissue infection was suspected, and emergency debridement of the swollen forearm was performed 4 hours after the admission. However, unfortunately, he died of sepsis approximately 5 hours later. Histological examination of the biopsy specimen revealed features consistent with those of necrotizing fasciitis. The bacterial cultures of blood and the wound identified E. tarda. Since this microorganism is usually isolated from aquatic environments and can cause intestinal infection, sometimes followed by bacteremia especially in immunocompromised hosts, two possible infection routes were suspected. One route was from the skin injury, leading to bacteremia. Another possible route was per oral: orally taken E. tarda invaded deeper tissues from the intestine and reach the bloodstream, leading to extraintestinal infections, although direct evidence remains elusive. Raw fish eaten 1 week prior is considered to be the most possible contaminated food. Overall mortality rate of E. tarda bacteremia is very high and the clinician should pay attention on characteristic clinical findings of E. tarda infection on cirrhotic patients.

Impact of a new liver immune status index among patients with hepatocellular carcinoma after initial hepatectomy.

Aim: The anti-tumor effects of natural killer (NK) cells vary among individuals. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressed on liver NK cells is a marker of anti-tumor cytotoxicity against hepatocellular carcinoma (HCC) in immune cell therapy. This study aimed to develop a liver immune status index (LISI) that predicts low TRAIL expression and validates its ability to predict recurrence after initial hepatectomy for primary HCC. Methods: A functional analysis of liver NK cells co-cultured with interleukin-2 for 3 days was performed of 40 liver transplant donors. The LISI, which predicted low TRAIL expression (25% quartile: <33%) in liver NK cells, was calculated using multiple logistic regression analysis. Next, 586 initial hepatectomy cases were analyzed based on the LISI. Results: Our model was based on the Fibrosis-4 index+0.1 (odds ratio [OR], 1.33), body mass index (OR, 0.61), and albumin levels+0.1 (OR, 0.54). The area under the receiver operating characteristic curve (AUC) of the LISI for low TRAIL expression was 0.89. Stratification of the recurrence rates (RR) revealed that LISI was an independent predictive factor of RR (moderate risk: hazard ratio, 1.44; high risk: hazard ratio, 3.02). The AUC was similar for the LISI, albumin-indocyanine green evaluation grade, albumin-bilirubin score, and geriatric nutritional risk index for predicting RR. Among the vascular invasion cases, the LISI was more useful than the other indexes. Conclusion: Our model facilitates the prediction of RR in high-risk patients by providing LISI to predict the anti-tumor effects of NK cells.

Efficacy and safety of lenvatinib-transcatheter arterial chemoembolisation sequential therapy followed by surgical resection for intermediate-stage hepatocellular carcinoma beyond Up-to-7 criteria: a study protocol for a multicentre, single-arm, prospective study.

INTRODUCTION: The feasibility and efficacy of surgical resection following systemic therapy for intermediate-stage hepatocellular carcinoma (HCC) beyond the Up-to-7 criteria is unclear. The combination of lenvatinib (LEN) and transcatheter arterial chemoembolisation (TACE), termed LEN-TACE sequential therapy, has shown a high response rate and survival benefit in patients with intermediate-stage HCC. This trial aims to evaluate the efficacy and safety of LEN-TACE sequential therapy and the feasibility of surgical resection for intermediate-stage HCC beyond the Up-to-7 criteria. METHODS AND ANALYSIS: This is a multicentre, single-arm, prospective clinical trial. Thirty patients with intermediate-stage HCC beyond the Up-to-7 criteria will be enrolled. Patients eligible for this study will undergo LEN-TACE sequential therapy in which LEN is administered for 4 weeks, followed by TACE, and then further LEN for another 4 weeks. Patients will be assessed for efficacy of LEN-TACE sequential therapy and resectability, and surgical resection will be performed if the HCC is considered radically resectable. The primary outcome of this study is the resection rate after LEN-TACE sequential therapy. The secondary outcomes are the objective response rate of LEN-TACE sequential therapy, safety, curative resection rate, overall survival and recurrence-free survival. ETHICS AND DISSEMINATION: This trial was approved by the Institutional Review Board of Hiroshima University, Japan (approval no. CRB210003), and has been registered with the Japan Registry of Clinical Trials (jRCTs061220007). The results of this study will be submitted for publication in a peer-reviewed journal and shared with the scientific community at international conferences. TRIAL REGISTRATION NUMBER: jRCTs061220007 (https://jrct.niph.go.jp/latest-detail/jRCTs061220007).

Preoperative percutaneous or transvascular marking for curative resection of small liver tumours with potential for missing during hepatectomy: a study protocol for an open-label, single-arm phase II study.

INTRODUCTION: Small liver tumours are difficult to identify during hepatectomy, which prevents curative tumour excision. Preoperative marking is a standard practice for small, deep-seated tumours in other solid organs; however, its effectiveness for liver tumours has not been validated. The objective of this study is to evaluate the effectiveness of preoperative markings for curative resection of small liver tumours. METHODS AND ANALYSIS: This is an open-label, single-arm, single-centre, phase II study. Patients with liver tumours of ≤15 mm requiring hepatectomy will be enrolled and will undergo preoperative marking by placing a microcoil near the tumour using either the percutaneous or transvascular approach. The tumours, including the indwelling markers, will be excised. The primary endpoint will be the successful resection rate of liver tumours, defined as achieving a surgical margin of ≥5 mm and ≤15 mm. Secondary endpoints will include the results of preoperative marking and hepatectomy. ETHICS AND DISSEMINATION: Ethical approval for this trial was obtained from the Ethical Committee for Clinical Research of Hiroshima University, Japan. The results will be published at an academic conference or by submitting a paper to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs062220088.

Antidonor T-Cell Responses Are Not Attenuated in Elderly Kidney Transplant Recipients.

OBJECTIVES: Although the number of kidney transplants among elderly patients has been steadily increasing, no specific recommendations have been established for treatment of elderly patients. In general, elderly recipients are considered to be at lower risk of cell rejection and require less intense immunosuppression than younger recipients. However, a recent report from Japan reported that chronic T-cell-mediated rejection was more frequent in elderly living-donor kidney transplant recipients. In this study, we investigated the effects of aging on antidonor T-cell responses in living-donor kidney transplantrecipients. MATERIALS AND METHODS: We retrospectively evaluated 70 adultliving-donor kidney transplantrecipients with negative crossmatches and cyclosporine-based immunosuppressive regimens. To evaluate antidonor T-cell responses, serial mixed lymphocyte reaction assays were performed.We compared results in elderly (≥65 years) versus nonelderly recipients. RESULTS: Regarding donor characteristics, elderly recipients were more likely than nonelderly recipients to receive a transplant from their spouse. The number of mismatches at the HLA-DRB1 loci was significantly higher in the elderly group than in the nonelderly group. As a result, the proportion of patients with antidonor hyporesponsiveness in the elderly group did not increase over the postoperative course. CONCLUSIONS: Antidonor T-cell responses in elderly living-donor kidney transplant recipients were not attenuated over time. Thus, caution is required regarding the imprudent reduction of immunosuppressants in elderly living-donor kidney transplant recipients. A rigorously designed, large-scale, prospective study is required to validate these results.

Heterophile carbohydrate antigen N-glycolylneuraminic acid as a potential biomarker in patients with hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) has a high recurrence rate even after radical hepatectomy. More optimal biomarkers may help improve recurrence and prognosis. METHODS: We investigated whether the oncological properties of N-glycolylneuraminic acid (NeuGc) can participate in the prognosis of HCC. We evaluated the NeuGc antigen (Ag) expression in the HCC tissues and measured the preoperative anti-NeuGc IgG antibodies (Abs) in the sera of the patients with HCC. We compared the clinical characteristics and survival rate in the hepatectomized patients (initial; n = 66, recurrent; n = 34) with and without the NeuGc Ag or Abs. RESULTS: Multivariate analyses showed positive expression of NeuGc Ag in HCC tissues (Odds ratio; initial = 6.3, recurrent = 14.0) and higher titers of preoperative anti-NeuGc Ab (Odds ratio; initial = 4.9; recurrent = 3.8), which could be the predictive factors related to early recurrence. Both the NeuGc Ag-positive and Ab-positive groups in the initial hepatectomized patients exhibited significantly shorter recurrent free survival compared to those in the negative groups. CONCLUSIONS: Our findings suggested that anti-NeuGc Ab titers and NeuGc Ag expression in the HCC tissues can be used as the predictive factors for the postoperative recurrence and prognosis of HCC.

Genetic Polymorphisms in Follicular Helper T Cell-Related Molecules Predispose Patients to De Novo Donor-Specific Antibody Formation After Kidney Transplantation.

BACKGROUND: Risk prediction of de novo donor-specific antibody (dnDSA) formation is crucial for understanding the long-term prognostic impact of kidney transplantation (KT). Recently, follicular helper T (Tfh) cells, a subtype of CD4+ T cells, have been reported to play an important role in dnDSA formation after solid organ transplantation. Given the growing recognition of the importance of Tfh cells in generating a strong humoral immune response, we examined whether polymorphisms in Tfh cell-related molecules were associated with dnDSA formation after KT. METHODS: Eighty-three patients who underwent living-donor KT between January 2013 and February 2020 at Hiroshima University Hospital were included in the study. Six Tfh cell-related molecules (BCL6, CXCR5, CXCL13, ICOS, CD40L, and IL21) that are important for Tfh cell differentiation and maturation in secondary lymphoid tissues were investigated. CTLA4, which is important for Tfh-cell activation, was also investigated. Single nucleotide polymorphisms (SNPs) in the genes for these molecules were detected using Taq Man SNP genotyping and evaluated for their association with dnDSA formation after KT. RESULTS: Of the 83 KT recipients, 8 developed dnDSAs during the observation period. No statistically significant differences were observed in the baseline characteristics between patients with and without dnDSA formation, except for donor age. Among the 7 Tfh cell-related molecules, the incidence of dnDSA formation was associated with CXCR5 and CTLA4 SNPs. Furthermore, combining these 2 SNPs enabled more significant stratification of dnDSA formation. CONCLUSION: Our findings indicate that genetic polymorphisms in Tfh cell-related molecules are predisposing factors for dnDSA formation after KT.

Evaluation of T-Cell Immune Status of Reduced-Dose Cyclosporine and Everolimus Combination Therapy in Kidney Transplant Patients.

BACKGROUND: Kidney transplantation (KT) outcomes have significantly improved with calcineurin inhibitors (CNIs) administration. In recent years, the dose of CNIs has been reduced, and everolimus (EVR) has been used in combination with CNIs to avoid complications from the long-term use of CNIs. However, T-cell immune responses to these protocols have not been fully evaluated. This study evaluated the anti-donor T-cell responses to our CNI-sparing regimen. METHODS: Fifty-five de novo KT patients were enrolled. Three months after KT, the patients were randomly assigned to either the EVR group, which received low-dose cyclosporine (CsA) (n = 28), or the standard-exposure CsA control group (n = 27), which was treated with both mycophenolate mofetil and methylprednisolone. Graft function, adverse events, and immunologic status were evaluated 3 years after KT. Mixed lymphocyte reaction (MLR) assays were performed to evaluate anti-donor T-cell responses in KT patients. RESULTS: Both groups maintained graft function well, but total cholesterol levels tended to increase annually in the EVR group. The incidence of cytomegalovirus (CMV) infection tended to be lower in the EVR group, regardless of the CMV serologic status. Immunologic evaluation by MLR assay showed that anti-donor T-cell responses were adequately maintained in both groups. CONCLUSIONS: EVR starting 3 months after KT can reduce the trough levels of CsA without affecting graft function or compromising the immunosuppressive effects. The EVR combination protocol is expected to reduce CNI toxicity and improve long-term prognosis after KT.

Effectiveness of Thermal Barrier Bag for Prolonged Vascular Anastomosis in Kidney Transplantation.

BACKGROUND: In kidney transplantation (KT), efforts to minimize rewarming and optimize anastomosis time during vascular anastomosis improve graft outcomes. We recently reported the safety and efficacy of a pouch-type thermal barrier bag (TBB) made of elastomer gel to reduce second-warm ischemic injury during vascular anastomosis. We aimed to examine the usefulness of the TBB in prolonged vascular anastomosis in KT performed by young transplant fellows. METHODS: Young transplant fellows performed KT under the supervision of certified transplant surgeons. The kidney graft was placed inside the TBB with an outlet for vessels and preserved during vascular anastomosis. A non-contact infrared thermometer measured the graft surface temperature before and after vascular anastomosis. After completion of the anastomosis, the TBB was manually slid out of the transplanted kidney and removed before graft reperfusion. Clinical data, including patient characteristics and perioperative variables, were collected. The primary endpoint was the median graft surface temperature at the end of the anastomosis. RESULTS: Ten living-donor kidney transplant recipients with a median age of 56.5 years (range, 40-69 years) underwent KT procedures performed by young transplant fellows. The median anastomosis time was 53 (43-67) min. At the end of anastomosis, the median graft surface temperature was 17.7°C (16.3-18.3°C); no serious adverse events or delayed graft function were observed. CONCLUSION: The TBB can keep transplanted kidneys at a low temperature even with prolonged vascular anastomosis time, thus contributing to the functional preservation of transplanted kidneys and stable transplant outcomes.

Arteriosclerosis Decreases Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression on Liver Natural Killer Cells in Living Donor Liver Transplantation.

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is critical for natural killer (NK) cell-mediated anti-tumor and anti-microbe killing. The TRAIL expression on the donor's liver NK cells from the liver perfusate after interleukin-2 stimulation varies between individuals and is unpredictable. This study aimed to clarify the risk factors for low TRAIL expression by analyzing perioperative donor characteristics. METHODS: This retrospective study of living donor liver transplant (LDLT) donors between 2006 and 2022 was performed to analyze low TRAIL expression risk factors. Seventy-five donors who had undergone hepatectomy for LDLT were divided into 2 groups, low and high TRAIL, according to their TRAIL expression on liver NK cells, using median values. RESULTS: The low TRAIL group (N = 38) was older and had lower nutrition and a higher low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, related to arteriosclerosis, than the high TRAIL group (N = 37). In multivariate analysis, the geriatric nutritional risk index (GNRI) (odds ratio, 0.86; 95% CI, 0.76-0.94; P < .001) and LDL/HDL cholesterol ratio (odds ratio, 2.32; 95% CI, 1.10-4.86; P = .005) were independent predictive factors for low TRAIL expression on liver NK cells. Furthermore, the TRAIL expression of liver NK cells decreased in donors who already had atherosclerosis and in donors at risk of potentially developing atherosclerosis. CONCLUSIONS: The TRAIL expression on liver NK cells in donors had a strong relationship with atherosclerosis and GNRI. Atherosclerosis can reflect the TRAIL expression on liver NK cells.