Toshihiro Nakayama

All Publications

• Listing for blood type A2 donors is highly variable and impacts waitlist outcomes among blood type O liver transplantation candidates in the United States. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Nakayama, T., Imaoka, Y., Esquivel, C. O., Sasaki, K. 2025

  Abstract

  Blood type O liver transplantation (LT) candidates in the United States face the highest waitlist mortality due to the broader compatibility of type O grafts. Although blood-type compatible transplant is a gold standard, type O candidates might benefit from listing for A2 donors, whose antigen is known for its decreased immunogenicity. This study examines the trends and impact on waitlist outcomes of listing for A2 donors among 67,756 type O LT candidates listed between 2010 and 2023 using data from the United Network for Organ Sharing database. The number of A2-to-O LTs increased steadily, with 117 LTs performed in 2023. 61.1% of type O candidates were listed for A2 donors, with considerable regional variations. Fine-Gray competing risk analysis revealed that listing for A2 donors was associated with reduced waitlist dropout rates (subdistribution hazard: 0.94, P < 0.001) and increased transplant probabilities (subdistribution hazard: 1.07, P < 0.001), especially in regions with longer wait times, among candidates with listing Model for End-Stage Liver Disease (MELD)-Na scores between 15 and 34, and candidates listed after the Acuity Circles policy implementation. These findings suggest listing for A2 donors should be encouraged to improve waitlist outcomes for type O candidates.

  View details for DOI 10.1016/j.ajt.2025.03.012

  View details for PubMedID 40096944

• Hepatitis C-positive grafts for hepatitis C-negative recipients in liver transplantation: Buried treasure or depleting resource? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Nakayama, T., Krist, D. T., Akabane, M., Imaoka, Y., Esquivel, C. O., Kwong, A. J., Kwo, P. Y., Melcher, M. L., Sasaki, K. 2024

  Abstract

  Long-term outcomes of using hepatitis C virus (HCV) positive donors in HCV-negative recipients in liver transplantation (LT) are not well established. Data from the United Network for Organ Sharing (UNOS) database between July 1, 2015, and December 31, 2023, were analyzed. The cohort included 44,447 HCV antibody-negative (Ab-) candidates who underwent deceased donor LT. Changes in case numbers and utilization rates of HCV-positive donors, divided into HCV-viremic (NAT+) or Ab+ nonviremic (Ab+/NAT-), were assessed. Kaplan-Meier analysis and propensity score matching were used to evaluate 5-year graft survival (GS). The number of HCV-viremic donation after brain death (DBD) donors and their use in LT for HCV Ab- recipients peaked at 640 donors in 2019 and 289 LTs in 2022. In contrast, Ab+ nonviremic DBD donations are rising, with 536 donors and 284 LTs in 2023. The utilization rate of viremic DBD grafts has continuously decreased despite increased willingness by waitlist candidates to accept them. HCV-positive donation after circulatory death (DCD) donors were seldom utilized in the study period. The 5-year GS rates for HCV-viremic, Ab+ nonviremic, and naïve donors were not significantly different in either DBD (p=0.56) or DCD (p=0.52). Furthermore, Ishak stage 2 or 3 fibrotic DBD grafts had similar 5-year GS to non-fibrotic grafts. The findings suggest that the long-term outcome of using HCV-viremic DBD or DCD grafts for HCV-negative recipients is comparable to that of other graft types, and that fibrotic grafts have the potential to expand the DBD donor pool.

  View details for DOI 10.1097/LVT.0000000000000557

  View details for PubMedID 39679922

• Does the introduction of acuity circle policy change split liver transplantation practice? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Nakayama, T., Akabane, M., Imaoka, Y., Esquivel, C. O., Melcher, M. L., Sasaki, K. 2024

  Abstract

  With the Acuity Circles (AC) policy aiming to reduce disparities in liver transplantation (LT) access, the allocation of high-quality grafts has shifted, potentially affecting the use and outcomes of split LT. Data from the United Network for Organ Sharing (UNOS) database (February 4, 2016, to February 3, 2024) were analyzed, including 1,470 candidates who underwent deceased donor split LT, with 681 adult and 789 pediatric cases. The study periods were divided into pre-AC (February 4, 2016, to February 3, 2020) and post-AC (February 4, 2020, to February 3, 2024). The study assessed changes in split LT volumes and examined the impact of center practices. Both adult and pediatric split LTs decreased in the initial three years post-policy change, followed by an increase in the final year, with an overall 11.9% and 13.9% decrease between the eras. Adult female split LT cases remained consistent, ensuring access for smaller recipients. High-quality "splittable" livers were increasingly allocated to high MELD patients (MELD-Na ≥30). Despite the overall decrease in case volume, adult split LT volume increased in newly active LDLT centers, with six centers increasing LDLT volume by over 50.0%. Pediatric split LT volumes decreased despite additional priorities for pediatric candidates. The number of split LTs decreased in the initial period after the AC policy introduction, but there was a consistent need for small female candidates. In the adult population, LDLT and split LT demonstrated a synergistic effect in boosting center transplant volumes, potentially improving access for female candidates who need small grafts.

  View details for DOI 10.1097/LVT.0000000000000513

  View details for PubMedID 39412327

• Out of Sequence Allocation in Liver Transplantation: A Poorly Used Tool to Improve Organ Utilization. Annals of surgery Wehrle, C. J., Gross, A., Satish, S., Shanmugarajah, K., Nakayama, T., Fleischer, C. M., Sheetz, K., Aucejo, F., Sasaki, K., Kwon, D. C., Fujiki, M., Pinna, A. D., Miller, C., Hashimoto, K., Schlegel, A., Wakam, G. K. 2025

  Abstract

  We evaluated the impact of OOS on organ utilization and also what factors impact the decision to employ OOS.Deceased donor liver allocation typically follows a ranked match-run of potential recipients. Organ procurement organizations (OPOs) may deviate from liver transplant standardized allocation using "out-of-sequence" (OOS) matches.All eligible donors from the Scientific Registry of Transplant Recipients (SRTR) (1/1/2013-8/31/2023) were identified and merged with associated match-runs in the Potential Transplant Recipient (PTR) data. OOS offers were defined as bypass codes (861-863; 760-765). Hierarchical mixed-effects models with eligible donors nested in OPOs assessed OOS-practices versus organ utilization, controlling for liver graft risk with the Discard Risk Index (DSRI) by risk quintile, blood type, and year.OOS were more common each progressive year. Neither TC's (R2<0.01) nor OPO's (R2<0.01) OOS-rate correlated with increased utilization. OOS was not associated with improved utilization (OR=1.11, 95%CI=0.90-1.38). Increasing graft risk in DBD&DCD grafts was associated with reduced utilization. Introducing OOS-allocation interaction terms improved utilization for DCD's of all risk levels but only improved utilization for DSRI 5th-Quintile DBD's. 38% of utilization was explained by graft factors versus 5% by TC-&OPO-variability (Conditional-R2=0.431, Marginal-R2=0.380). High-risk DCD grafts in DSRI 3rd-5th-Quintiles were not more likely to be allocated through OOS despite these grafts demonstrating improved utilization with this approach. Only 15% of variation in OOS-allocation was explained by graft factors versus 23% by TC-and OPO-variability (Conditional R2=0.388, Marginal R2=0.154).OOS improves utilization in high-risk grafts, but graft risk is not correlated with their actual use. This highlights utility in OOS, but also that this practice is currently incorrectly used.

  View details for DOI 10.1097/SLA.0000000000006738

  View details for PubMedID 40255174

• Geospatial analysis of liver donation after death by drug intoxication. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kadri, H., Handley, T. J., Nakayama, T., Sasaki, K., Melcher, M. L. 2025

  Abstract

  Increases in deaths from drug intoxication in the United States could be contributing to more liver donations. This study investigates regional variation in liver donation following death by drug intoxication over a decade.The number of drug intoxication-related deaths in the continental United States (2011-2020) was collected from CDC WONDER. Reports from UNOS provided the number of liver donors who died of drug intoxication over the decade. County-level ratios of liver donors after drug intoxication to the total number of drug intoxication-related deaths were calculated. Missed donation opportunities were quantified by comparing the actual number of donors to the hypothetical number if all counties achieved the efficiency of counties in the 90th and 50th percentiles. Regression analysis was used to assess the relationship between missed opportunities for liver donation per drug intoxication-related death and county-level variables.County-level proportions of liver donors after drug intoxication to all eligible drug intoxications ranged from 0 to 0.600. If every county matched the efficiency of the 90th and 50th percentile county, the liver donor pool could grow by 7572 or 1550 donors over the decade, respectively. The national rate of missed opportunities for liver donation per death by drug intoxication was 0.114 or 0.022 depending on whether the 90th or 50th percentile donation ratio was used in calculation. The number of missed donations per drug intoxication increased with higher social vulnerability, distance from a trauma center, and rural county status. Conversely, it decreased as the rate of deaths by drug intoxication rose.Assessing liver donation following drug intoxication allows for targeted efforts to increase donations in regions with the greatest potential for improvement.

  View details for DOI 10.1097/LVT.0000000000000618

  View details for PubMedID 40167364

• Pathological complete response after chemotherapy in initially unresectable distal cholangiocarcinoma. Clinical journal of gastroenterology Nakayama, T., Nakano, H., Matsushita, R., Hayakawa, T., Takagi, S., Tanaka, Y., Ozaki, T., Matsushita, T., Sumi, Y., Takagi, M. 2025; 18 (2): 357-362

  Abstract

  Surgical resection is the only curative treatment for cholangiocarcinoma, but it is often diagnosed at advanced stages, making surgical resection infeasible. Recently, the concept of conversion surgery has expanded the indications for surgical treatment, thanks to advancements in both perioperative management and chemotherapy. However, it remains unclear which patients benefit most from this treatment strategy. We present a case of initially unresectable cholangiocarcinoma in which a pathologic complete response was achieved following chemotherapy. A man in his seventies presented with jaundice and was referred to our hospital. Abdominal computed tomography revealed dilation of the intrahepatic bile ducts and thickening of the common bile duct, suggestive of distal cholangiocarcinoma. The tumor was initially unresectable due to metastatic para-aortic lymph nodes, and chemotherapy with gemcitabine and cisplatin was initiated. After six courses of chemotherapy, the lymph nodes showed a partial response, and tumor markers returned to normal levels. However, further chemotherapy was intolerable due to thrombocytopenia. Our cancer board then decided to perform a pancreaticoduodenectomy. Pathologic examination of the resected specimen showed complete disappearance of the primary tumor, but viable cancer cells were found in the resected lymph nodes. Seven months post-surgery, recurrence in the para-aortic nodes was detected through imaging and elevated tumor markers. Despite this, the patient remains alive 16 months post-surgery with normal tumor marker levels, following additional chemotherapy. Pathologic complete response of the primary tumor is rarely observed in patients with initially unresectable distal cholangiocarcinoma, and a multidisciplinary approach, including conversion surgery, may be effective in such cases.

  View details for DOI 10.1007/s12328-024-02084-w

  View details for PubMedID 39731697

  View details for PubMedCentralID PMC11922966

• Mixed neuroendocrine-non-neuroendocrine neoplasm of the colon treated with laparoscopic resection and adjuvant chemotherapy: a case report. Clinical journal of gastroenterology Tanaka, Y., Takagi, M., Nakayama, T., Kawada, S., Matsushita, R., Matsushita, T., Ozaki, T., Takagi, S., Komai, S., Sumi, Y. 2025; 18 (2): 314-323

  Abstract

  Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) of the colon is rare with a poor prognosis. Since the first description of a mixed neoplasm 100 years ago, the nomenclature has evolved, most recently with the 2022 World Health Organization (WHO) classification system. We describe our experience of a case of locoregionally advanced MiNEN of the descending colon treated with curative laparoscopic resection and adjuvant chemotherapy. The patient is a 72 year old woman who presented with haematochezia. Initial clinical diagnosis was poorly differentiated adenocarcinoma of the descending colon, cT2N0M0, cStage I. Laparoscopic partial colectomy of the descending colon with D3 lymph node dissection and intracorporeal overlap anastomosis was performed. The pathological diagnosis however, returned mixed adenocarcinoma-neuroendocrine carcinoma (MANEC) of the descending colon, pT4aN1bM0, pStage IIIB, a subgroup of MiNEN: 70% was neuroendocrine carcinoma (NEC), whilst poorly differentiated mucinous carcinoma constituted 30% of the tumour. She completed 4 courses of irinotecan plus cisplatin (IP) adjuvant chemotherapy and is currently recurrence-free at postoperative year 2. The clinical course of MiNEN depends on the biology of the two components, both of which must be pathologically characterised. Even quantitatively discrete components should be carefully subtyped as their prognostic relevance is undetermined.

  View details for DOI 10.1007/s12328-024-02089-5

  View details for PubMedID 39799545

  View details for PubMedCentralID 3712682

• Time to Expand Selection Criteria for MELD Exception Points in Liver Transplantation for Hepatocellular Carcinoma. Transplantation Wehrle, C. J., Kusakabe, J., Nakayama, T., Miller, C., Hashimoto, K., Pawlik, T. M., Sasaki, K., Mazzaferro, V., Schlegel, A., Aucejo, F. 2025

  View details for DOI 10.1097/TP.0000000000005396

  View details for PubMedID 40128166

• Exploring the Viability of Matching Marginal Donors With Low Renal Function Recipients in Liver Transplantation. Clinical transplantation Akabane, M., Imaoka, Y., Nakayama, T., Esquivel, C. O., Sasaki, K. 2025; 39 (3): e70123

  Abstract

  BACKGROUND: Renal function varies among liver transplantation (LT) candidates with the same Model for End-Stage Liver Disease (MELD)3.0 score. The impact of marginal grafts on post-LT renal function and prognosis varies based on the pre-LT renal function. We explored the effects of matching recipients with low renal function to marginal donors on graft survival (GS) and post-LT kidney function.METHODS: We analyzed data from the Scientific Registry of Transplant Recipients (SRTR), categorizing pre-LT renal function by estimated glomerular filtration rate (eGFR) into low (<30mL/min/1.73m2) and high (≥30mL/min/1.73m2). Marginal donors were defined by criteria including donation after cardiac death, age ≥65, severe macrosteatosis (≥30%), or body mass index≥40kg/m2. The primary outcome was to compare 3-year post-LT GS between patients with low and high pre-LT renal function. Additionally, we examined post-LT eGFR 1-3 months post-LT.RESULTS: Of 13279 LT recipients, 12851 had high pre-LT eGFR and 428 had low pre-LT eGFR. Kaplan-Meier survival analysis showed that recipients with low pre-LT eGFR had significantly lower 3-year GS compared to those with high eGFR (p<0.01). Recipients of organs from marginal donors also exhibited a significant reduction in 3-year GS (p<0.01). This adverse effect persisted within the same MELD3.0 category. Additionally, lower pre-LT eGFR was associated with an increased risk of post-LT kidney function deterioration, especially among those receiving grafts from marginal donors. Multivariable logistic regression identified recipient age>65 as a significant risk factor for post-LT kidney function decline (OR 3.34 [1.05-10.7]; p = 0.03).DISCUSSION: GS was notably worse in recipients with low pre-LT eGFR, particularly when matched with marginal donors. A recipient age>65 is a risk indicator for post-LT kidney function deterioration with marginal donors, underscoring the importance of careful donor-recipient matching, especially with compromised pre-LT kidney function.

  View details for DOI 10.1111/ctr.70123

  View details for PubMedID 40062522

• Effect of sarcopenia on the survival of patients undergoing liver transplantation: a meta-analysis. Surgery today Akabane, M., Imaoka, Y., Nakayama, T., Esquivel, C. O., Sasaki, K. 2025

  Abstract

  PURPOSE: The relationship between sarcopenia and post-liver transplant (LT) mortality is still not well understood. This study aims to provide an updated and comprehensive meta-analysis evaluating the impact of sarcopenia on the survival of LT patients.METHODS: We conducted searches in PubMed, Web of Science, and EMBASE up until May 2, 2024, without language restrictions. The primary outcome measured was the overall post-LT mortality risk associated with sarcopenia. The DerSimonian-Laird random effects model was used to calculate pooled adjusted hazard ratios (HRs).RESULTS: Eighteen cohort studies comprising a total 6297 LT patients were included. The overall prevalence of sarcopenia was 27% (95% CI: 26%-28%), and this rate was lower when sarcopenia was defined using the third lumbar-skeletal muscle index in men, and among patients with lower Child-Pugh class. Sarcopenia remained significantly associated with higher mortality, with a pooled adjusted HR of 1.55 (95% CI 1.28-1.89). This association held across subgroups based on sex, study location, sarcopenia definition, study quality, and living donor LT recipients. A sensitivity analysis excluding groups with a high proportion of hepatocellular carcinoma patients showed similar findings (HR 1.63, 95% CI 1.13-2.35). No significant heterogeneity was identified in any of the analyses.CONCLUSIONS: This meta-analysis shows that sarcopenia is significantly associated with increased mortality after LT. Thus, the risk of sarcopenia should be factored into the initial evaluation of LT candidates.

  View details for DOI 10.1007/s00595-025-03008-y

  View details for PubMedID 39928119

• Cluster analysis of hepatocellular carcinoma prognosis using preoperative alpha-fetoprotein and des-gamma-carboxy prothrombin levels: a multi-institutional study. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract Saegusa, Y., Imaoka, Y., Ohira, M., Kobayashi, T., Honmyo, N., Hamaoka, M., Onoe, T., Takei, D., Oishi, K., Abe, T., Nakayama, T., Akabane, M., Sasaki, K., Ohdan, H. 2025; 29 (4): 101980

  Abstract

  Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related mortality worldwide and is characterized by high recurrence rates after curative resection. The tumor markers des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are crucial for HCC diagnosis and prognosis. However, their roles in the modern era of HCC epidemiology require reevaluation.This multi-institutional retrospective study analyzed 1515 patients who underwent hepatectomy for primary HCC. Patients were classified into 4 clusters using k-means analysis based on preoperative DCP and AFP levels. Clinicopathologic characteristics, overall survival (OS), and recurrence rate (RR) were evaluated using Cox proportional hazards models and area under the receiver operating characteristic curve (AUROC) comparisons.Cluster 3 (concurrent elevations of DCP and AFP) had the poorest 5-year OS (52.8%) and the highest RR (79.3%), whereas cluster 4 (low levels of both markers) had the most favorable outcomes, with a 5-year OS rate of 71.5% and an RR of 55.7%. Cluster 1 (elevated DCP alone) was associated with larger tumors (median of 45 mm) and more frequent vascular invasion (43%) than cluster 2 (elevated AFP alone, median tumor size of 24 mm, and vascular invasion of 36%). DCP was a stronger predictor of 5-year OS in patients with preserved liver function (AUROC, 0.63), whereas AFP was more effective in stratifying RR in patients with impaired liver function (AUROC, 0.57). Non-B, non-C hepatitis (NBNC)-related HCC exhibited a distinct biomarker profile, with an elevated DCP level correlating with a higher 5-year RR (67%) than other etiologies.Our study introduces tumor marker clustering as a novel analytical approach, providing a nuanced understanding of AFP and DCP's combined utility in predicting prognosis and recurrence. Our findings highlight the independent and complementary roles of these biomarkers, particularly in NBNC-related HCC and in cases with impaired liver function. AFP and DCP remain crucial tools for recurrence risk assessment, guiding personalized management strategies, such as surveillance, neoadjuvant therapies, and tailored postoperative interventions.

  View details for DOI 10.1016/j.gassur.2025.101980

  View details for PubMedID 39884550

• The urgent need for standardization in liver transplantation for unresectable colorectal liver metastases in the United States Chavez-Villa, M., Sasaki, K., Nakayama, T., Byrne, M., Jimenez-Soto, C., Ruffolo, L., Endo, Y., Dokus, K., Tomiyama, K., Wall, A., Hernandez-Alejandro, R. ELSEVIER SCIENCE INC. 2025

  View details for Web of Science ID 001460906400112

• Long-term outcomes of pediatric hepatoblastoma patients who present with metastasis and receive liver transplantation Pan, J., Nakayama, T., Samreth, S., Marshall, A., Sasaki, K. ELSEVIER SCIENCE INC. 2025

  View details for Web of Science ID 001460906400016

• The impact of sex and body mass index in liver transplantation for acute-on-chronic liver failure. Journal of hepato-biliary-pancreatic sciences Akabane, M., Imaoka, Y., Nakayama, T., Esquivel, C. O., Sasaki, K. 2024

  Abstract

  There have been no studies evaluating how body mass index (BMI) impacts on waitlist and post-liver transplant (LT) mortality in acute-on-chronic liver failure (ACLF) by sex. We aimed to determine these impacts using the United Network for Organ Sharing (UNOS) database.Adults listed for LT with estimated ACLF (Est-ACLF) (2005-2023) were identified and subdivided by sex and BMI (high/middle/low). Competing-risk analyses evaluated impacts on waitlist mortality. Kaplan-Meier analyses assessed post-LT survival. Multivariable Cox regression identified risk factors.Of 37 251 Est-ACLF patients, 14 534 (39.0%) were female. Females had higher 90-day waitlist mortality than males (subhazard ratio [sHR]: 1.20, p < .01). High/low BMI patients had higher mortality than middle (sHR: 1.08/1.11, p < .01). In females, high BMI was associated with higher mortality than low (sHR: 1.10, p = .02); in males, low BMI was associated with higher mortality than high/middle (sHR: 1.16/1.16 vs. high/middle, p < .01). Multivariable analyses showed in females, high BMI was a significant risk factor for waitlist mortality (sHR:1.21, p < .01), while low was not; in males, high/low BMI was significant, with low having higher sHR (1.17) than high (1.09). Post-LT survival showed no significant difference in females; in males, low BMI showed worse post-3-/5-year-LT survival (p < .01). Multivariable Cox regression showed for females, neither low nor high BMI was significant for post-LT survival; for males, low BMI was significant for 1-/3-/5-year-LT survival (HR: 1.30/1.30/1.22, p < .01).Our analysis of BMI's impact on LT outcomes in ACLF by sex enables risk stratification and provides a basis for adjusting BMI.

  View details for DOI 10.1002/jhbp.12100

  View details for PubMedID 39727045

• Revisiting the Prognostic Influences of Donor-Recipient Size Mismatch in Deceased Donor Liver Transplantation. Transplantation direct Nakayama, T., Akabane, M., Imaoka, Y., Esquivel, C. O., Melcher, M. L., Sasaki, K. 2024; 10 (11): e1722

  Abstract

  Background: Liver transplantation (LT) outcomes are influenced by donor-recipient size mismatch. This study re-evaluated the impact on graft size discrepancies on survival outcomes.Methods: Data from 53389 adult LT recipients from the United Network for Organ Sharing database (2013-2022) were reviewed. The study population was divided by the body surface area index (BSAi), defined as the ratio of donor body surface area (BSA) to recipient BSA, into small-for-size (BSAi<0.78), normal-for-size (BSAi 0.78-1.24), and large-for-size (BSAi>1.24) grafts in deceased donor LT (SFSD, NFSD, and LFSD). Multivariate Cox regression and Kaplan-Meier survival analyses were conducted.Results: The frequency of size mismatch in deceased donor LT increased over the past 10 y. SFSD had significantly worse 90-d graft survival (P<0.01), and LFSD had inferior 1-y graft survival among 90-d survivors (P=0.01). SFSD was hazardous within 90 d post-LT because of vascular complications. Beyond 1 y, graft size did not affect graft survival. LFSD risk within the first year was mitigated with lower model for end-stage liver disease (MELD) 3.0 scores (<35) or shorter cold ischemia time (<8h).Conclusions: The negative impacts on donor-recipient size mismatch on survival outcomes are confined to the first year post-LT. SFSD is associated with a slight decrease in 90-d survival rates. LFSD should be utilized more frequently by minimizing cold ischemia time to <8h, particularly in patients with MELD 3.0 scores below 35. These findings could improve donor-recipient matching and enhance LT outcomes.

  View details for DOI 10.1097/TXD.0000000000001722

  View details for PubMedID 39440201

• Evaluation of prognostic efficacy of liver immune status index in predicting postoperative outcomes in hepatocellular carcinoma patients: A multi-institutional retrospective study. Journal of hepato-biliary-pancreatic sciences Imaoka, Y., Ohira, M., Kobayashi, T., Honmyo, N., Hamaoka, M., Onoe, T., Takei, D., Oishi, K., Abe, T., Nakayama, T., Akabane, M., Sasaki, K., Ohdan, H. 2024

  Abstract

  Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths globally. Despite treatment advances, high post-hepatectomy recurrence rates (RR), especially with liver fibrosis and hepatitis C virus infection, remain challenging. Key prognostic factors include vascular invasion and perioperative blood loss, impacting extrahepatic recurrence. Natural killer (NK) cells are crucial in countering circulating tumor cells through TRAIL-mediated pathways. The aim of this study was to validate the liver immune status index (LISI) as a predictive tool for liver NK cell antitumor efficiency, particularly in HCC patients with vascular invasion.A retrospective analysis of 1337 primary HCC hepatectomies was conducted by the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). Clinicodemographic data were extracted from electronic medical records. Prognostic indices (FIB-4, ALBI, ALICE, GNRI, APRI, and LISI) were evaluated using area under the receiver operating characteristic curve values. Survival analyses employed Kaplan-Meier estimations and log-rank tests.LISI significantly correlated with other prognostic markers and stratified patients into risk groups with distinct overall survival (OS) and RR. It showed superior predictive performance for 2-year OS and RR, especially in patients with vascular invasion. Over longer periods, APRI and FIB-4 index reliabilities improved. The HISCO-HCC score, combining LISI, tumor burden score, and alpha-fetoprotein levels, enhanced prognostic accuracy.LISI outperformed existing models, particularly in HCC with vascular invasion. The HISCO-HCC score offers improved prognostic precision, guiding immunotherapeutic strategies and individualized patient care in HCC.

  View details for DOI 10.1002/jhbp.12070

  View details for PubMedID 39313837

• Advanced viability assessment in machine perfusion: what lies ahead? EBioMedicine Nakayama, T., Sasaki, K. 2024; 108: 105351

  View details for DOI 10.1016/j.ebiom.2024.105351

  View details for PubMedID 39278109

• Comment on "Age Matters: What Affects the Cumulative Lifespan of a Transplanted Liver?". Annals of surgery open : perspectives of surgical history, education, and clinical approaches Akabane, M., Imaoka, Y., Nakayama, T., Sasaki, K. 2024; 5 (3): e475

  View details for DOI 10.1097/AS9.0000000000000475

  View details for PubMedID 39310331

  View details for PubMedCentralID PMC11415112

• Effect of transjugular intrahepatic portosystemic shunt insertion on waitlist mortality and access to liver transplantation in budd-chiari syndrome. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Akabane, M., Imaoka, Y., Nakayama, T., Esquivel, C. O., Sasaki, K. 2024

  Abstract

  BACKGROUND: The impact of transjugular intrahepatic portosystemic shunt (TIPS) on waitlist mortality and liver transplantation (LT) urgency in Budd-Chiari Syndrome (BCS) patients remains unclear.METHOD: We analyzed BCS patients listed for LT in the UNOS database(2002-2024) to assess TIPS's impact on waitlist mortality and LT access via competing-risk analysis. We compared trends across two phases:Phase1(2002-2011) and Phase2(2012-2024).RESULTS: Of 815 BCS patients, 263(32.3%) received TIPS at listing. TIPS group had lower MELD-Na scores(20vs22,p<0.01), milder ascites(p=0.01), and fewer Status1 patients(those at risk of imminent death while awaiting LT)(2.7%vs8.3%,p<0.01) at listing compared to those without TIPS. TIPS patients had lower LT rates(43.3%vs56.5%,p<0.01) and longer waitlist times(350vs113d,p<0.01). TIPS use increased in Phase2(64.3%vs35.7%,p<0.01). Of 426 transplanted patients, 134(31.5%) received TIPS, showing lower MELD-Na scores(24vs27,p<0.01) and better medical conditions(Intensive care unit:14.9%vs21.9%,p<0.01) at LT. Status1 patients were fewer (3.7%vs12.3%,p<0.01), with longer waiting days(97vs26d,p<0.01) in TIPS group. TIPS use at listing increased from Phase1(25.6%) to Phase2(37.7%). From Phase1 to Phase2, ascites severity improved, re-LT cases decreased(Phase1:9.8%vsPhase2:2.2%,p<0.01), and cold ischemic time slightly decreased(Phase1:7.0vsPhase2:6.4 hours,p=0.14). Median donor body mass index significantly increased. No significant differences were identified in patient/graft survival at 1-/5-/10-year intervals between phases or TIPS/non-TIPS patients. While 90-day waitlist mortality showed no significant difference(p=0.11), TIPS trended towards lower mortality(subHazard ratio[sHR]:0.70[0.45-1.08]). Multivariable analysis indicated that TIPS was a significant factor in decreasing mortality(sHR:0.45[0.27-0.77],p<0.01). TIPS group also showed significantly lower LT access(sHR:0.65[0.53-0.81],p<0.01). Multivariable analysis showed that TIPS was a significant factor in decreasing access to LT(sHR:0.60[0.46-0.77],p<0.01). Sub-group analysis excluding Status1 or HCC showed similar trends.CONCLUSION: TIPS in BCS patients listed for LT reduces waitlist mortality and LT access, supporting its bridging role.

  View details for DOI 10.1097/LVT.0000000000000469

  View details for PubMedID 39177578

• Interleukin-33 and liver natural killer cells: A novel perspective on antitumor activity in liver fibrosis. Hepatology research : the official journal of the Japan Society of Hepatology Imaoka, Y., Ohira, M., Imaoka, K., Bekki, T., Nakano, R., Yano, T., Tanaka, Y., Nakayama, T., Akabane, M., Tajima, T., Yokota, S., Krams, S. M., Martinez, O. M., Esquivel, C. O., Sasaki, K., Ohdan, H. 2024

  Abstract

  Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway.Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl4)-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity.The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence.Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis.

  View details for DOI 10.1111/hepr.14102

  View details for PubMedID 39134448

• Pancreaticoduodenectomy after bilirubin adsorption for distal cholangiocarcinoma with severe obstructive jaundice refractory to repeat preoperative endoscopic biliary drainage: a case report. Clinical journal of gastroenterology Nakayama, T., Ito, K., Nakamura, M., Inagaki, F., Katagiri, D., Yamamoto, N., Mihara, F., Takemura, N., Kokudo, N. 2024; 17 (4): 711-716

  Abstract

  The necessity of biliary drainage before pancreaticoduodenectomy remains controversial in cases involving malignant obstructive jaundice; however, the benefits of biliary drainage have been reported in cases with severe hyperbilirubinemia. Herein, we present the case of a 61-year-old man suffering from jaundice due to distal cholangiocarcinoma. In this case, obstructive jaundice was refractory to repeat endoscopic drainage and bilirubin adsorption. Hyperbilirubinemia persisted despite successful implementation of biliary endoscopic sphincterotomy and two rounds of plastic stent placements. Stent occlusion and migration were unlikely and oral cholagogues proved ineffective. Owing to the patient's surgical candidacy and his aversion to nasobiliary drainage due to discomfort, bilirubin adsorption was introduced as an alternative therapeutic intervention. Following repeated adsorption sessions, a gradual decline in serum total bilirubin levels was observed and pancreaticoduodenectomy was scheduled. The patient successfully underwent pancreaticoduodenectomy with portal vein resection and reconstruction and D2 lymph node dissection. After the surgery, the serum bilirubin levels gradually decreased and the patient remained alive, with no recurrence at 26 months postoperatively. Therefore, this case highlights the feasibility and safety of performing pancreaticoduodenectomy in patients with severe, refractory jaundice who have not responded to repeated endoscopic interventions and have partially responded to bilirubin adsorption.

  View details for DOI 10.1007/s12328-024-01966-3

  View details for PubMedID 38589719

  View details for PubMedCentralID 6232618

• Evaluating Predictors of Quality in Liver NK Cells Among Deceased Donors. Cell transplantation Imaoka, Y., Ohira, M., Nakayama, T., Akabane, M., Tajima, T., Yokota, S., Krams, S. M., Martinez, O. M., Esquivel, C. O., Sasaki, K., Ohdan, H. 2024; 33: 9636897241283289

  Abstract

  This study investigated the substantial variability in the quality of liver natural killer (NK) cells from deceased donors (DDs). This study assessed liver nonparenchymal cells from 51 DDs for activation receptors and cytotoxicity against K562 (leukemia) and HepG2 (hepatoma) cell lines. The results indicated variability in TNF-related apoptosis-inducing ligand (TRAIL) and NK stimulatory receptor NK group 2 member D (NKG2D) expression in liver NK cells from DDs, which correlated with cytotoxicity against tumor cell lines. In addition, the white blood cell (WBC) count, aspartate aminotransferase (AST) level, body mass index (BMI), and platelet count were significantly associated with enhanced TRAIL and NKG2D expression. A predictive score integrating AST/platelet ratio index, BMI, and WBC count was developed to effectively identify DDs with high antitumor activity in liver NK cells. This score is expected to predict DDs with high-quality liver NK cells, which can be used for the purpose of immunotherapies.

  View details for DOI 10.1177/09636897241283289

  View details for PubMedID 39907091

• Pheochromocytoma Crisis Rescued by Veno-Arterial Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy. The American surgeon Nakayama, T., Ito, K., Inagaki, F., Miyake, W., Katagiri, D., Mihara, F., Takemura, N., Kokudo, N. 2023; 89 (6): 2857-2860

  Abstract

  Pheochromocytoma is a rare catecholamine producing adrenal tumor. Pheochromocytoma crisis is a life-threatening condition inducing multiple organ failure and hemodynamic instability caused by too much catecholamines produced from pheochromocytoma. We report a 59-year-old woman with pheochromocytoma crisis rescued by veno-arterial extracorporeal membrane oxygenation (VA-ECMO), continuous renal replacement therapy (CRRT), and interval tumor resection. In June 2020, the patient was taken to our institution complaining of headache and left lower back pain. The patient developed cardiopulmonary arrest while at the emergency department. After extracorporeal cardiopulmonary resuscitation, the patient required VA-ECMO for hemodynamic support, and subsequently CRRT for catecholamine removal and acute kidney injury. After 1 month of hemodynamic management, the patient underwent left adrenalectomy. The postoperative course was uneventful and she was discharged on postoperative day 23. CRRT would be a safe and feasible option for catecholamine control in patients with acute kidney injury in pheochromocytoma crisis.

  View details for DOI 10.1177/00031348211063573

  View details for PubMedID 34962830

• Repeat hepatectomy for massive liver metastases from pheochromocytoma: a case report. Clinical journal of gastroenterology Nakayama, T., Ito, K., Inagaki, F., Kobayashi, M., Tanabe, A., Mihara, F., Takemura, N., Kokudo, N. 2023; 16 (3): 457-463

  Abstract

  In malignant pheochromocytoma, the survival benefit of metastasectomy remains unclear. However, excessive catecholamines secreted from pheochromocytomas can cause cardiovascular and cerebrovascular complications. Debulking metastasectomy can be performed to reduce excess catecholamine secretion when curative resection is impossible. We present a case of metastatic pheochromocytoma to the liver, wherein a significant reduction in catecholamine secretion was achieved by repeat debulking hepatectomy. A 62-year-old woman who had undergone left adrenalectomy for primary pheochromocytoma 10 years prior to our surgical management, had multiple liver metastases of pheochromocytoma. Curative hepatectomy was infeasible because of insufficient remnant liver volume; thus, debulking hepatectomy was conducted. Preoperatively, increased doses of alpha-blockers and catecholamine synthesis inhibitors were administered. Nevertheless, substantial fluctuations in blood pressure and massive hemorrhage were observed intraoperatively. Eight months after the initial hepatectomy, repeat hepatectomy for the remnant lesions was performed due to the worsening of catecholamine levels and catecholamine-related symptoms. The patient survived, with serum catecholamines remaining within the normal range after repeat hepatectomy. Repeat debulking hepatectomy for metastatic pheochromocytoma to the liver is a feasible treatment strategy to effectively decrease catecholamine secretion and alleviate the symptoms thereof. However, special attention should be paid to perioperative catecholamine management and intraoperative surgical techniques.

  View details for DOI 10.1007/s12328-023-01784-z

  View details for PubMedID 36943552

  View details for PubMedCentralID 5587061

• Infectious Pulmonary Artery Pseudoaneurysm That Resolved with Conservative Treatment. Internal medicine (Tokyo, Japan) Nakayama, T., Suzuki, M., Yamaguchi, Y., Iikura, M., Izumi, S., Takeda, Y., Hojo, M., Sugiyama, H. 2022; 61 (20): 3089-3093

  Abstract

  Pulmonary artery pseudoaneurysms (PAPs) are rare but can cause massive hemoptysis if they rupture. Infectious PAPs are often treated by surgery or transcatheter embolization and are rarely treated conservatively with antibiotics. We herein report a case of PAP treated conservatively in a 21-year-old woman with lung abscess. Except for one massive hemoptysis early in the course, the patient responded well to the empirical therapy with ampicillin/sulbactam and systemic hemostatic agents. After six weeks of antibiotics, the pseudoaneurysm disappeared. Conservative therapy with careful observation can be considered in small infectious PAPs when there is a good clinical response to initial conservative therapy.

  View details for DOI 10.2169/internalmedicine.9021-21

  View details for PubMedID 35283388

  View details for PubMedCentralID PMC9646333