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The authors provided six 180-minute interpersonal assistance workshops using teaching materials from the End-of-Life Care Association: 90 minutes each on supportive communication and role-playing. The content included the following: ・ Suffering people are "at peace" with someone who understands their suffering, which starts with building a relationship through empathetic listening. The goal is not to "understand them" but for them to "feel understood." ・ Realizing the suffering of others and recognizing the internal moral and emotional strength of those who live with suffering. ・ Resilience building: helping caregivers face difficulties even when helpless; remembering one's support networks and valuing oneself. Participants (n = 114) wrote reflective journals after each session. Two domains and 10 key themes were identified through thematic analysis. The domains comprised topics on the importance of using listening techniques, such as repetition, waiting in silence, and asking questions (not to understand but for dialogue). The 3-month postinterviews revealed that participants could ease their sense of weakness by helping suffering people, which is relevant to work, grief care, and daily life. Changes in relationships between participants and patients were also identified. Role-playing can teach supportive communication, such as listening attentively and accepting others, which may help supporters engage with people experiencing incurable suffering. [ABSTRACT FROM AUTHOR]

Liquid biopsies are not used in practice for hepatocellular carcinoma (HCC). Epi proColon is the first commercial blood‐based test for colorectal cancer screening based on methylated DNA testing of the septin 9 gene (SEPT9). However, Epi proColon has some disadvantages, including the requirement of a large amount of blood and lack of quantitative performance. Therefore, we previously developed a novel liquid biopsy test that can quantitatively detect even a single copy of methylated SEPT9 in a small amount of DNA. In the current study, we evaluated the application potential of this assay for diagnosing HCC. Study subjects included 80 healthy volunteers, 45 patients with chronic liver disease (CLD) without HCC, and 136 patients with HCC (stage 0, 12; stage A, 50; stage B, 31; stage C, 41; and stage D, 2), according to the Barcelona Clinic Liver Cancer staging system. For the assay, DNA was treated with methylation‐sensitive restriction enzymes in two steps, followed by multiplex droplet digital polymerase chain reaction. The median copy number of methylated SEPT9 was 0.0, 2.0, and 6.4 in the healthy control, CLD, and HCC groups, respectively, with significant differences among the groups (HCC vs. healthy control, P < 0.001; HCC vs. CLD, P = 0.002; CLD vs. healthy control, P = 0.008). Assay sensitivity and specificity were 63.2% and 90.0%, respectively (cutoff value, 4.6 copies), in detecting HCC when compared with healthy subjects. The positive rate of methylated SEPT9 increased with HCC progression (stage 0, 41.7%; stage A, 58.0%; stage B, 61.3%; stage C, 75.6%; and stage D, 100%). Conclusion: We developed a sensitive methylated SEPT9 assay that might serve as a liquid biopsy test for diagnosing HCC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC). Background: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003). Methods: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m2) every 2 weeks; or S-1 (80 mg/m2/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%). Results: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245–0.927). Conclusion: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC. [ABSTRACT FROM AUTHOR]

Objective: To analyze 10,000 cases of living donor liver transplantation (LDLT) recipient data to elucidate outcomes with special reference to the graft-versus-recipient weight ratio (GRWR), based on the Japanese Liver Transplantation Society (JLTS) registry., Background: The JLTS registry has been accurate and complete in characterizing and following trends in patient characteristics and survival of all patients with LDLT., Methods: Between November 1989 and August 2021, 10,000 patients underwent LDLT in Japan. The procedures performed during the study period included pediatric liver transplantation (age <18 years, n = 3572) and adult liver transplantation (age ≥18 years, n=6428). Factors related to patient survival (PS) and graft survival (GS) were also analyzed., Results: The GRWR was <0.7, 0.7 to <0.8, 0.8 to <3, 3 to <5, and ≥5 in 0.2%, 2.0%, 61.8%, 31.8%, and 2.6% of pediatric patients and <0.6, 0.6 to <0.7, 0.7 to <0.8, and ≥0.8 in 8.0%, 12.7%, 17.7%, and 61.5% of adult patients, respectively. Among pediatric recipients, the PS rate up to 5 years was significantly better in cases with a GRWR ≤5 than in those with a GRWR >5. When the GRWR and donor age were combined, among adult recipients 50 to 60 years old, the early PS and GS up to 5 years were significantly better in cases with a GRWR ≥0.7, than in those with a GRWR <0.7. (P = 0.02). In adults, a multivariate analysis showed that GRWR <0.6, transplant era (<2011), donor age (>60 years), recipient age (>60 years), model for end-stage liver disease score (≥20), and center volume (<10) were significant prognostic factors for long-term PS., Conclusion: Although a satisfactory long-term PS and GS, especially in the recent era (2011-2021), was achieved in the JLTS series, a GRWR ≥5 in pediatric cases and relatively old donors with a GRWR <0.7 in adult cases should be managed with caution., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To identify optimal surgical methods and the risk factors for long-term survival in patients with hepatocellular carcinoma accompanied by macroscopic bile duct tumor thrombus (BDTT)., Summary Background Data: Prognoses of patients with hepatocellular carcinoma accompanied by BDTT have been known to be poor. There have been significant controversies regarding optimal surgical approaches and risk factors because of the low incidence and small number of cases in previous reports., Methods: Records of 257 patients from 32 centers in Korea and Japan (1992-2014) were analyzed for overall survival and recurrence rate using the Cox proportional hazard model., Results: Curative surgery was performed in 244 (94.9%) patients with an operative mortality of 5.1%. Overall survival and recurrence rate at 5 years was 43.6% and 74.2%, respectively. TNM Stage (P < 0.001) and the presence of fibrosis/cirrhosis (P = 0.002) were independent predictors of long-term survival in the Cox proportional hazards regression model. Both performing liver resection equal to or greater than hemihepatectomy and combined bile duct resection significantly increased overall survival [hazard ratio, HR = 0.61 (0.38-0.99); P = 0.044 and HR = 0.51 (0.31-0.84); P = 0.008, respectively] and decreased recurrence rate [HR = 0.59 (0.38-0.91); P = 0.018 and HR = 0.61 (0.42-0.89); P = 0.009, respectively]., Conclusions: Clinical outcomes were mostly influenced by tumor stage and underlying liver function, and the impact of BDTT to survival seemed less prominent than vascular invasion. Therefore, an aggressive surgical approach, including major liver resection combined with bile duct resection, to increase the chance of R0 resection is strongly recommended.

We previously found that heat-shock protein 70 (HSP70) is expressed on hepatocellular carcinoma cells and developed an HSP70 mRNA-transfected dendritic cell therapy for treating unresectable or recurrent hepatocellular carcinoma. The phase I trial was completed successfully. The purpose of this study is to identify a promiscuous epitope peptide derived from HSP70 for the purpose of developing a novel cancer peptide vaccine. Using a computational algorithm to analyze the specificity of previously reported major histocompatibility complex class I-binding peptides, we selected candidates that bound to >2 of the 3 HLA types. Twenty-nine HSP70-derived peptides (9-mers) that bound to HLA-class I was selected. The peptides were prioritized based on the results of peptide binding experiments. Using dendritic cells stimulated with the candidate peptide described previously as stimulators and CD8 T cells as effectors, an ELISPOT assay was performed. Cytotoxicity of CD8 lymphocytes stimulated with the candidate peptides toward HSP70-expressing cancer cells was analyzed using an xCELLigence System. Peptides were administered to HLA-A 24 transgenic mice as vaccines, and peptide-specific T-cell induction was measured in vivo. We identified a multi-HLA-class I-binding epitope peptide that bound to HLA-A*02:01, *02:06, and *24:02 in vitro using an interferon-γ ELISPOT immune response induction assay. Cytotoxicity was confirmed in vitro, and safety and immune response induction were confirmed in vivo using HLA-A 24 transgenic mice. Our study demonstrated that the promiscuous HSP70-derived peptide is applicable to cancer immunotherapy in patients with HLA-A*24:02-positive, *02:01-positive, and *02:06-positive HSP70-expressing cancers.

Objectives: This study evaluated individual risks of malignancy and proposed a nomogram for predicting malignancy of branch duct type intraductal papillary mucinous neoplasms (BD-IPMNs) using the large database for IPMN., Background: Although consensus guidelines list several malignancy predicting factors in patients with BD-IPMN, those variables have different predictability and individual quantitative prediction of malignancy risk is limited., Methods: Clinicopathological factors predictive of malignancy were retrospectively analyzed in 2525 patients with biopsy proven BD-IPMN at 22 tertiary hospitals in Korea and Japan. The patients with main duct dilatation >10 mm and inaccurate information were excluded., Results: The study cohort consisted of 2258 patients. Malignant IPMNs were defined as those with high grade dysplasia and associated invasive carcinoma. Of 2258 patients, 986 (43.7%) had low, 443 (19.6%) had intermediate, 398 (17.6%) had high grade dysplasia, and 431 (19.1%) had invasive carcinoma. To construct and validate the nomogram, patients were randomly allocated into training and validation sets, with fixed ratios of benign and malignant lesions. Multiple logistic regression analysis resulted in five variables (cyst size, duct dilatation, mural nodule, serum CA19-9, and CEA) being selected to construct the nomogram. In the validation set, this nomogram showed excellent discrimination power through a 1000 times bootstrapped calibration test., Conclusion: A nomogram predicting malignancy in patients with BD-IPMN was constructed using a logistic regression model. This nomogram may be useful in identifying patients at risk of malignancy and for selecting optimal treatment methods. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

Objectives: We previously described adoptive immunotherapy (AIT) with cytotoxic T lymphocytes (CTLs) stimulated by the mucin 1 (MUC1)-expressing human pancreatic cancer cell line YPK-1 (MUC1-CTLs) and demonstrated that MUC1-CTLs might prevent liver metastasis. In the present study, we combined gemcitabine (GEM) and AIT for the treatment of pancreatic cancer., Methods: A total of 43 patients who underwent radical pancreatectomy received treatment with MUC1-CTLs and GEM. After surgery, MUC1-CTLs were induced and administered intravenously 3 times, and GEM administered according to the standard regimen for 6 months. The patients whose relative dose intensity of GEM was 50% or more and who received 2 or more MUC1-CTL treatments were used as the adequate treatment group (n = 21)., Results: In the adequate treatment group, disease-free survival was 15.8 months, and overall survival was 24.7 months. Liver metastasis was found only in 7 patients (33%), and local recurrence occurred in 4 patients (19%). The independent prognostic factor of long-term disease-free survival on multivariate analysis was the average number of CTLs administered (P = 0.0133)., Conclusions: The combination therapy with AIT and GEM prevented liver metastasis and local recurrence. Moreover, the disease free-survival was improved in patients who received sufficient CTLs.

Objectives: To improve the detection of pancreatic cancer (PC), a robust diagnostic biomarker is essential. We have previously discovered 4 serum metabolites (PC-594, lysophosphatidylcholine, phosphatidylcholine, and sphingomyelin) in distinguishing patients with PC from healthy controls. Here, we report the results of our validation phase by using larger numbers of independent and blinded samples., Methods: We collected 3 mL of serum from 116 patients with PC and 138 healthy controls. Samples were blinded and expression of the 4 candidate metabolites in each sample was determined by triple quadrupole tandem mass spectrometry. We then used cutoffs established in the discovery phase to predict the disease state of each of the validation samples., Results: All 4 metabolites showed significantly lower expression in patients with PC compared with healthy controls. PC-594 showed 73.3% sensitivity and 92.0% specificity, whereas the other 3 metabolites showed 58.6% and 92.0%, 76.7% and 69.6%, and 58.6% and 81.9% sensitivity and specificity, respectively. Area under the receiver operating characteristic curve for PC-594 alone was 0.92, whereas a combination method using all 4 metabolites showed 86.2% sensitivity and 84.8% specificity., Conclusions: Our validation results confirmed that a reduction in PC-594, along with 3 other serum-based choline metabolites, is highly associated with PC.

Objectives: The aim of this study was to evaluate in a multicenter randomized controlled trial (RCT) whether pancreaticojejunostomy (PJ) of pancreatic stump decreases the incidence of pancreatic fistula after distal pancreatectomy (DP) compared with stapler closure., Background: Several studies reported that PJ of pancreatic stump reduces the incidence of pancreatic fistula after DP. However, no RCT has confirmed the efficacy of PJ of pancreatic stump., Methods: One hundred thirty-six patients scheduled for DP were enrolled in this study between June 2011 and March 2014 at 6 high-volume surgical centers in Japan. Enrolled patients were randomized to either stapler closure or PJ. The primary endpoint was the incidence of pancreatic fistula based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01384617)., Results: Sixty-one patients randomized to stapler and 62 patients randomized to PJ were analyzed by intention-to-treat. Pancreatic fistula occurred in 23 patients (37.7%) in the stapler closure group and 24 (38.7%) in the PJ group (P = 0.332) in intention-to-treat analysis. The incidence of clinically relevant pancreatic fistula (grade B or C) was 16.4% for stapler closure and 9.7% for PJ (P = 0.201). Mortality was zero in both groups. In a subgroup analysis for thickness of pancreas greater than 12 mm, the incidence of clinically relevant pancreatic fistula occurred in 22.2% of the patients in the stapler closure group and in 6.2% of the PJ group (P = 0.080)., Conclusions: PJ of the pancreatic stump during DP does not reduce pancreatic fistula compared with stapler closure.

Objectives: Leucine-rich α2-glycoprotein-1 (LRG-1) is an inflammatory protein. Serum LRG-1 levels can reportedly be used as a cancer biomarker for several types of carcinoma. In the present study, we investigated the clinical usefulness of serum LRG-1 levels as a biomarker of pancreatic cancer., Methods: A total of 124 patients with pancreatic cancer, 35 patients with chronic pancreatitis (CP), and 144 healthy volunteers were enrolled in the study. Serum LRG-1 levels were assayed by enzyme-linked immunosorbent assay. Immunohistochemistry was used to examine LRG-1 expression in pancreatic cancer tissues., Results: Serum LRG-1 levels were significantly increased in patients with pancreatic cancer compared with CP patients and healthy volunteers. The LRG-1 levels increased with progressive clinical stages of pancreatic cancer. Receiver operator curve analysis showed that a combination of carbohydrate antigen 19-9 and LRG-1 resulted in a higher area under the curve for the diagnosis of pancreatic cancer. Positive staining was observed in all cases of pancreatic cancer, but positive signal was scarcely detected in tissues from CP patients or normal surrounding tissue., Conclusions: These results suggest that serum LRG-1 is a promising biomarker for pancreatic cancer.

Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

Objectives: Gemcitabine is taken up by cells mainly via human equilibrative nucleoside transporter 1 (hENT1). Pretreatment of cancer cell lines with 5-fluorouracil (5-FU) leads to an increase in the expression of hENT1 and augments the effect of single-agent gemcitabine treatment in vitro. The purpose of the present study was to evaluate the relationship between the schedules of gemcitabine/uracil-tegafur (UFT) combination therapy and their effects in pancreatic cancer in vivo., Methods: The expression level of hENT1 mRNA was examined using 6 types of human pancreatic cancer cell lines treated with 5-FU and MiaPaCa-2 xenograft tumors in BALB/c nu/nu mice treated with UFT. A [H] gemcitabine cellular uptake assay was performed using MiaPaCa-2 cells treated with 5-FU. We compared the effects of 6 different schedules of treatment using UFT and/or gemcitabine on MiaPaCa-2 xenograft tumors., Results: MiaPaCa-2 cell line was one of the lines that showed the highest rate of 5-FU-induced increase in the hENT1 mRNA level. Gemcitabine uptake was significantly increased when cells were treated with 5-FU. Treatment with UFT significantly increased the hENT1 mRNA expression in MiaPaCa-2 tumors. A significant growth inhibition of MiaPaCa-2 tumors was observed in the mice treated with UFT followed by gemcitabine as compared with either untreated mice or UFT alone-treated mice., Conclusions: Our results suggest that the schedule in which the gemcitabine is administered after UFT may be the optimal combination for gemcitabine/UFT treatment in pancreatic cancer.

Background: End-stage liver disease is often accompanied by large spontaneous splenorenal shunts and thrombosed portal vein. Renoportal anastomosis for spontaneous splenorenal shunts in living-donor liver transplantations is one of the solutions for the treatment of these patients. However, the long-term outcome, portal venous hemodynamics after liver transplantation, and the effects of altering the renal venous drainage remained unknown., Methods: We performed three living-donor liver transplantations with renoportal anastomosis for the treatment of spontaneous splenorenal shunts between 1999 and 2004. We then evaluated the outcome of this procedure using short- and long-term follow-ups in which the postoperative graft function, renal function, radiological images and portal hemodynamics were examined., Results: All three patients who underwent a living-donor liver transplantation with renoportal anastomosis are alive with normal graft function and a patent renoportal anastomosis. The portal hemodynamics were similar to those in conventional living-donor liver transplantation recipients, and had no harmful effect on allograft function. Left renal function returned to normal after the temporal impairment in two cases, and remained slightly impaired in one, although it was negligible clinically., Conclusions: Living-donor liver transplantation with renoportal anastomosis for the treatment of spontaneous splenorenal shunts in patients with end-stage liver disease is a life-saving and safe technique and should be discussed as a treatment option for patients with splenorenal shunts.

To examine the benefits of steroid avoidance in adult living donor liver transplantation, we compared the clinical courses of nine recipients receiving basiliximab or daclizumab and 13 historical patients who received steroids. The 1-year patient and graft survival and the incidence of acute cellular rejection were similar in both groups. The side effects of immunosuppression tended to be more frequent in the steroid group. Hepatitis C virus (HCV)-RNA levels measured early after transplantation remained suppressed in the steroid-free group. Steroid avoidance was beneficial in the recipients, as both steroid side effects and recurrence of HCV could be avoided.

Objective: The purpose of this study was to separately measure the arterial and portal venous tissue blood flow (TBF) of hepatocellular carcinoma (HCC) with a noninvasive method using xenon inhalation CT (xenon-CT) and to differentiate between well-differentiated HCCs and moderately and poorly differentiated HCCs., Materials and Methods: Total, arterial and portal venous TBFs of 38 surgically proven HCC nodules from 38 patients were measured by means of xenon-CT. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was computed using the Fick principle, after which the correlation between TBF and pathologic features of the tumors was determined., Results: Total, arterial, and portal venous TBFs of HCC were 125.7 +/- 59.9 mL/min/100g, 102.5 +/- 37.3, and 22.2 +/- 11.4, respectively, and the corresponding findings for hepatic parenchyma were 67.3 +/- 13.1, 25.2 +/-9.6, and 42.4 +/- 11.0. Total and arterial TBFs of HCC were significantly higher than those of the hepatic parenchyma (P < 0.01), whereas portal venous TBF of HCC was significantly lower than that of hepatic parenchyma (P < 0.01). Arterial TBF of moderately or poorly differentiated HCC (120.4 +/- 38.2) was significantly higher than that of well-differentiated HCC (60.4 +/- 43.5) (P < 0.01)., Conclusions: Arterial and portal venous TBFs of HCC could be measured separately, noninvasively, and safely with xenon-CT. Correlation between TBF and pathologic features of tumors indicate that xenon-CT can be used to differentiate between well-differentiated HCCs and moderately and poorly differentiated HCCs.

Background: A large splenorenal collateral must be interrupted during liver transplantation to secure adequate portal perfusion. However, this process increases the complexity of the operative procedure and may cause hazardous bleeding. Recently, renoportal anastomosis in portal reconstruction was reported in cadaveric liver transplantation for patients with surgically created splenorenal shunts. We used this technique in a living-related liver transplantation., Methods: A 29-year-old female with a large spontaneous splenorenal collateral and a portal venous thrombus underwent a living-related liver transplantation. At surgery, the left renal vein was divided and the distal stump was anastomosed to the portal vein of the graft without interrupting collaterals., Results: Adequate portal venous blood flow was maintained throughout the postoperative course. The patient was discharged 9 weeks after transplantation and remains well., Conclusion: The renoportal anastomosis could be used for portal reconstruction in living-related liver transplantation for patients with a large splenorenal collateral. It provides adequate portal perfusion without interrupting collateral circulation.