Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma.

The role of the ferroptosis-related gene glutathione peroxidase 4 (GPX4) in oncology has been extensively investigated. However, the clinical implications of GPX4 in patients with intrahepatic cholangiocarcinoma (ICC) remain unknown. This study aimed to evaluate the prognostic impact of GPX4 and its underlying molecular mechanisms in patients with ICC. Fifty-seven patients who underwent surgical resection for ICC between 2010 and 2017 were retrospectively analyzed. Based on the immunohistochemistry, patients were divided into GPX4 high (n = 15) and low (n = 42) groups, and clinical outcomes were assessed. Furthermore, the roles of GPX4 in cell proliferation, migration and gene expression were analyzed in ICC cell lines in vitro and in vivo. The results from clinical study showed that GPX4 high group showed significant associations with high SUVmax on 18F-fluorodeoxyglucose-positron emission tomography (≥8.0, P = 0.017), multiple tumors (P = 0.004), and showed glucose transporter 1 (GLUT1) high expression with a trend toward significance (P = 0.053). Overall and recurrence-free survival in the GPX4 high expression group were significantly worse than those in the GPX4 low expression group (P = 0.038 and P < 0.001, respectively). In the experimental study, inhibition of GPX4 attenuated cell proliferation and migration in ICC cell lines. Inhibition of GPX4 also decreased the expression of glucose metabolism-related genes, such as GLUT1 or HIF1α. Mechanistically, these molecular changes are regulated in Akt-mechanistic targets of rapamycin axis. In conclusion, this study suggested the pivotal value of GPX4 serving as a prognostic marker for patients with ICC. Furthermore, GPX4 can mediate glucose metabolism of ICC.

Characterization and role of collagen gene expressing hepatic cells following partial hepatectomy in mice.

BACKGROUND AND AIMS: The mechanism underlying liver regeneration following partial hepatectomy (PH) is not fully elucidated. We aimed to characterize collagen gene expressing hepatic cells following PH and examine their contribution to liver regeneration. APPROACH AND RESULTS: Col-GFP mice, which express GFP under the control of the collagen gene promoter, were used to detect collagen gene expressing cells following PH. The GFP-expressing cells were analyzed via single-cell RNA sequencing (scRNA-seq). Additionally, Col-ER Cre/RFP and Col-ER Cre/DTA mice were utilized to examine the cell fates and functional roles of collagen gene expressing cells in liver regeneration, respectively. The number of collagen gene expressing cells was found to be increased on day 3 and subsequently decreased on day 7 following PH. ScRNA-seq analysis of sorted collagen gene expressing cells showed that the regenerating liver was characterized by three distinct hepatic stellate cell (HSC) clusters, including one representing classic myofibroblasts. The other HSC clusters included an intermediately activated HSC cluster and a proliferating HSC cluster. Of these, the latter cluster was absent in the CCl 4 -induced liver fibrosis model. Cell fate tracing analysis using Col-ER Cre/RFP mice demonstrated that the collagen gene expressing cells escaped death during regeneration and remained in an inactivated state in the liver. Further, depletion of these cells using Col-ER Cre/DTA mice resulted in impaired liver regeneration. CONCLUSIONS: Heterogeneous HSC clusters, one of which was a unique proliferating cluster, were found to appear in the liver following PH. Collagen gene expressing cells, including HSCs, were found to promote liver regeneration.

High expression of autotaxin is associated with poor recurrence-free survival in cholangiocarcinoma.

BACKGROUND AND AIM: Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive. METHODS: In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining. RESULTS: High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells. CONCLUSIONS: Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.

Usefulness of an interprofessional work manual for perioperative glucose control of an artificial pancreas.

BACKGROUND: A closed-loop bedside-type artificial pancreas for perioperative glucose control has previously been introduced. However, artificial pancreas therapy was often interrupted due to continuous blood sampling failure. We developed an interprofessional work manual to reduce the interruption time of artificial pancreatic therapy for perioperative blood glucose control due to continuous blood sampling failure. This study aimed to investigate the usefulness of this manual. METHODS: The manual consisted of the following sections: (1) the roles of the professionals in the preparation and management of the artificial pancreas, (2) how to address continuous blood sampling failure, and (3) checkpoints for interprofessional transfer of the artificial pancreas. We compared the results before the introduction of the manual and 2 years after the introduction of the manual. RESULTS: There were 35 and 37 patients in the Before and After groups, respectively. There were no significant differences in patient backgrounds between the two groups, although there was significantly less blood loss in the After group (1164 vs. 366 mL; p < 0.001). The mean artificial pancreas therapy and artificial pancreas therapy interruption times were 847 min and 20 min, respectively. Artificial pancreas therapy interruption time (34 vs. 8 min; p = 0.078) and time per interruption (24 vs. 4 min; p < 0.001) were significantly shorter in the After group than in the Before group. CONCLUSIONS: The interprofessional working manual was useful in reducing the artificial pancreatic therapy interruption time for perioperative glucose control.

Blood flow evaluation of reconstructed gastric tube in esophageal surgery using near-infrared imaging and retrospective time-intensity curve analysis.

PURPOSE: Near-infrared fluorescence imaging using indocyanine green (ICG-NIFI) can visualize a blood flow in reconstructed gastric tube; however, it depends on surgeon's visual assessment. The aim of this study was to re-analyze the ICG-NIFI data by an evaluator independent from the surgeon and feasibility of creating the time-intensity curve (TIC). METHODS: We retrospectively reviewed 97 patients who underwent esophageal surgery with gastric tube reconstruction between January 2017 and November 2022. From the stored ICG videos, fluorescence intensity was examined in the four regions of interest (ROIs), which was set around the planned anastomosis site on the elevated gastric tube. After creation the TICs using the OpenCV library, we measured the intensity starting point and time constant and assessed the correlation between the anastomotic leakage. RESULTS: Postoperative leakage occurred for 12 patients. The leakage group had significantly lack of blood flow continuity between the right and left gastroepiploic arteries (75.0% vs. 22.4%; P < 0.001) and tended to have slower ICG visualization time assessed by the surgeon's eyes (40 vs. 32 s; P = 0.066). TIC could create in 65 cases. Intensity starting point at all ROIs was faster than the surgeon's assessment. The leakage group tended to have slower intensity starting point at ROI 3 compared to those in the non-leakage group (22.5 vs. 19.0 s; P = 0.087). CONCLUSION: A TIC analysis of ICG-NIFI by an independent evaluator was able to quantify the fluorescence intensity changes that the surgeon had visually determined.

Usefulness of laparoscopic surgery for colorectal perforation: a single-center retrospective cohort study.

PURPOSE: This study aimed to determine the safety and efficacy of laparoscopic surgery in patients with colorectal perforation owing to a significant lack of evidence in this field. METHODS: This retrospective cohort study analyzed the data of 70 patients who underwent emergency surgery for colorectal perforations between January 2017 and December 2023. The surgical outcomes of the patients who underwent open and laparoscopic surgeries were statistically compared. The primary endpoints were postoperative mortality and complications. The secondary endpoints included blood loss, surgical time, length of hospital stay, and 1-year overall survival. RESULTS: Overall, 28 patients underwent open surgery and 42 underwent laparoscopic surgery. No significant difference was noted in the postoperative mortality or overall rate of severe complications between the two groups. The incidence of superficial and deep incisional surgical site infection was lower in the laparoscopic surgery group (35.7% vs. 0.0%, p < 0.001), while the surgical time was significantly longer in the laparoscopic group (175.6 ± 92.2 min vs. 290.0 ± 102.3 min, p < 0.001). No significant differences were found in blood loss, length of hospital stay, or 1-year overall survival. CONCLUSIONS: Laparoscopic surgery for colorectal perforation markedly reduced superficial and deep incisional surgical site infection, with no substantial difference in mortality or severe complications.

[Current Status of ICG Fluorescence Navigation in Laparoscopic Liver Resection].

The indocyanine green(ICG)fluorescence navigation that we have standardized for laparoscopic liver resection is useful for partial liver resection and anatomical liver resection for liver cancer, and extended cholecystectomy for gallbladder cancer. In partial liver resection we believe that it is possible to secure a resection margin by not exposing the fluorescence emission around the tumor. In anatomical liver resection, real-time navigation becomes possible by transecting the liver at the boundary between colored and non-colored area, which contributes to precise liver surgery. In extended cholecystectomy, it is difficult to inject ICG from the cystic artery which was performed in open liver resection. So, we encircled Calot's triangle using the Glissonean approach from the ventral side of the gallbladder plate and then taped the hilar Glissonean pedicles. After clamping this tape, ICG was injected into the vein. By using this method, laparoscopic surgery has become possible in the same way as open surgery. With further spread in the future, it is hoped that liver resection using ICG fluorescence navigation will not only be precise, but also safe and highly curative surgery.

Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Clinically relevant model of oxaliplatin-induced sinusoidal obstruction syndrome.

AIM: Sinusoidal obstruction syndrome (SOS) induced by oxaliplatin-including chemotherapies (OXCx) is associated with impaired hepatic reserve and higher morbidity after hepatic resection. However, in the absence of an appropriate animal experimental model, little is known about its pathophysiology. This study aimed to establish a clinically relevant reproducible model of FOLFOX-induced SOS and to compare the clinical/histopathological features between the clinical and animal SOS settings. METHODS: We performed clinical/pathological analyses of colorectal liver metastasis (CRLM) patients who underwent hepatectomy with/without preoperative treatment of FOLFOX (n = 22/18). Male micro-minipigs were treated with 50% of the standard human dosage of the FOLFOX regimen. RESULTS: In contrast to the monocrotaline-induced SOS model in rats, hepatomegaly, ascites, congestion, and coagulative necrosis of hepatocytes were absent in patients with CRLM with OXCx pretreatment and OXCx-treated micro-minipigs. In parallel to CRLM cases with OXCx pretreatment, OXCx-challenged micro-minipigs exhibited deteriorated indocyanine green clearance, morphological alteration of liver sinusoidal endothelial cells, and upregulated matrix metalloproteinase-9. Using our novel porcine SOS model, we identified the hepatoprotective influence of recombinant human soluble thrombomodulin in OXCx-SOS. CONCLUSIONS: With distinct differences between monocrotaline-induced rat SOS and human/pig OXCx-SOS, our pig OXCx-SOS model serves as a preclinical platform for future investigations to dissect the pathophysiology of OXCx-SOS and seek preventive strategies.

Impact of the Intermittent Pringle Maneuver for Predicting Post-hepatectomy Liver Failure: A Cohort Study of 597 Consecutive Patients.

BACKGROUND: Intermittent Pringle maneuver (PM) is widely performed to reduce blood loss during hepatectomy; however, its impact on clinically relevant post-hepatectomy liver failure (PHLF) remains controversial. This study aimed to assess the impact of PM on PHLF and explore whether PM provides additional value for predicting PHLF. METHODS: Consecutive patients, who underwent hepatectomy without biliary and/or vascular reconstruction between 2011 and 2018 in a single institution, were retrospectively analyzed. The main outcome was PHLF grades B/C as defined by the International Study Group of Liver Surgery. A multivariable logistic regression model of variables significantly associated with PHLF was established. The model's predictive ability was assessed by the area under the receiver operating characteristic curve (AUROC). RESULTS: Among 597 patients, PHLF occurred in 42 (7.0%). PM was applied in 421 patients (70.5%) and was associated with the development of PHLF (PM vs. no-PM: 9.7 vs. 0.6%, P < 0.001). After the propensity score matching, patients with PM experienced significantly increased rates of PHLF (P = 0.010). Rem-ALPlat index (including future liver remnant, preoperative albumin level, and platelet count; P < 0.001), the number of PMs (P = 0.032), and blood loss (P = 0.007) were identified as significant predictors of PHLF. The model's AUROC combined with the intraoperative variables was higher than that of the preoperative model alone (0.877 vs. 0.789, P = 0.004). CONCLUSIONS: PM was involved in the occurrence of clinically relevant PHLF. Further, intraoperative factors including PM may provide additional value to predict PHLF and may facilitate early post-hepatectomy intervention.

A Conceptual Classification of Resectability for Hepatocellular Carcinoma.

BACKGROUNDS: In the era of multidisciplinary treatment strategy, resectability for hepatocellular carcinoma (HCC) should be defined. This study aimed to propose and validate a resectability classification of HCC. METHODS: We proposed following the three groups; resectable-(R), borderline resectable-(BR), and unresectable (UR)-HCCs. Resectable two groups were sub-divided according to the value of indocyanine green clearance of remnant liver (ICG-Krem) and presence of macrovascular invasion (MVI); BR-HCC was defined as resectable HCCs with MVI and/or ICG-Krem≥0.03-<0.05, and R-HCC was the remaining. Consecutive patients with HCC who underwent liver resection (LR) and non-surgical treatment(s) (i.e., UR-HCC) between 2011 and 2017 were retrospectively analyzed to validate the proposed classification. RESULTS: A total of 361 patients were enrolled in the study. Of these, R-, BR- and UR-HCC were found in 251, 46, and 64 patients, respectively. In patients with resected HCC, ICG-Krem≥0.05 was associated with decreased risk of clinically relevant posthepatectomy liver failure (p=0.013) and the presence of MVI was associated with worse overall survival (OS) (p<0.001). The 3-5-years OS rates according to the proposed classification were 80.3, and 68.3% versus 51.4, and 35.6%, in the R and BR groups, respectively (both p<0.001). Multivariate analysis showed BR-HCC was independently associated with poorer OS (p<0.001) after adjusting for known tumor prognostic factors. Meanwhile, BR-HCC was associated with benefit in terms of OS compared with UR-HCC (p<0.001). CONCLUSION: Our proposal of resectability for HCC allows for stratifying survival outcomes of HCC and may help to determine treatment strategy.

What is the optimal range of glycemic control for non-diabetic patients undergoing gastroenterological surgery? A single-center randomized controlled trial using an artificial pancreas.

BACKGROUND: This study aimed to determine the optimal target range of perioperative glycemic control for gastroenterological surgery. A closed-loop-type artificial pancreas (AP) was used to diminish the negative impact of hypoglycemia and glycemic variability during tight glycemic control. METHODS: In this single-center randomized trial, non-diabetic patients were assigned to tight (80-110 mg/dL) or moderate glycemic control (110-140 mg/dL) groups between August 2017 and May 2021. AP was used from the intraoperative period until discharge from the intensive care unit. The primary endpoint was the serum interleukin (IL)-6 level on the third postoperative day (3POD), and the secondary endpoints included clinical outcomes. RESULTS: Recruitment was closed before reaching the planned number of patients due to slow enrollment. Tight glycemic control (n = 62) resulted in lower mean glucose levels than moderate glycemic control (n = 66) (121.3 ± 10.8 mg/dL vs. 133.5 ± 12.0 mg/dL, p < 0.001). Insulin was administered at a 65% higher rate for tight glycemic control, achieving appropriate glucose control more than 70% of the treatment time. No hypoglycemia occurred during the AP treatment. No significant difference was observed in serum IL-6 levels on 3POD (23.4 ± 31.1 vs. 32.1 ± 131.0 pg/mL, p = 0.64), morbidity rate, surgical mortality rate, or length of hospital stay between the two groups. CONCLUSIONS: Clinically relevant short-term results did not differ, implying that 80-110 and 110-140 mg/dL are permissible glycemic control ranges when using AP in non-diabetic patients undergoing gastroenterological surgery. (Registered in UMIN; UMIN000028036).

Laparoscopic-assisted robotic distal gastrectomy for gastric cancer by Billroth II reconstruction.

BACKGROUND: There are several reconstructions in distal gastrectomy for gastric cancer, and there is no clear definition regarding the method selection. The optimal reconstruction is likely to vary according to the surgical setting, and the optimal reconstruction for robotic distal gastrectomy is urgently needed. In addition, as robotic gastrectomy is getting popular, cost and operative time are pressing issues of robotic gastrectomy. METHODS: Gastrojejunostomy was planned with Billroth II reconstruction using a linear stapler arranged specifically for a robotic approach. After firing the stapler, the common insertion orifice of the stapler was closed using a 30 cm long non-absorbable barbed suture, and continuously, the afferent loop of the jejunum was lifted to the stomach with the same barbed suture. In addition, we introduced laparoscopic-assisted robotic gastrectomy, using extracorporeally inserted laparoscopic devices from the assistant port. Scissors, clips, and linear staplers were all laparoscopic tools inserted extracorporeally. RESULTS: Twenty-one gastric cancer patients underwent laparoscopic-assisted robotic distal gastrectomy by Billroth II reconstruction with our modifications. There were no anastomosis-related complications such as leakage, stenosis, or bleeding. There were 2 cases of aspiration pneumonia (Clavien-Dindo grade 2), 1 case of pancreatic juice leakage (grade 3a), and 1 case of delayed gastric emptying (grade 1). CONCLUSION: We successfully arranged Billroth II reconstruction for robotic distal gastrectomy with fewer operative and postoperative complications. Laparoscopic-assisted robotic gastrectomy using extracorporeally inserted devices, and continuous suturing using a barbed suture will reduce the time and cost of robotic gastrectomy.

Impact of liver volumetric regeneration on survival outcomes in patients with hepatocellular carcinoma after major hepatectomy.

PURPOSE: Prognostic value of liver volumetric regeneration (LVR) in patients with hepatocellular carcinoma (HCC) who undergo major hepatectomy remains unknown. The aim of this study was to investigate the impact of LVR on long-term outcomes in these patients. METHODS: Data of 399 consecutive patients with HCC who underwent major hepatectomy between 2000 to 2018 were retrieved from a prospectively maintained institutional database. The LVR-index was defined as the relative increase in liver volume from 7 days to 3 months (RLV3m/RLV7d, where RLV3m and RLV7d is the remnant liver volume around 3 months and postoperative 7 days after surgery). The optimal cut-off value was determined using the median value of LVR-index. RESULTS: A total of 131 patients were eligible in this study. The optimal cut off value of LVR-index was 1.194. The 1-, 3-, 5- and 10-year overall survival (OS) rate of patients in the high LVR-index group were significantly better compared to those in the low LVR-index group (95.5%, 84.8%, 75.4% and 49.1% vs. 95.4%, 70.2%, 56.4%, and 19.9%, p = 0.002). Meanwhile, there was no significant difference with regards to time to recurrence between the two groups (p = 0.607). Significance of LVR-index for OS was retained after adjusting for known prognostic factors (p = 0.002). CONCLUSION: In patients with HCC undergoing major hepatectomy, LVR-index may serve as a prognostic indicator for OS.

A case of perioperative artificial pancreas therapy for a patient with esophageal cancer with type 1 diabetes.

A 72-year-old female with type 1 diabetes, a history of interstitial pneumonia, and diabetic ketoacidosis was admitted to our hospital with dysphagia. Endoscopy revealed a circumferential neoplastic lesion in the upper to middle esophagus, and a biopsy revealed squamous cell carcinoma. Computed tomography revealed invasion of the left main bronchus, and induction chemotherapy was initiated with a diagnosis of unresectable locally advanced esophageal cancer. After one course of induction chemotherapy, the tumor size reduced, bronchial invasion improved, and thoracoscopic esophagectomy was performed. During surgery and until 3 days after surgery, the patient's blood glucose level was controlled using an artificial pancreas, and the target blood glucose range was set at 140-180 mg/dL. On the fourth postoperative day, the patient was managed using a sliding scale. Mean blood glucose was 186.7 ± 70.0 mg/dL for 3 days before surgery, 190.5 ± 25.0 mg/dL during artificial pancreas therapy from the surgery to the next day, 169.8 ± 22.0 mg/dL during artificial pancreas therapy on the second to third postoperative days, and 174.5 ± 25.0 mg/dL during sliding scale therapy for 4-15 days after surgery. No hypoglycemia or ketoacidosis was noted.

Impact of patient-specific three-dimensional printed liver models on hepatic surgery safety: a pilot study.

BACKGROUND: Simulation and navigation technologies in hepatobiliary surgery have been developed recently. In this prospective clinical trial, we evaluated the accuracy and utility of our patient-specific three dimensional (3D)-printed liver models as an intraoperative navigation system to ensure surgical safety. METHOD: Patients requiring advanced hepatobiliary surgeries during the study period were enrolled. Three cases were selected for comparison of the computed tomography (CT) scan data of the models with the patients' original data. Questionnaires were completed after surgeries to evaluate the utility of the models. Psychological stress was used as subjective data and operation time and blood loss as objective data. RESULTS: Thirteen patients underwent surgery using the patient-specific 3D liver models. The difference between patient-specific 3D liver models and the original data was less than 0.6 mm in the 90% area. The 3D model assisted with intra-liver hepatic vein recognition and the definition of the cutting line. According to the post-operative subjective evaluation, surgeons found the models improved safety and reduced psychological stress during operations. However, the models did not reduce operative time or blood loss. CONCLUSION: The patient-specific 3D-printed liver models accurately reflected patients' original data and were an effective intraoperative navigation tool for meticulously difficult liver surgeries. CLINICAL TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trial Registry (UMIN000025732).

[Long-Term Survival of an Adolescent and Young Adult Patient with Unresectable Advanced Gastric Cancer in Whom Multidisciplinary Treatment Was Effective].

We report the case of a long-term-surviving adolescent and young adult patient with unresectable advanced gastric cancer for whom multidisciplinary treatment was effective. A 29-year-old woman was referred to our hospital for further examination following a diagnosis of gastric cancer by a local physician. Esophagogastroduodenoscopy showed a deep ulcerated lesion in the lower third of the stomach, and analysis of biopsy specimens revealed an adenocarcinoma. Abdominal contrast- enhanced computed tomography showed gastric wall thickening in the lower third of the stomach. The patient underwent distal gastrectomy with lymph node dissection, including resection of localized peritoneal metastases, followed by Roux-en- Y reconstruction. The pathological diagnosis was serosa-invading poorly differentiated adenocarcinoma with 1 lymph node metastasis measuring 6.0×5.5 cm in the posterior wall of the lower third of the stomach and negative immunohistochemical staining for human epidermal growth factor receptor 2. The patient received postoperative chemotherapy with S-1 and oxaliplatin. She developed bilateral ovarian metastases measuring 13.0 cm and 7.8 cm after 17 months. The patient presented with severe lower abdominal pain and underwent an emergency bilateral ovarian metastasectomy, which revealed torsion of the right ovarian tumor, which had twisted twice on its pedicle, and a left ovarian mass. After the operation, 41 courses of ramucirumab with nab-paclitaxel were administered as a second-line treatment, and she received systemic drug treatment. Sixty months after the gastrectomy, the patient developed left hydronephrosis due to peritoneal metastases and was treated with nivolumab after ureteral stent replacement. No effective treatment was proposed in cancer multigene panel testing, and she died 66 months after the initial treatment because of disease progression. Comprehensive multidisciplinary treatment, including surgical and local therapy for peritoneal dissemination based on drug therapy for unresectable advanced gastric cancer, may result in long-term survival. Further research and accumulation of such cases would lead to the development of novel treatments.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

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

Increased Expressions of Programmed Death Ligand 1 and Galectin 9 in Transplant Recipients Who Achieved Tolerance After Immunosuppression Withdrawal.

Programmed death 1 (PD1)/its ligand PD-L1 concomitant with T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)/its ligand galectin 9 (Gal-9) and the forkhead box P3 (FOXP3) might be involved in tolerance after liver transplantation (LT). Liver biopsies from 38 tolerant, 19 nontolerant (including 16 samples that triggered reintroduction of immunosuppression [IS] and 19 samples after IS reintroduction), and 38 control LT patients were studied. The expressions of PD1, PD-L1, Gal-9, and FOXP3 were determined by immunohistochemical and immunofluorescence (IF) staining. The success period of IS withdrawal was calculated using Kaplan-Meier curve analysis. Tolerant and control patients exhibited higher PD-L1, Gal-9, and FOXP3 levels than nontolerant patients at the moment of triggering IS reintroduction. High expressions of PD-L1 and Gal-9 were associated with prolonged success of tolerance (83.3% versus 36.7% [P < 0.01] and 73.1% versus 42.9% [P = 0.03]). A strong correlation between PD-L1 and Gal-9 expression levels was detected (Spearman r = 0.73; P ≤ 0.001), and IF demonstrated colocalization of PD-L1 and Gal-9 in the cytoplasm of hepatocytes. In conclusion, the present study demonstrated that increased expressions of PD-L1 and Gal-9 were associated with sustained tolerance after IS withdrawal in pediatric liver transplantation.

Impact of Preoperative CEA Uptrend on Survival Outcomes in Patients with Colorectal Liver Metastasis After Hepatectomy.

BACKGROUND: Preoperative carcinoembryonic antigen (CEA) has been reported as a prognostic factor in patients with colorectal liver metastasis (CRLM) after hepatectomy. However, the impact of a preoperative "CEA uptrend" on prognosis after hepatectomy in these patients remains unknown. This study assessed the impact of CEA uptrend on prognosis in patients undergoing hepatectomy for CRLM. METHODS: Consecutive patients with CRLM who underwent hepatectomy between 2009 and 2018 were retrospectively analyzed. Patients with CRLM for whom CEA was measured both around 1 month before (CEA-1m) and within 3 days (CEA-3d) before hepatectomy were enrolled. A CEA-3d higher than both the upper limit of normal (5 ng/ml) and CEA-1m was defined as a CEA uptrend. RESULTS: Study participants comprised 212 patients with CRLM. Of these, 88 patients (41.5%) showed a CEA uptrend. CEA uptrend indicated better discriminatory ability (corrected Akaike information criteria, 733.72) and homogeneity (likelihood ratio chi-square value, 18.80) than CEA-3d or CEA-1m. Patients with CEA uptrend showed poorer overall survival than those without CEA uptrend (p < 0.001). After adjusting for known prognostic factors, the prognostic significance of CEA uptrend retained (hazard ratio 2.63, 95% confidence interval 1.63-4.26, p < 0.001). In subgroup analyses, the prognostic significance of CEA uptrend was retained irrespective of the status of RAS mutation or response to preoperative chemotherapy. CONCLUSIONS: CEA uptrend offers better prediction of survival outcomes than conventional CEA measurements in patients undergoing hepatectomy for CRLM.