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Purpose: Pancreatoduodenectomy (PD) is a highly invasive procedure. Intra-abdominal infections and pancreatic fistulas are strongly correlated complications. In the present study, we identified the risk factors for postoperative early drain colonization (POEDC) and established a perioperative management strategy., Methods: A total of 205 patients who underwent pancreatoduodenectomy were included in the study. POEDC was defined as a positive drain fluid culture before postoperative day (POD) 4. We retrospectively investigated the correlation between POEDC, postoperative outcomes, and clinical factors., Results: POEDC was observed in 26 patients (12.6%) with poor postoperative outcomes, including pancreatic fistulas (P < 0.001). A multivariate analysis demonstrated a correlation between these postoperative outcomes and the age (P = 0.002), body mass index (BMI) (P = 0.002), procalcitonin (PCT) level (P < 0.001), and drain amylase level on POD 1 (P = 0.032). Enterococcus was detected most frequently, being found in 15 patients., Conclusion: We observed a strong correlation between POEDC and poor postoperative outcomes. The BMI, age, and PCT and drain amylase level on POD 1 should be considered POEDC risk factors, with the need to propose an antibiotic perioperative strategy. POEDC control may represent the key to improving postoperative outcomes after PD., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Microvascular invasion (MVI) is a risk factor for postoperative recurrence of hepatocellular carcinoma (HCC), even in early-stage HCC. In small HCC ≤ 3 cm, treatment options include anatomical resection or non-anatomical resection, and MVI has a major effect on treatment decisions. We aimed to identify the predictors of MVI in small HCC ≤ 3 cm., Methods: We retrospectively studied 129 patients with very early or early-stage HCC ≤ 3 cm who had undergone 18 F-fluorodeoxyglucose positron emission tomography/computed tomography and subsequent hepatic resection from January 2016 to August 2023. These patients were divided into the derivation cohort (n = 86) and validation cohort (n = 43). We examined the risk factors for MVI using logistic regression analysis, and established a predictive scoring system in the derivation cohort. We evaluated the accuracy of our scoring system in the validation cohort., Results: In the derivation cohort, a Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3), prothrombin induced by vitamin K deficiency or antagonist-II (PIVKA-II), and metabolic tumor volume (MTV) were independent predictors of MVI. We established the scoring system using these three factors. In the validation test, there were no MVI-positive cases with a score of 0 and 1, and all cases were MVI-positive with a score of 4. Moreover, with a score ≥ 2, the sensitivity, specificity, and accuracy of our scoring system were 100%, 71.4%, and 81.4%, respectively., Conclusions: Our scoring system can accurately predict MVI in small HCC ≤ 3 cm, and could contribute to establishing an appropriate treatment strategy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Pancreatic cancer is still a difficult disease to treat, despite recent advances in surgical techniques and chemotherapeutic drugs. Its incidence continues to rise, as does the number of older patients. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass and strength. Sarcopenia is present in approximately 40% in patients with pancreatic cancer. Sarcopenia is primarily diagnosed through imaging, and progress is being made in the development of automated methods and artificial intelligence, as well as biomarker research. Sarcopenia has been linked to a poor prognosis in pancreatic cancer patients. However, some studies suggest that sarcopenia is not always associated with a poor prognosis, depending on the resectability of pancreatic cancer and the nature of treatment, such as surgery or chemotherapy. Recent meta-analyses have found that sarcopenia is not linked to postoperative complications. It is still debated whether there is a link between sarcopenia and drug toxicity during chemotherapy. The relationship between sarcopenia and immunity has been investigated, but the mechanism is still unknown., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Sarcopenia is a poor prognostic factor in cancer patients. In recent years, there have been reports that serum creatinine and cystatin C (Cr/CysC) ratio is associated with sarcopenia. However, the prognostic value of the Cr/CysC ratio in biliary tract cancer is unclear. We evaluated the impact of the Cr/CysC ratio on sarcopenia and prognosis in biliary tract cancer., Methods: We retrospectively reviewed the records of 190 patients with biliary tract cancer who had undergone surgical resection from January 2017 to March 2023. Frozen serum samples collected at the time of surgery were used to measure CysC. We calculated the Cr/CysC ratio and investigated the relationship with sarcopenia and the prognostic significance., Results: We calculated the cutoff value of the Cr/CysC ratio for low skeletal muscle index (SMI) (< 42 cm 2 /m 2 for males and < 38 cm 2 /m 2 for females). The optimal cutoff value of the Cr/CysC ratio was 0.848. The low Cr/CysC ratio group was significantly associated with higher preoperative CRP and lower albumin, lower SMI, lower handgrip strength, and higher intramuscular adipose tissue content. In multivariate analysis, patients with a low Cr/CysC ratio showed poorer overall survival (hazard ratio 2.60, 95% confidence interval 1.07-6.29, p = 0.033), which was significantly worse than in those with a high Cr/CysC ratio., Conclusions: In patients with biliary tract cancer, the Cr/CysC ratio showed weak correlation with sarcopenic indicators. However, the Cr/CysC ratio could be strong prognostic factor in biliary tract cancer., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: Chyle leakage (CL) is a common complication in pancreatic surgery. Lymphangiography is a therapeutic option for CL in cases of conservative treatment failure. This study investigated the effect of lymphangiography on the healing time of CL., Methods: We retrospectively evaluated 283 patients who underwent pancreatic resection between January 2016 and June 2022. The risk factors for CL and the treatment period were evaluated according to whether or not lymphangiography was performed., Results: Of the 29 patients (10.2%) that had CL, lymphangiography was performed in 6. Malignant disease, the number of harvested lymph nodes, and drain fluid volume on postoperative day 2 were identified as independent risk factors for CL. Lymphangiography was associated with the cumulative healing rate of CL, and patients who underwent lymphangiography had a significantly shorter treatment period. No lymphangiography-related adverse events were observed., Conclusion: Lymphangiography is a feasible and safe treatment option for CL. The CL treatment period after pancreatic surgery was significantly shorter in patients who underwent lymphangiography than in those who did not. Our results suggest that lymphangiography may contribute to early improvement of persistent CL., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Aims: This study aimed to determine the value of the drainage fluid volume and direct bilirubin level for predicting significant bile leakage (BL) after hepatectomy and establish novel criteria for early drain removal., Methods: Data from 351 patients who underwent hepatic resection at Gunma University in Japan between October 2018 and March 2022 were retrospectively analyzed. Clinical characteristics and surgical outcomes of patients with and without significant BL were compared. Criteria for early drain removal were determined and verified., Results: Bile leakage occurred in 27 (7.1%) patients; 8 (2.3%) had grade A leakage and 19 (5.4%) had grade B leakage. The optimal cut-off value for the drainage fluid direct bilirubin level on postoperative day (POD) 2 was 0.16 mg/dL, which had the highest area under the curve and negative predictive value (NPV). Patients with BL had significantly larger drainage volumes on POD 2. The best cut-off value was 125 mL because it had the greatest NPV. Patients in both the primary and validation (n = 90) cohorts with bilirubin levels less than 0.16 mg/dL and drainage volumes less than 125 mL did not experience leakage., Conclusions: A drainage fluid volume less than 125 mL and direct bilirubin level less than 0.16 mg/dL on POD 2 are criteria for safe early drain removal after hepatectomy., (© 2024 Japan Society of Hepatology.)

Background: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG-PET/CT) parameters are prognostic factors in multiple malignancies. However, the prognostic value in bile duct carcinoma is unclear. We evaluated the impact of metabolic parameters of 18 F-FDG-PET/CT in resectable extrahepatic bile duct carcinoma., Methods: We retrospectively reviewed the records of 100 patients with extrahepatic bile duct carcinoma who had undergone 18 F-FDG-PET/CT and subsequent surgical resection between January 2017 and January 2023. We calculated maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and investigated their prognostic significance., Results: The optimal cutoff values of SUVmax, MTV, and TLG for predicting overall survival (OS) after surgery were 3.88, 3.55 and 7.55, respectively. In multivariate analysis, each metabolic parameter influenced both OS and recurrence-free survival (RFS). TLG showed the lowest Akaike information criteria statistic value, indicating that it had the best ability to predict OS and RFS. High TLG was significantly associated with the number of lymph node metastases and poorly differentiated type. Patients with high TLG showed poorer RFS and OS, which were significantly worse than in those with low TLG., Conclusions: Tumor TLG predicted tumor malignancy potential and could be a useful prognostic predictor for extrahepatic bile duct carcinoma., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Pancreatic cancer (PC) is a challenging malignancy to treat. Mac-2-binding protein glycan isomer (M2BPGi) is a novel serum marker of liver fibrosis and hepatocellular carcinoma and is secreted by hepatic stellate and stroma cells. Serum M2BPGi levels are upregulated in PC patients. We measured the expression of M2BPGi in the serum of 27 PC patients and determined whether M2BPGi affects the malignant potential of PC cells in vitro. We also examined the effect of M2BP on PC tumor growth and gemcitabine sensitivity in vivo. Serum M2BPGi levels in PC patients were higher compared with those of healthy subjects. M2BPGi extraction in cancer-associated fibroblasts (CAFs) was higher compared with that of PC cells. M2BPGi treatment promoted the proliferation and invasion of PC cells. The suppression of galectin-3, which binds to M2BPGi, did not affect the proliferation-promoting effect of M2BPGi in PC cells. The suppression of M2BP reduced tumor growth and enhanced gemcitabine sensitivity in PC-bearing xenograft mice. CAF-derived M2BPGi promotes the proliferation and invasion of PC cells. Targeting M2BPGi may represent a new therapeutic strategy to circumvent refractory PC., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Increasing evidence suggests that nutritional indices, including the geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI), are predictors of poor prognosis in patients with hepatocellular carcinoma (HCC). Hence, this study aimed to explore the value of the GNRI and PNI in evaluating postoperative prognosis in patients with HCC, particularly regarding its recurrence patterns. We performed a retrospective analysis of 203 patients with HCC who underwent initial hepatic resection. Patients were divided into two groups according to the GNRI (cutoff: 98) and PNI (cutoff: 45). The GNRI and PNI were significantly associated with body composition (body mass index and skeletal muscle mass index), hepatic function (Child-Pugh Score), tumor factors (tumor size and microvascular invasion), and perioperative factors (blood loss and postoperative hospitalization). Patients with a low PNI or low GNRI had significantly worse overall survival (OS) and recurrence-free survival. Patients with early recurrence had lower PNI and GNRI scores than those without early recurrence. Patients with extrahepatic recurrence had lower PNI and GNRI scores than those without extrahepatic recurrence. The PNI and GNRI might be useful in predicting the prognosis and recurrence patterns of patients with HCC after hepatic resection.

Aim: Laparoscopic segmentectomy (LS) using indocyanine green (ICG) fluorescence navigation with negative staining method has potential for performing accurate and safe anatomical excision. This study aimed to evaluate the significance of LS using ICG fluorescence navigation compared with open segmentectomy (OS)., Methods: Eighty-seven patients who underwent anatomical segmentectomies were evaluated for OS ( n  = 44) and LS ( n  = 43). The Glissonean pedicle approach was performed using either extra- or intrahepatic method, depending on the location of segment in LS. After clamping pedicle, negative staining method was performed. Liver transection was done along intersegmental plane visualizing by overlay mode of ICG camera. Surgical outcomes were compared between two groups. Correlation between predicted resecting liver volume (PRLV) calculated using volumetry and actual resected liver volume (ARLV) was assessed in two groups., Results: Patients who underwent LS showed better outcomes in operative time, blood loss, and length of hospital stay. There were significantly fewer Grade II and Grade III or higher postoperative complications in LS group. Both values of AST ( p  < 0.001) and ALT ( p  < 0.001) on postoperative day 1 were significantly lower in LS group than in OS group. PRLV and ARLV were more strongly correlated in LS ( r  = 0.896) than in OS ( r  = 0.773). The difference between PRLV and ARLV was significantly lower in LS group than in OS group ( p  = 0.022), and this trend was particularly noticeable in posterosuperior segment ( p  = 0.008) than in anterolateral segment ( p  = 0.811)., Conclusion: LS using ICG navigation allows precise resection and may contribute to safer short-term outcomes than OS, particularly in posterosuperior segment., Competing Interests: Ken Shirabe, who is a co‐author of this article, is an editorial member in the Annals of Gastroenterological Surgery. The authors declare no other conflicts of interest for this article., (© 2024 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Background: Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. As reported in previous studies, the loss of skeletal muscle mass is associated with poor liver regeneration after hepatectomy. It is considered important to clarify the effect of sarcopenia on liver regeneration; however, there are no reports about model animals for sarcopenia. We focused on the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) transgenic mice that overexpressed PGC-1α, specifically for skeletal muscle, and showed significant atrophy of type 2B fiber-rich muscles like sarcopenia., Methods: We performed 70% hepatectomy using PGC-1α transgenic mice and examined the liver regeneration rate and the effects of branched-chain amino acids (BCAA) after hepatectomy., Results: Liver regeneration after 70% hepatectomy was significantly suppressed in the PGC-1α transgenic mice. In addition, a decrease in the blood BCAA concentration and a decrease in the liver glycogen content after 70% hepatectomy were observed in the PGC-1α transgenic mice. By administering BCAA before and after surgery, it was clarified that a significant increase in the blood BCAA concentration was observed and the liver regeneration rate was improved in the PGC-1α transgenic mice., Conclusions: BCAA administration may improve the suppression of liver regeneration in patients with sarcopenia., (© 2023 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The recurrence rate after curative resection for hepatocellular carcinoma (HCC) reaches over 70% after 5 years and early recurrence (within 1 year) is now recognized as having a poor prognosis and has limited treatment options., Methods: We retrospectively reviewed 184 consecutive patients who underwent curative hepatic resection for HCC. Severe early recurrence was defined as multiple (beyond up-to-7) liver recurrence or distant metastasis after hepatic resection within 1 year. We divided the participants into two groups according to severe early recurrence and analyzed clinicopathological and long-term outcomes., Results: Among the patients with multiple or distant metastasis (n = 59), 49 patients (83%) had recurrence within 1 year. Overall survival (OS) and recurrence-free survival (RFS) were significantly worse in the severe early recurrence group than in the others group. Logistic regression analysis revealed that severe early recurrence was significantly associated with macroscopic vascular invasion (MVI), tumor burden score (TBS) > 4.70, and ALBI grade 2. In patients with scores of 2 and 3 (the sum of the three factors), OS and RFS rates were significantly poorer than those of patients with scores of 0 or 1. Positive predictive value and negative predictive value for severe early recurrence was 68.4% and 84.2%, respectively. Furthermore, a validation study demonstrated that cases with these factors were at high risk of severe early recurrence and had poor prognosis., Conclusions: In this retrospective analysis, MVI, TBS, and ALBI could predict severe early recurrence after hepatic resection for HCC, and patients with these risk factors had a poor prognosis., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Antibody-mimetic drug conjugate (AMDC) is a cancer cell-targeted drug delivery system based on the non-covalent binding of mutated streptavidin and modified biotin, namely Cupid and Psyche. However, the development of AMDCs is hampered by difficulties in post-translational modification or poor internalization activity. Here, we report an expression, refolding, and purification method for AMDC using a variable heavy chain of heavy chain-only antibodies (VHHs). Monomeric anti-HER2 VHH fused to Cupid was expressed in Escherichia coli inclusion bodies. Solubilization and refolding at optimized reducing conditions and pH levels were selected to form a functional, tetrameric protein (anti-HER2 VHH-Cupid) that can be easily purified based on molecular weight. Anti-HER2 VHH-Cupid non-covalently creates a tight complex with Psyche linked to a potent DNA-alkylating agent, duocarmycin. This complex can be absorbed by the HER2-expressing human breast cancer cell line, KPL-4, and kills KPL-4 cells in vitro and in vivo. The production of a targeting protein with internalizing activity, combined with the non-covalent conjugation of a highly potent payload, renders AMDC a promising platform for developing cancer-targeted therapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nitric oxide (NO) is a natural reactive nitrogen species (RNS) that alters proteins, DNA, and lipids and damages biological activities. Although microorganisms respond to and detoxify NO, the regulation of the cellular metabolic mechanisms that cause cells to tolerate RNS toxicity is not completely understood. We found that the proline and arginine auxotrophic proA5 and argB2 mutants of the fungus Aspergillus nidulans require more arginine and proline for normal growth under RNS stress that starves cells by accumulating fewer amino acids. Fungal transcriptomes indicated that RNS stress upregulates the expression of the biosynthetic genes required for global amino acids, including proline and arginine. A mutant of the gene disruptant, cpcA , which encodes the transcriptional regulation of the cross-pathway control of general amino acid synthesis, did not induce these genes, and cells accumulated fewer amino acids under RNS stress. These results indicated a novel function of CpcA in the cellular response to RNS stress, which is mediated through amino acid starvation and induces the transcription of genes for general amino acid synthesis. Since CpcA also controls organic acid biosynthesis, impaired intermediates of such biosynthesis might starve cells of amino acids. These findings revealed the importance of the mechanism regulating amino acid homeostasis for fungal responses to and survival under RNS stress.

RNF31 is a multifunctional RING finger protein implicated in various inflammatory diseases and cancers. It functions as a core component of the linear ubiquitin chain assembly complex (LUBAC), which activates the nuclear factor kappaB (NF-κB) pathway via the generation of the Met1-linked linear ubiquitin chain. We aimed to clarify the role of RNF31 in the pathogenesis of hepatocellular carcinoma (HCC) and its relevance as a therapeutic target. High RNF31 expression in HCC, assessed by both immunohistochemistry and mRNA levels, was related to worse survival rates among patients with HCC. In vitro experiments showed that RNF31 knockdown in HCC cell lines led to decreased cell proliferation and invasion, as well as suppression of tumor necrosis factor (TNF)-α-induced NF-κB activation. Treatment with HOIPIN-8, a specific LUBAC inhibitor that suppresses RNF31 ubiquitin ligase (E3) activity, showed similar effects, resulting in decreased cell proliferation and invasion. Our clinical and in vitro data showed that RNF31 is a prognostic factor for HCC that promotes tumor aggressiveness via NF-κB activation., (© 2024. The Author(s).)

Background: There are few studies that examined the relationship between preoperative zinc (Zn) concentrations and postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP)., Methods: Data from 98 patients who underwent DP between January 2016 and April 2022 were retrospectively reviewed. Patients' clinicopathological and surgical outcomes were analyzed, and we examined the relationship between Zn and clinically relevant POPF (CR-POPF) after DP., Results: In this series, 41 (41.8%) patients had POPF and 31 (31.8%) patients had CR-POPF. The cut-off value for the preoperative Zn concentration was 74 μg/dL for POPF and CR-POPF. Patients with low Zn concentrations were significantly related with high age, low albumin concentrations, higher CRP concentrations, higher NLR, lower PNI, higher rates of POPF and CR-POPF, longer POPF healing time, longer hospital stay, and postoperative complications than patients with high Zn concentrations. The healing time of POPF after DP was significantly negatively correlated with serum Zn concentrations. A multivariate logistic regression analysis showed that preoperative lower Zn concentrations and a prolonged operation time were independent predictors of CR-POPF and the healing time of POPF after DP. The POPF healing time in patients with high Zn was significantly shorter than that in patients with low Zn concentrations., Conclusions: This retrospective study showed the association between the preoperative Zn concentrations and the occurrence of POPF and the healing time after DP. Zn is a simple biomarker for malnutrition, which may lead to POPF after DP., (© 2023 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Hepatocellular carcinoma (HCC) is a life-threatening complication of hemophilia. Reports of patients with hemophilia undergoing hepatectomy for HCC are scarce. We report the cases of patients with hemophilia A and B who underwent laparoscopic hepatectomy for HCC. Perioperative hemophilia management was supervised by the hematology team. The patients received coagulation factor bolus injections immediately preoperatively, then continuous intravenous infusions intra- and postoperatively. A laparoscopic segment II partial hepatectomy was performed in case 1. Due to severe adhesions, intermittent pedicle clamping could not be used during parenchymal transection. The surgical duration was 235 min, and the estimated blood loss was 13 mL. The patient was discharged 11 days postoperatively without any complications. In case 2, laparoscopic partial hepatectomy for segments V/VI was performed. An intermittent pedicle clamp (Pringle method) was used during parenchymal transection. The surgical duration and estimated blood loss were 219 min and 18 mL, respectively. The patient was discharged 8 days postoperatively without complications. In both cases, intraoperative bleeding was minimal, and the patients were discharged without postoperative hemorrhage with appropriate perioperative coagulation factor management. Laparoscopic hepatectomy can be safely performed and appears to be a feasible treatment option for HCC in patients with hemophilia., (© 2023. Japanese Society of Gastroenterology.)

Aim: A recent study reported the utility of the definition of malnutrition according to the Global Leadership Initiative on Malnutrition (GLIM) criteria in many types of cancers and chronic inflammatory disease. The present retrospective study aimed to investigate the significance of malnutrition defined with GLIM criteria in patients with hepatic resection for hepatocellular carcinoma (HCC) and also to compare malnutrition using handgrip strength., Methods: We retrospectively reviewed data from 174 patients who had undergone curative hepatic resection for HCC including both skeletal muscle area and handgrip strength. Patients were divided according to malnutrition defined by GLIM or modified GLIM and clinicopathologic and short- and long-term outcomes were analyzed. The modified GLIM criteria was defined using both handgrip strength and skeletal muscle area., Results: Malnutrition defined by GLIM criteria was diagnosed in 47 patients (26.7%) and malnutrition defined by modified GLIM criteria was diagnosed in 21 patients (11.9%). Malnutrition defined by GLIM or modified GLIM criteria was associated with poorer liver function and malignant tumor behavior, but modified GLIM criteria predicted the postoperative complication and recurrence-free survival outcome independently. In patients with poor liver function, malnutrition defined by modified GLIM criteria predicted postoperative complication and overall and recurrence-free survival., Conclusions: Malnutrition defined by modified GLIM criteria using both handgrip strength and skeletal muscle area can more accurately predict short- and long-term outcomes compared to malnutrition defined by the GLIM criteria. Nutritional and exercise therapy could become more important in patients with malnutrition and poor liver function., (© 2023 Japan Society of Hepatology.)

Background: Fibrolamellar hepatocellular carcinoma (HCC) (FL-HCC) is rare in Japan. FL-HCC develops in young patients with no history of cirrhosis and tends to manifest lymphatic metastasis with clinical features similar to those of HCC. We present a case of FL-HCC in a young male patient., Case Presentation: A 14-year-old male patient underwent abdominal computed tomography (CT) to diagnose appendicitis, wherein a hepatic tumor was detected. Dynamic enhanced CT revealed a 35-mm solid tumor, which contrasted at the early phase of dynamic enhanced study of the right hepatic segments, with occlusion of the right portal vein. We performed right hepatectomy for these lesions. The patient experienced a single lymphatic recurrence on the hepatoduodenal ligament 12 months after the initial surgery. We performed lymphadenectomy for the recurrent tumor. We performed RNA sequencing (RNA-seq) and targeted DNA sequencing of the resected specimens (primary tumor, lymphatic metastasis, and normal liver). RNA-seq detected DNAJB1-PRKACA in both primary and metastatic lesions as previously reported. Furthermore, The Cancer Genome Atlas (TCGA) database was used to compare other gene expressions in this case with those of previously reported cases of FL-HCC and HCC in young patients. Principal component analysis of differentially expressed genes in the top 10% revealed that the gene expression in our case was similar to that of previous FL-HCC cases but was a different cluster from that in HCC cases in young patients. Mutational analysis did not detect any somatic mutations associated with carcinogenesis, including previously reported mutations (Kastenhuber et al. in Proc Natl Acad Sci USA 114: 13076-84, 2017)., Conclusion: We encountered a case of FL-HCC, a rare hepatic tumor in an adolescent patient, and evaluated the genetic background. Our findings could contribute to the elucidation of the mechanisms underlying carcinogenesis and progression in patients with FL-HCC and thereby contribute to the development of new therapeutic strategies in the future that may improve patient prognosis., (© 2023. Japan Surgical Society.)

Background: Chemotherapy for colorectal liver metastasis (CRLM) has improved dramatically over the past few decades. However, sinusoidal obstruction syndrome (SOS) induced by oxaliplatin leads to increased severe morbidity after hepatectomy for CRLM. Autotaxin is a novel liver fibrosis marker known to be taken up and metabolized by sinusoidal endothelial cells. This study aimed to evaluate whether autotaxin levels could be a novel surrogate marker of SOS for CRLM., Methods: We retrospectively evaluated 73 consecutive patients who underwent hepatectomy for CRLM, and assessed the relationship between their preoperative autotaxin levels and SOS., Results: Median autotaxin level was 0.750 mg/L. Preoperative oxaliplatin-based chemotherapy for CRLM was administered to 51 patients, and SOS was histologically observed in 45 patients. Patients who received the oxaliplatin-based chemotherapy had significantly higher autotaxin levels than those who did not (p = 0.038). Furthermore, autotaxin levels were higher in patients with SOS than in those without (p = 0.011). Univariate and multivariate analyses revealed that autotaxin level can be an independent predictive factor for SOS preoperatively (p = 0.001)., Conclusions: Autotaxin level is a noninvasive and promising surrogate marker for predicting SOS before surgical resection for CRLM., (© 2023 Japan Society of Hepatology.)

Background: Pancreatic cancer has an extremely poor prognosis and is one of the most chemoresistant cancers. Targeting cancer cell transcriptional complexes may enhance chemotherapy effectiveness. RNA-polymerase I (Pol-I)-mediated transcription is an essential initial step for ribosome biogenesis and is related to cancer cell proliferation. RRN3 is a Pol-I-specific transcription initiation factor. In this study, we aimed to elucidate the function and clinical significance of RRN3 in pancreatic cancer., Methods: We performed immunohistochemical staining to detect RRN3 protein expression in 96 pancreatic cancer tissues and analyzed the relationship between RRN3 protein expression, clinicopathological factors, and cancer patient prognosis. Moreover, we evaluated RRN3 function in vitro and in vivo using proliferation, invasion, and chemosensitivity assays in PANC-1 and SW1990 cell lines, with/without depleting RRN3 expression., Results: RRN3 was mainly expressed in cancer cell nuclei. High levels of RRN3 expression were associated with Ki-67 expression and shorter overall survival. Additionally, proliferation and invasion ability were decreased when RRN3 was silenced with siRNA, compared to non-targeting siRNA-transfected cells. Chemosensitivity analysis showed that inhibition of RRN3 enhanced the sensitivity of pancreatic cancer cell lines to gemcitabine and paclitaxel. RRN3 siRNA-transfected PANC-1 tumors showed significantly reduced tumor volumes and high gemcitabine sensitivity compared to the control in a mouse xenograft model., Conclusion: High levels of RRN3 expression are associated with poor prognosis and cancer malignancy, such as proliferation, invasion ability, and chemosensitivity in pancreatic cancer. RRN3 targeting with anticancer drugs may be a promising therapeutic strategy to overcome refractory pancreatic cancer., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background/aim: Theoretically, laparoscopic procedures reduce the incidence of surgical site infection (SSI) compared with open surgery. This study aimed to investigate whether laparoscopic liver resection (LLR) attenuates organ-space SSI compared with open liver resection (OLR) using propensity score-matched (PSM) analysis., Patients and Methods: This study included 530 patients who underwent liver resection as the original cohort. PSM was conducted to adjust for confounding factors between OLR and LLR. Two groups were compared regarding the incidence of postoperative complications, including organ-space SSI. We also evaluated risk factors for organ-space SSI using univariate and multivariate analyses., Results: In the original cohort, incidence of bile leakage (p<0.001) and organ-space SSI (p<0.001) were significantly lower in the LLR group than those in the OLR group. A pair of 105 patients were selected for the PSM analysis. After matching, LLR was significantly associated with lower blood loss (p<0.001), longer Pringle clamp time (p<0.001), lower incidence of bile leakage (p=0.035), organ-space SSI (p=0.035), Clavien-Dindo grade ≥III complications (p=0.005), and longer length of hospital stay (p<0.001) than OLR. In multivariate analysis, OLR (p=0.045) was an independent risk factor for organ-space SSI., Conclusion: LLR has potential to reduce the risk of organ-space SSI caused by intra-abdominal abscess and bile leakage more than OLR., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study aimed to evaluate the usefulness of the serum creatinine/cystatin C (Cr/CysC) ratio as a prognostic factor after pancreatic surgery in patients with pancreatic cancer., Methods: We retrospectively analyzed the data of 88 patients with pancreatic ductal carcinoma who underwent pancreatic surgery from January 2017 to December 2020. CysC measured from frozen serum samples and circulating Cr levels were used to calculate the Cr/CysC ratio. The cutoff value of the Cr/CysC ratio was determined using receiver operating characteristic curves. Cox proportional hazards model analysis and survival curves were applied to identify the prognostic factors., Results: The optimal cutoff value of the Cr/CysC ratio for predicting mortality after surgery was 1.05. This study included 20 (22.7%) and 68 (77.3%) patients with high and low Cr/CysC ratios, respectively. The low Cr/CysC ratio was significantly associated with female sex ( p  = 0.020) and higher levels of C-reactive protein ( p  = 0.020). The postoperative length of stay was significantly longer in patients with low Cr/CysC rates ( p  = 0.044). Patients with low Cr/CysC ratio showed poorer prognosis in relapse-free survival (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.54-4.20; p  = 0.002) and overall survival (HR = 2.52, 95% CI: 1.04-6.10, p  = 0.041), respectively, which were significantly worse than in those with high Cr/CysC ratios ( p  = 0.003 and 0.049, respectively)., Conclusion: The Cr/CysC ratio could be a useful screening tool for predicting the prognosis of patients with pancreatic ductal carcinoma undergoing pancreatic surgery., Competing Interests: Author Ken Shirabe is an editorial board member of Annals of Gastroenterological Surgery. The other authors declare no conflict of interest for this article. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Background/purpose: To overcome liver failure, we focused on liver regeneration mechanisms by the activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs). It is known that the HSC-secreted Mac-2-binding protein glycan isomer (M2BPGi) activates KC in the fibrotic liver. However, its importance for liver regeneration of the HSCs/M2BPGi/KCs axis after hepatectomy is still unknown. The aim of this study was to clarify whether the HSC-derived M2BPGi can activate KCs after hepatectomy, and elucidate the new molecular mechanism of liver regeneration., Methods: We examined the effect of M2BPGi on human hepatocytes and KCs, and explored secretory factors from M2BPGi-activated KCs using proteomics. Furthermore, the effect on liver regeneration of glucose-regulated protein 78 (GRP78) as one of the M2BPGi-related secreted proteins was examined in vitro and in murine hepatectomy models., Results: Although M2BPGi had no hepatocyte-promoting effect, M2BPGi promoted the production of GRP78 in KCs. The KC-driven GRP78 promoted hepatocyte proliferation. GRP78 administration facilitated liver regeneration after 70% hepatectomy and increased the survival rate after 90% hepatectomy in mice., Conclusions: The M2BPGi-activated KCs secrete GRP78, which facilitates liver regeneration and improves the survival in a lethal mice model. Our data suggest that the new hepatotrophic factor GRP78 may be a promising therapeutic tool for lethal liver failure., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: Curative surgical treatment of biliary tract cancer is highly invasive and involves postoperative complications. Abdominal aortic calcification is a parameter that is reportedly linked to systemic arteriosclerosis. We measured the abdominal aortic calcification volume (AACV), assessed the correlation between AACV and postoperative complications, and evaluated the clinical utility of AACV., Methods: We retrospectively evaluated 97 patients (ampullary carcinoma, n = 21; distal bile duct cancer, n = 43; hilar bile duct cancer, n = 33). We assessed the calcification volume of the abdominal aorta from the renal artery ramification to the common iliac artery bifurcation. The correlation between AACV, clinical factors, and postoperative complications was evaluated., Results: The average AACV was 5.02 cm 3 , and the median AACV was 3.74 (range 0-27.4) cm 3 . The AACV was significantly related to age (P = 0.009), Brinkman index (P = 0.007), and history of cardiovascular disease (P = 0.015). The AACV was strongly correlated with postoperative complications (P < 0.001) and Clavien-Dindo grade > III postoperative complications (P < 0.001). The AACV was also correlated with pancreatic fistula in pancreatectomy cases (P < 0.001). A multivariate analysis revealed that the AACV was an independent predictor of postoperative complications., Conclusion: The AACV was significantly associated with postoperative complications. The AACV could be used for the preoperative assessment of surgical risk., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Hepatic vein embolization (HVE) added to portal vein embolization (PVE) can further increase future remnant liver volume (FRLV) compared with PVE alone. This study was aimed to evaluate feasibility of sequential HVE in a prospective trial and to verify surgical strategy using functional FRLV (fFRLV)., Methods: Hepatic vein embolization was prospectively indicated for post-PVE patients scheduled for right-sided major hepatectomy if the resection limit of fFRLV using EOB-magnetic resonance imaging was not satisfied. The resection limit was fFRLV: 615 mL/m 2 for predicting post-hepatectomy liver failure. Patients who underwent sequential PVE-HVE (n = 12) were compared with those who underwent PVE alone (n = 31)., Results: All patients underwent HVE with no severe complications. Median fFRLV increased from 396 (range: 251-581) to 634 (range: 422-740) mL/m 2 by sequential PVE-HVE. From PVE to HVE, both of FRLV (P < .001) and fFRLV (P = .005) significantly increased. The increased width of fFRLV was larger than that of FRLV after performing HVE. Median growth rate was 71.3 (range: 33.3-80.3) %, which was higher than that of PVE alone (27.0%, range: 6.0-78.0). All-cohort resection rate was 88.3%. Strategy of using fFRLV for the resection limit and performing HVE in patients with insufficient functional volume resulted in no liver failure in all patients who underwent hepatectomy., Conclusions: Sequential HVE after PVE is feasible and safe, and HVE induced possibility of further liver growth and its functional improvement. Our surgical strategy using fFRLV may be justified., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background/aim: The relationship between body composition including skeletal muscle and liver hypertrophy initiated by portal vein embolization (PVE) for major hepatectomy has not been clarified. This study aimed to investigate the effects of skeletal muscle, body adipose, and nutritional indicators on liver hypertrophy., Patients and Methods: Fifty-nine patients who underwent PVE scheduled for major right-sided hepatectomy were included. The skeletal muscle area of L3 as skeletal muscle index was calculated. The relationship between skeletal muscle loss and clinical variables was assessed. We also evaluated the relationship between >30% liver growth or >12% liver growth/week after PVE., Results: Skeletal muscle loss was observed in 39 patients (66.1%) and associated with zinc deficiency, visceral adipose index, liver growth rate, and liver growth rate/week. Multivariate analysis indicated that future liver volume and skeletal muscle index were associated with >30% liver growth, and functional future liver volume and skeletal muscle index were associated with >12% liver growth/week., Conclusion: Loss of skeletal muscle, and a small future remnant liver volume, attenuates liver hypertrophy initiated by PVE. Strength building and nutritional supplementation may have positive effects on liver hypertrophy after PVE., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study aimed to identify the potential risk for postoperative pancreatic fistula (POPF), a major complication of pancreaticoduodenectomy., Patients and Methods: This retrospective study included 124 patients with biliary and pancreatic disorders who underwent pancreaticoduodenectomy between 2015 and 2020. Bone marrow density (BMD) was determined in the 11th thoracic vertebra using preoperative computed tomographic images. Delta BMD (dBMD=measured BMD - standard BMD) was calculated using standard BMD determined on the basis of age and sex, and dBMD <0 was defined as osteopenia. The relationship between clinicopathological factors and dBMD was investigated., Results: The average BMD level was 140 Hounsfield units. BMD was significantly lower in women than in men (p<0.01) and in older patients than in younger patients (p<0.01). POPF was significantly correlated with low dBMD (p=0.032). Osteopenia was a risk factor for POPF in patients with soft pancreas (p=0.016)., Conclusion: Osteopenia was an independent risk factor for POPF after pancreaticoduodenectomy in patients with soft pancreas. Preoperative osteopenia assessment may be useful for the prediction of POPF, and preoperative vitamin D supplementation might be considered in patients with osteopenia., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Antibody-mimetic drug conjugate is a novel noncovalent conjugate consisting of an antibody-mimetic recognizing a target molecule on the cancer cell surface and low-molecular-weight payloads that kill the cancer cells. In this study, the efficacy of a photo-activating antibody-mimetic drug conjugate targeting HER2-expressing tumors was evaluated in mice, by using the affibody that recognize HER2 (Z HER2:342 ) as a target molecule and an axially substituted silicon phthalocyanine (a novel potent photo-activating compound) as a payload. The first treatment with the photo-activating antibody-mimetic drug conjugates reduced the size of all HER2-expressing KPL-4 xenograft tumors macroscopically. However, during the observation period, relapsed tumors gradually appeared in approximately 50% of the animals. To evaluate the efficacy of repeated antibody-mimetic drug conjugate treatment, animals with relapsed tumors were treated again with the same regimen. After the second observation period, the mouse tissues were examined histopathologically. Unexpectedly, all relapsed tumors were eradicated, and all animals were diagnosed with pathological complete remission. After the second treatment, skin wounds healed rapidly, and no significant side effects were observed in other organs, except for occasional microscopic granulomatous tissues beneath the serosa of the liver in a few mice. Repeated treatments seemed to be well tolerated. These results indicate the promising efficacy of the repeated photo-activating antibody-mimetic drug conjugate treatment against HER2-expressing tumors., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Factor V (FV) deficiency is an extremely rare disease, with an incidence of 1 in 1 million. The bleeding symptoms are mild, and the prognosis is good; however, the safety of surgical treatment is unclear, because there are few available reports. Herein, we report a case of hepatocellular carcinoma with congenital FV deficiency in a patient who safely underwent laparoscopic hepatectomy., Case Presentation: A 79-year-old man, diagnosed with hepatocellular carcinoma of liver segment 5, with type C cirrhosis and sustained virological response visited our hospital. He had congenital FV deficiency, and blood tests showed coagulation deficiencies with an FV activity of < 2.6%, prothrombin time activity of 11%, and activated partial thromboplastin time of 100.3 s. Surgery and radiofrequency ablation were considered for treatment. Since the tumor was in contact with the Glissonean pedicle 5 + 6, surgery was judged to be superior from the viewpoint of safety and curability. After discussing the safety of the surgery with a hematologist, it was determined that the operation could be performed safely by transfusing sufficient fresh frozen plasma (FFP). Laparoscopic hepatic segment 5 + 6 subsegmental resection was performed with FFP transfusion, fluid restriction, airway pressure control, and central venous pressure reduction to control the bleeding. Bleeding was minimized during the transection of the liver parenchyma and no bleeding tendency was observed. The operative time was 445 min, and the amount of intraoperative bleeding was 171 mL. No complications, such as postoperative bleeding, were observed, and the patient was discharged on the eighth postoperative day., Conclusions: Liver surgery can be performed safely in FV-deficient patients with strict coagulation capacity monitoring and appropriate transfusion of FFP. Preoperative evaluation of cardiac function to determine tolerance to high doses of FFP and ingenuity of surgery and intraoperative management to minimize blood loss are important., (© 2022. The Author(s).)

Background: The ratio of creatinine and cystatin C estimated glomerular filtration rates (eGFRcre/eGFRcys) is significantly positively correlated with sarcopenia. However, there are no published reports on the relationship between eGFRcre/eGFRcys and long-term prognosis in patients after hepatic resection for hepatocellular carcinoma (HCC)., Methods: A total of 157 patients who had undergone curative hepatic resection for HCC were retrospectively reviewed. Cystatin C levels were measured in serum samples that had been frozen after collection at surgery. We aimed to investigate the significance of cystatin C in prognostic value following hepatic resection for HCC., Results: The best cut-off eGFRcre/eGFRcys value for overall survival after hepatic resection for HCC was 1.0025. High eGFRcre/eGFRcys was significantly associated with poor liver function, low skeletal muscle mass, large tumor size, large ascitic volume, worse overall and recurrence-free survival. The eGFRcre/eGFRcys was significantly related to severe recurrence patterns (multiple liver recurrences, distant metastasis)., Conclusions: Preoperative eGFRcre/eGFRcys can predict overall and recurrence-free survival in HCC patients undergoing hepatic resection. The eGFRcre/eGFRcys is a simple and reliable surrogate marker that indicates eligibility for hepatic resection for HCC., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Although visceral aneurysms are relatively rare, it can be life-threatening in case it ruptures. We report a case of Mirizzi syndrome accompanied by a pseudoaneurysm that ruptured into the gallbladder., Case Presentation: The patient was a 73-year-old woman with persistent gastrointestinal bleeding and progressive jaundice. Examination revealed a pseudoaneurysm in the gallbladder artery or hepatic artery branch, and biliary hemorrhage due to gallbladder perforation was suspected. Urgent abdominal angiography revealed a pseudoaneurysm measuring 50 × 32 mm that had ruptured directly from the right hepatic artery or the cystic artery into the gallbladder. The pseudoaneurysm was successfully coiled and the bleeding was stopped. The presence of ongoing obstruction due to Mirizzi syndrome resulted in an emergency cholecystectomy being performed on the same day. On removing the impacted gallstone from the neck of the gallbladder, we found an obstruction between the lateral wall of the common bile duct and the gallbladder, this condition was diagnosed as Mirizzi syndrome with a biliobiliary fistula. After removing the impacted gallstone, a T-tube was inserted into the common bile duct. Bile leakage was observed postoperatively, but it improved with drainage. The patient fully recovered., Conclusions: We present our experience with a case of Mirizzi syndrome accompanied by a ruptured pseudoaneurysm successfully treated with coil embolization followed by cholecystectomy. In this case, the pseudoaneurysm may have been caused by inflammation due to cholecystitis or compression of the arterial wall by a gallstone. To the best of our knowledge, Mirizzi syndrome associated with pseudoaneurysm rupture is rare. Our study suggested that cholecystectomy preceded by transcatheter arterial embolization is an effective strategy to control bleeding in patients with hemobilia due to aneurysm., (© 2022. The Author(s).)