Potential of Mac-2-binding protein glycan isomer as a new therapeutic target in pancreatic cancer.

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.

Early drain removal after hepatectomy based on bile leakage prediction using drainage fluid volume and direct bilirubin level.

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.

Preoperative zinc status predicts the occurrence and healing time of pancreatic fistula after distal pancreatectomy.

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.

Impact of the serum creatinine and cystatin C ratio for prediction of sarcopenia and prognosis in biliary tract cancer.

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 cm2/m2 for males and < 38 cm2/m2 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.

Predictors for early recurrence beyond up-to-7 or distant metastasis after hepatocellular carcinoma resection: proposal for borderline resectable HCC.

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.

New predictors of microvascular invasion for small hepatocellular carcinoma ≤ 3 cm.

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 18F-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.

Perioperative pancreaticoduodenectomy management strategy focusing on postoperative early drain colonization.

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.

Significance of malnutrition defined with Global Leadership Initiative on Malnutrition criteria in patients with hepatocellular carcinoma after hepatic resection.

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.

Autotaxin is a novel surrogate marker for oxaliplatin-related sinusoidal obstruction syndrome in patients with colorectal liver metastasis.

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.

High RRN3 expression is associated with malignant characteristics and poor prognosis in pancreatic cancer.

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.

Abdominal aortic calcification volume (AACV) is a predictive factor for postoperative complications associated with biliary tract cancer.

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 cm3, and the median AACV was 3.74 (range 0-27.4) cm3. 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.

The impact of lymphangiograpy on chyle leakage treatment duration after pancreatic surgery.

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.

Significance of zinc deficiency in patients with hepatocellular carcinoma undergoing hepatic resection.

AIM: Few reported studies examine the relationship between zinc (Zn) deficiency and short- and long-term outcomes in patients with hepatocellular carcinoma undergoing hepatic resection. METHODS: We retrospectively reviewed data from 179 consecutive patients who had undergone curative hepatic resection for hepatocellular carcinoma in our institute between January 2016 and May 2019. Zn deficiency was defined in accordance with the Japanese Society of Clinical Nutrition guidelines. We allocated the participants into two groups according to Zn deficiency status, and analyzed the clinicopathological and short- and long-term outcomes. RESULTS: In this series, 32 patients (17.8%) had Zn deficiency. Zn deficiency was significantly associated with older age, lower serum albumin, higher aspartate aminotransferase, lower hemoglobin, higher creatinine, lower prognostic nutritional index, higher liver fibrosis markers, albumin-bilirubin 2, portal hypertension, larger amount of estimated blood loss, larger amount of maximum ascites, longer hospital stay, postoperative complications, and liver-related complications. Concentrations of liver fibrosis markers were negatively correlated with serum Zn concentrations. Zn deficiency, albumin-bilirubin 2, and non-laparoscopic approach were identified as independent predictors of postoperative complications. Multivariate analyses revealed that the overall survival rate decreased in parallel with decreasing Zn concentrations. CONCLUSIONS: In this study, Zn deficiency was significantly associated with poorer liver function, more severe liver fibrosis, higher incidence of postoperative complications, and worse overall survival according to multivariate analysis. Serum Zn status could serve as a new surrogate marker for predicting short- and long-term outcomes in patients undergoing hepatic resection for hepatocellular carcinoma.

Direct Bilirubin in Drainage Fluid 3 days after Hepatectomy Is Useful for Detecting Severe Bile Leakage.

INTRODUCTION: The International Study Group of Liver Surgery (ISGLS) definition of bile leakage is an elevated total bilirubin concentration in the drainage fluid after post-operative day (POD) 3, which has been widely accepted. However, there were no reports about direct bilirubin in drainage fluid to predict bile leakage. METHODS: Data from 257 patients who underwent hepatectomy were retrospectively reviewed. The optimal cut-off value was investigated using receiver-operating characteristic curves. The predictive power of drainage fluid total bilirubin (dTB) and drainage fluid direct bilirubin (dDB) to predict bile leakage, which was defined using ISGLS grade B or grade C, were compared. RESULTS: ISGLS grade B bile leakage occurred in 16 patients (6.2%). Area under the curve (AUC) of dDB was always higher than that of dTB on each POD. The AUC of dDB was >0.75 on PODs 2, 3, and 5, and then it increased with the increasing POD. The dDB on POD 5 showed the highest accuracy (0.91) and positive predictive value (PPV) (0.67), which was followed by dTB/serum total bilirubin (sTB) on POD 3 (accuracy, 0.91; PPV, 0.33). Because the PPV of dDB increased as the POD increased, dDB was better than dTB for predicting clinically significant bile leakage. dDB on POD 3 showed the highest negative predictive value (0.97). The positive likelihood of dDB increased and the negative likelihood of dDB decreased on the basis of the POD. Among patients with dTB/sTB ≤3 on POD 3, 19.1% of these patients had bile leakage when dDB was >0.44 on POD 3. CONCLUSIONS: Measurement of both dDB and dTB, which are easy to perform, can be used to effectively predict clinically significant bile leakage.

Gastrectomy history as a predictor of post-hepatectomy complications.

PURPOSE: The effect of a history of gastrectomy on patients undergoing hepatectomy is unclear. We investigated the relationship between postoperative complications of Clavien-Dindo grade III or higher and a history of gastrectomy in patients undergoing hepatectomy. METHODS: The subjects of this retrospective analysis were 474 consecutive patients who underwent hepatectomy at our institute for hepatic malignancy, classified into groups of those with or without a history of gastrectomy and those with or without postoperative complications. We compared the clinicopathological factors between the groups. RESULTS: There were no hospital deaths. Gastrectomy history was identified in 22 patients (4.6%) and was significantly associated with advanced age, low body mass index, male sex, decreased serum albumin level, decreased hemoglobin level, low PNI, low CONUT score, high incidence of postoperative complications, and longer hospital stay. Multivariate analyses revealed that the independent risk factors for postoperative complications were gastrectomy history, an albumin-bilirubin score of 2/3, primary liver cancer, high serum creatinine level, advanced age, and prolonged operation time. CONCLUSIONS: Gastrectomy history was an independent predictor of postoperative complications in patients undergoing hepatectomy for hepatic malignancies. Patients with a history of gastrectomy were likely to suffer postoperative bile leakage and pneumonia.

Does intraoperative and postoperative analgesia cause bile leakage after hepatectomy?

PURPOSE: To evaluate the effect of morphine or morphine equivalents on the risk of bile leakage (BL) after hepatectomy. METHODS: The subjects of this retrospective study were 379 patients who underwent hepatectomy without biliary reconstruction and biliary decompression tube insertion at Gunma University between 2016 and 2020. Clinical BL was defined as International Study Group of Liver Surgery post-hepatectomy bile leakage Grade B or C. RESULTS: Intra- and post-operative analgesia comprised intravenous patient-controlled analgesia (IV-PCA) with fentanyl (n = 58), epidural analgesia with fentanyl (n = 157), epidural analgesia with morphine (n = 151), and epidural analgesia with ropivacaine or levobupivacaine (n = 13). Clinical BL was diagnosed in 14 of the 379 (3.7%) patients. The significant risk factors for clinical BL were hepatocellular carcinoma (HCC), elevated serum total bilirubin, high indocyanine green retention at 15 min, elevated Mac-2-binding protein glycosylated isomer, prolonged duration of surgery, and a large volume of blood loss. There was no significant correlation of clinical BL with intra- and post-operative analgesia and total oral morphine equivalents. CONCLUSION: Intra- and post-operative IV-PCA and epidural analgesia were not related to clinical BL after hepatectomy. Based on our data, fentanyl and morphine can be administered safely as epidural or intravenous analgesic agents.

Prediction with functional liver volume assessment to achieve the resection limit after portal vein embolization in patients scheduled major hepatectomy.

BACKGROUND: Preoperative portal vein embolization (PVE) stimulates liver hypertrophy and improves the safety of major hepatectomy. It is essential to predict the future remnant liver volume (FRLV) and resection limit following PVE. Previously, we reported that evaluating functional FRLV (fFRLV) using EOB-MRI could predict post-hepatectomy liver failure. In this study, we investigated the usefulness of fFRLV in predicting the achieving of adequate resection limit for safe hepatectomy following PVE. METHODS: We included 55 patients who underwent PVE and were scheduled for major hepatectomy. We calculated the liver-to-muscle ratio in the remnant liver and fFRLV using EOB-MRI. We investigated the pre-PVE variables in determining the nonachievement of the resection limit. RESULTS: The median observation period between PVE and the first evaluation was 21 days, and the median growth rate of FRLV was 26.4%. In 54.5% of patients, the resection limit of fFRLV (615 mL/m2) was achieved. In logistic regression and receiver-operating characteristic analyses, pre-PVE fFRLV (p < 0.001, area under the curve: 0.852) was the reliable predictor of achieving the resection limit; the cutoff value of pre-PVE fFRLV was 446 mL/m2. CONCLUSION: Pre-PVE fFRLV can be useful in predicting the achievement of adequate resection limit following PVE.

High membrane expression of CMTM6 in hepatocellular carcinoma is associated with tumor recurrence.

CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) maintains membrane PD-L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma (HCC), the correlation among CMTM6, B7 family ligands, and CD8-positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6-knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki-67 and shorter recurrence-free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6-knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity.

FDG-PET for preoperative evaluation of tumor invasion in ampullary cancer: A retrospective analysis.

BACKGROUND: Tumor invasion is the most significant prognostic factor in ampullary cancer and is thus a crucial factor in decision making for treatment. Endoscopic ultrasound can be performed to evaluate tumor invasion, but its diagnostic accuracy varies depending on the endoscopist. This study aimed to assess the usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) for preoperatively predicting tumor invasion in ampullary cancer. METHODS: We retrospectively evaluated 44 patients with ampullary cancer (adenoma, n = 6; adenocarcinoma, n = 38) who underwent surgical resection. The SUVmax of the ampullary tumor site was assessed using FDG-PET, and the correlation among tumor invasion, lymph node metastasis, and other clinicopathological factors was evaluated. RESULTS: The SUVmax of the ampullary tumor site gradually increased depending on the extent of tumor invasion (p = 0.0075). Moreover, the SUVmax was significantly different between ≤T1a and ≥T1b, which is an indication for endoscopic papillectomy or surgical resection (p = 0.0015). The SUVmax of the ampullary section was significantly correlated with lymph node metastasis (p = 0.035). CONCLUSION: The SUVmax of the ampullary tumor site is correlated with tumor invasion and lymph node metastasis in ampullary cancer. Thus, FDG-PET can be a useful modality for preoperative staging and treatment strategy.

Hepatic stellate cell as a Mac-2-binding protein-producing cell in patients with liver fibrosis.

BACKGROUND: Mac-2 binding protein (M2BP) glycosylated isomer (M2BPGi) is a serum marker of liver fibrosis; M2BPGi is a glycosylated form of M2BP. Hepatocytes and hepatic stellate cells (HSCs) have been studied to determine the source of M2BP. This study proposes to identify the origin of M2BP in fibrotic liver. METHODS: Using liver fibrosis tissue specimens from 15 patients with liver cancer, M2BP mRNA and M2BP were detected by in situ hybridization and immunohistochemistry, respectively. The expression levels of M2BP mRNA were evaluated with scores of 3, 2, and 1. Fluorescent in situ hybridization was carried out to evaluate the distribution of M2BP mRNA and the activated-HSC marker αSMA mRNA; multicolor fluorescent immunohistochemistry was used for protein localization of M2BP, αSMA, and CD68. The Kruskal-Wallis test analyzed the relationship between M2BP mRNA expression and existing serum fibrosis markers. RESULTS: M2BP mRNA was expressed in spindle-shaped cells along the fibrous septa and in the perisinusoidal area of the fibrotic liver. The HSC markers αSMA mRNA and M2BP mRNA were colocalized in the spindle-shaped cells; on the protein level, M2BP was expressed in Kupffer cells. M2BP mRNA expression was positively correlated with serum M2BPGi levels. Aspartate transaminase-to-platelet ratio index, Fibrosis-4, hyaluronic acid, and the 15-minute indocyanine green retention rate were significantly correlated with M2BP mRNA expression. CONCLUSIONS: M2BP mRNA transcription in fibrotic liver was primarily observed in HSCs but not at the M2BP level, which suggests that HSCs might produce and introduce M2BP to Kupffer cells and serum.