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.

Lower Geriatric Nutritional Risk Index and Prognostic Nutritional Index Predict Postoperative Prognosis in Patients with Hepatocellular Carcinoma.

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.

Proposal for Prognosis-Oriented Definition of Borderline Resectable Hepatocellular Carcinoma.

BACKGROUND: Owing to advances in the multidisciplinary treatment of hepatocellular carcinoma (HCC), a conceptualization and definition for borderline resectable (BR) HCC, which carries a high risk of recurrence, is warranted. In this study, we aimed to define BR-HCC using a prognosis-oriented approach. STUDY DESIGN: The study included an original cohort of 221 patients and an independent validation cohort of 181 patients who had undergone primary hepatic resection for HCC. To define biological BR-HCC, we evaluated the risk factors for early recurrence beyond the Milan criteria within 1 year after hepatic resection using multivariable logistic regression models. Subsequently, we developed high-risk scores using the identified risk factors and defined BR-HCC. The utility of high-risk score was validated in the validation cohort. RESULTS: In the original cohort (hepatitis B virus:hepatitis C virus = 20%:29%), recurrence beyond the Milan criteria within 1 year was observed in 28 patients (13%), with a 5-year survival rate of 25%. Multivariable analysis identified risk factors for recurrence beyond the Milan criteria within 1 year, including serum alpha-fetoprotein levels of 12 ng/mL or more (p = 0.02), tumor diameters less than 5 cm (p = 0.02), tumor number 3 or more (p = 0.001), and macrovascular invasion (p = 0.04). BR-HCC was defined as a tumor with 2 or more identified risk factors, and 42 patients (19%) were diagnosed with BR-HCC, with a 5-year survival rate of 51%. In the validation cohort, 45 (25%) patients had BR-HCC, with a 5-year survival rate of 42%. CONCLUSIONS: The prognosis-oriented definition of BR-HCC enabled us to identify patients who are susceptible to early unresectable recurrence and have poor survival after hepatic resection for HCC. For patients with BR-HCC, preoperative systemic therapy may be a viable option to improve postresection outcomes.

Total lesion glycolysis by 18F-fluorodeoxyglucose positron emission tomography predicts tumor aggressiveness in patients with extrahepatic bile duct carcinoma.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-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 18F-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 18F-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.

Advantages of laparoscopic segmentectomy of the liver using ICG fluorescent navigation by the negative staining method: A comparison with open procedure.

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.

Successful radical surgery for lymph node metastasis in a patient with hepatocellular carcinoma following atezolizumab plus bevacizumab combination therapy: a case report and literature review.

A woman in her early 80 s was followed up in our hospital for chronic hepatitis C after viral eradication. We detected rapid-growing lymph node metastasis of hepatocellular carcinoma (HCC) after treatment with transcatheter arterial chemoembolization and/or radiofrequency ablation. We found that the metastasis was operable, but the size and location of the metastasis obliged the patient to receive pancreatoduodenectomy, which was too invasive. Then we initiated systemic chemotherapy to perform radical minimally invasive surgery. We treated the patient with 3 weekly cycles of atezolizumab 1200 mg plus bevacizumab 15 mg/kg. The patient tolerated the treatment well, and treatment-emergent adverse events included deterioration of hypertension and increased uric protein. After a total of 4 cycles of therapy, abdominal computed tomography findings showed that the metastasis evidently decreased, and a complete response was achieved based on the Revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Seventeen days later, the metastasis was dissected. Subsequently, we confirmed that there was no pathological metastatic lesion in the resected lymph node. Our case is the first report of successful application of the radical therapy to lymph node metastasis of HCC via combination therapy with atezolizumab/bevacizumab.

RNF31 promotes proliferation and invasion of hepatocellular carcinoma via nuclear factor kappaB activation.

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.