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.

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.

Liver regeneration after hepatectomy is significantly suppressed in a muscular atrophy mouse model.

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.

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.

Usefulness of serum creatinine and cystatin C ratio as a screening tool for predicting prognosis in patients with pancreatic cancer.

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.

Fibrolamellar hepatocellular carcinoma: a case report and gene analysis.

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.

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.

Laparoscopic Liver Resection Procedure Attenuates Organ-space Surgical Site Infection Compared With Open Procedure: A Propensity Score-matched Analysis.

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.

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.

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.

Significance of Skeletal Muscle Loss in Liver Hypertrophy in Patients Undergoing Portal Vein Embolization Before Major Hepatectomy: Assessment With Body Composition and Nutritional Indicators.

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.

Impact of Osteopenia on Pancreatic Fistula in Patients Undergoing Pancreaticoduodenectomy.

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.

Laparoscopic hepatectomy for hepatocellular carcinoma in a patient with congenital factor V deficiency: a case report.

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.

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.

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.

Skeletal Muscle Loss and Octogenarian Status Are Associated with S-1 Adjuvant Therapy Discontinuation and Poor Prognosis after Pancreatectomy.

The efficacy and prognosis of adjuvant chemotherapy for resected pancreatic cancer remain unclear. We investigated the utility and risk factors of S-1 adjuvant chemotherapy in patients with pancreatic cancer undergoing pancreatectomy. This study comprised 80 patients, including 58 patients who received S-1 adjuvant chemotherapy. Skeletal muscle loss was defined using cutoff values of skeletal muscle mass index. In total, 16 (20%) octogenarian patients underwent pancreatectomy. Skeletal muscle loss was present in 56 (70%) patients. The entire course of S-1 adjuvant chemotherapy for 6 months was completed in 33 patients (41%). S-1 adjuvant chemotherapy <6 months was an independent prognostic indicator of poor overall survival. Patients who completed S-1 adjuvant chemotherapy exhibited significantly longer overall and relapse-free survival rates than those did not complete the chemotherapy (p < 0.0001 and p = 0.0003, respectively). Being an octogenarian and skeletal muscle loss were independent variables associated with the discontinuation of S-1 adjuvant chemotherapy. Finally, the S-1 adjuvant chemotherapy rates were 6.3% (1/16) and 28.6% (16/56) in octogenarian patients and those with skeletal muscle loss, respectively. S-1 adjuvant chemotherapy completion was associated with improved prognosis in patients with pancreatic cancer. Skeletal muscle loss and octogenarian status predicted the failure of S-1 adjuvant chemotherapy completion.

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.

Impact of preoperative nutritional support and rehabilitation therapy in patients undergoing pancreaticoduodenectomy.

BACKGROUND: Sarcopenia is closely associated with morbidity after pancreatic surgery. We investigated the impact of preoperative nutritional support and rehabilitation on patients undergoing pancreaticoduodenectomy. METHODS: This was a retrospective analysis of 101 patients who underwent pancreaticoduodenectomy. Skeletal muscle (SM) loss was defined using the SM index (cutoff level: 42 cm2/m2 in men and 38 cm2/m2 in women). A total of 33 and 30 patients received preoperative nutrition and prehabilitation, respectively. The neutrophil-to-lymphocyte ratio (NLR), Prognostic Nutritional Index (PNI), and modified Glasgow Prognostic Score (mGPS) values were calculated during the first visit and immediately before surgery. RESULTS: SM loss was present in 65 of 101 patients and was significantly correlated with female sex, older age, lower body mass index, and low PNI. Preoperative nutritional support and prehabilitation prevented the decrease in PNI values in patients with SM loss. The NLR significantly improved in patients with SM loss who received nutritional support and prehabilitation. In patients with SM loss, the lack of preoperative nutrition and prehabilitation was an independent risk factor for postoperative pancreatic fistula. CONCLUSIONS: Preoperative nutritional support and prehabilitation may reduce the incidence of pancreatic fistula in patients with SM loss and improve the surgical outcomes of patients undergoing pancreaticoduodenectomy.

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.

Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein-coupled Receptor 68.

Treatment of hepatocellular carcinoma (HCC) is currently challenging. Cancer-associated fibroblasts (CAFs) promote the malignancy of HCC cells via production of cytokines. Conophylline (CnP), a vinca alkaloid obtained from Ervatamia microphylla leaves, has been reported to suppress activation of hepatic stellate cells and liver fibrosis in rats. We examined the efficacy of CnP in suppressing tumor growth in HCC. Specifically, we investigated whether CnP could inhibit CAFs, which were derived from HCC tissues in vitro and in vivo Same as previous reports, CAFs promoted proliferative and invasive ability of HCC cells. CnP suppressed α-smooth muscle actin expression of CAFs, and inhibited their cancer-promoting effects. CnP significantly suppressed CAFs producting cytokines such as IL6, IL8, C-C motif chemokine ligand 2, angiogenin, and osteopontin (OPN). Combined therapy with sorafenib and CnP against HCC cells and CAFs in vivo showed to inhibit tumor growth the most compared with controls and single treatment with CnP or sorafenib. Transcriptome analysis revealed that GPR68 in CAFs was strongly suppressed by CnP. The cancer-promoting effects of cytokines were eliminated by knockdown of GPR68 in CAFs. CnP inhibited the HCC-promoting effects of CAFs by suppressing several HCC-promoting cytokines secreted by CAFs expressing GPR68. Combination therapy with CnP and existing anticancer agents may be a promising strategy for treating refractory HCC associated with activated CAFs.